# 20 - PART 13 Neurologic Disorders # 01 - SECTION 1 Diagnosis of Neurologic Disorders ## SECTION 1 Diagnosis of Neurologic Disorders Section 1 Diagnosis of Neurologic Disorders Daniel H. Lowenstein, S. Andrew Josephson, Stephen L. Hauser Approach to the Patient with Neurologic Disease Neurologic diseases are common and costly. According to estimates by the World Health Organization, neurologic disorders affect nearly one in three individuals and represent the leading cause of disability and the second leading cause of death worldwide (Fig. 433-1). These numbers have increased significantly over the past 30 years and are expected to double by 2050, due to multiple factors, including aging of the population, population growth, and a rising prevalence of meta­ bolic risk conditions. Motor neuron diseases | 0.3% Multiple sclerosis | 0.4% Tetanus | 0.9% Parkinson’s disease | 1.2% Other neurologic disorders | 1.3% Encephalitis | 2.4% Tension-type headache | 2.6% Brain and other CNS cancer | 2.8% Traumatic brain injury | 2.9% Spinal cord injury | 3.5% Idiopathic epilepsy | 4.9% Meningitis | 7.9% Alzheimer’s disease and other dementias | 10.4% Migraine | 16.3% Stroke | 42.2% DALYs FIGURE 433-1  Proportional contributions to the overall global burden of neurologic disorders. Proportions (%) of disability-adjusted life-years (DALYs) and deaths. (Based on data from GBD 2016 Neurology Collaborators: Lancet Neurol 18:459, 2019.) Neurologic Disorders PART 13 Because therapies now exist for many neurologic disorders, a skillful approach to diagnosis is essential. Errors commonly result from an over­ reliance on costly neuroimaging procedures and laboratory tests, which, while useful, do not substitute for an adequate history and examination. The proper approach begins with the patient and focuses the clinical problem, first in anatomic and then in pathophysiologic terms; only then should a specific neurologic diagnosis be entertained. This method ensures that technology is judiciously applied, a correct diagnosis is established in an efficient manner, and treatment is promptly initiated. THE NEUROLOGIC METHOD ■ ■DEFINE THE ANATOMY The first priority is to identify the region of the nervous system that is likely to be responsible for the symptoms. Can the disorder be mapped to one specific location, is it multifocal, or is a diffuse process present? Are the symptoms restricted to the nervous system, or do they arise in the context of a systemic illness? Is the problem in the central nervous system (CNS), the peripheral nervous system (PNS), or both? In the CNS, is the cerebral cortex, basal ganglia, brainstem, cerebellum, or spinal cord responsible? Are the pain-sensitive meninges involved? In the PNS, could the disorder be located in peripheral nerves and, if Multiple sclerosis | 0.2% Motor neuron diseases | 0.4% Tetanus | 0.4% Other neurologic disorders | 0.6% Encephalitis | 1.1% Idiopathic epilepsy | 1.4% Parkinson’s disease | 2.3% Brain and other CNS cancer | 2.5% Meningitis | 3.5% Alzheimer’s disease and other dementias | 26.4% Stroke | 61.2% Deaths # 02 - 433 Approach to the Patient with Neurologic Disease ### 433 Approach to the Patient with Neurologic Disease Section 1 Diagnosis of Neurologic Disorders Daniel H. Lowenstein, S. Andrew Josephson, Stephen L. Hauser Approach to the Patient with Neurologic Disease Neurologic diseases are common and costly. According to estimates by the World Health Organization, neurologic disorders affect nearly one in three individuals and represent the leading cause of disability and the second leading cause of death worldwide (Fig. 433-1). These numbers have increased significantly over the past 30 years and are expected to double by 2050, due to multiple factors, including aging of the population, population growth, and a rising prevalence of meta­ bolic risk conditions. Motor neuron diseases | 0.3% Multiple sclerosis | 0.4% Tetanus | 0.9% Parkinson’s disease | 1.2% Other neurologic disorders | 1.3% Encephalitis | 2.4% Tension-type headache | 2.6% Brain and other CNS cancer | 2.8% Traumatic brain injury | 2.9% Spinal cord injury | 3.5% Idiopathic epilepsy | 4.9% Meningitis | 7.9% Alzheimer’s disease and other dementias | 10.4% Migraine | 16.3% Stroke | 42.2% DALYs FIGURE 433-1  Proportional contributions to the overall global burden of neurologic disorders. Proportions (%) of disability-adjusted life-years (DALYs) and deaths. (Based on data from GBD 2016 Neurology Collaborators: Lancet Neurol 18:459, 2019.) Neurologic Disorders PART 13 Because therapies now exist for many neurologic disorders, a skillful approach to diagnosis is essential. Errors commonly result from an over­ reliance on costly neuroimaging procedures and laboratory tests, which, while useful, do not substitute for an adequate history and examination. The proper approach begins with the patient and focuses the clinical problem, first in anatomic and then in pathophysiologic terms; only then should a specific neurologic diagnosis be entertained. This method ensures that technology is judiciously applied, a correct diagnosis is established in an efficient manner, and treatment is promptly initiated. THE NEUROLOGIC METHOD ■ ■DEFINE THE ANATOMY The first priority is to identify the region of the nervous system that is likely to be responsible for the symptoms. Can the disorder be mapped to one specific location, is it multifocal, or is a diffuse process present? Are the symptoms restricted to the nervous system, or do they arise in the context of a systemic illness? Is the problem in the central nervous system (CNS), the peripheral nervous system (PNS), or both? In the CNS, is the cerebral cortex, basal ganglia, brainstem, cerebellum, or spinal cord responsible? Are the pain-sensitive meninges involved? In the PNS, could the disorder be located in peripheral nerves and, if Multiple sclerosis | 0.2% Motor neuron diseases | 0.4% Tetanus | 0.4% Other neurologic disorders | 0.6% Encephalitis | 1.1% Idiopathic epilepsy | 1.4% Parkinson’s disease | 2.3% Brain and other CNS cancer | 2.5% Meningitis | 3.5% Alzheimer’s disease and other dementias | 26.4% Stroke | 61.2% Deaths so, are motor or sensory nerves primarily affected, or is a lesion in the neuromuscular junction or muscle more likely? The first clues to defining the anatomic area of involvement appear in the history, and the examination is then directed to confirm or rule out these impressions and to clarify uncertainties. A more detailed examination of a particular region of the CNS or PNS is often indi­ cated. For example, the examination of a patient who presents with a history of ascending paresthesias and weakness should be directed toward deciding, among other things, if the lesion is in the spinal cord or peripheral nerves. Focal back pain, a spinal cord sensory level, and incontinence suggest a spinal cord origin, whereas a stocking-glove pattern of sensory loss suggests peripheral nerve disease; areflexia usu­ ally indicates peripheral neuropathy but may also be present, typically transiently, with acute spinal cord disorders. Deciding “where the lesion is” accomplishes the task of limiting the possible etiologies to a manageable, finite number. In addition, this strategy safeguards against making serious errors. Symptoms of recurrent vertigo, diplopia, and nystagmus should not trigger “multiple sclerosis” as an answer (etiology) but “brainstem” or “pons” (location); then a diagnosis of brainstem arteriovenous malformation will not be missed for lack of consideration. Similarly, the combination of visual blurring and spastic ataxic paraparesis suggests possible optic nerve and spinal cord disease; multiple sclerosis (MS), CNS syphilis, and vitamin B12 deficiency are treatable disorders that can produce this syndrome. Once the question, “Where is the lesion?” is answered, then the question “What is the lesion?” can be addressed. PART 13 Neurologic Disorders ■ ■IDENTIFY THE PATHOPHYSIOLOGY Clues to the pathophysiology of the disease process may also be present in the history. Primary neuronal (gray matter) disorders often pres­ ent as early cognitive disturbances, movement disorders, or seizures, whereas disorders of the connecting pathways (white matter involve­ ment) produce “long tract” motor, sensory, visual, and/or cerebellar manifestations. Progressive and symmetric symptoms often have a metabolic or degenerative origin; in such cases, lesions are usually not sharply circumscribed. Thus, a patient with paraparesis and a clear spinal cord sensory level is unlikely to have vitamin B12 deficiency as the explanation. A Lhermitte symptom (electric shock–like sensations evoked by neck flexion) is due to ectopic impulses that arise in white matter pathways and occurs with demyelination in the cervical spinal cord; among many possible causes, this symptom may indicate MS in a young adult or compressive cervical spondylosis in an older person. Symptoms that worsen after exposure to heat or exercise may indicate conduction block in demyelinated axons, as occurs in MS. A patient with recurrent episodes of diplopia and dysarthria associated with exercise or fatigue may have a disorder of neuromuscular transmission such as myasthenia gravis. Slowly advancing visual scotoma with lumi­ nous edges, termed fortification spectra, indicates spreading cortical depression, typically with migraine. THE NEUROLOGIC HISTORY Attention to the description of symptoms experienced by the patient and substantiated by family members and others often permits an accu­ rate localization and determination of the probable cause, even before the neurologic examination is performed. The history also helps focus the neurologic examination that follows. Each complaint should be pursued as far as possible to identify the location of the lesion, the likely underlying pathophysiology, and potential etiologies. For example, a patient complains of weakness of the right arm. What are the associated features? Does the patient have difficulty with brushing hair or reach­ ing upward (proximal) or fastening buttons or opening a plastic bottle (distal)? Negative associations may also be crucial. A right-handed patient with a right hemiparesis without a language deficit likely has a lesion (internal capsule, brainstem, or spinal cord) different from that of a patient with a right hemiparesis and aphasia (left hemisphere). Other pertinent features of the history include the following: 1. Temporal course of the illness. It is important to determine the pre­ cise time of appearance and rate of progression of the symptoms experienced by the patient. The rapid onset of a neurologic com­ plaint, occurring within seconds or minutes, usually indicates a vascular event, a seizure, or migraine. The onset of sensory symp­ toms located in one extremity that spread over a few seconds to adjacent portions of that extremity and then to the other regions of the body suggests a seizure. A similar but slower temporal march of symptoms accompanied by headache, nausea, or visual disturbance suggests migraine. Less well-localized symptoms that are maximum at onset and persist for seconds, minutes, or much less commonly hours, point to the possibility of a transient ischemic attack (TIA). The presence of “positive” sensory symptoms (e.g., tingling or sensa­ tions that are difficult to describe) or involuntary motor movements suggests a seizure; in contrast, transient loss of function (negative symptoms) suggests a TIA. A stuttering onset where symptoms appear, stabilize, and then progress over hours or days also suggests cerebrovascular disease; an additional history of transient remis­ sion or regression indicates that the process is more likely due to ischemia rather than hemorrhage. A gradual evolution of symptoms over hours or days suggests a toxic, metabolic, infectious, or inflam­ matory process. Progressing symptoms associated with the systemic manifestations of fever, stiff neck, and altered level of consciousness imply an infectious process. Relapsing and remitting symptoms involving different levels of the nervous system suggest MS or other inflammatory processes. Slowly progressive symptoms with­ out remissions are characteristic of neurodegenerative disorders, chronic infections, gradual intoxications, and neoplasms. 2. Patients’ descriptions of the complaint. The same words often mean different things to different patients. “Dizziness” may imply impending syncope, a sense of disequilibrium, or true spinning vertigo. “Numbness” may mean a complete loss of feeling, a positive sensation such as tingling, or even weakness. “Blurred vision” may be used to describe unilateral visual loss, as in transient monocular blindness, or diplopia. The interpretation of the true meaning of the words used by patients to describe symptoms obviously becomes even more complex when there are differences in primary languages and cultures. 3. Corroboration of the history by others. It is almost always helpful to obtain additional information from family, friends, or other observ­ ers to corroborate or expand the patient’s description. Memory loss, aphasia, loss of insight, intoxication, and other factors may impair the patient’s capacity to communicate normally with the examiner or prevent openness about factors that have contributed to the ill­ ness. Episodes of loss of consciousness necessitate that details be sought from observers to ascertain precisely what has happened during the event. 4. Family history. Many neurologic disorders have an underlying genetic component. The presence of a Mendelian disorder, such as Huntington’s disease or Charcot-Marie-Tooth neuropathy, is often obvious if family data are available. Clearly note if the family history has been fully ascertained or if some branches of the family could not be traced. More detailed questions about family history are often necessary in polygenic disorders such as MS, migraine, and many types of epilepsy. It is important to elicit family history about all illnesses, in addition to neurologic and psychiatric disorders. A familial propensity to hypertension or heart disease is relevant in a patient who presents with a stroke. Numerous inherited neurologic diseases are associated with multisystem manifestations that may provide clues to the correct diagnosis (e.g., neurofibromatosis, Wilson’s disease, mitochondrial disorders). 5. Medical illnesses. Many neurologic diseases occur in the context of systemic disorders. Diabetes mellitus, hypertension, and abnormali­ ties of blood lipids predispose to cerebrovascular disease. A solitary mass lesion in the brain may be an abscess in a patient with valvular heart disease, a primary hemorrhage in a patient with a coagu­ lopathy, a lymphoma or toxoplasmosis in a patient with AIDS, or a metastasis in a patient with underlying cancer. Patients with malig­ nancy may also present with a neurologic paraneoplastic syndrome (Chap. 99) or complications from chemotherapy, immunotherapy, or radiotherapy. Marfan’s syndrome and related collagen disorders predispose to dissection of the cranial arteries and aneurysmal subarachnoid hemorrhage; the latter may also occur with polycystic kidney disease and fibromuscular dysplasia. Various neurologic dis­ orders occur with dysthyroid states or other endocrinopathies. It is especially important to look for the presence of systemic diseases in patients with peripheral neuropathy. Most patients with coma in a hospital setting have a metabolic, toxic, or infectious cause. 6. Drug use and abuse and toxin exposure. It is essential to inquire about the history of drug use, both prescribed and illicit. Sedatives, antidepressants, and other psychoactive medications are frequently associated with acute confusional states, especially in the elderly. Aminoglycoside antibiotics may exacerbate symptoms of weakness in patients with disorders of neuromuscular transmission, such as myasthenia gravis, and may cause dizziness secondary to ototoxic­ ity. Vincristine and other antineoplastic drugs can cause peripheral neuropathy, immunosuppressive agents such as cyclosporine can produce encephalopathy, and immunotherapies with checkpoint inhibitors and chimeric antigen receptor (CAR) T cells are associ­ ated with various neurotoxicities including brain edema, inflamma­ tion, and demyelination (Chap. 318). Excessive vitamin ingestion can lead to disease; examples include vitamin A and intracranial hypertension (“pseudotumor cerebri”) or pyridoxine and periph­ eral neuropathy. Many patients are unaware that over-the-counter sleeping pills, cold preparations, and diet pills are actually drugs. Alcohol, the most prevalent neurotoxin, is often not recognized as such by patients, and other drugs of abuse such as cocaine, meth­ amphetamine, and heroin can cause a wide range of neurologic abnormalities. A history of environmental or industrial exposure to neurotoxins may provide an essential clue; consultation with the patient’s coworkers or employer may be required. 7. Formulating an impression of the patient. Use the opportunity while taking the history to form an impression of the patient. Is the infor­ mation forthcoming, or does it take a circuitous course? Is there evidence of anxiety, depression, or hypochondriasis? Are there any clues to problems with language, memory, insight, comportment, or behavior? The neurologic assessment begins as soon as the patient comes into the room and the first introduction is made. THE NEUROLOGIC EXAMINATION The neurologic examination can be challenging and complex; it has many components and includes a number of skills that can be mastered only through repeated use of the same techniques on a large number of individuals with and without neurologic disease. Mastery of the complete neurologic examination is usually important only for physi­ cians in neurology and associated specialties. However, knowledge of the basics of the examination, especially those components that are effective in screening for neurologic dysfunction, is essential for all clinicians, especially generalists. There is no single, universally accepted sequence of the examina­ tion that must be followed, but most clinicians begin with assessment of mental status followed by the cranial nerves (CN), motor system, reflexes, sensory system, coordination, and gait. Whether the exami­ nation is basic or comprehensive, it is essential that it is performed in an orderly and systematic fashion to avoid errors and serious omis­ sions. Thus, the best way to learn and gain expertise in the examination is to choose one’s own approach and practice it frequently and do it in the same exact sequence each time. Essential tools for the examina­ tion should be accessible whenever the exam goes beyond screening, including a Snellen visual chart, portable ophthalmoscope, reflex hammer, a 128-Hz tuning fork, and disposable cotton wisps, tongue depressors, and pins. The detailed description that follows describes the more commonly used parts of the neurologic examination, with a particular emphasis on the components that are considered most helpful for the assess­ ment of common neurologic problems. Each section also includes a brief description of the minimal examination necessary to adequately screen for abnormalities in a patient who has no symptoms suggesting neurologic dysfunction. A screening examination done in this way can be completed in 3–5 min. Video demonstrations of the neurologic screening examination (V6) and the detailed neurologic examination (V7) can be found in the Harrison’s Video Collection included in this textbook. Several additional points about the examination are worth noting. First, in recording observations, it is important to describe what is found rather than to apply a poorly defined medical term (e.g., “patient groans to sternal rub” rather than “obtunded”). Second, subtle CNS abnormalities are best detected by carefully comparing a patient’s per­ formance on tasks that require simultaneous activation of both cerebral hemispheres (e.g., eliciting a pronator drift of an outstretched arm with the eyes closed; extinction on one side of bilaterally applied light touch, also with eyes closed; or decreased arm swing or a slight asymmetry when walking). Third, if the patient’s complaint is brought on by some activity, reproduce the activity in the office. If the complaint is of dizzi­ ness when the head is turned in one direction, have the patient do this and also look for associated signs on examination (e.g., nystagmus or dysmetria). If pain or weakness occurs after walking two blocks, have the patient leave the office and walk this distance and immediately return, and repeat the relevant parts of the examination. Finally, the use of tests that are individually tailored to the patient’s problem can be of value in assessing changes over time. Tests of walking a 7.5-m (25-ft) distance (normal, 5–6 s; note assistance, if any), repetitive finger or toe tapping (normal, 20–25 taps in 5 s), or handwriting are examples. CHAPTER 433 Approach to the Patient with Neurologic Disease ■ ■MENTAL STATUS EXAMINATION • The bare minimum: During the interview, look for difficulties with communication and determine whether the patient has recall and insight into recent and past events. The mental status examination is underway as soon as the physician begins observing and speaking with the patient. If the history raises any concern for abnormalities of higher cortical function or if cogni­ tive problems are observed during the interview, then detailed testing of the mental status is indicated. The patient’s ability to understand the language used for the examination, cultural background, educational experience, sensory or motor problems, or comorbid conditions must be factored into the applicability of the tests and interpretation of results. The Mini-Mental State Examination (MMSE) is a standardized screening examination of cognitive function that is extremely easy to administer and takes <10 min to complete (Chap. 31). Using ageadjusted values for defining normal performance, the test is ~85% sensitive and 85% specific for making the diagnosis of dementia that is moderate or severe, especially in educated patients. When there is suf­ ficient time available in the outpatient setting, the MMSE is one of the best methods for documenting the current mental status of the patient, and this is especially useful as a baseline assessment to which future scores of the MMSE can be compared. Individual elements of the mental status examination can be sub­ divided into level of consciousness, orientation, speech and language, memory, fund of information, insight and judgment, abstract thought, and calculations. Level of consciousness is the patient’s relative state of awareness of self and the environment, and ranges from fully awake to comatose. When the patient is not fully awake, the examiner should describe the responses to the minimum stimulus necessary to elicit a reaction, ranging from verbal commands to a brief, painful stimulus such as a squeeze of the trapezius muscle. Responses that are directed toward the stimulus and signify some degree of intact cerebral function (e.g., opening the eyes and looking at the examiner or reaching to push away a painful stimulus) must be distinguished from reflex responses of a spinal origin (e.g., triple flexion response—flexion at the ankle, knee, and hip in response to a painful stimulus to the foot). Orientation is tested by asking the person to state their name, loca­ tion, and time (day of the week and date); time is usually the first to be affected in a variety of conditions. Speech is assessed by observing articulation, rate, rhythm, and pros­ ody (i.e., the changes in pitch and accentuation of syllables and words). Language is assessed by observing the content of the patient’s verbal and written output, response to spoken commands, and ability to read. A typical testing sequence is to ask the patient to name successively more detailed components of clothing, a watch, or a pen; repeat the phrase “No ifs, ands, or buts”; follow a three-step, verbal command; write a sentence; and read and respond to a written command. Memory should be analyzed according to three main time scales: (1) immediate memory is assessed by saying a list of three items and having the patient repeat the list immediately; (2) short-term memory is tested by asking the patient to recall the same three items 5 and 15 min later; and (3) long-term memory is evaluated by deter­ mining how well the patient is able to provide a coherent chronologic history of their illness or personal events. Fund of information is assessed by asking questions about major historic or current events, with special attention to educational level and life experiences. PART 13 Neurologic Disorders Abnormalities of insight and judgment are usually detected during the interview; a more detailed assessment can be elicited by asking the patient to describe how they would respond to situations having a variety of potential outcomes (e.g., “What would you do if you found a wallet on the sidewalk?”). Abstract thought can be tested by asking the patient to describe similarities between various objects or concepts (e.g., apple and orange, desk and chair, poetry and sculpture) or to list items having the same attributes (e.g., a list of four-legged animals). Calculation ability is assessed by having the patient carry out a computation that is appropriate to the patient’s age and education (e.g., serial subtraction of 7 from 100 or 3 from 20; or word problems involv­ ing simple arithmetic). ■ ■CRANIAL NERVE EXAMINATION • The bare minimum: Check the fundi, visual fields, pupil size and reac­ tivity, extraocular movements, and facial movements. The CNs are best examined in numerical order, except for grouping together CN III, IV, and VI because of their similar function. CN I (Olfactory)  Testing is often omitted unless there is suspicion for inferior frontal lobe disease (e.g., meningioma). With eyes closed, ask the patient to sniff a mild stimulus such as toothpaste or coffee and identify the odorant. CN II (Optic)  Check visual acuity (with eyeglasses or contact lens correction) using a Snellen chart or similar tool. Test the visual fields by confrontation, i.e., by comparing the patient’s visual fields to your own. As a screening test, it is usually sufficient to examine the visual fields of both eyes simultaneously; individual eye fields should be tested if there is any reason to suspect a problem of vision by the history or other elements of the examination, or if the screening test reveals an abnormality. Face the patient at a distance of ~0.6–1.0 m (2–3 ft) and place your hands at the periphery of your visual fields in the plane that is equidistant between you and the patient. Instruct the patient to look directly at the center of your face and to indicate when and where they see one of your fingers moving. Beginning with the two inferior quadrants and then the two superior quadrants, move your index finger of the right hand, left hand, or both hands simultaneously and observe whether the patient detects the movements. A single smallamplitude movement of the finger is sufficient for a normal response. Focal perimetry and tangent screen examinations should be used to map out visual field defects fully or to search for subtle abnormalities. Optic fundi should be examined with an ophthalmoscope, and the color, size, and degree of swelling or elevation of the optic disc noted, as well as the color and texture of the retina. The retinal vessels should be checked for size, regularity, arteriovenous nicking at crossing points, hemorrhage, and exudates. CN III, IV, VI (Oculomotor, Trochlear, Abducens)  Describe the size and shape of the pupils and reaction to light and accommoda­ tion (i.e., as the eyes converge while following your finger as it moves toward the bridge of the nose). To check extraocular movements, ask the patient to keep their head still while tracking the movement of the tip of your finger. Move the target slowly in the horizontal and vertical planes; observe any paresis, nystagmus, or abnormalities of smooth pursuit (saccades, oculomotor ataxia, etc.). If necessary, the relative position of the two eyes, both in primary and multidirectional gaze, can be assessed by comparing the reflections of a bright light off both pupils. However, in practice it is typically more useful to determine whether the patient describes diplopia in any direction of gaze; true diplopia should almost always resolve with one eye closed. Horizontal nystagmus is best assessed at 45° and not at extreme lateral gaze (which is uncomfortable for the patient); the target must often be held at the lateral position for at least a few seconds to detect an abnormality. CN V (Trigeminal)  Examine sensation within the three territories of the branches of the trigeminal nerve (ophthalmic, maxillary, and mandibular) on each side of the face. As with other parts of the sensory examination, testing of two sensory modalities derived from different anatomic pathways (e.g., light touch and temperature) is sufficient for a screening examination. Testing of other modalities, the corneal reflex, and the motor component of CN V (jaw clench—masseter muscle) is indicated when suggested by the history. CN VII (Facial)  Look for facial asymmetry at rest and with spon­ taneous movements. Test eyebrow elevation, forehead wrinkling, eye closure, smiling, and cheek puff. Look in particular for differences in the lower versus upper facial muscles; weakness of the lower two-thirds of the face with preservation of the upper third suggests an upper motor neuron lesion, whereas weakness of an entire side suggests a lower motor neuron lesion. CN VIII (Vestibulocochlear)  Check the patient’s ability to hear a finger rub or whispered voice with each ear. Further testing for air versus mastoid bone conduction (Rinne) and lateralization of a 512-Hz tuning fork placed at the center of the forehead (Weber) should be done if an abnormality is detected by history or examination. Any suspected problem should be followed up with formal audiometry. For further discussion of assessing vestibular nerve function in the set­ ting of dizziness, coma, or hearing loss, see Chaps. 24, 30, and 36, respectively. CN IX, X (Glossopharyngeal, Vagus)  Observe the position and symmetry of the palate and uvula at rest and with phonation (“aah”). The pharyngeal (“gag”) reflex is evaluated by stimulating the posterior pharyngeal wall on each side with a sterile, blunt object (e.g., tongue blade), but the reflex may be absent in normal individuals. CN XI (Spinal Accessory)  Check shoulder shrug (trapezius muscle) and head rotation to each side (sternocleidomastoid) against resistance. CN XII (Hypoglossal)  Inspect the tongue for atrophy or fascicu­ lations, position with protrusion, and strength when extended against the inner surface of the cheeks on each side. ■ ■MOTOR EXAMINATION • The bare minimum: Look for muscle atrophy and check extremity tone. Assess upper extremity strength by checking for pronator drift and strength of wrist or finger extensors. Assess lower extremity strength by checking strength of the toe extensors. The motor examination includes observations of muscle appearance, tone, and strength. Although gait is in part a test of motor function, it is usually evaluated separately at the end of the examination. Appearance  Inspect and palpate muscle groups under good light and with the patient in a comfortable and symmetric position. Check for muscle fasciculations, tenderness, and atrophy or hypertrophy. Involuntary movements may be present at rest (e.g., tics, myoclonus, choreoathetosis, pill-rolling tremor of Parkinson’s disease), during maintained posture (essential tremor), or with voluntary movements (intention tremor of cerebellar disease or familial tremor). Tone  Muscle tone is tested by measuring the resistance to passive movement of a relaxed limb. Patients often have difficulty relaxing during this procedure, so it is useful to distract the patient to minimize active movements. In the upper limbs, tone is assessed by rapid prona­ tion and supination of the forearm and flexion and extension at the wrist. In the lower limbs, while the patient is supine, the examiner’s hands are placed behind the knees and rapidly raised; with normal tone, the ankles drag along the table surface for a variable distance before rising, whereas increased tone results in an immediate lift of the heel off the surface. Decreased tone is most commonly due to lower motor neuron or peripheral nerve disorders. Increased tone may be evident as spasticity (resistance determined by the angle and velocity of motion; corticospinal tract disease), rigidity (similar resistance in all angles of motion; extrapyramidal disease), or paratonia (fluctuat­ ing changes in resistance; frontal lobe pathways; or normal difficulty in relaxing). Cogwheel rigidity, in which passive motion elicits jerky interruptions in resistance, is seen in parkinsonism. Strength  Testing for pronator drift is an extremely useful method for screening upper limb weakness. The patient is asked to hold both arms fully extended and parallel to the ground with eyes closed. This position should be maintained for ~10 s; any flexion at the elbow or fingers or pronation of the forearm, especially if asymmetric, is a sign of potential weakness. Patients with shoulder pain or a limited range of motion may have an apparent pronator drift that is not due to true weakness. Muscle strength is further assessed by having the patient exert maximal effort for the particular muscle or muscle group being tested. It is important to isolate the muscles as much as possible, i.e., hold the limb so that only the muscles of interest are active. It is also helpful to palpate accessible muscles as they contract. Grading muscle strength and evaluating the patient’s effort are an art that takes time and practice. Muscle strength is traditionally graded using the follow­ ing scale:   0 = no movement   1 = flicker or trace of contraction but no associated movement at a joint   2 = movement with gravity eliminated   3 = movement against gravity but not against resistance   4– = movement against a mild degree of resistance   4 = movement against moderate resistance   4+ = movement against strong resistance   5 = full power However, in many cases, it is more practical to use the following terms: Paralysis = no movement Severe weakness = movement with gravity eliminated Moderate weakness = movement against gravity but not against mild resistance Mild weakness = movement against moderate resistance Full strength Noting the pattern of weakness is as important as assessing the magnitude of weakness. Unilateral or bilateral weakness of the upper limb extensors and lower limb flexors (“pyramidal weakness”) sug­ gests a lesion of the pyramidal tract, bilateral proximal weakness suggests myopathy, and bilateral distal weakness suggests peripheral neuropathy. ■ ■REFLEX EXAMINATION • The bare minimum: Check the biceps, patellar, and Achilles reflexes. Muscle Stretch Reflexes  Those that are typically assessed include the biceps (C5, C6), brachioradialis (C5, C6), triceps (C6, C7), and sometimes finger flexor (C8, T1) reflexes in the upper limbs and the patellar or quadriceps (L3, L4) and Achilles (S1, S2) reflexes in the lower limbs. The patient should be relaxed and the muscle positioned midway between full contraction and extension. Reflexes may be enhanced by asking the patient to voluntarily contract other, distant muscle groups (Jendrassik maneuver). For example, upper limb reflexes may be reinforced by voluntary teeth-clenching, and the Achil­ les reflex by hooking the flexed fingers of the two hands together and attempting to pull them apart. For each reflex tested, the two sides should be tested sequentially, and it is important to determine the smallest stimulus required to elicit a reflex rather than the maximum response. Reflexes are graded according to the following scale:   0 = absent   1 = present but diminished   2 = normoactive   3 = increased   4 = clonus Cutaneous Reflexes  The plantar reflex is elicited by stroking, with a noxious stimulus such as a tongue blade, the lateral surface of the sole of the foot beginning near the heel and moving across the ball of the foot to the great toe. The normal reflex consists of plantar flexion of the toes. With upper motor neuron lesions above the S1 level of the spinal cord, a paradoxical extension of the toe is observed, associ­ ated with fanning and extension of the other toes (termed an extensor plantar response, or Babinski sign). However, despite its popularity, the reliability and validity of the Babinski sign for identifying upper motor neuron weakness are limited—it is far more useful to rely on tests of tone, strength, stretch reflexes, and coordination. Superficial abdomi­ nal reflexes are elicited by gently stroking the abdominal surface near the umbilicus in a diagonal fashion with a sharp object (e.g., the wooden end of a cotton-tipped swab) and observing the movement of the umbilicus. Normally, the umbilicus will pull toward the stimulated quadrant. With upper motor neuron lesions, these reflexes are absent. They are most helpful when there is preservation of the upper (spinal cord level T9) but not lower (T12) abdominal reflexes, indicating a spinal lesion between T9 and T12, or when the response is asymmet­ ric. Other useful cutaneous reflexes include the cremasteric (ipsilateral elevation of the testicle following stroking of the medial thigh; medi­ ated by L1 and L2) and anal (contraction of the anal sphincter when the perianal skin is scratched; mediated by S2, S3, S4) reflexes. It is particu­ larly important to test for these reflexes in any patient with suspected injury to the spinal cord or lumbosacral roots. Primitive Reflexes  With disease of the frontal lobe pathways, several primitive reflexes not normally present in the adult may appear. The suck response is elicited by lightly touching with a tongue blade the center of the lips, and the root response the corner of the lips; the patient will move the lips to suck or root in the direction of the stimulus. The grasp reflex is elicited by touching the palm between the thumb and index finger with the examiner’s fingers; a positive response is a forced grasp of the examiner’s hand. In many instances, stroking the back of the hand will lead to its release. The palmomental response is contraction of the mentalis muscle (chin) ipsilateral to a scratch stimulus diagonally applied to the palm. CHAPTER 433 Approach to the Patient with Neurologic Disease ■ ■SENSORY EXAMINATION • The bare minimum: Ask whether the patient can feel light touch and the temperature of a cool object in each distal extremity. Check double simultaneous stimulation using light touch on the hands. Perform the Romberg maneuver. Evaluating sensation is usually the most unreliable part of the examination because it is subjective and is difficult to quantify. In the compliant and discerning patient, the sensory examination can be extremely helpful for the precise localization of a lesion. With patients who are uncooperative or lack an understanding of the tests, it may be useless. The examination should be focused on the suspected lesion. For example, in spinal cord, spinal root, or peripheral nerve abnormali­ ties, all major sensory modalities should be tested while looking for a pattern consistent with a spinal level and dermatomal or nerve distri­ bution. In patients with lesions at or above the brainstem, screening the primary sensory modalities in the distal extremities along with tests of “cortical” sensation is usually sufficient. The five primary sensory modalities—light touch, pain, tempera­ ture, vibration, and joint position—are tested in each limb. Light touch is assessed by stimulating the skin with single, very gentle touches of the examiner’s finger or a wisp of cotton. Pain is tested using a new pin, and temperature is assessed using a metal object (e.g., tuning fork) that has been immersed in cold and warm water. Vibration is tested using a 128-Hz tuning fork applied to the distal phalanx of the great toe or index finger just below the nail bed. By placing a finger on the oppo­ site side of the joint being tested, the examiner compares the patient’s threshold of vibration perception with their own. For joint position testing, the examiner grasps the digit or limb laterally and distal to the joint being assessed; small 1- to 2-mm excursions can usually be sensed. The Romberg maneuver is primarily a test of proprioception. The patient is asked to stand with the feet as close together as neces­ sary to maintain balance while the eyes are open, and the eyes are then closed. A loss of balance with the eyes closed is an abnormal response. “Cortical” sensation is mediated by the parietal lobes and represents an integration of the primary sensory modalities; testing cortical sen­ sation is only meaningful when primary sensation is intact. Double simultaneous stimulation is especially useful as a screening test for cortical function; with the patient’s eyes closed, the examiner lightly touches one or both hands and asks the patient to identify the stimuli. With a parietal lobe lesion, the patient may be unable to identify the stimulus on the contralateral side when both hands are touched. Other modalities relying on the parietal cortex include the discrimination of two closely placed stimuli as separate (two-point discrimination), iden­ tification of an object by touch and manipulation alone (stereognosis), and the identification of numbers or letters written on the skin surface (graphesthesia). PART 13 Neurologic Disorders ■ ■COORDINATION EXAMINATION • The bare minimum: Observe the patient at rest and during spontane­ ous movements. Test rapid alternating movements of the hands and feet and finger to nose. Coordination refers to the orchestration and fluidity of movements. Even simple acts require cooperation of agonist and antagonist muscles, maintenance of posture, and complex servomechanisms to control the rate and range of movements. Part of this integration relies on normal function of the cerebellar and basal ganglia systems. How­ ever, coordination also requires intact muscle strength and kinesthetic and proprioceptive information. Thus, if the examination has disclosed abnormalities of the motor or sensory systems, the patient’s coordina­ tion should be assessed with these limitations in mind. Rapid alternating movements in the upper limbs are tested sepa­ rately on each side by having the patient make a fist, partially extend the index finger, and then tap the index finger on the distal thumb as quickly as possible. In the lower limb, the patient rapidly taps the foot against the floor or the examiner’s hand. If these rapid alternating movements are imprecise or vary in amplitude or rhythm, a cerebel­ lar lesion is suspected; if, however, they are slow compared with the other side, a lesion of the pyramidal tract is most likely. Finger-to-nose testing is primarily a test of cerebellar function; the patient is asked to touch their index finger repetitively to the nose and then to the exam­ iner’s outstretched finger, which moves with each repetition. A similar test in the lower extremity is to have the patient raise the leg and touch the examiner’s finger with the great toe. Another coordination test in the lower limbs is the heel-knee-shin maneuver; in the supine position, the patient is asked to slide the heel of each foot from the knee down the shin of the other leg. For all these movements, the accuracy, speed, and rhythm are noted. ■ ■GAIT EXAMINATION • The bare minimum: Observe the patient while walking normally, on the heels and toes, and along a straight line. Watching the patient walk is the most important part of the neurologic examination. Normal gait requires that multiple systems—including strength, sensation, and coordination—function in a highly integrated fashion. Unexpected abnormalities may be detected that prompt the examiner to return in more detail to other aspects of the examination. The patient should be observed while walking and turning normally, walking on the heels, walking on the toes, and walking heel-to-toe along a straight line. The examination may reveal decreased arm swing on one side (corticospinal tract disease), a stooped posture and shortstepped gait (parkinsonism), a broad-based unstable gait (ataxia), scis­ soring (spasticity), or a high-stepped, slapping gait (posterior column or peripheral nerve disease), or the patient may appear to be stuck in place (apraxia with frontal lobe disease). NEUROLOGIC DIAGNOSIS The clinical data obtained from the history and examination are interpreted to arrive at an anatomic localization that best explains the clinical findings (Table 433-1), to narrow the list of diagnostic possi­ bilities, and to select the laboratory tests most likely to be informative. The laboratory assessment may include (1) serum electrolytes; com­ plete blood count; and renal, hepatic, endocrine, and immune studies; (2) cerebrospinal fluid examination; (3) focused neuroimaging studies (Chap. 434); or (4) electrophysiologic studies. The anatomic localiza­ tion, mode of onset and course of illness, other medical data, and labo­ ratory findings are then integrated to establish an etiologic diagnosis. The neurologic examination may be normal even in patients with a serious neurologic disease, such as seizures, chronic meningitis, or a TIA. A comatose patient may arrive with no available history, and in such cases, the approach is as described in Chap. 30. In other patients, an inadequate history may be overcome by a succession of examina­ tions from which the course of the illness can be inferred. In perplex­ ing cases, it is useful to remember that uncommon presentations of common diseases are more likely than rare etiologies. Thus, even in TABLE 433-1  Findings Helpful for Localizations within the Nervous System   SIGNS Cerebrum Abnormal mental status or cognitive impairment Seizures Unilateral weaknessa and sensory abnormalities including head and limbs Visual field abnormalities Movement abnormalities (e.g., diffuse incoordination, tremor, chorea) Brainstem Isolated cranial nerve abnormalities (single or multiple) “Crossed” weaknessa and sensory abnormalities of head and limbs, e.g., weakness of right face and left arm and leg Spinal cord Back pain or tenderness Weaknessa and sensory abnormalities sparing the head Mixed upper and lower motor neuron findings Sensory level Sphincter dysfunction Spinal roots Radiating limb pain Weaknessb or sensory abnormalities following root distribution (see Figs. 27-2 and 27-3) Loss of reflexes Peripheral nerve Mid or distal limb pain Weaknessb or sensory abnormalities following nerve distribution (see Figs. 27-2 and 27-3) “Stocking or glove” distribution of sensory loss Loss of reflexes Neuromuscular junction Bilateral weakness including face (ptosis, diplopia, dysphagia) and proximal limbs Increasing weakness with exertion Sparing of sensation Muscle Bilateral proximal or distal weakness Sparing of sensation aWeakness along with other abnormalities having an “upper motor neuron” pattern, i.e., spasticity, weakness of extensors > flexors in the upper extremity and flexors > extensors in the lower extremity, and hyperreflexia. bWeakness along with other abnormalities having a “lower motor neuron” pattern, i.e., flaccidity and hyporeflexia. # 03 - 434 Neuroimaging in Neurologic Disorders ### 434 Neuroimaging in Neurologic Disorders tertiary care settings, multiple strokes are usually due to emboli and not vasculitis, and dementia with myoclonus is usually Alzheimer’s disease and not a prion disorder or a paraneoplastic illness. Finally, the most important task of a primary care physician faced with a patient who has a new neurologic complaint is to assess the urgency of referral to a spe­ cialist. Here, the imperative is to rapidly identify patients likely to have nervous system infections, acute strokes, and spinal cord compression or other treatable mass lesions and arrange for immediate care. ■ ■FURTHER READING Brazis P et al: Localization in Clinical Neurology, 8th ed. Philadelphia, Lippincott William & Wilkins, 2021. Campbell WW, Barohn RJ: DeJong’s The Neurological Examination, 8th ed. Philadelphia, Lippincott William & Wilkins, 2019. Feigin VL et al: The global burden of neurological disorders: Translating evidence into policy. Lancet Neurol 19:255, 2020. GBD 2019 Diseases and Injuries Collaborators: Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet 396:1204, 2020. O’Brien M: Aids to the Examination of the Peripheral Nervous System, 6th ed. Elsevier, Amsterdam, 2023. William P. Dillon Neuroimaging in Neurologic Disorders Numerous noninvasive imaging options are available to clinicians evaluating patients with neurologic disorders. These include computed tomography (CT) and magnetic resonance (MR) imaging (MRI), plus their variations, including CT angiography (CTA); perfusion CT (pCT); dual-energy CT; photon counting CT; MR angiography (MRA); MR vessel wall imaging; functional MRI (fMRI); MR spectroscopy (MRS); MR neurography (MRN); diffusion-weighted MR imaging (DWI); diffusion tensor MR imaging (DTI); susceptibility-weighted MR imaging (SWI); arterial spin label imaging (ASL); and perfusion MRI (pMRI). Furthermore, a number of interventional neuroradio­ logic techniques have matured including catheter embolization, stent retrieval thrombectomy, aneurysm coiling and stenting, as well as numerous techniques for spine disorders including CT and fluoro­ scopic myelography and CT-guided spine procedures for diagnosing and treating pain and oncology, including dynamic CT myelography, radiofrequency and cold ablation techniques, image-guided blood and fibrin glue patches and transvenous embolization of cerebrospinal fluid (CSF) venous fistulae. Multidetector CTA (MDCTA) and gadoliniumenhanced MRA techniques have reduced the need for catheter-based angiography, which is now reserved for patients in whom small-vessel detail is essential for diagnosis or for whom concurrent interventional therapy is planned (Table 434-1). In general, MRI is more sensitive than CT for the detection of lesions affecting the peripheral and central nervous system (CNS). Diffusion MR, a sequence sensitive to the microscopic motion of water, is the most sensitive technique for detecting acute ischemic stroke of the brain or spinal cord and is also useful in the detection and charac­ terization of encephalitis, abscess, Creutzfeldt-Jacob disease, cerebral tumors, and acute demyelinating lesions. CT, however, is acquired more quickly, making it a pragmatic choice for uncooperative patients, or those with suspected acute stroke, hemorrhage, and acute intracra­ nial or spinal trauma. CT is also more sensitive than MRI for visual­ izing fine osseous detail and thus is appropriate for the initial imaging TABLE 434-1  Guidelines for the Use of CT, Ultrasound, and MRI CONDITION RECOMMENDED TECHNIQUE Hemorrhage     Acute parenchymal CT, MR   Subacute/chronic MRI   Subarachnoid hemorrhage CT, CTA, lumbar puncture → angiography   Aneurysm Angiography > CTA, MRA   Chronic subarachnoid blood MR with SWI Ischemic infarction     Hemorrhagic infarction CT or MRI   Bland infarction MRI with diffusion > CT, CTA, angiography   Carotid or vertebral dissection MRI/MRA> CTA CHAPTER 434   Vertebral basilar insufficiency CTA, MRI with DWI MRA   Carotid stenosis CTA, MRA > US Suspected mass lesion     Neoplasm, primary or metastatic MRI ± contrast   Infection/abscess MRI ± contrast Neuroimaging in Neurologic Disorders   Immunosuppressed with focal findings MRI ± contrast Vascular malformation MRI ± angiography White matter disorders MRI   Acute demyelinating disease MRI ± contrast Dementia MRI > CT, contrast if mass Trauma     Acute trauma CT   Shear injury/chronic hemorrhage MRI + SWI Headache/migraine MRI > CT Seizure     First time, no focal neurologic deficits MRI > CT   With neurologic deficit, or MRI ± contrast > CT immunocompromised or cancer   Partial complex/refractory MRI Cranial neuropathy MRI ± contrast Meningeal disease MRI ± contrast Spine Low-back pain     No neurologic deficits MRI or CT after >6 weeks   With focal deficits MRI > CT Spinal stenosis MRI or CT Cervical spondylosis MRI, CT, CT myelography Infection MRI ± contrast CT Myelopathy MRI ± contrast Arteriovenous malformation MRI ± contrast angiography Abbreviations: CT, computed tomography; CTA, CT angiography; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; SWI, susceptibilityweighted imaging. evaluation of conductive hearing loss, and lesions affecting the osseous skull and spine. MR may, however, add important diagnostic informa­ tion regarding bone marrow infiltrative processes that can be difficult to detect on CT. COMPUTED TOMOGRAPHY ■ ■TECHNIQUE The CT image is a cross-sectional representation of anatomy created by a computer-generated analysis of the attenuation of x-ray beams passed through a section of the body. The x-ray beam, collimated to the desired slice width, rotates around the patient and passes through selected regions in the body. X-rays are variably attenuated by body structures and converted into light photons by ceramic scintillators as part of the detectors aligned 180° from the x-ray tube. These photons A B FIGURE 434-1  Computed tomography (CT) angiography (CTA) of ruptured anterior cerebral artery aneurysm in a patient presenting with acute headache. A. Noncontrast CT demonstrates subarachnoid and intraventricular hemorrhage and mild obstructive hydrocephalus. B. Axial maximum-intensity projection from CTA demonstrates enlargement of the anterior cerebral artery (arrow). C. Three-dimensional surface reconstruction using a workstation confirms the anterior cerebral aneurysm and demonstrates its orientation and relationship to nearby vessels (arrow). CTA image is produced by 0.5- to 1-mm helical CT scans performed during a rapid bolus infusion of IV contrast medium. PART 13 Neurologic Disorders are then converted into electric signals. A computer calculates a “back projection” image from the 360° x-ray attenuation profile. Greater x-ray attenuation (e.g., as caused by bone) results in areas of high “density” (whiter) on the scan, whereas soft-tissue structures that have poor attenuation of x-rays, such as organs and air-filled cavities, are lower (gray-black) in density. The resolution of an image depends on the radiation dose, the detector size, collimation (slice thickness), the field of view, and the matrix size of the display. A modern CT scanner can obtain sections as thin as 0.5–1 mm with 0.4-mm in-plane resolution at a speed of 0.3 s per rotation; complete studies of the brain are com­ pleted in 1–10 s. Multidetector CT (MDCT) is now standard. Single or multiple (from 4 to 320) solid-state ceramic detectors positioned opposite to the x-ray source result in multiple slices per revolution of the beam around the patient. In helical mode, the table moves continuously through the rotating x-ray beam, generating a continuous “helix” of x-ray infor­ mation that is reformatted into various slice thicknesses and planes. Advantages of MDCT include shorter scan times, reduced patient and organ motion, and the ability to acquire images dynamically during the infusion of intravenous (IV) contrast, the basis of CTA and CT perfusion (Figs. 434-1B and C). CTA is displayed in three dimensions to yield angiogram-like images (Figs. 434-1C, 434-2E and F, and see Fig. 438-3). However, the detectors, while numerous, have inefficiencies based on their physical architecture. New so-called photon-counting CT scanners use different technology for detectors, converting x-ray directly into an electric signal, rather than photon light, resulting in improved resolution, reduced electronic noise and thus dose reduction, improved spectral energy detection that reduces calcium and bone arti­ fact, and improved contrast-to-noise ratio, which permits a reduction in the dose of contrast material required. Photon counting scanners are now able to produce CT images with 0.2 mm resolution often at reduced radiation dose (Fig. 434-3). IV iodinated contrast is used to identify vascular structures and to detect defects in the blood-brain barrier (BBB) that are caused by tumors, infarcts, and infections. In the normal CNS, only vessels and structures lacking a BBB (e.g., the pituitary gland, choroid plexus, and dura) enhance after contrast administration. While helpful in characterizing mass lesions as well as essential for the acquisition of CTA studies, the decision to use contrast material should always be considered carefully as it carries a small risk of allergic reaction and adds additional expense. ■ ■INDICATIONS CT is the primary study of choice in the evaluation of an acute change in mental status, focal neurologic findings, acute trauma to the brain and spine, suspected subarachnoid hemorrhage, and conductive C hearing loss (Table 434-1). CT often is complementary to MR in the evaluation of the skull base, orbit, and osseous structures of the spine. In the spine, CT is useful in evaluating patients with osseous spinal stenosis and spondylosis, as well as in patients with failed back surgery; however, MRI is often preferred when neurologic deficits are present. CT is often acquired following intrathecal contrast injection to evaluate for spinal and intracranial CSF fistula, as well as the spinal subarach­ noid space (CT myelography) in failed back surgery syndromes. ■ ■COMPLICATIONS CT is safe, fast, and reliable. Radiation exposure depends on the dose used but is normally 2–5 mSv (millisievert) for a routine brain CT study. In comparison, the average American receives about 6.2 mSv per year from all sources of radiation, including 3.1 mSv from naturally occurring sources and a similar amount from man-made sources and applications such as jet plane trips, smoke detectors, and medical imag­ ing. While ionizing radiation can potentially induce damage to DNA, such risks are felt to be minimal at normal background radiation levels, especially at the low-dose levels related to diagnostic imaging. The risk of harm from radiation depends on the amount of dose, the delivery rate, the type of radiation, sensitivity of the tissue exposed, and the gender and age and health of the person exposed. Cancers that might develop from a radiation exposure usually have a latency period of 2–10 years or longer, after exposure. Nevertheless, for all patients, espe­ cially children, it is important to use as low a radiation dose as possible for diagnostic imaging purposes. Where feasible, MR or ultrasound is preferred. With the advent of MDCT, CTA, and CT perfusion, the diag­ nostic benefit must always be weighed against any increased radiation exposure. Advances in postprocessing software now permit acceptable diagnostic CT scans at 30–40% lower radiation doses compared with prior technology. The most frequent CT-related complications are those associated with use of IV contrast agents. Ionic contrast agents have been largely replaced by safer nonionic compounds. Contrast-associated acute kidney injury (CA-AKI) is a general term used to describe a sudden deterioration in renal function that occurs within 48 h following the intravascular administration of iodinated contrast medium. This rare complication appears to be more frequent with intraarterial injections during coronary angiography than with IV administration. CA-AKI from gadolinium-based contrast media probably does not occur or is exceptionally rare. CA-AKI is a cor­ relative diagnosis and may result from hemodynamic changes, renal tubular obstruction and cell damage, or immunologic reactions to contrast agents. Although there is no accepted definition of CA-AKI, the diagnosis of AKI is made according to the Kidney Disease Improv­ ing Global Outcomes (KDIGO) criteria if one of the following occurs B A D E H G FIGURE 434-2  Acute left hemiparesis due to right middle cerebral artery occlusion. A. Axial noncontrast computed tomography (CT) scan demonstrates high density within the right middle cerebral artery (arrow) associated with subtle low density involving the right putamen (arrowheads). B. Mean transit time CT perfusion parametric map indicating prolonged mean transit time involving the right middle cerebral territory (arrows). C. Cerebral blood volume (CBV) map shows reduced CBV involving an area within the defect shown in B, indicating a high likelihood of infarction (arrows). D. Axial maximum-intensity projection from a CT angiography (CTA) study through the circle of Willis demonstrates an abrupt occlusion of the proximal right middle cerebral artery (arrow). E. Sagittal reformation through the right internal carotid artery demonstrates a lowdensity lipid-laden plaque (arrowheads) narrowing the lumen (black arrow). F. Three-dimensional surface-rendered CTA image demonstrates calcification and narrowing of the right internal carotid artery (arrow), consistent with atherosclerotic disease. G. Coronal maximum-intensity projection from magnetic resonance angiography shows right middle cerebral artery (MCA) occlusion (arrow). H. and I. Axial diffusion-weighted image (H) and apparent diffusion-coefficient image (I) document the presence of a right middle cerebral artery infarction. CHAPTER 434 C Neuroimaging in Neurologic Disorders F I PART 13 Neurologic Disorders FIGURE 434-3  Photon-counting CT of the temporal bone. This 0.2-mm-thick image was obtained on a photon-counting CT scanner. It demonstrates an otosclerosis lesion (arrow) at the oval window in a patient with mixed hearing loss. The resolution of this image exceeds that of conventional 64-slice CT scanners (0.625 mm) due to improved detectors (see explanation in chapter). (Courtesy of Ian Mark, MD, and the Mayo Clinic.) within 48 h after a nephrotoxic event (e.g., intravascular iodinated contrast medium exposure): 1. Absolute serum creatinine increase ≥0.3 mg/dL (>26.4 µmol/L) 2. A percentage increase in serum creatinine ≥50% (≥1.5-fold above baseline) 3. Urine output reduced to ≤0.5 mL/kg per h for at least 6 h However, other causes of acute renal failure must be excluded. The prognosis is usually favorable, with serum creatinine levels returning to baseline within 1–2 weeks. Risk factors for contrast nephropathy are also controversial, but consensus is that the most important risk factor is preexisting severe renal insufficiency. Other proposed risk factors include diabetes mellitus, dehydration, cardiovascular disease, diuretic use, advanced age, hypertension, hyperuricemia, and multiple iodin­ ated contrast medium doses in a short time interval (<24 h), but these have not been rigorously confirmed. Patients with diabetes and those with mild renal failure should be well hydrated prior to the administra­ tion of contrast agents; careful consideration should be given to alter­ native imaging techniques. Estimated glomerular filtration rate (eGFR) is a more reliable indicator of renal function compared to creatinine alone because it considers age and sex in the calculation. In one study, 15% of outpatients with a normal serum creatinine had an eGFR of ≤50 mL/min per 1.73 m2 (normal is ≥90 mL/min per 1.73 m2). The exact eGFR threshold, below which withholding IV contrast should be considered, is also controversial. The risk of contrast nephropathy is minimal in patients with eGFR >30 mL/min per 1.73 m2; however, most of these patients will have only a temporary rise in creatinine. The risk of dialysis after receiving contrast significantly increases in patients with eGFR <30 mL/min per 1.73 m2. Little evidence exists that IV iodinated contrast material is an independent risk factor for acute kid­ ney injury in patients with eGFR ≥30 mL/min per 1.73 m2. The Ameri­ can College of Radiology suggests, if a threshold for risk is used at all, an eGFR of <30 mL/min per 1.73 m2 seems to have the greatest level of evidence. If contrast must be administered to a patient with an eGFR <30 mL/min per 1.73 m2, the patient should be well hydrated. The decision to administer closely spaced contrast-enhanced studies is a clinical one, as there is insufficient data on this topic. High-risk patients should, however, be treated with greater caution than the general population. Use of other agents such as bicarbonate and acetylcysteine were previously thought to be protective against CA-AKI; however, recent meta-analyses have failed to show protection over normal saline. Patients with renal failure who require contrast administration should not have acute dialysis or continuous renal replacement therapy initi­ ated, or alter their schedule due to the risks, costs, and lack of benefit. Below are suggested guidelines for creatinine testing prior to con­ trast administration. If a recent serum creatinine (within 60 days in most clinical settings) is not available, creatinine testing should be performed if the patient has any of the following risk factors: • Age >60 years or hypertension (however, this results in a large falsepositive rate for those with eGFR <30 mL/min per 1.73 m2) • Personal history of “kidney disease” as an adult, including kidney surgery, ablation, transplant, or prior dialysis • Diabetes mellitus treated with insulin or other prescribed medications • Metformin or metformin-containing drug combinations • Collagen vascular disease (e.g., systemic lupus erythematosus [SLE], scleroderma, rheumatoid arthritis) Allergy  Immediate reactions following IV contrast media occur through several mechanisms. The most severe are related to allergic hypersensitivity (anaphylaxis) and range from mild hives to broncho­ spasm and death. The pathogenesis of allergic hypersensitivity reac­ tions is thought to include the release of mediators such as histamine, antibody-antigen reactions, and complement activation. Severe allergic reactions occur in ~0.04% of patients receiving nonionic media, sixfold lower than with ionic media. Risk factors include a history of prior contrast reaction (fivefold increased likelihood), food and or drug aller­ gies, and atopy (asthma and hay fever). The predictive value of specific allergies, such as those to shellfish, once thought important, is now recognized to be unreliable. Nonetheless, in patients with a history wor­ risome for potential allergic reaction, a noncontrast CT or MRI proce­ dure should be considered as an alternative to contrast administration. If iodinated contrast is absolutely required, a nonionic agent should be used in conjunction with pretreatment with glucocorticoids and anti­ histamines (Table 434-2); however, pretreatment does not guarantee safety. Patients with allergic reactions to iodinated contrast material do not usually react to gadolinium-based MR contrast material, although such reactions can occur. It would be wise to pretreat patients with a prior allergic history to MR contrast administration in a similar fash­ ion. Subacute (>1 h after injection) reactions are frequent and probably related to T cell–mediated immune reactions. These are typically urti­ carial but can occasionally be more severe. Additives or contaminants, such as calcium-chelating substances or substances eluted from rubber stoppers in bottles or syringes, may be contributory in some allergy-like contrast reactions. Drug provocation and skin testing may be required to determine both the culprit agent involved and a safe alternative. Other side effects of CT contrast include a sensation of warmth throughout the body and a metallic taste during IV administration. Extravasation of contrast media, although rare, can be painful and lead to a compartment syndrome. When this occurs, immediate consulta­ tion with plastic surgery is indicated. Patients with significant cardiac disease may be at increased risk for contrast reactions, and in these patients, limits to the volume and osmolality of the contrast media should be considered. Patients who may undergo systemic radioactive iodine therapy for thyroid disease or cancer should not receive iodin­ ated contrast media, if possible, because this will decrease the uptake of the radioisotope into the tumor or thyroid (see the American College of Radiology Manual on Contrast Media, 2023; https://www.acr.org/-/ media/ACR/Files/Clinical-Resources/Contrast_Media.pdf). MAGNETIC RESONANCE IMAGING ■ ■TECHNIQUE MRI is a complex interaction between protons in biologic tissues, a static magnetic field (the magnet), and energy in the form of radiofrequency (Rf) waves of a specific frequency introduced by coils placed next to the body part of interest. Images are made by computerized processing of resonance information received from protons (typically hydrogen) TABLE 434-2  Guidelines for Premedication of Patients with Prior Contrast Allergy 13 h prior to examination:   Prednisone, 50 mg PO or methylprednisolone, 32 mg PO 7 h prior to examination:   Prednisone, 50 mg PO or methylprednisolone, 32 mg PO  1 h prior to examination:   Prednisone, 50 mg PO   Diphenhydramine, 50 mg intravenously, intramuscularly, or by mouth (optional) Immediately prior to examination:   Benadryl, 50 mg IV (alternatively, can be given PO 2 h prior to exam)  If a patient is unable to take oral medication, 200 mg hydrocortisone IV for each dose of oral prednisone may be used  If a patient is allergic to diphenhydramine in a situation where diphenhydramine would otherwise be considered, an alternate antihistamine without cross-reactivity may be considered, or the antihistamine portion of the regimen may be removed Accelerated IV Premedication 1.  Methylprednisolone sodium succinate (e.g., Solu-Medrol) 40 mg IV or Hydrocortisone sodium succinate (e.g., Solu-Cortef) 200 mg IV immediately, and then every 4 h until contrast medium administration. plus Diphenhydramine 50 mg IV 1 h before contrast medium administration. This regimen is usually 4–5 h in duration. 2.  Dexamethasone sodium sulfate (e.g., Decadron) 7.5 mg IV immediately, and then every 4 h until contrast medium administration plus Diphenhydramine 50 mg IV 1 h before contrast medium administration. This regimen may be useful in patients with an allergy to methylprednisolone and is also usually 4–5 h in duration. 3.  Methylprednisolone sodium succinate (e.g., Solu-Medrol) 40 mg IV or hydrocortisone sodium succinate (e.g., Solu-Cortef) 200 mg IV plus Diphenhydramine 50 mg IV, each 1 h before contrast medium administration. This regimen, and all other regimens with a duration <4–5 h, has no evidence of efficacy. It may be considered in emergent situations when there are no alternatives. Note: Premedication regimens <4–5 h in duration (oral or IV) have not been shown to be effective. in the body. Field strength of the magnet is directly related to signalto-noise ratio. While 1.5-Tesla (T) and 3-T magnets are now widely available and have distinct advantages in the brain and musculoskeletal systems, even higher field magnets (7 and 11+ T) and positron emission tomography (PET)-MR machines promise increased resolution and anatomic-functional information on a variety of disorders. Lower field strength magnets (0.55 T and lower) are available, having advantages of smaller size and weight, as well as improvement in signal-to-noise and susceptibility artifacts due to de-noising software and machine learning algorithms. Spatial localization of proton signal is achieved by magnetic gradients surrounding the main magnet, which impart slight changes in magnetic field throughout the imaging volume. Rf pulses transiently excite the energy state of the hydrogen protons in the body. Rf is admin­ istered at a frequency specific for the proton element (hydrogen) and the field strength of the magnet. The subsequent return to equilibrium energy state (relaxation) of the hydrogen protons results in a release of specific Rf energy (the echo), which is detected by the coils that delivered the Rf pulses. Fourier analysis is used to transform the echo into the information used to form an MR image. The MR image thus consists of a map of the distribution of hydrogen protons, with signal intensity imparted by both density of hydrogen protons and differences in the relaxation times and phase (see below) of hydrogen protons on different molecules. Although clinical MRI currently makes use of the ubiquitous hydrogen proton, sodium and carbon imaging and spectroscopy are also possible, but have yet to be integrated into mainstream practice. T1 and T2 Relaxation Times  The rate of return to equilibrium of perturbed protons is called the relaxation rate. The relaxation rate TABLE 434-3  Some Common Intensities on T1- and T2-Weighted MRI Sequences SIGNAL INTENSITY IMAGE TR TE CSF FAT BRAIN EDEMA T1W Short Short Low High Low Low T2W Long Long High High Medium High FLAIR (T2) Long Long Low High Medium High Abbreviations: CSF, cerebrospinal fluid; FLAIR, fluid-attenuated inversion recovery; TE, interval between radiofrequency pulse and signal reception; TR, interval between radiofrequency pulses; T1W and T2W, T1- and T2-weighted. varies among normal and pathologic tissues. The relaxation rate of a hydrogen proton in a tissue is influenced by local interactions with surrounding molecules and atomic neighbors. Two relaxation rates, T1 and T2, influence the signal intensity of the image. The T1 relaxation time is the time, measured in milliseconds, for 63% of the hydrogen protons to return to their normal equilibrium state, whereas the T2 relaxation is the time for 63% of the protons to become dephased owing to interactions among nearby protons. The intensity and image contrast of the signal within various tissues can be modulated by altering acquisition parameters such as the interval between Rf pulses (TR) and the time between the Rf pulse and the signal reception (TE). T1-weighted (T1W) images are produced by keeping the TR and TE relatively short, whereas using longer TR and TE times pro­ duces T2-weighted (T2W) images. Fat and subacute hemorrhage have relatively shorter T1 relaxation rates and thus higher signal intensity than brain on T1W images. Structures containing more water, such as CSF and edema, have long T1 and T2 relaxation rates, resulting in relatively lower signal intensity on T1W images and higher signal intensity on T2W images (Table 434-3). Gray matter contains 10–15% more water than white matter, which accounts for much of the intrin­ sic contrast between the two on MRI (Fig. 434-5A). T2W images are more sensitive than T1W images to edema, demyelination, infarction, and chronic hemorrhage, whereas T1W imaging is more sensitive to subacute hemorrhage and fat-containing structures. CHAPTER 434 Neuroimaging in Neurologic Disorders Many different MR pulse sequences exist, and each can be obtained with two-dimensional or three-dimensional techniques and in vari­ ous planes (Figs. 434-2, 434-4, and 434-5). The selection of a proper protocol that will best answer a clinical question depends on an accurate clinical history and indication for the examination. Fluid-attenuated inversion recovery (FLAIR) is a very useful pulse sequence in which the normally high signal intensity of CSF on T2W images is suppressed, improving the conspicuity of edematous lesions (Fig. 434-5B). FLAIR images are more sensitive than standard spin echo images for water-containing lesions or edema, especially those close to CSF-filled cisterns and sulci. Diffusion-weighted imaging is also routinely obtained in most brain protocols. This sequence inter­ rogates the microscopic motion of water, which is reduced in areas of infarction, abscess, and some tumors. Susceptibility-weighted imaging (SWI) is a gradient echo sequence that is very sensitive to alterations in local magnetic field generated by blood, calcium, and air. SWI is routinely obtained to detect microhemorrhages, such as is typical of amyloid angiopathy, hypertension, hemorrhagic metastases, traumatic brain injury, and thrombotic states (Fig. 434-6C). MR images can be generated in any plane without changing the patient’s position. Each sequence, however, is currently obtained separately and takes 1–10 min on average to complete. Three-dimensional volumetric imaging is rou­ tine, resulting in a volume of data that can be reformatted in any orien­ tation to highlight certain disease processes. Perfusion techniques such as arterial spin labeling also provide quantitative imaging information regarding cerebral blood flow, and fat-suppressed imaging obtained with T1W and T2W imaging is useful for detection of fat-containing structures as well as improving contrast with other structures such as nerves in the case of peripheral nerve imaging, skull base imaging, and spinal cord imaging. MR Contrast Material  The heavy-metal element gadolinium forms the basis of all currently approved IV MR contrast agents. A PART 13 Neurologic Disorders B FIGURE 434-4  Cerebral abscess in a patient with fever and a right hemiparesis. A. Coronal postcontrast T1-weighted image demonstrates a ring-enhancing mass in the left frontal lobe. B. Axial diffusion-weighted image demonstrates restricted diffusion (high signal intensity) within the lesion, which in this setting is highly suggestive of cerebral abscess. Gadolinium reduces the T1 and T2 relaxation times of nearby water protons in the presence of a magnetic field, resulting in a contrast enhancement on T1W images and a low signal on T2W images (the latter require a sufficient local concentration, usually in the form of an IV bolus). Unlike iodinated contrast agents, the effect of MR contrast agents depends on the presence of local hydrogen protons on which it must act to achieve the desired effect. There are multiple gadolinium agents approved in the United States for use with MRI. These dif­ fer according to the attached chelated moiety, which also affects the strength of chelation of the otherwise toxic gadolinium element. The chelating carrier molecule for gadolinium can be classified by whether it is macrocyclic or has linear geometry and whether it is ionic or non­ ionic. Macrocyclic ligands (group 2 agents) are considered more stable as the gadolinium ion is “caged” in the cavity of the ligand, and thus the rate of dissociation of gadolinium is slower compared to linear ligands (group 1 agents). Most agents are excreted by the renal system. BRAIN ACCUMULATION OF GADOLINIUM  It has been shown that gadolinium can accumulate in certain areas of the brain, primarily the dentate nuclei and globus pallidus, after serial administration of all types of gadolinium-based contrast agents (GBCAs). Autopsy studies have shown all GBCAs can lead to gadolinium deposition in brain; however, most clinical studies have demonstrated that linear GBCAs have more detectable gadolinium deposition than macrocyclic GBCAs. Gadolinium deposition in the brain appears to be dose dependent and occurs in patients with no clinical evidence of kidney or liver disease. To date, there have been no reports to suggest that these deposits are associated with histologic changes that would suggest neurotoxicity, even among agents with the highest rates of deposition. GBCAs can not only deposit in the brain but also in the skin, bone, liver, and other organs. This had importance in patients with renal failure who were exposed to linear gadolinium agents in the past, resulting in a rare but serious illness of the skin and organs secondary to accumulation of toxic gadolinium (nephrogenic systemic sclerosis). A B C FIGURE 434-5  Herpes simplex encephalitis in a patient presenting with altered mental status and fever. A. and B. Coronal (A) and axial (B) T2-weighted fluidattenuated inversion recovery images demonstrate expansion and high signal intensity involving the right medial temporal lobe and insular cortex (arrows). C. Coronal diffusion-weighted image demonstrates high signal intensity indicating restricted diffusion involving the right medial temporal lobe and hippocampus (arrows) as well as subtle involvement of the left inferior temporal lobe (arrowhead). This is most consistent with neuronal death and can be seen in acute infarction as well as encephalitis and other inflammatory conditions. The suspected diagnosis of herpes simplex encephalitis was confirmed by cerebrospinal fluid polymerase chain reaction analysis. ALLERGIC HYPERSENSITIVITY  Gadolinium-DTPA (diethylenetri­ aminepentaacetic acid) does not normally cross the intact BBB imme­ diately but will enhance lesions lacking a BBB (Fig. 434-4A) as well as areas of the brain that normally are devoid of the BBB (pituitary, dura, choroid plexus). However, gadolinium contrast slowly crosses an intact BBB over time and especially in the setting of reduced renal clearance or inflamed meninges. The agents are generally well tolerated; overall adverse events after injection range from 0.07–2.4%. True allergic reactions are rare (0.004–0.7%) but have been reported. Severe lifethreatening reactions are exceedingly rare; in one report, only 55 reac­ tions out of 20 million doses occurred. However, the adverse reaction rate in patients with a prior history of reaction to gadolinium is eight A B FIGURE 434-6  Susceptibility-weighted imaging in a patient with familial cavernous malformations. A. Noncontrast computed tomography scan shows one hyperdense lesion in the right hemisphere (arrow). B. T2-weighted fast-spin echo image shows subtle low-intensity lesions (arrows). C. Susceptibility-weighted image shows numerous low-intensity lesions consistent with hemosiderin-laden cavernous malformations (arrow). times higher than normal. Other risk factors include atopy or asthma (3.7%). There is rare cross-reactivity between different classes of con­ trast media; a prior reaction to gadolinium-based contrast does not predict a future reaction to iodinated contrast medium, or vice versa, more than any other unrelated allergy. Gadolinium contrast material can be administered safely to children as well as adults, although these agents are generally avoided in those aged <6 months. NEPHROTOXICITY  Contrast-induced renal failure does not occur with gadolinium agents. A rare complication, nephrogenic systemic fibrosis (NSF), has occurred in patients with severe renal insufficiency who have been exposed to linear (group 1 and 3) gadolinium contrast agents. The onset of NSF has been reported between 5 and 75 days following exposure; histologic features include thickened collagen bundles with surrounding clefts, mucin deposition, and increased numbers of fibrocytes and elastic fibers in skin. In addition to derma­ tologic symptoms, other manifestations include widespread fibrosis of the skeletal muscle, bone, lungs, pleura, pericardium, myocardium, kidney, muscle, bone, testes, and dura. The American College of Radi­ ology recommends that a glomerular filtration rate (GFR) assessment be obtained within 6 weeks prior to elective gadolinium-based MR contrast agent administration in patients with: 1. A history of renal disease (including solitary kidney, renal trans­ plant, renal tumor) 2. Age >60 years 3. History of hypertension 4. History of diabetes 5. History of severe hepatic disease, liver transplantation, or pending liver transplantation; for these patients, it is recommended that the patient’s GFR assessment be nearly contemporaneous with the MR examination. The incidence of NSF in patients with severe renal dysfunction (GFR <30 mL/min per 1.73 m2) varies from 0.19 to 4%. Other risk factors for NSF include acute kidney injury, the use of nonmacrocyclic agents, and repeated or high-dose exposure to gadolinium. The American College of Radiology Committee on Drugs and Contrast Media considers the risk of NSF among patients exposed to standard or lower doses of group 2 gadolinium agents (macrocyclic agents) to be sufficiently low or possibly nonexistent such that the assessment of renal function is optional prior to administration. Group 2 agents are strongly preferred in patients at risk for NSF. Renal function, dialysis status, or informed consent are not recommended prior to injection of group 2 agents, but deference is made to local practice preferences. Patients receiving any group 1 (linear) or 3 gadolinium-containing agents should be consid­ ered at risk of NSF if they are on dialysis (of any form); have severe or end-stage chronic renal disease (eGFR <30 mL/min per 1.73 m2) with­ out dialysis; have eGFR of 30–40 mL/min per 1.73 m2 without dialysis CHAPTER 434 C (as the GFR may fluctuate); or have acute renal insufficiency. The use of gadolinium in young children and infants is discouraged due to the unknown risks and their immature renal systems. Neuroimaging in Neurologic Disorders ■ ■COMPLICATIONS AND CONTRAINDICATIONS From the patient’s perspective, an MRI examination can be intimidat­ ing, and a higher level of cooperation is required than with CT. The patient lies on a table that is moved into a long, narrow gap within the magnet. Approximately 5% of the population experiences severe claustrophobia in the MR environment. This can be reduced by mild sedation but remains a problem for some. Movement of the patient during an MR examination may distort all the images in sequence; therefore, uncooperative patients should either be sedated for the MR study or scanned with CT. Generally, children aged <8 years usually require anesthesia monitored sedation to complete the MR examina­ tion without motion degradation. MRI is considered safe for patients, even at 3- to 7-T field strengths. Serious injuries have been caused, however, by attraction of external ferromagnetic objects into the magnet, which act as missiles if brought too close to the magnet. Likewise, ferromagnetic implants, such as aneurysm clips, may torque within the magnet, causing damage to vessels and even death. Metallic foreign bodies in the eye have moved and caused intraocular hemorrhage; screening for ocular metallic fragments is indicated in those with a history of metal work or ocular metallic foreign bodies. Implanted cardiac pacemakers are generally a contraindication to MRI owing to the risk of induced arrhythmias; however, some newer pacemakers have been shown to be safe, and if necessary, MR may be performed if the pacemaker can be safely turned off during the scan. All health care personnel and patients must be screened and educated thoroughly to prevent such disasters because the magnet is always “on.” Table 434-4 lists common contraindications for MRI. MAGNETIC RESONANCE ANGIOGRAPHY On routine spin echo MR sequences, moving protons (e.g., flowing blood, CSF) exhibit complex MR signals that range from high to low signal intensity relative to background stationary tissue. Fast-flowing blood returns no signal (flow void) on routine T1W or T2W spin echo MR images. Slower-flowing blood, as occurs in veins or distal to arte­ rial stenosis, may appear high in signal. MR angiography makes use of pulse sequences called gradient echo sequences that increase the signal intensity of moving protons in contrast to suppressed low signal back­ ground intensity of stationary tissue. This results in a stack of images, which can be reformatted in any plane to highlight vascular anatomy and relationships. Several types of MRA techniques exist. Time-of-flight (TOF) MRA is normally done without contrast administration and relies on the sup­ pression of nonmoving tissue to provide a low-intensity background TABLE 434-4  Common Contraindications to Magnetic Resonance Imaging Cardiac pacemaker or permanent pacemaker leads Internal defibrillatory device Cochlear prostheses Bone growth stimulators Spinal cord stimulators Electronic infusion devices Intracranial aneurysm clips (some but not all) Ocular implants (some) or ocular metallic foreign body McGee stapedectomy piston prosthesis DuraPhase penile implant Swan-Ganz catheter Magnetic stoma plugs Magnetic dental implants Magnetic sphincters Ferromagnetic inferior vena cava filters, coils, stents—safe 6 weeks after implantation Tattooed eyeliner (contains ferromagnetic material and may irritate eyes) PART 13 Neurologic Disorders Note: See also http://www.mrisafety.com. for the high signal intensity of flowing blood entering the section. A typical TOF MRA sequence results in a series of contiguous, thin MR sections (0.6–0.9 mm thick), which can be viewed as a stack and manipulated to create an angiographic image data set that can be refor­ matted and viewed in various planes and angles, much like that seen with conventional angiography (Fig. 434-2G). Phase-contrast MRA has a longer acquisition time than TOF MRA, but in addition to providing anatomic information like that of TOF imaging, it can be used to reveal the velocity and direction of blood flow in each vessel. MRA is also often acquired during infusion of IV gadolinium con­ trast material. Advantages include faster imaging times (1–2 min vs 10 min), fewer flow-related artifacts, and four-dimensional temporal imaging resulting in arterial and venous phases. Recently, contrastenhanced MRA has become the standard for assessment of the extra­ cranial vascular structures. This technique entails rapid imaging using coronal three-dimensional TOF sequences during a bolus infusion of gadolinium contrast agent. MRA has lower spatial resolution compared with conventional film-based angiography and, therefore, is inherently less sensitive to detection of small-vessel abnormalities, such as vasculitis and distal vasospasm. MRA is also less sensitive to slowly flowing blood and thus may not reliably differentiate complete from near-complete occlusions. Motion, either by the patient or by anatomic structures, may distort the MRA images, creating artifacts. These limitations notwithstanding, MRA has proved useful in evaluation of the extracranial carotid and vertebral circulation as well as of larger-caliber intracranial arteries and dural sinuses. It has also proved useful in the noninvasive detection of intracranial aneurysms and vascular malformations. Vessel wall MR imaging (VWI) is an MR technique that relies on sup­ pression of all moving protons within vessels and CSF, combined with IV contrast administration (Fig. 434-7). Unlike MRA, VWI is a high spatial resolution, three-dimensional, T1W technique used to assess pathology of the vessel wall itself. This technique can be used to detect, characterize, and differentiate such pathologies as atherosclerosis, vas­ culitis (e.g., primary angiitis of the central nervous system [PACNS]), and vasculopathies such as reversible cerebral vasoconstriction syn­ drome (RCVS) and has been used to assess the wall of aneurysms. ECHO-PLANAR MRI Echo-planar MRI (EPI) forms the basis of several important MR imag­ ing sequences. EPI uses fast gradients that are switched on and off at high speeds to create the information used to form an image. With EPI, all the information required for processing an image is accumulated in milliseconds, and the information for the entire brain can be obtained in <1–2 min, depending on the degree of resolution required or desired. Fast MRI reduces patient and organ motion and is the basis of perfu­ sion imaging during contrast infusion and kinematic motion studies. EPI is also the sequence used to obtain diffusion-weighted imaging (DWI) and tractography (DTI), as well as functional MRI (fMRI) and arterial spin-labeled (ASL) perfusion studies (Figs. 434-2H, 434-4, 434-5C, and 434-7; and Fig. 437-13). Perfusion and diffusion imaging are EPI techniques that are useful in early detection of ischemic injury of the brain and may be useful together to demonstrate infarcted tissue as well as ischemic but poten­ tially viable tissue at risk of infarction (e.g., the ischemic penumbra). DWI assesses microscopic motion of water; water protons that move reduce signal intensity on diffusion-weighted images. Pathology that reduces microscopic water motion results in relatively higher signal. Infarcted tissue reduces the water motion within cells and in the interstitial tissues, resulting in high signal on DWI. DWI is the most sensitive technique for detection of acute cerebral infarction of <7 days in duration (Fig. 434-2H). It is also quite sensitive for detecting dying or dead brain tissue secondary to encephalitis, as well as abscess and purulent formations (Fig. 434-4B). Perfusion MRI can be performed by the acquisition of fast EPI dur­ ing a rapid IV bolus of gadolinium contrast material or by noncontrast ASL techniques. With contrast perfusion imaging, parametric maps of relative cerebral blood volume, mean transit time (MTT), time to maximum (tMAX), and cerebral blood flow can be derived. Prolonged MTT and tMAX and reduction in cerebral blood volume and cerebral blood flow are typical of infarction. In the setting of reduced blood flow, a prolonged MTT of contrast but normal or elevated cerebral blood volume may indicate tissue supplied by slower collateral flow that is at risk of infarction. Perfusion MRI imaging can also be used in the assessment of brain tumors to differentiate intraaxial primary tumors, whose BBB is relatively intact, from extraaxial tumors or metastases, which demonstrate a relatively more permeable BBB. DTI is derived from diffusion MRI sequences. This technique assesses the direction and integrity of protons flowing within white matter architecture. It has proven valuable in the assessment of sub­ cortical white matter tract anatomy prior to brain tumor surgery, as well as in determining normal and abnormal white matter architecture in congenital and acquired pathologies such as traumatic brain injury and assessing the integrity of peripheral nerves and spinal cord lesions (Fig. 434-8). fMRI is an EPI technique that localizes regions of activity in the brain following task activation or at rest (so-called resting-state fMRI). Neu­ ronal activity elicits a slight increase in the delivery of oxygenated blood flow to a specific region of activated brain. This results in an alteration in the balance of oxyhemoglobin and deoxyhemoglobin, which yields a 2–3% increase in signal intensity within veins and local capillaries. Cur­ rently, preoperative somatosensory, motor, and auditory cortex localiza­ tion is performed, and methods to assess motor and language function are in development. This technique has proved useful to neuroscientists interested in interrogating the localization of specific brain functions. ARTERIAL SPIN LABELING ASL is a quantitative noninvasive MR technique that measures cerebral blood flow (Fig. 434-7). Blood traversing in the neck is labeled by an MR pulse and then imaged in the brain after a short (2 s) delay. The signal is reflective of blood flow. ASL has become almost standard in many MR protocols because it is relatively fast to acquire and does not require contrast administration. Increased cerebral flow is more easily identified than slow flow, which can be sometimes difficult to quantify. This tech­ nique has also been useful in detecting shunting in arteriovenous mal­ formations and fistulas, as well as increased blood flow in brain tumors, and in patients after transient ischemic attack, seizure, or migraine. MAGNETIC RESONANCE NEUROGRAPHY MRN is an MR technique that shows promise in detecting increased signal in irritated, inflamed, or infiltrated peripheral nerves. T1W and T2W imaging are obtained with fat-suppressed fast-spin echo imag­ ing or short inversion recovery sequences. Inflamed peripheral nerves will demonstrate high signal on T2W imaging. MRN is indicated in A C E FIGURE 434-7  Arterial spin label and vessel wall imaging in a 25-year-old woman with focal cerebral arteriopathy. The patient had an 8-month history of intermittent weakness of the right side with spasms. Imaging shows evidence of cerebral ischemia. Cerebrospinal fluid was transiently inflammatory. A. Diffusion-weighted image shows focal region of reduced diffusion in left parietal lobe. B. T2 fluid-attenuated inversion recovery images show several foci of high signal in left deep subcortical white matter. C. Arterial spin label image demonstrates reduced cerebral blood flow in left parietal lobe (arrows). D. Three-dimensional (3D) T1 image without contrast administration. E. 3D T1-weighted cube vessel wall image following gadolinium contrast shows focal enhancement of the left proximal middle cerebral artery (arrow). F. 3D time-of-flight magnetic resonance angiography shows focal narrowing of the left supraclinoid internal carotid artery and proximal middle cerebral artery (arrow). CHAPTER 434 B Neuroimaging in Neurologic Disorders D F A PART 13 Neurologic Disorders D C FIGURE 434-8  Diffusion tractography in cerebral glioma. A, B and C are images showing a left temporal mass lesion (T) that medially displaces the inferior longitudinal fasciculus (arrow). D. Different patient showing: Associative and descending pathways in a healthy subject (A) and in a patient with parietal lobe glioblastoma (B) presenting with a language deficit: the mass causes a disruption of the arcuate-SLF complex, in particular of its anterior portion (SLF III). Also shown are bilateral optic tract and left optic radiation pathways in a healthy subject (C) and in a patient with left occipital grade II oligoastrocytoma (D): the mass causes a disruption of the left optic radiation. Shown in neurologic orientation, i.e., the left brain appears on the left side of the image. AF, long segment of the arcuate fascicle; CST, corticospinal tract; IFOF, inferior fronto-occipital fascicle; ILF, inferior longitudinal fascicle; SLF III, superior longitudinal fascicle III or anterior segment of the arcuate fascicle; SLF-tp, temporo-parietal portion of the superior longitudinal fascicle or posterior segment of the arcuate fascicle; T, tumor; UF, uncinated fascicle. (Part D used with permission from Eduardo Caverzasi and Roland Henry.) patients with radiculopathy whose conventional MR studies of the spine (cervical or lumbar) are normal or in those suspected of periph­ eral nerve entrapment or trauma. This technique is now also being used to assess peripheral nerve damage after trauma or from compres­ sive and autoimmune neuropathies. POSITRON EMISSION TOMOGRAPHY PET relies on the detection of positrons emitted during the decay of a radionuclide that has been injected into a patient. The most fre­ quently used moiety is 2-[18F] fluoro-2-deoxy-d-glucose (FDG), which is an analogue of glucose and is taken up by cells competitively with 2-deoxyglucose. Many other radioisotopes are used in other indica­ tions. With FDG, multiple images of glucose uptake activity are formed 45–60 min after IV administration of FDG. Images reveal differences in regional glucose activity among normal and pathologic brain struc­ tures. FDG-PET is used primarily for the detection of extracranial metastatic disease; however, a lower activity of FDG in the parietal lobes is associated with Alzheimer’s disease, a finding that may simply reflect atrophy that occurs in the later stages of the disease. Combina­ tion PET-CT scanners, in which both CT and PET are obtained at one sitting, have largely replaced PET scans alone. MR-PET scanners have also been developed and may prove useful for imaging the brain and other organs without the radiation exposure of CT. More recent PET ligand developments include beta-amyloid and tau PET tracers (Chap. 442). Studies have shown an increased percentage of amyloid deposition in patients with Alzheimer’s disease compared with mild cognitive impairment and healthy controls; however, up to 25% of cognitively “normal” older patients show abnormalities on amyloid B PET imaging. This may either reflect subclinical disease processes or a variation of normal. Tau imaging may be more specific for Alzheimer’s disease, and clinical studies are in progress. MYELOGRAPHY ■ ■TECHNIQUE Myelography involves the intrathecal instillation of specially for­ mulated water-soluble iodinated contrast medium into the lumbar or cervical subarachnoid space. CT scanning is typically performed after myelography to better demonstrate the spinal cord and roots, which appear as filling defects in the opacified subarachnoid space. CT myelography, in which CT is performed after the subarachnoid injection of a small amount of contrast material, has replaced conven­ tional myelography for many indications, thereby reducing exposure to radiation and contrast media. CT is obtained at a slice thickness of ~2.5 mm and reconstructed at 0.625-mm thick slices, which can quickly be reformatted in sagittal and coronal planes, equivalent to traditional myelography projections. ■ ■INDICATIONS CT myelography and MRI have largely replaced conventional myelog­ raphy for the diagnosis of diseases of the spinal canal and cord (Table 434-1). Remaining indications for conventional plain film myelography include the evaluation of suspected meningeal or arach­ noid cysts and the localization of CSF fistulas. Conventional myelog­ raphy and CT myelography provide the most precise information in patients with failed back syndrome following spinal fusion procedures. ■ ■CONTRAINDICATIONS Myelography is relatively safe; however, it should be performed with caution in any patient with elevated intracranial pressure, evidence of a spinal block, or a history of allergic reaction to intrathecal contrast media. In patients with a suspected spinal block, MR is the preferred imaging technique. If myelography is necessary, only a small amount of contrast medium should be instilled below the block to minimize the risk of neurologic deterioration. Lumbar puncture (LP) is to be avoided in patients with bleeding disorders and those with infections of the overlying soft tissues. Anticoagulant therapy should be withheld prior to elective LP to avoid epidural or intradural hemorrhage, unless required in emergent situations (Chap. S3). ■ ■COMPLICATIONS Headache is the most frequent complication of myelography and is reported to occur in 5–30% of patients. Nausea and vomiting may also occur rarely. Postural headache (post-LP headache) is generally due to continued epidural leakage of CSF from the dural puncture site. A higher incidence is noted among younger women and with the use of larger gauge cutting-type spinal needles. If significant headache persists for >48 h, placement of an epidural blood patch should be considered. Vasovagal syncope may occur during LP; it is accentuated by the upright position used during conventional lumbar myelography. Adequate hydration before and after myelography will reduce the incidence of this complication. Management of LP headache is discussed in Chap. 17. Hearing loss is a rare complication of myelography. It may result from a direct toxic effect of the contrast medium or from an alteration of the pressure equilibrium between CSF and perilymph in the inner ear. Puncture of the spinal cord is a rare but serious complication of cervical (C1–2) or high LP. The risk of cord puncture is greatest in patients with spinal stenosis, Chiari malformations, or conditions that reduce CSF volume. CT myelography following a lumbar injec­ tion and MRI are safer alternatives to cervical puncture. Reactions to intrathecal contrast administration are rare; aseptic meningitis and encephalopathy are reported rare complications. The latter is usually dose related and associated with contrast entering the intracranial sub­ arachnoid space. Seizures rarely occur following myelography, histori­ cally reported in 0.1–0.3% of patients. Risk factors include a preexisting seizure disorder and the use of a total iodine dose of >4500 mg. Other reported complications include hyperthermia, hallucinations, depres­ sion, and anxiety states. These side effects have been reduced by the development of nonionic, water-soluble contrast agents as well as by head elevation and generous hydration following myelography. SPINE INTERVENTIONS ■ ■DISKOGRAPHY The evaluation of back pain and radiculopathy (Chap. 18) may require diagnostic procedures that attempt either to reproduce the patient’s pain or relieve it, indicating its correct source prior to lumbar fusion. Diskography is now rarely indicated. It is performed by CT or fluoro­ scopic placement of a 22- to 25-gauge needle into the intervertebral disk and subsequent injection of 1–3 mL of contrast media. The intra­ discal pressure is recorded, as is an assessment of the patient’s response to the injection of contrast material. Little or no pain is felt during injection of a normal disk, which does not accept much more than 1 mL of contrast material, even at pressures as high as 415–690 kPa (60–100 lb./in2). CT and plain films are obtained following the proce­ dure. Concerns have been raised that diskography may contribute to an accelerated rate of disk degeneration; furthermore, patients who suffer from depression or anxiety are more likely to find diskography painful, and in some cases, the procedure-associated pain became persistent, lasting a year or longer. Thus, it is rarely used as a reliable biomarker of pain generation. Newer spectroscopic disc techniques are being explored for the detection of painful degenerative disks. ■ ■SELECTIVE NERVE ROOT AND EPIDURAL SPINAL INJECTIONS Percutaneous selective nerve root and epidural administration of glucocorticoid and anesthetic mixtures may be both therapeutic and diagnostic. Typically, 1–2 mL of an equal mixture of a long-acting glu­ cocorticoid such as betamethasone or dexamethasone combined with a long-acting anesthetic such as bupivacaine is instilled under CT or fluoroscopic guidance in the intraspinal epidural space or adjacent to an existing nerve root in question as a pain source. This can also be per­ formed into the facet joints, or around the medial nerve branches that supply innervation to the facet joints as well. Radiofrequency ablation of the medial branches that supply sensation to the facet joints is com­ monly performed, and ablation techniques of the basivertebral nerves that conduct the sensation from degenerative disks have proven useful in certain cases of painful disk degeneration. Cement placement into compression fractures of the vertebral bodies, so-called vertebroplasty and kyphoplasty techniques, are commonly performed for pain-gen­ erating fractures, especially in elderly patients or those with pathologic fractures. ANGIOGRAPHY Catheter angiography is indicated for evaluating intracranial small-ves­ sel pathology (e.g., vasculitis), for assessing vascular malformations and aneurysms, and in endovascular therapeutic procedures (Table 434-1). As noted above, angiography has been replaced for many indications by CT/CTA or MRI/MRA. CHAPTER 434 Neuroimaging in Neurologic Disorders Angiography carries the greatest risk of morbidity of all diagnostic imaging procedures, owing to the necessity of inserting a catheter into a blood vessel, directing the catheter to the required location, inject­ ing contrast material to visualize the vessel, and removing the catheter while maintaining hemostasis. Therapeutic transcatheter procedures (see below) have become important options for the treatment of some cerebrovascular diseases. The decision to undertake a diagnostic or therapeutic angiographic procedure requires careful assessment of the goals of the investigation and its attendant risks. Patients undergoing angiography should be well hydrated before and after the procedure. Because the femoral route is used most, the femoral artery must be compressed after the procedure to prevent a hematoma from developing. The puncture site and distal pulses should be evaluated carefully after the procedure; complications can include thigh hematoma or lower-extremity emboli. ■ ■COMPLICATIONS A common femoral arterial puncture provides retrograde access via the aorta to the aortic arch and great vessels. The most feared complication of cerebral angiography is stroke. Thrombus can form on or inside the tip of the catheter, rarely arterial dissection or perforation can occur, and atherosclerotic thrombus or plaque can be dislodged by the cath­ eter or guide wire or by the force of injection and can embolize distally in the cerebral circulation. Risk factors for ischemic complications include limited experience on the part of the angiographer, athero­ sclerosis, vasospasm, low cardiac output, decreased oxygen-carrying capacity, advanced age, and prior history of migraine. The risk of a neurologic complication varies but is ~4% for transient ischemic attack and stroke, 0.5% for permanent deficit, and <0.1% for death. Nonionic contrast material is used exclusively in cerebral angiog­ raphy. Nonionic contrast injected into the cerebral vasculature can be neurotoxic if the BBB is breached, either by an underlying disease or by the injection of hyperosmolar contrast agent. Patients with dolicho­ ectasia of the basilar artery can suffer reversible brainstem dysfunction and acute short-term memory loss during angiography, owing to the slow percolation of the contrast material and the consequent prolonged exposure of the brain. Rarely, an intracranial aneurysm ruptures during an angiographic contrast injection, causing subarachnoid hemorrhage, perhaps because of injection under high pressure. ■ ■SPINAL ANGIOGRAPHY Spinal angiography is indicated to evaluate the location of vascular malformations and to identify the artery of Adamkiewicz (Chap. 453) prior to aortic aneurysm repair. The procedure is lengthy and requires the use of relatively large volumes of contrast; the incidence of seri­ ous complications, including paraparesis, subjective visual blurring, and altered speech, is <1%. Gadolinium-enhanced MRA has been # 04 - 435 Pathobiology of Neurologic Diseases ### 435 Pathobiology of Neurologic Diseases used successfully in this setting, as has iodinated contrast CTA, which has promise for replacing diagnostic spinal angiography for some indications. INTERVENTIONAL NEURORADIOLOGY This rapidly developing field is providing new therapeutic options for patients with challenging neurovascular problems. Available proce­ dures include detachable coil therapy for aneurysms, particulate or liquid adhesive embolization of arteriovenous malformations, stent retrieval systems for embolectomy in acute stroke, balloon angioplasty and stenting of arterial stenosis or vasospasm, transarterial or trans­ venous embolization of dural arteriovenous fistulas and CSF-venous fistulas of the spine, balloon occlusion of carotid-cavernous and verte­ bral fistulas, endovascular treatment of vein-of-Galen malformations, preoperative embolization of tumors, and thrombolysis of acute arte­ rial or venous thrombosis. Many of these disorders place the patient at high risk of cerebral hemorrhage, stroke, or death. The highest complication rates are found with the therapies designed to treat the highest risk diseases. The advent of electrolytically detach­ able coils ushered in a new era in the treatment of cerebral aneurysms (Chap. 440). Two randomized trials found reductions of morbidity and mortality at 1 year among those treated for aneurysm with detachable coils compared with neurosurgical clipping. In many centers, coil­ ing has become standard therapy for many proximal circle of Willis aneurysms. PART 13 Neurologic Disorders Finally, recent studies of stent retrieval systems used to withdraw emboli have shown improved clinical outcomes in patients presenting with large-vessel occlusions and signs of acute stroke (Chap. 438). ■ ■FURTHER READING Bambach S et al: Arterial spin labeling applications in pediatric and adult neurologic disorders. J Magn Reson Imaging 55:698, 2020. Choi JW, Moon WJ: Gadolinium deposition in the brain: Current updates. Korean J Radiol 20:134, 2019. Mandell DM et al: Intracranial vessel wall MRI: Principles and expert consensus recommendations of the American Society of Neuroradi­ ology. AJNR Am J Neuroradiol 38:218, 2017. Nadjir R et al: Neuroradiology: The Core Requisites, 5th ed. Philadelphia, Elsevier, 2024. Pelz DM et al: Interventional neuroradiology: A review. Can J Neurol Sci 16:1, 2020. Schönmann C, Brockow K: Adverse reactions during procedures: Hypersensitivity to contrast agents and dyes. Ann Allergy Asthma Immunol 124:156, 2020. Tournier JD: Diffusion MRI in the brain—theory and concepts. Prog Nucl Magn Reson Spectrosc 112-113:1, 2019. Watson RE et al: MR imaging safety events: Analysis and improve­ ment. Magn Reson Imaging Clin N Am 28:593, 2020. Stephen L. Hauser, Arnold R. Kriegstein, Stanley B. Prusiner Pathobiology of Neurologic Diseases The human nervous system is the organ of consciousness, cognition, ethics, and behavior; as such, it is the most intricate structure known to exist. More than one-third of the 23,000 genes encoded in the human genome are expressed in the nervous system, and for many, different isoforms are expressed that further increase the result­ ing specificities and potential functionality. Each mature brain is composed of 100 billion neurons, several million miles of axons and dendrites, and >1015  synapses. Neurons exist within a dense paren­ chyma of multifunctional glial cells that synthesize myelin, preserve homeostasis, and regulate immune responses. Measured against this background of complexity, the achievements of molecular neurosci­ ence have been extraordinary. Advances have occurred in parallel with the development of new enabling technologies—in bioengineering and computational sciences; imaging; and cell, molecular, and chemical biology—and moving forward it is likely that the pace of new discover­ ies will only increase. This chapter reviews a few of the most dynamic areas in neuroscience, specifically highlighting advances in immunol­ ogy and inflammation, neurodegeneration, and stem cell biology. In each of these areas, recent discoveries are providing context for an understanding of the triggers and mechanisms of disease and offering new hope for prevention, treatment, and repair of nervous system inju­ ries. Discussions of the neurogenetics of behavior, advances in addic­ tion science, and diseases caused by network dysfunction can be found in Chap. 462 (Biology of Psychiatric Disorders); and new approaches to rehabilitation via harnessing of neuroplasticity, neurostimulation, and computer–brain interfaces are presented in Chap. 500 (Emerging Neurotherapeutic Technologies). NEUROIMMUNOLOGY AND NEUROINFLAMMATION Neuroimmunology traditionally comprises the science of immunemediated diseases of the nervous system, especially autoimmune diseases such as multiple sclerosis, myasthenia gravis, and GuillainBarré syndrome, as well as disorders in which immune-mediated neurologic damage occurs in the context of infection or neoplasia. More recently, recognition that neuroinflammation and the innate immune system play key roles in an expanded category of neurologic disorders, and neurodegenerative disorders in particular, has focused renewed attention on the intrinsic cellular components in the central nervous system (CNS) that mediate tissue damage, especially microg­ lia/macrophages and astrocytes, and also on oligodendrocytes, which are now recognized as central players across a wide range of brain disorders. It is also increasingly recognized that extensive networks of communication exist between each of these cell types and that result­ ing non-cell-autonomous pathologies are likely to underlie many human CNS disorders. ■ ■MICROGLIA AND MACROPHAGES These represent the most abundant cell types in the nervous system responsible for antigen presentation and innate immunity. Brain microglia (“small glue”) are derived from a primitive macrophage population in the yolk sac that migrates to the nervous system early in embryogenesis before the blood-brain barrier is formed. Once in the CNS, a variety of cell signals mediate microglial proliferation, migra­ tion, and differentiation. Microglia maintain their cell numbers pri­ marily through self-renewal and not repopulation from the circulation; however, it is now also clear that under some conditions peripherally derived macrophages that become microglia-like can replace damaged or defective microglia throughout the life span. Most microglia receive survival signals through colony-stimulating factor 1 receptor (Csf1r), via its natural ligands Csf1 produced by astrocytes and oligoden­ drocytes, and interleukin (IL) 34 produced by neurons. Depletion of microglia by administration of a selective inhibitor of Csf1r (PLX5622) was followed by rapid repopulation, which led to identification of a second population of ramified microglial precursor cells that do not require Csf1r signaling. Microglia have traditionally been divided into “resting” and “activated” states, the former characterized by an exten­ sively ramified appearance and the latter by a globular amoeboid phe­ notype. A variety of factors and cues, including type 1 interferons, can prime resting microglia toward an activated state, and these “primed” microglia are then hyperresponsive to a variety of secondary immune challenges including infection. Recently, single-cell transcriptome sequencing of microglia has also revealed a high degree of heterogene­ ity that was previously unappreciated, the functional consequences of which are largely unknown. Promote learning and memory BDNF Phagocytosis of debris Proinflammatory (A1) astrocyte Uptake of aggregated proteins FIGURE 435-1  The multifunctional microglial cell. Microglia have diverse functions that can support healthy development and maintain homeostasis or contribute to tissue damage in pathologic conditions. Homeostatic functions include promotion of learning and memory through secretion of soluble proteins such as brain-derived neurotrophic factor (BDNF); participation in normal synaptic pruning; and clearing cellular debris and protein aggregates via phagocytosis. However, in pathologic states, activated microglia also contribute to tissue damage by targeting normal healthy neurons and synapses; by promoting formation of β-amyloid or other misfolded proteins deposited in neurodegenerative diseases; and by secreting cytokines (such as interleukin 1α, tumor necrosis factor, and the complement component C1q) incriminated in induction of neurotoxic A1 astrocytes. In addition, microglia have diverse functions in adaptive immunity, including roles in antigen presentation and immune regulation (Fig. 435-2). (Reproduced with permission from J Herz et al: Myeloid cells in the central nervous system. Immunity 46:943, 2017.) Microglia play critical roles in sculpting neuronal populations dur­ ing development and across the life span, through secretion of brainderived neurotrophic factor (BDNF) and other trophic factors that promote neuronal survival, and also via production of reactive oxygen species (ROS) and other molecules that mediate cell death. Microglia regulate development and maintenance of neural circuits through pruning of excitatory synapses and control of dendritic spine densities (Fig. 435-1). Mice depleted of microglia during development exhibit a variety of cognitive, learning, and behavioral deficits, including abnor­ mal social behaviors. These processes are dependent on classical com­ plement pathway molecules, including secretion of C1q and expression of complement receptor 3 (CR3) and CR5. Abnormalities in these microglial-dependent networks are now recognized as critical to the pathogenesis of most neurodegenerative and age-related pathologies. Activation of the complement cascade has assumed a major place in current concepts of pathogenesis of Alzheimer’s disease (AD) and other dementias, as follows. Synapses targeted for elimination are tagged by the complement proteins C1q and C3, the levels of which increase in the presence of excess β-amyloid. C3-bearing synapses are targeted for elimination by microglia that express CR3, and knockout of C1q or C3 can rescue the clinical and pathologic abnormalities asso­ ciated with neurodegeneration. Modification of aberrant complement activity represents an attractive approach for treatment of neurodegen­ eration from multiple causes, not only AD, but also Parkinson’s and Huntington’s disease, among others, in which microglia are responsible for clearing pathologic protein aggregates. An ideal therapeutic would target the deleterious microglial functions while preserving ones that are central to homeostasis such as synaptic pruning. Another consid­ eration, especially given the diverse roles of the complement system in all organs of the body, is potential off-target toxicities. Clinical trials are now underway with an inhibitory monoclonal antibody against C1q for Huntington’s disease and amyotrophic lateral sclerosis (ALS). While the specific mechanisms of complement-dependent neurode­ generation will likely differ in distinct neurodegenerative conditions, these data provide hope that complement-pathway interventions could represent an approach to control of neurodegenerative pathologies mediated at least in part through the innate immune system. Genetic evidence also supports a primary role for microglia in numerous neurodegenerative conditions and disease states, in con­ trast to earlier views in which their role was seen as largely secondary Pruning or elimination of synapses IL-1α | TNF | C1q CHAPTER 435 Pathobiology of Neurologic Diseases and involving phagocytosis of cell debris. More than half of all genes implicated in genome-wide association studies in AD implicate innate immune processes and microglia. One direct genetic link is the phagocytosis-associated gene TREM2 (triggering receptor expressed on myeloid cells 2). TREM2 is a microglial receptor that can bind amyloid, induce proliferation and migration of microglia, and pos­ sibly limit the spread of disease-associated AD aggregates. Moreover, a soluble TREM2 cleavage product promotes neuroinflammation and inhibits aggregation of β-amyloid. Loss-of-function mutations in TREM2 increase AD risk up to fourfold. In one mouse model of AD, overexpression of TREM2 blocked AD pathology and rescued perfor­ mance on tests of learning and memory; however, in other models, including tau models, the effects of TREM2 targeting were found to be stage specific or inconsistent. A clinical trial of an agonist monoclonal antibody against TREM2 is underway. Immune system genes implicated in susceptibility to other late-life dementias also represent promising targets for therapy. For example, ~10% of all cases of frontotemporal degeneration (FTD) are due to heterozygous mutations of the gene granulin (GRN), which encodes the protein progranulin expressed in neurons and microglial cells (Chap. 443). Progranulin is a neurotrophic factor essential for lyso­ somal function and microglial homeostasis. GRN mutations with resulting haploinsufficiency of progranulin are highly penetrant for FTD. When progranulin is deleted in mice, an age-dependent microg­ lial activation phenotype results, associated with upregulation of proinflammatory neurotoxic cytokines, complement components, and other genes associated with innate immunity, along with enhanced pruning of inhibitory synapses and behavioral manifestations remi­ niscent of human FTD. Remarkably, inhibition of complement activa­ tion can rescue all of these deficits. These data indicate a primary role for microglial activation in FTD caused by mutations in GRN, likely mediated through increased production of C3 complement, enhanced lysosomal trafficking, and excessive synaptic pruning in affected brain regions affected. Clinical trials underway for neurodegeneration due to progranulin deficiency include a monoclonal antibody to block lysosomal degradation of progranulin, as well as gene and protein replacement therapies. Microglia are generally considered the most important source of antigen-presenting cells in the brain, as they express class II major histocompatibility complex molecules enabling antigen presentation to CD4 T cells. In Parkinson’s disease (PD), neurotoxic T cells reactive against epitopes of α-synuclein are commonly found, and it has been postulated that antigen presentation by microglia may have initiated this autoimmune response. Beyond a traditional role as antigenpresenting cells, microglia are now understood to also have a range of other interactions with T and B lymphocytes. For example, secre­ tion of CCL3 by microglia, which is enhanced with aging, promotes the recruitment of memory CD8 T cells, which might account for the presence of CD8 T cells in a wide range of neuropathologic conditions including multiple sclerosis (MS). Microglia are located throughout the brain parenchyma, while the closely related brain macrophages occur primarily in perivascular regions, including the meninges and choroid plexus. Like microglia, brain macrophages are derived from yolk sac precursors that appear to enter the brain at an early developmental stage and propagate locally, although some choroid plexus macrophages may also be replenished at low levels from the bloodstream on a continuing basis. Under inflammatory conditions, however, large numbers of hematog­ enously derived monocytes readily enter the brain parenchyma. In the disease model, experimental autoimmune encephalomyelitis (EAE), macrophages derived from bone marrow monocytes are the critical population that initiates inflammatory demyelination at paraxonal regions near nodes of Ranvier (Fig. 435-2). Brain macrophages have multiple proinflammatory functions, including promoting adhesion, attraction, and activation of B and T lymphocytes; providing antigenspecific activation of T cells via antigen presentation of immunogenic peptides, including autoantigens, complexed to surface class II major histocompatibility complex (MHC II) molecules; and contributing to cell injury through generation of oxidative stress and cytotoxicity. By contrast, microglia have been traditionally thought to downregulate PART 13 Neurologic Disorders Triggering Strong adhesion Rolling Flow Activated lymphocyte CD 31 Blood-brain barrier endothelium Chemokines and cytokines Astrocytes Heat shock proteins? Activated Microglia/ macrophages IFN-γ IL-2 Fc receptor Chemokines IL-1, IL-12 Brain tissue TNF, IFN, free radicals, vasoactive amines, complement, proteases, cytokines, eicosanoids Myelin damage FIGURE 435-2  A model for experimental allergic encephalomyelitis (EAE). Crucial steps for disease initiation and progression include peripheral activation of preexisting autoreactive T cells; homing to the central nervous system (CNS) and extravasation across the blood-brain barrier; reactivation of T cells by exposed autoantigens; secretion of cytokines; activation of microglia and astrocytes and recruitment of a secondary inflammatory wave; and immune-mediated myelin destruction. ICAM, intercellular adhesion molecule; IFN, interferon; IL, interleukin; LFA-1, leukocyte function-associated antigen-1; TNF, tumor necrosis factor; VCAM, vascular cell adhesion molecule. inflammatory responses and promote tissue repair in EAE. This model of the relative roles of macrophage and microglial cells is certainly an oversimplification, and more nuanced functions of these cell types have been revealed by single-cell sequencing methods, demonstrating previ­ ously unappreciated heterogeneity influenced by location, context, and environmental cues. ASTROCYTES Astrocytes represent half or more of all cells in the CNS. Thought ear­ lier to function as simple interstitial supporting cells that provide scaf­ folds for neuronal migration and contribute to homeostasis, emerging data indicate far more pleiotropic functions for this cell type. Astro­ cytes, like microglia, play profound roles in the life of synapses by secreting factors (such as apolipoprotein E, thrombospondins, and glypicans) that regulate development, maintenance, and pruning of presynaptic and postsynaptic structures. Influenced by local neuronal activity, astrocytes actively phagocytose synapses. Pruning of synapses and clearance of apoptotic cells by astrocytes are mediated through the scavenger receptor multiple EGF-like domains 10 (Megf10), a high-affinity receptor for C1q. Astrocytes also participate in dynamic regulation of vascular tone, in part through astrocyte-astrocyte com­ munication mediated through gap junctions and calcium waves modulated by neuronal activity; support blood-brain barrier and glymphatic (see below) integrity through extension of foot processes to vascular structures and expression of aquaporin-4 water channels; and carry out additional metabolic functions essential for mainte­ nance of neuron health. Recent work has highlighted the transcriptional and functional heterogeneity of reactive astrocytes that, depending on the con­ text, could regulate inflammation, promote neurotoxicity, or aid in Extravasation B cell Gelatinases LFA-1 α4 Integrin VCAM ICAM Basal lamina Microglia/macrophages T cell activation B cell T cell Antigen presentation TNFα, LT, and GM-CSF B cell Antibody complement protection and repair. As examples, in response to cytokines such as granulocyte-macrophage colony-stimulating factor (GM-CSF) pro­ duced by infiltrating lymphocytes, astrocytes can augment neuroin­ flammation via secretion of chemokines such as CCL2 and CXCL10 that attract lymphocytes and monocytes to the CNS. In MS and other neuroimmune disorders, production of B-cell activation factor (BAFF) by astrocytes within lesions promotes the survival and activation of pathogenic autoreactive B cells. Under other conditions, astrocytes appear to limit inflammation, through expression of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induced by interferon γ produced by natural killer cells, or by secretion of the regulatory cytokine IL-27. And in still other settings, astrocytes can secrete factors that promote neuronal survival and axon regeneration, for example, by secretion of wingless-type MMTV integration site 1 (Wnt1), a neuroprotective factor for dopaminergic neurons. It is also now clear that bidirectional crosstalk between immune system cells and astrocytes can profoundly influence the brain’s response to injury. In the best-studied example, activated microglia, through secretion of IL-1a, TNF, and C1q, can induce astrocytes to transform to a reactive disease-promoting phenotype. Such cells lose the capacity to phagocytose synapses and myelin debris and become toxic in vitro to neurons and mature oligodendrocytes, via different mechanisms including complement-mediated damage and production of nitric oxide (NO) and free radicals. Interestingly, oligodendrocyte progenitor cells (OPCs), abundant in active lesions of MS (Chap. 455) within the inflammatory milieu, are resistant to astrocyte-mediated killing. In ALS models modeled on human ALScausing mutations in SOD1 and C9orf72 genes, astrocyte expression of the mutant genes promoted neurotoxicity, indicating a noncell-autonomous disease mechanism mediated through astrocytes. Similarly, in AD, astrocytes have been implicated in several genetic forms of AD, including amyloid accumulation mediated through apolipoprotein E (ApoE), which in the nervous system is expressed primarily in astrocytes. Thus, reactive astrocytes could promote dam­ age in disorders as varied as MS (Chap. 455), AD (Chap. 442), PD (Chap. 446), and ALS (Chap. 448), despite the distinct etiologies and pathologies of these conditions. ■ ■OLIGODENDROCYTES AND MYELIN Myelin is the multilayered insulating substance that surrounds axons and speeds impulse conduction by permitting action potentials to jump between naked regions of axons (nodes of Ranvier) and across myelinated segments. Oligodendrocytes contact axons at paranodes, where sodium and potassium channels essential for saltatory con­ duction are clustered. Molecular interactions between the myelin membrane and axon are required to maintain the stability, function, and normal life span of both structures. The process of myelination is directed both by axon-derived cues as well as the physical proper­ ties of the axon-membrane curvature. Importantly, ongoing neuronal activity influences both the differentiation of oligodendrocytes as well as the extent of myelination, a process referred to as adaptive myelina­ tion. A single oligodendrocyte usually ensheaths multiple axons in the CNS, whereas in the peripheral nervous system (PNS), each Schwann cell typically myelinates a single axon. Oligodendrocytes can increase their surface length by as much as 2000-fold, the maintenance of which places significant metabolic demands on the cell. Myelin is a lipid-rich material formed by a spiraling process of the membrane of the myelinating cell around the axon, creating mul­ tiple membrane bilayers that are tightly apposed (compact myelin) by charged protein interactions. From an evolutionary perspective, an increase in the efficiency of nerve conduction enabled by CNS myelin has permitted expanded neuronal connectivity and brain complexity without the need to dramatically increase brain size. CNS myelin has also evolved to provide critical neuroprotective support to axons. Not surprisingly, myelin pathologies cause or contribute to many neurologic conditions. Several clinically important neuro­ logic disorders result from inherited mutations in myelin proteins (Chap. 457). Constituents of myelin have a propensity to be targeted as autoantigens in autoimmune demyelinating disorders, in part due to molecular similarities between myelin and microbial cell wall con­ stituents (Chaps. 455 and 456). Alterations in myelin are increasingly recognized as a contributor to cognitive changes associated with aging, including dementia. For example, in AD models, oligodendrocyte damage can promote the deposition of disease-associated amyloid plaques. Oligodendrocytes can also be the site of disease-associated protein deposition in some neurodegenerative disorders, for example, with toxic accumulation of α-synuclein aggregates in multiple system atrophy (Chap. 451). Evidence also supports a role for oligodendro­ cyte and myelin pathology in disorders as varied as ALS (Chap. 448), traumatic brain injury (Chap. 454), and stroke (Chap. 437), among other conditions. Premyelinating OPCs are highly motile cells that migrate exten­ sively during development and in the adult brain following injuries to the myelin sheath. OPCs migrate along the inner (or abluminal) surface of endothelial cells, a process regulated by Wnt pathway sig­ naling and upregulation of the chemokine receptor Cxcr4 that drives their attachment and retention to the vasculature. In the normal adult brain, large numbers of OPCs are widely distributed. Follow­ ing demyelination, remyelination is largely dependent on OPCs that differentiate into myelin-producing oligodendrocytes and produce characteristic thinly remyelinated fibers. In some situations, a second population of regenerating oligodendrocytes derived from neural stem cells can mediate more effective remyelination, with thicker lamellae and greater functional preservation of axons. A C14 labeling study from human MS lesions indicated that a third population of nonmitotic preexisting oligodendrocytes may represent an additional source of remyelinating cells. CHAPTER 435 Pathobiology of Neurologic Diseases Both acquired demyelinating disorders, such as MS, and inherited ones, such as Pelizaeus-Merzbacher disease (duplication or deletion of the CNS proteolipid protein gene) and adrenoleukodystrophy (muta­ tions in the ABCD1 gene responsible for transport of very-long-chain fatty acids into the peroxisome for degradation), are associated with progressive axonal loss. Loss of oligodendrocyte support can produce axonal damage through a variety of mechanisms, including reductions in the supply of glucose and other essential nutrients; an increased axonal workload; impaired glutamate and calcium buffering; mito­ chondrial damage; loss of neurotrophins; enhanced susceptibility to reactive oxygen species including nitric oxide; and failure to maintain normal synapses. A number of molecules have been identified that regulate oligo­ dendrocyte differentiation and myelination, including LINGO-1, hyaluronan, chondroitin sulfate proteoglycan, the Wnt pathway, Notch (and its receptor Jagged), fibrinogen, and the M1 muscarinic receptor Chrm1, all of which are inhibitory. Other targets are the retinoic acid receptor RXRγ, vitamin D, and thyroid hormone, all of which promote oligodendrocyte maturation. All are also potential targets for myelin repair therapies. In the EAE model of autoimmune demyelination (Fig. 435-2), oligodendrocyte-specific knockout of Chrm1 improved remyelination, protected axons, and restored function, directly dem­ onstrating that remyelination can be neuroprotective following injury. A pivotal trial of a monoclonal antibody against LINGO-1 in patients with acute optic neuritis failed to improve clinical outcomes, a disap­ pointing result given that the antibody appeared to have promising clinical effects in an earlier phase 2 trial. In a preliminary trial of chronic optic neuritis, a promising result was reported with clemastine, an antihistamine and M1 muscarinic receptor antagonist, raising hope that clinically effective remyelination might be achievable even in a chronic demyelinating condition. LYMPHATICS OF THE CENTRAL NERVOUS SYSTEM Two recently identified lymphatic structures of the CNS are the glym­ phatic and deep dural lymphoid systems, responsible for clearance of debris in the CNS, and likely also serving roles in immune surveil­ lance. The brain has traditionally been considered to lack a classical lymphatic system, and immune responses against antigens are less effectively generated in the CNS than in other organ systems, a con­ cept termed immune privilege. However, the immune privilege status of the brain is relative and not absolute. Also, given the high meta­ bolic demands of the brain, some mechanism for efficient removal of solute and debris must be present. One well-established pathway involves the passive flow of solutes from the brain parenchyma into the cerebrospinal fluid (CSF), and their exit via the arachnoid granu­ lations, as well as along cranial and spinal nerve roots to a series of lymphoid structures located in the cribriform plate, nasal mucosa, and elsewhere. The glymphatic system derives its name from a distinctive archi­ tecture involving lymphoid-like structures and astroglial cells. CSF synthesized in the arachnoid villi circulates through the ventricles and subarachnoid space surrounding the convexities of the brain and spinal cord and exits through conduits surrounding arterioles penetrat­ ing into the brain parenchyma. These spaces are lined by endothelial cells internally and by astrocyte foot processes that form the external walls. Aided by arterial propulsion, CSF moves out of these specialized conduits and into astrocytes via foot processes rich in aquaporin-4 water channels, and then in the interstitium of brain parenchyma, picks up solutes and particulate debris that are then carried to peri­ venous spaces where they passage to exit the brain and drain into the lymphatic system. In mice, knockout of aquaporin-4 markedly reduced the flow of interstitial fluids in the brain, underscoring the critical role of astrocyte uptake of CSF in this process. Interstitial flow in the CNS is also impaired with aging, possibly related to changes in astrocytic aquaporin-4 expression. A fascinating aspect of the glymphatic system is that the transport of fluids and solutes accelerates with sleep, arguing for a critical role for sleep in promoting clearance of debris needed to meet the high metabolic demands of the nervous system. Furthermore, in disease models, aggregated proteins associated with neurodegenera­ tive disease, such as β-amyloid associated with AD (Chap. 442), were also more efficiently cleared during sleep. Indeed, in mice genetically engineered to produce excess β-amyloid and develop AD-like cognitive decline, sleep deprivation increased accumulation of amyloid plaques. Glymphatic pathways are also likely to represent an important egress pathway for lymphocytes in the CNS and a route for lymphocyte encounters with CNS antigens in cervical lymph nodes. In this regard, deep cervical lymph nodes may be a site for antigen-specific stimula­ tion of B cells in MS (Chap. 455). PART 13 Neurologic Disorders A second pathway consists of a plexus of small lymphatic-like ves­ sels located on the external surface of meningeal arteries and deep dural sinuses (including the sagittal and transverse sinuses), structures that exit the brain along the surface of veins and arteries and drain to the deep cervical lymph nodes. These conduits appear to represent a lymphoid drainage system distinct from vascular endothelium. These sinus-associated lymphoid structures may be most important in clear­ ing solutes from the CSF, in contrast to the glymphatic system that likely functions to remove waste products from the brain interstitium; however, the exact functions of these two systems and their interrela­ tionships are only beginning to be understood. MICROBIOTA AND NEUROLOGIC DISEASE The human microbiome (Chap. 484) represents the collective set of genes from the 1014 organisms living in our gut, skin, mucosa, and other sites. The aggregate number of genes encoded by bacteria living in and around us (i.e., the microbiome) outnumber our own genome by a factor of 100, and these can encode a wide variety of molecules that directly or indirectly affect nervous system development, main­ tenance, and function. Distinctive microbial communities have been found in individuals with different genetic backgrounds, ethnicities, diets, and environments. While progressively evolving with age, in any individual, the predominant gut microbiota can be remarkably stable over decades, but also can be altered by exposure to certain microbial species (e.g., by ingestion of probiotics) or the frequent use of antibiotics. Gut microbes can shape immune responses through the interaction of their metabolism with that of humans. These gut–brain interac­ tions are likely to be important in understanding the pathogenesis of many autoimmune neurologic diseases. For example, mice raised in a germ-free environment (or treated with broad-spectrum antibiotics) are resistant to EAE, an effect associated with decreased production of proinflammatory cytokines and conversely more production of the immunosuppressive cytokines IL-10 and IL-13 as well as an increase in regulatory T and B lymphocytes. Intestinal microbiota from patients with MS were found to promote EAE when transferred to germ-free mice, possibly due to imbalances between bacterial species that pro­ mote inflammation (e.g., Akkermansia muciniphila and Acinetobacter calcoaceticus) and those that induce regulatory immune responses (e.g., Parabacteroides distasonis, Prevotella copri, and certain species of Clostridium). Recent studies have shown that the transcription fac­ tor aryl hydrocarbon receptor (AHR) is an important regulator of the differentiation of murine and human regulatory T cells and microglia. AHR is activated by endogenous physiologic ligands, but also by meta­ bolic products of the commensal flora. In addition to nonspecific effects on immune homeostasis mediated by cytokines and regulatory lymphocytes, some microbial proteins could trigger a cross-reactive immune response against a homolo­ gous protein in the nervous system, a mechanism termed molecular mimicry. Examples include cross-reactivity between the astrocyte water channel aquaporin-4 and an ABC transporter permease from Clostridia perfringens in neuromyelitis optica (Chap. 456); human leukocyte antigen (HLA) molecules with A. muciniphila peptides of A. muciniphila and Epstein-Barr virus in MS (Chap. 455); the neural ganglioside Gm1 and similar sialic acid–containing structures from Campylobacter jejuni in Guillain-Barré syndrome (Chap. 458); and the sleep-promoting protein hypocretin and hemagglutinin from an H1N1 influenza virus in narcolepsy (Chap. 33). Microbial genes also encode molecules that can affect development of neurons and glia, and influence myelination and plasticity. Bacterialderived short-chain fatty acids, for example, regulate production of brain-derived neurotrophic factor (BDNF). Bacteria produce a variety of neurotransmitters including γ-aminobutyric acid (GABA) and serotonin and other neuroactive peptides that can modulate the hypothalamic-pituitary axis. Gut microbiota influence development and activity of the enteric nervous system, which communicates bidi­ rectionally with the CNS via the vagus nerve that innervates the upper gut and proximal colon. As these gut–brain relationships become bet­ ter defined, a role for the microbial environment in the pathogenesis of a much wider spectrum of neurologic conditions and behaviors seems likely, extending well beyond the traditional boundaries of immune-mediated pathologies. In this regard, it has long been known that gut bacteria can influence brain function, based mostly on clas­ sic studies demonstrating that products of gut microbes can worsen hepatic encephalopathy, forming the basis of treatment with antibiot­ ics for this condition. Mice that develop in a germ-free environment display less anxiety, lower responses to stressful situations, more exploratory locomotive behaviors, and impaired memory formation compared with non-germfree counterparts. These behaviors were related to changes in gene expression in pathways related to neural signaling, synaptic function, and modulation of neurotransmitters. Moreover, this behavior could be reversed when the germ-free mice were co-housed with non-germ-free mice. As noted above, intestinal microbiota were found to be required for the normal development and function of brain microglia, poten­ tially linking these behavioral effects to specific cellular targets in the CNS. Some actions of gut microbial species on microglia also appear to be sex- and age-specific. The vagus nerve has been implicated in anxiety- and depressionlike behaviors in mice. Ingestion of Lactobacillus rhamnosus induced changes in expression of the inhibitory neurotransmitter GABA1b in neurons of the limbic cortex, hippocampus, and amygdala, associ­ ated with reduced levels of corticosteroids and reduced anxiety- and depression-like behaviors. Remarkably, these changes could be blocked by vagotomy. A related area of emerging interest is in a possible contribution of the gut microbiome to autism and related disorders. Children with autistic spectrum disorders (ASD) have long been known to have gas­ trointestinal disturbances, and the severity of dysbiosis appears to cor­ relate with the severity of autism. In several murine models of autism, manipulation of the gut microbiome ameliorated the behavioral abnor­ malities. A role for the proinflammatory cytokine IL-17 was implicated as a possible mediator in producing the ASD-like changes. In mice, an ASD-like disorder could be induced in offspring after injecting the pregnant mother with the viral RNA mimic, polyinosinic:polycytidylic acid (poly I:C); oral treatment of offspring with Bacteroides fragilis cor­ rected a range of autistic behaviors in these mice and also improved gastrointestinal dysfunction. These preclinical data led to a small uncontrolled study of fecal gut transplantation in children with ASD that reported encouraging results but will need to be confirmed in rigorous controlled trials. There has been considerable interest in the possible role of the microbiome in a variety of vascular, traumatic, and neurodegenera­ tive diseases, possibly mediated through actions on innate immunity and microglia. In SOD1 transgenic ALS-prone mice, a germ-free environment exacerbated disease progression, and symptoms could be ameliorated by increasing levels of A. muciniphila or its nicotinamide (vitamin B3) metabolite; a small preliminary clinical trial of nicotin­ amide supplementation subsequently reported encouraging results in ALS patients. In a PD model, injection of misfolded α-synuclein into the gut triggered deposition of α-synuclein in the brain, an effect that was blocked when the vagus nerve was severed. This supported a prion mechanism (see below) for PD pathogenesis, in which vagal transport of aggregated α-synuclein might seed the CNS via the vagus nerve. The concept of a gut origin of PD is also consistent with clinical and pathologic studies, and by some epidemiologic data suggesting that vagotomy may be protective against PD. In transgenic mice that over­ express human α-synuclein, transplantation of intestinal microbiota from PD patients worsened motor deficits, α-synuclein deposition, and neuroinflammation, and conversely, pathology could be ameliorated with germ-free housing conditions or antibiotic treatment. In other Sporadic NDs Prions causing neurodegradation Wt precursor + A A Age-dependent mutant prion formation Inherited NDs i ii Mutant prion form Mutant precursor + B FIGURE 435-3  Neurodegeneration caused by prions. A. In sporadic neurodegenerative diseases (NDs), wild-type (Wt) prions multiply through self-propagating cycles of posttranslational modification, during which the precursor protein (green circle) is converted into the prion form (red square), which generally is high in β-sheet content. Pathogenic prions are most toxic as oligomers and less toxic after polymerization into amyloid fibrils. The small polygons (blue) represent proteolytic cleavage products of the prion. Depending on the protein, the fibrils coalesce into Aβ amyloid plaques in Alzheimer’s disease (AD), neurofibrillary tangles in AD and other tauopathies, or Lewy bodies in Parkinson’s disease (PD) and dementia with Lewy bodies. Drug targets for the development of therapeutics include: (1) lowering the precursor protein, (2) inhibiting prion formation, and (3) enhancing prion clearance. B. Late-onset heritable neurodegeneration argues for two discrete events: The (i) first event is the synthesis of mutant precursor protein (green circle), and the (ii) second event is the age-dependent formation of mutant prions (red square). The highlighted yellow bar in the DNA structure represents mutation of a base pair within an exon, and the small yellow circles signify the corresponding mutant amino acid substitution. Green arrows represent a normal process; red arrows, a pathogenic process; and blue arrows, a process that is known to occur but unknown whether it is normal or pathogenic. (Used with permission of Annual Reviews, from [Biology and genetics of prions causing neurodegeneration, SB Prusiner, 47:601, 2013 permission conveyed through Copyright Clearance Center, Inc.) work, a protein of Escherichia coli, named Curli, has been shown to misfold and potentially serve as a template for subsequent propagation of misfolded α-synuclein. The possibility that a bacterial protein could initiate the cascade of events leading to PD is an extraordinary, but still unproven, hypothesis. Thus, there are a variety of mechanisms whereby the microbiome— in gut, skin, and other bodily surfaces—can modulate healthy brain function or influence susceptibility to and expression of a variety of brain diseases. The specific mechanisms are likely to vary with each condition but are likely to include promoting autoimmunity through molecular mimicry; disrupting immune homeostasis; modulating brain function via bacterial metabolites that travel in the circula­ tion and cross the blood-brain barrier; influencing neural activity through signals generated in the enteric nervous system; or even the possibility that prion-like aggregates are formed in the gut and passage to the CNS via the vagus nerve. Although no proven benefit of modulating the microbiome exists for any brain disease today, this situation is likely to change as information about specific disease-associated microbial communities rapidly increases, along with improved methods to fine-tune their proportions and overall diversity in humans. CHAPTER 435 Pathobiology of Neurologic Diseases PATHOLOGIC PROTEINS, PRIONS, AND NEURODEGENERATION (FIG. 435-3) ■ ■PROTEIN AGGREGATION AND CELL DEATH The term protein aggregation has become widely used to describe easily recognizable hallmarks of neurodegeneration. While such neuropatho­ logic hallmarks including plaques, neurofibrillary tangles (NFTs), and inclusion bodies are often thought to cause neurologic dysfunction, numerous new discoveries over the past several decades have rendered this view increasingly unlikely. Instead, protein aggregates represent Wt prion form Aβ plaque Amyloid fibrils Tau tangle α-Synuclein Lewy body accumulations of toxic proteins that may become less harmful when they are sequestered into plaques, NFTs, and inclusion bodies. Most mutations in the amyloid precursor protein (APP) gene caus­ ing familial AD are concentrated within the Aβ peptide. Many of these mutations increase production of the Aβ42 peptide composed of β-amyloid with 42 amino acids, which has an increased propensity to adopt a prion conformation, as compared to β-amyloid with 40 amino acids. In contrast, mutations in the APP that reduce the production of β-amyloid protect against the development of AD and are associated with preserved cognition in the elderly. The most common cause of NFTs is AD, but the precise molecular events that produce tangles are unknown. Mutations in the MAPT gene encoding tau stimulate NFT formation in familial frontotemporal dementia, inherited progressive supranuclear palsy, and other familial tauopathies. Like AD, the major­ ity of most tauopathies as well as PD are sporadic. The second most common neurodegenerative disease is PD. The saga of α-synuclein and PD begins in 1996 with the identification of a mutation in a family of Greek descent. With this family and others, there were sufficient patients to establish genetic linkage. Soon there­ after, immunostaining showed that α-synuclein was present in Lewy bodies, and the following year staining of glial cytoplasmic inclusions (GCIs) was identified in the brains of deceased multiple-system atro­ phy (MSA) patients. Subsequently, brains from deceased MSA patients transmitted the disease to transgenic mice, establishing that the α-synucleinopathies are prion diseases. Before the α-synuclein (SCNA) gene was found to cause familial PD, other genes such as the leucine-rich repeat kinase 2 (LRRK2) were found to modify the onset of PD; other similar PD modifier genes include parkin, PINK1, and DJ-1. PINK1 is a mitochondrial kinase (see below), and DJ-1 is a protein involved in protection from oxidative stress. Parkin, which causes autosomal reces­ sive early-onset PD-like illness, is a ubiquitin ligase. The characteristic histopathologic feature of PD is the Lewy body, an eosinophilic cyto­ plasmic inclusion that contains both neurofilaments and α-synuclein. Huntington’s disease (HD) and cerebellar degenerations are associated with expansions of polyglutamine repeats in proteins, which aggregate to produce neuronal intranuclear inclusions. Familial ALS is associated with superoxide dismutase (SOD1) mutations and cytoplasmic inclu­ sions containing superoxide dismutase. An important finding was the discovery that ubiquitinated inclusions observed in most cases of ALS and the most common form of frontotemporal dementia are composed of TAR DNA-binding protein 43 (TDP-43). Subsequently, mutations in the TDP-43 gene, and in the fused in sarcoma gene (FUS), were found in familial ALS. Both of these proteins are involved in transcription regulation as well as RNA metabolism. PART 13 Neurologic Disorders Another key mechanism linked to cell death is mitochondrial dynamics, which refers to the processes involved in movement of mitochondria, as well as in mitochondrial fission and fusion, which play a critical role in mitochondrial turnover and in replenishment of damaged mitochondria. Mitochondrial dysfunction is strongly linked to the pathogenesis of a number of neurodegenerative diseases such as Friedreich’s ataxia, which is caused by mutations in an iron-binding protein that plays an important role in transferring iron to iron-sulfur clusters in aconitase and complex I and II of the electron transport chain. Mitochondrial fission is dependent on the dynamin-related pro­ teins (Drp1), which bind to its receptor Fis, whereas mitofusins 1 and 2 (MFN 1/2) and optic atrophy protein 1 (OPA1) are responsible for fusion of the outer and inner mitochondrial membrane, respectively. Mutations in MFN2 cause Charcot-Marie-Tooth neuropathy type 2A, and mutations in OPA1 cause autosomal dominant optic atrophy. Both β-amyloid and mutant huntingtin protein induce mitochondrial frag­ mentation and neuronal cell death associated with increased activity of Drp1. In addition, mutations in genes causing autosomal recessive PD, parkin and PINK1, cause abnormal mitochondrial morphology and result in impairment of the ability of the cell to remove damaged mitochondria by autophagy. As noted above, one major scientific question is whether protein aggregates directly contribute to neuronal death or whether they are merely secondary bystanders. A focus in all the neurodegenerative diseases is on small-protein aggregates termed oligomers. How many monomers polymerize into a particular disease-specific oligomer has been elusive. Whether oligomers are the toxic species of β-amyloid, α-synuclein, or proteins with expanded polyglutamines such as the one causing HD remains to be established. Protein aggregates are usually ubiquitinated, which targets them for degradation by the 26S com­ ponent of the proteasome. An inability to degrade protein aggregates could lead to cellular dysfunction, impaired axonal transport, and cell death by apoptotic mechanisms. Autophagy is the degradation of cystolic components in lysosomes. There is increasing evidence that autophagy plays an important role in degradation of protein aggregates in the neurodegenerative diseases, and it is impaired in AD, PD, FTD, and HD. Autophagy is particularly important to the health of neurons, and failure of autophagy contrib­ utes to cell death. In HD, a failure of cargo recognition occurs, contrib­ uting to protein aggregates and cell death. There is other evidence for lysosomal dysfunction and impaired autophagy in PD. Mutations in glucocerebrosidase (GBA) are associ­ ated with 5% of all PD cases as well as 8–9% of patients with dementia with Lewy bodies. Notably, glucocerebrosidase and enzymatic activity are reduced in the substantia nigra of sporadic PD patients. α-Synuclein is degraded by chaperone-mediated and macro autophagy. The degra­ dation of α-synuclein has been shown to be impaired in transgenic mice deficient in glucocerebrosidase, and α-synuclein inhibits the activity of glucocerebrosidase; thus, there appears to be bidirectional feedback between α-synuclein and glucocerebrosidase. The retromer complex is a conserved membrane-associated protein complex that functions in endosome to Golgi transport. The retromer complex contains a cargo selective complex consisting of VPS35, VPS26, and VPS29, along with a sorting nexin dimer. Mutations in VPS35 were shown to be a cause of late-onset autosomal dominant PD. The retromer also traffics APP away from endosomes, where it is cleaved to generate β-amyloid. Deficiencies of VPS35 and VPS26 were also identified in hippocampal brain tissue from AD. A potential thera­ peutic approach to these diseases might therefore be to use chaperones to stabilize the retromer and reduce the generation of β-amyloid and α-synuclein. PRIONS AND NEURODEGENERATIVE DISEASES As we have learned more about the etiology and pathogenesis of the neurodegenerative diseases, it has become clear that the histologic abnormalities that were once curiosities, in fact, are likely to reflect the etiologies. For example, the amyloid plaques in kuru and CreutzfeldtJakob disease (CJD) are filled with the PrPSc prions that have assembled into fibrils. The past three decades have witnessed an explosion of new knowledge about prions. For many years, kuru, CJD, and scrapie of sheep were thought to be caused by slow-acting viruses, but a large body of experimental evidence argues that the infectious pathogens causing these diseases are devoid of nucleic acid. Such pathogens are called prions, which are composed of host-encoded proteins that adopt alternative conformations that undergo self-propagation. Prions impose their conformations on the normal, precursor proteins, which in turn become self-templating, resulting in faithful copies; most prions are enriched for β-sheet and can assemble into amyloid fibrils. Similar to the plaques in kuru and CJD that are composed of PrP prions, the amyloid plaques in AD are filled with Aβ prions that have polymerized into fibrils. This relationship between the neuropatho­ logic findings and the etiologic prion was strengthened by the genetic linkage between familial CJD and mutations in the PrP gene, as well as (as noted above) between familial AD and mutations in the APP gene. Moreover, a mutation in the APP gene that prevents Aβ peptide formation was correlated with a decreased incidence of AD in Iceland. The heritable neurodegenerative diseases offer an important insight into the pathogenesis of the more common sporadic ones. Although the mutant proteins that cause these disorders are expressed in the brains of people early in life, the diseases do not occur for many decades. Many explanations for the late onset of familial neurodegen­ erative diseases have been offered, but none is supported by substantial experimental evidence. The late onset might be due to a second event TABLE 435-1  Prion-Based Classification of Neurodegenerative Diseases CAUSATIVE PRION PROTEINS NEURODEGENERATIVE DISEASE Creutzfeldt-Jakob disease (CJD) Kuru Gerstmann-Sträussler-Scheinker disease (GSS) Fatal insomnia Bovine spongiform encephalopathy (BSE) Scrapie Chronic wasting disease (CWD) Feline spongiform encephalopathy Transmissible mink encephalopathy PrPSc PrPSc PrPSc PrPSc PrPSc PrPSc PrPSc PrPSc PrPSc Alzheimer’s disease (AD) Down syndrome ALS-parkinsonism dementia complex (PDC) of Guam Aβ → tau Aβ → tau Aβ → tau Parkinson’s disease (PD) Dementia with Lewy bodies Multiple-system atrophy α-Synuclein α-Synuclein α-Synuclein Frontotemporal dementias (FTDs) Posttraumatic FTD Chronic traumatic encephalopathy (CTE) Tau, TDP43, FUS (C9orf72, progranulin) Tau Amyotrophic lateral sclerosis (ALS) SOD1, TDP43, FUS (C9orf72) Huntington’s disease (HD) Huntingtin in which a mutant protein, after its conversion into a prion, begins to accumulate at some rather advanced age. Such a formulation is also consistent with data showing that the protein quality-control mecha­ nisms diminish in efficiency with age. Thus, the prion forms of both wild-type and mutant proteins are likely to be efficiently degraded in younger people but are less well handled in older individuals. This explanation is consistent with the view that neurodegenerative diseases are disorders of the aging nervous system. A new classification for neurodegenerative diseases can be proposed based on not only the traditional phenotypic presentation and neuro­ pathology but also the prion etiology (Table 435-1). An expanding body of experimental data has accumulated connecting prions in each of these illnesses. In addition to kuru and CJD, Gerstmann-SträusslerScheinker disease (GSS) and fatal insomnia in humans are caused by PrPSc prions. In animals, PrPSc prions cause scrapie of sheep and goats, bovine spongiform encephalopathy (BSE), chronic wasting dis­ ease (CWD) of deer and elk, feline spongiform encephalopathy, and transmissible mink encephalopathy (TME). Similar to PrP, Aβ, tau, α-synuclein, superoxide dismutase 1 (SOD1), and possibly huntingtin all adopt alternative conformations that become self-propagating, and thus, each protein can become a prion and be transferred to synapti­ cally connected neurons. Moreover, each of these prions causes a dis­ tinct constellation of neurodegenerative diseases. Evidence for a prion etiology of AD comes from a series of transmis­ sion experiments initially performed in marmosets and subsequently in transgenic mice expressing the mutant APP from which the Aβ peptide is derived (Table 435-1). Synthetic mutant Aβ peptides folded into a β-sheet-rich conformation exhibited prion infectivity in cultured cells. Studies of the tau protein have shown that it not only features in the pathogenesis of AD but also causes the frontotemporal dementias including chronic traumatic encephalopathy, which has been reported in both contact sport athletes and military personnel who have suffered traumatic brain injuries. A series of incisive studies using cultured cells and Tg mice have demonstrated that both tau and Aβ prions are found together in the brains of AD patients. These findings indicated that AD is a double-prion disease (Table 435-1); unexpectedly, two more double-prion diseases have been identified recently. Patients with Down syndrome, from 6–72 years of age, all had both Aβ and tau pri­ ons in their brains with the frequent diagnosis of AD. The third doubleprion disease has been found in the Chamorro people on Guam as well as Japanese living on the Kii peninsula: both groups of people develop ALS with dementia and both have Aβ and tau prions in their brains. In contrast to Aβ and tau prions, α-synuclein prions cause very dif­ ferent illnesses, i.e., PD, dementia with Lewy bodies (DLB), and MSA. Brains from MSA patients inoculated into Tg(SCNA∗A53T) mice died ~90 days after intracerebral inoculation, whereas mutant α-synuclein (A53T) prions formed spontaneously in Tg mouse brains that killed recipient Tg mice in ~200 days (Table 435-1). For many years, the most frequently cited argument against prions was the existence of strains that produced distinct clinical presenta­ tions and different patterns of neuropathologic lesions. Some investi­ gators argued that the biologic information carried in different prion strains could be encoded only within a nucleic acid. Subsequently, many studies demonstrated that strain-specified variation is enci­ phered in the conformation of PrPSc, but the molecular mechanisms responsible for the storage of this biologic information remains enig­ matic. The neuroanatomical patterns of prion deposition have been shown to be dependent on the particular strain of prion. Convincing evidence in support of this proposition has been accumulated for PrP, Aβ, tau, and α-synuclein prions. The most persuasive information on prion strains comes from studies in yeast where the tools of yeast genetics allowed inciteful investigations to be performed in ways that could not be accomplished in mammals. CHAPTER 435 Although the number of prions identified in mammals and in fungi continues to expand, the existence of prions in other phylogeny remains undetermined. Some mammalian prions perform vital func­ tions and do not cause disease; such nonpathogenic prions include the cytoplasmic polyadenylation element-binding (CPEB) protein, the mitochondrial antiviral-signaling (MAVS) protein, and T cell– restricted intracellular antigen 1 (TIA-1). Pathobiology of Neurologic Diseases Many but not all prion proteins adopt a β-sheet-rich conforma­ tion and appear to readily oligomerize as this process becomes self-propagating. Control of the self-propagating state of benign mam­ malian prions is less well understood than that of pathogenic mamma­ lian prions, which appear to multiply exponentially. We do not know if prions multiply as monomers or as oligomers; notably, the ionizing radiation target size of PrPSc prions suggests it is a trimer. The oligo­ meric states of pathogenic mammalian prions are thought to be toxic; larger polymers, such as amyloid fibrils, seem to be a mechanism for minimizing toxicity. The development of drugs designed to inhibit the conversion of the normal precursor proteins into prions or to enhance the degradation of prions focuses on the initial step in prion accumulation. Although a dozen drugs that cross the blood-brain barrier have been identified that prolong the lives of mice infected with scrapie prions, none has been identified that extends the lives of Tg mice that replicate human CJD prions. Despite doubling or tripling the length of incubation times in mice inoculated with scrapie prions, all of the mice eventually succumb to illness. Because all of the treated mice develop neurologic dysfunction at the same time, the mutation rate as judged by drug resis­ tance is likely to approach 100%, which is much higher than mutation rates recorded for bacteria and viruses. Mutations in prions seem likely to represent conformational variants that are selected for in mammals where survival becomes limited by the fastest-replicating prions. The results of these studies make it likely that cocktails of drugs that attack a variety of prion conformers will be required for the development of effective therapeutics. NEURAL STEM CELL BIOLOGY Normal and genetically modified (“transgenic”) mice are the most widely used model systems to study features of human nervous system diseases. However, modeling genetic diseases in rodents is limited to the relatively small number of monogenic human diseases where the specific gene mutations are known and is further limited by species differences. The latter can be particularly important in brain regions such as the cerebral cortex that have undergone significant evolutionary expansion in humans. These shortcomings, which likely contribute to the low probability that therapeutic efficacy translates from animal models to humans, can potentially be overcome through stem cell models that enable the use of human cells and tissues to model human diseases. The advent of new stem cell technologies is transforming our understanding of the pathobiology of human neurologic diseases. Stem cell platforms are being used to screen for therapeutic agents, to uncover adverse drug effects, and to discover novel therapeutic targets. Among the most exciting recent advances in stem cell technology is the ability to convert somatic cells, either skin fibroblasts or blood cells, into pluripotent stem cells known as induced pluripotent stem cells (iPSCs). This technology has introduced an entirely new and powerful approach to study the pathobiology of heritable diseases. Pluripotent stem cells can be easily obtained through minimally inva­ sive procedures such as a skin biopsy or blood sample and converted to pluripotency through application of a cocktail of reprogramming factors to create iPSCs. Initially, a set of four programming factors, Oct3/4, Klf-4, Sox2, and c-Myc, was delivered to cells using lenti­ viruses that stably integrated the reprogramming factor genes into the iPSC genome, potentially altering disease phenotypes and also abrogating expression of native genes at the DNA sites where the factors integrated. Newer techniques have been developed that use nonintegrating approaches such as through the use of Sendai virus, messenger RNA (mRNA), or episomal vectors that circumvent these problems. Once created, iPSC lines can be expanded indefinitely to produce a limitless supply of stem cells. These cells are the starting material for the derivation of specific cell types based on protocols that use small molecules, proteins, or direct gene induction to recapitulate developmental programs. Most current protocols derive neuronal progenitors through dual-SMAD inhibition, a step that involves the use of small-molecule inhibitors to block endoderm and mesodermal cell fates, thereby creating neural cells by default. Multiple protocols have been developed over the last decade for creating large numbers of human neuron progenitor cell types and directing them toward specific nervous system cell fates, including neuron subtypes from multiple regions of brain and spinal cord as well as retinal cells, glial cells including astrocytes and oligodendrocytes, immune cells, and peripheral nervous system cells. PART 13 Neurologic Disorders The primary medical benefit of iPSC technology is that it enables the creation of patient-specific cells or tissues that are genetically matched to individual subjects. This approach enables the study of not only monogenetic disorders but also sporadic forms of disease and complex polygenic disorders including those with unidentified risk loci. Furthermore, by deriving iPSC cell lines from multiple patients, it is possible to explore how disease phenotypes may vary accord­ ing to genetic background. Another approach that has been used to generate specific neuron and glial cell types from somatic cells such as fibroblasts is through direct reprogramming. This approach relies on a cocktail of specific transcription factors to directly convert somatic cells into the alternate desired cell type. This approach bypasses the epigenetic reset that accompanies cells as they are reprogrammed to a pluripotent state. The advantage of this approach is that age-related epigenetic signatures are not erased, so that derived neurons may more readily reflect diseases that manifest in older cells. Despite the advantages of using in vitro models of nervous system diseases derived from patient-specific iPSCs, several potential road­ blocks remain. There are no standard reprogramming or derivation protocols, and the different methods can result in considerable vari­ ability in the disease phenotypes reported by different laboratories. Confidence in the specificity of a particular phenotype is therefore increased if it has been validated across multiple laboratories. There is also the problem of inherent variability between patient lines that may result from their different genetic backgrounds. One solution, available only in the case of monogenic disorders, is to use isogenic controls generated using gene editing, such as with CRISPR-Cas9 technology, to create disease and control lines on an identical genetic background. However, because differences in genetic background can influence the penetrance of a particular trait, it will still be necessary to compare dis­ ease lines from multiple patients to discern a true disease phenotype. For polygenic disorders where the causative mutations are unknown, it will not be possible to create isogenic controls, and in these situations, the best strategy for improving reliability and sensitivity is to compare lines from multiple patients. ORGANOIDS Most nervous system disorders, including ASD, schizophrenia, PD, AD, and ALS, are complex disorders, resulting from an unknown combi­ nation of gene mutations, and manifest not only in specific cell types but also in alterations of the local tissue environment. These disorders are difficult to model in animals, but they are approachable using three-dimensional human iPSC stem cell models, often referred to as “organoids.” Organoids are derived from pluripotent stem cells that are directed along a tissue-specific lineage through the timed application of growth factors, genes, or small-molecule activators or inhibitors, and allowed to aggregate into three-dimensional structures. With time, cell intrinsic programs are spontaneously engaged and the cel­ lular aggregates begin to self-organize and develop into structures that recapitulate the complex topographical and cellular diversity of normal organ development. In this way, it has been possible to create, at least in part, in vitro brainlike organoids that resemble parts of the human brain at early stages of development. When allowed to develop from an anterior neural tube stage, these structures can become heterogeneous, containing regions with forebrain, midbrain, and/or hindbrain identity and can often include retina-like structures. The high degree of vari­ ability in such “whole-brain organoids” can be a liability for controlled studies and can be reduced by the use of directed protocols that restrict outcomes to more defined brain regions, such as forebrain, cortex, or ganglionic eminence. A variety of protocols have now been developed to generate organoids with specific regional identity, and fusing organoids of different regional identity with each other has been used to reproduce cellular interactions such as neuronal migration across regions. Many protocols are focused on modeling cortical development, and they can reproduce developmental features including a diversity of progenitor and neuronal cell types topographically distributed within ventricular and subventricular progenitor regions and rudimentary cortical layers. However, the organoids follow a human developmental timetable and still remain at stages roughly comparable to late fetal development even after 6–9 months of culture. Moreover, they lack key cell types such as endothelial cells, pericytes, and microglia, and have few if any astrocytes or oligodendrocytes. Recently, it has become possible to derive these cell types independently from stem cells and then combine them with brain organoids to create tissue-diverse brain organoids that also contain, for example, vascular or immune cells. Nonetheless, while still only reflect­ ing rudimentary organizational and compositional features, organoids have become attractive models to study human brain development and the pathophysiology of human nervous system diseases in the context of a partially organized brainlike structure. ■ ■BRAIN DEVELOPMENT AND DEVELOPMENTAL DISORDERS: MICROCEPHALY AND LISSENCEPHALY Transcriptional analysis has suggested that the neurons produced by most stem cell protocols resemble early- to mid-gestational stages of human brain development. The immaturity of stem cell–derived human neurons may limit their utility for modeling adult diseases, but it does make them ideally suited for the study of brain development and the pathophysiology of neurodevelopmental disorders. Primary autosomal recessive microcephaly (MCPH) is a rare neu­ rodevelopmental disorder producing severe microcephaly with simpli­ fied cortical gyration and intellectual disability. MCPH was one of the first disorders to be studied using cerebral organoids. Mutations in genes encoding microtubule spindle components and spindle-associ­ ated proteins are the most frequent causes of congenital microcephaly. Among them is cyclin-dependent kinase 5 related activator protein 2 (CDK5RAP2). Skin fibroblasts derived from a single microcephalic patient carrying a mutation in CDK5RAP2 were used to generate four iPSC lines. Cerebral organoids grown from these cell lines contained fewer proliferating progenitor cells and showed premature neural dif­ ferentiation compared to wild-type controls. Introducing functional CDK5RAP2 by electroporation partially rescued the disease pheno­ type, supporting the notion that failure of the founder population of neural progenitors to properly expand underlies the smaller brain. This study demonstrated that brain organoids derived from patients with microcephaly can be used to reproduce features of the disease but did not reveal new insights or disease features of CDK5RAP2 micro­ cephaly that had not already been described in mouse models. Organoids, however, are well-suited to model human microcephaly because the phenotype manifests at early prenatal ages and can be assessed by organoid size, which can serve as a proxy for a micro­ cephaly phenotype. For example, a loss-of-function screen of candi­ date microcephaly human genes was carried out in organoids using CRISPR-lineage tracing; 173 potential microcephaly genes were tested, and novel mechanisms involved in brain size control were discovered including a pathway involved in endoplasmic reticulum function and extracellular matrix production. Cortical organoids have also been used to model lissencephaly or “smooth brain.” Miller-Dieker syndrome (MDS), a severe congenital form of lissencephaly, was modeled in organoids and features of the human disease were observed that had not been noted in murine models. Classical lissencephaly is a genetic neurologic disorder associ­ ated with intellectual disability and intractable epilepsy, and MDS is a severe form of the disorder. Cortical folding in humans begins toward the end of the second trimester, but gyrencephaly depends upon earlier events such as neural progenitor cell proliferation and neuronal migra­ tion, which can be modeled in organoids. The human organoid model of MDS exhibited several neural progenitor cell phenotypes that had already been reported in mouse models, including altered mitotic spin­ dle orientation and neuronal migration defects. But the organoids also displayed a mitotic defect in a specific neural stem cell subtype, the outer radial glia cell (oRG), that had not been observed in mice. oRG cells are enriched in the outer subventricular zone, a proliferative region that is large in primates and not present in rodents. These cells are particularly numerous in the developing human cortex and are thought to underlie the developmental and evolutionary expansion of the human cortex. oRG cells from MDS patients behaved abnormally and had arrested or delayed mitoses. MDS organoids also identified noncell autonomous defects in Wnt signaling as an underlying mechanism. These insights into mechanistic and cell-type-specific features of human disease high­ light how organoid technology can provide new and valuable perspec­ tives on the pathophysiology of disorders of in utero development. ■ ■ACQUIRED NEURODEVELOPMENTAL DISORDERS: ZIKA The outbreak of Zika virus (ZIKV) and associated microcephaly cases in the Americas provided a test case for the utility of brain organoids to model acquired human microcephaly. Despite a correlation between Zika infection rates and the incidence of congenital microcephaly, compelling evidence that ZIKV caused microcephaly was lacking in the early phases of the epidemic. The causal link between ZIKV and congenital microcephaly was buttressed by two studies in 2016 that used human iPSC-derived neural progenitor cells and organoids to demonstrate ZIKV tropism for human neural progenitor cells. Neu­ ral  progenitor cells (radial glia) were readily infected in vitro with subsequent progenitor cell death and involution of organoid size. Fore­ brain organoids were further used to highlight the role of the flavivirus entry factor, AXL, in determining viral tropism, and were also used to explore the disease mechanism by demonstrating upregulation of the innate immune receptor toll-like receptor 3 (TLR) in response to ZIKV infection. Stem cell–derived models of human brain development have also demonstrated centrosomal abnormalities in radial glia and altera­ tion in the cleavage plane of mitotic radial glia associated with prema­ ture neural differentiation. Mouse models are also being used to study the pathophysiology of congenital ZIKV syndrome, but the availability of unlimited numbers of human neural cells produced using stem cell technology has enabled high-throughput screening assays to test librar­ ies of clinically approved compounds for potential therapeutic agents. This strategy has already highlighted several compounds that could potentially help protect against ZIKV microcephaly. ■ ■NEURODEVELOPMENTAL DISORDERS: AUTISM AND SCHIZOPHRENIA ASDs are complex and heterogeneous neurodevelopmental disorders usually manifesting in childhood with difficulties in social interaction, verbal and nonverbal communication, and repetitive behaviors. The cellular and molecular mechanisms underlying ASD are thought to arise at stages of fetal brain development, making them well-suited for exploration using human iPSC-derived disease models. iPSC-derived neurons have been used to study the pathophysiology of disorders associated with ASD that are caused by monogenic mutations, includ­ ing fragile X, Rett, and Timothy syndromes. Fragile X is the most common heritable cause of intellectual dis­ ability, affecting 1 in 4000 males and 1 in 8000 females, and is a lead­ ing genetic cause of ASD. Patients also have speech delay, growth and motor abnormalities, hyperactivity, and anxiety. The causative muta­ tion lies in the FMR1 gene and produces a CGG triplet repeat expan­ sion from a normal number of 5–20 to >200, leading to epigenetic silencing of the FMR1 gene and loss of the fragile X mental retardation protein. The epigenetic mechanism means that unlike a simple gene deletion that would lead to ubiquitous loss of expression, the FMR1 locus becomes hypermethylated and epigenetically silenced during differentiation; thus, FMR1 protein is expressed by the early embryo and becomes absent only around the beginning of the second trimester. Interestingly, this expression pattern is recapitulated during cellular differentiation in stem cell models. Pluripotent fragile X stem cell lines have been derived from embryos identified through preimplantation genetic diagnosis and by reprogramming skin fibroblasts from fragile X patients to create iPSC lines. In both cases, FMR1 was expressed by the pluripotent stem cells but underwent transcriptional silencing fol­ lowing differentiation. Fragile X stem cell lines can therefore be used to study the mechanism of FMR1 silencing, an effort that is ongoing. Neu­ rons generated from fragile X iPSC cells reproduce features observed in neurons from transgenic FMR1 mouse models and patients, including stunted neurites with decreased branching, increasing confidence in the iPSC model. In addition to providing a model that can be used to study disease pathogenesis, fragile X iPSC-derived neurons could be used to screen for potential therapeutic agents or gene-editing strate­ gies to remove the repressive epigenetic marks induced by the mutation and rescue the phenotype. CHAPTER 435 Pathobiology of Neurologic Diseases Rett syndrome is an X-linked neurodevelopmental disorder with dominant inheritance caused by a mutation in the MECP2 gene. Because males carrying one copy of the defective gene usually die in infancy, most patients are girls. Random inactivation of the X chromo­ some in girls results in mosaic cellular expression of the mutation that circumvents fatality and produces a variable phenotype. The symptoms are present in early childhood and include microcephaly associated with developmental delay, autistic-like behaviors and cognitive dys­ function, seizures, and repetitive motor actions; these then progress to include difficulties with gait, swallowing, and breathing before usually stabilizing with patients surviving to adulthood. The pathophysiology of Rett syndrome is presumed to involve abnormal epigenetic regula­ tion leading to decreased transcriptional repression of genes whose overexpression produces the disease phenotype, although this concept has been contested. In one of the first studies to use iPSC modeling to study Rett syndrome, it was discovered that when fibroblasts from patients were reprogrammed to pluripotent stem cells, X inactiva­ tion was erased. In apparent recapitulation of endogenous events, X chromosome inactivation re-occurred during neuronal differentiation, producing a mosaic of cells carrying the mutant gene intermingled with normal cells. Rett neurons had fewer dendritic spines and syn­ apses, smaller cell bodies, and reduced network activity. Another iPSC model of Rett syndrome highlighted the potential role of altered inhibitory function. Rett neurons were found to have a deficit of potas­ sium/chloride cotransporter (KCC2) that is developmentally regulated and normally leads to a switch in GABA signaling from excitatory at embryonic ages to inhibitory by birth. In Rett neurons, KCC2 expres­ sion level was low, and the functional switch in GABA effects was delayed, contributing to some of the disease features and possibly accounting for the developmental onset of the disease. One curious feature of some iPSC Rett lines was that despite the mosaic expression of the mutation, disease phenotypes were observed in all cells. Possibly, this could reflect a noncell autonomous effect, but as in all iPSC disease models, confidence in disease-specific features will be increased when similar phenotypes are seen across multiple independent studies. Timothy syndrome, another severe neurodevelopmental disease associated with ASD, has been modeled using iPSC-derived organoids. Timothy syndrome is caused by a mutation in the CACNA1C gene cod­ ing for a voltage-gated calcium channel, and neuron defects in Timothy syndrome organoids were rescued by selectively altering calcium chan­ nel activity. In one study, two separate organoids were produced with different regional identity, one represented neocortex and one a more ventral structure known as the medial ganglionic eminence, which is the source of most cortical interneurons. The two organoids were then fused together to allow the interneurons to migrate into the cortex, mimicking their endogenous behavior. The ability to model interneu­ ron migration led to the discovery of a cell-autonomous migration defect in the disease-carrying neurons. The majority of nervous system diseases, including ASD, are poly­ genic and cannot be modeled in animals but can be modeled using patient-derived iPSCs. For example, a subset of patients with ASD have large head size, and a cohort of patients with this phenotype was used to generate iPSCs that were converted to neural progenitor cells and forebrain neurons. The progenitors had an accelerated cell cycle and produced an excess of inhibitory interneurons and had exuber­ ant cellular overgrowth of neurites and synapses. This last feature is in contrast to the decrease in spines and synapses observed in other iPSC models of ASD such as fragile X and Rett syndrome and under­ scores the need for replication and validation of purported disease phenotypes given the high variability based on differences between stem cell lines, protocols, patient genetic background, and other fac­ tors. Moreover, the clinical features of most neuropsychiatric diseases reflect disorders in processes such as circuit formation and refinement that occur after birth and may be difficult to capture at the fetal stage of development reflected in stem cell models. PART 13 Neurologic Disorders Patient stem cells have also been used by multiple groups to study the pathophysiology of schizophrenia, producing a variety of diverse and sometimes contradictory results. Reports claim obvious pheno­ types such as disruptions in the adherens junctions of forebrain radial glia or aberrant neuronal migration, although such gross abnormalities observed at the equivalent of in utero stages of development seem very unlikely to underlie a disease that usually manifests at adolescence or young adulthood. Other studies report abnormalities related to abnor­ mal microRNA expression, disordered cyclic AMP and Wnt signaling, abnormal stress responses, diminished neuronal connectivity, fewer neuronal processes, problems with neuronal differentiation, and mito­ chondrial abnormalities, among others. While the pathophysiology of as complex a neurodevelopmental disorder as schizophrenia may be multidimensional, it is unclear which, if any, of the reported findings in iPSC models reflect the true pathology of schizophrenia. Progress will likely depend on the adoption of more standard and reproducible pro­ tocols, more rigorous identification of cell types, markers of regional identity, and indicators of maturity. ■ ■ALZHEIMER’S DISEASE As noted above, the leading concept of AD pathogenesis, the amyloid hypothesis, suggests that an imbalance between production and clear­ ance of β-amyloid leads to excessive accumulation of β-amyloid peptide and the formation of NFTs within neurons, composed of aggregated hyperphosphorylated tau proteins. Additionally, aggregates of amyloid fibrils are deposited outside neurons in the form of neuritic plaques. Among the causes of familial AD are mutations in genes involved in β-amyloid production, including amyloid precursor protein (APP) and presenilin 1 and 2. Shortly after the introduction of iPSC technology, human stem cell–derived neurons were generated from patients carry­ ing mutations in AD-causative genes as well as from sporadic AD cases. The disease neurons developed hallmarks of AD including intracel­ lular accumulation of β-amyloid and phosphorylated tau, as well as secretion of APP cleavage products, features that could be reduced by adding β- or γ-secretase inhibitors or β-amyloid-specific antibodies. The neurons also demonstrated other disease features observed in postmortem AD tissues. However, extracellular β-amyloid aggregation and NFTs were not robustly modeled in these two-dimensional sys­ tems, presumably because secreted factors were able to readily diffuse away. The use of three-dimensional organoids to model AD overcame this limitation, presumably by recreating a more faithful extracellular matrix. Organoid models promoted the aggregation of β-amyloid, and more readily recapitulated the pathologic features of AD, including the formation of NFTs and neuritic plaques. It is hoped that the new stem cell models, particularly organoid models, will accelerate our understanding of AD by enabling the study of human disease-carrying cells in a quasi in situ setting. These new models may lead to discovery of novel druggable targets and new diag­ nostic and prognostic biomarkers. One concern is that the pathogenic features of AD usually appear in the sixth or seventh decade of life and progress slowly over years, while most protocols for the deriva­ tion of human cortical neurons generate cells over weeks or months and most remain comparable to immature neurons at fetal stages of development. Nonetheless, these young cells have been used to model neurodegenerative diseases such as AD and HD that strike patients in middle to late adulthood. Possibly the onset of disease phenotype is accelerated in stem cell models due to increased cellular stress, which appears to be a feature of stem cell culture, or disease features may actually have a subtle onset at earlier stages than generally suspected. Indeed, 3-year-old children at genetic risk of developing early-onset AD appear to have smaller hippocampal size and lower scores on memory tests than children in a nonrisk group. The phenotypes of adult neurodegenerative diseases that are visible at fetal stages may or may not correspond to those manifest at later, adult stages, but they may offer the possibility of devising preventative strategies effective at very early stages of the disease. ■ ■CELL TYPE DISORDERS: ALS AND HUNTINGTON’S DISEASE In diseases such as ALS, PD, and HD, that mostly target specific neuron subtypes, stem cells provide an ideal means to study the vulnerable human cell populations. By enabling the production of unlimited num­ bers of normal and diseased human midbrain dopaminergic neurons for the study of PD, medium spiny striatal neurons for HD, and spinal and cortical motor neurons for ALS, iPSC approaches have the poten­ tial to transform our understanding and management of these diseases. Stem cell–derived neurons serve as platforms to explore mechanisms of cell vulnerability, to screen drugs for neural protection, and potentially to derive neurons for replacement therapy. ■ ■AMYOTROPHIC LATERAL SCLEROSIS One of the first protocols for producing neurons of a specific subtype from embryonic stem cells recapitulated normal developmental pro­ grams to generate mouse spinal motor neurons. Pluripotent mouse stem cells underwent neural induction and adopted a caudal identity through the application of retinoic acid, and subsequently adopted motor neuron fate through the action of Sonic hedgehog (Shh), a ven­ tralizing factor. Generating human motor neurons proved more com­ plex, requiring additional steps, such as early exposure to the growth factor, FGF2. The first application of stem cell–derived motor neurons to study ALS involved the use of mouse motor neurons generated from transgenic mice expressing a mutation in the superoxide dismutase 1 (SOD1) gene, the most common mutation responsible for familial ALS. Only 5–10% of ALS cases are familial, but the known mutations provide a useful entry point to tease apart the causative pathophysiol­ ogy. Mutations in SOD1 produce ALS through a toxic gain of function for which the mechanism remains unclear, despite the use of multiple transgenic animal and iPSC models. The use of mouse embryonic stem cell–derived motor neurons, however, demonstrated that toxic factors secreted by SOD1 astrocytes contribute to the death of motor neurons. Interestingly, stem cell–derived interneurons were spared, indicating a specific vulnerability of motor neurons. These findings helped establish the notion that a non-cell-autonomous toxic mecha­ nism contributes to ALS pathogenesis and may ultimately lead to novel treatment strategies. These findings also highlight that modeling the full pathophysiology of ALS may require the reproduction of a complex environment including motor neurons, astrocytes, and possibly addi­ tional cell types such as microglia. A variety of approaches including co-culture of specific cell types, three-dimensional spinal cord organ­ oids, and microfluidic organ-on-chip models are being explored to achieve a more complete facsimile of spinal cord organization. Similar to other neurologic disorders where a clearly defined phenotype has been observed in human stem cell–derived models, there is hope that drug screening using human disease-expressing cells will identify a potential therapeutic compound. ■ ■HUNTINGTON’S DISEASE HD is caused by an expansion in CAG triplet repeats in the huntingtin gene, which leads to an expanded polyglutamine tract in the hunting­ tin protein. HD is dominantly inherited, with symptoms of cognitive decline and uncontrollable gait and limb motions beginning in the third to fifth decade of life with progression to dementia and death approximately 20 years later. Mutant huntingtin causes a toxic gain of function, with the degree of effect related to the CAG repeat length. For example, a CAG length of 40–60 repeats produces adult-onset HD, whereas repeats of 60 or more produce juvenile-onset disease. Although it has been 25 years since the discovery of this causative mutation, the disease mechanism remains poorly understood. Excess huntingtin protein and protein fragments accumulate in specific subtypes of neu­ rons where they misfold and form aggregates that are visible as cellular inclusions. Affected cells eventually die, possibly as a result of meta­ bolic toxicity. The medium spiny neurons of the striatum are the most vulnerable neurons, spurring ongoing attempts to produce replacement cells derived from stem cells, but neuron loss is widespread including in the cortex, complicating a cell replacement approach for this disease. HD iPSCs have been generated from patients with various CAG repeat lengths, but those from juvenile-onset disease with the longest repeat lengths have been favored as being most likely to express robust disease phenotypes at an early stage. This is particularly important given the immature stage of maturation of stem cell–derived human neurons. This approach has been able to produce disease phenotypes observed in patients including huntingtin protein aggregation, decreased meta­ bolic capacity, increased oxidative stress with mitochondrial fragmen­ tation, and apoptosis enhanced by withdrawal of growth factor support. However, many of these phenotypes were observed in pluripotent cells prior to neural differentiation and in neural progenitors and a broad array of CNS neurons in contrast to the cell type–specific features of the disease. Nonetheless, neurons that assumed striatal fate appear to be more vulnerable to stress and apoptosis than other cell types. As with other iPSC models of nervous system diseases, there have so far been few efforts to validate results in multiple iPSC lines having different genetic backgrounds but with similar CAG repeat lengths. An HD con­ sortium has been formed to address this problem by generating a series of iPSC lines from multiple patients. An alternative strategy to validate disease phenotypes has been to use gene editing to create isogenic iPSC lines that are corrected to produce wild-type control and HD iPSC lines against the same genetic background. FUTURE PERSPECTIVES Despite early successes, it may prove difficult to reconstitute neuro­ degenerative disease conditions in human cells in vitro over a short course of time because the pathogenic changes of degenerative dis­ eases progress slowly and commence in the later stages of life. The differentiation and maturation of human neurons from stem cell lines occur over a span of months, which may not be long enough to establish the aged-brain conditions under which patients develop robust neurodegenerative pathology. Possible manipulation through gene editing or by application of aging-associated stresses, such as DNA-damaging agents or proteasome inhibitors, may accelerate the expression of degenerative phenotypes in human iPSC-derived cellular models. Stem cell–derived organoid models are also ideal platforms to apply methods for cellular-level visualization such as CLARITY and multielectrode recording techniques to better evaluate threedimensional organoid structures and explore early-forming circuits. These applications are only just beginning. Two-dimensional cell cultures are ideal for production and evalua­ tion of large numbers of specific cells of a particular identity but may not provide the complex extracellular environment necessary to model certain disease processes, such as extracellular protein aggregation. These features can be best modeled using three-dimensional organ­ oids, but current methods do not reproduce all the relevant features of brain tissue. Optimization will be needed to better reproduce the cellular composition of brain, including endothelial cells, astrocytes, microglia, and oligodendrocytes. It may also be necessary to combine different brain regions generated separately, possibly by fusion of tis­ sues such as dorsal cortex, subpallium, thalamus, retina, and others in so-called “assembloids.” One roadblock has been the limited ability to recreate tissues or neurons with regional brain identity, such as hip­ pocampus, thalamus, or cerebellum. However, recently regionalized organoids have been created using innovative microfluidic chambers and the imposition of morphogen gradients such as bone morpho­ genetic proteins (BMPs) and WNTs. More faithful organoid models could also emerge through the application of bioengineered scaffolds, matrices, or perfusion systems that might allow the growth of larger structures, a feature currently limited due to the emergence of a necrotic core when nonperfused organoids exceed a certain size. Of course, not all aspects of mature brain architecture and function will be modeled by these tissue structures, particularly as they generally repre­ sent prenatal stages of development, but perhaps the most precocious events in disease etiology can be captured and investigated, and these may share mechanistic pathways with disease features that manifest at later stages. CHAPTER 435 Pathobiology of Neurologic Diseases The current excitement surrounding human stem cells has more to do with their promise to improve on animal models of disease, for which their potential appears unlimited, rather than on their use as a source for cell-based therapies, where the potential has thus far been relatively limited. Even without new insights into disease pathogen­ esis, it is likely that iPSC models such as brain organoids will serve as drug-screening platforms for discovery of novel therapeutics and for detection of off-target and toxic effects. The failure of many neu­ rotherapeutic approaches to translate from animal models to clinical practice underscores the need for better predictive models, and stem cell models and brain organoids based on human cells may be ideally suited to bridge this divide. A CURRENT PERSPECTIVE ON NEURAL STEM CELLS IN THE CLINIC The prospect of stem cell therapies to treat diseases or injuries of the nervous system has captured the attention of researchers, clinicians, and the public. The pace of research is usually slow and deliberate, but in the stem cell arena, there has been enormous pressure to accelerate the pace of progress in order to bring cell-based therapies to the clinic. Expectations have been raised, and clinics have already begun offering unproven or dangerous treatments to a public that can be, in some situ­ ations, ill-informed and vulnerable to exploitation. Nonetheless, there has been remarkable progress over the past few years toward legitimate stem cell–based therapies for a number of nervous system disorders. There are multiple clinical trials underway fueling cautious optimism that stem cells will eventually realize the promise of regenerative therapy for at least some currently untreatable or incurable nervous system diseases. ■ ■PARKINSON’S DISEASE Pursuit of a cell-based therapy for PD using fetal-derived midbrain cells has been ongoing for many decades but with disappointing results. Following anecdotal success in a handful of patients who appeared to improve following striatal grafts of fetal midbrain dopaminergic cells, two National Institutes of Health (NIH)-sponsored double-blind con­ trol studies were launched in the 1990s. However, only a small number of younger patients showed some benefit, and several patients devel­ oped spontaneous dyskinetic movements related to the therapy. These efforts constituted a failed trial as the treated patients who did not experience side effects failed to improve significantly. However, tech­ niques to extract dopaminergic cells from fetal tissue have improved, and on the basis of encouraging results in individual transplanted patients, some of whom have managed to go off their Parkinson’s medication, a new trial of fetal cell transplantation for PD was con­ ducted in Europe. Unfortunately, enrollment was unexpectedly slow and the trial was terminated after several years without reaching the anticipated number of patients. There was no clear clinical improve­ ment among the treated patients, possibly due to difficulty harvesting sufficient fetal cells to reach the targeted number per patient. Despite the disappointing clinical outcome, enthusiasm remains high for a bet­ ter outcome with stem cell–derived dopamine neurons where, among other differences, cell number is not a limitation. The dyskinesias that curtailed the NIH trials in the 1990s were eventually ascribed to an abundance of serotonergic neurons that were inadvertently included in some of the cell grafts. Protocols for deriving dopaminergic neurons from stem cells would presumably avoid this complication by providing a more purified cell population, and sev­ eral groups around the world have been aggressively pursuing a stem cell–based approach to PD. In 2018, researchers from Kyoto University in Japan started a phase 1/2 clinical trial to treat PD using stem cells. The investigators chose to use iPSCs derived from a healthy person who had the most common HLA haplotype in Japan. The iPSCs were used to make dopamine-secreting neurons. Seven patients have had the reprogrammed stem cells surgically delivered into the brain and have been followed for two years postinjection to assess safety and pos­ sible efficacy. The U.S. Food and Drug Administration (FDA) recently approved the first clinical trial of a stem cell–derived dopamine neuron for the treatment of PD in the United States. These cells, derived from an embryonic stem cell line, have been delivered to 10 patients in a phase 1 clinical trial to assess safety, tolerability, and preliminary effi­ cacy. A European trial of embryonic stem cell–derived dopaminergic neurons led by scientists in Sweden and the United Kingdom began in 2023. Four patients given a low dose experienced no acute adverse effects, and four more will be treated with a higher dose, and all will be followed for 36 months to evaluate safety and tolerability. PART 13 Neurologic Disorders A clinical trial using iPSC-generated dopaminergic neurons to treat patients with PD was begun in 2018 in Japan. The cell line was derived from a healthy individual with the most common HLA hap­ lotype in the Japanese population. The clinical product consisted of 80% dopamine neuron progenitor cells and a population of glial cells. Because the cell line was genetically altered, the karyotype, plasmid survival, and genomic and epigenomic abnormalities were evaluated and known carcinogenic gene mutations were screened. A single-arm, nonrandomized and open-phase 1/2 study was begun in 2018 with ~5 million cells transplanted stereotactically to the putamen bilaterally. Seven patients have been treated thus far. ■ ■BATTEN’S DISEASE AND PELIZAEUSMERZBACHER DISEASE One of the first cell-based clinical trials for a neurologic disease tar­ geted patients suffering from an untreatable childhood disorder, Batten disease. Batten disease is an autosomal recessive metabolic disorder resulting from an inability to synthesize a lysosomal enzyme critical to brain function. The phase 1 trial involved six patients with infantile and late-infantile forms of the disease who received neural stem cells rather than any specific postmitotic cell type. Neural stem cells derived from donated fetal tissue were expanded in vitro prior to surgical graft­ ing into the brain. This approach was not without risk, as the neural stem cells were proliferating and could potentially form an abnormal growth. The rationale was that the cells would be capable of synthesiz­ ing and secreting the missing lysosomal enzyme and would therefore serve as a delivery device. Animal studies using a transgenic mouse model of Batten disease demonstrated rescue, and this promising result led to a small phase 1 trial. The phase 1 study was considered a success as no adverse events were reported and the cells appeared to be safe, though there was no clinical improvement and no clear evidence of whether the cells had dispersed, transformed into neurons or glia, or indeed survived at all. Despite clearing the phase 1 trial, the company did not pursue further trials for Batten disease, but instead initiated clinical trials using the same cell product for several other indica­ tions, including an inherited fatal dysmyelination syndrome known as Pelizaeus-Merzbacher disease (PMD). The human neural stem cells have both neurogenic and gliogenic potential, and when delivered to white matter regions in experimental animals, most persisting cells had become oligodendrocytes. This supported use of the cells to promote myelin formation in conditions such as PMD. The company also initi­ ated trials in spinal cord injury. However, the spinal cord trial failed to achieve sufficient benefit in phase 2 and the company ceased its work on stem cell therapies. ■ ■SPINAL CORD INJURY There is a pressing need for novel therapies for spinal cord injury, with >1 million patients worldwide suffering from spinal cord injuries and no effective treatment options. Not surprisingly, there has been intense interest in achieving a stem cell treatment for this condition and dozens of early-stage clinical trials, and anecdotal treatment results have been reported by investigators around the globe. The vast majority have not been blinded controlled trials, but rather individual reports treating a handful of patients, and somewhat surprisingly, most are using mes­ enchymal stem cells (MSCs) or hematopoietic stem cells that normally generate either bone, cartilage, fat, or blood cells. As described below, the rationale for the use of MSCs for neurologic conditions is based on vague and poorly understood mechanisms of action. A series of stem cell trials designed to treat subacute spinal cord injury is underway in the United States and Europe using neural stem cells or their derivatives as potential therapeutic agents. The first to enter clinical trials in the United States was based on a protocol designed to generate oligodendrocytes from pluripotent embryonic stem cells. Evidence of efficacy was obtained in animal models fol­ lowing surgical grafting of cells to sites of spinal cord injury. However, evidence of myelination of host axons was minimal, and other mecha­ nisms were invoked for improvement in gait, including trophic support and immune modulation. Regulatory permission for a phase 1 trial for subacute midthoracic injury was initially stalled by concern over abnormal growths at sites of cell deposit in some animals, but this was satisfactorily addressed and patient trials commenced. However, fol­ lowing a change in leadership, the stem cell program was terminated. The program was acquired by another company that has resumed the spinal cord injury trial and received regulatory approval to advance to include cervical-level injuries. The current phase 1/2a multicenter clinical trial is an open-label, single-arm trial testing three sequential escalating doses administered 21–42 days after injury in 25 patients with subacute severe cervical spinal cord injuries. No adverse events have been reported for 21 patients at 2 years posttreatment. A laterstage comparative clinical trial is now planned to probe for possible efficacy. In 2020, an open-label, single-arm clinical trial for subacute spinal cord injury patients was begun in Japan using iPSC-derived neural stem and progenitor cells injected directly into the damaged spinal cord. The rationale for injecting neuronal precursor cells into the injured spinal cord is not clear as no specific mechanism of action has been demonstrated. Trophic support and neuroimmune modulation have been proposed, and while studies in mice show that newborn neu­ rons can form synapses onto host spinal neurons, how this could lead to improved locomotor or sensory function remains unclear. Results of the trial have yet to be reported. Initial clinical trials for stem cell therapies that address grave medi­ cal conditions such as spinal cord injury often involve small numbers of patients, and larger pivotal trials that can confirm clinical benefit can take a long time to conduct. In a controversial move designed to accelerate the regulatory approval process, in 2014 the Ministry of Health of Japan authorized the use of conditional and time-limited (CTL) approval for regenerative medical products. This designation can be applied when safety has been demonstrated but efficacy has not yet been fully established and enables the manufacturer to market and sell the product. CTL approval converts to full approval if postmar­ keting clinical data demonstrate clinical benefit, but if no convincing clinical benefit can be demonstrated within 7 years, the product must be withdrawn. The effort to bring MSC treatments to patients with currently untreatable neurologic conditions has consequently had a recent boost in Japan. Autologous bone marrow–derived stem cells were evaluated in an open-label trial involving 13 patients who had experienced severe spinal cord injury 1 month prior to treatment. Mesenchymal stem cells were taken from the patient’s own bone marrow, expanded in number, and delivered back to the patient by intravenous infusion. Six months after treatment, 12 of the patients improved by at least one level on the American Spinal Injury Association impairment scale that ranks muscle contraction and touch, although patients with the same or even greater degree of injury can show spontaneous improvement. As is the case for most MSC therapies, the proposed mechanism of action was quite vague, including reducing inflammation, protecting existing neu­ rons, or replacing damaged neurons. It is also unclear how intravenous delivery could accomplish any of the proposed actions. In 2018, on the basis of the results, unpublished at the time, Japan’s health ministry gave conditional (CTL) approval for the treatment, called Stemirac. This became the first stem cell therapy for spinal cord injury to receive government approval for sale to patients. But the approval of a therapy that may carry risk following a small, unblinded, and uncontrolled study without actual proof of efficacy raised considerable concern among scientists in the stem cell community. Charging patients for such an unproven therapy raises even more ethical concerns. Patients in Japan can now be charged for their treatment while trials to test efficacy are still proceeding. ■ ■AMYOTROPHIC LATERAL SCLEROSIS The possibility of treating ALS by replacing dying motor neurons with stem cell–derived substitutes has excited interest, but this pros­ pect seems very remote. Even if new neurons are able to integrate into spinal cord circuits and become properly innervated, they would have to grow long axons that would take many months to years to project to appropriate targets and attract myelinating Schwann cells. Furthermore, cells would need to be grafted at multiple spinal cord and brainstem levels, and the upper motor neuron deficit would need to be treated by replacing projecting neurons in the motor cortex. An additional complication is the recent finding that spinal motor neurons have unique segmental identity, and replacement cells might need to be generated with a range of molecular identities in order to integrate at multiple spinal levels. This would still leave unaddressed the toxic effects recently shown to be produced in ALS by diseased astrocytes and microglia that could attack the replacement cells. A more tractable near-term solution would be to graft support cells that could rescue or protect endogenous motor neurons from damage. This approach was tried in a mouse model of ALS. Human fetal stem cell–derived neural progenitor cells engineered to express glial cell line–derived neurotrophic factor (GDNF), a growth factor known to provide tro­ phic support for neurons, were grafted to the spinal cord of young ALS mice. The cells dispersed and were able to rescue motor neurons, a very promising result, but disappointingly, the animals became weak and died at the same rate as untreated control animals. ALS is a deadly disease with no known treatment; thus in the hope that patients will respond differently from mice, a phase 1/2a clinical trial based on this approach was approved by the FDA in 2016 and completed in 2019. Patients had the GDNF-producing progenitor cells surgically grafted unilaterally into the lumbar spinal cord. Although disease progression appeared to slow in some treated patients, this was not statistically significant. Of note, several patients developed painful schwannomas, a result of off-targeting deposit of the GDNF-secreting cells close to the dorsal horn root entry zone. Autopsy study of 13 of the 18 treated patients who died within 2 years of treatment showed that the grafted cells had survived. Based on these results, a new trial has begun. With the notion that rescuing lower motor neurons alone may not be suffi­ cient to arrest progression of a disease that affects both upper and lower motor neurons, this trial aims to enroll 16 patients who will have the GDNF-secreting progenitor cells grafted to the motor cortex in an area controlling hand movement. The goal is to try to slow the progression of the upper motor deficit associated with ALS. Among the many MSC-based clinical trials for ALS, two are par­ ticularly notable. Corestem, a stem cell company in South Korea, launched a phase 1 open-label study demonstrating the safety and feasibility of intrathecal injections of autologous bone marrow–derived MSCs in seven patients with ALS. This was followed by a phase 2 trial that demonstrated safety and efficacy for slowing disease progression. On the basis of these results, Corestem received conditional approval in South Korea in 2014 to market the first stem cell therapy for ALS. By 2021, >300 patients had received this cell treatment. However, full approval is contingent on the results of a randomized, double-blind, placebo-controlled, multicenter phase 3 study, which began in 2021. The trial aims to enroll 115 patients who will receive repeated intrathe­ cal injections of the autologous cells. The goal is to slow or prevent ALS progression and delay death for up to 3 years. The importance of conducting proper phase 3 clinical trials to deter­ mine therapeutic efficacy in ALS is underscored by the recent experi­ ence of BrainStorm Cell Therapeutics. In 2016, the company reported preliminary positive results for its bone marrow MSC cell therapy in an uncontrolled study of nearly 50 ALS patients. Based on those results, the company launched a phase 3, multicenter, placebo-controlled, ran­ domized, double-blind trial of 189 ALS patients. In 2020, the company reported that there was no significant clinical improvement in the treatment group. Interestingly, despite the failed clinical trial, a public campaign led by ALS patients and advocates called on the FDA to approve the stem cell treatment. The social media response prompted the FDA to take the unusual step of releasing a public statement under­ scoring the lack of efficacy, and in 2023, an FDA advisory committee voted against approval. The company responded by withdrawing its Biologics License Application and announcing a phase 3b trial that will focus on early-stage patients. CHAPTER 435 Pathobiology of Neurologic Diseases ■ ■EPILEPSY A phase 1/2 clinical trial was launched in 2022 using stem cell– derived inhibitory interneurons to treat medically intractable temporal lobe epilepsy. Somatostatin (SST)-expressing inhibitory interneurons, matching the predominant cortical interneuron subtype, were derived from an embryonic stem cell line. Following demonstration of efficacy in a mouse model of temporal lobe epilepsy, 10 patients who had been determined to have a seizure focus in the hippocampus had stem cell– derived interneurons surgically delivered to the epileptic hippocampus. The first five patients received a low dose followed by five patients who received a higher dose. All 10 patients will be followed for 2 years after treatment. As in the PD clinical trials, all patients received antirejec­ tion therapy for the first 12 months. The current standard of care for patients with intractable temporal lobe epilepsy is surgical ablation or resection of the epileptic hippocampus. Surgically treated patients can have seizure remission but often have cognitive decline, particularly if the focus is in the dominant hemisphere. Early indications are that the cell-based therapy can not only reduce seizures but also spare or improve cognitive function. ■ ■MACULAR DEGENERATION Because iPSC technology enables the generation of pluripotent stem cells from adult somatic cells, it has enabled the production of patientspecific autologous cells for cell replacement therapy. Following Shinya Yamanaka’s discovery of iPSCs, the Japanese government has invested in bringing iPSC-derived cell therapy to the clinic. Banks of iPSC lines selected to capture the diversity of HLA haplotypes found in the Japanese population have been produced in the hope that these will allow cell therapies to be matched to individual patient haplotypes in order to avoid immune rejection. While these stem cell banks were still being produced, the first Japanese study to use stem cells was approved in 2013 and involved patients who were to receive customized therapy using cells derived from their own skin fibroblasts. The targeted disease was age-related macular degeneration, a common cause of blindness in the elderly that results from loss of retinal pigment epithelial (RPE) cells. RPE cells are relatively easy to generate from pluripotent stem cells, making replacement therapy an attractive target in this condition. A challenge is to coax the replacement cells to recreate an epithelium in the subretinal space. The Japanese approach involves surgical inser­ tion of a biofilm seeded with RPE cells into the retina. One patient was treated with their own stem cell–derived RPE cells, but prior to treating # 05 - SECTION 2 Diseases of the Central Nervous System ## SECTION 2 Diseases of the Central Nervous System a second patient, the genome of the RPE cell line was sequenced, and a mutation was discovered in a known oncogene. The trial was halted and a decision made to discontinue the effort for customized cell therapy in favor of using RPE cells derived from the national repository of banked iPSC lines which undergo extensive gene sequencing and quality controls. This outcome serves as a caution for the challenges involved in bringing a customized cell therapy to the clinic. ■ ■MESENCHYMAL STEM CELLS By far the largest number of human trials have been performed using MSCs sourced from a variety of sites including bone marrow, periph­ eral blood, adipose tissue, umbilical cord, and other sites. Interest in the potential utility of MSCs for regenerative therapy began with the optimistic report that bone marrow stem cells were pluripotent and capable of generating nerve and heart muscle as well as blood cells. The possibility that easily obtainable MSCs could be used to regenerate injured or diseased cells or organs to treat diseases ranging from stroke, neurodegenerative disease, myocardial infarct, and even diabetes, generated enormous enthusiasm. The enthusiasm proved irresistible to many, and even after the initial reports were discredited—MSCs turned out not to be pluripotent stem cells as initially thought—a veritable flood of papers began to appear claiming disease-modifying activity of MSCs in mouse models of a wide range of degenerative disease and injury models. But when it became clear that the MSCs were not transforming into or generating new neurons or cardiac myo­ cytes, alternative mechanisms of action were invoked, including the release of trophic factors, cytokines, or inflammatory modulators that were credited with producing their remarkable restorative effects. The relative ease with which blood or adipose tissue can be harvested from patients or donors and MSCs extracted has led to a rapidly expanding number of clinical trials for conditions ranging from stroke and MS to AD, ALS, and PD. Furthermore, a loophole in the regulatory frame­ work of the FDA allows autologous cell therapy to escape regulation provided that the cells have not been significantly processed. This lax regulation has spawned a veritable industry of stem cell clinics making unsubstantiated claims of success in treating nervous system diseases. Patients have died from treatments in unregulated clinics operating in countries around the world, and three patients became blind in a well-publicized incident following stem cell treatments delivered by a Florida clinic. The “stem cells” were derived from the patients’ own fat tissue and blood. These activities represent the dark side of the stem cell revolution perpetrated by practitioners who exploit the desperation of patients and their families. Legitimate and effective stem cell thera­ pies will emerge over time, but given the prevalence and abundance of misleading information available on the Internet and elsewhere, a trusted and well-informed physician can play a key role in helping patients navigate the current cell therapy minefield. PART 13 Neurologic Disorders ■ ■MSCS FOR TRAUMATIC BRAIN INJURY An allogeneic bone marrow–derived MSC line received conditional marketing approval in Japan in 2024 for the indication of improving chronic motor paralysis resulting from traumatic brain injury. The MSCs were transiently transfecting with the human Notch-1 intracel­ lular domain gene to promote FDF-2 secretion in order to “enhance their ability to regenerate nerve cells” according to the pharmaceutical company that developed the cell-based therapy. The approval fol­ lowed results of a phase 2 clinical trial conducted in Japan and the United  States. Forty-six patients with moderate to severe traumatic brain injury and chronic motor deficits had MSCs stereotactically infused into an area of encephalomalacia identified on MRI scan while a sham group of 15 patients had burr holes only. The trial met the primary endpoint showing significant improvement in motor function at 24 weeks on the Fugle-Meyer Motor Scale (FMMS) (p = .04). Inter­ estingly, a small improvement was noted in the sham-treated group as well, indicating the presence of a placebo effect. A larger, double-blind, randomized, sham-controlled study is now planned. ■ ■PERSPECTIVE The premise that stem cell biology would herald an era of regenerative medicine has fueled exaggerated claims, false starts, and a proliferation of bogus clinics. But now we may be on the threshold of a new era of stem cell-based therapies for neurologic diseases and disorders includ­ ing PD, spinal cord injury, ALS, and epilepsy. Whether this promise becomes reality will depend on the outcome of the first wave of piv­ otal double-blind controlled trials that are now being conducted or planned. ■ ■FURTHER READING Ayers JI et al: Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy. Proc Natl Acad Sci USA 119:e2113489119, 2022. Batista AF et al: The importance of complement-mediated immune signaling in Alzheimer’s disease pathogenesis. Int J Mol Sci 25:817, 2024. Carlson GA, Prusiner SB: How an infection of sheep revealed prion mechanisms in Alzheimer’s disease and other neurodegenerative disorders. Int J Mol Sci 22:4861, 2021. Condello C et al: Expanding the prion paradigm to include Parkinson and Alzheimer diseases. JAMA Neurol 81:1023, 2024. Eichmüller OL, Knoblich JA: Human cerebral organoids: A new tool for clinical neurology research. Nat Rev Neurol 18:661, 2022. Garton T et al: Neurodegeneration and demyelination in multiple sclerosis. Neuron 112:3231, 2024. Kandel ER et al (eds): Principles of Neural Science, 6th ed. McGraw Hill, New York, 2021. Kim TW et al: Pluripotent stem cell therapies for Parkinson disease: Present challenges and future opportunities. Front Cell Dev Biol 8:729, 2020. Lee HG et al: Neuroinflammation: An astrocyte perspective. Sci Transl Med 15:eadi7828, 2023. Li Q, Barres BA: Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18:225, 2018. Liu L et al: Microbiota and the gut-brain-axis: Implications for new therapeutic design in the CNS. EBioMedicine 77:103908, 2022. Pallarés-Moratalla C, Bergers G: The ins and outs of microglial cells in brain health and disease. Front Immunol 15:1305087, 2024. Pease-Raissi SE, Chan JR: Building a (w)rapport between neurons and oligodendroglia: Reciprocal interactions underlying adaptive myelination. Neuron 109:1258, 2021. Section 2 Diseases of the Central Nervous System Patricia Dugan, Vikram R. Rao Seizures and Epilepsy A seizure (from the Latin sacire, “to take possession of”) is a transient occurrence of signs or symptoms due to abnormal excessive or syn­ chronous neuronal activity in the brain. Depending on the distribution of discharges, this abnormal brain activity can have various manifesta­ tions, ranging from dramatic convulsive activity to experiential phe­ nomena not readily discernible by an observer. Although a variety of factors influence the incidence and prevalence of seizures, ~5–10% of the population will have at least one seizure, with the highest incidence occurring in early childhood and late adulthood. The meaning of the term seizure needs to be carefully distinguished from that of epilepsy. Epilepsy describes a condition in which a person has a risk of recurrent seizures due to a chronic, underlying process. This definition implies that a person with a single seizure, or recurrent # 06 - 436 Seizures and Epilepsy ### 436 Seizures and Epilepsy a second patient, the genome of the RPE cell line was sequenced, and a mutation was discovered in a known oncogene. The trial was halted and a decision made to discontinue the effort for customized cell therapy in favor of using RPE cells derived from the national repository of banked iPSC lines which undergo extensive gene sequencing and quality controls. This outcome serves as a caution for the challenges involved in bringing a customized cell therapy to the clinic. ■ ■MESENCHYMAL STEM CELLS By far the largest number of human trials have been performed using MSCs sourced from a variety of sites including bone marrow, periph­ eral blood, adipose tissue, umbilical cord, and other sites. Interest in the potential utility of MSCs for regenerative therapy began with the optimistic report that bone marrow stem cells were pluripotent and capable of generating nerve and heart muscle as well as blood cells. The possibility that easily obtainable MSCs could be used to regenerate injured or diseased cells or organs to treat diseases ranging from stroke, neurodegenerative disease, myocardial infarct, and even diabetes, generated enormous enthusiasm. The enthusiasm proved irresistible to many, and even after the initial reports were discredited—MSCs turned out not to be pluripotent stem cells as initially thought—a veritable flood of papers began to appear claiming disease-modifying activity of MSCs in mouse models of a wide range of degenerative disease and injury models. But when it became clear that the MSCs were not transforming into or generating new neurons or cardiac myo­ cytes, alternative mechanisms of action were invoked, including the release of trophic factors, cytokines, or inflammatory modulators that were credited with producing their remarkable restorative effects. The relative ease with which blood or adipose tissue can be harvested from patients or donors and MSCs extracted has led to a rapidly expanding number of clinical trials for conditions ranging from stroke and MS to AD, ALS, and PD. Furthermore, a loophole in the regulatory frame­ work of the FDA allows autologous cell therapy to escape regulation provided that the cells have not been significantly processed. This lax regulation has spawned a veritable industry of stem cell clinics making unsubstantiated claims of success in treating nervous system diseases. Patients have died from treatments in unregulated clinics operating in countries around the world, and three patients became blind in a well-publicized incident following stem cell treatments delivered by a Florida clinic. The “stem cells” were derived from the patients’ own fat tissue and blood. These activities represent the dark side of the stem cell revolution perpetrated by practitioners who exploit the desperation of patients and their families. Legitimate and effective stem cell thera­ pies will emerge over time, but given the prevalence and abundance of misleading information available on the Internet and elsewhere, a trusted and well-informed physician can play a key role in helping patients navigate the current cell therapy minefield. PART 13 Neurologic Disorders ■ ■MSCS FOR TRAUMATIC BRAIN INJURY An allogeneic bone marrow–derived MSC line received conditional marketing approval in Japan in 2024 for the indication of improving chronic motor paralysis resulting from traumatic brain injury. The MSCs were transiently transfecting with the human Notch-1 intracel­ lular domain gene to promote FDF-2 secretion in order to “enhance their ability to regenerate nerve cells” according to the pharmaceutical company that developed the cell-based therapy. The approval fol­ lowed results of a phase 2 clinical trial conducted in Japan and the United  States. Forty-six patients with moderate to severe traumatic brain injury and chronic motor deficits had MSCs stereotactically infused into an area of encephalomalacia identified on MRI scan while a sham group of 15 patients had burr holes only. The trial met the primary endpoint showing significant improvement in motor function at 24 weeks on the Fugle-Meyer Motor Scale (FMMS) (p = .04). Inter­ estingly, a small improvement was noted in the sham-treated group as well, indicating the presence of a placebo effect. A larger, double-blind, randomized, sham-controlled study is now planned. ■ ■PERSPECTIVE The premise that stem cell biology would herald an era of regenerative medicine has fueled exaggerated claims, false starts, and a proliferation of bogus clinics. But now we may be on the threshold of a new era of stem cell-based therapies for neurologic diseases and disorders includ­ ing PD, spinal cord injury, ALS, and epilepsy. Whether this promise becomes reality will depend on the outcome of the first wave of piv­ otal double-blind controlled trials that are now being conducted or planned. ■ ■FURTHER READING Ayers JI et al: Different α-synuclein prion strains cause dementia with Lewy bodies and multiple system atrophy. Proc Natl Acad Sci USA 119:e2113489119, 2022. Batista AF et al: The importance of complement-mediated immune signaling in Alzheimer’s disease pathogenesis. Int J Mol Sci 25:817, 2024. Carlson GA, Prusiner SB: How an infection of sheep revealed prion mechanisms in Alzheimer’s disease and other neurodegenerative disorders. Int J Mol Sci 22:4861, 2021. Condello C et al: Expanding the prion paradigm to include Parkinson and Alzheimer diseases. JAMA Neurol 81:1023, 2024. Eichmüller OL, Knoblich JA: Human cerebral organoids: A new tool for clinical neurology research. Nat Rev Neurol 18:661, 2022. Garton T et al: Neurodegeneration and demyelination in multiple sclerosis. Neuron 112:3231, 2024. Kandel ER et al (eds): Principles of Neural Science, 6th ed. McGraw Hill, New York, 2021. Kim TW et al: Pluripotent stem cell therapies for Parkinson disease: Present challenges and future opportunities. Front Cell Dev Biol 8:729, 2020. Lee HG et al: Neuroinflammation: An astrocyte perspective. Sci Transl Med 15:eadi7828, 2023. Li Q, Barres BA: Microglia and macrophages in brain homeostasis and disease. Nat Rev Immunol 18:225, 2018. Liu L et al: Microbiota and the gut-brain-axis: Implications for new therapeutic design in the CNS. EBioMedicine 77:103908, 2022. Pallarés-Moratalla C, Bergers G: The ins and outs of microglial cells in brain health and disease. Front Immunol 15:1305087, 2024. Pease-Raissi SE, Chan JR: Building a (w)rapport between neurons and oligodendroglia: Reciprocal interactions underlying adaptive myelination. Neuron 109:1258, 2021. Section 2 Diseases of the Central Nervous System Patricia Dugan, Vikram R. Rao Seizures and Epilepsy A seizure (from the Latin sacire, “to take possession of”) is a transient occurrence of signs or symptoms due to abnormal excessive or syn­ chronous neuronal activity in the brain. Depending on the distribution of discharges, this abnormal brain activity can have various manifesta­ tions, ranging from dramatic convulsive activity to experiential phe­ nomena not readily discernible by an observer. Although a variety of factors influence the incidence and prevalence of seizures, ~5–10% of the population will have at least one seizure, with the highest incidence occurring in early childhood and late adulthood. The meaning of the term seizure needs to be carefully distinguished from that of epilepsy. Epilepsy describes a condition in which a person has a risk of recurrent seizures due to a chronic, underlying process. This definition implies that a person with a single seizure, or recurrent seizures due to correctable or avoidable circumstances, does not neces­ sarily have epilepsy (although a single seizure associated with clinical or electroencephalographic features portending high risk of recurrence may establish the diagnosis of epilepsy). Epilepsy refers to a clinical phenomenon rather than a single disease entity because many forms and causes exist. However, among the many causes of epilepsy, there are various epilepsy syndromes in which the clinical and pathologic characteristics are distinctive and suggest a specific underlying etiology. Using the definition of epilepsy as two or more unprovoked sei­ zures, the incidence of epilepsy is ~0.3–0.5% in different populations throughout the world, and the prevalence of epilepsy has been esti­ mated at 5–30 persons per 1000. CLASSIFICATION OF SEIZURES Determining the type of seizure that has occurred is essential for focusing the diagnostic approach on particular etiologies, selecting appropriate therapy, and providing information regarding prognosis. The International League Against Epilepsy (ILAE) Commission on Classification and Terminology updated their approach to classifica­ tion of seizures in 2017 (Table 436-1). This system is based on the clinical features of seizures and associated electroencephalographic findings. Other potentially distinctive features such as etiology or cel­ lular substrate are not considered in this classification system, although this will undoubtedly change in the future as more is learned about the pathophysiologic mechanisms that underlie specific seizure types. A fundamental principle is that seizures may be either focal or gen­ eralized. Focal seizures originate within networks limited to one brain region (note that the term partial seizures is no longer used). Gener­ alized seizures arise within and rapidly engage networks distributed across both cerebral hemispheres. Focal seizures are often associated with structural abnormalities of the brain. In contrast, generalized seizures may result from cellular, biochemical, or structural abnormali­ ties with a more widespread distribution. There are exceptions in both cases, however. ■ ■FOCAL ONSET SEIZURES Focal seizures arise from a neuronal network either discretely localized within one brain region or more broadly distributed but still within a cerebral hemisphere. With the new classification system, the subcate­ gories of “simple focal seizures” and “complex focal seizures” have been eliminated. Instead, the classification emphasizes the effect on aware­ ness (intact or impaired) and nature of the onset (motor or nonmotor). Focal seizures can also evolve into generalized seizures. In the past, this was referred to as focal seizures with secondary generalization, but the new system relies on descriptions of the type of generalized seizures that evolve from the focal seizure. The routine interictal (i.e., between seizures) electroencephalogram (EEG) in patients with focal seizures is often normal or may show brief discharges termed epileptiform spikes, or sharp waves. Because focal seizures can arise from the medial temporal lobe or inferior frontal lobe (i.e., regions distant from the scalp), the EEG recorded during the seizure may be nonlocalizing. However, the region of seizure onset may be defined using surgically placed intracranial electrodes. TABLE 436-1  Classification of Seizuresa 1. Focal Onset (Can be further described as having intact or impaired awareness, motor or nonmotor onset, or evolve from focal to bilateral tonic clonic) 2. Generalized Onset a. Motor Tonic-clonic Other motor (e.g., atonic, myoclonic) b. Nonmotor (absence) 3. Unknown Onset Motor, nonmotor, or unclassified aBased on the 2017 International League Against Epilepsy classification of seizure types. (Data from RS Fisher et al: Operational classification of seizure types by the International League Against Epilepsy: Position Paper of the ILAE Commission for Classification and Terminology. Epilepsia 58:522, 2017.) Focal Seizures with Intact Awareness  Focal seizures can have motor manifestations (such as tonic, clonic, or myoclonic move­ ments) or nonmotor manifestations (such as sensory, autonomic, or emotional symptoms) without impairment of awareness. For example, a patient having a focal motor seizure arising from the right primary motor cortex near the area controlling hand movement will experi­ ence involuntary movements of the contralateral left hand. Since the cortical region controlling hand movement is immediately adjacent to the region for facial expression, the seizure may also cause abnormal movements of the face synchronous with the movements of the hand. The EEG recorded with scalp electrodes during the seizure (i.e., an ictal EEG) may show abnormal focal discharges over the corresponding area of cerebral cortex. Three additional features of focal motor seizures are worth noting. First, in some patients, the abnormal motor movements may begin in a very restricted region, such as the fingers, and gradually progress (over seconds to minutes) to include a larger portion of the extremity. This phenomenon, described by Hughlings Jackson and known as a “Jack­ sonian march,” represents the spread of seizure activity over a progres­ sively larger region of motor cortex. Second, patients may experience a localized paresis (Todd’s paralysis) for minutes to many hours in the involved region following the seizure. Third, in rare instances, the sei­ zure may continue for hours or days. This condition, termed epilepsia partialis continua, is often refractory to medical therapy. CHAPTER 436 Seizures and Epilepsy Focal seizures may also manifest as changes in somatic sensation (e.g., paresthesias), vision (flashing lights or formed hallucinations), equilibrium (sensation of falling or vertigo), or autonomic function (flushing, sweating, piloerection). Focal seizures arising from the tem­ poral lobe may also cause the sensation of acrid odors (e.g., bleach or burning rubber) or tastes (e.g., bitter or metallic), or hearing sounds (simple noise or complex sounds), or an epigastric sensation that rises to the head. Some patients describe intense internal feelings such as fear, a dreamlike sense, depersonalization, déjá vu, or illusions that objects are growing smaller (micropsia) or larger (macropsia). These subjective, “experiential” events that are not directly observable by someone else are referred to as auras. Focal Seizures with Impaired Awareness  Focal seizures may also be accompanied by a transient impairment of the patient’s abil­ ity to maintain normal contact with the environment. The patient is unable to respond appropriately to visual or verbal commands during the seizure and has impaired recollection or awareness of the ictal phase. The seizures frequently begin with an aura (i.e., a focal seizure without cognitive disturbance) that is stereotypic for the patient. The start of the ictal phase is often a motionless stare, which marks the onset of the period of impaired awareness. The impaired awareness may be accompanied by automatisms, involuntary movements that can involve basic behaviors, such as chewing, lip smacking, swallowing, or “picking” hand movements, or more elaborate behaviors, such as a display of emotion or running. The patient is typically disoriented fol­ lowing the seizure, and the transition to full recovery of consciousness may range from seconds to hours. Examination immediately following the seizure may show an anterograde amnesia or transient neurologic deficits (such as aphasia, hemi-neglect, or visual loss) caused by postic­ tal inhibition of the cortical regions most involved in the seizure. The range of potential clinical behaviors linked to focal seizures is so broad that extreme caution is advised before concluding that parox­ ysmal, stereotypic episodes of bizarre or atypical behavior are not due to seizure activity. In such cases, additional detailed EEG studies may be helpful. ■ ■EVOLUTION OF FOCAL SEIZURES TO GENERALIZED SEIZURES Focal seizures can spread to involve both cerebral hemispheres and produce a generalized seizure, usually of the tonic-clonic variety (discussed below). This evolution is observed frequently following focal seizures arising from a region in the frontal lobe but may also be associated with focal seizures occurring elsewhere in the brain. A focal seizure that evolves into a generalized seizure is often difficult to distinguish from a primary generalized onset tonic-clonic seizure because bystanders tend to emphasize the more dramatic, generalized convulsive phase of the seizure and overlook the more subtle, focal symptoms present at onset. In some cases, the focal onset of the seizure becomes apparent only when a careful history identifies a preceding aura. Often, however, the focal onset is not clinically evident and may be established only through careful EEG analysis. Nonetheless, distin­ guishing between these two entities is extremely important, because there are substantial differences in the evaluation and treatment of epilepsies characterized by focal versus generalized onset seizures. ■ ■GENERALIZED ONSET SEIZURES Generalized seizures arise at some point in the brain but immediately and rapidly engage neuronal networks in both cerebral hemispheres. Several types of generalized seizures have features that place them in distinctive categories and facilitate clinical diagnosis. Typical Absence Seizures  Typical absence seizures are character­ ized by sudden, brief lapses of consciousness without loss of postural control. The seizure usually lasts for only seconds, consciousness returns as suddenly as it was lost, and there is no postictal confusion. Although the brief loss of consciousness may be clinically inapparent or the sole manifestation of the seizure, absence seizures are usually accompanied by subtle, bilateral motor signs such as rapid blinking, chewing movements, or small-amplitude, clonic movements of the hands. PART 13 Neurologic Disorders Typical absence seizures are associated with a group of genetically determined epilepsies with onset usually in childhood (ages 4–10 years) or early adolescence and are the main seizure type in 15–20% of children with epilepsy. The seizures can occur hundreds of times per day, but the child may be unaware of or unable to convey their existence. Because the clinical signs of the seizures are subtle, especially to parents who may not have had previous experience with seizures, it is not surprising that the first clue to absence epilepsy is often unex­ plained “daydreaming” and a decline in school performance recog­ nized by a teacher. Indeed, absence epilepsy is often misdiagnosed as an attention deficit disorder. The electrophysiologic hallmark of typical absence seizures is a burst of generalized, symmetric, 3-Hz, spike-and-slow-wave discharges that begins and ends suddenly, superimposed on a normal EEG background. Periods of spike-and-slow-wave discharges lasting more than a few seconds usually correlate with clinical signs, but the EEG often shows many more brief bursts of abnormal cortical activity than suspected clinically. Hyperventilation tends to provoke these electro­ graphic discharges and even the seizures themselves and is routinely used when recording the EEG. Atypical Absence Seizures  Atypical absence seizures have fea­ tures that deviate both clinically and electrophysiologically from typical absence seizures. For example, the lapse of consciousness is usually longer and less abrupt in onset and cessation, and the seizure is accompanied by more obvious motor signs that may include focal or lateralizing features. The EEG shows a generalized, slow spikeand-slow-wave pattern with a frequency of ≤2.5 Hz, as well as other abnormal activity. Atypical absence seizures are usually associated with diffuse or multifocal structural abnormalities of the brain and therefore may accompany other signs of neurologic dysfunction, such as developmental delay. Furthermore, the seizures are less responsive to anticonvulsants compared to typical absence seizures. Generalized, Tonic-Clonic Seizures  Generalized onset tonicclonic seizures are the main seizure type in ~10% of all persons with epilepsy. They are also the most common seizure type resulting from metabolic derangements and are therefore frequently encountered in many different clinical settings. The seizure usually begins abruptly without warning, although some patients describe vague premonitory symptoms in the hours leading up to the seizure. This prodrome is distinct from the stereotypic auras associated with focal seizures that generalize. The initial phase of the seizure is usually tonic contraction of muscles throughout the body, accounting for several classic features of the event. Tonic contraction of the muscles of expiration and the larynx at the onset will produce a loud moan or “ictal cry.” Respirations are impaired, secretions pool in the oropharynx, and cyanosis devel­ ops. Contraction of the jaw muscles may cause biting of the tongue. A marked enhancement of sympathetic tone leads to increases in heart rate, blood pressure, and pupillary size. After 10–20 s, the tonic phase of the seizure typically evolves into the clonic phase, produced by the superimposition of periods of muscle relaxation on the tonic muscle contraction. The periods of relaxation progressively increase until the end of the ictal phase, which usually lasts no more than 1 min. The postictal phase is characterized by unresponsiveness, muscular flac­ cidity, and excessive salivation that can cause stridorous breathing and partial airway obstruction. Bladder or bowel incontinence may occur at this point. Patients gradually regain consciousness over minutes to hours, and, during this transition, there is typically a period of postictal confusion. Patients subsequently complain of headache, fatigue, and muscle ache that can last for many hours. The duration of impaired consciousness in the postictal phase can be extremely long (i.e., many hours) in patients with prolonged seizures or underlying central ner­ vous system (CNS) disease. The EEG during the tonic phase of the seizure shows a progressive increase in generalized low-voltage fast activity, followed by general­ ized high-amplitude, polyspike discharges. In the clonic phase, the high-amplitude activity is typically interrupted by slow waves to create a spike-and-slow-wave pattern. Generalized seizures tend to terminate synchronously over widespread brain regions. The postictal EEG shows diffuse suppression of all cerebral activity, followed by slowing that gradually recovers as the patient awakens. There are several variants of generalized motor seizures, including pure tonic and pure clonic seizures. Brief tonic seizures lasting only a few seconds are especially noteworthy since they are usually associated with specific epilepsy syndromes having mixed seizure phenotypes, such as the Lennox-Gastaut syndrome (discussed below). Atonic Seizures  Atonic seizures are characterized by sudden loss of postural muscle tone lasting 1–2 s. Consciousness is briefly impaired, but there is usually no postictal confusion. A very brief sei­ zure may cause only a quick head drop or nodding movement, whereas a longer seizure will cause the patient to collapse (hence, the less formal term, drop attacks). This can be extremely dangerous because there is a substantial risk of direct head injury with the fall. The EEG shows brief, generalized spike-and-wave discharges followed immediately by diffuse slow waves that correlate with the loss of muscle tone. Like pure tonic seizures, atonic seizures are usually seen in association with known epilepsy syndromes. Myoclonic Seizures  Myoclonus is a sudden and brief muscle contraction that may involve one part of the body or the entire body. A normal, common physiologic form of myoclonus is the sudden jerking movement observed while falling asleep. Pathologic myoclonus is most often seen in association with metabolic disorders, degenerative CNS diseases, or anoxic brain injury (Chap. 318). Although the distinction from other forms of myoclonus is imprecise, myoclonic seizures are true epileptic events because they are caused by cortical (vs subcorti­ cal or spinal) dysfunction. The EEG shows bilaterally synchronous spike-and-slow-wave discharges immediately prior to the movement and muscle artifact associated with the myoclonus. Myoclonic seizures usually coexist with other forms of generalized seizures but are the predominant feature of juvenile myoclonic epilepsy (JME) (discussed below). Epileptic Spasms  Epileptic spasms are characterized by a briefly sustained flexion or extension of predominantly proximal muscles, including truncal muscles. The EEG usually shows hypsarrhythmia, a chaotic background of diffuse, large-amplitude slow waves and irregu­ lar, multifocal spikes and sharp waves. During the clinical spasm, there is a marked suppression of the EEG background (the “electrodecre­ mental response”). The electromyogram (EMG) also reveals a charac­ teristic rhomboid pattern that may help distinguish spasms from brief tonic and myoclonic seizures. Epileptic spasms occur predominantly in infants and likely result from differences in neuronal function and connectivity in the immature versus mature CNS. EPILEPSY SYNDROMES Epilepsy syndromes are disorders in which epilepsy is a predominant feature, and there is sufficient evidence (e.g., through clinical, EEG, radiologic, or genetic observations) to suggest a common underlying mechanism. Three important epilepsy syndromes are listed below; addi­ tional examples with a known genetic basis are shown in Table 436-2. ■ ■JUVENILE MYOCLONIC EPILEPSY JME is a generalized seizure disorder of unknown cause that appears in early adolescence and is usually characterized by bilateral myoclonic jerks that may be single or repetitive. The myoclonic seizures are most frequent in the morning after awakening and can be provoked by sleep deprivation. Awareness is preserved unless the myoclonus is especially severe. Many patients also experience generalized tonic-clonic seizures, and up to one-third have absence seizures. Although complete remis­ sion is uncommon, the seizures usually respond well to appropriate antiseizure medication. There is often a family history of epilepsy, and genetic studies suggest a polygenic cause. ■ ■LENNOX-GASTAUT SYNDROME Lennox-Gastaut syndrome occurs in children and is defined by the following triad: (1) multiple seizure types (usually including general­ ized tonic-clonic, atonic, and atypical absence seizures); (2) an EEG with slow (<3 Hz) spike-and-wave discharges and a variety of other abnormalities; and (3) developmental delay. Lennox-Gastaut syndrome is associated with CNS disease or dysfunction from a variety of causes, including de novo mutations, developmental abnormalities, perinatal hypoxia/ischemia, trauma, infection, and other acquired lesions. The multifactorial nature of this syndrome suggests that it is a nonspecific response of the brain to diffuse neuronal dysfunction. Unfortunately, many patients have a poor prognosis due to the underlying CNS dis­ ease and the physical and psychosocial consequences of severe, poorly controlled epilepsy. Implanted neurostimulation devices (discussed below) are now being investigated for treatment of seizures in LennoxGastaut syndrome and other generalized epilepsies. ■ ■MESIAL TEMPORAL LOBE EPILEPSY SYNDROME Mesial temporal lobe epilepsy (MTLE) is the most common syndrome associated with focal seizures with impairment of consciousness and is an example of an epilepsy syndrome with distinctive clinical, EEG, and pathologic features (Table 436-3). High-resolution magnetic resonance imaging (MRI) can detect the characteristic hippocampal sclerosis that appears to be essential in the pathophysiology of MTLE for many patients (Fig. 436-1). Recognition of this syndrome is espe­ cially important because it tends to be refractory to treatment with anticonvulsants but responds well to surgical intervention. Advances in the understanding of basic mechanisms of epilepsy have come through studies of experimental models of MTLE, discussed below. THE CAUSES OF SEIZURES AND EPILEPSY Seizures are a result of a shift in the normal balance of excitation and inhibition within the CNS. Given the numerous properties that control neuronal excitability, it is not surprising that there are many ways to perturb this normal balance and, therefore, many different causes of both seizures and epilepsy. Three clinical observations emphasize how a variety of factors determine why certain conditions may cause sei­ zures or epilepsy in a given patient. 1. The normal brain can have a seizure under the appropriate circum­ stances, and there are differences between individuals in the suscepti­ bility or threshold for seizures. For example, seizures may be induced by high fever in children who are otherwise normal and who never develop other neurologic problems, including epilepsy. However, febrile seizures occur only in a relatively small proportion of chil­ dren. This implies there are various underlying endogenous factors that influence the threshold for having a seizure. Some of these fac­ tors are genetic, as a family history of epilepsy has a clear influence on the likelihood of seizures occurring in otherwise normal indi­ viduals. Normal development also plays an important role, because the brain appears to have different seizure thresholds at different maturational stages. 2. There are a variety of conditions that have an extremely high likeli­ hood of resulting in a chronic seizure disorder. One of the best exam­ ples of this is severe, penetrating head trauma, which is associated with up to a 45% risk of subsequent epilepsy. The high propensity for severe traumatic brain injury to lead to epilepsy suggests that the injury results in a long-lasting pathologic change in the CNS that transforms a presumably normal neuronal network into one that is abnormally hyperexcitable. This process is known as epileptogenesis, and the specific changes that result in a lowered seizure threshold can be considered epileptogenic factors. Other processes associated with epileptogenesis include stroke, infection, neurodegeneration, and abnormalities of CNS development. 3. Seizures are episodic. Seizures occur intermittently, and, depending CHAPTER 436 on the underlying cause, people with epilepsy may feel completely normal for months or years between seizures. This implies there are important provocative or precipitating factors that induce seizures in people with epilepsy. Similarly, precipitating factors are responsible for causing the single seizure in someone without epilepsy. Pre­ cipitants include those due to intrinsic physiologic processes, such as psychological or physical stress, sleep deprivation, or hormonal changes. They also include exogenous factors such as exposure to toxic substances, certain medications, and intermittent photic stimulation from strobe lights or some video games. Seizures and Epilepsy These observations emphasize the concept that the many causes of seizures and epilepsy result from a dynamic interplay between endoge­ nous factors, epileptogenic factors, and precipitating factors. The potential role of each needs to be considered when determining the appropriate management of a patient with seizures. For example, the identification of predisposing factors (e.g., family history of epilepsy) in a patient with febrile seizures may increase the necessity for closer follow-up and a more aggressive diagnostic evaluation. Finding an epileptogenic lesion may help in the estimation of seizure recurrence and duration of therapy. Removal or modification of a precipitating factor may be an effective and safer method for preventing further seizures than the pro­ phylactic use of anticonvulsant drugs. An emerging concept holds that underlying seizure risk itself fluctuates cyclically, potentially explaining why the same precipitating factor (e.g., sleep deprivation) can be well tolerated on some occasions but result in a seizure on others. ■ ■CAUSES ACCORDING TO AGE In practice, it is useful to consider the etiologies of seizures based on the age of the patient, because age is one of the most important factors determining both the incidence and the likely causes of seizures or epilepsy (Table 436-4). During the neonatal period and early infancy, potential causes include hypoxic-ischemic encephalopathy, trauma, CNS infection, congenital CNS abnormalities, and metabolic disorders. Babies born to mothers using neurotoxic drugs such as cocaine, heroin, or ethanol are susceptible to drug-withdrawal seizures in the first few days after delivery. Hypoglycemia and hypocalcemia, which can occur as secondary complications of perinatal injury, are also causes of early postnatal seizures. Seizures due to inborn errors of metabolism usu­ ally present once regular feeding begins, typically 2–3 days after birth. Pyridoxine (vitamin B6) deficiency, an important cause of neonatal seizures, is treated with pyridoxine replacement. Idiopathic or familial forms of benign neonatal seizures are also seen during this time. The most common seizures arising in late infancy and early child­ hood are febrile seizures, which are seizures associated with fevers but without evidence of CNS infection or other defined causes. The overall prevalence is 3–5% and even higher in some parts of the world such as Asia. Patients often have a family history of febrile seizures or epilepsy. Febrile seizures usually occur between 3 months and 5 years of age and have a peak incidence between 18 and 24 months. The typical scenario is a child who has a generalized, tonic-clonic seizure during a febrile illness in the setting of a common childhood infection such as otitis TABLE 436-2  Examples of Genes Associated with Epilepsy Syndromesa GENE (LOCUS) FUNCTION OF GENE CLINICAL SYNDROME COMMENTS CHRNA4 (20q13.2) Nicotinic acetylcholine receptor subunit; mutations cause alterations in Ca2+ flux through the receptor; this may reduce the amount of GABA release in presynaptic terminals Sleep-related hypermotor epilepsy (SHE); childhood onset; brief, nighttime seizures with prominent motor movements; often misdiagnosed as primary sleep disorder KCNQ2 (20q13.3) Voltage-gated potassium channel subunits; mutation in pore regions may cause a 20–40% reduction of potassium currents, which will lead to impaired repolarization Self-limited familial neonatal epilepsy; autosomal dominant inheritance; onset in first week of life in infants who are otherwise normal; remission usually within weeks to months; long-term epilepsy in 10–15% SCN1A (2q24.3) α-Subunit of a voltage-gated sodium channel; numerous mutations affecting sodium currents that cause either gain or loss of function; network effects appear related to expression in excitatory or inhibitory cells Very common cause of Dravet syndrome (severe myoclonic epilepsy of infancy) and some cases of Lennox-Gastaut syndrome. Also found in other syndromes, including genetic epilepsy with febrile seizures plus (GEFS+); autosomal dominant inheritance; presents with febrile seizures at median 1 year, which may persist >6 years, then variable seizure types not associated with fever PART 13 Neurologic Disorders LGI1 (10q24) Leucine-rich glioma-inactivated 1 gene; previous evidence for role in glial tumor progression; recent studies suggest an influence in the postnatal development of glutamatergic circuits in the hippocampus Autosomal dominant epilepsy with auditory features (ADEAF); a form of lateral temporal lobe epilepsy with auditory symptoms or aphasia as a major focal seizure manifestation; age of onset usually between 10 and 25 years DEPDC5 (22q12.2) Disheveled, Egl-10, and pleckstrin domain containing protein 5; exerts an inhibitory effect on mammalian target of rapamycin (mTOR)–mediated processes, such as cell growth and proliferation Autosomal dominant familial focal epilepsy with variable foci (FFEVF); family members have seizures originating from different cortical regions; neuroimaging usually normal but may harbor subtle malformations; recent studies also suggest association with benign epilepsy with centrotemporal spikes GRIN2A (16p13.2) Encodes NMDA receptor (NMDAR) subunit GluN2A Spectrum of phenotypes ranging from benign childhood epilepsy with centrotemporal spikes (BECTS) to epilepsy-aphasia syndromes such as Landau-Kleffner syndrome (LKS) and other epileptic encephalopathies CDKL-5 (Xp22.13) Encodes cyclin-dependent kinase-like 5 (CDKL-5), a serine-threonine kinase involved in neural maturation and synaptogenesis CDKL-5 deficiency disorder (CDD) results from pathogenic mutation in the CDKL5 gene that causes absence or nonfunctional CDKL-5 protein. CDD is a severe developmental epileptic encephalopathy characterized by very-earlyonset seizures. X-linked, affects females more than males SLC2A1 (1p34.2) Glucose transporter protein type 1 (GLUT1); transports glucose across the blood-brain barrier Loss of function of one allele leads to GLUT1 deficiency, a severe metabolic encephalopathy including intractable epilepsy, complex motor dysfunction, and intellectual disability. Milder GLUT1 deficiency causes a combination of movement disorder (paroxysmal exertional dyskinesia) and epilepsy with prominent absence seizures, though intellect is often normal CSTB (21q22.3) Cystatin B, a noncaspase cysteine protease inhibitor; normal protein may block neuronal apoptosis by inhibiting caspases directly or indirectly (via cathepsins), or controlling proteolysis Progressive myoclonus epilepsy (PME) (Unverricht-Lundborg disease); autosomal recessive inheritance; age of onset between 6 and 15 years, myoclonic seizures, ataxia, and progressive cognitive decline; brain shows neuronal degeneration EPM2A (6q24) Laforin, a protein tyrosine phosphatase (PTP); involved in glycogen metabolism and may have antiapoptotic activity Progressive myoclonus epilepsy (Lafora’s disease); autosomal recessive inheritance; age of onset 6–19 years, death within 10 years; brain degeneration associated with polyglucosan intracellular inclusion bodies in numerous organs Doublecortin (Xq21-24) Doublecortin, expressed primarily in frontal lobes; directly regulates microtubule polymerization and bundling Classic lissencephaly associated with severe mental retardation and seizures in males; subcortical band heterotopia with more subtle findings in females (presumably due to random X inactivation); X-linked dominant aThe first seven syndromes listed in the table (SHE, benign familial neonatal convulsions, GEFS+, ADEAF, FFEVF, BECTS, LKS, CDD) are examples of genetic epilepsies associated with identified gene mutations. The last three syndromes are examples of the numerous Mendelian disorders in which seizures are one part of the phenotype. Abbreviation: GABA, γ-aminobutyric acid. Rare; first identified in a large Australian family; other families found to have mutations in CHRNA2 or CHRNB2, and some families appear to have mutations at other loci Rare; other families found to have mutations in KCNQ3; sequence and functional homology to KCNQ1, mutations of which cause long QT syndrome and a cardiac-auditory syndrome Incidence of Dravet syndrome is 1 in 20,000 births, and de novo SCN1A mutation is found in ~80% of cases. Incidence in GEFS+ uncertain; identified in other families with mutations in other sodium channel subunits (SCN2B and SCN2A) and GABAA receptor subunit (GABRG2 and GABRA1); significant phenotypic heterogeneity within same family, including members with febrile seizures only. Avoid sodium channel–blocking antiseizure medications Mutations found in up to 50% of families containing two or more subjects with focal epilepsy with ictal auditory symptoms, suggesting that at least one other gene may underlie this syndrome Study of families with the limited number of affected members revealed mutations in ~12% of families; thus, may be a relatively common cause of lesion-negative focal epilepsies with suspected genetic basis. Also associated with mutations in the GATOR1 genes NPRL2 and NPRL3 Complex inheritance is implicated, and studies have shown considerable inter- and intrafamilial phenotypic variability and incomplete penetrance Ganaxolone is a recently approved antiseizure drug that has been shown to significantly reduce CDD-associated seizures Milder forms of epilepsy due to GLUT1 deficiency may respond to standard antiseizure medications, but the gold standard treatment for refractory forms is the ketogenic diet, which bypasses defective glucose transport to provide an alternative energy supply to the brain Overall rare, but relatively common in Finland and western Mediterranean (>1 in 20,000); precise role of cystatin B in human disease unknown, although mice with null mutations of cystatin B have similar syndrome Most common PME in southern Europe, Middle East, northern Africa, and Indian subcontinent; genetic heterogeneity; unknown whether seizure phenotype due to degeneration or direct effects of abnormal laforin expression Relatively rare but of uncertain incidence; recent increased ascertainment due to improved imaging techniques; relationship between migration defect and seizure phenotype unknown TABLE 436-3  Characteristics of the Mesial Temporal Lobe Epilepsy Syndrome History History of febrile seizures Rare generalized seizures Family history of epilepsy Seizures may remit and reappear Early onset Seizures often intractable Clinical Observations Aura common Postictal disorientation Behavioral arrest/stare Memory loss Complex automatisms Dysphasia (with focus in dominant hemisphere) Unilateral posturing   Laboratory Studies Unilateral or bilateral anterior temporal spikes on EEG Hypometabolism on interictal PET Hyperperfusion on ictal SPECT Material-specific memory deficits on intracarotid amobarbital (Wada) test MRI Findings Small hippocampus with increased signal on T2-weighted sequences and loss of trilaminar hippocampal internal architecture Small temporal lobe Enlarged temporal horn Pathologic Findings Highly selective loss of specific cell populations within hippocampus in most cases, granule cell layer dispersion, gliosis Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging; PET, positron emission tomography; SPECT, single-photon emission computed tomography. media, respiratory infection, or gastroenteritis. The seizure is likely to occur during the rising phase of the temperature curve (i.e., during the first day) rather than well into the course of the illness. A simple febrile seizure is a single, isolated event, brief, and symmetric in appearance. Complex febrile seizures are characterized by repeated seizure activity, a duration >15 minutes, or by focal features. Approximately one-third FIGURE 436-1  Mesial temporal lobe epilepsy. The electroencephalogram and seizure semiology were consistent with a left temporal lobe focus. This coronal high-resolution T2-weighted fast spin echo magnetic resonance image obtained at 3 Tesla is at the level of the hippocampal bodies and shows abnormal high signal intensity, blurring of internal laminar architecture, and reduced size of the left hippocampus (arrow) relative to the right. This triad of imaging findings is consistent with hippocampal sclerosis. TABLE 436-4  Causes of Seizures Neonates (<1 month) Perinatal hypoxia and ischemia Intracranial hemorrhage and trauma CNS infection Metabolic disturbances (hypoglycemia, hypocalcemia, hypomagnesemia, pyridoxine deficiency) Drug withdrawal Developmental disorders Genetic disorders Infants and children (>1 month and <12 years) Febrile seizures Genetic disorders (metabolic, degenerative, primary epilepsy syndromes) CNS infection Developmental disorders Trauma CHAPTER 436 Adolescents (12–18 years) Trauma Genetic disorders Infection Illicit drug use Brain tumor Seizures and Epilepsy Young adults (18–35 years) Trauma Alcohol withdrawal Illicit drug use Brain tumor Autoantibodies Older adults (>35 years) Cerebrovascular disease Brain tumor Alcohol withdrawal Metabolic disorders (uremia, hepatic failure, electrolyte abnormalities, hypoglycemia, hyperglycemia) Alzheimer’s disease and other degenerative CNS diseases Autoantibodies Abbreviation: CNS, central nervous system. of patients with febrile seizures will have a recurrence, but <10% have three or more episodes. Recurrences are much more likely when the febrile seizure occurs in the first year of life. Simple febrile seizures are not associated with increased risk of developing epilepsy, while complex febrile seizures have a risk of 2–5%; other risk factors include the presence of preexisting neurologic deficits and a family history of nonfebrile seizures. Childhood marks the age at which many of the well-defined epilepsy syndromes present. Some children who are otherwise normal develop idiopathic, generalized tonic-clonic seizures without other features that fit into specific syndromes. Temporal lobe epilepsy usually presents in childhood and may be related to mesial temporal lobe sclerosis (as part of the MTLE syndrome) or other focal abnormalities, such as cortical dysgenesis. Other types of focal seizures, including those that evolve into generalized seizures, may be late manifestations of a developmen­ tal disorder, an acquired lesion such as head trauma, CNS infection (e.g., viral encephalitis), or a CNS tumor. The period of adolescence and early adulthood is one of transition during which the idiopathic or genetically based epilepsy syndromes, including JME and juvenile absence epilepsy, become less common, while epilepsies secondary to acquired CNS lesions begin to predomi­ nate. Seizures that arise in patients in this age range may be associated with head trauma, CNS infections (including parasitic infections such as cysticercosis), brain tumors, congenital CNS abnormalities, illicit drug use, or alcohol withdrawal. Autoantibodies directed against CNS antigens such as potassium channels or glutamate receptors are a cause of epilepsy that also begins to appear in this age group (although cases of autoimmunity are being increasingly described in the pediatric pop­ ulation), including patients without an identifiable cancer. This etiol­ ogy should be suspected when a previously normal individual presents with fulminant seizures, especially when combined with psychiatric symptoms and changes in cognitive function. Head trauma is a common cause of epilepsy in adolescents and adults. The head injury can be caused by a variety of mechanisms, and the likelihood of developing epilepsy is strongly correlated with the severity of the injury. A patient with a penetrating head wound, depressed skull fracture, intracranial hemorrhage, or prolonged post­ traumatic coma or amnesia has a 30–50% risk of developing epilepsy, whereas a patient with a closed head injury and cerebral contusion has a 5–25% risk. Recurrent seizures usually develop within 1 year after head trauma, although intervals of >10 years are well known. In controlled studies, mild head injury, defined as a concussion with amnesia or loss of consciousness of <30 min, was found to be associ­ ated with only a slightly increased likelihood of epilepsy. Nonetheless, some patients experience focal seizures within hours or days of a mild head injury and subsequently develop chronic seizures of the same type; such cases may represent rare examples of epilepsy resulting from mild head injury. PART 13 Neurologic Disorders The causes of seizures in older adults include cerebrovascular disease, trauma (including subdural hematoma), CNS tumors, and degenerative diseases. Cerebrovascular disease may account for ~50% of new cases of epilepsy in patients >65 years. Acute poststroke seizures (i.e., occurring within the first 24 h after acute stroke) are more com­ mon after hemorrhagic strokes compared to ischemic strokes. Chronic seizures typically appear months to years after the initial event and are associated with all forms of stroke. Metabolic disturbances such as electrolyte imbalance, hypo- or hyperglycemia, renal failure, and hepatic failure may cause seizures at any age. Similarly, endocrine disorders, hematologic disorders, vas­ culitides, and many other systemic diseases may cause seizures over a broad age range. Many medications and abused substances can precipi­ tate seizures as well (Table 436-5). BASIC MECHANISMS ■ ■MECHANISMS OF SEIZURE INITIATION AND PROPAGATION Focal seizure activity can begin in a discrete region of cortex and then slowly invade the surrounding regions. The hallmark of an established seizure is typically an electrographic “spike” due to intense near-simultaneous firing of many local excitatory neurons, resulting in an apparent hypersynchronization of the excitatory bursts across a relatively large cortical region. The bursting activity in individual neu­ rons (the “paroxysmal depolarization shift”) is caused by a relatively long-lasting depolarization of the neuronal membrane due to influx of extracellular calcium (Ca2+), which leads to the opening of voltagedependent sodium (Na+) channels, influx of Na+, and generation of repetitive action potentials. This is followed by a hyperpolarizing afterpotential mediated by γ-aminobutyric acid (GABA) receptors or potassium (K+) channels, depending on the cell type. The synchronized bursts from enough neurons result in summation of field potentials producing a spike discharge on the EEG. The spreading seizure wavefront is thought to slow and ultimately halt by intact hyperpolarization and a “surround” inhibition created by feedforward activation of inhibitory neurons. With sufficient activation, there is a recruitment of surrounding neurons via a number of synaptic and nonsynaptic mechanisms, including (1) an increase in extracel­ lular K+, which blunts hyperpolarization and depolarizes neighboring neurons; (2) accumulation of Ca2+ in presynaptic terminals, leading to enhanced neurotransmitter release; (3) depolarization-induced activa­ tion of the N-methyl-d-aspartate (NMDA) subtype of the excitatory amino acid receptor, which causes additional Ca2+ influx and neuronal activation; and (4) ephaptic interactions related to changes in tissue osmolarity and cell swelling. The recruitment of a sufficient number of neurons leads to the propagation of excitatory currents into contiguous areas via local cortical connections and to more distant areas via long commissural pathways such as the corpus callosum. Many factors control neuronal excitability, and thus, there are many potential mechanisms for altering a neuron’s propensity to have TABLE 436-5  Drugs and Other Substances That Can Cause Seizures Alkylating agents (e.g., busulfan, chlorambucil) Antimalarials (chloroquine, mefloquine) Antimicrobials/antivirals   β-Lactam and related compounds   Quinolones   Acyclovir   Isoniazid   Ganciclovir Anesthetics and analgesics   Meperidine   Fentanyl   Tramadol   Local anesthetics Dietary supplements   Ephedra (ma huang)   Gingko Immunomodulatory drugs   Cyclosporine   OKT3 (monoclonal antibodies to T cells)   Tacrolimus   Interferons Psychotropics   Antidepressants (e.g., bupropion)   Antipsychotics (e.g., clozapine)   Lithium Radiographic contrast agents Drug withdrawal   Alcohol   Baclofen   Barbiturates (short-acting)   Benzodiazepines (short-acting)   Zolpidem Drugs of abuse   Amphetamine   Cocaine   Phencyclidine   Methylphenidate Flumazenila aIn benzodiazepine-dependent patients. bursting activity. Mechanisms intrinsic to the neuron include changes in the conductance of ion channels, response characteristics of mem­ brane receptors, cytoplasmic buffering, second-messenger systems, and protein expression as determined by gene transcription, transla­ tion, and posttranslational modification. Mechanisms extrinsic to the neuron include changes in the amount or type of neurotransmitters present at the synapse, modulation of receptors by extracellular ions and other molecules, and temporal and spatial properties of synaptic and nonsynaptic input. Glial cells, such as astrocytes and oligodendro­ cytes, have an important role in many of these mechanisms as well. Certain recognized causes of seizures are explained by these mecha­ nisms. For example, accidental ingestion of domoic acid, an analogue of glutamate (the principal excitatory neurotransmitter in the brain) produced by naturally occurring microscopic algae, causes profound seizures via direct activation of excitatory amino acid receptors throughout the CNS. Penicillin, which can lower the seizure threshold in humans and is a potent convulsant in experimental models, reduces inhibition by antagonizing the effects of GABA at its receptor. The basic mechanisms of other precipitating factors of seizures, such as sleep deprivation, fever, alcohol withdrawal, hypoxia, and infection, are not as well understood but presumably involve analogous perturbations in neuronal excitability. Similarly, the endogenous factors that determine an individual’s seizure threshold may relate to these properties as well. Knowledge of the mechanisms responsible for initiation and propa­ gation of most generalized seizures (including tonic-clonic, myoclonic, and atonic types) remains rudimentary and reflects the limited under­ standing of the connectivity of the brain at a systems level. Much more is understood about the origin of generalized spike-and-wave discharges in absence seizures. These appear to be related to oscilla­ tory rhythms normally generated during sleep by circuits connecting the thalamus and cortex. This oscillatory behavior involves an interac­ tion between GABAB receptors, T-type Ca2+ channels, and K+ channels located within the thalamus. Pharmacologic studies indicate that mod­ ulation of these receptors and channels can induce absence seizures, and there is good evidence that the genetic forms of absence epilepsy may be associated with mutations of components of this system. ■ ■MECHANISMS OF EPILEPTOGENESIS Epileptogenesis refers to the transformation of a normal neuronal network into one that is chronically hyperexcitable. There is often a delay of months to years between an initial CNS injury such as trauma, stroke, or infection and the first clinically evident seizure. The injury appears to initiate a process that gradually lowers the seizure threshold in the affected region until a spontaneous seizure occurs. In many genetic and idiopathic forms of epilepsy, epileptogenesis is presumably determined by developmentally regulated events. Pathologic studies of the hippocampus from patients with temporal lobe epilepsy suggest that some forms of epileptogenesis are related to structural changes in neuronal networks. For example, many patients with MTLE have a highly selective loss of neurons that normally con­ tribute to inhibition of the main excitatory neurons within the dentate gyrus. There is also evidence that, in response to the loss of neurons, there is reorganization of surviving neurons in a way that affects the excitability of the network. Some of these changes can be seen in experi­ mental models of prolonged electrical seizures or traumatic brain injury. Thus, an initial injury such as head injury may lead to a focal region of structural change that causes local hyperexcitability. The local hyperex­ citability leads to further structural changes that evolve over time until the focal lesion produces clinically evident seizures. Similar models have provided strong evidence for long-term alterations in intrinsic, bio­ chemical properties of cells within the network such as chronic changes in glutamate or GABA receptor function. Induction of inflammatory cascades may be a critical factor in these processes as well. ■ ■GENETIC CAUSES OF EPILEPSY An area of ongoing progress in epilepsy research has been the iden­ tification of genetic mutations associated with a variety of epilepsy syndromes (Table 436-2). Although most of the mutations identified to date cause rare forms of epilepsy, their discovery has led to extremely important conceptual advances. For example, it appears that many of the inherited epilepsies are due to mutations affecting ion channel function. These syndromes are therefore part of the larger group of channelopathies causing paroxysmal disorders such as cardiac arrhyth­ mias, episodic ataxia, periodic weakness, and familial hemiplegic migraine. Other gene mutations are proving to be associated with path­ ways influencing CNS development, synaptic physiology, or neuronal homeostasis. De novo and somatic mutations may explain a significant proportion of these syndromes, especially those with onset in early childhood. A current challenge is to identify the multiple susceptibility genes that underlie the more common forms of idiopathic epilepsies. Ion channel mutations and copy number variants may be pathogenic in a subset of these patients. ■ ■MECHANISMS OF ACTION OF ANTISEIZURE DRUGS Antiseizure drugs appear to act primarily by blocking the initiation or spread of seizures. This occurs through a variety of mechanisms that modify the activity of ion channels or neurotransmitters, and in most cases, the drugs have pleiotropic effects. The mechanisms include inhi­ bition of Na+-dependent action potentials in a frequency-dependent manner (e.g., phenytoin, carbamazepine, lamotrigine, topiramate, zonisamide, lacosamide, rufinamide, cenobamate), inhibition of voltage-gated Ca2+ channels (phenytoin, gabapentin, pregabalin), facili­ tating the opening of potassium channels (ezogabine), attenuation of glutamate activity (lamotrigine, topiramate, felbamate, perampanel), potentiation of GABA receptor function (benzodiazepines, barbitu­ rates), increase in the availability of GABA (valproic acid, gabapentin, tiagabine), and modulation of release of synaptic vesicles (levetirace­ tam, brivaracetam). Two of the effective drugs for absence seizures, ethosuximide and valproic acid, probably act by inhibiting T-type Ca2+ channels in thalamic neurons. Cannabidiol (CBD), a derivative of can­ nabis plants, is effective for reducing seizures in children with Dravet syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis but does not act through endogenous cannabinoid receptors. Rather, CBD has a multimodal mechanism of action involving modulation of intracellular calcium via G protein–coupled receptor 55, extracellular calcium influx via transient receptor potential vanilloid type 1 (TRPV1) channels, and adenosine-mediated signaling. Fenfluramine is an amphetamine deriv­ ative that probably exerts its antiseizure effect by inhibiting serotonin reuptake and increasing extracellular levels. Ganaxolone is a synthetic analogue of allopregnanolone and an allosteric modulator of GABAA receptors that reduces seizures associated with cyclin-dependent kinase-like 5 (CDKL-5) deficiency disorder. CHAPTER 436 Seizures and Epilepsy In contrast to the relatively large number of antiseizure drugs that can attenuate seizure activity, there are currently no drugs known to prevent the formation of a seizure focus following CNS injury. Eventual development of such “antiepileptogenic” drugs will provide means of preventing the emergence of epilepsy following injuries such as head trauma, stroke, and CNS infection. APPROACH TO THE PATIENT Seizure When a patient presents shortly after a seizure, the first priorities are attention to vital signs, respiratory and cardiovascular support, and treatment of seizures if they resume (see “Treatment: Seizures and Epilepsy”). Life-threatening conditions such as CNS infection, metabolic derangement, or drug toxicity must be recognized and managed appropriately. When the patient is not acutely ill, the evaluation will initially focus on whether there is a history of earlier seizures (Fig. 436-2). If this is the first seizure, then the emphasis will be to (1) establish whether the reported episode was a seizure rather than another paroxysmal event, (2) determine the cause of the seizure by identi­ fying risk factors and precipitating events, and (3) decide whether antiseizure drug therapy is required in addition to treatment for any underlying illness. In the patient with prior seizures or a known history of epilepsy, the evaluation is directed toward (1) identification of the underly­ ing cause and precipitating factors, and (2) determination of the adequacy of the patient’s current therapy. ■ ■HISTORY AND EXAMINATION The first goal is to determine whether the event was truly a seizure. A detailed history is essential, because in many cases the diagnosis of a seizure is based solely on clinical grounds—the examination and labora­ tory studies are often normal. Questions should focus on the symptoms before, during, and after the episode to differentiate a seizure from other paroxysmal events (see “Differential Diagnosis of Seizures” below). Seizures frequently occur out-of-hospital, and the patient may be unaware of the ictal and immediate postictal phases; thus, witnesses to the event should be interviewed carefully. The history should also focus on risk factors and predisposing events. Clues for a predisposition to seizures include a history of febrile seizures, a family history of seizures, and, of particular importance, earlier auras or brief seizures not recognized as such. Epileptogenic factors such as prior head trauma, stroke, tumor, or CNS infection should be identified. In children, a careful assessment of developmental Adult Patient with a Seizure History Physical examination Exclude Syncope Transient ischemic attack Migraine Acute psychosis Other causes of episodic cerebral dysfunction History of epilepsy; currently treated with antiseizure drugs PART 13 Neurologic Disorders Assess: adequacy of antiseizure drug therapy Side effects   Serum levels Consider CBC Electrolytes, calcium, magnesium Serum glucose Liver and renal function tests Urinalysis Toxicology screen Normal Abnormal or change in neurologic examination Treat identifiable metabolic abnormalities Assess cause of   neurologic change Therapeutic antiseizure drug levels Subtherapeutic antiseizure drug levels Increase antiseizure drug therapy to maximum tolerated dose; consider alternative antiepileptic drugs Appropriate increase or resumption of dose Yes No Consider: Mass lesion; stroke; CNS infection; trauma; degenerative disease Treat underlying disorder Consider: Antiseizure drug therapy FIGURE 436-2  Evaluation of the adult patient with a seizure. CBC, complete blood count; CNS, central nervous system; CT, computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging. milestones may provide evidence for underlying CNS disease. Precipi­ tating factors such as sleep deprivation, systemic diseases, electrolyte or metabolic derangements, acute infection, drugs that lower the seizure threshold (Table 436-5), or alcohol or illicit drug use should also be identified. The general physical examination includes a search for signs of infection or systemic illness. Careful examination of the skin may No history of epilepsy Laboratory studies CBC Electrolytes, calcium, magnesium Serum glucose Liver and renal function tests Urinalysis Toxicology screen Negative metabolic screen Positive metabolic screen or symptoms/signs suggesting a metabolic or infectious disorder MRI scan and EEG Further workup   Lumbar puncture   Cultures   Endocrine studies   CT   MRI if focal    features present Focal features of seizures Focal abnormalities on clinical or lab examination Other evidence of neurologic dysfunction Treat underlying metabolic abnormality Consider: Antiseizure drug therapy Idiopathic seizures Consider: Antiseizure drug therapy reveal signs of neurocutaneous disorders, such as tuberous sclerosis or neurofibromatosis, or chronic liver or renal disease. A finding of organomegaly may indicate a metabolic storage disease, and limb asymmetry may provide a clue to brain injury early in development. Signs of head trauma and use of alcohol or illicit drugs should be sought. Auscultation of the heart and carotid arteries may identify an abnormality that predisposes to cerebrovascular disease. All patients require a complete neurologic examination, with par­ ticular emphasis on eliciting signs of cerebral hemispheric disease (Chap. 433). Careful assessment of mental status (including memory, language function, and abstract thinking) may suggest lesions in the anterior frontal, parietal, or temporal lobes. Testing of visual fields will help screen for lesions in the optic pathways and occipital lobes. Screening tests of motor function such as pronator drift, deep tendon reflexes, gait, and coordination may suggest lesions in motor (frontal) cortex, and cortical sensory testing (e.g., double simultaneous stimula­ tion) may detect lesions in the parietal cortex. ■ ■LABORATORY STUDIES Routine blood studies are indicated to identify the more common metabolic causes of seizures such as abnormalities in electrolytes, glu­ cose, calcium, or magnesium, and hepatic or renal disease. A screen for toxins in blood and urine should also be obtained from all patients in appropriate risk groups, especially when no clear precipitating factor has been identified. A lumbar puncture is indicated if there is any sus­ picion of meningitis or encephalitis, and it is mandatory in all patients infected with HIV, even in the absence of symptoms or signs suggesting infection. Testing for autoantibodies in the serum and cerebrospinal fluid (CSF) should be considered in patients presenting with fulminant onset of epilepsy associated with other abnormalities such as psychiat­ ric symptoms or cognitive disturbances (Chap. 99). ■ ■ELECTROPHYSIOLOGIC STUDIES The electrical activity of the brain (the EEG) is easily recorded from electrodes placed on the scalp. The potential difference between pairs of electrodes on the scalp (bipolar derivation) or between individual scalp electrodes and a relatively inactive common reference point (ref­ erential derivation) is amplified and displayed on a computer monitor. Digital systems allow the EEG to be displayed with any desired format and to be manipulated for more detailed analysis, and they also enable computational algorithms that can automatically detect certain abnor­ malities. The characteristics of the nor­ mal EEG depend on the patient’s age and level of arousal. The rhythmic activity normally recorded represents the post­ synaptic potentials of vertically oriented pyramidal cells of the cerebral cortex and is characterized by its frequency. In normal awake adults lying quietly with the eyes closed, an 8- to 13-Hz alpha rhythm is seen posteriorly in the EEG, intermixed with a variable amount of generalized faster (beta) activity (>13 Hz); the alpha rhythm is attenuated when the eyes are opened (Fig. 436-3). During drowsiness and light sleep, slower activity in the theta (4–7 Hz) and delta (<4 Hz) ranges becomes more conspicuous. Eyes open Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 A B F3-A1 C3-A1 All patients who have a possible sei­ zure disorder should be evaluated with an EEG as soon as possible. In the evalu­ ation of a patient with suspected epilepsy, the presence of electrographic seizure activity during the clinical event (i.e., abnormal, repetitive, rhythmic activity having a discrete onset and termination) clearly establishes the diagnosis. The EEG is always abnormal during general­ ized tonic-clonic seizures. The absence of electrographic seizure activity does not exclude a seizure disorder, however, because focal seizures may originate from a region of the cortex that cannot be detected by standard scalp electrodes. Because seizures are typically infrequent and unpredictable, it is often not possible P3-A1 O1-A1 F4-A2 C4-A2 P4-A2 O2-A2 C D FIGURE 436-3  Electroencephalograms. A. Normal electroencephalogram (EEG) showing a posteriorly situated 9-Hz alpha rhythm that attenuates with eye opening. B. Abnormal EEG showing irregular diffuse slow activity in an obtunded patient with encephalitis. C. Irregular slow activity in the right central region, on a diffusely slowed background, in a patient with a right parietal glioma. D. Periodic complexes occurring once every second in a patient with CreutzfeldtJakob disease. Horizontal calibration: 1 s; vertical calibration: 200 μV in A, 300 μV in other panels. In this and the following figure, electrode placements are indicated at the left of each panel and accord with the international 10–20 system. A, earlobe; C, central; F, frontal; Fp, frontal polar; O, occipital; P, parietal; T, temporal. Right-sided placements are indicated by even numbers, left-sided placements by odd numbers, and midline placements by Z. (Reproduced with permission from MJ Aminoff: Aminoff’s Electrodiagnosis in Clinical Neurology, 6th ed. Oxford: Elsevier Saunders, 2012.) to obtain the EEG during a clinical event. In such situations, activating procedures are generally undertaken to provoke abnormalities while the EEG is recorded. These procedures commonly include hyperven­ tilation, photic stimulation, sleep, and sleep deprivation on the night prior to the recording. Continuous monitoring for prolonged periods in video-EEG telemetry units for hospitalized patients or the use of portable equipment to record the EEG continuously for ≥24 h in ambu­ latory patients has made it easier to capture the electrophysiologic correlates of clinical events. Video-EEG telemetry is now a routine approach for the accurate diagnosis of epilepsy in patients with poorly characterized events or seizures that are difficult to control. A variety of technologies, including sub-scalp EEG devices, are being developed to enable ultra-long-term ambulatory recordings of brain activity, analo­ gous to implanted loop recorders used to capture infrequent cardiac arrhythmias. The EEG may also be helpful in the interictal period by showing certain abnormalities that are highly supportive of the diagnosis of epilepsy. Such epileptiform activity consists of bursts of abnormal dis­ charges containing spikes or sharp waves. The presence of epileptiform activity is not entirely specific for epilepsy, but it has a much greater prevalence in patients with epilepsy than in other individuals. How­ ever, even in an individual who is known to have epilepsy, the initial routine interictal EEG may be normal 50–80% of the time. Thus, the EEG has limited sensitivity and cannot establish the diagnosis of epi­ lepsy in many cases. CHAPTER 436 Seizures and Epilepsy The EEG is also used for classifying seizure disorders and aiding in the selection of antiseizure medications (Fig. 436-4). For example, episodic generalized spike-wave activity is usually seen in patients with typical absence epilepsy and may be seen with other generalized epilepsy syndromes. Focal interictal epileptiform discharges would support the diagnosis of a focal seizure disorder such as temporal lobe epilepsy or frontal lobe seizures, depending on the location of the discharges. F3-C3 C3-P3 P3-O1 F4-C4 C4-P4 P4-O2 T3-CZ CZ-T4 Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 F3-C3 C3-P3 P3-O1 F4-C4 C4-P4 P4-O2 T3-CZ CZ-T4 A Fp1-F7 F7-T3 PART 13 Neurologic Disorders T3-T5 T5-O1 Fp2-F8 F8-T4 T4-T6 T6-O2 B Fp1-A1 F7-A1 T3-A1 T5-A1 Fp2-A2 F8-A2 T4-A2 T6-A2 C FIGURE 436-4  Electrographic seizures. A. Onset of a tonic seizure showing generalized repetitive sharp activity with synchronous onset over both hemispheres. B. Burst of repetitive spikes occurring with sudden onset in the right temporal region during a clinical spell characterized by transient impairment of awareness. C. Generalized 3-Hz spike-wave activity occurring synchronously over both hemispheres during an absence seizure. Horizontal calibration: 1 s; vertical calibration: 400 μV in A, 200 μV in B, and 750 μV in C. (Reproduced with permission from MJ Aminoff: Aminoff’s Electrodiagnosis in Clinical Neurology, 6th ed. Oxford: Elsevier Saunders, 2012.) The routine scalp EEG may also be used to assess the prognosis of seizure disorders; in general, a normal EEG implies a better prognosis, whereas an abnormal background or frequent epileptiform activity suggests a worse outcome. Unfortunately, the EEG has not proved to be useful in predicting which patients with predisposing conditions such as head injury or brain tumor will go on to develop epilepsy, because in such circumstances, epileptiform activity is commonly encountered regardless of whether seizures occur. High-density EEG provides higher resolution localization by utiliz­ ing up to 257 scalp electrodes, as opposed to the 21 electrodes used in a standard EEG recording. This makes use of scalp voltage field data to determine dipole location, orientation, and propagation. EEG source imaging (ESI) permits visualization of these dipoles by mapping them onto a three-dimensional model that is co-registered on brain MRI. Magnetoencephalography (MEG) provides another way of look­ ing noninvasively at cortical activity. Instead of measuring electrical activity of the brain, it measures the small magnetic fields that are gen­ erated by this activity. The epileptiform activity seen on MEG can be analyzed, and its source in the brain can be estimated using a variety of mathematical techniques. These source estimates can then be plotted on an anatomic image of the brain such as an MRI (discussed below) to generate a magnetic source image (MSI). MSI can be useful to localize potential seizure foci. ■ ■BRAIN IMAGING Almost all patients with new-onset seizures should have a brain imag­ ing study to determine whether there is an underlying structural abnormality that is responsible. The only potential exception to this rule is children who have an unambiguous history and examination suggestive of a benign, generalized seizure disorder such as absence epilepsy. MRI has been shown to be superior to computed tomography (CT) for the detection of cerebral lesions associated with epilepsy. In some cases, MRI will identify lesions such as tumors, vascular malfor­ mations, or other pathologies that need urgent therapy. The availability of newer MRI methods, such as three-dimensional structural imaging at submillimeter resolution, has increased the sensitivity for detection of abnormalities of cortical architecture, including hippocampal atro­ phy associated with mesial temporal sclerosis, as well as abnormalities of neuronal migration. In such cases, the findings provide an explana­ tion for the patient’s seizures and point to the need for chronic antisei­ zure drug therapy or possible surgical resection. In the patient with a suspected CNS infection or mass lesion, CT scanning should be performed emergently when MRI is not immedi­ ately available. Otherwise, it is usually appropriate to obtain an MRI study within a few days of the initial evaluation. Functional imaging procedures such as positron emission tomography (PET) and singlephoton emission computed tomography (SPECT) are also used to eval­ uate certain patients with medically refractory seizures (Table 436-3). ■ ■GENETIC TESTING With the increasing recognition of specific gene mutations causing epi­ lepsy (Table 436-2), genetic testing is beginning to emerge as part of the diagnostic evaluation of patients with epilepsy. In addition to provid­ ing a definitive diagnosis (which may be of great benefit to the patient and family members and curtail the pursuit of additional, unrevealing laboratory testing), genetic testing may offer a guide for therapeutic options (see section “Selection of Antiseizure Drugs” below). Genetic testing is currently being done mainly in infants and children with epilepsy syndromes thought to have a genetic cause but should also be considered in older patients with a history suggesting an undiagnosed genetic epilepsy syndrome that began early in life. DIFFERENTIAL DIAGNOSIS OF SEIZURES Disorders that may mimic seizures are listed in Table 436-6. In most cases, seizures can be distinguished from other conditions by meticu­ lous attention to the history and relevant laboratory studies. On occa­ sion, additional studies such as video-EEG monitoring, sleep studies, tilt-table analysis, or cardiac electrophysiology may be required to reach a correct diagnosis. Two of the more common nonepileptic syn­ dromes in the differential diagnosis are discussed below. ■ ■SYNCOPE The diagnostic dilemma encountered most frequently is the distinc­ tion between a generalized seizure and syncope. Observations by the patient and bystanders that can help differentiate between the two are listed in Table 436-7. Characteristics of a seizure include the presence of an aura, cyanosis, unconsciousness, motor manifestations lasting >15 s, postictal disorientation, muscle soreness, and sleepiness. In contrast, a syncopal episode is more likely if the event was provoked by acute pain or emotional stress or occurred immediately after arising from the lying or sitting position. Patients with syncope often describe a stereotyped transition from consciousness to unconsciousness that includes tiredness, sweating, nausea, and tunneling of vision, and they experience a relatively brief loss of consciousness with rapid recov­ ery of normal mentation. Headache and incontinence are unreliable TABLE 436-6  Differential Diagnosis of Seizures Syncope Vasovagal syncope Cardiac arrhythmia Valvular heart disease Cardiac failure Orthostatic hypotension Psychological disorders Psychogenic seizure Hyperventilation Panic attack Metabolic disturbances Alcoholic blackouts Delirium tremens Hypoglycemia Hypoxia Psychoactive drugs (e.g., hallucinogens) Migraine Confusional migraine Basilar migraine Transient ischemic attack (TIA) Basilar artery TIA Sleep disorders Narcolepsy/cataplexy Benign sleep myoclonus Movement disorders Tics Nonepileptic myoclonus Paroxysmal choreoathetosis Special considerations in children Breath-holding spells Migraine with recurrent abdominal pain and cyclic vomiting Benign paroxysmal vertigo Apnea Night terrors Sleepwalking features in differentiating between syncope and seizure. A brief period (i.e., 1–10 s) of convulsive motor activity is frequently seen immedi­ ately at the onset of a syncopal episode, especially if the patient remains in an upright posture after fainting (e.g., in a dentist’s chair) and there­ fore has a sustained decrease in cerebral perfusion. Rarely, a syncopal episode can induce a full tonic-clonic seizure. In such cases, the evalu­ ation must focus on both the cause of the syncopal event as well as the possibility that the patient has a propensity for recurrent seizures. Postictal symptoms can be helpful when differentiating convulsive syn­ cope from seizure, as confusion and disorientation are typically much less prominent following syncope. ■ ■PSYCHOGENIC SEIZURES Psychogenic seizures are nonepileptic behaviors that resemble seizures. They are often part of a conversion reaction precipitated by underlying psychological distress. Certain behaviors such as side-to-side turning of the head, ictal eye closure, asynchronous and large-amplitude shak­ ing movements of the limbs, twitching of all four extremities without TABLE 436-7  Features That Distinguish Generalized Tonic-Clonic Seizure from Syncope FEATURES SEIZURE SYNCOPE Immediate precipitating factors Usually none Emotional stress, Valsalva, orthostatic hypotension, cardiac etiologies Premonitory symptoms None or aura (e.g., odd odor) Tiredness, nausea, diaphoresis, tunneling of vision Posture at onset Variable Usually erect Transition to unconsciousness Often immediate Gradual over secondsa Duration of unconsciousness Minutes Seconds Duration of tonic or clonic movements 30–60 s Never >15 s Facial appearance during event Cyanosis, frothing Pallor at mouth Disorientation and sleepiness after event Many minutes to hours <5 min Aching of muscles after event Often Sometimes Biting of tongue Sometimes Rarely Incontinence Sometimes Sometimes Headache Sometimes Rarely aMay be sudden with certain cardiac arrhythmias. loss of consciousness, and pelvic thrusting are more commonly asso­ ciated with psychogenic rather than epileptic seizures. Psychogenic seizures often last longer than epileptic seizures and may wax and wane over minutes to hours. However, the distinction is sometimes difficult on clinical grounds alone, and there are many examples of diagnostic errors made by experienced epileptologists. This is especially true for psychogenic seizures that resemble focal seizures, because the behav­ ioral manifestations of focal seizures (especially of frontal lobe origin) can be extremely unusual, and, in both cases, the routine surface EEG may be normal. Video-EEG monitoring is very useful when historic features are nondiagnostic. Generalized tonic-clonic seizures always produce marked EEG abnormalities during and after the seizure. For suspected focal seizures, the use of additional electrodes may help to localize a seizure focus. Most generalized seizures and some focal seizures are accompanied by a rise in serum prolactin during the immediate 30-min postictal period, whereas psychogenic seizures are not, though this is not always reliable because baseline prolactin levels are rarely available and certain medications can elevate prolactin levels. The diagnosis of psychogenic seizures also does not exclude a concur­ rent diagnosis of epilepsy, because the two often coexist. CHAPTER 436 TREATMENT Seizures and Epilepsy Seizures and Epilepsy Therapy for a patient with a seizure disorder is almost always multimodal and includes treatment of underlying conditions that cause or contribute to the seizures, avoidance of precipitating fac­ tors, suppression of recurrent seizures by prophylactic therapy with antiseizure medications or surgery, and addressing a variety of psychological and social issues. Treatment plans must be individu­ alized, given the many different types and causes of seizures as well as the differences in efficacy and toxicity of antiseizure medications for each patient. In almost all cases, a neurologist with experience in the treatment of epilepsy should design and oversee implementa­ tion of the treatment strategy. Furthermore, patients with refractory epilepsy or those who require polypharmacy with antiseizure drugs should remain under the regular care of a neurologist. TREATMENT OF UNDERLYING CONDITIONS If the sole cause of a seizure is a metabolic disturbance such as an abnormality of serum electrolytes or glucose, then treatment is aimed at reversing the metabolic problem and preventing its recurrence. Therapy with antiseizure drugs is usually unnecessary unless the metabolic disorder cannot be corrected promptly and the patient is at risk of having further seizures. If the apparent cause of a seizure was a medication (e.g., bupropion) or illicit drug use (e.g., cocaine), then appropriate therapy is avoidance of the drug; there is usually no need for antiseizure medications unless subsequent seizures occur in the absence of these precipitants. Seizures caused by a structural CNS lesion such as a brain tumor, vascular malformation, or brain abscess may not recur after appro­ priate treatment of the underlying lesion. However, despite removal of the structural lesion, there is a risk that the seizure focus will remain in the surrounding tissue or develop de novo as a result of gliosis and other processes induced by surgery, radiation, or other therapies. Most patients are therefore maintained on an antiseizure medication for 6–12 months, and an attempt is made to withdraw medications only if the patient has been completely seizure free. If seizures are refractory to medication, the patient may benefit from surgical removal of the seizure-producing brain tissue (see below). AVOIDANCE OF PRECIPITATING FACTORS Unfortunately, little is known about the specific factors that deter­ mine precisely when a seizure will occur in a patient with epilepsy. An almost universal precipitating factor for seizures is sleep depri­ vation, so patients should do everything possible to optimize their sleep quality. Many patients can identify other avoidable situations that appear to lower their seizure threshold. For example, patients may note an association between alcohol intake and seizures, and they should be encouraged to modify their drinking habits accord­ ingly. There are also relatively rare cases of patients with seizures that are induced by highly specific stimuli such as a video game monitor, music, startling sounds, or an individual’s voice (“reflex epilepsy”). Because there is often an association between stress and seizures, stress reduction techniques such as physical exercise, meditation, or counseling may be helpful. ANTISEIZURE DRUG THERAPY Antiseizure drug therapy is the mainstay of treatment for most people with epilepsy. The overall goal is to completely prevent sei­ zures without causing any untoward side effects, preferably with a single medication and a dosing schedule that is easy for the patient to follow. Seizure classification is an important element in designing the treatment plan, because some antiseizure drugs have different activities against various seizure types. However, there is consider­ able overlap between antiseizure drugs, and choice of therapy is often determined by anticipated side effects, drug-drug interac­ tions, medical comorbidities, dosing frequency, and cost. PART 13 Neurologic Disorders When to Initiate Antiseizure Drug Therapy  Antiseizure drug therapy should be started in any patient with recurrent seizures of unknown etiology or a known cause that cannot be reversed. Whether to initiate therapy in a patient with a single seizure is con­ troversial. Patients with a single seizure due to an identified lesion such as a CNS tumor, infection, or trauma, in which there is strong evidence that the lesion is epileptogenic, should be treated. The risk of seizure recurrence in a patient with an apparently unprovoked seizure is uncertain, with estimates ranging from 31 to 71% in the first 12 months after the initial seizure. This uncertainty arises from differences in the underlying seizure types and etiologies in various published epidemiologic studies. Generally accepted risk factors associated with recurrent seizures include the following: (1) prior brain insult such as a stroke or trauma, (2) an EEG with epilep­ tiform abnormalities, (3) a significant brain imaging abnormality, or (4) a nocturnal seizure. Most patients with one or more of these risk factors should be treated. Issues such as employment or driving may influence the decision regarding whether to start medications as well. For example, a patient with a single unprovoked seizure whose job depends on driving may prefer taking an antiseizure drug to reduce risk of seizure recurrence and the potential loss of driving privileges. Selection of Antiseizure Drugs  Antiseizure drugs available in the United States are shown in Table 436-8, and the main phar­ macologic characteristics of commonly used drugs are listed in Table 436-9. Worldwide, older medications such as phenytoin, valproic acid, carbamazepine, phenobarbital, and ethosuximide are generally used as first-line therapy for most seizure disorders because, overall, they are as effective as more recent drugs and significantly less expensive overall. Most of the new drugs that have become available in the past decade are used as adjunctive therapy, although many are now also being used as first-line monotherapy. In addition to efficacy, factors influencing the choice of an initial medication include the convenience of dosing (e.g., once daily vs three times daily) and potential side effects. In this regard, many of the newer drugs have the advantage of reduced drug-drug interac­ tions and easier dosing. Almost all the commonly used antiseizure drugs can cause similar, dose-related side effects such as sedation, ataxia, dizziness, and diplopia. Long-term use of some agents in adults, especially the elderly, can lead to osteoporosis. Close followup is required to ensure these side effects are promptly recognized and reversed. Most of the older drugs and some of the newer ones can also cause idiosyncratic toxicity such as rash, bone marrow suppression, or hepatotoxicity. Although rare, these side effects should be considered during drug selection, and patients must be instructed about symptoms or signs that should signal the need to alert their health care provider. For some drugs, laboratory tests (e.g., complete blood count and liver function tests) are recom­ mended prior to the institution of therapy (to establish baseline TABLE 436-8  Selection of Antiseizure Drugs GENERALIZEDONSET TONIC-CLONIC FOCAL ATYPICAL ABSENCE, MYOCLONIC, ATONIC TYPICAL ABSENCE First-Line Lamotrigine Valproic acid Lamotrigine Carbamazepine Oxcarbazepine Eslicarbazepine Phenytoin Levetiracetam Valproic acid Ethosuximide Lamotrigine Valproic acid Lamotrigine Topiramate Alternatives Zonisamidea Zonisamidea Clonazepam Zonisamide Levetiracetam Clonazepam Felbamate Clobazam Rufinamide Fenfluramine Phenytoin Levetiracetam Carbamazepine Oxcarbazepine Topiramate Phenobarbital Primidone Felbamate Perampanel Brivaracetam Topiramate Valproic acid Tiagabinea Gabapentina Lacosamidea Phenobarbital Primidone Felbamate Perampanel Cenobamatea aAs adjunctive therapy. values) and during initial dosing and titration of the agent. Moni­ toring serum concentrations of antiseizure medications can help determine when a therapeutic dose has been reached, though clini­ cal response is paramount (see below). An important advance in the care of people with epilepsy has been the application of genetic testing to help guide the choice of therapy (as well as establishing the underlying cause of a patient’s syndrome; Table 436-2). For example, the identification of a muta­ tion in the SLC2A1 gene, which encodes the glucose type 1 trans­ porter (GLUT-1) and is a cause of GLUT-1 deficiency, should prompt immediate treatment with the ketogenic diet. Mutations of the ALDH7A1 gene, which encodes antiquitin, can cause altera­ tions in pyridoxine metabolism that are reversed by treatment with pyridoxine. There is also mounting evidence that certain gene mutations may indicate better or worse response to specific anti­ seizure drugs. For example, patients with mutations in the sodium channel subunit SCN1A should generally avoid taking phenytoin or lamotrigine, whereas patients with mutations in the SCN2A or SCN8A sodium channel subunits appear to respond favorably to high-dose phenytoin. Genetic testing may also help predict antiseizure drug toxicity. Studies have shown that individuals of Asian descent who carry the human leukocyte antigen (HLA) allele HLA-B*1502 are at particularly high risk of developing serious skin reactions from carbamazepine, phenytoin, oxcarbazepine, and lamotrigine. HLA-A*31:01 has also been found to be associated with carbamazepine-induced hypersensitivity reactions in patients of European or Japanese ancestry. Antiseizure Drug Selection for Focal Seizures  Carbam­ azepine (or related drugs, oxcarbazepine and eslicarbazepine), lamotrigine, phenytoin, and levetiracetam are currently the drugs of choice approved for the initial treatment of focal seizures, including those that evolve into generalized seizures. Overall, they have very similar efficacy, but differences in pharmacokinetics and toxicity are the main determinants for use in a given patient. For example, an advantage of carbamazepine (which is also available in an extended-release form) is that its metabolism follows first-order pharmacokinetics, which allows for a linear relationship between drug dose, serum levels, and toxicity. Carbamazepine can cause leu­ kopenia, aplastic anemia, or hepatotoxicity and would therefore be TABLE 436-9  Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs TRADE NAME PRINCIPAL USES TYPICAL DOSE; DOSE INTERVAL HALF-LIFE GENERIC NAME Brivaracetam Briviact Focal onset 100–200 mg/d; bid 7–10 h Not established Cannabidiol Epidiolex Dravet and Lennox-Gastaut syndromes 10–20 mg/kg per d; bid   Tuberous sclerosis complexassociated seizures Carbamazepine Tegretolc Tonic-clonic Focal onset 600–1800 mg/d (15–35 mg/ kg, child); bid (capsules or tablets), tid-qid (oral suspension) Cenobamate Xcopri Focal onset 100–400 mg/d; daily (tablets) Clobazam Onfi Lennox-Gastaut syndrome 10–40 mg/d (5–20 mg/d for patients <30 kg body weight); bid Clonazepam Klonopin Absence Atypical absence Myoclonic 1–12 mg/d; qd-tid 24–48 h 10–70 ng/mL Ataxia Sedation Lethargy Eslicarbazepine Aptiom Focal onset 400–1600 mg/d; qd 20–24 h 10–35 μg/mL (as oxcarbazepine mono-hydroxy derivative) Ethosuximide Zarontin Absence 750–1250 mg/d (20–40 mg/kg); qd-bid Felbamate Felbatol Focal onset Lennox-Gastaut syndrome Tonic-clonic 2400–3600 mg/d, tid-qid Fenfluramine Fintepla Dravet and Lennox-Gastaut syndromes 0.1–0.35 mg/kg/ dose bid (oral solution); dosage depends on coadministration with stiripentol and/or clobazam ADVERSE EFFECTS DRUG INTERACTIONSa NEUROLOGIC SYSTEMIC THERAPEUTIC RANGE Fatigue Dizziness Weakness Ataxia Mood changes Gastrointestinal irritation May increase carbamazepineepoxide causing decreased tolerability May increase phenytoin 18–32 h Not established Sedation Elevated transaminases Anorexia Weight loss Diarrhea Increases clobazam causing somnolence CHAPTER 436 10–17 h (variable due to autoinduction: complete 3–5 wk after initiation) 4–12 μg/mL Ataxia Dizziness Diplopia Vertigo Aplastic anemia Leukopenia Gastrointestinal irritation Hepatotoxicity Hyponatremia Rash Level decreased by enzymeinducing drugsb Level increased by erythromycin, propoxyphene, isoniazid, cimetidine, fluoxetine Seizures and Epilepsy 50–60 h Not established Cognitive dysfunction Dizziness Disequilibrium Gait disturbance Headache   Anorexia Constipation Diarrhea Dyspepsia Nausea   Major CYP3A4 inducer; moderate CYP2C19 inhibitor 36–42 h (71–82 h for less active metabolite) Not established Fatigue Sedation Ataxia Aggression Insomnia Constipation Anorexia Skin rash Level increased by CYP2C19 inhibitors Anorexia Level decreased by enzymeinducing drugsb Sedation Ataxia Dizziness Diplopia Vertigo See carbamazepine Level decreased by enzymeinducing drugsb 60 h, adult 30 h, child 40–100 μg/mL Ataxia Lethargy Headache Gastrointestinal irritation Skin rash Bone marrow suppression Level decreased by enzymeinducing drugsb Level increased by valproic acid 16–22 h 30–60 μg/mL Insomnia Dizziness Sedation Headache Aplastic anemia Hepatic failure Weight loss Gastrointestinal irritation Increases phenytoin, valproic acid, active carbamazepine metabolite 20 h Not established Ataxia Behavioral disturbance Headache Somnolence Anorexia Constipation Hypertension Serotonin syndrome Weight loss  CYP1A2, CYP2B6, CYP2D6, CYPDA4 substrate (Continued) TABLE 436-9  Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs TRADE NAME PRINCIPAL USES TYPICAL DOSE; DOSE INTERVAL HALF-LIFE GENERIC NAME Gabapentin Neurontin Focal onset 900–2400 mg/d; tid-qid 5–9 h 2–20 μg/mL Sedation Dizziness Ataxia Fatigue Ganaxolone Ztalmy CDKL-5 deficiency disorder– associated seizures 450–1800 mg/d; tid (oral suspension) 34 h Not established Lacosamide Vimpat Focal onset 200–400 mg/d; bid 13 h Not established PART 13 Neurologic Disorders Lamotrigine Lamictalc Focal onset Tonic-clonic Atypical absence Myoclonic Lennox-Gastaut syndrome 150–500 mg/d; bid (immediate release), daily (extended release) (lower daily dose for regimens with valproic acid; higher daily dose for regimens with an enzyme inducer) 25 h 14 h (with enzyme inducers), 59 h (with valproic acid) Levetiracetam Keppra Focal onset 1000–3000 mg/d; bid (immediate release), daily (extended release) 6–8 h 5–45 μg/mL Sedation Fatigue Incoordination Mood changes Oxcarbazepinec Trileptal Focal onset Tonic-clonic 900–2400 mg/d (30–45 mg/kg, child); bid 10–17 h (for active metabolite) Perampanel Fycompa Focal onset Tonic-clonic 4–12 mg; qd 105 h Not established Phenobarbital Luminal Tonic-clonic Focal onset 60–180 mg/d; qd-tid 90 h 10–40 μg/mL Sedation Ataxia Confusion Dizziness Decreased libido Depression Phenytoinc (diphenylhydantoin) Dilantin Tonic-clonic Focal onset 300–400 mg/d (3–6 mg/kg, adult; 4–8 mg/kg, child); qd-tid 24 h (wide variation, dosedependent) Primidone Mysoline Tonic-clonic Focal onset 750–1000 mg/d; bid-tid Primidone, 8–15 h Phenobarbital, 90 h (Continued) ADVERSE EFFECTS DRUG INTERACTIONSa NEUROLOGIC SYSTEMIC THERAPEUTIC RANGE Gastrointestinal irritation Weight gain Edema No known significant interactions Gait disturbance Somnolence Bronchitis Fever Nasal congestion CYP2B6, CYP2C19, CYP3A4 substrate Dizziness Ataxia Diplopia Vertigo Gastrointestinal irritation Cardiac conduction (PR interval prolongation) Level decreased by enzymeinducing drugsb 2.5–20 μg/mL Dizziness Diplopia Sedation Ataxia Headache Skin rash Stevens-Johnson syndrome Level decreased by enzymeinducing drugsb and oral contraceptives Level increased by valproic acid Anemia Leukopenia No known significant interactions 10–35 μg/mL Fatigue Ataxia Dizziness Diplopia Vertigo Headache See carbamazepine Level decreased by enzymeinducing drugsb May increase phenytoin Dizziness Somnolence Aggression Ataxia Anxiety Paranoia Headache Nausea Level decreased by enzymeinducing drugsb Skin rash Level increased by valproic acid, phenytoin 10–20 μg/mL Dizziness Diplopia Ataxia Incoordination Confusion Gingival hyperplasia Lymphadenopathy Hirsutism Osteomalacia Facial coarsening Skin rash Level increased by isoniazid, sulfonamides, fluoxetine Level decreased by enzymeinducing drugsb Altered folate metabolism Primidone, 4–12 μg/mL Phenobarbital, 10–40 μg/mL Same as phenobarbital   Level increased by valproic acid Level decreased by phenytoin (increased conversion to phenobarbital) (Continued) TABLE 436-9  Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs TRADE NAME PRINCIPAL USES TYPICAL DOSE; DOSE INTERVAL HALF-LIFE GENERIC NAME Rufinamide Banzel Lennox-Gastaut syndrome 3200 mg/d (45 mg/ kg, child); bid Tiagabine Gabitril Focal onset 32–56 mg/d; bidqid (as adjunct to enzyme-inducing antiepileptic drug regimen) Topiramatec Topamax Focal onset Tonic-clonic Lennox-Gastaut syndrome 200–400 mg/d; bid (immediate release), daily (extended release) Valproic acid (valproate sodium, divalproex sodium) Depakene Depakote Tonic-clonic Absence Atypical absence Myoclonic Focal onset Atonic 750–2000 mg/d (20–60 mg/kg); bidqid (immediate and delayed release), daily (extended release) Zonisamide Zonegran Focal onset Tonic-clonic 200–400 mg/d; qd-bid aExamples only; please refer to other sources for comprehensive listings of all potential drug-drug interactions. bPhenytoin, carbamazepine, phenobarbital. cExtendedrelease product available. contraindicated in patients with predispositions to these problems. Oxcarbazepine has the advantage of being metabolized in a way that avoids an intermediate metabolite (“toxic epoxide”) associated with some of the side effects of carbamazepine. Oxcarbazepine also has fewer drug interactions than carbamazepine. Eslicarbazepine has a long serum half-life and is dosed once daily. Lamotrigine tends to be well tolerated in terms of side effects and has mood-stabilizing properties that can be beneficial. However, patients need to be particularly vigilant about the possibility of a skin rash during the initiation of therapy. This can be extremely severe and lead to Stevens-Johnson syndrome if unrecognized and if the medication is not discontinued immediately. This risk can be reduced by using low initial doses and slow titration. Lamotrigine must be started at even lower initial doses when used as add-on therapy with valproic acid, because valproic acid inhibits lamotrig­ ine metabolism and substantially prolongs its half-life. Phenytoin has a relatively long half-life and offers the advantage of once- or twice-daily dosing compared to twice- or thrice-daily dosing for many of the other drugs. However, phenytoin shows properties of nonlinear kinetics, such that small increases in phe­ nytoin doses above a standard maintenance dose can precipitate marked side effects. This is one of the main causes of acute phe­ nytoin toxicity (dizziness, diplopia, ataxia). Long-term use of phe­ nytoin is associated with untoward cosmetic effects (e.g., hirsutism, (Continued) ADVERSE EFFECTS DRUG INTERACTIONSa NEUROLOGIC SYSTEMIC THERAPEUTIC RANGE 6–10 h Not established Sedation Fatigue Dizziness Ataxia Headache Diplopia Gastrointestinal irritation Leukopenia Cardiac conduction (QT interval shortening) Level decreased by enzymeinducing drugsb Level increased by valproic acid May increase phenytoin 2–5 h (with enzyme inducer), 7–9 h (without enzyme inducer) Not established Confusion Sedation Depression Dizziness Speech or language problems Paresthesias Psychosis Gastrointestinal irritation Level decreased by enzymeinducing drugsb CHAPTER 436 20 h (immediate release), 30 h (extended release) 2–20 μg/mL Psychomotor slowing Sedation Speech or language problems Fatigue Paresthesias Renal stones (avoid use with other carbonic anhydrase inhibitors) Glaucoma Weight loss Hypohidrosis Level decreased by enzymeinducing drugsb Seizures and Epilepsy 15 h 50–125 μg/mL Ataxia Sedation Tremor Hepatotoxicity Thrombocytopenia Gastrointestinal irritation Weight gain Transient alopecia Hyperammonemia Level decreased by enzymeinducing drugsb 50–68 h 10–40 μg/mL Sedation Dizziness Confusion Headache Psychosis Anorexia Renal stones Hypohidrosis Level decreased by enzymeinducing drugsb coarsening of facial features, gingival hypertrophy) and osteoporo­ sis. Due to these side effects, phenytoin is often avoided in young patients who are likely to require the drug for many years. Levetiracetam has the advantage of having no known clinically relevant drug-drug interactions, making it especially useful in the elderly and patients on other medications. However, a significant number of patients taking levetiracetam complain of irritability, anxiety, and other psychiatric symptoms. Topiramate can be used for both focal and generalized seizures. Like some of the other antiseizure drugs, topiramate can cause sig­ nificant psychomotor slowing and other cognitive problems. Addi­ tionally, it should not be used in patients at risk for renal stones. Valproic acid is an effective alternative for some patients with focal seizures, especially when the seizures generalize. Gastro­ intestinal side effects are fewer when using the delayed-release formulation. Laboratory testing is required to monitor toxicity because valproic acid can rarely cause reversible bone marrow suppression and hepatotoxicity. This drug should generally be avoided in patients with preexisting bone marrow or liver disease. Valproic acid also has relatively high risks of unacceptable adverse effects for women of childbearing age, including hyperandrogen­ ism, that may affect fertility and teratogenesis (e.g., neural tube defects) in offspring. Irreversible, fatal hepatic failure appearing as an idiosyncratic rather than dose-related side effect is a relatively rare complication; its risk is highest in children <2 years old, espe­ cially those taking other antiseizure drugs or with inborn errors of metabolism. Zonisamide, brivaracetam, tiagabine, gabapentin, perampanel, and lacosamide are additional drugs currently used for the treat­ ment of focal seizures with or without evolution into generalized seizures. Phenobarbital and other barbiturate compounds were commonly used in the past as first-line therapy for many forms of epilepsy. However, the barbiturates frequently cause sedation in adults, hyperactivity in children, and other more subtle cognitive changes; thus, their use should be limited to situations in which no other suitable treatment alternatives exist. Cenobamate is a recently approved antiseizure drug that has been shown to significantly improve seizure control in patients with focal epilepsy who were not adequately treated with up to three medications. Antiseizure Drug Selection for Generalized Seizures  Lamotrigine, valproic acid, and levetiracetam are currently consid­ ered the best initial choice for the treatment of primary generalized, tonic-clonic seizures. Topiramate, zonisamide, perampanel, phe­ nytoin, carbamazepine, and oxcarbazepine are suitable alternatives, although carbamazepine, oxcarbazepine, and phenytoin can worsen certain types of generalized seizures. Valproic acid is particularly effective in absence, myoclonic, and atonic seizures. It is therefore commonly used in patients with generalized epilepsy syndromes having mixed seizure types. However, levetiracetam, rather than valproic acid, is increasingly considered the initial drug of choice for women with epilepsies having mixed seizure types given the adverse effects of valproic acid for women of childbearing age (discussed below). Lamotrigine is also an alternative to valproate, especially for absence epilepsies. Ethosuximide is a particularly effective drug for the treatment of absence seizures, but it is not useful for tonic-clonic or focal seizures. Periodic monitoring of blood cell counts is required since ethosuximide rarely causes bone marrow suppression. INITIATION AND MONITORING OF THERAPY Because the response to any antiseizure drug is unpredictable, patients should be carefully educated about the approach to ther­ apy. The goal is to prevent seizures and minimize the side effects of treatment; determination of the optimal medication and the optimal dose typically involves trial and error. This process may take months or longer if the baseline seizure frequency is low. Most antiseizure drugs need to be introduced relatively slowly to mini­ mize side effects. Patients should expect that minor side effects such as mild sedation, slight changes in cognition, or imbalance will typically resolve within a few days. Starting doses are usually the lowest value listed under the dosage column in Table 436-9. Subsequent increases should be made only after achieving a steady state with the previous dose (i.e., after an interval of five or more half-lives). PART 13 Neurologic Disorders Monitoring of serum antiseizure drug levels can be very useful for establishing the initial dosing schedule. However, the pub­ lished therapeutic ranges of serum drug concentrations are only an approximate guide for determining the proper dose for a given patient. The key determinants are the clinical measures of seizure frequency and presence of side effects, not the laboratory values. Conventional assays of serum drug levels measure the total drug (i.e., both free and protein bound). However, it is the concentra­ tion of free drug that reflects extracellular levels in the brain and correlates best with efficacy. Thus, patients with decreased levels of serum proteins (e.g., decreased serum albumin due to impaired liver or renal function) may have an increased ratio of free to bound drug, yet the concentration of free drug may be adequate for seizure control. These patients may have a “subtherapeutic” drug level, but the dose should be changed only if seizures remain uncontrolled, not just to achieve a “therapeutic” level. It is also useful to moni­ tor free drug levels in such patients. In practice, other than during the initiation or modification of therapy, monitoring of antiseizure drug levels is most useful for documenting adherence, assessing clinical suspicion of toxicity, or establishing baseline serum con­ centrations prior to pregnancy, when clearance of many antiseizure drugs increases significantly. If seizures continue despite gradual increases to the maximum tolerated dose and documented compliance, then it becomes neces­ sary to switch to another antiseizure drug. This is usually done by maintaining the patient on the first drug while a second drug is added. The dose of the second drug should be adjusted to decrease seizure frequency without causing toxicity. Once this is achieved, the first drug can be gradually withdrawn (usually over weeks unless there is significant toxicity). The dose of the second drug is then further optimized based on seizure response and side effects. Monotherapy should be the goal whenever possible. WHEN TO DISCONTINUE THERAPY Some patients who have their seizures completely controlled with antiseizure drugs can eventually discontinue therapy. The following patient profile yields the greatest chance of remaining seizure free after drug withdrawal: (1) complete medical control of seizures for 1–5 years; (2) single seizure type, with generalized seizures having a better prognosis than focal seizures; (3) normal neurologic exami­ nation, including intelligence; (4) no family history of epilepsy; and (5) normal EEG. The appropriate seizure-free interval is unknown and depends on the form of epilepsy and whether or not the causal factor is still present (e.g., resection of a brain tumor causing seizures). However, it seems reasonable to attempt withdrawal of therapy after 2 years in a patient who meets all the above criteria, is motivated to discontinue the medication, and clearly understands the potential risks and benefits. In most cases, it is preferable to reduce the dose of the drug gradually over 2–3 months. Most recur­ rences occur in the first 3 months after discontinuing therapy, and patients should be advised to avoid potentially dangerous situations such as driving or swimming during this period. Rarely, seizure-free patients who discontinue antiseizure medications but then have a recurrent seizure may not regain full control when these medica­ tions are resumed. TREATMENT OF REFRACTORY EPILEPSY Approximately half of people with epilepsy do not respond to treat­ ment with the first antiseizure drug, and it becomes necessary to try additional drugs alone or in combination. Patients who have focal epilepsy related to an underlying structural lesion or those with multiple seizure types and developmental delay are particularly likely to require multiple drugs. There are currently no clear guide­ lines for rational polypharmacy, although in theory, a combination of drugs with different mechanisms of action may be most useful. In most cases, the initial combination therapy combines first-line drugs (i.e., carbamazepine, oxcarbazepine, lamotrigine, valproic acid, levetiracetam, and phenytoin). If these drugs are unsuccessful, then the addition of other drugs such as cenobamate, zonisamide, brivaracetam, topiramate, or lacosamide is indicated. Patients with myoclonic seizures resistant to valproic acid may benefit from the addition of levetiracetam, zonisamide, clonazepam, or clobazam, and those with absence seizures may respond to a combination of valproic acid and ethosuximide. The same principles concerning the monitoring of therapeutic response, toxicity, and serum levels for monotherapy apply to polypharmacy, and potential drug inter­ actions need to be recognized. If there is no improvement, a third drug can be added while the first two are maintained. If there is a response, the less effective or less well tolerated of the first two drugs should be gradually withdrawn. SURGICAL TREATMENT OF REFRACTORY EPILEPSY Approximately 30% of patients with epilepsy continue to have seizures despite efforts to find an effective combination of anti­ seizure drugs. For some patients with focal epilepsy, surgery can be extremely effective in substantially reducing seizure frequency and even providing complete seizure control. Understanding the potential value of surgery is especially important when a patient’s seizures are not controlled with initial treatment, as such patients often do not respond to subsequent medication trials. Rather than submitting the patient to years of unsuccessful medical therapy and the psychosocial trauma and increased mortality associated with ongoing seizures, the patient should have an efficient but relatively brief attempt at medical therapy and then be referred for surgical evaluation. The most common surgical procedure for patients with temporal lobe epilepsy involves resection of the anteromedial temporal lobe (temporal lobectomy) or a more limited removal of the underlying hippocampus and amygdala (amygdalohippocampectomy). Focal seizures arising from extratemporal regions may be abolished by a focal neocortical resection with precise removal of an identified lesion (lesionectomy). Localized neocortical resection without a clear lesion identified on MRI is also possible when other tests (e.g., MEG, PET, SPECT) implicate a focal cortical region as a seizure onset zone. When the cortical region cannot be removed, multiple subpial transection, which disrupts intracortical connections, is sometimes used to prevent seizure spread. Hemispherectomy or multilobar resection is useful for some patients with severe seizures due to hemispheric abnormalities such as hemimegalencephaly or other dysplastic abnormalities, and corpus callosotomy has been shown to be effective for disabling tonic or atonic seizures, usually when they are part of a mixed-seizure syndrome (e.g., LennoxGastaut syndrome). Presurgical evaluation is designed to identify the functional and structural basis of the patient’s seizure disorder. Inpatient videoEEG monitoring is used to localize the seizure focus and to cor­ relate the abnormal electrophysiologic activity with neuroimaging and behavioral manifestations of the seizure. Routine scalp EEG recordings and a high-resolution MRI scan are often sufficient for localization of the epileptogenic focus, especially when the findings are concordant. Functional imaging studies such as SPECT, PET, and MEG are adjunctive tests that may help to reveal or verify the localization of an apparent epileptogenic region. Once the pre­ sumed location of the seizure onset is identified, additional studies, including neuropsychological testing, the intracarotid amobarbital (Wada) test, and functional MRI may be used to assess language and memory localization and to determine the possible functional consequences of surgical removal of the epileptogenic region. In some cases, standard noninvasive evaluation is not sufficient to localize the seizure onset zone, and invasive electrophysiologic monitoring is required for more definitive localization. Tradition­ ally, this required open craniotomy and subdural electrode place­ ment. Robot-assisted stereotactic EEG (stereo-EEG) has surged in use as a less invasive surgical option that involves placing depth electrodes through burr holes in the skull and into the brain paren­ chyma to record from regions suspected of generating seizures. Although subdural electrodes provide extensive cortical sampling, they are unable to record from deep structures; depth electrodes permit sampling of both cortical and subcortical tissue, albeit with more restricted spatial resolution. Stereo-EEG studies are typically associated with shorter hospital stays and lower complication rates than subdural electrode studies. The exact extent of the resection to be undertaken can also be determined by performing cortical mapping at the time of the sur­ gical procedure, allowing for a tailored resection. This involves elec­ trocorticographic recordings made with electrodes on the surface of the brain to identify the extent of epileptiform disturbances. If the region to be resected is within or near brain regions suspected of having sensorimotor or language function, electrical cortical stimu­ lation mapping is performed on the awake patient to determine the function of cortical regions in question to avoid resection of socalled eloquent cortex and thereby minimize postsurgical deficits. Advances in presurgical evaluation and microsurgical techniques have led to a steady increase in the success of epilepsy surgery. Clinically significant complications of surgery are <5%, and the use of functional mapping procedures has markedly reduced the neurologic sequelae due to removal or sectioning of brain tissue. For example, ~70% of well-selected patients treated with temporal lobectomy will become seizure free, and another 15–25% will have at least a 90% reduction in seizure frequency. Marked improvement is also usually seen in patients treated with hemispherectomy for catastrophic seizure disorders due to large hemispheric abnormali­ ties. Postoperatively, patients generally need to remain on antisei­ zure drug therapy, but the marked reduction of seizures following resective surgery can have a very beneficial effect on quality of life. Recently, catheter-based stereotactic laser thermal ablation has been developed as a less invasive means for destroying the seizure focus in select patients. Not all medically refractory patients are suitable candidates for resective surgery or laser ablation. For example, some patients have seizures arising from more than one brain region or from a single “eloquent” region that mediates a critical function (e.g., vision, movement, language), such that the potential harm from removal is unacceptably high. In these patients, implanted neurostimula­ tion devices that deliver electrical energy to the brain to reduce seizures represent palliative treatment options. Vagus nerve stimu­ lation (VNS) involves an extracranial device that works through scheduled intermittent (“open loop”) stimulation of the left vagus nerve. Efficacy of VNS is limited, and side effects related to recur­ rent laryngeal nerve activation (e.g., hoarseness, throat pain, dys­ pnea) can be significant and dose-limiting. By contrast, responsive neurostimulation (RNS) involves an implanted device connected to two lead wires that are placed intracranially at the site(s) from where seizures arise. The neurostimulator detects the onset of a seizure (often before the seizure becomes clinically apparent) and delivers electrical stimulation—typically imperceptible—directly to the brain to reduce seizures over time, a form of “closed loop” neurostimulation. RNS is the only device that provides chronic EEG, which has a growing number of clinical applications, such as quantifying the lateralization of seizures arising from both sides of the brain, characterizing clinical spells, assessing effects of medica­ tions and other therapeutic interventions, and revealing cyclical patterns of epileptic brain activity that may help anticipate future events. A third modality, thalamic deep brain stimulation (DBS), involves open loop stimulation of deep, bilateral cerebral structures, the anterior thalamic nuclei, which are key nodes in limbic circuits mediating certain types of seizures. Whereas precise seizure local­ ization is necessary for RNS, it is not required for VNS or DBS. Stimulation of thalamic nuclei, which project broadly to different cortical regions, with RNS or DBS is an appealing approach to treat­ ing poorly localized, spatially extensive, or multifocal seizure foci. CHAPTER 436 Seizures and Epilepsy Long-term clinical trials of all three neurostimulation devices demonstrate significant reductions in frequency with outcomes improving over time, but only a minority of patients treated with these devices achieve seizure freedom (e.g., ~15% with RNS). Fur­ thermore, no head-to-head device trials exist to establish relative superiority, so choice of a device is guided by patient-specific fac­ tors and by the strengths and limitations of each technology. ■ ■STATUS EPILEPTICUS Status epilepticus refers to continuous seizures or repetitive, discrete seizures with impaired consciousness in the interictal period. Status epilepticus has numerous subtypes, including generalized convulsive status epilepticus (GCSE) (e.g., persistent, generalized electrographic seizures, coma, and tonic-clonic movements) and nonconvulsive status epilepticus (NCSE; e.g., persistent absence seizures or focal seizures with confusion or partially impaired consciousness, and minimal motor abnormalities). The duration of seizure activity sufficient to meet the definition of status epilepticus has traditionally been specified as 15–30 min. However, a more practical definition is to consider status epilepticus as a situation in which the duration of seizures prompts the acute use of anticonvulsant therapy. For GCSE, this is typically when seizures last beyond 5 min. GCSE is an emergency and must be treated immediately, because cardiorespiratory dysfunction, hyperthermia, and metabolic derange­ ments can develop as a consequence of prolonged seizures, and these can lead to irreversible CNS injury. Furthermore, CNS injury can occur even when the patient is paralyzed with neuromuscular blockade but continues to have electrographic seizures. The most common causes of GCSE are anticonvulsant withdrawal or noncompliance, metabolic disturbances, drug toxicity, CNS infection, CNS tumors, refractory epilepsy, and head trauma. GCSE is obvious when the patient is having overt seizures. How­ ever, after 30–45 min of uninterrupted seizures, the signs may become increasingly subtle. Patients may have mild clonic movements of only the fingers or fine, rapid movements of the eyes. There may be parox­ ysmal episodes of tachycardia, hypertension, and pupillary dilation. In such cases, the EEG may be the only method of establishing the diagnosis. Thus, if the patient stops having overt seizures, yet remains comatose, an EEG should be performed to rule out ongoing status epilepticus. This is obviously also essential when a patient with GCSE has been paralyzed with neuromuscular blockade in the process of protecting the airway. The first steps in the management of a patient in GCSE are to attend to any acute cardiorespiratory problems or hyperthermia, perform a brief medical and neurologic examination, establish venous access, and send samples for laboratory studies to identify metabolic abnormalities. Anticonvulsant therapy should then begin without delay (Fig. 436-5). PART 13 Neurologic Disorders The treatment of NCSE is thought to be less urgent than GCSE, because the ongoing seizures are not accompanied by the severe metabolic disturbances seen with GCSE. However, evidence suggests that NCSE, especially that caused by ongoing, focal seizure activity, is associated with cellular injury in the region of the seizure focus; there­ fore, this condition should be treated as promptly as possible using the general approach described for GCSE. Portable headband devices that provide a limited form of EEG can be rapidly applied without skilled technicians to help rule out NCSE in acute care settings. Impending and early SE (5–30 min) Generalized convulsive or “subtle” SE Established and early refractory SE (30 min to 48 h) IV MDZ 0.2 mg/kg → 0.2–0.6 mg/kg/h and/or IV PRO 2 mg/kg → 2–10 mg/kg/h Late refractory SE (>48 h) Other medications Lidocaine, verapamil, magnesium, ketogenic diet, immunomodulation FIGURE 436-5  Pharmacologic treatment of generalized tonic-clonic status epilepticus (SE) in adults. CLZ, clonazepam; ECT, electroconvulsive therapy; LCM, lacosamide; LEV, levetiracetam; LZP, lorazepam; MDZ, midazolam; PGB, pregabalin; PHT, phenytoin or fosphenytoin; PRO, propofol; PTB, pentobarbital; RNS, responsive neurostimulation; rTMS, repetitive transcranial magnetic stimulation; THP, thiopental; TPM, topiramate; VNS, vagus nerve stimulation; VPA, valproic acid. (Data from AO Rossetti, DH Lowenstein: Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol 10:922, 2011.) BEYOND SEIZURES: OTHER MANAGEMENT ISSUES ■ ■EPILEPSY COMORBIDITIES The adverse effects of epilepsy often go beyond clinical seizures. Many people with epilepsy feel completely normal between seizures and live highly successful and productive lives. However, a significant propor­ tion of patients suffer from varying degrees of cognitive dysfunction, including psychiatric disease, and it has become increasingly clear that the network dysfunction underlying epilepsy can have effects well beyond the occurrence of seizures. For example, patients with seizures secondary to developmental abnormalities or acquired brain injury may have impaired cognitive function and other neurologic deficits due to abnormal brain structure. Frequent interictal EEG abnormali­ ties are associated with subtle dysfunction of memory and attention. Patients with many seizures, especially those emanating from the tem­ poral lobe, often note an impairment of short-term memory that may progress over time. The psychiatric problems associated with epilepsy include depres­ sion, anxiety, and psychosis. This risk varies considerably depending on many factors, including the etiology, frequency, and severity of seizures and the patient’s age and previous personal or family history of psychiatric disorder. Depression occurs in ~20–30% of patients, and the incidence of suicide is higher in people with epilepsy than in the general population. Depression should be treated through counsel­ ing and/or medication. The selective serotonin reuptake inhibitors (SSRIs) typically have minimal effect on seizures, whereas tricyclic antidepressants may lower the seizure threshold. Anxiety can be a seizure symptom, and anxious or psychotic behavior can occur dur­ ing a postictal delirium. Postictal psychosis is a rare phenomenon that typically occurs after a period of increased seizure frequency. There is IV benzodiazepine LZP 0.1 mg/kg, or MDZ 0.2 mg/kg, or CLZ 0.015 mg/kg IV antiseizure drug PHT 20 mg/kg, or VPA 20–30 mg/kg, or LEV 20–30 mg/kg Focal-complex, myoclonic or absence SE Further IV/PO antiseizure drug VPA, LEV, LCM, TPM, PGB, or other PTB (THP) 5 mg/kg (1 mg/kg) → 1–5 mg/kg/h Other approaches Surgery, VNS, RNS, rTMS, ECT, hypothermia Other anesthetics Isoflurane, desflurane, ketamine usually a brief lucid interval lasting up to a week, followed by days to weeks of agitated, psychotic behavior. The psychosis usually resolves spontaneously but frequently will require short-term treatment with antipsychotic or anxiolytic medications. ■ ■MORTALITY OF EPILEPSY People with epilepsy have a risk of death that is roughly two to three times greater than expected in a matched population without epilepsy. Most of the increased mortality is due to the underlying etiology of epilepsy (e.g., tumors or strokes in older adults). However, a signifi­ cant number of patients die from accidents, status epilepticus, and a syndrome known as sudden unexpected death in epilepsy (SUDEP), which usually affects young people with convulsive seizures and tends to occur at night. The cause of SUDEP is unknown; it may result from brainstem-mediated effects of seizures on pulmonary, cardiac, and arousal functions. Genetic mutations may be the cause of both epilepsy and a cardiac conduction defect that gives rise to sudden death. ■ ■PSYCHOSOCIAL ISSUES There continues to be a cultural stigma about epilepsy, although it is slowly declining in societies with effective health education programs. Many people with epilepsy harbor fear of progressive cognitive decline or dying during a seizure. These issues need to be carefully addressed by educating the patient about epilepsy and by ensuring that family members, teachers, fellow employees, and other associates are equally well informed. A useful source of educational material is the website www.epilepsy.com. ■ ■EMPLOYMENT, DRIVING, AND OTHER ACTIVITIES Many patients with epilepsy face difficulty in obtaining or maintaining employment, even when their seizures are well controlled. Federal and state legislation is designed to prevent employers from discriminating against people with epilepsy, and patients should be encouraged to understand and claim their legal rights. Patients in these circumstances also benefit greatly from the assistance of health providers who act as strong patient advocates. Loss of driving privileges is one of the most disruptive social con­ sequences of epilepsy. Physicians should be very clear about local regulations concerning driving and epilepsy because the laws vary con­ siderably among states and countries. In all cases, it is the physician’s responsibility to warn patients of the danger imposed on themselves and others while driving if their seizures are uncontrolled (unless the seizures are not associated with impairment of consciousness or motor control). In general, most states in the United States allow patients to drive after a seizure-free interval (on or off medications) of 3–18 months. Patients with incompletely controlled seizures must also contend with the risk of being in other situations where an impairment of con­ sciousness or loss of motor control could lead to major injury or death. Thus, depending on the type and frequency of seizures, many patients need to be instructed to avoid working at heights or with machinery or to have someone close by for activities such as bathing and swimming. The importance of quantifying seizures in people living with epi­ lepsy has catalyzed a burgeoning industry of wearable sensors, such as wristwatches, that can detect seizures through noninvasive measure­ ment of physiologic variables. Generally, non-EEG devices either have low sensitivity or high false alarm rate, but reliability is highest for detection of tonic-clonic seizures. SPECIAL ISSUES RELATED TO WOMEN AND EPILEPSY ■ ■CATAMENIAL EPILEPSY Some women experience a marked increase in seizure frequency around the time of menses. This is believed to be mediated by either the effects of estrogen and progesterone on neuronal excitability or changes in antiseizure drug levels due to altered protein binding or metabolism. Vulnerability to seizures is typically highest just before and during menses and during ovulation due to relatively high estrogen and low progesterone levels. Some women with epilepsy may benefit from increases in antiseizure drug dosages during menses. Natural progestins or intramuscular medroxyprogesterone may be of benefit to a subset of women. ■ ■PREGNANCY Most women with epilepsy who become pregnant will have an uncom­ plicated gestation and deliver a normal baby. However, epilepsy poses some important risks to a pregnancy. Seizure frequency during preg­ nancy will remain unchanged in ~50% of women, increase in ~30%, and decrease in ~20%. Changes in seizure frequency are attributed to endocrine effects on the CNS, variations in antiseizure drug pharma­ cokinetics (such as acceleration of hepatic drug metabolism, increased renal blood flow, increased volume of distribution, or effects on plasma protein binding), or decreased antiseizure medication absorption due to nausea and vomiting. It is useful to see patients at frequent intervals during pregnancy and monitor serum antiseizure drug levels monthly; the risk of seizure exacerbation increases when serum levels decrease >35% from prepregnancy levels. Measurement of the unbound drug concentrations may be useful if there is an increase in seizure fre­ quency or worsening of side effects of antiseizure drugs. CHAPTER 436 The overall incidence of fetal abnormalities in children born to mothers with epilepsy is 5–6%, compared to 2–3% in healthy women. Part of the higher incidence is due to teratogenic effects of antiseizure drugs, and the risk increases with the number of medications used (e.g., 10–20% risk of malformations with three drugs) and possibly with higher doses. A meta-analysis of published pregnancy registries and cohorts found that the most common malformations were defects in the cardiovascular and musculoskeletal system (1.4–1.8%). Valproic acid is strongly associated with an increased risk of adverse fetal out­ comes (7–20%). Findings from a large pregnancy registry suggest that the newer antiseizure drugs are far safer than valproic acid. Seizures and Epilepsy Because the potential harm of uncontrolled convulsive seizures on the mother and fetus is considered greater than the teratogenic effects of antiseizure drugs, it is currently recommended that pregnant women be maintained on effective drug therapy. When possible, it seems prudent to have the patient on monotherapy at the lowest effective dose, especially during the first trimester. For some women, however, the type and frequency of their seizures may allow for them to safely wean off antiseizure drugs prior to conception. Patients should also take folate (1–4 mg/d), because the antifolate effects of anticonvulsants are thought to play a role in the development of neural tube defects, although the benefits of this treatment remain unproven in this setting. Enzyme-inducing drugs such as phenytoin, carbamazepine, oxcar­ bazepine, topiramate, phenobarbital, and primidone cause a transient and reversible deficiency of vitamin K–dependent clotting factors in ~50% of newborn infants. Although neonatal hemorrhage is uncom­ mon, the mother should be treated with oral vitamin K (20 mg/d, phylloquinone) in the last 2 weeks of pregnancy, and the infant should receive intramuscular vitamin K (1 mg) at birth. ■ ■CONTRACEPTION Special care should be taken when prescribing antiseizure medications for women who are taking oral contraceptive agents. Drugs such as carbamazepine, phenytoin, phenobarbital, and topiramate can signifi­ cantly decrease the efficacy of oral contraceptives via enzyme induc­ tion and other mechanisms. Patients should be advised to consider alternative forms of contraception, including intrauterine devices and other long-acting reversible contraceptives, or their oral contraceptive medications should be modified to offset the effects of the antiseizure medications. Estrogen-containing oral contraceptive agents induce glucuronidation of lamotrigine and can decrease lamotrigine serum levels by >50%. ■ ■BREAST-FEEDING Antiseizure medications are excreted into breast milk, and the ratio of drug concentration in breast milk relative to serum ranges from ~5% (valproic acid) to 300% (levetiracetam). Given the overall benefits of breast-feeding and the lack of evidence for long-term harm to the infant by being exposed to antiseizure drugs, mothers with epilepsy should be encouraged to breast-feed unless there is evidence of drug effects on the infant, such as lethargy or poor feeding. # 07 - 437 Introduction to Cerebrovascular Diseases ### 437 Introduction to Cerebrovascular Diseases SPECIAL ISSUES RELATED TO EPILEPSY IN THE ELDERLY Epilepsy has a bimodal distribution according to age, with the highest incidence in the very young and in the elderly. The increased incidence in the elderly may be attributed to age- and aging-related epileptogenic factors. The most common cause is stroke, followed by neoplasm, and dementia, resulting in a preponderance of extratemporal epilepsy. Antiseizure medication selection requires careful consideration of medical and psychiatric comorbidities, side effect profiles, effects on mood and cognition, and drug-drug interactions. ■ ■FURTHER READING Bui E: Women’s issues in epilepsy. Continuum (Minneap Minn) 28:399, 2022. Cornes SB, Shih T: Evaluation of the patient with spells. Continuum (Minneap Minn) 17:984, 2011. Crepeau AZ, Sirven JI: Management of adult onset seizures. Mayo Clin Proc 92:306, 2017. Ellis CA et al: Epilepsy genetics: Clinical impacts and biological PART 13 Neurologic Disorders insights. Lancet Neurol 19:93, 2020. Fisher RS et al: Operational classification of seizure types by the Inter­ national League Against Epilepsy: Position paper of the ILAE Com­ mission for Classification and Terminology. Epilepsia 58:522, 2017. Gavvala JR, Schuele SU: New-onset seizure in adults and adoles­ cents: A review. JAMA 316:2657, 2016. jetté N et al: Surgical treatment for epilepsy: The potential gap between evidence and practice. Lancet Neurol 15:982, 2016. Kanner AM: Management of psychiatric and neurological comorbidi­ ties in epilepsy. Nat Rev Neurol 12:106, 2016. Krumholz A et al: Evidence-based guideline: Management of an unprovoked first seizure in adults: Report of the Guideline Develop­ ment Subcommittee of the American Academy of Neurology and the American Epilepsy Society. Neurology 84:1705, 2015. Kwan P, Brodie MJ: Early identification of refractory epilepsy. N Engl J Med 342:314, 2000. Markert MS, Fisher RS: Neuromodulation: Science and practice in epilepsy: Vagus nerve simulation, thalamic deep brain stimulation, and responsive neurostimulation. Expert Rev Neurother 19:17, 2019. Rao VR et al: Cues for seizure timing. Epilepsia 62:S15, 2021. Sen A et al: Epilepsy in older people. Lancet 395:735, 2020. Wade S. Smith, J. Claude Hemphill, III Introduction to Cerebrovascular Diseases Cerebrovascular diseases include some of the most common and devas­ tating disorders: ischemic stroke and hemorrhagic stroke. Stroke is the second leading cause of death worldwide, with 7.1 million dying from stroke in 2020. Nearly 7 million Americans age 20 or older report having had a stroke, and the prevalence is estimated to rise by 3.4 million adults in the next decade, representing 4% of the entire adult population. Although mortality is increased from 6.2 million in 2010, the age standardized death rate has fallen by 15% in this decade, likely due to better prevention and treatment. However, overall disease burden will continue to climb as the population ages, and stroke is likely to remain the second most common disabling condition in individuals aged 50 or older worldwide. A stroke, or cerebrovascular accident, is defined as an abrupt onset of a neurologic deficit that is attributable to a vascular cause. Thus, the definition of stroke is clinical, and laboratory studies including brain imaging are used to support the diagnosis. The clinical manifestations of stroke are highly variable because of the complex anatomy of the brain and its vasculature. Cerebral ischemia is caused by a reduction in blood flow that lasts longer than several seconds. Neurologic symp­ toms are manifest within seconds because neurons lack glycogen, so energy failure is rapid. If the cessation of flow lasts for more than a few minutes, infarction or death of brain tissue results. When blood flow is quickly restored, brain tissue can recover fully and the patient’s symp­ toms are only transient: this is called a transient ischemic attack (TIA). The definition of TIA requires that all neurologic signs and symptoms resolve within 24 h without evidence of brain infarction on brain imaging. Stroke has occurred if the neurologic signs and symptoms last for >24 h or brain infarction is demonstrated. A generalized reduc­ tion in cerebral blood flow due to systemic hypotension (e.g., cardiac arrhythmia, sepsis, or hemorrhagic shock) usually produces syncope (Chap. 23). If low cerebral blood flow persists for a longer duration, then infarction in the border zones between the major cerebral artery distributions may develop. In more severe instances as in cardiac arrest, global hypoxia-ischemia causes widespread brain injury; the constel­ lation of cognitive sequelae that ensues is called hypoxic-ischemic encephalopathy (Chap. 318). Focal ischemia or infarction, conversely, is usually caused by thrombosis of the cerebral vessels themselves or by emboli from a proximal arterial source or the heart (Chap. 438). Intra­ cranial hemorrhage is caused by bleeding directly into or around the brain; it produces neurologic symptoms by producing a mass effect on neural structures, from the toxic effects of blood itself, or by increasing intracranial pressure (Chap. 439). APPROACH TO THE PATIENT Cerebrovascular Disease Rapid evaluation is essential for use of acute treatments such as thrombolysis or thrombectomy. However, patients with acute stroke often do not seek medical assistance on their own because they may lose the appreciation that something is wrong (anosognosia) or lack the knowledge that acute treatment is beneficial; it is often a fam­ ily member or a bystander who calls for help. Therefore, patients and their family members should be counseled to call emergency medical services immediately if they experience or witness the sudden onset of any of the following: loss of sensory and/or motor function on one side of the body (nearly 85% of ischemic stroke patients have hemiparesis); change in vision, gait, or ability to speak or understand; or a sudden, severe headache. The acronym FAST (facial weakness, arm weakness, speech abnormality, and time) is simple and helpful to teach to the lay public about the common physical symptoms of stroke and to underscore that treatments are highly time sensitive. Other causes of sudden-onset neurologic symptoms that may mimic stroke include seizure, intracranial tumor, migraine, and metabolic encephalopathy. An adequate history from an observer that no convulsive activity occurred at the onset usually excludes seizure (Chap. 436), although ongoing complex partial seizures without tonic-clonic activity can on occasion mimic stroke. Tumors (Chap. 95) may present with acute neurologic symptoms due to hemorrhage, seizure, or hydrocephalus. Surprisingly, migraine (Chap. 441) can mimic stroke, even in patients without a sig­ nificant migraine history. When migraine develops without head pain (acephalgic migraine), the diagnosis can be especially dif­ ficult. Patients without any prior history of migraine may develop acephalgic migraine even after age 65. A sensory disturbance is often prominent, and the sensory deficit, as well as any motor defi­ cits, tends to migrate slowly across a limb, over minutes rather than seconds as with stroke. The diagnosis of migraine becomes more secure as the cortical disturbance begins to cross vascular bound­ aries or if classic visual symptoms are present such as scintillating scotomata. At times, it may be impossible to make the diagnosis of migraine until there have been multiple episodes with no residual symptoms or signs and no changes on brain magnetic resonance imaging (MRI). Metabolic encephalopathies typically produce fluc­ tuating mental status changes without focal neurologic findings. However, in the setting of prior stroke or brain injury, a patient with Stroke or TIA ABCs, glucose Obtain brain imaging Ischemic stroke/ TIA, 85% Hemorrhage 15% Consider BP lowering Consider thrombolysis/ thrombectomy Establish cause Establish cause Atrial fibrillation, 17% Carotid disease, 4% Aneurysmal SAH, 4% Hypertensive ICH, 7% Other, 64% Other, 4% Consider oral anticoagulant Consider CEA or stent Treat specific cause Consider surgery Clip or coil (Chap. 440) Deep venous thrombosis prophylaxis Physical, occupational, speech therapy Evaluate for rehab, discharge planning Secondary prevention based on disease FIGURE 437-1  Medical management of stroke and TIA. Rounded boxes are diagnoses; rectangles are interventions. Numbers are percentages of stroke overall. ABCs, airway, breathing, circulation; BP, blood pressure; CEA, carotid endarterectomy; ICH, intracerebral hemorrhage; SAH, subarachnoid hemorrhage; TIA, transient ischemic attack. fever or sepsis may manifest a recurrent hemiparesis, which clears rapidly when the infection is treated. The metabolic process serves to “unmask” a prior deficit and is termed “stroke recrudescence.” Once the diagnosis of stroke is made, a brain imaging study is necessary to determine if the cause of stroke is ischemia or hemor­ rhage (Fig. 437-1). Computed tomography (CT) imaging of the brain is the standard imaging modality to detect the presence or absence of intracranial hemorrhage (see “Imaging Studies,” below). If the stroke is ischemic, administration of recombinant tissue plas­ minogen activator (rtPA) or endovascular mechanical thrombec­ tomy may be beneficial in restoring cerebral perfusion (Chap. 438). Medical management to reduce the risk of complications becomes the next priority, followed by plans for secondary prevention. For ischemic stroke, several strategies can reduce the risk of subsequent stroke in all patients, while other strategies are effective for patients with specific causes of stroke such as cardiac embolus and carotid atherosclerosis. For hemorrhagic stroke, aneurysmal subarachnoid hemorrhage (SAH) and hypertensive intracerebral hemorrhage are two important causes. The treatment and prevention of hyperten­ sive intracerebral hemorrhage are discussed in Chap. 439. SAH is discussed in Chap. 440. ■ ■STROKE SYNDROMES A careful history and neurologic examination can often localize the region of brain dysfunction; if this region corresponds to an arterial distribution, the possible causes responsible for the syndrome can be narrowed. This is of particular importance when the patient presents with a TIA and a normal examination. For example, if a patient devel­ ops language loss and a right homonymous hemianopia, a search for causes of left middle cerebral emboli should be performed. A finding of an isolated stenosis of the right internal carotid artery in that patient, for example, suggests an asymptomatic carotid stenosis, and the search for other causes of stroke should continue. The following sections describe the clinical findings of cerebral ischemia associated with cere­ bral vascular territories depicted in Figs. 437-2 through 437-11. Stroke syndromes are divided into (1) large-vessel stroke within the anterior circulation, (2) large-vessel stroke within the posterior circulation, and (3) small-vessel disease of either vascular bed. Stroke within the Anterior Circulation  The internal carotid artery and its branches compose the anterior circulation of the brain. These vessels can be occluded by intrinsic disease of the vessel (e.g., atherosclerosis or dissection) or by embolic occlusion from a proximal source as discussed above. Occlusion of each major intracranial vessel has distinct clinical manifestations. MIDDLE CEREBRAL ARTERY  Occlusion of the proximal middle cere­ bral artery (MCA) or one of its major branches is most often due to an embolus (artery-to-artery, cardiac, or of unknown source) rather than intracranial atherothrombosis. Atherosclerosis of the proximal MCA may cause distal emboli to the middle cerebral territory or, less com­ monly, may produce low-flow TIAs. Collateral formation via leptomen­ ingeal vessels often prevents MCA stenosis from becoming symptomatic. The cortical branches of the MCA supply the lateral surface of the hemisphere except for (1) the frontal pole and a strip along the superomedial border of the frontal and parietal lobes supplied by the anterior cerebral artery (ACA) and (2) the lower temporal and occipital pole convolutions supplied by the posterior cerebral artery (PCA) (Figs. 437-2–437-5). CHAPTER 437 Treat specific cause The proximal MCA (M1 segment) gives rise to penetrating branches (termed lenticulostriate arteries) that supply the putamen, outer globus pallidus, posterior limb of the internal capsule, adjacent corona radiata, and most of the caudate nucleus (Fig. 437-2). In the sylvian fissure, the MCA in most patients divides into superior and inferior divisions (M2 branches). Branches of the inferior division supply the inferior parietal and temporal cortex, and those from the superior division supply the frontal and superior parietal cortex (Fig. 437-3). Introduction to Cerebrovascular Diseases If the entire MCA is occluded at its origin (blocking both its pen­ etrating and cortical branches) and the distal collaterals are limited, the clinical findings are contralateral hemiplegia, hemianesthesia, homonymous hemianopia, and a day or two of gaze preference to the ipsilateral side. Dysarthria is common because of facial weakness. When the dominant hemisphere is involved, global aphasia is present also, and when the nondominant hemisphere is affected, anosognosia, constructional apraxia, and neglect are found (Chap. 32). Complete MCA syndromes occur most often when an embolus occludes the stem of the artery. Cortical collateral blood flow and differ­ ing arterial configurations are probably responsible for the development of many partial syndromes. Partial syndromes may also be due to emboli that enter the proximal MCA without complete occlusion, occlude distal MCA branches, or fragment and move distally. Partial syndromes due to embolic occlusion of a single branch include hand, or arm and hand, weakness alone (brachial syndrome) or facial weakness with nonfluent (Broca) aphasia (Chap. 32), with or without arm weakness (frontal opercular syndrome). A combination of sensory disturbance, motor weakness, and nonfluent aphasia suggests that an embolus has occluded the proximal superior division and infarcted large portions of the frontal and parietal cortices (Fig. 437-3). If a fluent (Wernicke’s) aphasia occurs without weakness, the inferior division of the MCA supplying the posterior part (temporal cortex) of the domi­ nant hemisphere is probably involved. Jargon speech and an inability to comprehend written and spoken language are prominent features, often accompanied by a contralateral, homonymous superior quadrantanopia. Hemineglect or spatial agnosia without weakness indicates that the infe­ rior division of the MCA in the nondominant hemisphere is involved. Occlusion of a lenticulostriate vessel produces small-vessel (lacu­ nar) stroke within the internal capsule (Fig. 437-2). This produces pure motor stroke or sensory-motor stroke contralateral to the lesion. Ischemia within the genu of the internal capsule causes primarily facial weakness followed by arm and then leg weakness as the ischemia moves posterior within the capsule. Alternatively, the contralateral hand may become ataxic, and dysarthria will be prominent (clumsy hand, dysarthria lacunar syndrome). Lacunar infarction affecting the globus pallidus and putamen often has few clinical signs, but parkin­ sonism and hemiballismus have been reported. ANTERIOR CEREBRAL ARTERY  The ACA is divided into two seg­ ments: the precommunal (A1) circle of Willis, or stem, which connects Internal capsule Claustrum Caudate Middle cerebral a. (M2) Anterior cerebral a. (A2) Putamen Lenticulostriate as. Anterior cerebral a. (A1) Uncus Internal carotid a. Middle cerebral a. (M1) PART 13 Neurologic Disorders KEY Ant. cerebral a. Middle cerebral a. Deep branches of middle cerebral a. Post cerebral a. Deep branches of ant. cerebral a. FIGURE 437-2  Diagram of a cerebral hemisphere in coronal section showing the territories of the major cerebral vessels that branch from the internal carotid arteries. Ant. parietal a. Rolandic a. Prerolandic a. Lateral orbitofrontal a. Sup. division middle cerebral a. Temporopolar a. Inf. division middle cerebral a. Ant. temporal a. KEY Broca’s area Sensory cortex Auditory area Contraversive eye center Wernicke’s aphasia area Visual cortex FIGURE 437-3  Diagram of a cerebral hemisphere, lateral aspect, showing the branches and distribution of the middle cerebral artery (MCA) and the principal regions of cerebral localization. Note the bifurcation of the MCA into a superior and inferior division. Signs and symptoms: Structures involved Paralysis of the contralateral face, arm, and leg; sensory impairment over the same area (pinprick, cotton touch, vibration, position, two-point discrimination, stereog­ nosis, tactile localization, barognosis, cutaneographia): Somatic motor area for face and arm and the fibers descending from the leg area to enter the corona radiata and corresponding somatic sensory system Motor aphasia: Motor speech area of the dominant hemisphere Central aphasia, word deafness, anomia, jargon speech, sensory agraphia, acalculia, alexia, finger agnosia, right-left confusion (the last four comprise the Gerstmann syndrome): Central, suprasylvian speech area and parietooccipital cortex of the dominant hemisphere Conduction aphasia: Central speech area (parietal operculum) Apractagnosia of the nondominant hemisphere, anosognosia, hemiasomatognosia, unilateral neglect, agnosia for the left half of external space, dressing “apraxia,” constructional “apraxia,” distortion of visual coordinates, inaccurate localization in the half field, impaired ability to judge distance, upside-down reading, visual illu­ sions (e.g., it may appear that another person walks through a table): Nondominant parietal lobe (area corresponding to speech area in dominant hemisphere); loss of topographic memory is usually due to a nondominant lesion, occasionally to a dominant one Homonymous hemianopsia (or less frequently a superior quadrantanopsia due to isolated anterior temporal lobe infarction or inferior quadrantanopsia due to isolated parietal lobe infarction) Paralysis of conjugate gaze to the opposite side: Frontal contraversive eye field or projecting fibers. the internal carotid artery to the anterior communicating artery, and the postcommunal (A2) segment distal to the anterior communicating artery (Figs. 437-2 and 437-4). The A1 segment gives rise to several deep penetrating branches that supply the anterior limb of the internal capsule, the anterior perforate substance, amygdala, anterior hypo­ thalamus, and the inferior part of the head of the caudate nucleus. Occlusion of the proximal ACA is usually well tolerated because of collateral flow through the anterior communicating artery and col­ laterals through the MCA and PCA. Occlusion of a single A2 segment results in the contralateral symptoms noted in Fig. 437-4. If both A2 segments arise from a single anterior cerebral stem (contralateral A1 segment atresia), the occlusion may affect both hemispheres. Profound abulia (a delay in verbal and motor response) and bilateral pyramidal signs with paraparesis or quadriparesis and urinary incontinence result. ANTERIOR CHOROIDAL ARTERY  This artery arises from the internal carotid artery and supplies the posterior limb of the internal capsule and the white matter posterolateral to it, through which pass some of the geniculocalcarine fibers (Fig. 437-5). The complete syndrome of anterior choroidal artery occlusion consists of contralateral hemiple­ gia, hemianesthesia (hypesthesia), and homonymous hemianopia. However, because this territory is also supplied by penetrating vessels of the proximal MCA and the posterior communicating and posterior choroidal arteries, minimal deficits may occur, and patients frequently recover substantially. Anterior choroidal strokes are usually the result of in situ thrombosis of the vessel, and the vessel is particularly vul­ nerable to iatrogenic occlusion during surgical clipping of aneurysms arising from the internal carotid artery. Post. parietal a. Angular a. Post. temporal a. Visual radiation Motor cortex Pericallosal a. Post. parietal a. Secondary motor area Medial prerolandic a. Callosomarginal a. Frontopolar a. Ant. cerebral a. Medial orbitofrontal a. Post. communicating a. Penetrating thalamosubthalamic paramedian As. Post. cerebral stem FIGURE 437-4  Diagram of a cerebral hemisphere, medial aspect, showing the branches and distribution of the anterior cerebral artery and the principal regions of cerebral localization. Signs and symptoms: Structures involved Paralysis of opposite foot and leg: Motor leg area A lesser degree of paresis of opposite arm: Arm area of cortex or fibers descending to corona radiata. Cortical sensory loss over toes, foot, and leg: Sensory area for foot and leg Urinary incontinence: Sensorimotor area in paracentral lobule Contralateral grasp reflex, sucking reflex, gegenhalten (paratonic rigidity): Medial surface of the posterior frontal lobe; likely supplemental motor area Abulia (akinetic mutism), slowness, delay, intermittent interruption, lack of spontaneity, whispering, reflex distraction to sights and sounds: Uncertain localization— probably cingulate gyrus and medial inferior portion of frontal, parietal, and temporal lobes Impairment of gait and stance (gait apraxia): Frontal cortex near leg motor area Dyspraxia of left limbs, tactile aphasia in left limbs: Corpus callosum INTERNAL CAROTID ARTERY  The clinical picture of internal carotid occlusion varies depending on whether the cause of ischemia is propa­ gated thrombus, embolism, or low flow. The cortex supplied by the MCA territory is affected most often. With a competent circle of Willis, occlu­ sion may go unnoticed. If the thrombus propagates up the internal carotid artery into the MCA or embolizes it, symptoms are identical to proximal MCA occlusion (see above). Sometimes there is massive infarction of the entire deep white matter and cortical surface. When the origins of both the ACA and MCA are occluded at the top of the carotid artery, abulia or stupor occurs with hemiplegia, hemianesthesia, and aphasia or anosogno­ sia. When the PCA arises from the internal carotid artery (a configuration called a fetal PCA), it may also become occluded and give rise to symp­ toms referable to its peripheral territory (Figs. 437-4 and 437-5). In addition to supplying the ipsilateral brain, the internal carotid artery perfuses the optic nerve and retina via the ophthalmic artery. In ~25% of symptomatic internal carotid disease, recurrent transient monocular blindness (amaurosis fugax) warns of the lesion. Patients typically describe a horizontal shade that sweeps down or up across the field of vision. They may also complain that their vision was blurred in that eye or that the upper or lower half of vision disappeared. In most cases, these symptoms last only a few minutes. Rarely, ischemia or infarction of the ophthalmic artery or central retinal arteries occurs at the time of cerebral TIA or infarction. A high-pitched prolonged carotid bruit fading into diastole is often associated with tightly stenotic lesions. As the stenosis grows tighter and flow distal to the stenosis becomes reduced, the bruit becomes fainter and may disappear when occlusion is imminent. COMMON CAROTID ARTERY  All symptoms and signs of internal carotid occlusion may also be present with occlusion of the common carotid artery. Jaw claudication may result from low flow in the exter­ nal carotid branches. Bilateral common carotid artery occlusions at their origin may occur in Takayasu’s arteritis (Chap. 375). Medial rolandic a. Motor cortex Sensory cortex Splenial a. Lateral posterior choroidal a. Post. thalamic a. Parietooccipital a. Visual cortex Striate area along calcarine sulcus CHAPTER 437 Calcarine a. Post. temporal a. Medial posterior choroidal a. Introduction to Cerebrovascular Diseases Hippocampal As. Ant. temporal a. Stroke within the Posterior Circulation  The posterior circulation is composed of the paired vertebral arteries, the basilar artery, and the paired PCAs. The vertebral arteries join to form the basilar artery at the pontomedullary junction. The basilar artery divides into two PCAs in the interpeduncular fossa (Figs. 437-4–437-6). These major arteries give rise to long and short circumferential branches and to smaller deep pen­ etrating branches that supply the cerebellum, medulla, pons, midbrain, subthalamus, thalamus, hippocampus, and medial temporal and occipital lobes. Occlusion of each vessel produces its own distinctive syndrome. POSTERIOR CEREBRAL ARTERY  In 75% of cases, both PCAs arise from the bifurcation of the basilar artery; in 20%, one has its origin from the ipsilateral internal carotid artery via the posterior commu­ nicating artery; in 5%, both originate from the respective ipsilateral internal carotid arteries (Figs. 437-4–437-6). The precommunal, or P1, segment of the true PCA is atretic in such cases. PCA syndromes usually result from atheroma formation or emboli that lodge at the top of the basilar artery; posterior circulation disease may also be caused by dissection of either vertebral artery or fibromus­ cular dysplasia. Two clinical syndromes are commonly observed with occlusion of the PCA: (1) P1 syndrome: midbrain, subthalamic, and thalamic signs, which are due to disease of the proximal P1 segment of the PCA or its penetrating branches (thalamogeniculate, Percheron, and posterior choroidal arteries); and (2) P2 syndrome: cortical temporal and occipi­ tal lobe signs, due to occlusion of the P2 segment distal to the junction of the PCA with the posterior communicating artery. P1 SYNDROMES  Infarction usually occurs in the ipsilateral subthala­ mus and medial thalamus and in the ipsilateral cerebral peduncle and midbrain (Figs. 437-5 and 437-11). A third nerve palsy with contra­ lateral ataxia (Claude’s syndrome) or with contralateral hemiplegia (Weber’s syndrome) may result. The ataxia indicates involvement of Ant. cerebral a. Internal carotid a. Post. communicating a. Post. cerebral a. Ant. choroidal a. Medial posterior choroidal a. Mesencephalic paramedian As. Ant. temporal a. Splenial a. Parietooccipital a. Hippocampal a. PART 13 Neurologic Disorders Calcarine a. Post. temporal a. Post. thalamic a. Visual cortex Lateral posterior choroidal a. FIGURE 437-5  Inferior aspect of the brain with the branches and distribution of the posterior cerebral artery and the principal anatomic structures shown. Signs and symptoms: Structures involved Peripheral territory (see also Fig. 437-9). Homonymous hemianopia (often upper quadrantic): Calcarine cortex or optic radiation nearby. Bilateral homonymous hemianopia, cortical blindness, awareness or denial of blindness; tactile naming, achromatopia (color blindness), failure to see to-and-fro movements, inability to perceive objects not centrally located, apraxia of ocular movements, inability to count or enumerate objects, tendency to run into things that the patient sees and tries to avoid: Bilateral occipital lobe with possibly the parietal lobe involved. Verbal dyslexia without agraphia, color anomia: Dominant calcarine lesion and posterior part of corpus callosum. Memory defect: Hippocampal lesion bilaterally or on the dominant side only. Topographic disorientation and prosopagnosia: Usually with lesions of nondominant, calcarine, and lingual gyrus. Simultanagnosia, hemivisual neglect: Dominant visual cortex, contralateral hemisphere. Unformed visual halluci­ nations, peduncular hallucinosis, metamorphopsia, teleopsia, illusory visual spread, palinopsia, distortion of outlines, central photophobia: Calcarine cortex. Complex hallucinations: Usually nondominant hemisphere. Central territory. Thalamic syndrome: sensory loss (all modalities), spontaneous pain and dysesthesias, choreoathetosis, intention tremor, spasms of hand, mild hemiparesis: Posteroventral nucleus of thalamus; involvement of the adjacent sub­ thalamus body or its afferent tracts. Thalamoperforate syndrome: crossed cerebel­ lar ataxia with ipsilateral third nerve palsy (Claude’s syndrome): Dentatothalamic tract and issuing third nerve. Weber’s syndrome: third nerve palsy and contralateral hemiplegia: Third nerve and cerebral peduncle. Contralateral hemiplegia: Cerebral peduncle. Paralysis or paresis of vertical eye movement, skew deviation, sluggish pupillary responses to light, slight miosis and ptosis (retraction nystagmus and “tucking” of the eyelids may be associated): Supranuclear fibers to third nerve, interstitial nucleus of Cajal, nucleus of Darkschewitsch, and posterior commissure. Contralateral rhythmic, ataxic action tremor; rhythmic postural or “holding” tremor (rubral tremor): Dentatothalamic tract. the red nucleus or dentatorubrothalamic tract; the hemiplegia is local­ ized to the cerebral peduncle (Fig. 437-11). If the subthalamic nucleus is involved, contralateral hemiballismus may occur. Occlusion of the artery of Percheron produces paresis of upward gaze and drowsiness and often abulia. Extensive infarction in the midbrain and subthalamus occurring with bilateral proximal PCA occlusion presents as coma, unreactive pupils, bilateral pyramidal signs, and decerebrate rigidity. Occlusion of the penetrating branches of thalamic and thalamoge­ niculate arteries produces less extensive thalamic and thalamocapsular lacunar syndromes. The thalamic Déjérine-Roussy syndrome consists of contralateral hemisensory loss followed later by an agonizing, sear­ ing, or burning pain in the affected areas. It is persistent and responds poorly to analgesics. Anticonvulsants (carbamazepine or gabapentin) or tricyclic antidepressants may be beneficial. P2 SYNDROMES  (Figs. 437-4 and 437-5) Occlusion of the distal PCA causes infarction of the medial temporal and occipital lobes. Superior cerebellar a. Middle cerebral a. Posterior cerebral a. Deep branches of the basilar a. Basilar a. Vertebral a. Posterior Inferior cerebellar a. Anterior Inferior cerebellar a. FIGURE 437-6  Diagram of the posterior circulation, showing the intracranial vertebral arteries forming the basilar artery that gives off the anterior inferior cerebellar, superior cerebellar, and posterior cerebral arteries. The posterior inferior cerebellar artery arises from each of the vertebral segments. The majority of brainstem blood flow arises from numerous deep branches of the basilar artery that penetrate directly into the brainstem. Contralateral homonymous hemianopia without macula sparing is the usual manifestation. (MCA strokes often produce hemianopia but typically spare the macula as calcarine cortex is perfused by the P2 segment.) Occasionally, only the upper quadrant of visual field is involved or the macula vision is spared. If the visual association areas are spared and only the calcarine cortex is involved, the patient may be aware of visual defects. Medial temporal lobe and hippocampal involvement may cause an acute disturbance in memory, particularly if it occurs in the dominant hemisphere. The defect usually clears because memory has bilateral representation. If the dominant hemi­ sphere is affected and the infarct extends to involve the splenium of the corpus callosum, the patient may demonstrate alexia without agraphia. Visual agnosia for faces, objects, mathematical symbols, and colors and anomia with paraphasic errors (amnestic aphasia) may also occur, even without callosal involvement. Occlusion of the PCA can produce peduncular hallucinosis (visual hallucinations of brightly colored scenes and objects). Bilateral infarction in the distal PCAs produces cortical blindness (blindness with preserved pupillary light reaction). The patient is often unaware of the blindness or may even deny it (Anton’s syndrome). Tiny islands of vision may persist, and the patient may report that vision fluctuates as images are captured in the preserved portions. Rarely, only peripheral vision is lost and central vision is spared, resulting in “gun-barrel” vision. Bilateral visual association area lesions may result in Balint’s syndrome, a disorder of the orderly visual scanning of the environment (Chap. 32), usually resulting from infarctions second­ ary to low flow in the “watershed” between the distal PCA and MCA territories, as occurs after cardiac arrest. Patients may experience per­ sistence of a visual image for several minutes despite gazing at another scene (palinopsia) or an inability to synthesize the whole of an image (asimultanagnosia). Embolic occlusion of the top of the basilar artery can produce any or all the central or peripheral territory symptoms. The hallmark is the sudden onset of bilateral signs, including ptosis, pupillary asymmetry or lack of reaction to light, and somnolence. Patients will often have posturing and myoclonic jerking that simulates seizure. Interrogation of the noncontrast CT scan for a hyperdense basilar artery sign (indicating thrombus in the basilar artery) or CT angiography (CTA) establishes this diagnosis. Physicians should be suspicious of this rare but potentially treatable stroke syndrome in the setting of presumed new-onset seizure and cranial nerve deficits. VERTEBRAL AND POSTERIOR INFERIOR CEREBELLAR ARTERIES  The vertebral artery, which arises from the innominate artery on the right and the subclavian artery on the left, consists of four segments. The first (V1) extends from its origin to its entrance into the sixth or fifth transverse vertebral foramen. The second segment (V2) traverses the vertebral foramina from C6 to C2. The third (V3) passes through the transverse foramen and circles around the arch of the atlas to pierce the dura at the foramen magnum. The fourth (V4) segment courses Pyramid Medial lemniscus Spinothalamic tract Ventral spinocerebellar tract Dorsal spinocerebellar tract Nucleus ambiguus – motor 9 +10 Descending nucleus and tract - 5th n. Tractus solitarius with nucleus Vestibular nucleus 12th n. nucleus Medullary syndrome: Lateral Medial FIGURE 437-7  Axial section at the level of the medulla, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Note that in Figs. 437-7 through 437-11, all drawings are oriented with the dorsal surface at the bottom, matching the orientation of the brainstem that is commonly seen in all modern neuroimaging studies. Approximate regions involved in medial and lateral medullary stroke syndromes are shown. Signs and symptoms: Structures involved 1. Medial medullary syndrome (occlusion of vertebral artery or of branch of vertebral or lower basilar artery) On side of lesion Paralysis with atrophy of one-half half the tongue: Ipsilateral twelfth nerve Paralysis of arm and leg, sparing face; impaired tactile and proprioceptive sense over one-half the body: Contralateral pyramidal tract and medial lemniscus Pain, numbness, impaired sensation over one-half the face: Descending tract and nucleus fifth nerve Ataxia of limbs, falling to side of lesion: Uncertain—restiform body, cerebellar hemisphere, cerebellar fibers, spinocerebellar tract (?) Nystagmus, diplopia, oscillopsia, vertigo, nausea, vomiting: Vestibular nucleus Horner’s syndrome (miosis, ptosis, decreased sweating): Descending sympathetic tract Dysphagia, hoarseness, paralysis of palate, paralysis of vocal cord, diminished gag reflex: Issuing fibers ninth and tenth nerves Loss of taste: Nucleus and tractus solitarius Numbness of ipsilateral arm, trunk, or leg: Cuneate and gracile nuclei Weakness of lower face: Genuflected upper motor neuron fibers to ipsilateral facial nucleus Impaired pain and thermal sense over half the body, sometimes face: Spinothalamic tract 5. Basilar artery syndrome (the syndrome of the lone vertebral artery is equivalent): A combination of the various brainstem syndromes plus those arising in the posterior cerebral artery distribution. Bilateral long tract signs (sensory and motor; cerebellar and peripheral cranial nerve abnormalities): Bilateral long tract; cerebellar and peripheral cranial nerves Paralysis or weakness of all extremities, plus all bulbar musculature: Corticobulbar and corticospinal tracts bilaterally upward to join the other vertebral artery to form the basilar artery (Fig. 437-6); only the fourth segment gives rise to branches that supply the brainstem and cerebellum. The posterior inferior cerebellar artery (PICA) in its proximal segment supplies the lateral medulla and, in its distal branches, the inferior surface of the cerebellum. Atherothrombotic lesions have a predilection for V1 and V4 seg­ ments of the vertebral artery. The first segment may become diseased at the origin of the vessel and may produce posterior circulation emboli; collateral flow from the contralateral vertebral artery or the ascending cervical, thyrocervical, or occipital arteries is usually sufficient to pre­ vent low-flow TIAs or stroke. When one vertebral artery is atretic and an atherothrombotic lesion threatens the origin of the other, the collat­ eral circulation, which may also include retrograde flow down the basi­ lar artery, is often insufficient (Figs. 437-5 and 437-6). In this setting, low-flow TIAs may occur, consisting of syncope, vertigo, and alternat­ ing hemiplegia; this state also sets the stage for thrombosis. Disease of the distal fourth segment of the vertebral artery can promote thrombus formation manifest as embolism or with propagation as basilar artery thrombosis. Stenosis proximal to the origin of the PICA can threaten the lateral medulla and posterior inferior surface of the cerebellum. If the subclavian artery is occluded proximal to the origin of the verte­ bral artery, there is a reversal in the direction of blood flow in the ipsilateral vertebral artery. Exercise of the ipsilateral arm may increase demand on vertebral flow, producing posterior circulation TIAs, or “subclavian steal.” Although atheromatous disease rarely narrows the second and third segments of the vertebral artery, this region is subject to dissection, fibromuscular dysplasia, and, rarely, encroachment by osteophytic spurs within the vertebral foramina. 12th n. Inferior olive Medulla 10th n. Descending sympathetic tract Restiform body Olivocerebellar fibers Cerebellum CHAPTER 437 Medial longitudinal fasciculus Introduction to Cerebrovascular Diseases Embolic occlusion or thrombosis of a V4 segment causes isch­ emia of the lateral medulla. The constellation of vertigo, numbness of the ipsilateral face and contralateral limbs, diplopia, hoarseness, dysarthria, dysphagia, and ipsilateral Horner’s syndrome is called the lateral medullary (or Wallenberg’s) syndrome (Fig. 437-7). Ipsilateral upper motor neuron facial weakness can also occur. Most cases result from ipsilateral vertebral artery occlusion; in the remainder, PICA occlusion is responsible. Occlusion of the medullary penetrating branches of the vertebral artery or PICA results in partial syndromes. Hemiparesis is not a typical feature of vertebral artery occlusion; how­ ever, quadriparesis may result from occlusion of the anterior spinal artery. Rarely, a medial medullary syndrome occurs with infarction of the pyramid and contralateral hemiparesis of the arm and leg, sparing the face. If the medial lemniscus and emerging hypoglossal nerve fibers are involved, contralateral loss of joint position sense and ipsilateral tongue weakness occur. Cerebellar infarction can lead to respiratory arrest due to brainstem herniation from cerebellar swelling, closure of the aqueduct of Silvius or fourth ventricle, followed by hydrocephalus and central herniation. This added downward displacement of the brainstem from hydroceph­ alus will exacerbate respiratory and hemodynamic instability. Drowsi­ ness, Babinski signs, dysarthria, and bifacial weakness may be absent, or present only briefly, before respiratory arrest ensues. Gait unsteadi­ ness, headache, dizziness, nausea, and vomiting may be the only early symptoms and signs and should arouse suspicion of this impending complication, which may require neurosurgical decompression, often with an excellent outcome. Separating these symptoms from those of Corticospinal and corticobulbar tract Spinothalamic tract Medial lemniscus 6th n. Descending tract and nucleus of 5th n. 7th n. 8th n. Dorsal cochlear nucleus 7th n. nucleus Restiform body PART 13 Neurologic Disorders Medial longitudinal fasciculus Vestibular nucleus 6th n. nucleus complex Inferior pontine syndrome: Lateral Medial FIGURE 437-8  Axial section at the level of the inferior pons, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Approximate regions involved in medial and lateral inferior pontine stroke syndromes are shown. Signs and symptoms: Structures involved Paralysis of conjugate gaze to side of lesion (preservation of convergence): Center for conjugate lateral gaze Nystagmus: Vestibular nucleus Ataxia of limbs and gait: Likely middle cerebellar peduncle Diplopia on lateral gaze: Abducens nerve Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract in lower pons Impaired tactile and proprioceptive sense over one-half of the body: Medial lemniscus Horizontal and vertical nystagmus, vertigo, nausea, vomiting, oscillopsia: Vestibular nerve or nucleus Facial paralysis: Seventh nerve Paralysis of conjugate gaze to side of lesion: Center for conjugate lateral gaze Deafness, tinnitus: Auditory nerve or cochlear nucleus Ataxia: Middle cerebellar peduncle and cerebellar hemisphere Impaired sensation over face: Descending tract and nucleus fifth nerve Impaired pain and thermal sense over one-half the body (may include face): Spinothalamic tract viral labyrinthitis can be a challenge, but headache, neck stiffness, and unilateral dysmetria favor stroke. BASILAR ARTERY  Branches of the basilar artery (Fig. 437-6) supply the base of the pons and superior cerebellum and fall into three groups: (1) paramedian, 7–10 in number, which supply a wedge of pons on either side of the midline; (2) short circumferential, 5–7 in number, that supply the lateral two-thirds of the pons and middle and superior cerebellar peduncles; and (3) bilateral long circumferential (superior cerebellar and anterior inferior cerebellar arteries), which course around the pons to supply the cerebellar hemispheres. Atheromatous lesions can occur anywhere along the basilar trunk but are most frequent in the proximal basilar and distal vertebral seg­ ments. Typically, lesions occlude either the proximal basilar and one or both vertebral arteries. The clinical picture varies depending on the availability of retrograde collateral flow from the posterior communi­ cating arteries. Rarely, dissection of a vertebral artery may involve the basilar artery and, depending on the location of true and false lumen, may produce multiple penetrating artery strokes. Although atherothrombosis occasionally occludes the distal por­ tion of the basilar artery, emboli from the heart or proximal vertebral or basilar segments are more commonly responsible for “top of the basilar” syndromes. Because the brainstem contains many structures in close apposition, a diversity of clinical syndromes may emerge with ischemia, reflecting involvement of the corticospinal and corticobulbar tracts, ascending sensory tracts, and cranial nerve nuclei (Figs. 437-7 to 437-11). The symptoms of transient ischemia or infarction in the territory of the basilar artery often do not indicate whether the basilar artery Middle cerebellar peduncle 7th and 8th cranial nerves Inferior pons Cerebellum itself or one of its branches is diseased, yet this distinction has impor­ tant implications for therapy. The picture of complete basilar occlusion, however, is easy to recognize as a constellation of bilateral long tract signs (sensory and motor) with signs of cranial nerve and cerebellar dysfunction. Patients may have spontaneous posturing movements that are myoclonic in nature and simulate seizure activity. These move­ ments are brief, repetitive, and multifocal and often confused with status epilepticus. CT or magnetic resonance angiography can rapidly detect basilar thrombosis, and rapid treatment (thrombectomy) can be lifesaving. A “locked-in” state of preserved consciousness with quad­ riplegia and cranial nerve signs suggests complete pontine and lower midbrain infarction. The therapeutic goal is to identify impending basilar occlusion before devastating infarction occurs. A series of TIAs and a slowly progressive, fluctuating stroke are extremely significant, because they often herald an atherothrombotic occlusion of the distal vertebral or proximal basilar artery. TIAs in the proximal basilar distribution may produce vertigo (often described by patients as “swimming,” “swaying,” “moving,” “unsteadi­ ness,” or “light-headedness”). Other symptoms that warn of basilar thrombosis include diplopia, dysarthria, facial or circumoral numb­ ness, and hemisensory symptoms. In general, symptoms of basilar branch TIAs affect one side of the brainstem, whereas symptoms of basilar artery TIAs usually affect both sides, although a “herald” hemi­ paresis has been emphasized as an initial symptom of basilar occlusion. Most often, TIAs, whether due to impending occlusion of the basilar artery or a basilar branch, are short lived (5–30 min) and repetitive, occurring several times a day. The pattern suggests intermittent reduc­ tion of flow. Although treatment with intravenous heparin or various Medial lemniscus 5th n. Lateral lemniscus Middle cerebellar peduncle Spinothalamic tract 5th n. motor nucleus 5th n. sensory nucleus Superior cerebellar peduncle Medial longitudinal fasciculus Midpontine syndrome: Lateral Medial FIGURE 437-9  Axial section at the level of the midpons, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Approximate regions involved in medial and lateral midpontine stroke syndromes are shown. Signs and symptoms: Structures involved Ataxia of limbs and gait (more prominent in bilateral involvement): Pontine nuclei Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract Variable impaired touch and proprioception when lesion extends posteriorly: Medial lemniscus Ataxia of limbs: Middle cerebellar peduncle Paralysis of muscles of mastication: Motor fibers or nucleus of fifth nerve Impaired sensation over side of face: Sensory fibers or nucleus of fifth nerve Impaired pain and thermal sense on limbs and trunk: Spinothalamic tract combinations of antiplatelet agents has been used to prevent clot propagation, there is no specific evidence to support any one approach, and endovascular intervention is also an option. Atherothrombotic occlusion of the basilar artery with infarction usually causes bilateral brainstem signs. A gaze paresis or inter­ nuclear ophthalmoplegia associated with ipsilateral hemiparesis may be the only manifestation of bilateral brainstem ischemia. More often, unequivocal signs of bilateral pontine disease are present. Complete basilar thrombosis carries a high mortality. Occlusion of a branch of the basilar artery usually causes unilateral symptoms and signs involving motor, sensory, and cranial nerves. If symptoms remain unilateral, concern over pending basilar occlusion should be reduced. Occlusion of the superior cerebellar artery results in severe ipsi­ lateral cerebellar ataxia, nausea and vomiting, dysarthria, and con­ tralateral loss of pain and temperature sensation over the extremities, body, and face (spino- and trigeminothalamic tract). Partial deafness, ataxic tremor of the ipsilateral upper extremity, Horner’s syndrome, and palatal myoclonus may occur rarely. Partial syndromes occur fre­ quently (Fig. 437-10). With large strokes, swelling and mass effects may compress the midbrain or produce hydrocephalus; these symptoms may evolve rapidly. Neurosurgical intervention may be lifesaving in such cases. Occlusion of the anterior inferior cerebellar artery produces vari­ able degrees of infarction because the size of this artery and the ter­ ritory it supplies vary inversely with those of the PICA. The principal symptoms include (1) ipsilateral deafness, facial weakness, vertigo, nausea and vomiting, nystagmus, tinnitus, cerebellar ataxia, Horner’s syndrome, and paresis of conjugate lateral gaze; and (2) contralateral loss of pain and temperature sensation. An occlusion close to the origin of the artery may cause corticospinal tract signs (Fig. 437-8). Corticospinal and corticopontine tracts Temporal lobe Mid-pons 5th cranial nerve CHAPTER 437 Cerebellum Introduction to Cerebrovascular Diseases Occlusion of one of the short circumferential branches of the basilar artery affects the lateral two-thirds of the pons and middle or supe­ rior cerebellar peduncle, whereas occlusion of one of the paramedian branches affects a wedge-shaped area on either side of the medial pons (Figs. 437-8–437-10). ■ ■IMAGING STUDIES See also Chap. 434. CT Scans  CT radiographic images identify or exclude hemorrhage as the cause of stroke, and they identify extraparenchymal hemor­ rhages, neoplasms, abscesses, and other conditions masquerading as stroke. Brain CT scans obtained in the first several hours after an infarction generally show no abnormality (Fig. 437-12A), and the infarct may not be seen reliably for 24–48 h. The decision to treat patients with IV plasminogen activators is based on the clinical diag­ nosis of stroke and a CT scan showing no hemorrhage. CT may fail to show small ischemic strokes in the posterior fossa because of bone artifact; small infarcts on the cortical surface may also be missed. Contrast-enhanced CT scans add specificity by showing contrast enhancement of subacute infarcts and allow visualization of venous structures. Coupled with multidetector scanners, CT angiography can be performed with administration of IV iodinated contrast allowing visualization of the cervical and intracranial arteries, intracranial veins, and aortic arch in one imaging session. Carotid disease and intracranial vascular occlusions are readily identified with this method (see Fig. 438-2). After an IV bolus of contrast, deficits in brain perfusion produced by vascular occlusion can also be demonstrated (Fig. 437-12D) and used to predict the region of infarcted brain and the brain at risk of further infarction (i.e., the ischemic penumbra, see “Pathophysiology of Isch­ emic Stroke” in Chap. 438). CT imaging is also sensitive for detecting SAH (although by itself does not rule it out), and CTA can readily Pontine nuclei and pontocerebellar fibers Corticospinal tract Spinothalamic tract PART 13 Neurologic Disorders Superior cerebellar peduncle Medial longitudinal fasciculus Superior pontine syndrome: Lateral Medial FIGURE 437-10  Axial section at the level of the superior pons, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Approximate regions involved in medial and lateral superior pontine stroke syndromes are shown. Signs and symptoms: Structures involved Cerebellar ataxia (probably): Superior and/or middle cerebellar peduncle Internuclear ophthalmoplegia: Medial longitudinal fasciculus Myoclonic syndrome, palate, pharynx, vocal cords, respiratory apparatus, face, oculomotor apparatus, etc.: Localization uncertain—central tegmental bundle, dentate projection, inferior olivary nucleus Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract Rarely touch, vibration, and position are affected: Medial lemniscus Ataxia of limbs and gait, falling to side of lesion: Middle and superior cerebellar peduncles, superior surface of cerebellum, dentate nucleus Dizziness, nausea, vomiting; horizontal nystagmus: Vestibular nucleus Paresis of conjugate gaze (ipsilateral): Pontine contralateral gaze Skew deviation: Uncertain Miosis, ptosis, decreased sweating over face (Horner’s syndrome): Descending sympathetic fibers Tremor: Localization unclear—Dentate nucleus, superior cerebellar peduncle Impaired pain and thermal sense on face, limbs, and trunk: Spinothalamic tract Impaired touch, vibration, and position sense, more in leg than arm (there is a tendency to incongruity of pain and touch deficits): Medial lemniscus (lateral portion) 3rd n. Crus cerebri Substantia nigra 3rd nerve nucleus Superior colliculus Cerebral aqueduct Midbrain syndrome: Lateral Medial FIGURE 437-11  Axial section at the level of the midbrain, depicted schematically on the left, with a corresponding magnetic resonance image on the right. Approximate regions involved in medial and lateral midbrain stroke syndromes are shown. Signs and symptoms: Structures involved Eye “down and out” secondary to unopposed action of fourth and sixth cranial nerves, with dilated and unresponsive pupil: Third nerve fibers Paralysis of face, arm, and leg: Corticobulbar and corticospinal tract descending in crus cerebri Eye “down and out” secondary to unopposed action of fourth and sixth cranial nerves, with dilated and unresponsive pupil: Third nerve fibers and/or third nerve nucleus Hemiataxia, hyperkinesias, tremor: Red nucleus, dentatorubrothalamic pathway Temporal lobe Medial lemniscus Basilar artery Central tegmental bundle Lateral lemniscus Superior pons Basilar artery Internal carotid artery Red nucleus Medial lemniscus Spinothalamic tract Midbrain Periaqueductal gray matter P A B CBF R CBF <30%: 112 ml Mismatch volume: 43 ml Mismatch ratio: 1.4 D FIGURE 437-12  (A) Noncontrast head computed tomography (CT) image of an 83-year-old man with sudden onset left hemiplegia, left homonymous hemianopia, rightward gaze deviation and left hemineglect showing no clear brain infarction and hyperdensity within the right middle cerebral artery (MCA) suggestive of clot. (B) CT angiography performed at the same time as the CT showing absence of the right MCA and anterior cerebral artery (ACA) vessels consistent with occlusion of the bifurcation of the right intracranial internal carotid artery. (C) Follow-up head CT 1 day later showing extensive infarction of the right frontal lobe with brain herniation. (D) CT perfusion performed with studies shown in A and B. This predicts a large core infarction (pink regions) despite attempts at revascularization with thrombectomy. CBF, cerebral blood flow. identify intracranial aneurysms (Chap. 440). Because of its speed and wide availability, noncontrast head CT is the imaging modality of choice in patients with acute stroke (Fig. 437-1), and CTA and CT per­ fusion imaging may also be useful and convenient adjuncts. ■ ■MRI MRI reliably documents the extent and location of infarction in all areas of the brain, including the posterior fossa and cortical surface. Diffusion-weighted imaging (DWI) identifies regions of brain infarc­ tion within minutes of the stroke onset (Fig. 437-13A, B), while fluidattenuated inversion recovery (FLAIR) imaging reliably reveals areas of prior brain infarction from a few days to years later (Fig. 437-13C). CT is poorly sensitive to brain infarction in the posterior fossae compared to MRI DWI images (Fig. 437-13D, E). MRI also identifies intracranial hemorrhage and other abnormalities and, using special sequences, can be as sensitive as CT for detecting acute intracerebral hemorrhage. MRI scanners with magnets of higher field strength produce more reli­ able and precise images. Using IV administration of gadolinium con­ trast, magnetic resonance (MR) perfusion studies can be performed. Brain regions showing poor perfusion but no abnormality on diffusion provide, compared to CT, an equivalent measure of the ischemic pen­ umbra. MR angiography is highly sensitive for stenosis of extracranial internal carotid arteries and of large intracranial vessels. With higher CHAPTER 437 C P A Tmax Introduction to Cerebrovascular Diseases L Tmax >6.0s: 155 ml degrees of stenosis, MR angiography tends to overestimate the degree of stenosis when compared to conventional x-ray angiography. MRI with fat saturation is an imaging sequence used to visualize extra- or intracranial arterial dissection. This sensitive technique images clotted blood within the dissected vessel wall. Iron-sensitive imaging (ISI) is helpful to detect cerebral microbleeds that may be present in cerebral amyloid angiopathy and other hemorrhagic disorders. MRI is more expensive and time consuming than CT and less read­ ily available. Claustrophobia and the logistics of imaging acutely criti­ cally ill patients also limit its application. Most acute stroke protocols use CT because of these limitations. However, MRI is useful outside the acute period by more clearly defining the extent of tissue injury and discriminating new from old regions of brain infarction. MRI may have utility in patients with TIA, because it is also more likely to iden­ tify new infarction, which is a strong predictor of subsequent stroke. Cerebral Angiography  Conventional x-ray cerebral angiography is the gold standard for identifying and quantifying atherosclerotic stenoses of the cerebral arteries and for identifying and characteriz­ ing other pathologies, including aneurysms, vasospasm, intraluminal thrombi, fibromuscular dysplasia, arteriovenous fistulae, vasculitis, and collateral channels of blood flow. Conventional angiography car­ ries risks of arterial damage, groin hemorrhage, embolic stroke, and PART 13 Neurologic Disorders A AHL D E B C FIGURE 437-13  Examples of magnetic resonance imaging (MRI) imaging of acute ischemic infarcts. (A) Diffusion-weighted image (DWI) revealing bright region in the left pons (arrow), and (B) dark region on apparent diffusion coefficient (ADC) in the same region. Bright regions on DWI and corresponding dark regions on ADC are consistent with acute brain ischemia (within minutes to hours of stroke onset). (C) Same region of the brain 2 days later showing bright region in the infarcted tissue on fluid-attenuated inversion recovery (FLAIR) images. The DWI and ADC values will return to normal after 10–14 days while the FLAIR abnormality will persist long term. (D) DWI MRI and (E) computed tomography (CT) images of a patient with acute-onset vertigo. The DWI image shows an acute ischemic infarction of the right posterior inferior cerebellar artery territory within the cerebellum, whereas the CT scan is only subtly hypodense in the same region. MRI is superior to CT imaging for identifying ischemic infarction especially within the posterior fossa. renal failure from contrast nephropathy, so it should be reserved for situations where less invasive means are inadequate. Acute stroke treatment with endovascular thrombectomy has proven effective in ischemic strokes caused by internal carotid terminus or MCA occlu­ sions and is now part of routine clinical practice at centers that have this capability (see Chap. 438). Ultrasound Techniques  Stenosis at the origin of the internal carotid artery can be identified and quantified reliably by ultrasonog­ raphy that combines a B-mode ultrasound image with a Doppler ultra­ sound assessment of flow velocity (“duplex” ultrasound). Transcranial Doppler (TCD) assessment of MCA, ACA, and PCA flow and of verte­ brobasilar flow is also useful. This latter technique can detect stenotic lesions in the large intracranial arteries because such lesions increase systolic flow velocity. TCD can also detect microemboli from other­ wise asymptomatic carotid plaques. In many cases, MR angiography combined with carotid and transcranial ultrasound studies eliminates the need for conventional x-ray angiography in evaluating vascular stenosis. Alternatively, CTA of the entire head and neck can be per­ formed during the initial imaging of acute stroke. Because this images the entire arterial system relevant to stroke, with the exception of the heart, much of the clinician’s stroke workup can be completed with this single imaging study. Radionuclide Perfusion Techniques  Both xenon techniques (principally xenon-CT) and positron emission tomography (PET) can quantify cerebral blood flow. These tools are generally used for research (Chap. 434) but can be useful for determining the significance of arterial stenosis and planning for revascularization surgery. Singlephoton emission computed tomography (SPECT) and CT or MR per­ fusion techniques report relative cerebral blood flow. As noted above, CT imaging is used as the initial imaging modality for acute stroke, and # 08 - 438 Ischemic Stroke ### 438 Ischemic Stroke some centers combine both CTA and CT perfusion imaging together with the noncontrast CT scan. CT perfusion imaging increases the sen­ sitivity for detecting ischemia and can measure the ischemic penumbra (Fig. 437-12). Alternatively, MR perfusion can be combined with MR diffusion imaging to identify the ischemic penumbra as the mismatch between these two imaging sequences. ■ ■FURTHER READING Blumenfeld H: Neuroanatomy Through Clinical Cases, 3rd ed. New York, Sinauer Associates, 2020. Tsao CW: Heart disease and stroke statistics-2023 update: A report from the American Heart Association. Circulation 147:e93, 2023. Wade S. Smith, Anthony S. Kim, J. Claude Hemphill, III Ischemic Stroke The clinical diagnosis of stroke is discussed in Chap. 437. Once this diagnosis is made and either a noncontrast computed tomography (CT) scan or magnetic resonance imaging (MRI) scan has been per­ formed, rapid reversal of ischemia is paramount. This chapter will focus on the stroke treatment timeline and subsequent secondary stroke prevention. ■ ■PATHOPHYSIOLOGY OF ISCHEMIC STROKE Acute occlusion of an intracranial vessel causes reduction in blood flow to the brain region it supplies (Fig. 438-1). The magnitude of flow reduction is a function of collateral blood flow, and this depends on an individual’s vascular anatomy (which may be altered by disease), the site of occlusion, and systemic blood pressure. A decrease in cerebral blood flow to zero causes death of brain tissue (neuron cell bodies, dendrites, axons, and glial cells) within 4–10 min; values <16–18 mL/100 g tissue Ischemic energy failure Glutamate release Spreading depression Glutamate receptors Ca2+/Na+ influx Proteolysis Membrane and cytoskeletal breakdown Cell death FIGURE 438-1  Major steps in the cascade of cerebral ischemia. See text for details. iNOS, inducible nitric oxide synthase; PARP, poly-A ribose polymerase. per minute cause infarction within an hour; and values <20 mL/100 g tissue per minute cause ischemia without infarction unless prolonged for several hours or days. If blood flow is restored to ischemic tissue before significant infarction develops, the patient may experience only transient symptoms, and the clinical syndrome is called a transient ischemic attack (TIA). Another important concept is the ischemic penumbra, defined as the ischemic but reversibly dysfunctional tissue surrounding a core area of infarction. The penumbra can be imaged by perfusion imaging using MRI or CT (see Fig. 438-3 and Figs. 437-12 and 437-13). The ischemic penumbra will eventually progress to infarction if no change in flow occurs, and hence, saving the ischemic penumbra is the goal of revascularization therapy. Restoration of blood flow provides oxygen and glucose to the penumbral tissue, preventing infarction not only by supplying fuel for metabolism but by reversing tissue acidosis, clearing glutamate and toxic oxygen species, and halting waves of corti­ cal spreading depression emanating from the ischemic core that add metabolic stress to the tissue. CHAPTER 438 Ischemia causes a reduction in glucose and oxygen delivery, which in turn results in reduced capacity of cells to generate ATP. Without ATP, membrane ion pumps stop functioning and cells depolarize, allowing intracellular sodium and calcium to rise. Cellular depolar­ ization also causes glutamate release from synaptic terminals and a failure of glutamate uptake by glial cells. The resulting sustained elevation in extracellular glutamate produces neurotoxicity by activat­ ing postsynaptic glutamate receptors that increase neuronal calcium influx and the production of reactive oxygen species. Reactive oxygen species damage DNA, lipid membranes, and likely other vital func­ tions of cells. An innate immune response becomes apparent within a few hours after stroke, consisting of activation of proinflamma­ tory microglia (the resident immune cells in brain) and infiltration of immune cells from the circulation. While important in repairing stroke damage, this acute inflammatory response may also contribute to tissue injury after stroke by release of proteases and reactive oxygen species. Ischemia and the postischemic inflammatory response also injure or destroy axons and dendrites at some distance from the infarct itself. Fever dramatically worsens brain injury during ischemia, as does hyperglycemia (glucose >11.1 mmol/L [200 mg/dL]), so it is reason­ able to suppress fever and prevent hyperglycemia during and after brain ischemia. The value of induced mild hypothermia to improve stroke outcomes has not been clearly demonstrated and remains the subject of continuing clinical research. Ischemic Stroke Arterial occlusion Thrombolysis and thrombectomy Mitochondrial damage PARP Reperfusion Inflammatory response INOS Free oxygen species Leukocyte adhesion Lipolysis Arachidonic acid production Phospholipase TREATMENT Acute Ischemic Stroke (Fig. 438-2) After the clinical diagnosis of stroke is made (Chap. 437), an orderly and prompt process of evaluation and treatment should follow. The first goal is to prevent or reverse brain injury. Attend to the patient’s airway, breathing, and circulation (ABCs), and treat hypoglycemia or hyperglycemia if identified by finger stick testing. Perform an emergency noncontrast head CT scan to differentiate between ischemic stroke and hemorrhagic stroke (Chap. 439); there are no reliable clinical findings that conclusively separate ischemia from hemorrhage, although a more depressed level of con­ sciousness, higher initial blood pressure, or worsening of symptoms after onset favor hemorrhage, and a deficit that is maximal at onset, or remits, suggests ischemia. Treatments designed to reverse or lessen the amount of tissue infarction and improve clinical outcome fall within six categories: (1) medical support, (2) IV thrombolysis, (3) endovascular revascularization, (4) antithrombotic treatment, (5) neuroprotection, and (6) stroke centers and rehabilitation. MEDICAL SUPPORT When ischemic stroke occurs, the immediate goal is to optimize cerebral perfusion in the surrounding ischemic penumbra. Atten­ tion is also directed toward preventing the common complications of bedridden patients—infections (pneumonia, urinary, and skin) PART 13 Neurologic Disorders Suspected acute stroke Prehospital call ahead Code stroke activation Onset <6 h Onset 6–24 h CT no hemorrhage No Yes IV PA eligible? Favorable perfusion? Give IV PA No Yes ICA/M1-2 or BA occlusion? Thrombectomy Inpatient management Perform CTA FIGURE 438-2  Management of acute stroke (pathway followed by the authors). For suspected stroke identified by prehospital professionals, we encourage calling ahead to the destination hospital. This allows early “stroke code” activation to prepare for an emergent computed tomography (CT) on arrival. For patients with onset <6 h from last time seen normal, we expedite a noncontrast head CT scan, and if free of hemorrhage and the patient is IV thrombolysis eligible (typically <4.5 h of last seen well time), this is administered in the CT scanner. (For IV tissue PA [tPA], the bolus is given and infusion initiated; for tenecteplase, the full dose is given as a bolus.) Then CT angiography (CTA) from left atrium to skull vertex is performed to identify an eligible target lesion for thrombectomy. For a patient presenting in the 6- to 24-h time window, thrombolysis is not considered, and the decision to perform thrombectomy is based on perfusion imaging. Priorities of Acute Stroke Consultation: Once stroke is suspected, the first priorities are to assess airway and blood pressure, followed by establishing the time last seen normal. Patients with disabling neurologic deficits (particularly with National Institutes of Health Stroke Scale >5) may be eligible for thrombolytic and/or endovascular therapy. Based on the onset time, we follow the protocol shown in the figure. Following acute treatments, if any, we proceed with establishing the cause of the ischemic stroke. If atrial fibrillation is established or newly discovered, we favor use of apixaban 5 mg twice daily (or a reduced dose of 2.5 mg twice daily for impaired glomerular filtration rate) lifelong. If atrial fibrillation is not detected during the hospital encounter, we obtain an ambulatory electrocardiogram monitor to surveil for intermittent atrial fibrillation while treating with antiplatelet agents, then convert to oral anticoagulation if intermittent atrial fibrillation is detected. If we identify significant internal carotid stenosis, we refer for carotid endarterectomy during the same hospitalization regardless of infarct size. For all else, we use the dual antiplatelet agents aspirin (81 mg) and either clopidogrel (600 mg-load, followed by 75 mg daily) or ticagrelor (180-mg load, followed by 90 mg twice daily) daily for 21–30 days then continue aspirin at 81 mg daily. Ticagrelor has the advantage of not being affected by common polymorphisms of CYP2C19 that limit efficacy of clopidogrel in significant proportions of patients, particularly those of Asian descent. If the CTA revealed significant intracranial atherosclerosis or other precranial vessel stenosis within the vascular territory of the infarct (lumen caliber reduced by >50%), we continue dual antiplatelet agents for at least 3 months and then convert to a single agent. Unless contraindicated, all patients receive a highintensity statin such as atorvastatin 80 mg or rosuvastatin 40 mg, with goal low-density lipoprotein level of <70 mg/dL unless the stroke has a nonatherothrombotic cause. Patients who are statin intolerant can receive PCSK9 inhibitors. Blood pressure control should target systolic blood pressure <120 mmHg long term, but we allow permissive hypertension for the first few days or weeks to help with collateral flow to the brain. BA, basilar artery; CTP, computed tomography perfusion; ICA, internal carotid artery; IV, intravenous; M1, middle cerebral artery first division; M2, middle cerebral artery second division; PA, plasminogen activator (tissue plasminogen activator or tenecteplase). and deep-venous thrombosis (DVT) with pulmonary embolism. Subcutaneous heparin (unfractionated and low-molecular-weight) is safe and can be used concomitantly. Use of pneumatic compres­ sion stockings is of proven benefit in reducing risk of DVT and is a safe alternative to heparin. Because collateral blood flow within the ischemic brain may be blood pressure dependent, there is controversy about whether blood pressure should be lowered acutely. Blood pressure should be reduced if it exceeds 220/120 mmHg, if there is malignant hypertension (Chap. 288) or concomitant myocardial ischemia, or if blood pressure is >185/110 mmHg and thrombolytic therapy is anticipated. When faced with the competing demands of myo­ cardium and brain, lowering the heart rate with a β1-adrenergic blocker (such as esmolol) can be a first step to decrease cardiac work and maintain blood pressure. Routine lowering of blood pres­ sure below the limits listed above has the potential to worsen out­ comes. Fever is detrimental and should be treated with antipyretics and surface cooling. Serum glucose should be monitored and kept <10.0 mmol/L (180 mg/dL), and above at least 3.3 mmol/L (60 mg/dL); a more intensive glucose control strategy does not improve outcome. Between 5 and 10% of patients develop enough cerebral edema to cause obtundation and brain herniation. Edema peaks on the second or third day but can cause mass effect for ~10 days. The larger the infarct, the greater the likelihood that clinically sig­ nificant edema will develop. Water restriction and IV mannitol CT no hemorrhage CTA/CTP Yes No or hypertonic saline may be used to raise the serum osmolarity, but hypovolemia should be avoided because this may contribute to hypotension and worsening infarction. Combined analysis of three randomized European trials of hemicraniectomy (craniotomy and temporary removal of part of the skull) shows that hemicra­ niectomy reduces mortality by 50%, and the clinical outcomes of survivors are significantly improved. Older patients (age >60 years) benefit less but still significantly. The size of the diffusion-weighted imaging volume of brain infarction during the acute stroke is a pre­ dictor of future deterioration requiring hemicraniectomy. Special vigilance is warranted for patients with cerebellar infarc­ tion. These strokes may mimic labyrinthitis because of prominent vertigo and vomiting; the presence of head or neck pain should alert the physician to consider cerebellar stroke due to vertebral artery dissection. Even small amounts of cerebellar edema can acutely increase intracranial pressure (ICP) by obstructing cerebrospinal fluid (CSF) flow leading to hydrocephalus or by directly compress­ ing the brainstem. The resulting brainstem compression can mani­ fest as coma and respiratory arrest and require emergency surgical decompression. Suboccipital decompression is recommended in patients with cerebellar infarcts who demonstrate neurologic dete­ rioration and should be performed before significant brainstem compression occurs. INTRAVENOUS THROMBOLYSIS The National Institute of Neurological Disorders and Stroke (NINDS) Recombinant Tissue Plasminogen Activator (rtPA) Stroke Study showed a clear benefit for IV rtPA in selected patients with acute stroke. The NINDS study used IV rtPA (0.9 mg/kg to a 90-mg maxi­ mum; 10% as a bolus, then the remainder over 60 min) versus pla­ cebo in ischemic stroke within 3 h of onset. One-half of the patients were treated within 90 min. Symptomatic intracranial hemorrhage occurred in 6.4% of patients on rtPA and 0.6% on placebo. In the rtPA group, there was a significant 12% absolute increase in the number of patients with only minimal disability (32% on placebo and 44% on rtPA) and a nonsignificant 4% reduction in mortality (21% on placebo and 17% on rtPA). Thus, despite an increased incidence of symptomatic intracranial hemorrhage, treatment with IV rtPA within 3 h of the onset of ischemic stroke improved clinical outcome. Three subsequent trials of IV rtPA did not confirm this benefit, perhaps because of the dose of rtPA used, the timing of its delivery, and small sample size. When data from all randomized IV rtPA trials were combined, however, efficacy was confirmed in the <3-h time window, and efficacy likely extended to 4.5 h and possibly to 6 h. Based on these combined results, the European Cooperative Acute Stroke Study (ECASS) III explored the safety and efficacy of rtPA in the 3- to 4.5-h time window. Unlike the NINDS study, patients aged >80 years and diabetic patients with a previous stroke were excluded. In this 821-patient randomized study, efficacy was again confirmed, although the treatment effect was less robust than in the 0- to 3-h time window. In the rtPA group, 52.4% of patients achieved a good outcome at 90 days, compared to 45.2% of the placebo group (odds ratio [OR] 1.34, p = .04). The symptomatic intracranial hemorrhage rate was 2.4% in the rtPA group and 0.2% in the placebo group (p = .008). Based on these data, rtPA is approved in the 3- to 4.5-h win­ dow in Europe and Canada but is only approved for 0–3 h in the United States. A dose of 0.6 mg/kg is typically used in Japan and other Asian countries based on observation of >600 patients given this lower dose and observing similar outcomes to historical con­ trols and a lower rate of intracranial hemorrhage. This dose also mitigates concerns that patients of Asian descent have a higher propensity to bleed from most antithrombotic and thrombolytic medications. The infrastructure to efficiently administer IV rtPA to eligible patients is a central component of primary stroke centers (see below). It represents the first treatment proven to improve clinical outcomes in ischemic stroke and is cost-effective and cost-saving. The time of stroke onset is defined as the time the patient’s symptoms were witnessed to begin or the time the patient TABLE 438-1  Administration of Intravenous Recombinant Tissue Plasminogen Activator (rtPA) or Tenecteplase for Acute Ischemic Stroke (AIS)a INDICATION CONTRAINDICATION Clinical diagnosis of stroke Onset of symptoms to time of drug administration ≤4.5 hb Sustained BP >185/110 mmHg despite treatment Bleeding diathesis Recent head injury or intracerebral hemorrhage Major surgery in preceding 14 days Gastrointestinal bleeding in preceding 21 days Recent myocardial infarction CT scan showing no hemorrhage, and no edema > 1/3 of the MCA territory Age ≥18 years Administration of stroke thrombolysis IV access with two peripheral IV lines (avoid arterial or central line placement) CHAPTER 438 Review eligibility for stroke thrombolysis Administer 0.9 mg/kg IV (maximum 90 mg) rtPA IV as 10% of total dose by bolus, followed by remainder of total dose over 1 hc Or Administer 0.25 mg/kg IV (maximum 25 mg) tenecteplase IV push over 5 sd Frequent cuff BP monitoring Ischemic Stroke No other antithrombotic treatment for 24 h For decline in neurologic status or uncontrolled BP, stop infusion, give cryoprecipitate, and reimage brain emergently Avoid urethral catheterization for ≥2 h aSee Activase (tissue plasminogen activator) package insert for complete list of contraindications and dosing. bDepending on the country, IV rtPA may be approved for up to 4.5 h with additional restrictions. cAn rtPA dose of 0.6 mg/kg is commonly used in Asia (Japan and China) based on randomized data indicating less hemorrhage and similar efficacy using this lower dose. dUse of tenecteplase for acute ischemic stroke is off-label. Abbreviations: BP, blood pressure; CT, computed tomography; MCA, middle cerebral artery. was last seen as normal. Patients who awaken with stroke have the onset defined as when they went to bed. Advanced neuroimaging techniques (see Chap. 437) may help to select patients beyond the 4.5-h window who will benefit from thrombolysis. Two trials using MRI selection beyond 4.5 h have shown clinical benefit from IV rtPA. Patients with minor stroke (nondisabling deficit and National Institutes of Health Stroke Scale [NIHSS] 0–5) appear to respond to acute aspirin or short-term dual antiplatelet therapy using the com­ bination of aspirin and clopidogrel as well as IV rtPA. Table 438-1 summarizes eligibility criteria and instructions for administration of IV rtPA. The plasminogen activator tenecteplase (0.25 mg/kg IV bolus over 5 s with a maximum dose of 25 mg) has been directly com­ pared to rtPA and is being adopted by many centers because it is given without need for a 1-h infusion. This improves the effi­ ciency of transferring patients to comprehensive stroke centers for thrombectomy because the IV infusion required for IV rtPA is not required for tenecteplase, thus obviating need for critical care trans­ port. Several trials using tenecteplase prior to endovascular therapy have found it to be safe. ENDOVASCULAR REVASCULARIZATION Ischemic stroke from large-vessel intracranial occlusion results in high rates of mortality and morbidity. Occlusions in such large vessels (middle cerebral artery [MCA], intracranial internal carotid artery, and the basilar artery) generally involve a large clot burden and often fail to open with IV thrombolysis alone. Endovascular mechanical thrombectomy has been studied as an alternative or adjunctive treatment of acute stroke in patients who are ineligible for, or have contraindications to, thrombolytics or in those who failed to achieve vascular recanalization with IV thrombolytics (Fig. 438-3). In 2015, the results of six randomized trials were published, all demonstrating that endovascular therapy improved clinical outcomes for internal carotid and MCA occlu­ sions proven by CT angiography (CTA), under 6 h from stroke A B C PART 13 Neurologic Disorders E G F D FIGURE 438-3  (A) Noncontrast head computed tomography (CT) scan of a 78-year-old man with atrial fibrillation and hypertension who was not taking oral anticoagulants and awoke with right hemiparesis and expressive aphasia. The head CT shows no intracerebral hemorrhage. He was not treated with plasminogen activators because his last seen normal time was 8 h prior. Head CT also shows hyperdensity in the left middle cerebral artery (MCA, arrow); this finding is highly specific for MCA occlusion but is poorly sensitive, as only 20% of patients with MCA occlusion show hyperdensity. (B) To confirm a large-vessel occlusion, CT angiography (CTA) performed in the same session reveals an occlusion of a secondary branch of the left MCA (arrow). (C) CT perfusion performed immediately following the CTA shows no core infarct (no pink signal in the left image) but a large region (green shading in the right image) of ischemic tissue that will die if revascularization is not achieved. (D) Catheter angiography shows the occluded branch of the left MCA (arrow) and (E) restored flow after successful clot removal (F). (G) A subsequent diffusion-weighted imaging scan shows a very small residual brain infarction. CBF, cerebral blood flow. onset, with or without pretreatment with IV tissue plasminogen activator (tPA). One study concluded that patients were home nearly 2 months earlier if they received endovascular therapy. A combined meta-analysis of all patients in these trials confirmed a large benefit with endovascular therapy (OR, 2.49; 95% confidence interval [CI], 1.76–3.53; p <.001). The percentage of patients who achieved modi­ fied Rankin scores of 0–2 (normal or symptomatic but independent) was 46% in the endovascular group and 26.5% in the medical arm. A more recent meta-analysis reveals a mortality benefit with throm­ bectomy as well. As with IV rtPA treatment, clinical outcome is dependent on time to effective therapy. The odds of a good outcome exceed 3 if groin puncture occurs within 2 h of symptom onset but is only 2 if 8 h elapse. Over 80% of patients who had vessel open­ ing within 1 h of arrival to the emergency department had a good outcome, whereas only one-third had a good outcome if 6 h elapsed. The outcomes from endovascular therapy are likely improved with IV rtPA treatment prior to thrombectomy if the patient is eligible for rtPA and it is safe to administer. Recent data support replacing IV rtPA with IV tenecteplase because its simple bolus administration makes transporting the patient to an endovascular center less cumbersome. Extending the time window beyond 6 h appears to be effective if the patient has specific imaging findings demonstrating good vas­ cular collaterals (CT perfusion or magnetic resonance [MR] perfu­ sion techniques, see Chap. 437) and can be treated within 24 h. The Clinical Mismatch in the Triage of Wake Up and Late Presenting Strokes Undergoing Neurointervention with Trevo (DAWN) trial reported good outcomes more frequently with endovascular ther­ apy than with medical care alone (47 vs 13%, p <.0001). The Endo­ vascular Therapy Following Imaging Evaluation for Ischemic Stroke 3 (DEFUSE-3) trial confirmed these results (45 vs 17%, p <.001) if CBF <30%: 0 ml Tmax >6.0s: 57 ml Mismatch volume: 57 ml Mismatch ratio: infinite treated up to 16 h from stroke onset. Nonrandomized data of throm­ bectomy for basilar occlusion have found this treatment to be safe up to 24 h from symptom onset and associated with lower 3-month Rankin scores. An example of how advanced imaging techniques (CT, CTA, CT perfusion, catheter-based angiography), endovascu­ lar thrombectomy with clot removal, and follow-up MRI can lead to a better than predicted stroke outcome is shown in Fig 438-3. Now that endovascular stroke therapy is proven to be effective, the creation of comprehensive stroke centers designed to rapidly identify and treat patients with large-vessel cerebral ischemia has been a major focus internationally. Creating regional systems of care whereby stroke patients are first evaluated at acute stroke ready hospitals or primary stroke centers (which can administer IV rtPA or tenecteplase) then transferred to thrombectomy-capable or comprehensive stroke centers if needed, or directly triaged to thrombectomy-capable or comprehensive centers based on field assessment, appears to be an effective strategy to improve outcomes. ANTITHROMBOTIC TREATMENT Platelet Inhibition  Aspirin is the only antiplatelet agent that has been proven to be effective for the acute treatment of ischemic stroke; there are several antiplatelet agents proven for the secondary prevention of stroke (see below). Two large trials, the International Stroke Trial (IST) and the Chinese Acute Stroke Trial (CAST), found that the use of aspirin within 48 h of stroke onset reduced both stroke recurrence risk and mortality minimally. Among 19,435 patients in IST, those allocated to aspirin, 300 mg/d, had slightly fewer deaths within 14 days (9.0 vs 9.4%), significantly fewer recurrent ischemic strokes (2.8 vs 3.9%), no excess of hemorrhagic strokes (0.9 vs 0.8%), and a trend toward a reduction in death or dependence at 6 months (61.2 vs 63.5%). In CAST, 21,106 patients with ischemic stroke received 160 mg/d of aspirin or a placebo for up to 4 weeks. In the aspirin group, there were very small reductions in early mortality (3.3 vs 3.9%), recurrent ischemic strokes (1.6 vs 2.1%), and dependency at discharge or death (30.5 vs 31.6%). These trials demonstrate that the use of aspirin in the treatment of acute ischemic stroke is safe and produces a small net benefit. For every 1000 acute strokes treated with aspirin, ~9 deaths or nonfatal stroke recurrences will be prevented in the first few weeks, and ~13 fewer patients will be dead or dependent at 6 months. The short-term combination of aspirin with clopidogrel or with ticagrelor following minor stroke or TIA is effective at preventing early second stroke (see below). Anticoagulation  Numerous clinical trials have failed to demon­ strate any benefit of routine anticoagulation in the primary treat­ ment of atherothrombotic cerebral ischemia and have also shown an increase in the risk of brain and systemic hemorrhage. Therefore, the routine use of heparin or other anticoagulants for patients with atherothrombotic stroke is not warranted. Heparin and oral anticoagulation are likely no more effective than aspirin for stroke associated with arterial dissection. However, there may be benefit of anticoagulation for halting progression of dural sinus thrombosis. NEUROPROTECTION Neuroprotection is the concept of providing a treatment that pro­ longs the brain’s tolerance to ischemia. Drugs that block the excit­ atory amino acid pathways have been shown to protect neurons and glia in animals, but despite multiple clinical trials, they have not yet been proven to be beneficial in humans. Hypothermia is a powerful neuroprotective treatment in patients with cardiac arrest (Chap. 318) and is neuroprotective in animal models of stroke, but it has not been adequately studied in patients with ischemic stroke and is associated with an increase in pneumonia rates that could adversely impact stroke outcomes. Hypothermia combined with hemicrani­ ectomy is no more effective than hemicraniectomy with euthermia. STROKE CENTERS AND REHABILITATION Patient care in stroke units followed by rehabilitation services improves neurologic outcomes and reduces mortality. Use of clinical Intracranial atherosclerosis Penetrating artery disease Carotid plaque with arteriogenic emboli Flowreducing carotid stenosis Atrial fibrillation Cardiogenic emboli Valve disease Left ventricular thrombi A B C FIGURE 438-4  Pathophysiology of ischemic stroke. A. Diagram illustrating the three major mechanisms that underlie ischemic stroke: (1) occlusion of an intracranial vessel by an embolus (e.g., cardiogenic sources such as atrial fibrillation or artery-to-artery emboli from carotid atherosclerotic plaque), often affecting the large intracranial vessels; (2) in situ thrombosis of an intracranial vessel, typically affecting the small penetrating arteries that arise from the major intracranial arteries; and (3) hypoperfusion caused by flow-limiting stenosis of a major extracranial (e.g., internal carotid) or intracranial vessel, often producing “watershed” ischemia. B. and C. Diagram and reformatted computed tomography angiogram of the common, internal, and external carotid arteries. High-grade stenosis of the internal carotid artery, which may be associated with either cerebral emboli or flow-limiting ischemia, was identified in this patient. pathways and staff dedicated to the stroke patient can improve care. This includes use of standardized stroke order sets. Stroke teams that provide emergency 24-h evaluation of acute stroke patients for acute medical management and consideration of thrombolysis or endovascular treatments, potentially provided using telemedicine/ telestroke services, are essential components of primary and com­ prehensive stroke centers, respectively. Proper rehabilitation of the stroke patient includes early physical, occupational, and speech therapy. It is directed toward educating the patient and family about the patient’s neurologic deficit, pre­ venting the complications of immobility (e.g., pneumonia, DVT and pulmonary embolism, pressure sores of the skin, and muscle contractures), and providing encouragement and instruction in overcoming the deficit. Use of pneumatic compression stockings is of proven benefit in reducing risk of DVT and is a safe alternative to heparin. The goal of rehabilitation is to return the patient home and to maximize recovery by providing a safe, progressive regimen suited to the individual patient. Additionally, the use of constrained movement therapy (immobilizing the unaffected side) has been shown to improve hemiparesis following stroke, even years after the stroke, suggesting that physical therapy can recruit unused neural pathways. Controversy exists regarding whether selective serotonin uptake inhibitors improve motor recovery, but they may be helpful in preventing poststroke depression. Newer robotic therapies and neuromodulation approaches using transcranial magnetic stimu­ lation or transcranial direct current stimulation are under active investigation (Chap. 500). The human nervous system is more adaptable than previously thought, and developing physical and pharmacologic strategies to enhance long-term neural recovery are the subject of ongoing research. CHAPTER 438 Ischemic Stroke ■ ■ETIOLOGY OF ISCHEMIC STROKE (Fig. 438-4 and Table 438-2) Although the initial management of acute ischemic stroke often does not depend on the etiology, establishing a cause is essential to reduce the risk of recurrence. Focus should be on atrial fibrillation and carotid atherosclerosis, because these etiologies Internal carotid External carotid Common carotid TABLE 438-2  Causes of Ischemic Stroke COMMON CAUSES UNCOMMON CAUSES Thrombosis   Lacunar stroke (small vessel)   Large-vessel thrombosis   Dehydration Embolic occlusion   Artery-to-artery     Carotid bifurcation     Aortic arch     Arterial dissection   Cardioembolic     Atrial fibrillation     Mural thrombus     Myocardial infarction     Dilated cardiomyopathy     Valvular lesions     Mitral stenosis     Mechanical valve     Bacterial endocarditis   Paradoxical embolus     Atrial septal defect     Patent foramen ovale   Atrial septal aneurysm   Spontaneous echo contrast   Stimulant drugs: cocaine, Hypercoagulable disorders   Protein C deficiencya   Protein S deficiencya   Antithrombin III deficiencya   Antiphospholipid syndrome   Factor V Leiden mutationa   Prothrombin G20210A mutationa   Systemic malignancy   Sickle cell anemia   β Thalassemia   Polycythemia vera   Systemic lupus erythematosus   Homocysteinemia   Thrombotic thrombocytopenic purpura   Disseminated intravascular coagulation   Dysproteinemiasa PART 13 Neurologic Disorders   Nephrotic syndromea   Inflammatory bowel diseasea   Oral contraceptives   COVID-19 infection Venous sinus thrombosisb Fibromuscular dysplasia Vasculitis   Systemic vasculitis (PAN, granulomatosis amphetamine with polyangiitis, Takayasu’s, giant cell arteritis)   Primary CNS vasculitis   Meningitis (syphilis, tuberculosis,   fungal, bacterial, zoster) Noninflammatory vasculopathy   Reversible vasoconstriction syndrome   Fabry’s disease   Angiocentric lymphoma Cardiogenic   Mitral valve calcification   Atrial myxoma   Intracardiac tumor   Marantic endocarditis   Libman-Sacks endocarditis Subarachnoid hemorrhage vasospasm Moyamoya disease Eclampsia aChiefly cause venous sinus thrombosis. bMay be associated with any hypercoagulable disorder. Abbreviations: CNS, central nervous system; PAN, polyarteritis nodosa. have proven secondary prevention strategies. The clinical presentation and examination findings often establish the cause of stroke or narrow the possibilities to a few. Judicious use of laboratory testing and imag­ ing studies completes the initial evaluation. Nevertheless, nearly 30% of strokes remain unexplained despite extensive evaluation. Clinical examination should focus on the peripheral and cervical vascular system (measuring blood pressure), the heart (dysrhythmia, murmurs), extremities (peripheral emboli), and retina (effects of hypertension and cholesterol emboli [Hollenhorst plaques]). A com­ plete neurologic examination is performed to localize the anatomic site of stroke (Chap. 437). An imaging study of the brain is nearly always indicated and is required for patients being considered for thrombolysis; it may be combined with CT- or MRI-based angiogra­ phy to visualize the vasculature of the neck and intracranial vessels (see “Imaging Studies,” Chap. 437). A chest x-ray, electrocardiogram (ECG), urinalysis, complete blood count, erythrocyte sedimentation rate (ESR), serum electrolytes, blood urea nitrogen (BUN), creatinine, blood glucose, serum lipid profile, prothrombin time (PT), and partial thromboplastin time (PTT) are often useful and should be considered in all patients. An ECG, and subsequent cardiac telemetry, may dem­ onstrate arrhythmias or reveal evidence of recent myocardial infarction (MI). Of all these studies, only brain imaging and finger stick blood glucose are necessary prior to IV thrombolysis; the results of other studies should not delay the rapid administration of IV thrombolysis if the patient is eligible. Cardioembolic Stroke  Cardioembolism is responsible for ~20% of all ischemic strokes. Stroke caused by heart disease is primarily due to embolism of thrombotic material forming on the atrial or ventricu­ lar wall or the left heart valves. These thrombi then detach and embo­ lize into the arterial circulation. The thrombus may fragment or lyse quickly, producing only a TIA. Alternatively, the arterial occlusion may last longer, producing stroke. Embolic strokes tend to occur suddenly with maximum neurologic deficit present at onset. With reperfusion following more prolonged ischemia, petechial hemorrhages can occur within the ischemic territory. These are usually of no clinical signifi­ cance and should be distinguished from frank intracranial hemorrhage into a region of ischemic stroke where the mass effect from the hemor­ rhage can cause a significant decline in neurologic function. Emboli from the heart most often lodge in the intracranial internal carotid artery, the MCA, the posterior cerebral artery (PCA), or one of their branches; infrequently, the anterior cerebral artery (ACA) is involved. Emboli large enough to occlude the stem of the MCA (3–4 mm) or internal carotid terminus lead to large infarcts that involve both deep gray and white matter and some portions of the cortical surface and its underlying white matter. A smaller embolus may occlude a small cortical or penetrating arterial branch. The location and size of an infarct within a vascular territory depend on the extent of the col­ lateral circulation. The most significant cause of cardioembolic stroke in most of the world is nonrheumatic (often called nonvalvular) atrial fibrillation. MI, prosthetic valves, rheumatic heart disease, and ischemic cardiomyopa­ thy are other considerations (Table 438-2). Cardiac disorders causing brain embolism are discussed in the chapters on heart diseases, but a few pertinent aspects are highlighted here. Nonrheumatic atrial fibrillation is the most common cause of cere­ bral embolism overall. The presumed stroke mechanism is thrombus formation in the fibrillating atrium or atrial appendage, with subse­ quent embolization. Patients with atrial fibrillation have an average annual risk of stroke of ~5%. The risk of stroke can be estimated by calculating the CHA2DS2-VASc score (Table 438-3). Left atrial enlargement is an additional risk factor for formation of atrial thrombi. Rheumatic heart disease usually causes ischemic stroke when there is prominent mitral stenosis or atrial fibrillation. Recent MI may be a source of emboli, especially when transmural and involving the antero­ apical ventricular wall, and prophylactic anticoagulation following MI with left ventricular thrombus has been shown to reduce ischemic stroke risk. Mitral valve prolapse is not usually a source of emboli unless the prolapse is severe. Paradoxical embolization occurs when venous thrombi migrate to the arterial circulation, usually via a patent foramen ovale (PFO) or atrial septal defect. Bubble-contrast echocardiography (IV injection of agitated saline coupled with either transthoracic or transesopha­ geal echocardiography) can demonstrate a right-to-left cardiac shunt, revealing the conduit for paradoxical embolization. Alternatively, a right-to-left shunt is implied if immediately following IV injection of agitated saline, the ultrasound signature of bubbles is observed during transcranial Doppler insonation of the MCA; pulmonary arteriove­ nous malformations should be considered if this test is positive yet an echocardiogram fails to reveal an intracardiac shunt. Both tech­ niques are highly sensitive for detection of right-to-left shunts. Besides venous clot, fat and tumor emboli, bacterial endocarditis, IV air, and amniotic fluid emboli at childbirth may occasionally be responsible for paradoxical embolization. The importance of a PFO as a cause of stroke is debated, particularly because they are present in ~15% of the general population. The presence of a venous source of embolus, TABLE 438-3  Recommendations on Chronic Use of Antithrombotics for Various Cardiac Conditions CONDITION RECOMMENDATION Nonvalvular atrial fibrillation Calculate CHA2DS2-VASc scorea • CHA2DS2-VASc score of 0 Aspirin or no antithrombotic • CHA2DS2-VASc score of 1 Aspirin or OAC • CHA2DS2-VASc score of ≥2 OAC Rheumatic mitral valve disease • With atrial fibrillation, previous OAC embolization, or atrial appendage thrombus, or left atrial diameter >55 mm • Embolization or appendage clot despite OAC plus aspirin OAC • Mitral valve prolapse • Asymptomatic No therapy • With otherwise cryptogenic stroke or TIA Aspirin • Atrial fibrillation OAC Mitral annular calcification • Without atrial fibrillation but systemic Aspirin embolization, or otherwise cryptogenic stroke or TIA • Recurrent embolization despite aspirin OAC • With atrial fibrillation OAC Aortic valve calcification • Asymptomatic No therapy • Otherwise cryptogenic stroke or TIA Aspirin Aortic arch mobile atheroma • Otherwise cryptogenic stroke or TIA Aspirin or OAC Patent foramen ovale • Otherwise cryptogenic ischemic stroke Aspirin or closure with device or TIA • Indication for OAC (deep-venous OAC thrombosis or hypercoagulable state) Mechanical heart value • Aortic position, bileaflet or Medtronic Hall VKA INR 2.5, range 2–3 tilting disk with normal left atrial size and sinus rhythm • Mitral position tilting disk or bileaflet valve VKA INR 3.0, range 2.5–3.5 • Mitral or aortic position, anterior-apical VKA INR 3.0, range 2.5–3.5 myocardial infarct or left atrial enlargement • Mitral or aortic position, with atrial Aspirin plus VKA INR 3.0, range 2.5–3.5 fibrillation, or hypercoagulable state, or low ejection fraction, or atherosclerotic vascular disease • Systemic embolization despite target INR Add aspirin and/or increase INR: prior target was 2.5, increase to 3.0, range 2.5–3.5; prior target was 3.0, increase to 3.5, range 3–4 Bioprosthetic valve • No other indication for VKA therapy Aspirin Infective endocarditis Avoid antithrombotic agents Nonbacterial thrombotic endocarditis • With systemic embolization Full-dose, unfractionated heparin or SC LMWH, or Xa inhibitor aCHA2DS2-VASc score is calculated as follows: 1 point for congestive heart failure, 1 point for hypertension, 2 points for age ≥75 years, 1 point for diabetes mellitus, 2 points for stroke or TIA, 1 point for vascular disease (prior myocardial infarction, peripheral vascular disease, or aortic plaque), 1 point for age 65–74 years, 1 point for female sex category; sum of points is the total CHA2DS2-VASc score. Note: Dose of aspirin is 50–325 mg/d; target INR for VKA is between 2 and 3 unless otherwise specified. Abbreviations: INR, international normalized ratio; LMWH, low-molecular-weight heparin; OAC, oral anticoagulant (VKA, thrombin inhibitor, or oral factor Xa inhibitors); TIA, transient ischemic attack; VKA, vitamin K antagonist. Sources: Data from DE Singer et al: Chest 133:546S, 2008; DN Salem et al: Chest 133:593S, 2008; CT January et al: JACC 64:2246, 2014. most commonly a deep-venous thrombus, may provide confirmation of the importance of a PFO with an accompanying right-to-left shunt in a particular case. Meta-analysis of three recent randomized trials reported a hazard ratio of 0.41 for recurrent stroke (about a 1% per year absolute reduction) using percutaneous occlusion devices in patients with larger PFOs and no other explanation for their stroke. Guidelines now endorse PFO closure with percutaneous devices after consultation with a neurologist and a cardiologist. Bacterial endocarditis can be a source of valvular vegetations that give rise to septic emboli. The appearance of multifocal symptoms and signs in a patient with stroke makes bacterial endocarditis more likely. Infarcts of microscopic size occur, and large septic infarcts may evolve into brain abscesses or cause hemorrhage into the infarct, which generally precludes use of anticoagulation or thrombolytics. Mycotic aneurysms caused by septic emboli may also present as subarachnoid hemorrhage (SAH) or intracerebral hemorrhage. Artery-to-Artery Embolic Stroke  Thrombus formation on ath­ erosclerotic plaques may embolize to intracranial arteries producing an artery-to-artery embolic stroke. Less commonly, a diseased vessel may acutely thrombose. Unlike the myocardial vessels, artery-to-artery embolism, rather than local thrombosis, appears to be the dominant vascular mechanism causing large-vessel brain ischemia. Any diseased vessel may be an embolic source, including the aortic arch, common carotid, internal carotid, vertebral, and basilar arteries. CHAPTER 438 Ischemic Stroke CAROTID ATHEROSCLEROSIS  Atherosclerosis within the carotid artery occurs most frequently within the common carotid bifurca­ tion and proximal internal carotid artery; the carotid siphon (portion within the cavernous sinus) is also vulnerable to atherosclerosis. Male gender, older age, smoking, hypertension, diabetes, and hypercholes­ terolemia are risk factors for carotid disease, as they are for stroke in general (Table 438-4). Carotid atherosclerosis produces an estimated 10% of ischemic stroke. For further discussion of the pathogenesis of atherosclerosis, see Chap. 244. Carotid disease can be classified by whether the stenosis is symp­ tomatic or asymptomatic and by the degree of stenosis (percent nar­ rowing of the narrowest segment compared to a nondiseased segment). Symptomatic carotid disease implies that the patient has experienced a recent (within 6 months) stroke or TIA within the vascular distribution of the artery, and it is associated with a greater risk of subsequent stroke than asymptomatic stenosis, in which the patient is symptom free and the stenosis is detected through screening. Greater degrees of arterial narrowing are generally associated with a higher risk of stroke, except that those with near occlusions are at lower risk of stroke. OTHER CAUSES OF ARTERY-TO-ARTERY EMBOLIC STROKE  Intracranial atherosclerosis produces stroke either by an embolic mechanism or by in situ thrombosis of a diseased vessel. It is more common in patients of Asian and African-American descent. Recurrent stroke risk is ~15% per year, similar to untreated symptomatic carotid atherosclerosis. Dissection of the internal carotid or vertebral arteries or even ves­ sels beyond the circle of Willis is a common source of embolic stroke in young (age <60 years) patients. The dissection is usually painful and precedes the stroke by several hours or days. Extracranial dis­ sections do not cause hemorrhage, presumably because of the tough adventitia of these vessels. Intracranial dissections, conversely, may produce SAH because the adventitia of intracranial vessels is thin and pseudoaneurysms may form, requiring urgent treatment to prevent rerupture. Treating asymptomatic pseudoaneurysms following extra­ cranial dissection is likely not necessary. The cause of dissection is usu­ ally unknown, and recurrence is rare. Ehlers-Danlos type IV, Marfan’s disease and related disorders of connective tissue (Chap. 425), and fibromuscular dysplasia (Chap. 292) are associated with dissections. Trauma (usually a motor vehicle accident or a sports injury) can cause carotid and vertebral artery dissections. Spinal manipulative therapy is associated with vertebral artery dissection and stroke. Most dissections heal spontaneously, and stroke or TIA is uncommon beyond 2 weeks. One trial showed no difference in stroke prevention with antiplatelet regimens compared to anticoagulation, with a low recurrent stroke rate of 2%. TABLE 438-4  Risk Factors for Stroke RELATIVE RISK REDUCTION WITH TREATMENT RISK FACTOR RELATIVE RISK Hypertension 2–5 38% 100–300 50–100 Atrial fibrillation 1.8–2.9 68% warfarin, 21% aspirin 20–83 Diabetes 1.8–6 No proven effect Smoking 1.8 50% at 1 year, baseline risk at 5 years postcessation Hyperlipidemia 1.8–2.6 16–30% Asymptomatic carotid stenosis 2.0 53% N/A Symptomatic carotid stenosis (70–99%) 65% at 2 years N/A Symptomatic carotid stenosis (50–69%) 29% at 5 years N/A aNumber needed to treat to prevent one stroke annually. Prevention of other cardiovascular outcomes is not considered here. Abbreviation: N/A, not applicable. PART 13 Neurologic Disorders ■ ■SMALL-VESSEL STROKE The term lacunar infarction refers to infarction following atherothrom­ botic or lipohyalinotic occlusion of a small artery in the brain. The term small-vessel stroke denotes occlusion of such a small penetrating artery and is now the preferred term. Small-vessel strokes account for ~20% of all strokes. Pathophysiology  The MCA stem, the arteries comprising the circle of Willis (A1 segment, anterior and posterior communi­ cating arteries, and P1 segment), and the basilar and vertebral arteries all give rise to 30- to 300-μm branches that penetrate the deep gray and white matter of the cerebrum or brainstem (Fig. 438-5). Each of these small branches can occlude either by ath­ erothrombotic disease at its origin or by the development of lipohyalinotic thickening. Thrombosis of these vessels causes small infarcts that are referred to as lacunes (Latin for “lake” of fluid noted at autopsy). These infarcts range in size from 3 mm to 2 cm in diameter. Hypertension and age are the principal risk factors. Anterior cerebral a. Clinical Manifestations  The most common small-vessel stroke syndromes are the following: (1) pure motor hemiparesis from an infarct in the posterior limb of the internal capsule or the pons; the face, arm, and leg are almost always involved; (2) pure sensory stroke from an infarct in the ventral thalamus; (3) ataxic hemiparesis from an infarct in the ventral pons or internal cap­ sule; (4) and dysarthria and a clumsy hand or arm due to infarction in the ventral pons or in the genu of the internal capsule. Internal carotid a. Transient symptoms (small-vessel TIAs) may herald a small-vessel infarct; they may occur several times a day and last only a few minutes. Recovery from small-vessel strokes tends to be more rapid and complete than recovery from large-vessel strokes; in some cases, however, there is early worsening of symptoms or a stuttering course and severe permanent disability may result. Basilar a. Vertebral a. FIGURE 438-5  Diagrams and reformatted computed tomography (CT) angiograms in the coronal section illustrating the deep penetrating arteries involved in small-vessel strokes. In the anterior circulation, small penetrating arteries called lenticulostriates arise from the proximal portion of the anterior and middle cerebral arteries and supply deep subcortical structures (upper panels). In the posterior circulation, similar arteries arise directly from the vertebral and basilar arteries to supply the brainstem (lower panels). Occlusion of a single penetrating artery gives rise to a discrete area of infarct (pathologically termed a “lacune,” or lake). Note that these vessels are too small to be visualized on CT angiography. A large-vessel source (either thrombosis or embolism) may manifest initially as a small-vessel infarction. Therefore, the search for embolic sources (carotid and heart) should not be completely abandoned in the evaluation of these patients. Secondary NUMBER NEEDED TO TREATa PRIMARY PREVENTION SECONDARY PREVENTION prevention of small-vessel stroke involves risk factor modification, specifically reduction in blood pressure (see “Treatment: Primary and Secondary Prevention of Stroke and TIA,” below). ■ ■LESS COMMON CAUSES OF STROKE (Table 438-2) Hypercoagulable disorders (Chap. 69) primarily increase the risk of cortical vein or cerebral venous sinus thrombosis. Systemic Deep branches of the middle cerebral a. Anterior cerebral a. Internal carotid a. Middle cerebral a. Middle cerebral a. Basilar a. Vertebral a. Deep branches of the basilar a. lupus erythematosus (Chap. 368) with Libman-Sacks endocarditis can be a cause of embolic stroke. These conditions overlap with the antiphospholipid syndrome (Chap. 369), which probably requires long-term anticoagulation to prevent further stroke. Homocysteinemia may cause arterial thromboses as well; this disorder is caused by vari­ ous mutations in the homocysteine pathways and responds to different forms of cobalamin depending on the mutation. Disseminated intra­ vascular coagulopathy can cause both venous and arterial occlusive events; COVID-19 infection may predispose for acute ischemic stroke due to large-vessel occlusion. Venous sinus thrombosis of the lateral or sagittal sinus or of small cortical veins (cortical vein thrombosis) occurs as a complication of oral contraceptive use, pregnancy and the postpartum period, inflammatory bowel disease, intracranial infections (meningitis), and dehydration. It is also seen in patients with laboratory-confirmed thrombophilia including antiphospholipid syndrome, polycythemia, sickle cell anemia, deficiencies of proteins C and S, factor V Leiden mutation (resistance to activated protein C), antithrombin III defi­ ciency, homocysteinemia, and the prothrombin G20210A mutation. Women who take oral contraceptives and have the prothrombin G20210A mutation may be at particularly high risk for sinus thrombo­ sis. Patients present with headache and may also have focal neurologic signs (especially paraparesis) and seizures. Often, CT imaging is nor­ mal unless an intracranial venous hemorrhage has occurred, but the venous sinus occlusion is readily visualized using MR or CT venogra­ phy or conventional x-ray angiography. With greater degrees of sinus thrombosis, the patient may develop signs of increased ICP and coma. Intravenous heparin, regardless of the presence of intracranial hemor­ rhage, reduces morbidity and mortality, and the long-term outcome is generally good. Heparin prevents further thrombosis and reduces venous hypertension and ischemia. If an underlying hypercoagulable state is not found, many physicians treat with oral anticoagulants for 3–6 months and then convert to aspirin, depending on the degree of resolution of the venous sinus thrombus. Anticoagulation is often con­ tinued indefinitely if thrombophilia is diagnosed. Sickle cell anemia (SS disease) is a common cause of stroke in chil­ dren. A subset of homozygous carriers of this hemoglobin mutation develop stroke in childhood, and this may be predicted by document­ ing high-velocity blood flow within the MCAs using transcranial Doppler ultrasonography. In children who are identified to have high velocities, treatment with aggressive exchange transfusion dramati­ cally reduces risk of stroke, and if exchange transfusion is ceased, their stroke rate increases again along with MCA velocities. Fibromuscular dysplasia (Chap. 292) affects the cervical arteries and occurs mainly in women. The carotid or vertebral arteries show multiple rings of segmental narrowing alternating with dilatation. Vascular occlusion is usually incomplete. The process is often asymp­ tomatic but occasionally is associated with an audible bruit, TIAs, or stroke. Involvement of the renal arteries is common and may cause hypertension. The cause and natural history of fibromuscular dysplasia are unknown. TIA or stroke generally occurs only when the artery is severely narrowed or dissects. Anticoagulation or antiplatelet therapy may be helpful. Temporal (giant cell) arteritis (Chap. 375) is a relatively common affliction of elderly individuals in which the external carotid system, particularly the temporal arteries, undergoes subacute granulomatous inflammation with giant cells. Occlusion of posterior ciliary arteries derived from the ophthalmic artery results in blindness in one or both eyes and can be prevented with glucocorticoids. It rarely causes stroke because the internal carotid artery is usually not inflamed. Idiopathic giant cell arteritis involving the great vessels arising from the aortic arch (Takayasu’s arteritis) may cause carotid or vertebral thrombosis; it is rare in the Western Hemisphere. Necrotizing (or granulomatous) arteritis (Chap. 375), occurring alone or in association with generalized polyarteritis nodosa or granulomatosis with polyangiitis, involves the distal small branches (<2 mm diameter) of the main intracranial arteries and produces small ischemic infarcts in the brain, optic nerve, and spinal cord. The CSF often shows pleocytosis, and the protein level is elevated. Primary CHAPTER 438 FIGURE 438-6  Cerebral angiogram from a 32-year-old male with central nervous system vasculopathy. Dramatic beading (arrows) typical of vasculopathy is shown. Ischemic Stroke central nervous system vasculitis is rare; small or medium-sized ves­ sels are usually affected, without apparent systemic vasculitis. The differential diagnosis includes other inflammatory vasculopathies including infection (tuberculous, fungal), sarcoidosis, angiocentric lymphoma, carcinomatous meningitis, and noninflammatory causes such as atherosclerosis, emboli, connective tissue disease, vasospasm, migraine-associated vasculopathy, and drug-associated causes. Some cases develop in the postpartum period and are self-limited. Patients with any form of vasculopathy may present with insidious progression of combined white and gray matter infarctions, prominent headache, and cognitive decline. Brain biopsy or high-resolution con­ ventional x-ray angiography is usually required to make the diagnosis (Fig. 438-6). A lumbar puncture (elevated white blood cells, elevated IgG index, bands on electrophoresis) can provide support for an inflammatory etiology of a neurovascular problem. When inflamma­ tion is confirmed, aggressive immunosuppression with glucocorticoids, and often cyclophosphamide, is usually necessary to prevent progres­ sion; a diligent investigation for infectious causes such as tuberculosis is essential prior to immunosuppression. With prompt recognition and treatment, many patients can make an excellent recovery. Drugs, in particular amphetamines and perhaps cocaine, may cause stroke on the basis of acute hypertension or drug-induced vasculopa­ thy. This vasculopathy is commonly due to vasospasm or atheroscle­ rosis, but cases of inflammatory vasculitis have also been reported. No data exist on the value of any treatment, but cessation of stimulants is prudent. Phenylpropanolamine has been linked with intracranial hemorrhage, as has cocaine and methamphetamine, perhaps related to a vasculopathy. Moyamoya disease is a poorly understood occlusive disease involving large intracranial arteries, especially the distal inter­ nal carotid artery and the stem of the MCA and ACA. Vascular inflam­ mation is absent. The lenticulostriate arteries develop a rich collateral circulation around the occlusive lesion, which gives the impression of a “puff of smoke” (moyamoya in Japanese) on conventional x-ray angi­ ography. Other collaterals include transdural anastomoses between the cortical surface branches of the meningeal and scalp arteries. The dis­ ease occurs mainly in Asian children or young adults, but the appear­ ance may be identical in adults who have atherosclerosis, particularly in association with diabetes. Intracranial hemorrhage may result from rupture of the moyamoya collaterals; thus, anticoagulation is risky. Progressive occlusion of large surface arteries can occur, producing large-artery distribution strokes. Surgical bypass of extracranial carotid arteries to the dura or MCAs may prevent stroke and hemorrhage. Posterior reversible encephalopathy syndrome (PRES) can occur with head injury, seizure, migraine, sympathomimetic drug use, and eclampsia and in the postpartum period. The pathophysiology is uncertain but likely involves a hyperperfusion state where blood pressure exceeds the upper limit of cerebral autoregulation resulting in cerebral edema (Chap. 318). Patients complain of headache and manifest fluctuating neurologic symptoms and signs, especially visual symptoms. Sometimes cerebral infarction ensues, but typically, the clinical and imaging findings reverse completely. MRI findings are characteristic with edema present within the occipital lobes but also can be generalized and do not respect any single vascular territory. A closely related reversible cerebral vasoconstriction syndrome (RCVS) typically presents with sudden, severe headache closely mimicking SAH. Patients may experience ischemic infarction and intracerebral hemorrhage and typically have new-onset, severe hypertension. Con­ ventional x-ray angiography reveals changes in the vascular caliber throughout the hemispheres resembling vasculitis, but the process is noninflammatory. Oral calcium channel blockers may be effective in producing remission, and recurrence is rare. Leukoaraiosis, or periventricular white matter disease, is the result of multiple small-vessel infarcts within the subcortical white matter. It is readily seen on CT or MRI scans as areas of white matter injury surrounding the ventricles and within the corona radiata. The patho­ physiologic basis of the disease is lipohyalinosis of small penetrating arteries within the white matter, likely produced by chronic hyperten­ sion. Patients with periventricular white matter disease may develop a subcortical dementia syndrome, and it is likely that this common form of dementia may be delayed or prevented with antihypertensive medications (Chap. 444). PART 13 Neurologic Disorders CADASIL (cerebral autosomal dominant arteriopathy with subcor­ tical infarcts and leukoencephalopathy) is an inherited disorder that presents as small-vessel strokes, progressive dementia, and extensive symmetric white matter changes often including the anterior temporal lobes visualized by MRI. Approximately 40% of patients have migraine with aura, often manifest as transient motor or sensory deficits. Onset is usually in the fourth or fifth decade of life. This autosomal dominant condition is caused by one of several mutations in Notch-3, a member of a highly conserved gene family characterized by epidermal growth factor repeats in its extracellular domain. Other monogenic ischemic stroke syndromes include cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) and hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS). Fabry’s disease also produces both a large-vessel arteriopa­ thy and small-vessel infarctions. The COL4A1 mutation is associated with multiple small-vessel strokes with hemorrhagic transformation. ■ ■TRANSIENT ISCHEMIC ATTACKS TIAs are episodes of stroke symptoms that last only briefly; the stan­ dard definition of duration is <24 h, but most TIAs last <1 h. If a rel­ evant brain infarction is identified on brain imaging, the clinical entity is now classified as stroke regardless of the duration of symptoms. A normal brain imaging study following a TIA does not rule out TIA; rather, the clinical syndrome is diagnostic. The causes of TIA are simi­ lar to those of ischemic stroke, but because TIAs may herald stroke, they are an important risk factor that should be considered urgently. TIAs may arise from emboli to the brain or from in situ thrombosis of an intracranial vessel. With a TIA, the occluded blood vessel reopens and neurologic function is restored. The risk of stroke after a TIA is ~10–15% in the first 3 months, with most events occurring in the first 2 days. This risk can be directly esti­ mated using the well-validated ABCD2 score (Table 438-5). Therefore, urgent evaluation and treatment are justified. Because etiologies for stroke and TIA are identical, evaluation for TIA should parallel that of stroke. TREATMENT Transient Ischemic Attack The improvement characteristic of TIA is a contraindication to thrombolysis. However, because the risk of subsequent stroke in the first few hours and days following TIA is high, some physicians admit the patient to the hospital so a plasminogen activator can be rapidly administered if symptoms return. The combination of aspirin and clopidogrel was found to prevent stroke following TIA better than aspirin alone in a large Chinese randomized trial and TABLE 438-5  Risk of Stroke Following Transient Ischemic Attack: The ABCD2 Score CLINICAL FACTOR SCORE A: Age ≥60 years B: SBP >140 mmHg or DBP >90 mmHg C: Clinical symptoms   Unilateral weakness   Speech disturbance without weakness D: Duration   >60 min   10–59 min D: Diabetes (oral medications or insulin) TOTAL SCORE SUM EACH CATEGORY ABCD2 Score Total 3-Month Rate of Stroke (%)a aData ranges are from five cohorts. Abbreviations: DBP, diastolic blood pressure; SBP, systolic blood pressure. Source: Data from SC Johnston et al: Validation and refinement of scores to predict very early stroke risk after transient ischaemic attack. Lancet 369:283, 2007. the National Institutes of Health (NIH)–sponsored POINT trial. Failure to respond to the combination of aspirin and clopidogrel is linked to carriage of a common CYP2C19 polymorphism that leads to poor metabolism of clopidogrel into its active form. This muta­ tion is common, particularly in Asians. Recently, ticagrelor, 180-mg loading dose and then 90 mg twice daily, was tested in combination with aspirin compared to aspirin alone, and this also showed benefit in preventing stroke; this dual antiplatelet regimen may be favored because of the lack of genetic heterogeneity in platelet inhibition. Primary and Secondary Prevention of Stroke and TIA GENERAL PRINCIPLES Many medical and surgical interventions, as well as lifestyle modi­ fications, are available for preventing stroke. Some of these can be widely applied because of their low cost and minimal risk; others are expensive and carry substantial risk but may be valuable for selected high-risk patients. Identification and control of modifi­ able risk factors, and especially hypertension, is the best strategy to reduce the burden of stroke, and the total number of strokes could be reduced substantially by these means (Table 438-4). ATHEROSCLEROSIS RISK FACTORS The relationship of various factors to the risk of atherosclerosis is described in Chaps. 244 and 245. Older age, diabetes mellitus, hypertension, tobacco smoking, abnormal blood cholesterol (par­ ticularly, low high-density lipoprotein [HDL] and/or elevated lowdensity lipoprotein [LDL]), lipoprotein (a) excess, and other factors are either proven or probable risk factors for ischemic stroke, largely by their link to atherosclerosis. Risk of stroke is much greater in those with prior stroke or TIA. Many cardiac conditions predispose to stroke, including atrial fibrillation and recent MI. Oral contra­ ceptives and hormone replacement therapy increase stroke risk, and although rare, certain inherited and acquired hypercoagulable states predispose to stroke. Hypertension is the most significant of the risk factors; in general, all hypertension should be treated to a target of <130/80 mmHg. Recent data (the Systolic Blood Pressure Intervention Trial—SPRINT) suggest that lowering systolic blood pressure <120 mmHg reduces stroke and heart attack by 43% compared to systolic blood pressure <140 mmHg, without an increased risk of syncope or falls, although patients with a history of stroke were specifically excluded from this study. The presence of known cerebrovascular disease is not a contraindication to treatment aimed at achieving normotension. Data are particularly strong in support of thiazide diuretics and angiotensin-converting enzyme inhibitors. Several trials have confirmed that statin drugs reduce the risk of stroke even in patients without elevated LDL or low HDL. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) trial showed benefit in secondary stroke reduction for patients with recent stroke or TIA who were prescribed atorvas­ tatin, 80 mg/d. The primary prevention trial, Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER), found that patients with an elevated C-reactive protein benefitted by daily use of this statin, despite LDL <130 mg/dL. Primary stroke occurrence was reduced by 51% (hazard ratio, 0.49; p = .004), and there was no increase in the rates of intracranial hemorrhage. Meta-analysis has also supported a pri­ mary treatment effect for statins given acutely for ischemic stroke. A serum LDL <70 mg/dL lowers recurrent stroke risk better than an LDL of 90–110 mg/dL. Therefore, a statin should be considered in all patients with prior ischemic stroke. Tobacco smoking should be discouraged in all patients (Chap. 465). The use of pioglitazone (an agonist of peroxisome proliferator-activated receptor gamma) in patients with type 2 diabetes and previous stroke does not lower stroke, MI, or vascular death rates but is effective in lowering vas­ cular events in patients with stroke and prediabetes or insulin resis­ tance alone. Diabetes prevention is likely the most effective strategy for primary and secondary stroke prevention. ANTIPLATELET AGENTS FOR STROKE PREVENTION Platelet antiaggregation agents can prevent atherothrombotic events, including TIA and stroke, by inhibiting the formation of intra­ arterial platelet aggregates. These can form on diseased arteries, induce thrombus formation, and occlude or embolize into the distal circulation. Aspirin, clopidogrel, the combination of aspirin plus extended-release dipyridamole, and recently ticagrelor are the anti­ platelet agents most commonly used for this purpose. Ticagrelor has not been found to be better than aspirin for stroke prevention except in combination with aspirin following TIA. Aspirin is the most widely studied antiplatelet agent. Aspirin acetylates platelet cyclooxygenase, which irreversibly inhibits the formation in platelets of thromboxane A2, a platelet aggregating and vasoconstricting prostaglandin. This effect is permanent and lasts for the usual 8-day life of the platelet. Paradoxically, aspirin also inhibits the formation in endothelial cells of prostacyclin, an antiag­ gregating and vasodilating prostaglandin. This effect is transient. As soon as aspirin is cleared from the blood, the nucleated endothelial cells again produce prostacyclin. Aspirin in low doses given once daily inhibits the production of thromboxane A2 in platelets with­ out substantially inhibiting prostacyclin formation. Higher doses of aspirin have not been proven to be more effective than lower doses. Clopidogrel and ticagrelor block the adenosine diphosphate (ADP) receptor on platelets and thus prevent the cascade result­ ing in activation of the glycoprotein IIb/IIIa receptor that leads to fibrinogen binding to the platelet and consequent platelet aggrega­ tion. Clopidogrel can cause rash and, in rare instances, thrombotic thrombocytopenic purpura. The Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events (CAPRIE) trial, which led to U.S. Food and Drug Administration (FDA) approval, found that it was only marginally more effective than aspirin in reducing risk of stroke. The Management of Atherothrombosis with Clopidogrel in High-Risk Patients (MATCH) trial was a large multicenter, randomized, double-blind study that compared clopidogrel in com­ bination with aspirin to clopidogrel alone in the secondary preven­ tion of TIA or stroke. The MATCH trial found no difference in TIA or stroke prevention with this combination but did show a small but significant increase in major bleeding complications (3 vs 1%). In the Clopidogrel for High Atherothrombotic Risk and Ischemic Sta­ bilization, Management, and Avoidance (CHARISMA) trial, which included a subgroup of patients with prior stroke or TIA along with other groups at high risk of cardiovascular events, there was no ben­ efit of clopidogrel combined with aspirin compared to aspirin alone. Lastly, the SPS3 trial looked at the long-term combination of clopi­ dogrel and aspirin versus clopidogrel alone in small-vessel stroke and found no improvement in stroke prevention and a significant increase in both hemorrhage and death. Thus, the long-term use of clopidogrel in combination with aspirin is not recommended for stroke prevention. The short-term combination of clopidogrel with aspirin may be effective in preventing second stroke, however. A large trial of Chi­ nese patients enrolled within 24 h of TIA or minor ischemic stroke found that a clopidogrel-aspirin regimen (clopidogrel 300 mg load then 75 mg/d with aspirin 75 mg for the first 21 days) was superior to aspirin (75 mg/d) alone, with 90-day stroke risk decreased from 11.7 to 8.2% (p <.001) and no increase in major hemorrhage. This benefit was limited to those not carrying the CYP2C19 polymor­ phism associated with clopidogrel hypometabolism. An interna­ tional NIH-sponsored trial demonstrated similar results; therefore, the combination of aspirin and clopidogrel should be administered for TIA or minor ischemic stroke for the first 21 days before switch­ ing to monotherapy. CHAPTER 438 Ischemic Stroke A recent study of oral ticagrelor plus aspirin versus aspirin alone has shown similar benefits in secondary stroke reduction and car­ ries the likely advantage that ticagrelor’s antiplatelet effect is not genetically variable, as is the case with clopidogrel. Dipyridamole is an antiplatelet agent that inhibits the uptake of adenosine by a variety of cells, including those of the vascular endothelium. The accumulated adenosine is an inhibitor of aggre­ gation. At least in part through its effects on platelet and vessel wall phosphodiesterases, dipyridamole also potentiates the antiaggrega­ tory effects of prostacyclin and nitric oxide produced by the endo­ thelium and acts by inhibiting platelet phosphodiesterase, which is responsible for the breakdown of cyclic AMP. The resulting eleva­ tion in cyclic AMP inhibits aggregation of platelets. Dipyridamole is erratically absorbed depending on stomach pH, but a newer formu­ lation combines timed-release dipyridamole, 200 mg, with aspirin, 25 mg, and has better oral bioavailability. This combination drug was studied in three trials. The European Stroke Prevention Study (ESPS) II showed efficacy of both 50 mg/d of aspirin and extendedrelease dipyridamole in preventing stroke and a significantly better risk reduction when the two agents were combined. The open-label ESPRIT (European/Australasian Stroke Prevention in Reversible Ischaemia Trial) trial confirmed the ESPS-II results. After 3.5 years of follow-up, 13% of patients on aspirin and dipyridamole and 16% on aspirin alone (hazard ratio, 0.80; 95% CI, 0.66–0.98) met the pri­ mary outcome of death from all vascular causes. In the Prevention Regimen for Effectively Avoiding Second Strokes (PRoFESS) trial, the combination of extended-release dipyridamole and aspirin was compared directly with clopidogrel with and without the angioten­ sin receptor blocker telmisartan; there were no differences in the rates of second stroke (9% each) or degree of disability in patients with median follow-up of 2.4 years. Telmisartan also had no effect on these outcomes. This suggests that these antiplatelet regimens are similar and raises questions about default prescription of agents to block the angiotensin pathway in all stroke patients. The prin­ cipal side effect of dipyridamole is headache. The combination capsule of extended-release dipyridamole and aspirin is approved for prevention of stroke. Many large clinical trials have demonstrated clearly that most antiplatelet agents reduce the risk of all important vascular ath­ erothrombotic events (i.e., ischemic stroke, MI, and death due to all vascular causes) in patients at risk for these events. The overall relative reduction in risk of nonfatal stroke is ~25–30% and of all vascular events is ~25%. The absolute reduction varies consider­ ably, depending on the patient’s risk. Individuals at very low risk for stroke seem to experience the same relative reduction, but their risks may be so low that the “benefit” is meaningless. Conversely, individuals with a 10–15% risk of vascular events per year experi­ ence a reduction to ~7.5–11%. Aspirin is inexpensive, can be given in low doses, and could be recommended for all adults to prevent both stroke and MI. However, it causes epigastric discomfort, gastric ulceration, and gastrointestinal hemorrhage, which may be asymptomatic or life threatening. Consequently, not every 40- or 50-year-old should be advised to take aspirin regularly because the risk of atherothrom­ botic stroke is extremely low and is outweighed by the risk of adverse side effects. Conversely, every patient who has experienced an atherothrombotic stroke or TIA and has no contraindication to antiplatelet therapy (or indication for anticoagulation) should be taking an antiplatelet agent regularly because the average annual risk of another stroke is 8–10%; another few percent will experi­ ence an MI or vascular death. Clearly, the likelihood of benefit far outweighs the risks of treatment. PART 13 Neurologic Disorders The choice of antiplatelet agent and dose must balance the risk of stroke, the expected benefit, and the risk and cost of treat­ ment. However, there are no definitive data, and opinions vary. Many authorities believe low-dose (30–75 mg/d) and high-dose (650–1300 mg/d) aspirin are about equally effective. Some advocate very low doses to avoid adverse effects, and still others advocate very high doses to be sure the benefit is maximal. Most physicians in North America recommend 81–325 mg/d, whereas most Euro­ peans recommend 50–100 mg. Clopidogrel and extended-release dipyridamole plus aspirin are being increasingly recommended as first-line drugs for secondary prevention. Similarly, the choice of aspirin, clopidogrel, or dipyridamole plus aspirin must balance the fact that the latter are more effective than aspirin but the cost is higher, and this is likely to affect long-term patient adherence. The use of platelet aggregation studies in individual patients taking aspirin is controversial because of limited data. In our practices, when considering antithrombotic therapy for secondary stroke prevention for noncardioembolic strokes and TIAs, we prescribe aspirin 81 mg/d in aspirin-I patients after an initial load of 325 mg. We add either clopidogrel (600-mg load, then 75 mg daily) or ticagrelor (180-mg load, then 90 mg twice daily) for TIA or minor stroke (NIHSS <5) for 21–30 days, followed by monotherapy with aspirin alone at 81 mg daily. We treat stroke due to intracranial atherosclerosis with aspirin 81 mg plus clopidogrel 75 mg daily for 3 months, after which time treatment is continued with aspirin alone. ANTICOAGULATION THERAPY AND EMBOLIC STROKE PREVENTION Several trials have shown that anticoagulation (international nor­ malized ratio [INR] range, 2–3) in patients with chronic nonval­ vular (nonrheumatic) atrial fibrillation (NVAF) prevents cerebral embolism and stroke and is safe. For primary prevention and for patients who have experienced stroke or TIA, anticoagulation with a vitamin K antagonist (VKA) reduces the risk by ~67%, which clearly outweighs the 1–3% risk per year of a major bleeding com­ plication. VKAs are difficult to dose, their effects vary with dietary intake of vitamin K, and they require frequent blood monitoring of the PTT/INR. Several direct oral anticoagulants (DOACs) have recently been shown to be more convenient and efficacious for stroke prevention in NVAF. A randomized trial compared the oral thrombin inhibitor dabigatran to VKAs in a noninferiority trial to prevent stroke or systemic embolization in NVAF. Two doses of dabigatran were used: 110 mg/d and 150 mg/d. Both dose tiers of dabigatran were noninferior to VKAs in preventing second stroke and systemic embolization, and the higher dose tier was supe­ rior (relative risk, 0.66; 95% CI, 0.53–0.82; p <.001) and the rate of major bleeding was lower in the lower dose tier of dabigatran compared to VKAs. Dabigatran requires no blood monitoring to titrate the dose, and its effect is independent of oral intake of vita­ min K. Newer oral factor Xa inhibitors have also been found to be equivalent or safer and more effective than VKAs in NVAF stroke prevention. In the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial, patients were randomized between apixaban, 5 mg twice daily, and dose-adjusted warfarin (INR 2–3). The combined endpoint of ischemic or hemorrhagic stroke or system embolism occurred in 1.27% of patients in the apixaban group and in 1.6% in the warfarin group (p <.001 for noninferiority and p <.01 for superiority). Major bleeding was 1% less, favoring apixaban (p <.001). Similar results were obtained in the Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET-AF). In this trial, patients with NVAF were randomized to rivaroxaban versus warfarin: 1.7% of the factor Xa group and 2.2% of the war­ farin group reached the endpoint of stroke and systemic embolism (p <.001 for noninferiority); intracranial hemorrhage was also lower with rivaroxaban. Finally, the factor Xa inhibitor edoxaban was also found to be noninferior to warfarin. Thus, oral factor Xa inhibi­ tors are at least a suitable alternative to VKAs, for both primary and secondary prevention, and likely are superior both in efficacy and perhaps compliance. Recent FDA approval of a reversal agent for the Xa inhibitors apixaban and rivaroxaban (andexanet alfa) provides an antidote in the case of major bleeding. Idarucizumab has been available for reversal of dabigatran. Randomized trials have not demonstrated the superiority of anticoagulants over anti­ platelet medications for strokes that appear embolic without a clear source, even when limited to the subset with evidence of an atrial cardiopathy. For patients who cannot take anticoagulant medications, clopi­ dogrel plus aspirin was compared to aspirin alone in the Atrial Fibrillation Clopidogrel Trial with Irbesartan for Prevention of Vascular Events (ACTIVE-A). Clopidogrel combined with aspirin was more effective than aspirin alone in preventing vascular events, principally stroke, but increased the risk of major bleeding (relative risk, 1.57; p <.001). Left atrial appendage occlusion followed by antiplatelet therapy was found to be noninferior to oral Xa inhibi­ tors in patients at moderate to high risk of bleeding in a single trial. If confirmed, this may be a safer strategy than management with aspirin alone for these patients at high risk of atrial fibrillation– related stroke. The decision to use anticoagulation for primary prevention is based primarily on risk factors (Table 438-3). The history of a TIA or stroke tips the balance in favor of anticoagulation regard­ less of other risk factors. Intermittent atrial fibrillation carries the same risk of stroke as chronic atrial fibrillation, and several ambulatory studies of seemingly “cryptogenic” stroke have found evidence of intermittent atrial fibrillation in nearly 20% of patients monitored for a few weeks. Interrogation of implanted pacemakers also confirms an association between subclinical atrial fibrillation and stroke risk. Therefore, for patients with otherwise cryptogenic embolic stroke (no evidence of any other cause for stroke), ambu­ latory monitoring for at least 30 days is a reasonable strategy to determine the best prophylactic therapy, and some patients may benefit from placement of longer-term implantable loop recorders. Because of the high annual stroke risk in untreated rheumatic heart disease with atrial fibrillation, primary prophylaxis against stroke has not been studied in a double-blind fashion. These patients generally should receive long-term anticoagulation. Dabi­ gatran and the oral Xa inhibitors have not been studied in this population. Anticoagulation also reduces the risk of embolism in acute MI. Most clinicians recommend a 3-month course of anticoagulation when there is anterior Q-wave infarction, substantial left ventricu­ lar dysfunction, congestive heart failure, mural thrombosis, or atrial fibrillation. Oral anticoagulants are recommended long term if atrial fibrillation persists. Stroke secondary to thromboembolism is one of the most serious complications of prosthetic heart valve implantation. The intensity of anticoagulation and/or antiplatelet therapy is dictated by the type of prosthetic valve and its location. Dabigatran may be less effective than warfarin, and the oral Xa inhibitors have not been studied in this population. If the embolic source cannot be eliminated, anticoagulation should in most cases be continued indefinitely. Many neurologists recommend combining antiplatelet agents with anticoagulants for patients who “fail” anticoagulation (i.e., have another stroke or TIA), but the evidence basis for this is lacking. It is our practice to prescribe apixaban 5 mg twice daily (adjusted to 2.5 mg twice daily if age, weight, and renal function criteria are met) for nonvalvular atrial fibrillation with CHA2DS2-VASc score of ≥2, aspirin 81 mg plus clopidogrel 75 mg daily for patients who cannot take oral anticoagulation, and VKAs for valvular atrial fibrillation or mechanical heart valve. ANTICOAGULATION THERAPY AND NONCARDIOGENIC STROKE Data do not support the use of long-term VKAs for prevent­ ing atherothrombotic stroke for either intracranial or extracranial cerebrovascular disease. The Warfarin-Aspirin Recurrent Stroke Study (WARSS) found no benefit of warfarin sodium (INR 1.4–2.8) over aspirin, 325 mg, for secondary prevention of stroke but did find a slightly higher bleeding rate in the warfarin group; a Euro­ pean study confirmed this finding. The Warfarin and Aspirin for Symptomatic Intracranial Disease (WASID) study (see below) demonstrated no benefit of warfarin (INR 2–3) over aspirin in patients with symptomatic intracranial atherosclerosis and found a higher rate of bleeding complications. Two trials testing factor Xa medications for prevention of embolic stroke of undetermined source (ESUS) failed to show benefit compared to treatment with antiplatelet medications and a third trial limited to ESUS patients with atrial cardiopathy had similar results. The oral factor Xa inhibitor apixaban was found to be noninferior to subcutaneous dalteparin for patients with cancer and venous thromboembolism; many oncologists are using Xa inhibitors to prevent second stroke in patients with malignancy. It is our practice to prescribe aspirin for secondary stroke pre­ vention in noncardiogenic cerebral embolism except for stroke associated with cancer (apixaban 5 mg twice daily) and the antiphos­ pholipid syndrome (warfarin with target INR 2–3). TREATMENT Carotid Atherosclerosis Carotid atherosclerosis can be removed surgically (endarterec­ tomy), mitigated with endovascular stenting with or without bal­ loon angioplasty, or using the transcarotid artery revascularization (TCAR) approach. Anticoagulation has not been directly compared with antiplatelet therapy for carotid disease. SURGICAL THERAPY Symptomatic carotid stenosis was studied in the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgery Trial (ECST). Both showed a substantial benefit for surgery in patients with stenosis of ≥70%. In NASCET, the average cumulative ipsilateral stroke risk at 2 years was 26% for patients treated medically and 9% for those receiving the same medical treatment plus a carotid endarterectomy. This 17% abso­ lute reduction in the surgical group is a 65% relative risk reduction favoring surgery (Table 438-4). NASCET also showed a significant, although less robust, benefit for patients with 50–70% stenosis. ECST found harm for patients with stenosis <30% treated surgically. A patient’s risk of stroke and possible benefit from surgery are related to the presence of retinal versus hemispheric symptoms, degree of arterial stenosis, extent of associated medical conditions (of note, NASCET and ECST excluded “high-risk” patients with significant cardiac, pulmonary, or renal disease), institutional surgi­ cal morbidity and mortality, timing of surgery relative to symptoms, and other factors. A recent meta-analysis of the NASCET and ECST trials demonstrated that endarterectomy is most beneficial when performed within 2 weeks of symptom onset. In addition, benefit is more pronounced in patients >75 years, and men appear to benefit more than women. In summary, a patient with recent symptomatic hemispheric ischemia, high-grade stenosis in the appropriate internal carotid artery, and an institutional perioperative morbidity and mortal­ ity rate of ≤6% generally should undergo carotid endarterectomy. If the perioperative stroke rate is >6% for any particular surgeon, however, the benefits of carotid endarterectomy are questionable. The indications for surgical treatment of asymptomatic carotid disease have been clarified by the results of the Asymptomatic Carotid Atherosclerosis Study (ACAS) and the Asymptomatic Carotid Surgery Trial (ACST). ACAS randomized asymptomatic patients with ≥60% stenosis to medical treatment with aspirin or the same medical treatment plus carotid endarterectomy. The surgical group had a risk over 5 years for ipsilateral stroke (and any perioperative stroke or death) of 5.1%, compared to a risk in the medical group of 11%. Although this demonstrates a 53% relative risk reduction, the absolute risk reduction is only 5.9% over 5 years, or 1.2% annually (Table 438-4). Nearly one-half of the strokes in the surgery group were caused by preoperative angiograms. ACST randomized asymptomatic patients with >60% carotid stenosis to endarterectomy or medical therapy. The 5-year risk of stroke in the surgical group (including perioperative stroke or death) was 6.4%, compared to 11.8% in the medically treated group (46% relative risk reduction and 5.4% absolute risk reduction). CHAPTER 438 Ischemic Stroke In both ACAS and ACST, the perioperative complication rate was higher in women, perhaps negating any benefit in the reduction of stroke risk within 5 years. It is possible that with longer follow-up, a clear benefit in women will emerge. At present, carotid endarter­ ectomy in asymptomatic women remains particularly controversial. In summary, the natural history of asymptomatic stenosis is an ~2% per year stroke rate, whereas symptomatic patients experi­ ence a 13% per year risk of stroke. Whether to recommend carotid revascularization for an asymptomatic patient is somewhat contro­ versial and depends on many factors, including patient preference, degree of stenosis, age, gender, and comorbidities. Medical therapy for reduction of atherosclerosis risk factors, including cholesterollowering agents and antiplatelet medications, is generally recom­ mended for patients with asymptomatic carotid stenosis. As with atrial fibrillation, it is imperative to counsel the patient about TIAs so that therapy can be revised if symptoms develop. ENDOVASCULAR THERAPY Balloon angioplasty coupled with stenting is one option to open stenotic carotid arteries and maintain their patency. These tech­ niques can treat carotid stenosis not only at the bifurcation but also near the skull base and in the intracranial segments. The Stent­ ing and Angioplasty with Protection in Patients at High Risk for Endarterectomy (SAPPHIRE) trial randomized high-risk patients (defined as patients with clinically significant coronary or pulmo­ nary disease, contralateral carotid occlusion, restenosis after end­ arterectomy, contralateral laryngeal-nerve palsy, prior radical neck surgery or radiation, or age >80) with symptomatic carotid stenosis >50% or asymptomatic stenosis >80% to either stenting combined with a distal emboli-protection device or endarterectomy. The risk of death, stroke, or MI within 30 days and ipsilateral stroke or death within 1 year was 12.2% in the stenting group and 20.1% in the endarterectomy group (p = .055), suggesting that stenting is at the very least comparable to endarterectomy as a treatment option for this patient group at high risk of surgery. However, the outcomes with both interventions may not have been better than leaving the carotid stenoses untreated, particularly for the asymptomatic patients, and much of the benefit seen in the stenting group was due to a reduction in periprocedure MI. Two randomized trials com­ paring stents to endarterectomy in lower-risk patients have been published. The Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) enrolled patients with either asymptomatic # 09 - 439 Intracerebral Hemorrhage ### 439 Intracerebral Hemorrhage or symptomatic stenosis. The 30-day risk of stroke was 4.1% in the stent group and 2.3% in the surgical group, but the 30-day risk of MI was 1.1% in the stent group and 2.3% in the surgery group, suggest­ ing relative equivalence of risk between the procedures. At median follow-up of 2.5 years, the combined endpoint of stroke, MI, and death was the same (7.2% stent vs 6.8% surgery) and remained so at 10-year follow-up. The rate of restenosis at 2 years was also similar in both groups. The International Carotid Stenting Study (ICSS) randomized symptomatic patients to stents versus endarterectomy and found a different result: at 120 days, the incidence of stroke, MI, or death was 8.5% in the stenting group versus 5.2% in the endarterectomy group (p = .006). At median follow-up of 5 years, these differences were no longer significant except a small increase in nondisabling stroke in the stenting group but no change in the average disability. In meta-analysis, carotid endarterectomy (CEA) is less morbid in older patients (aged ≥70) than is stenting. Recently, transcarotid artery revascularization (TCAR), which involves the reversal of blood flow during an angioplasty and stenting proce­ dure, has been offered as an alternative to transfemoral carotid artery stenting or when CEA presents high risks. Investigation is ongoing in asymptomatic patients to compare medical therapy to stenting and CEA. This will likely answer how well medical patients do with more modern medical therapy (statins, close blood pres­ sure control, and lifestyle modification). BYPASS SURGERY Extracranial-to-intracranial (EC-IC) bypass surgery has been proven ineffective for atherosclerotic stenoses that are inaccessible to conventional CEA. In patients with recent stroke, an associated carotid occlusion, and evidence of inadequate perfusion of the brain as measured with positron emission tomography, no benefit from EC-IC bypass was found in a trial stopped for futility. PATENT FORAMEN OVALE In patients with PFO and/or atrial septal aneurysm with an embolic stroke and no other cause identified, three randomized trials using various endovascular closure devices individually and in metaanalysis reported a significant (1% per year) reduction in second stroke compared to antiplatelet agents. If the neurologic opinion is that no other source of stroke is identified and consultation with a cardiologist knowledgeable about PFO closure supports interven­ tion, we recommend endovascular PFO closure. INTRACRANIAL ATHEROSCLEROSIS The WASID trial randomized patients with symptomatic stenosis (50–99%) of a major intracranial vessel to either high-dose aspirin (1300 mg/d) or warfarin (target INR, 2.0–3.0), with a combined primary endpoint of ischemic stroke, brain hemorrhage, or death from vascular cause other than stroke. The trial was terminated early because of an increased risk of adverse events related to warfarin anticoagulation. With a mean follow-up of 1.8 years, the primary endpoint was seen in 22.1% of patients in the aspirin group and 21.8% of the warfarin group. Death from any cause was seen in 4.3% of the aspirin group and 9.7% of the warfarin group; 3.2% of patients on aspirin experienced major hemorrhage, compared to 8.3% of patients taking warfarin. PART 13 Neurologic Disorders Intracranial stenting of intracranial atherosclerosis was found to be dramatically harmful compared to aspirin in the Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS) trial. This trial enrolled newly symptomatic TIA or minor stroke patients with associated 70–99% intracranial stenosis to primary stenting with a self-expanding stent or to medical management. Both groups received clopidogrel, aspi­ rin, statin, and aggressive control of blood pressure. The endpoint of stroke or death occurred in 14.7% of the stented group and 5.8% of the medically treated groups (p = .002). This low rate of second stroke was significantly lower than in the WASID trial and suggests that aggressive medical management had a marked influence on secondary stroke risk. A concomitant study of balloon-expandable stenting was halted early at 125 patients because of the negative SAMMPRIS results and due to harm. Therefore, routine use of intracranial stenting is harmful, and medical therapy is superior for intracranial atherosclerosis. Dural Sinus Thrombosis  Limited evidence exists to support shortterm use of anticoagulants, regardless of the presence of intracranial hemorrhage, for venous infarction following sinus thrombosis. The long-term outcome for most patients, even those with intracerebral hemorrhage, is excellent. Acknowledgment The authors acknowledge the contributions of S. Claiborne Johnston to earlier editions of this chapter. ■ ■FURTHER READING Goyal M et al: Endovascular thrombectomy after large-vessel isch­ aemic stroke: A meta-analysis of individual patient data from five randomised trials. Lancet 387:1723, 2016. Grotta JC et al: Prospective, multicenter, controlled trial of mobile stroke units. N Engl J Med 385:971, 2021. Jiang H et al: An updated meta-analysis on the clinical outcomes of percutaneous left atrial appendage closure versus direct oral anti­ coagulation in patients with atrial fibrillation. J Am Coll Cardiol 200:135, 2023. Joglar JA et al: 2023 ACC/AHA/ACCP/HRS guideline for the diag­ nosis and management of atrial fibrillation: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 149:e1, 2024. Powers WJ et al: Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 50:e344, 2019. Saver JL et al: Time to treatment with endovascular thrombec­ tomy and outcomes from ischemic stroke: A meta-analysis. JAMA 316:1279, 2016. Sprint Research Group et al: A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 373:2103, 2015. Torbey MT et al: Evidence-based guidelines for the management of large hemispheric infarction: A statement for health care profes­ sionals from the Neurocritical Care Society and the German Society for Neuro-intensive Care and Emergency Medicine. Neurocrit Care 22:146, 2015. J. Claude Hemphill, III, Edilberto Amorim, Wade S. Smith Intracerebral Hemorrhage Intracerebral hemorrhage (ICH) is a form of stroke (see Chap. 437). Compared to ischemic stroke, patients with ICH are more likely to present with headache; however, brain imaging is required to distin­ guish these entities. CT imaging of the head is highly sensitive and specific for intracranial hemorrhage and determines the location(s) of bleeding. Hemorrhages are classified by their location and the under­ lying vascular pathology. ICH is defined as spontaneous hemorrhage directly into the brain parenchyma and will be considered here along with intracranial vascular anomalies such as arteriovenous malforma­ tions (AVMs) of the brain. Other categories of intracranial hemorrhage include bleeding into subarachnoid, subdural, or epidural spaces, usu­ ally caused by trauma (Chap. 454), and subarachnoid hemorrhage due to trauma or the rupture of an intracranial aneurysm (Chap. 440). FIGURE 439-1  Hypertensive intracerebral hemorrhage. Transaxial noncontrast computed tomography scan through the region of the basal ganglia reveals a hematoma involving the left putamen in a patient with rapidly progressive onset of right hemiparesis. ■ ■DIAGNOSIS Intracranial hemorrhage is often identified on noncontrast computed tomography (CT) imaging of the head during the acute evaluation of stroke. Because CT is more widely available and may be logistically easier to perform than magnetic resonance imaging (MRI), CT imag­ ing is generally the preferred method for acute stroke evaluation (Fig. 439-1). The location of the hemorrhage narrows the differential diagnosis to a few entities. Table 439-1 lists the causes and anatomic spaces involved in intracranial hemorrhages. ■ ■EMERGENCY MANAGEMENT Close attention should be paid to airway management because deterio­ ration in the level of consciousness is common and often progressive. The initial blood pressure should be maintained until the results of the CT scan are reviewed and demonstrate ICH. A higher blood pressure may promote hematoma expansion, but it remains unclear if lower­ ing of blood pressure reduces hematoma growth. Recent clinical trials have shown that systolic blood pressure (SBP) can be safely lowered acutely and rapidly to <140 mmHg in patients with spontaneous ICH whose initial SBP was 150–220 mmHg. The INTERACT2 trial was a large phase 3 clinical trial to address the effect of acute blood pres­ sure lowering on ICH functional outcome. INTERACT2 randomized patients with spontaneous ICH within 6 h of onset and a baseline SBP of 150–220 mmHg to two different SBP targets (<140 and <180 mmHg). In those with the target SBP <140 mmHg, 52% had an outcome of death or major disability at 90 days compared with 55.6% of those with a target SBP <180 mmHg (p = .06). There was a significant shift to improved outcomes in the lower blood pressure arm, whereas both groups had a similar mortality. ATACH2 was a similarly designed clini­ cal trial that assessed the same blood pressure targets but demonstrated no difference in outcome between groups; however, aggressive blood pressure lowering did increase renal adverse events. Current U.S. and European guidelines emphasize that blood pressure lowering to a target SBP is likely safe and possibly beneficial. While the specific optimal target remains a point of debate, the most recent American Heart Asso­ ciation/American Stroke Association guidelines for the management of spontaneous ICH endorse achieving and maintaining a target SBP of 130–150 mmHg in these patients to avoid unintended hypoperfusion. It is unclear whether these clinical trial results apply to patients who have higher SBP on presentation or who are deeply comatose with possible elevated intracranial pressure (ICP). In patients who have ICP monitors in place, maintaining the cerebral perfusion pressure (mean arterial pressure [MAP] minus ICP) of 60 to ≥70 mmHg is reasonable, TABLE 439-1  Causes of Intracerebral Hemorrhage (ICH) CAUSE LOCATION COMMENTS Primary ICH     Cerebral amyloid angiopathy Lobar Degenerative disease of intracranial vessels; associated with dementia, rare in patients <60 years Coagulopathy Any Risk for hematoma expansion Drug Any, lobar, subarachnoid Cocaine, amphetamine Hypertension Putamen, globus pallidus, thalamus, cerebellar hemisphere, pons Chronic hypertension produces hemorrhage from small (~30–100 μm) vessels in these regions Secondary ICH     Aneurysm Subarachnoid, intraparenchymal, rarely subdural Mycotic and nonmycotic forms of aneurysms CHAPTER 439 Arteriovenous malformation Lobar, intraventricular, subarachnoid Risk is ~2–4% per year for bleeding if previously unruptured Capillary telangiectasias Usually brainstem Rare cause of hemorrhage Intracerebral Hemorrhage Cavernous angioma Intraparenchymal Multiple cavernous angiomas linked to mutations in KRIT1, CCM2, and PDCD10 genes Dural arteriovenous fistula Lobar, subarachnoid Produces bleeding from venous hypertension Dural sinus thrombosis Along sagittal sinus, posterior temporal/ inferior parietal Sagittal sinus thrombosis can cause hemispheric parasagittal hemorrhage with edema; vein of Labbé occlusion from transverse sinus occlusion produces posterior temporal and/or inferior parietal hemorrhage Metastatic or primary brain tumors Lobar Lung, choriocarcinoma, melanoma, renal cell carcinoma, thyroid, hepatocellular carcinoma, and pilocytic astrocytoma are more commonly associated with bleeding complications Transformation of prior ischemic infarction Basal ganglion, subcortical regions, lobar Occurs in a significant proportion of ischemic strokes, more commonly in large hemispheric infarctions; is symptomatic in 3–9% of patients undergoing acute intervention depending on the individual patient’s cerebral autoregulation status (Chap. 318). Blood pressure should be lowered using IV drugs with less cerebral vasodilating action such as nicardipine, clevidipine, labet­ alol, or esmolol. Patients with radiographic evidence of hydrocephalus or cerebellar ICH with depressed mental status should undergo urgent neurosurgical evaluation; these patients require close monitoring because they can deteriorate rapidly. Based on the clinical examination and CT findings, further imaging studies may be necessary, includ­ ing MRI or conventional x-ray angiography. Stuporous or comatose patients with clinical and imaging signs of herniation can be presump­ tively treated for elevated ICP with tracheal intubation and sedation, administration of osmotic diuretics such as mannitol or hypertonic saline, and elevation of the head of the bed while surgical consultation is obtained (Chap. 318). Rapid reversal of coagulopathy ideally within 1 h of presentation and consideration of surgical evacuation of the hematoma (detailed below) are two other principal aspects of initial emergency management. ■ ■INTRACEREBRAL HEMORRHAGE ICH accounts for ~10% of all strokes, and ~35–45% of patients die within the first month. Incidence rates are particularly high in Asian and Black patient groups. Hypertension, coagulopathy, sympathomimetic drugs (cocaine, methamphetamine), and cerebral amyloid angiopathy (CAA) cause most of these hemorrhages. Advanced age, heavy alcohol, and low-dose aspirin use in those without symptomatic cardiovascular disease increase ICH risk, and cocaine or methamphetamine use is one of the most important causes in the young. Hypertensive ICH  •  PATHOPHYSIOLOGY  Hypertensive ICH usually results from spontaneous rupture of a small penetrating artery deep in the brain. The most common sites are the basal ganglia (espe­ cially the putamen), thalamus, cerebellum, and pons. The small arter­ ies in these areas seem most prone to hypertension-induced vascular injury. When hemorrhages occur in other brain areas or in nonhyper­ tensive patients, greater consideration should be given to other causes such as hemorrhagic disorders, neoplasms, vascular malformations, vasculitis, and CAA. The hemorrhage may be small, or a large clot may form and compress adjacent tissue, causing herniation and death. Blood may also dissect into the ventricular space, which substantially increases morbidity and may cause hydrocephalus. PART 13 Neurologic Disorders Most hypertensive ICHs initially develop over 30–90 min, whereas those associated with anticoagulant therapy may evolve for as long as 24–48 h. It is now recognized that about a third of patients even with no coagulopathy may have significant hematoma expansion within the first day. Within 48 h, macrophages begin to phagocytize the hemorrhage at its outer surface. After 1–6 months, the hemor­ rhage is generally resolved to a slitlike cavity lined with a glial scar and hemosiderin-laden macrophages. CLINICAL MANIFESTATIONS  ICH generally presents as the abrupt onset of a focal neurologic deficit. Seizures are uncommon on pre­ sentation but may occur in 6–15% of patients within the first 3 days. Although clinical symptoms may be maximal at onset, more com­ monly, the focal deficit worsens over 30–90 min and is associated with a diminishing level of consciousness and signs of increased ICP such as headache and vomiting. The putamen is the most common site for hypertensive hemorrhage, and the adjacent internal capsule is usually damaged (Fig. 439-1). Contralateral hemiparesis is therefore the sentinel sign. When mild, the face sags on one side over 5–30 min, speech becomes slurred, the arm and leg gradually weaken, and the eyes deviate away from the side of the hemiparesis. The paralysis may worsen until the affected limbs become flaccid or extend rigidly. When hemorrhages are large, drowsi­ ness gives way to stupor as signs of upper brainstem compression appear. Coma ensues, accompanied by deep, irregular, or intermittent respiration, a dilated and fixed ipsilateral pupil, and decerebrate rigid­ ity. Edema in adjacent brain tissue may cause progressive deterioration over 24–96 h. Thalamic hemorrhages may also produce a contralateral hemiple­ gia or hemiparesis from pressure on, or dissection into, the adjacent internal capsule. A prominent sensory deficit involving all modalities is usually present. Aphasia, often with preserved verbal repetition, may occur after hemorrhage into the dominant thalamus, and construc­ tional apraxia or mutism occurs in some cases of nondominant hemor­ rhage. There may also be a homonymous visual field defect. Thalamic hemorrhages cause several typical ocular disturbances by extension inferiorly into the upper midbrain. These include deviation of the eyes downward and inward so that they appear to be looking at the nose, unequal pupils with absence of light reaction, skew deviation with the eye opposite the hemorrhage displaced downward and medially, ipsi­ lateral Horner’s syndrome, absence of convergence, paralysis of vertical gaze, and retraction nystagmus. Patients may later develop a chronic, contralateral pain syndrome (Déjérine-Roussy syndrome). In pontine hemorrhages, deep coma with quadriplegia often occurs over a few minutes. Typically, there is prominent decerebrate rigidity and “pinpoint” (1 mm) pupils that react to light. There is impairment of reflex horizontal eye movements evoked by head turning (doll’shead or oculocephalic maneuver) or by irrigation of the ears with ice water (Chap. 30). Hyperpnea, severe hypertension, and hyperhidrosis are common. Most patients with deep coma from pontine hemorrhage ultimately die or develop a locked-in state, but small hemorrhages are compatible with survival and significant recovery. Cerebellar hemorrhages usually develop over several hours and are characterized by occipital headache, repeated vomiting, and ataxia of gait. In mild cases, there may be no other neurologic signs except for gait ataxia. Dizziness or vertigo may be prominent. There is often pare­ sis of conjugate lateral gaze toward the side of the hemorrhage, forced deviation of the eyes to the opposite side, or an ipsilateral sixth nerve palsy. Less frequent ocular signs include blepharospasm, involuntary closure of one eye, ocular bobbing, and skew deviation. Dysarthria and dysphagia may occur. As the hours pass, the patient often becomes stu­ porous and then comatose from brainstem compression or obstructive hydrocephalus; immediate surgical evacuation before severe brainstem compression occurs may be lifesaving. Hydrocephalus from fourth ventricle compression can be relieved by external ventricular drainage; however, in this situation, definitive hematoma evacuation is recom­ mended rather than treatment with ventricular drainage alone. If the deep cerebellar nuclei are spared, full recovery is common. Lobar hemorrhages usually present with symptoms related to the specific site of origin. The major neurologic deficit with an occipital hemorrhage is hemianopsia; with a left temporal hemorrhage, aphasia and confusion; with a parietal hemorrhage, hemisensory loss; and with frontal hemorrhage, arm weakness. Large hemorrhages may be associ­ ated with stupor or coma if they compress the thalamus or midbrain. Most patients with lobar hemorrhages have focal headaches, and more than one-half vomit or are drowsy. Seizures may occur. Other Causes of ICH and Intracranial Hemorrhage  CAA is a disease of the elderly in which arteriolar degeneration occurs and amyloid is deposited in the walls of the cerebral arteries. Amyloid angiopathy causes both single and recurrent lobar hemorrhages and is probably the most common cause of lobar hemorrhage in the elderly. It accounts for some intracranial hemorrhages associated with IV thrombolysis given for myocardial infarction. This disorder can be suspected in patients who present with multiple hemorrhages (and infarcts) over several months or years or in patients with “microbleeds” in the cortex, seen on brain MRI sequences sensitive for hemosiderin (susceptibility weighted imaging), but it is definitively diagnosed by pathologic demonstration of Congo red staining of amyloid in cerebral vessels. The ε2 and ε4 allelic variations of the apolipoprotein E gene are associated with increased risk of recurrent lobar hemorrhage and may therefore be markers of amyloid angiopathy. Positron emission tomog­ raphy imaging can image amyloid-beta deposits in CAA using specific antibody labels and may be helpful in diagnosing CAA noninvasively. Although cerebral biopsy is the most definitive method of diagnosis, evidence of inflammation on lumbar puncture should prompt con­ sideration of CAA-associated vasculitis as an underlying cause, and oral glucocorticoids may be beneficial. Noninflammatory CAA has no specific treatment. Oral anticoagulants are typically avoided. Cocaine and methamphetamine are frequent causes of stroke in young (age <45 years) patients. ICH, ischemic stroke, and subarach­ noid hemorrhage (SAH) are all associated with stimulant use. Angio­ graphic findings vary from completely normal arteries to large-vessel occlusion or stenosis, vasospasm, or changes consistent with vasculop­ athy. The mechanism of sympathomimetic-related stroke is not known, but cocaine enhances sympathetic activity causing acute, sometimes severe, hypertension, and this may lead to hemorrhage. Slightly more than one-half of stimulant-related intracranial hemorrhages are intra­ cerebral and the rest are subarachnoid. In cases of SAH, a saccular aneurysm is usually identified. Presumably, acute hypertension causes aneurysmal rupture. Head injury often causes intracranial hemorrhage. The common sites are intraparenchymal (especially temporal and inferior frontal lobes) and into the subarachnoid, subdural, and epidural spaces. Trauma must be considered in any patient with an unexplained acute neurologic deficit (hemiparesis, stupor, or confusion), particularly if the deficit occurred in the context of a fall (Chap. 454). Intracranial hemorrhages associated with anticoagulant therapy can occur at any location; they are often lobar or subdural. Anticoagulantrelated ICHs may continue to evolve over 24–48 h, especially if coagu­ lopathy is insufficiently reversed. Coagulopathy and thrombocytopenia should be reversed rapidly, as discussed below. ICH associated with hematologic disorders (leukemia, aplastic anemia, thrombocytopenic purpura) can occur at any site and may present as multiple ICHs. Skin and mucous membrane bleeding may be evident and offers a diagnostic clue. Hemorrhage into a brain tumor may be the first manifestation of neoplasm. Choriocarcinoma, malignant melanoma, renal cell carci­ noma, and thyroid, lung, and hepatocellular carcinoma are among the most common metastatic tumors associated with ICH. Pilocytic astro­ cytoma and glioblastoma multiforme in adults and medulloblastoma in children may also have areas of ICH. Hypertensive encephalopathy is a complication of malignant hyper­ tension. In this acute syndrome, severe hypertension is associated with headache, nausea, vomiting, convulsions, confusion, stupor, and coma. Focal or lateralizing neurologic signs, either transitory or permanent, may occur but are infrequent and therefore suggest some other vas­ cular disease (hemorrhage, embolism, or atherosclerotic thrombosis). There may be retinal hemorrhages, exudates, papilledema (hyperten­ sive retinopathy), and evidence of renal and cardiac disease. MRI brain imaging shows a pattern of typically posterior (occipital > frontal) brain edema. The hypertension may be essential or due to chronic renal disease, acute glomerulonephritis, acute toxemia of pregnancy, pheochromocytoma, or other causes. Lowering the blood pressure reverses the process, but stroke can occur, especially if blood pressure is lowered too rapidly. Neuropathologic examination reveals multifocal to diffuse cerebral edema and hemorrhages of various sizes from pete­ chial to massive. Microscopically, there is necrosis of arterioles, minute cerebral infarcts, and hemorrhages. The terms hypertensive encepha­ lopathy and posterior reversible encephalopathy syndrome (Chap. 318) should be reserved for this syndrome and not for chronic recurrent headaches, dizziness, recurrent transient ischemic attacks, or small strokes that often occur in association with high blood pressure. Dis­ tinguishing hypertensive encephalopathy with ICH from hypertensive ICH is important since aggressive lowering of SBP to 130–150 mmHg acutely is often considered in hypertensive ICH, but less aggressive measures should be used in hypertensive encephalopathy. Having no alteration in mental status or other prodrome prior to the ICH favors hypertensive ICH as the disease. Primary intraventricular hemorrhage is rare and should prompt investigation for an underlying vascular anomaly. Sometimes bleeding begins within the periventricular substance of the brain and dissects into the ventricular system without leaving signs of intraparenchymal hemorrhage. Alternatively, bleeding can arise from periependymal veins. Vasculitis, usually polyarteritis nodosa or lupus erythematosus, can produce hemorrhage in any region of the central nervous system; most hemorrhages are associated with hypertension, but the arteritis itself may cause bleeding by disrupting the vessel wall. Nearly one-half of patients with primary intraventricular hemorrhage have identifiable bleeding sources seen using conventional angiography. Venous sinus thrombosis (Chap. 438) causes cortical vein hyperten­ sion, cerebral edema, and venous infarction. This may progress to cause intracranial hemorrhage surrounding the region of the occluded cerebral venous sinus or within the drainage region of the vein of Labbé, producing a posterior temporal or inferior parietal hematoma. Despite the presence of hemorrhage, IV anticoagulation is indicated to reduce the venous hypertension and limit venous ischemia and further bleeding. Sepsis can cause small petechial hemorrhages throughout the cere­ bral white matter. Moyamoya disease (Chap. 438), mainly an occlusive arterial disease that causes ischemic symptoms, may on occasion produce ICH. Hemorrhages into the spinal cord are usually the result of an AVM, cavernous malformation, or metastatic tumor. Epidural spinal hemorrhage produces a rapidly evolving syndrome of spinal cord or nerve root compression (Chap. 453). Spinal hemorrhages usually present with sudden back pain and some manifestation of myelopathy. Laboratory and Imaging Evaluation  Patients should have rou­ tine blood chemistries and hematologic studies. Specific attention to the platelet count, prothrombin time, partial thromboplastin time, and international normalized ratio is important to identify coagulopathy. CT imaging reliably detects acute focal hemorrhages in the supratento­ rial space. Rarely, very small pontine or medullary hemorrhages may not be well delineated because of motion and bone-induced artifact that obscure structures in the posterior fossa. After the first 2 weeks, x-ray attenuation values of clotted blood diminish until they become isodense with surrounding brain. Mass effect and edema may remain. In some cases, a surrounding rim of contrast enhancement appears after 2–4 weeks and may persist for months. MRI, although more sensi­ tive for delineating posterior fossa lesions, is generally not necessary for primary diagnosis. MR angiography (MRA), CT angiography (CTA), and conventional x-ray angiography are used when the cause of intra­ cranial hemorrhage is uncertain, particularly if the patient is young or not hypertensive and the hematoma is not in one of the usual sites for hypertensive hemorrhage. CTA or postcontrast CT imaging may reveal one or more small areas of enhancement within a hematoma; this “spot sign” is thought to represent ongoing bleeding. The presence of a spot sign is associated with an increased risk of hematoma expan­ sion, increased mortality, and lower likelihood of favorable functional outcome. Because patients typically have focal neurologic signs and obtundation and often show signs of increased ICP, a lumbar puncture is generally unnecessary and should usually be avoided because it may induce cerebral herniation. CHAPTER 439 Intracerebral Hemorrhage TREATMENT Intracerebral Hemorrhage ACUTE MANAGEMENT After immediate attention to blood pressure and airway protection (see above), focus can switch to medical and surgical management. Approximately 40% of patients with a hypertensive ICH die, but survivors can have a good to complete recovery. The ICH Score (Table 439-2) is a validated clinical grading scale that is useful for stratification of mortality risk and clinical outcome. However, a spe­ cific ICH clinical grading scale should not be used to precisely prog­ nosticate outcome because of the concern of creating a self-fulfilling prophecy of poor outcome if early aggressive care is withheld. Any identified coagulopathy should be corrected as soon as possible. For patients taking vitamin K antagonists (VKAs), rapid correction of coagulopathy can be achieved by infusing prothrombin complex concentrates (PCCs), which can be administered quickly, with TABLE 439-2  The Intracerebral Hemorrhage Score CLINICAL OR IMAGING FACTOR POINT SCORE Age <80 years ≥80 years Hematoma Volume <30 cc ≥30 cc Intraventricular Hemorrhage Present No Yes Infratentorial Origin of Hemorrhage No Yes Glasgow Coma Scale Score 13–15 5–12 3–4 Total Score 0–6 Sum of each category above Source: Reproduced with permission from JC Hemphill 3rd et al: The ICH score: A simple, reliable grading scale for intracerebral hemorrhage. Stroke 32:891, 2001. vitamin K administered concurrently. Fresh frozen plasma (FFP) is an alternative, but since it requires larger fluid volumes and longer time to achieve adequate reversal than PCC, it is not recommended if PCC is available. Idarucizumab is a monoclonal antibody to dabi­ gatran, and the administration of two doses reverses the anticoagula­ tion effect of dabigatran quickly. The oral Xa inhibitors apixaban and rivaroxaban can be reversed with andexanet alfa. PCC may partially reverse the effects of oral factor Xa inhibitors and are reasonable to administer if andexanet alfa is not available. When ICH is associated with thrombocytopenia (platelet count <50,000/μL), transfusion of fresh platelets is indicated. A clinical trial of platelet transfusions in patients with ICH and without thrombocytopenia who were taking antiplatelet drugs showed no benefit and possible harm. Hematomas may expand for several hours following the initial hemorrhage, even in patients without coagulopathy. The precise mechanism is unclear. A phase 3 trial of treatment with recombi­ nant factor VIIa reduced hematoma expansion; however, clinical outcomes were not improved, so use of this drug is not recom­ mended. The administration of tranexamic acid was not found to alter outcome in a large randomized trial. Blood pressure lowering has been considered due to the theoretical risk of acutely elevated blood pressure on hematoma expansion, although clinical trials did not find a difference in hematoma expansion between the SBP tar­ gets of 140–180 mmHg. In deep hemorrhages that involve the basal ganglia, more intensive blood pressure lowering reduced hematoma expansion but had no effect on functional outcome. PART 13 Neurologic Disorders Initial clinical trials of evacuation of supratentorial hemato­ mas, primarily via standard craniotomy, did not demonstrate clear benefit; however, recent focus on minimally-invasive surgi­ cal techniques holds promise. The International Surgical Trial in Intracerebral Haemorrhage (STICH) randomized patients with supratentorial ICH to either early surgical evacuation or initial medical management. No benefit was found in the early surgery arm, although analysis was complicated by the fact that 26% of patients in the initial medical management group ultimately had surgery for neurologic deterioration. The follow-up study, STICHII, found that craniotomy and hematoma evacuation within 24 h of lobar supratentorial hemorrhage did not improve overall outcome but might have a role in select severely affected patients. However, many centers still consider surgery for patients deemed salvage­ able and who are experiencing progressive neurologic deteriora­ tion due to herniation. Surgical techniques continue to evolve. In a clinical trial of minimally invasive hematoma evacuation using instillation of the thrombolytic agent alteplase into the clot, mor­ tality was decreased but there was not an improvement in func­ tional outcome. In 2024, the first randomized trial demonstrating improvement in functional outcome after surgical hematoma evac­ uation was published. The Early MiNimally-invasive Removal of IntraCerebral Hemorrhage (ENRICH) trial found that surgical removal of lobar hematomas within 24 hours of onset in selected patients (hematoma volume 30–80 mL; Glasgow Coma Score 5–14 [Table 454-1]; pre-ICH functionally independent) was beneficial compared with medical management alone. Several clinical trials testing other minimally invasive surgical hematoma evacuation techniques are ongoing. For cerebellar hemorrhages in patients with decreased level of consciousness or obstructive hydrocephalus, a neurosurgeon should be consulted immediately to assist with the evaluation. If the patient is alert without focal brainstem signs and the hematoma is small, surgical removal is usually unnecessary. Patients with hematomas >1 cm in diameter require careful observation for signs of impaired consciousness, progressive hydrocephalus, and precipi­ tous respiratory failure. Hydrocephalus due to cerebellar hematoma generally requires surgical evacuation and should usually not be treated solely with ventricular drainage. Tissue surrounding hematomas is displaced and compressed but not necessarily infarcted. Hence, major functional improvement often occurs as the hematoma is reabsorbed and the adjacent tis­ sue regains its function over several months following acute injury. Careful management of the patient during the acute phase of the hemorrhage can lead to considerable recovery. Bundles of care that incorporate multiple interventions may provide more value in the management of ICH patients than separating out different singular interventions. A hospital in the United Kingdom found that an ICH care bundle consisting of coagulopathy reversal, blood pressure lowering, and neurosurgical referral decreased patient mortality when implemented as a quality assurance project. In the INTERACT-3 randomized clinical trial performed in low- to middle-income countries, a bundle of care that included vitamin K coagulopathy reversal, acute blood pressure lowering, glucose control, and temperature control was associated with improved functional outcome and fewer adverse events. Surprisingly, ICP is often normal even with large ICHs. However, if the hematoma causes marked midline shift of structures with consequent obtundation, coma, or hydrocephalus, osmotic agents can be instituted in preparation for placement of a ventriculostomy or parenchymal ICP monitor (Chap. 318). Once ICP is recorded, CSF drainage (if available), osmotic therapy, and blood pressure management can be tailored to maintain cerebral perfusion pres­ sure (MAP minus ICP) of 60 to ≥70 mmHg. For example, if ICP is found to be high, CSF can be drained from the ventricular space and osmotic therapy continued; persistent or progressive elevation in ICP may prompt surgical evacuation of the clot. Alternately, if ICP is normal, interventions such as osmotic therapy may be tapered. Because hyperventilation may produce ischemia due to cerebral vasoconstriction, induced hyperventilation should be lim­ ited to acute resuscitation of the patient with presumptive high ICP and eliminated once osmotic therapy or surgical treatments have been instituted. Glucocorticoids are not recommended for the treatment of intracerebral hemorrhage. PREVENTION Hypertension is the leading cause of primary ICH. Prevention is aimed at reducing chronic hypertension, eliminating excessive alco­ hol use, and discontinuing use of illicit drugs such as cocaine and amphetamines. Oral anticoagulant medications should generally be avoided in patients with high-risk features for CAA, but antiplatelet agents may be administered if there is an indication based on ath­ erothrombotic vascular disease. Ongoing studies are investigating the risk-benefit ratio of reinitiation of anticoagulation in patients with recent ICH who have atrial fibrillation. VASCULAR ANOMALIES ■ ■ARTERIOVENOUS MALFORMATIONS True AVMs are shunts between the arterial and venous systems that may present with headache, seizures, and intracranial hemorrhage. AVMs consist of a tangle of abnormal vessels across the cortical surface or deep within the brain substance. AVMs vary in size from a small blemish a few millimeters in diameter to a large mass of tortuous chan­ nels composing an arteriovenous shunt of sufficient magnitude to raise cardiac output and precipitate heart failure. Blood vessels forming the tangle interposed between arteries and veins are usually abnormally thin and histologically resemble both arteries and veins. AVMs occur in all parts of the cerebral hemispheres, brainstem, and spinal cord, but the largest ones are most frequently located in the posterior half of the hemispheres, commonly forming a wedge-shaped lesion extending from the cortex to the ventricle. Most AVMs are congenital, but cases of acquired lesions have been reported. Bleeding, headache, and seizures are most common between the ages of 10 and 30, occasionally as late as the fifties. AVMs are more frequent in men, and rare familial cases have been described. Familial AVM may be a part of the autosomal dominant syndrome of hereditary hemor­ rhagic telangiectasia (Osler-Rendu-Weber) syndrome due to mutations in either endoglin or activin receptor-like kinase 1, both involved in transforming growth factor (TGF) signaling and angiogenesis. Headache (without bleeding) may be hemicranial and throbbing, like migraine, or diffuse. Focal seizures, with or without generalization, # 10 - 440 Subarachnoid Hemorrhage ### 440 Subarachnoid Hemorrhage occur in ~30% of cases. One-half of AVMs become evident as ICHs. In most, the hemorrhage is mainly intraparenchymal with extension into the subarachnoid space in some cases. Unlike primary SAHs (Chap. 440), blood from a ruptured AVM is usually not deposited in the basal cisterns, and symptomatic cerebral vasospasm is rare. The risk of AVM rupture is strongly influenced by a history of prior rup­ ture. Although unruptured AVMs have a hemorrhage rate of ~2–4% per year, previously ruptured AVMs may have a rate as high as 17% a year, at least for the first year. Hemorrhages may be massive, leading to death, or may be as small as 1 cm in diameter, leading to minor focal symptoms or no deficit. The AVM may be large enough to steal blood away from adjacent normal brain tissue or to increase venous pressure significantly to produce venous ischemia locally and in remote areas of the brain. This is seen most often with large AVMs in the territory of the middle cerebral artery. Large AVMs of the anterior circulation may be associated with a sys­ tolic and diastolic bruit (sometimes self-audible) over the eye, forehead, or neck and a bounding carotid pulse. Headache at the onset of AVM rupture is generally not as explosive as with aneurysmal rupture. MRI is better than CT for diagnosis, although noncontrast CT scanning sometimes detects calcification of the AVM and contrast may demon­ strate the abnormal blood vessels. Once identified, conventional x-ray angiography is the gold standard for evaluating the precise anatomy of the AVM. Surgical treatment of AVMs presenting with hemorrhage, often done in conjunction with preoperative embolization to reduce opera­ tive bleeding, is usually indicated for accessible lesions. Stereotactic radiosurgery, an alternative to conventional surgery, can produce a slow sclerosis of the AVM over 2–3 years. Several angiographic features can be used to help predict future bleeding risk. Paradoxically, smaller lesions seem to have a higher hem­ orrhage rate. The presence of deep venous drainage, venous outflow stenosis, and intranidal aneurysms may increase rupture risk. Because of the relatively low annual rate of hemorrhage and the risk of com­ plications due to surgical or endovascular treatment, the indications for surgery in asymptomatic AVMs are uncertain. The ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations) trial randomized patients to medical management versus interven­ tion (surgery, endovascular embolization, combination embolization and surgery, or gamma-knife). The trial was stopped prematurely for harm, with the medical arm achieving the combined endpoint of death or symptomatic stroke in 10% of patients compared to 31% in the intervention group at a mean follow-up time of 33 months. This highly significant finding argues against routine intervention for patients presenting without hemorrhage, although debate ensues regarding the generalizability of these results. ■ ■CAVERNOUS ANGIOMAS Cavernous angiomas (cavernous malformations) are tufts of capil­ lary sinusoids that form within the deep hemispheric white matter and brainstem with no normal intervening neural structures. The pathogenesis is unclear. Most cavernous angiomas are congenital, but they may occur during life as well. Familial cavernous angiomas have been mapped to several different genes: KRIT1, CCM2, and PDCD10. Both KRIT1 and CCM2 have roles in blood vessel formation, whereas PDCD10 is an apoptotic gene. Cavernous angiomas are typically <1 cm in diameter and are often associated with a venous anomaly. Bleeding is usually of small volume, causing slight mass effect only. The bleeding risk for single cavernous malformations is 0.7–1.5% per year and may be higher for patients with prior clinical hemorrhage or multiple malforma­ tions. Seizures may occur if the malformation is located near the cerebral cortex. Surgical resection eliminates bleeding risk and may reduce sei­ zure risk but is usually reserved for those malformations that form near the brain surface in patients with prior clinical episodes of bleeding or with medically refractory seizures. Stereotactic radiosurgery has been considered as a secondary treatment, but risks may outweigh benefits. Retrospective data show that intracranial hemorrhage from cavernous malformations is likely not increased with administration of antiplatelet and anticoagulant medications prescribed for other medical conditions. Developmental venous anomalies are the result of development of anomalous cerebral, cerebellar, or brainstem venous drainage. These structures, unlike AVMs, are functional venous channels. They are of little clinical significance and should be ignored if found incidentally on brain imaging studies. Surgical resection of these anomalies may result in venous infarction and hemorrhage. Venous anomalies may be associated with cavernous malformations, which do carry some bleeding risk. Capillary telangiectasias are true capillary malformations that often form extensive vascular networks through an otherwise normal brain structure. The pons and deep cerebral white matter are typical locations, and these capillary malformations can be seen in patients with hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber) syn­ drome. If bleeding does occur, it rarely produces mass effect or signifi­ cant symptoms. No treatment options exist. Dural arteriovenous fistulas are acquired connections usually from a dural artery to a dural sinus. Patients may complain of a pulse-synchro­ nous cephalic bruit (“pulsatile tinnitus”) and headache. Depending on the magnitude of the shunt, venous pressures may rise high enough to cause cortical ischemia or venous hypertension and hemorrhage, particularly SAH. Surgical and endovascular techniques are usually curative. These fistulas may form because of trauma, but most are idiopathic. There is an association between fistulas and dural sinus thrombosis. Fistulas have been observed to appear months to years fol­ lowing venous sinus thrombosis, suggesting that angiogenesis factors elaborated from the thrombotic process may cause these anomalous connections to form. Alternatively, dural arteriovenous fistulas can produce venous sinus occlusion over time, perhaps from the high pres­ sure and high flow through a venous structure. Subarachnoid Hemorrhage CHAPTER 440 ■ ■FURTHER READING Anderson CS et al: Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. N Engl J Med 368:2355, 2013. Christensen H et al: European stroke organization guideline on reversal of oral anticoagulants in acute intracerebral hemorrhage. Euro Stroke J 4:294, 2019. Greenberg SM et al: 2022 Guideline for the Management of Patients With Spontaneous Intracerebral Hemorrhage: A Guideline From the American Heart Association/American Stroke Association. Stroke 53:e282, 2022. Ma L et al: The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): An international, stepped wedge cluster randomised controlled trial. Lancet 402:27, 2023. Mohr JP et al: Medical management with or without interven­ tional therapy for unruptured brain arteriovenous malformations (ARUBA): A multicentre, non-blinded, randomised trial. Lancet 383:614, 2014. Pradilla G et al: Trial of early minimally invasive removal of intrace­ rebral hemorrhage. N Engl J Med 390:1277, 2024. 440 Subarachnoid Hemorrhage Wade S. Smith, Nerissa U. Ko, J. Claude Hemphill, III Subarachnoid hemorrhage (SAH) renders the brain critically ill from both primary and secondary brain insults. Excluding head trauma, the most common cause of SAH is rupture of a saccular aneurysm. Other causes include bleeding from a vascular malformation (arteriovenous malformation or dural arteriovenous fistula) and extension into the subarachnoid space from a primary intracerebral hemorrhage. Some idiopathic SAHs are localized to the perimesencephalic cisterns and are benign; they probably have a venous or capillary source, and angi­ ography is unrevealing. ■ ■SACCULAR (“BERRY”) ANEURYSM Autopsy and angiography studies have found that ~2% of adults harbor intracranial aneurysms, for a prevalence of 4 million persons in the United States. The incidence of SAH from aneurysmal rupture is estimated at between 6 and 11 per 100,000 person-years, resulting in 25,000–30,000 cases annually in the United States, with a 1.3 relative risk in women. Although most affected patients are under age 55, there is also an increas­ ing incidence with age. The overall mortality rate for aneurysmal SAH is ~35%, with approximately one-third of patients dying immediately and prior to hospital admission. Of those who survive, more than half are left with clinically significant neurologic deficits because of the initial hemor­ rhage, delayed cerebral ischemia, or hydrocephalus. If the patient survives but the aneurysm is not obliterated, the rate of rebleeding is ~20% in the first 2 weeks, 30% in the first month, and ~3% per year afterward. Given these alarming figures, the major therapeutic emphasis is on preventing the predictable early complications of the SAH. PART 13 Neurologic Disorders Unruptured, asymptomatic aneurysms are much less dangerous than recently ruptured ones. A large international observational study found that the annual risk of rupture for unruptured aneurysms <7 mm in size was 0% over 5 years. However, subsequent studies from Japan and Finland found that the majority of ruptured aneurysms were <6 mm in size. Aneurysms of <3 mm in size rarely, if ever, bleed. As the size of an aneurysm increases, so does the risk for rupture, but growth is not linear and appears to occur in phases, making surveillance for growing aneurysms problematic. The location of an unruptured aneurysm is also important in assessment, as basilar bifurcation and origin poste­ rior communicating artery aneurysms appear to have a higher risk for rupture than other sites. Because of their longer length of exposure to risk of rupture, younger patients with aneurysms >10 mm in size may benefit from prophylactic treatment (see below). As with the treatment of asymptomatic carotid stenosis (Chap. 438), this risk-benefit ratio strongly depends on the rate of procedural complications. Giant aneurysms, those >25 mm in diameter, occur at the same sites (see below) as small aneurysms, and account for 5% of cases. The three most common locations are the terminal internal carotid artery, middle cerebral artery (MCA) bifurcation, and top of the basilar artery. Their risk of rupture is ~8–10% annually after identification and may remain high indefinitely. They often cause symptoms by compressing the adjacent brain or cranial nerves. Mycotic aneurysms are usually located distal to the first bifurca­ tion of major arteries of the circle of Willis. Most result from infected emboli due to bacterial endocarditis causing septic degeneration of arteries and subsequent dilation and rupture. Whether these lesions should be sought and repaired prior to rupture or left to heal spontane­ ously with antibiotic treatment remains controversial. Pathophysiology  Saccular aneurysms occur at the bifurcations of the large- to medium-sized intracranial arteries; rupture is into the subarachnoid space in the basal cisterns and sometimes into the paren­ chyma of the adjacent brain. Approximately 89% of aneurysms occur in the anterior circulation, mostly on the circle of Willis (Fig. 440-1). About 20% of patients have multiple aneurysms, many at mirror sites bilaterally. As an aneurysm develops, it typically forms a neck with a dome. The length of the neck and the size of the dome vary greatly and are important factors in planning neurosurgical obliteration or endovascular embolization. The arterial internal elastic lamina disappears at the base of the neck. The media thins, and connective tissue replaces smooth-muscle cells. At the site of rupture (most often the dome), the wall thins, and the tear that allows bleeding is often ≤0.5 mm long. Fusiform aneurysms, where the locations of inflow and outflow are different, typically occur in the basilar artery and are very challenging to treat. Clinical Manifestations  Most unruptured intracranial aneurysms are completely asymptomatic. Symptoms are usually due to rupture Anterior cerebral artery Anterior communicating artery Ophthalmic artery Middle cerebral artery Anterior choroidal artery Posterior cerebral artery Internal carotid artery Superior cerebellar artery Pontine arteries Posterior communicating artery Anterior inferior cerebellar artery Basilar artery Vertebral artery Posterior inferior cerebellar artery Anterior spinal artery FIGURE 440-1  View of the major blood vessels supplying the brain and common locations of saccular aneurysms: (1) Anterior communicating (12%), (2) internal carotid (30%), (3) posterior communicating (12%), (4) middle cerebral (34%), (5) basilar terminus, (6) superior cerebellar, (7) anterior inferior cerebellar, and (8) posterior inferior cerebellar aneurysm. Locations 1–4 are considered anterior circulation aneurysms totaling 89% overall, while locations 5–8 total 11%. and resultant SAH, although some unruptured aneurysms present with mass effect on cranial nerves or brain parenchyma. At the moment of aneurysmal rupture with a major SAH, the intracranial pressure (ICP) suddenly rises. This may account for the sudden transient loss of consciousness that occurs in nearly half of patients. Sudden loss of consciousness may be preceded by a brief moment of excruciating headache, but most patients first complain of headache upon regaining consciousness. In 10% of cases, aneurysmal bleeding is severe enough to cause loss of consciousness for several days. In ~45% of cases, severe headache associated with exertion is the presenting complaint. The patient often calls the headache “the worst headache of my life”; how­ ever, the most important characteristic is sudden onset. Occasionally, these ruptures may present as headache of only moderate intensity or as a change in the patient’s usual headache pattern. The headache is usually generalized, often with neck stiffness, and vomiting is common. Although sudden headache in the absence of focal neurologic symp­ toms is the hallmark of aneurysmal rupture, focal neurologic deficits may occur. Anterior communicating artery or MCA bifurcation aneu­ rysms may rupture into the adjacent brain or subdural space and form a hematoma large enough to produce mass effect. The deficits that result can include hemiparesis, aphasia, and mental slowness (abulia). Occasionally, prodromal symptoms suggest the location of a pro­ gressively enlarging unruptured aneurysm. A third cranial nerve palsy, particularly when associated with pupillary dilation, loss of ipsilateral (but retained contralateral) light reflex, and focal pain above or behind the eye, may occur with an expanding aneurysm at the junction of the posterior communicating artery and the internal carotid artery. A sixth nerve palsy may indicate an aneurysm in the cavernous sinus, and visual field defects can occur with an expanding supraclinoid carotid or anterior cerebral artery (ACA) aneurysm. Occipital and posterior cer­ vical pain may signal a posterior inferior cerebellar artery or anterior inferior cerebellar artery aneurysm (Chap. 438). Pain in or behind the eye and in the low temple can occur with an expanding MCA aneu­ rysm. Thunderclap headache is a variant of migraine that simulates an SAH. Before concluding that a patient with sudden, severe headache has thunderclap migraine, a definitive workup for aneurysm or other intracranial pathology is required. TABLE 440-1  Grading Scales for Subarachnoid Hemorrhage WORLD FEDERATION OF NEUROSURGICAL SOCIETIES (WFNS) SCALE GRADE HUNT-HESS SCALE Asymptomatic, or minimal headache and slight nuchal rigidity. Normal mental status, no cranial nerve or motor findings GCSa score 15, no motor deficits Moderate to severe headache, nuchal rigidity, normal mental status and motor function, may have cranial nerve deficit GCS score 13–14, no motor deficits Somnolent, confused, may have cranial nerve or mild motor deficit GCS score 13–14, with motor deficits Stupor, moderate to severe motor deficit, may have intermittent reflex posturing GCS score 7–12, with or without motor deficits Coma, reflex posturing or flaccid GCS score 3–6, with or without motor deficits aGlasgow Coma Scale; see Table 454-1. Source: Reproduced with permission from WFNS Scale: Report of World Federation of Neurological Surgeons Committee on a Universal Subarachnoid hemorrhage Grading Scale. J Neurosurg 68:985, 1988. Aneurysms can undergo small ruptures and leaks of blood into the subarachnoid space, so-called sentinel bleeds. Sudden unexplained headache at any location should raise suspicion of SAH and be investi­ gated because a major hemorrhage may be imminent. The initial clinical manifestations of SAH can be graded using the Hunt-Hess or World Federation of Neurosurgical Societies classifica­ tion schemes (Table 440-1). For ruptured aneurysms, prognosis for a good outcome falls as the grade increases. For example, it is unusual for a Hunt-Hess grade 1 patient to die if the aneurysm is treated, but the mortality rate for grade 4 and 5 patients may be as high as 60%. Delayed Neurologic Deficits  There are four major causes of delayed neurologic deficits: rerupture, hydrocephalus, delayed cerebral ischemia, and hyponatremia. 1. Rerupture. The incidence of rerupture of an untreated aneurysm in the first month following SAH is ~30%, with the peak in the first 7 days. Rerupture is associated with a 50% mortality rate and poor outcome. Early treatment eliminates this risk, and advances in endovascular and surgical techniques contribute to better outcomes. 2. Hydrocephalus. Acute hydrocephalus can cause stupor and coma and can be mitigated by placement of an external ventricular drain. More often, subacute hydrocephalus may develop over a few days or weeks and cause progressive drowsiness or slowed mentation with incontinence. Hydrocephalus may clear spontaneously, require tem­ porary ventricular drainage, or in some cases require placement of a ventriculoperitoneal shunt. Chronic hydrocephalus may develop weeks to months after SAH and manifest as gait difficulty, inconti­ nence, or impaired mentation. Subtle signs may be a lack of initiative in conversation or a failure to recover independence. 3. Delayed cerebral ischemia. Vasospasm is the narrowing of the arter­ ies at the base of the brain following SAH and has been associated with delayed cerebral ischemia and infarction. Delayed cerebral ischemia occurs in ~30% of patients and is the major cause of delayed morbidity and death. Signs first appear 4–14 days after the hemorrhage, most often at 7 days. While therapies can be targeted for vasospasm, there are other complex mechanisms associated with delayed cerebral ischemia and progression to infarction indepen­ dent of vasospasm alone.   Narrowing of the arteries causing vasospasm and thickening of the vessel wall is believed to result from direct effects of clot­ ted blood and its breakdown products on the arteries within the subarachnoid space. In general, the more blood that surrounds the arteries, the greater is the chance of symptomatic vasospasm. Focal narrowing of major arteries produces symptoms referable to the appropriate vascular territory (Chap. 437). All of these focal symp­ toms may present abruptly, fluctuate, or develop over a few days. The clinical syndrome often manifests as a decline in mental status and worsening headache.   Vasospasm of the large arteries can be detected reliably with conventional x-ray angiography, but this procedure is invasive and carries the risk of stroke and other complications. Transcutaneous Doppler ultrasound is based on the principle that the velocity of blood flow within an artery will rise as the lumen diameter is nar­ rowed. By directing the probe along the MCA and proximal ACA, carotid terminus, and vertebral and basilar arteries on a daily or every-other-day basis, vasospasm can be reliably detected and treat­ ments initiated to prevent cerebral ischemia (see below). Computed tomography (CT) angiography is another method that can detect vasospasm. The addition of CT perfusion imaging may help identify reversible ischemic deficits. In high-grade patients, invasive neuro­ monitoring techniques can also be considered. 4. Hyponatremia. Hyponatremia may be profound and can develop Subarachnoid Hemorrhage CHAPTER 440 quickly in the first 2 weeks following SAH. There is both natriure­ sis and volume depletion with SAH, so that patients become both hyponatremic and hypovolemic. Both atrial natriuretic peptide and brain natriuretic peptide have a role in producing this “cerebral saltwasting syndrome.” Typically, it clears over the course of 1–2 weeks and, in the setting of SAH, should not be treated with free-water restriction as this may increase the risk of stroke (see below). Laboratory Evaluation and Imaging (Fig. 440-2)  The hall­ mark of aneurysmal rupture is blood in the CSF. More than 95% of cases have enough blood to be visualized on a high-quality noncontrast CT scan obtained within 72 h. If the scan fails to establish the diagnosis of SAH and no mass lesion or obstructive hydrocephalus is found, a lumbar puncture should be performed to establish the presence of sub­ arachnoid blood. Lysis of the red blood cells and subsequent conversion of hemoglobin to bilirubin stains the spinal fluid yellow within 6–12 h. This xanthochromic spinal fluid peaks in intensity at 48 h and lasts for 1–4 weeks, depending on the amount of subarachnoid blood present. The extent and location of subarachnoid blood on a noncontrast CT scan help locate the underlying aneurysm, identify the cause of any neurologic deficit, and predict the occurrence of vasospasm. The likelihood of symptomatic vasospasm in the MCA and ACA can be predicted based on the size and location of clotted blood (Table 440-2). CT scans less reliably predict vasospasm in the vertebral, basilar, or posterior cerebral arteries. Lumbar puncture prior to an imaging procedure is indicated only if a CT scan is not available at the time of the suspected SAH. Once the diagnosis of hemorrhage from a ruptured saccular aneurysm is confirmed, four-vessel conventional x-ray angiography (both carotids and both vertebrals) is generally performed to localize and define the anatomic details of the aneurysm and to determine if other unruptured aneurysms exist (Fig. 440-2C). The ruptured aneurysm can be treated using endovascular techniques at the time of the initial angiogram to expedite treatment and minimize the number of invasive procedures. CT angiography is an alternative method for locating the aneurysm and may be sufficient for planning definitive therapy. Close monitoring (daily or twice daily) of electrolytes is important because hyponatremia can occur precipitously during the first 2 weeks following SAH (see above). The electrocardiogram (ECG) frequently shows ST-segment and T-wave changes similar to those associated with cardiac ischemia. A prolonged QRS complex, increased QT interval, and prominent “peaked” or deeply inverted symmetric T waves are usually second­ ary to the intracranial hemorrhage. Structural myocardial lesions produced by circulating catecholamines and excessive discharge of sympathetic neurons may occur after SAH, causing these ECG changes and a reversible cardiomyopathy sufficient to cause shock. Echocar­ diography often reveals a pattern of regional wall motion abnormalities that follow the distribution of sympathetic nerves rather than the major coronary arteries, with relative sparing of the ventricular wall apex. The sympathetic nerves themselves appear to be injured by direct toxicity A B PART 13 Neurologic Disorders C D FIGURE 440-2  Subarachnoid hemorrhage. A. Computed tomography (CT) angiography revealing an aneurysm of the left superior cerebellar artery. B. Noncontrast CT scan at the level of the third ventricle revealing subarachnoid blood (bright) in the left sylvian fissure and within the left lateral ventricle. C. Conventional anteroposterior x-ray angiogram of the right vertebral and basilar artery showing the large aneurysm. D. Conventional angiogram following coil embolization of the aneurysm, whereby the aneurysm body is filled with platinum coils delivered through a microcatheter navigated from the femoral artery into the aneurysm neck. from the excessive catecholamine release. An asymptomatic troponin elevation is common. While arrythmias can occur after SAH, serious ventricular dysrhythmias occurring in-hospital are unusual. TREATMENT Subarachnoid Hemorrhage Early aneurysm repair prevents rerupture and allows the safe appli­ cation of techniques to improve blood flow (e.g., induced hyperten­ sion) should vasospasm and delayed cerebral ischemia develop. At many centers, definitive repair is carried out within 24 h of the bleed in all patients who are stable enough to tolerate the procedure. TABLE 440-2  Modified Fisher Grading System for Prediction of Vasospasm Risk RISK OF SYMPTOMATIC VASOSPASM GRADE CT SCAN FINDINGS No subarachnoid or intraventicular blood 0% Focal or diffuse thin subarachnoid blood without intraventricular blood 24% Focal or diffuse thin subarachnoid blood with intraventricular blood 33% Focal or diffuse thick subarachnoid blood without intraventricular blood 33% Focal or diffuse thick subarachnoid blood with intraventricular blood 40% Note: “Thin” is <1 mm, whereas “thick” is ≥1 mm. Abbreviation: CT, computed tomography. Source: JA Frontera et al: Prediction of symptomatic vasospasm after subarachnoid hemorrhage: The modified Fisher scale. Neurosurgery 59:21, 2006. An aneurysm can be “clipped” by a neurosurgeon or “coiled” by an endovascular surgeon. Surgical repair involves placing a metal clip across the aneurysm neck, thereby immediately eliminating the risk of rebleeding. This approach requires craniotomy and brain retrac­ tion, which is associated with neurologic morbidity. Endovascular techniques involve placing coils, or other embolic material, within the aneurysm via a catheter that is passed from the femoral or radial artery. The aneurysm is packed tightly to enhance thrombosis and over time is walled off from the circulation (Fig. 440-2D). There have been two prospective randomized trials of surgery versus endovas­ cular treatment for ruptured aneurysms: the first was the Interna­ tional Subarachnoid Aneurysm Trial (ISAT), which was terminated early when 24% of patients treated with endovascular therapy were dead or dependent at 1 year compared to 31% treated with surgery, a significant 23% relative reduction. After 5 years, the risk of death was still lower in the coiling group, although the proportion of sur­ vivors who were independent was the same in both groups. The risk of rebleeding was generally low, but was more common in the coil­ ing group. These results favoring coiling at 1 year were confirmed in a second trial, although the differences in functional outcome of survivors were no longer significant at 3 years. Because some aneurysms have a morphology that is not amenable to endovascular treatment, surgery remains an important treatment option, espe­ cially in cases where evacuation of a parenchymal hematoma could be beneficial. Newer endovascular devices and techniques using balloon-assisted coiling or placement of flow-diverting stents are increasing the types of aneurysms amenable to endovascular inter­ vention. Centers that combine both endovascular and neurosurgi­ cal expertise likely offer the best outcomes for patients, and transfer to centers that specialize in aneurysm treatment are associated with improved outcomes and lower mortality rates. The early medical management of SAH focuses on protecting the airway, managing blood pressure before and after repair of the aneurysm, preventing rebleeding prior to the intervention, and treating hydrocephalus. Subsequent management is focused on preventing late neurologic injury, including managing vasospasm and delayed cerebral ischemia, treating hyponatremia, limiting sec­ ondary brain insults from medical comorbidities, and preventing pulmonary emboli. Intracranial hypertension following aneurysmal rupture occurs secondary to subarachnoid blood, parenchymal hematoma, acute hydrocephalus, and/or loss of vascular autoregulation. Patients who are stuporous should undergo emergent ventriculostomy to measure and treat high ICP in order to prevent cerebral herniation and ischemia. Medical therapies designed to combat raised ICP (e.g., osmotic therapy and sedation) can also be used as needed. High ICP refractory to treatment is a poor prognostic sign. Drain­ age of CSF via a lumbar route has been shown to decrease the rate of delayed cerebral injury, vasospasm, and mortality but confounds measurement of true ICP. Prior to definitive treatment of the ruptured aneurysm, care is required to maintain adequate cerebral perfusion pressure while avoiding excessive elevation of arterial pressure. If the patient is alert, it is reasonable to lower the systolic blood pressure to below 160 mmHg using agents such as nicardipine, clevidipine, or labet­ alol to limit blood pressure variability. If the patient has a depressed level of consciousness, ICP should be measured and the cerebral perfusion pressure targeted to 60–70 mmHg. If headache or neck pain is severe, mild sedation and analgesia are prescribed. Extreme sedation is avoided if possible because it can obscure the ability to clinically detect changes in neurologic status. Goal-directed therapy to target euvolemia is recommended, while avoiding hypervolemia, which has been associated with a greater risk for complications. Seizures are uncommon at the onset of aneurysmal rupture, but in patients who present with seizures, treatment with a 7-day course of an anticonvulsant such as levetiracetam is reasonable. The quiv­ ering, jerking, and extensor posturing that often accompany loss of consciousness with SAH are probably related to the sharp rise in ICP rather than seizures. Monitoring with electroencephalogram (EEG) can help detect seizures in patients with poor mental sta­ tus or fluctuating exam findings. Anticonvulsants are sometimes administered as prophylactic therapy in high-risk patients, but if used, the treatment course should also not exceed >7 days. Phe­ nytoin should be avoided because of its association with increased morbidity and mortality in this setting. Glucocorticoids may reduce the headache and neckache caused by the irritative effect of the subarachnoid blood; however, there is no good evidence that steroids reduce cerebral edema, are neuro­ protective, or reduce vascular injury, and their routine use therefore is not recommended. Antifibrinolytic agents are not routinely prescribed but have been considered in patients in whom aneurysm repair cannot proceed immediately. They are associated with a reduced incidence of aneurysmal rerupture but may also increase the risk of delayed cerebral ischemia and deep-vein thrombosis (DVT). More recent studies showed no improvement in functional outcomes, and use of these agents is not currently recommended. Delayed cerebral ischemia remains the leading cause of mor­ bidity and mortality following aneurysmal SAH in patients who survive the initial hemorrhage. Treatment with the calcium channel antagonist nimodipine (60 mg PO every 4 h) has been shown to improve outcomes, perhaps by preventing ischemic injury rather than reducing the risk of vasospasm. Nimodipine can cause sig­ nificant hypotension in some patients, which may worsen cere­ bral ischemia in patients with vasospasm. Symptomatic cerebral vasospasm can also be treated by increasing the cerebral perfusion pressure by raising mean arterial pressure through plasma volume expansion and the judicious use of IV vasopressor agents, usually phenylephrine or norepinephrine. Increasing perfusion pressure has been associated with clinical improvement in many patients, but high arterial pressure may also promote rebleeding in unre­ paired aneurysms. Treatment with induced hypertension in symp­ tomatic patients requires close monitoring of arterial pressures. Prophylactic use of induced hypertension is not recommended, as it is associated with worse outcomes. Euvolemia should be targeted as significant hypervolemia may lead to cardiopulmonary complica­ tions. Hypovolemia should be strictly avoided. If delayed cerebral ischemia due to vasospasm persists despite optimal medical therapy, endovascular rescue therapies with intra­ arterial vasodilators and percutaneous transluminal angioplasty can be considered (Fig. 440-3). Vasodilatation by direct angioplasty appears to be permanent, allowing hypertensive therapy to be A B FIGURE 440-3  Vasospasm of the right middle cerebral artery. A. Catheter angiography demonstrates significant narrowing of the right middle cerebral artery (MCA). B. Because of symptomatic delayed cerebral ischemia, soft-balloon angioplasty was used to dilate the proximal portion of the main MCA stem. tapered sooner. In contrast, the pharmacologic vasodilators (vera­ pamil and nicardipine) do not last more than about 24 h, and there­ fore, multiple treatments may be required until the subarachnoid blood is reabsorbed. Newer therapies including milrinone, neural ganglia blocks, antithrombotic agents, and intrathecal and cisternal agents are currently under investigation. Severe cerebral edema in patients with infarction from vaso­ spasm may increase the ICP to levels that reduce cerebral perfusion pressure. Treatment may include cerebrospinal fluid (CSF) drain­ age, mannitol, or hypertonic saline; for intractable cases, hemicra­ niectomy, deep sedation, paralysis, and moderate hypothermia may be considered. Delayed cerebral ischemia may also occur in the absence of significant large-vessel vasospasm. Potential mechanisms include microthrombosis, activation of the inflammatory cascade, micro­ vascular dysregulation and constriction, and cortical spreading depolarization. Targeted treatments for these mechanisms are under investigation. Subarachnoid Hemorrhage CHAPTER 440 Acute hydrocephalus can cause stupor or coma. It may clear spontaneously or require temporary ventricular drainage. When chronic hydrocephalus develops, ventricular shunting is the treat­ ment of choice. Free-water restriction is contraindicated in patients with SAH at risk for delayed cerebral ischemia because hypovolemia and hypotension may occur and precipitate cerebral ischemia. Many patients continue to experience a decline in serum sodium due to cerebral salt wasting despite receiving parenteral fluids contain­ ing normal saline. Frequently, supplemental oral salt coupled with normal saline will mitigate hyponatremia, but often patients also require intravenous hypertonic (3%) saline. Care must be taken not to correct serum sodium too quickly in patients with marked hypo­ natremia of several days’ duration, as the osmotic demyelination syndrome (Chap. 318) may occur. All patients should have pneumatic compression stockings applied to prevent pulmonary emboli. Unfractionated heparin and low-molecular-weight heparinoids administered subcutaneously for DVT prophylaxis can be initiated within 1–2 days following endovascular treatment or craniotomy with surgical clipping; this approach is more effective than use of pneumatic compression stock­ ings alone. Treatment of pulmonary emboli depends on whether the aneurysm has been treated and whether or not the patient has had a craniotomy. Continuous systemic anticoagulation with heparin is contraindicated in patients with ruptured and untreated aneurysms. It is a relative contraindication following craniotomy for several days, and it may delay thrombosis of a coiled aneurysm. If DVT or pulmonary emboli occur within the first days following craniotomy, use of an inferior vena cava filter may be considered to prevent additional emboli, whereas systemic anticoagulation with heparin is preferred following successful endovascular treatment. In patients who survive their acute hospitalization, follow-up care is important to address the high prevalence of cognitive and behavioral deficits that greatly impact quality of life. Efficient recognition and treatment of these disorders can improve both short-term and long-term outcomes. In addition, some patients require ongoing follow-up to manage unruptured aneurysms that may require further care. ■ ■FURTHER READING Hoh BL et al: 2023 Guideline for the management of patients with aneurysmal subarachnoid hemorrhage: A guideline from the American Heart Association/American Stroke Association. Stroke 54:e314, 2023. Molyneux AJ et al: The durability of endovascular coiling versus neu­ rosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT). Lancet 385:691, 2015. Treggiari MM et al: Guidelines for the neurocritical care management of aneurysmal subarachnoid hemorrhage. Neurocrit Care 39:1, 2023. # 11 - 441 Migraine and Other Primary Headache Disorders ### 441 Migraine and Other Primary Headache Disorders Peter J. Goadsby Migraine and Other Primary Headache Disorders The general approach to headache as a cardinal symptom is covered else­ where (Chap. 17); here, disorders in which headache and associated features occur in the absence of any exogenous cause are discussed. The most common are migraine, tension-type headache (TTH), and the trigeminal autonomic cephalalgias (TACs), notably cluster headache; the complete list is summarized in Table 441-1. ■ ■MIGRAINE Migraine, the second most common cause of headache, and the most common headache-related, and indeed neurologic, cause of disability in the world, afflicts ~15% of women and 6% of men over a 1-year period. It is usually an episodic headache associated with certain features, such as sensitivity to light, sound, or movement; nausea and vomiting often accompany the headache. A useful description of migraine is a recur­ ring syndrome of headache associated with other symptoms of neu­ rologic dysfunction in varying admixtures (Table 441-2). A migraine attack has three phases: premonitory (prodrome), headache phase, and postdrome; each has distinct and sometimes disabling symptoms, which may overlap. About 20–25% of migraine patients have a fourth phase: aura. Migraine can often be recognized by its activators, referred to as triggers. PART 13 Neurologic Disorders Migraineurs are particularly sensitive to environmental and sen­ sory stimuli; migraine-prone patients do not habituate easily to sensory stimuli. This sensitivity is amplified in women during the menstrual cycle. Headache can be initiated or amplified by various triggers, including altered sleep patterns; hunger; let-down from stress; physical exertion; stormy weather or barometric pressure changes; hormonal fluctuations during menses; and alcohol or other chemical stimulation, such as with nitrates. Knowledge of a patient’s susceptibility to specific triggers can be useful in management strate­ gies involving lifestyle adjustments, although it is becoming recog­ nized that some apparent triggers, such as light sensitivity, may be part of the initial phase of the attack; i.e., the premonitory phase or prodrome. Pathogenesis  The sensory sensitivity that is characteristic of migraine is probably due to dysfunction of monoaminergic and other sensory control systems located in the brainstem and hypothalamus (Fig. 441-1). Activation of cells in the trigeminal nucleus results in the release of vasoactive neuropeptides, notably calcitonin gene–related pep­ tide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP), at vascular terminals of the trigeminal nerve and within the trigeminal nucleus. CGRP receptor antagonists, gepants, have now been shown to be effective in the acute and preventive treat­ ment of migraine, and four monoclonal antibodies to CGRP, or its receptor, have been shown to be effective in migraine prevention, as has one PACAP monoclonal antibody in a phase 2 study. Centrally, the second-order trigeminal neurons cross the midline and project to ventrobasal and posterior nuclei of the thalamus for further process­ ing. Additionally, there are projections to the periaqueductal gray and hypothalamus, from which reciprocal descending systems have established antinociceptive effects. Other brainstem regions likely to be involved in descending modulation of trigeminal pain include the locus coeruleus and parabrachial nucleus in the pons and the rostro­ ventromedial medulla. Pharmacologic and other data point to the involvement of the neu­ rotransmitter 5-hydroxytryptamine (5-HT; also known as serotonin) in migraine. In the late 1950s, methysergide was suggested to antagonize certain peripheral actions of 5-HT and was introduced, based on its anti-inflammatory properties, as a migraine preventive. The triptans were designed to stimulate selectively subpopulations of 5-HT recep­ tors; at least 14 different 5-HT receptors exist in humans. The triptans are potent agonists of 5-HT1B and 5-HT1D receptors, and some are active at the 5-HT1F receptor; the latter’s exclusive agonists are called ditans. Triptans arrest nerve signaling in the nociceptive pathways of the trigeminovascular system, at least in the trigeminal nucleus cauda­ lis and trigeminal sensory thalamus, in addition to promoting cranial vasoconstriction, whereas ditans, which are also effective in acute migraine, act only at neural targets. A range of other neural targets are currently under investigation for the acute and preventive management of migraine. Data also support a role for dopamine in the pathophysiology of migraine. Many migraine premonitory symptoms can be induced by dopaminergic stimulation. Moreover, there is dopamine receptor hypersensitivity in migraineurs, as demonstrated by the induction of yawning, nausea, vomiting, hypotension, and other symptoms of a migraine attack by dopaminergic agonists at doses that do not affect nonmigraineurs. Dopamine receptor antagonists are effective therapeutic agents in migraine, especially when given parenterally or concurrently with other antimigraine agents. Moreover, hypothalamic activation, anterior to that seen in cluster headache, has been shown in the premonitory (prodromal) phase of migraine using functional imaging, and this may hold a key to understanding some part of the role of dopamine in the disorder. Migraine genes identified by studying families with familial hemi­ plegic migraine (FHM) reveal involvement of ion channels, suggesting that alterations in membrane excitability can predispose to migraine aura. Mutations involving the Cav2.1 (P/Q)–type voltage-gated calcium channel CACNA1A gene are now known to cause FHM 1; this muta­ tion is responsible for about 50% of FHM cases. Mutations in the Na+- K+ ATPase ATP1A2 gene, designated FHM 2, are responsible for about 20% of FHMs. Mutations in the neuronal voltage-gated sodium chan­ nel SCN1A cause FHM 3. Functional neuroimaging has suggested that brainstem regions in migraine (Fig. 441-2) and the posterior hypotha­ lamic gray matter region close to the human circadian pacemaker cells of the suprachiasmatic nucleus in cluster headache (Fig. 441-3) are good candidates for specific involvement in these primary headache disorders. Diagnosis and Clinical Features  Classic diagnostic criteria for migraine headache are listed in Table 441-3 and should be considered together with the extended features in Table 441-2. A high index of suspicion is required to diagnose migraine: the migraine aura, consist­ ing of visual disturbances with flashing lights or zigzag lines moving across the visual field or of other neurologic symptoms, is reported in only 20–25% of patients. It should be distinguished from the pan-field television static-like disturbance now recognized as visual snow. The first phase of a migraine attack for most patients is the premonitory (prodromal) phase consisting of some or all of the following: yawning, sleepiness, fatigue, cognitive dysfunction, mood change, neck discom­ fort, polyuria, and food cravings; this can last from a few hours to days. Typically, the headache phase follows with its associated features, such as nausea, photophobia, and phonophobia as well as allodynia or vertigo. When questioned, these typical migraine symptoms also emerge in the premonitory phase, and typical premonitory symptoms also continue into the headache phase. As the headache lessens, many patients enter a postdrome, most commonly feeling tired/weary, hav­ ing problems concentrating, and experiencing mild neck discomfort that can last for hours and sometimes up to a day. A headache diary can often be helpful in making the diagnosis and in assessing dis­ ability and the frequency of acute attacks. Patients with episodes of migraine on 8 or more days per month and with at least 15 total days of headache per month are considered to have chronic migraine (see “Chronic Daily Headache” in Chap. 17). Migraine must be differen­ tiated from TTH (discussed below), which is reported to be the most common primary headache disorder. Migraine has several forms that have been defined (Table 441-1): migraine with and without aura and chronic migraine are the most important. Migraine at its most TABLE 441-1  Primary Headache Disorders, Modified from International Classification of Headache Disorders-III (Headache Classification Committee of the International Headache Society, 2018) 1. Migraine 1.1  Migraine without aura 1.2  Migraine with aura   1.2.1  Migraine with typical aura     1.2.1.1  Typical aura with headache     1.2.1.2  Typical aura without headache   1.2.2  Migraine with brainstem aura   1.2.3  Hemiplegic migraine     1.2.3.1  Familial hemiplegic migraine (FHM)       1.2.3.1.1  Familial hemiplegic migraine type 1       1.2.3.1.2  Familial hemiplegic migraine type 2       1.2.3.1.3  Familial hemiplegic migraine type 3       1.2.3.1.4  Familial hemiplegic migraine, other loci     1.2.3.2  Sporadic hemiplegic migraine   1.2.4  Retinal migraine 1.3  Chronic migraine 1.4  Complications of migraine   1.4.1  Status migrainosus   1.4.2  Persistent aura without infarction   1.4.3  Migrainous infarction   1.4.4  Migraine aura-triggered seizure 1.5  Probable migraine   1.5.1  Probable migraine without aura   1.5.2  Probable migraine with aura 1.6  Episodic syndromes that may be associated with migraine   1.6.1  Recurrent gastrointestinal disturbance     1.6.1.1  Cyclical vomiting syndrome     1.6.1.2  Abdominal migraine   1.6.2  Benign paroxysmal vertigo   1.6.3  Benign paroxysmal torticollis   A 1.6.4  Infantile colic   A 1.6.6  Vestibular migraine 2. Tension-type headache 2.1  Infrequent episodic tension-type headache 2.2  Frequent episodic tension-type headache 2.3  Chronic tension-type headache 2.4  Probable tension-type headache 3. Trigeminal autonomic cephalalgias 3.1  Cluster headache   3.1.1  Episodic cluster headache   3.1.2  Chronic cluster headache 3.2  Paroxysmal hemicrania   3.2.1  Episodic paroxysmal hemicrania   3.2.2  Chronic paroxysmal hemicrania 3.3  Short-lasting unilateral neuralgiform headache attacks   3.3.1  Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)     3.3.1.1  Episodic SUNCT     3.3.1.2  Chronic SUNCT   3.3.2  Short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA)     3.3.2.1  Episodic SUNA     3.3.2.2  Chronic SUNA 3.4  Hemicrania continua 3.5  Probable trigeminal autonomic cephalalgia 4. Other primary headache disorders 4.1  Primary cough headache 4.2  Primary exercise headache 4.3  Primary headache associated with sexual activity 4.4  Primary thunderclap headache 4.5  Cold-stimulus headache   4.5.1  Headache attributed to external application of a cold stimulus   4.5.2  Headache attributed to ingestion or inhalation of a cold stimulus 4.6  External-pressure headache   4.6.1  External-compression headache   4.6.2  External-traction headache 4.7  Primary stabbing headache 4.8  Nummular headache 4.9  Hypnic headache 4.10  New daily persistent headache (NDPH) Headache Classification Committee of the International Headache Society (IHS) 38(1), pp. 1-211. Copyright © 2018 by (International Headache Society) Reprinted by Permission of SAGE Publications. CHAPTER 441 Migraine and Other Primary Headache Disorders TABLE 441-2  Migraine Symptoms by Attack Phase Premonitory (prodromal) - Neck discomfort - Higher center • Cognitive impairment (brain “fog”) • Mood change • Fatigue - Homeostatic • Yawning/sleepiness • Polyuria/polydipsia • Food cravings Aura - Neurologic disturbance, such as scintillating scotoma Headache phase - Pain - Nausea/vomiting - Sensory sensitivity PART 13 Neurologic Disorders • Photophobia • Phonophobia • Osmophobia • Allodynia • Vertigo Postdrome - Tiredness - Weariness - Concentration impairment Source: Adapted from PJ Goadsby et al: Pathophysiology of migraine: A disorder of sensory processing. Physiol Rev 97:553, 2017. Cortex Cortex Thalamus Thalamus Hypothalamus Hypothalamus Dura FIGURE 441-1  Brainstem pathways that modulate sensory input. The key pathway for pain in migraine is the trigeminovascular input from the meningeal vessels, which passes through the trigeminal ganglion and synapses on second-order neurons in the trigeminocervical complex (TCC). These neurons in turn project in the quintothalamic tract and, after decussating in the brainstem, synapse on neurons in the thalamus. Important modulation of the trigeminovascular nociceptive input comes from the dorsal raphe nucleus, locus coeruleus, and nucleus raphe magnus. basic level is headache with associated features, and TTH is headache that is featureless. Most patients with disabling headache probably have migraine. Patients with acephalgic migraine (typical aura without headache, 1.2.1.2 in Table 441-1) experience recurrent neurologic symptoms, often with nausea or vomiting, but with little or no headache. Vertigo can be prominent; it has been estimated that one-third of patients referred for vertigo or dizziness have a primary diagno­ sis of migraine; the term vestibular migraine is often used in this setting (Table 441-1 A1.6.6). Migraine aura can have prominent brainstem symptoms, and the terms basilar artery and basilar-type migraine have now been replaced by migraine with brainstem aura (Table 441-1). TREATMENT Migraine Headache Once a diagnosis of migraine has been established, it is important to assess the extent of a patient’s disease and disability. The Migraine Disability Assessment Score (MIDAS) is a well-validated, easy-touse tool (Fig. 441-4). Patient education is an important aspect of migraine manage­ ment. Information for patients is available at websites such as the American Migraine Foundation (www.americanmigrainefounda­ tion.org) and the Migraine Trust (www.migrainetrust.org). It is helpful for patients to understand that migraine is an inherited tendency to headache; that migraine can be modified and con­ trolled by lifestyle adjustments and medications, but it cannot be eradicated; and that, except on some occasions in women on oral estrogens or contraceptives, migraine is not associated with serious or life-threatening illnesses. Quintothalamic tract Quintothalamic tract Dorsal raphe nucleus Dorsal raphe nucleus Locus coeruleus Locus coeruleus Superior salivatory nucleus Superior salivatory nucleus Magnus raphe nucleus Magnus raphe nucleus TCC Trigeminal ganglion Sphenopalatine ganglion A B C D FIGURE 441-2  Positron emission tomography (PET) and arterial spin labelled activations in migraine. Hypothalamic, dorsal midbrain, and dorsolateral pontine activation are seen in triggered attacks in the premonitory phase before pain, whereas in migraine attacks, dorsolateral pontine activation persists, as it does in chronic migraine (not shown). The dorsolateral pontine area, which includes the noradrenergic locus coeruleus, is fundamental to the expression of migraine. Moreover, lateralization of changes in this region of the brainstem correlates with lateralization of the head pain in hemicranial migraine; the scans shown in panels C and D are of patients with acute migraine headache on the right and left side, respectively. (Panel A from FH Maniyar et al: Brain activations in the premonitory phase of nitroglycerin-triggered migraine attacks. Brain 137:232, 2014. Panel B from unpublished data, Karsan and Goadsby. Panels C and D from SK Afridi et al: A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 128:932, 2005.) A B FIGURE 441-3  A. Posterior hypothalamic gray matter region activation demonstrated by positron emission tomography in a patient with acute cluster headache. B. Highresolution T1-weighted magnetic resonance image obtained using voxel-based morphometry demonstrates increased gray matter activity, lateralized to the side of pain in a patient with cluster headache. (Panel A from A May et al: Hypothalamic activation in cluster headache attacks. Lancet 352:275, 1998. Panel B from A May et al: Correlation between structural and functional changes in brain in an idiopathic headache syndrome. Nat Med 5:836, 1999.) CHAPTER 441 Migraine and Other Primary Headache Disorders TABLE 441-3  Simplified Diagnostic Criteria for Migraine REPEATED ATTACKS OF HEADACHE LASTING 4–72 H IN PATIENTS WITH A NORMAL PHYSICAL EXAMINATION, NO OTHER REASONABLE CAUSE FOR THE HEADACHE, AND: AT LEAST 2 OF THE FOLLOWING FEATURES: PLUS AT LEAST 1 OF THE FOLLOWING FEATURES: Unilateral pain Nausea/vomiting Throbbing pain Photophobia and phonophobia Aggravation by movement Moderate or severe intensity Source: Adapted from the International Headache Society Classification (Headache Classification Committee of the International Headache Society, Cephalalgia 38:1, 2018). NONPHARMACOLOGIC MANAGEMENT Migraine can often be managed to some degree by a variety of nonpharmacologic approaches. When patients can identify reli­ able triggers, their avoidance can be useful. A regulated lifestyle is helpful, including a healthy diet, regular exercise, regular sleep patterns, avoidance of excess caffeine and alcohol, and avoidance of acute changes in stress levels, being particularly wary of the letdown effect. PART 13 Neurologic Disorders The measures that benefit a given individual should be used routinely because they provide a simple, cost-effective approach to migraine management. Patients with migraine do not encounter more stress than headache-free individuals; overresponsiveness to changes in stress appears to be the issue. Because the stresses of everyday living cannot be eliminated, lessening one’s response to stress by various techniques is helpful for many patients. These may include yoga, transcendental meditation, hypnosis, and con­ ditioning techniques such as biofeedback. For most patients seen in clinical practice, this approach is, at best, an adjunct to pharma­ cotherapy. Nonpharmacologic measures are unlikely to prevent all migraine attacks, and pharmacologic approaches are often needed. *MIDAS Questionnaire INSTRUCTIONS: Please answer the following questions about ALL headaches you have had over the last 3 months. Write zero if you did not do the activity in the last 3 months. 1. On how many days in the last 3 months did you miss work or school because of your headaches? ............................................................................................... 2. How many days in the last 3 months was your productivity at work or school reduced by half or more because of your headaches (do not include days you counted in question 1 where you missed work or school)? On how many days in the last 3 months did you not do household work because of your headaches? 3. ................................................................................ 4. How many days in the last 3 months was your productivity in household work reduced by half or more because of your headaches (do not include days you counted in question 3 where you did not do household work)? 5. On how many days in the last 3 months did you miss family, social, or leisure activities because of your headaches? A. On how many days in the last 3 months did you have a headache? (If a headache lasted more than one day, count each day.) B. On a scale of 0–10, on average how painful were these headaches? (Where 0 = no pain at all, and 10 = pain as bad as it can be.) *Migraine Disability Assessment Score (Questions 1−5 are used to calculate the MIDAS score.) Grade I—Minimal or Infrequent Disability: 0–5 Grade II—Mild or Infrequent Disability: 6–10 Grade III—Moderate Disability: 11–20 Grade IV—Severe Disability: > 20 © Innovative Medical Research 1997 FIGURE 441-4  The Migraine Disability Assessment Score (MIDAS) Questionnaire. (Courtesy of Dr. Richard Lipton.)  ACUTE ATTACK THERAPIES FOR MIGRAINE The mainstay of pharmacologic therapy is the judicious use of one or more of the many medicines that are effective in migraine (Table 441-4). The selection of the optimal regimen for a given patient depends on a number of factors, the most important of which is the severity of the attack. Mild migraine attacks can usually be managed by oral agents; the average efficacy (pain relief) rate is 50–70%. Severe migraine attacks may require parenteral therapy. Most drugs effective in the treatment of migraine are members of one of five major pharmacologic classes: nonsteroidal antiinflammatory drugs; 5-HT1B/1D receptor agonists—triptans; CGRP receptor antagonists—gepants; 5-HT1F receptor agonists—ditans; and dopamine receptor antagonists. In general, an adequate dose of whichever agent is chosen should be used as soon as possible after the onset of an attack. If additional medication is required within 60 min because symptoms return or have not abated, the initial dose should be increased for subsequent attacks or a different class of drug tried as first-line treatment. Repeat dosing of the same medicine at 2 h, while safe, is ineffective for triptans, and in contrast effective for gepants. Migraine therapy must be individualized; a standard approach for all patients is not possible. A therapeutic regimen may need to be refined until one is identified that provides the patient with rapid, complete, and con­ sistent relief with minimal side effects (Table 441-5). Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)  Both the sever­ ity and duration of a migraine attack can be reduced significantly by NSAIDs (Table 441-4). Indeed, many undiagnosed migraineurs self-treat with nonprescription NSAIDs. A general consensus is that NSAIDs are most effective when taken early in the migraine attack. However, the effectiveness of these agents in migraine is usu­ ally less than optimal in moderate or severe migraine attacks. The combination of acetaminophen (paracetamol), aspirin, and caffeine has been approved for use by the U.S. Food and Drug Administra­ tion (FDA) for the treatment of mild to moderate migraine. The combination of aspirin and metoclopramide has been shown to be days days ............................ days ..................... days days ................................................................. ......................................... days .......................................... TABLE 441-4  TREATMENT of Acute Migraine DRUG TRADE NAME DOSAGE Simple Analgesics Acetaminophen, aspirin, caffeine Excedrin Migraine Two tablets or caplets q6h (max 8 per day) NSAIDs Naproxen Aleve, Anaprox, generic 220–550 mg PO bid Ibuprofen Advil, Motrin, Nuprin, generic 400 mg PO q3–4h Tolfenamic acid Clotam Rapid 200 mg PO; may repeat ×1 after 1–2 h Diclofenac K Cambia 50 mg PO with water 5-HT1B/1D Receptor Agonists—Triptans Oral Ergotamine 1 mg, caffeine 100 mg Cafergot One or two tablets at onset, then one tablet q½h (max 6 per day, 10 per week) Naratriptan Amerge 2.5-mg tablet at onset Rizatriptan Maxalt 5–10-mg tablet at onset Maxalt-MLT Sumatriptan Imitrex 50–100-mg tablet at onset Frovatriptan Frova 2.5-mg tablet at onset Almotriptan Axert 12.5-mg tablet at onset Eletriptan Relpax 40 or 80 mg at onset Zolmitriptan Zomig 2.5-mg tablet at onset Zomig Rapimelt Nasal Dihydroergotamine Migranal Nasal Spray Trudhesa Nasal Spray Prior to nasal spray, the pump must be primed 4 times; 1 spray (0.5 mg) is administered, followed in 15 min by a second spray One spray into each nostril Sumatriptan Imitrex Nasal Spray 5–20 mg intranasal spray as 4 sprays of 5 mg or a single 20 mg spray Zolmitriptan Zomig 5 mg intranasal spray as one spray Parenteral Dihydroergotamine DHE-45 1 mg IV, IM, or SC at onset and q1h (max 3 mg/d, 6 mg per week) Sumatriptan Imitrex Injection Alsuma Sumavel DosePro CGRP Receptor Antagonists—Gepants Oral Rimegepant Ubrogepant Nasal Zavegepant Nurtec Ubrelvy Zavzpret 10 mg intranasal, single spray to one nostril once in 24 h 5-HT1F Receptor Agonist—Ditans Oral Lasmiditan Reyvow 50, 100, or 200 mg PO Dopamine Receptor Antagonists Oral Metoclopramide Reglan,a generica 5–10 mg/d Prochlorperazine Compazine,a generica 1–25 mg/d Parenteral Chlorpromazine Generica 0.1 mg/kg IV at 2 mg/min; max 35 mg/d Metoclopramide Reglan,a generic 10 mg IV Prochlorperazine Compazine,a generica 10 mg IV Other Parenteral Opioids Other Neuromodulation Single-pulse transcranial magnetic stimulation (sTMS) Noninvasive vagus nerve stimulation (nVNS) Remote electrical neuromodulation (REN) Transcutaneous supraorbital nerve stimulation External concurrent occipital and trigeminal neurostimulation (eCOT-NS) Generica Savi Dual gammaCore Nerivio Cefaly Relivion aNot all drugs are specifically indicated by the U.S. Food and Drug Administration for migraine. Local regulations and guidelines should be consulted. Note: Antiemetics (e.g., domperidone 10 mg or ondansetron 4 or 8 mg) or prokinetics (e.g., metoclopramide 10 mg) are sometimes useful adjuncts. Abbreviations: 5-HT, 5-hydroxytryptamine; NSAIDs, nonsteroidal anti-inflammatory drugs; ODT, orally disintegrating tablets. CHAPTER 441 Migraine and Other Primary Headache Disorders 3, 4, or 6 mg SC at onset (may repeat once after 1 h for max of 2 doses in 24 h) 75 mg ODT PO 50 or 100 mg PO; a second dose may be taken 2 h after the first, if needed Multiple preparations and dosages; see Table 14-1 Two pulses at onset followed by two further pulses Two doses each of 120 s 30- to 45-min stimulation to the upper arm 60-min stimulation 30- to 60-min stimulation TABLE 441-5  Clinical Stratification of Acute Specific Migraine Treatments CLINICAL SITUATION TREATMENT OPTIONS Failed NSAIDs/ analgesics First tier Sumatriptan 50 mg or 100 mg PO Almotriptan 12.5 mg PO Rizatriptan 10 mg PO Eletriptan 40 mg PO Zolmitriptan 2.5 mg PO Rimegepant 75 mg Ubrogepant 50 or 100 mg Lasmiditan 50, 100, or 200 mg Slower effect/better tolerability Naratriptan 2.5 mg PO Frovatriptan 2.5 mg PO PART 13 Neurologic Disorders Infrequent headache Ergotamine/caffeine 1–2/100 mg PO Dihydroergotamine nasal spray 2 mg Early nausea or difficulties taking tablets Zolmitriptan 5 mg nasal spray Sumatriptan 20 mg nasal spray Rizatriptan 10 mg MLT wafer Zavegepant 10 mg nasal spray Headache recurrence Ergotamine 2 mg (most effective PR/usually with caffeine) Naratriptan 2.5 mg PO Almotriptan 12.5 mg PO Eletriptan 40 mg Rimegepant 75 mg Ubrogepant 50 or 100 mg Tolerating acute treatments poorly Naratriptan 2.5 mg Almotriptan 12.5 mg Rimegepant 75 mg Ubrogepant 50, 100 mg Single-pulse transcranial magnetic stimulation Noninvasive vagus nerve stimulation Remote electrical neuromodulation Early vomiting Zolmitriptan 5 mg nasal spray Zavegepant 10 mg nasal spray Sumatriptan 25 mg PR Sumatriptan 6 mg SC Menses-related headache Prevention Ergotamine PO at night Estrogen patches Rimegepant 75 mg PO taken during the menses Treatment Triptans Dihydroergotamine nasal spray Very rapidly developing symptoms Zolmitriptan 5 mg nasal spray Zavegepant 10 mg nasal spray Sumatriptan 6 mg SC Dihydroergotamine 1 mg IM Abbreviation: NSAIDs, nonsteroidal anti-inflammatory drugs. comparable to a single dose of oral sumatriptan. Important side effects of NSAIDs include dyspepsia and gastrointestinal irritation. 5-HT1B/1D RECEPTOR AGONISTS—TRIPTANS AND ERGOTS Oral  Stimulation of 5-HT1B/1D receptors can stop an acute migraine attack. Ergotamine and dihydroergotamine are nonselective recep­ tor agonists, whereas the triptans are selective 5-HT1B/1D recep­ tor agonists. A variety of triptans—sumatriptan, almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, and zolmitriptan— are available for the treatment of migraine. Each drug in the triptan class has similar pharmacologic proper­ ties, varying slightly in terms of clinical efficacy. Rizatriptan and eletriptan are, on a population basis, the most efficacious of the triptans. Sumatriptan and zolmitriptan have similar rates of effi­ cacy as well as time to onset, with an advantage of having multiple formulations, whereas almotriptan has a similar rate of efficacy to sumatriptan and is better tolerated, and frovatriptan and nara­ triptan are somewhat slower in onset and are also well tolerated. Clinical efficacy appears to be related more to the tmax (time to peak plasma level) than to the potency, half-life, or bioavailability. This observation is consistent with a large body of data indicating that faster-acting analgesics are more effective than slower-acting ones. Unfortunately, monotherapy with a selective oral 5-HT1B/1D receptor agonist does not result in rapid, consistent, and complete relief of migraine in all patients. Triptans are generally not effec­ tive in migraine with aura unless given after the aura is completed and the headache initiated. Side effects are common, although often mild and transient. Moreover, 5-HT1B/1D receptor agonists are contraindicated in individuals with a history, symptoms, or signs of ischemic cardiac, cerebrovascular, or peripheral vascular syn­ dromes. Recurrence of headache, within the usual time course of an attack, is another important limitation of triptan use and occurs at least occasionally in most patients. Evidence from randomized controlled trials shows that coadministration of a longer-acting NSAID, naproxen 500 mg, with sumatriptan will augment the ini­ tial effect of sumatriptan and, importantly, reduce rates of headache recurrence. Ergotamine preparations offer a nonselective means of stimulat­ ing 5-HT1 receptors. A nonnauseating dose of ergotamine should be sought because a dose that provokes nausea is too high and may intensify head pain. Oral (excluding sublingual) formulations of ergotamine also contain 100 mg caffeine (theoretically to enhance ergotamine absorption and possibly to add additional analgesic activity). The average oral ergotamine dose for a migraine attack is 2 mg. Because the clinical studies demonstrating the efficacy of ergotamine in migraine predated the clinical trial methodolo­ gies used with the triptans, it is difficult to assess the comparative efficacy of ergotamine versus the triptans. In general, with use of ergotamine there appears to be a much higher incidence of nausea than with triptans but less headache recurrence. Nasal  Nasal formulations of dihydroergotamine, zolmitriptan, or sumatriptan can be useful in patients requiring a nonoral route of administration. The nasal sprays result in substantial blood levels within 30–60 min. Although in theory nasal sprays might provide faster and more effective relief of a migraine attack than oral formu­ lations, their reported pain relief rate is only ~50–60%. Studies with a new inhalational formulation of dihydroergotamine indicate that its absorption problems can be overcome to produce rapid onset of action with good tolerability. Parenteral  Administration of drugs by injection, such as dihydro­ ergotamine and sumatriptan, is approved by the FDA for the rapid relief of a migraine attack. Peak plasma levels of dihydroergotamine are achieved 3 min after IV dosing, 30 min after intramuscular (IM) dosing, and 45 min after subcutaneous (SC) dosing. If an attack has not already peaked, SC or IM administration of 1 mg of dihydroergotamine is adequate for about 80–90% of patients. Sumatriptan, 3, 4, or 6 mg SC, depending on local availability, is effective in ~50–80% of patients and can now be administered by a needle-free device. CALCITONIN GENE-RELATED PEPTIDE (CGRP) RECEPTOR ANTAGONISTS—GEPANTS Gepants are small-molecule CGRP receptor antagonists that are effective in the acute treatment of migraine. Three are currently approved by the FDA: rimegepant, and ubrogepant are oral, and zavegepant is a nasal spray (Table 441-4). They are more likely to render patients pain-free at 2 h and most bothersome symptom– free when compared with placebo in large phase 3 clinical trials. The most bothersome symptom is derived by asking patients to identify which symptom—of nausea, photophobia, or phonophobia—was most bothersome during the treated attack; success required that this symptom was eliminated at 2 h. Gepants are extremely well tolerated with only a small percentage of patients reporting trouble­ some side effects, such as mild nausea. 5-HT1F RECEPTOR AGONISTS—DITANS Lasmiditan, a highly selective, orally available, 5-HT1F receptor agonist, has been approved by the FDA for the acute treatment of migraine based on large phase 3 studies where it was superior to placebo (Table 441-4). Ditans have no vascular effects because the 5-HT1F receptor is located in the central and peripheral nervous system but not vasculature; the class thus unequivocally fills a gap in therapy for patients with cardiovascular and cerebrovascular disease. The major side effect is dizziness, occurring in ~15% of patients in clinical trials, and somnolence in 6%. Patients are advised not to drive for 8 h after treatment. DOPAMINE RECEPTOR ANTAGONISTS Oral  Oral dopamine receptor antagonists can be considered as adjunctive therapy in migraine. Drug absorption is impaired dur­ ing migraine because of reduced gastrointestinal motility. Delayed absorption occurs even in the absence of nausea and is related to the severity of the attack and not its duration. Therefore, when oral NSAIDs and/or triptan agents fail, the addition of a dopamine receptor antagonist, such as metoclopramide 10 mg, prochlorpera­ zine 10 mg, or domperidone 10 mg (not available in the United States), should be considered to enhance gastric absorption. In addition, dopamine receptor antagonists decrease nausea/vomiting and restore normal gastric motility. Parenteral  Dopamine receptor antagonists (e.g., chlorpromazine, prochlorperazine, metoclopramide) by injection can also provide significant acute relief of migraine; they can be used in combination with parenteral 5-HT1B/1D receptor agonists. A common IV protocol used for the treatment of severe migraine is the administration over 2 min of a mixture of 5 mg of prochlorperazine and 0.5 mg of dihydroergotamine. OTHER OPTIONS FOR ACUTE MIGRAINE Oral  For milder attacks of migraine, the combination of acet­ aminophen, aspirin, and caffeine is FDA approved (Table 441-4). Parenteral  Opioids are modestly effective in the acute treatment of migraine. For example, IV meperidine (50–100 mg) is given fre­ quently in the emergency department (ED). This regimen “works” in the sense that the pain of migraine is eliminated. Importantly, it is clear from a randomized controlled trial that prochlorperazine is superior to hydromorphone in the ED setting. However, opioids are clearly suboptimal for patients with recurrent headache. Opi­ oids do not treat the underlying headache mechanism; rather, they act to alter the pain sensation, and there is evidence their use may decrease the likelihood of a response to triptans in the future. More­ over, in patients taking oral opioids, such as oxycodone or hydro­ codone, habituation or addiction can greatly confuse the treatment of migraine. Opioid craving and/or withdrawal can aggravate and accentuate migraine. Therefore, it is recommended that opioid use in migraine be limited to patients with severe, but infrequent, head­ aches that are unresponsive to other pharmacologic approaches or who have contraindications to other therapies. Neuromodulation  Single-pulse transcranial magnetic stimula­ tion (sTMS) is FDA cleared for the acute treatment of migraine. Two pulses can be applied at the onset of an attack, and this can be repeated. The use of sTMS is safe where there is no cranial metal implant and offers an option to patients seeking nonpharmaceuti­ cal approaches to treatment. Similarly, a noninvasive vagus nerve stimulator (nVNS) is FDA cleared for the treatment of migraine attacks in adults. One to two 120-s doses may be applied for attack treatment. Remote electrical neuromodulation using a smartphone app that stimulates the upper arm for 30–45 min is also effective for treatment of acute migraine. Transcutaneous supraorbital nerve stimulation for 60 min and external concurrent occipital and tri­ geminal neurostimulation (eCOT-NS) for 30–60 min are both FDA cleared. MEDICATION-OVERUSE HEADACHE Acute attack medications, particularly opioid or barbituratecontaining compound analgesics, have a propensity to aggravate headache frequency and induce a state of refractory daily or neardaily headache called medication-overuse headache. This condition is likely not a separate headache entity but a reaction of the patient’s underlying migraine biology to a particular medicine. Migraine patients who have two or more headache days a week should be cautioned about frequent analgesic use (see “Chronic Daily Headache” in Chap. 17). CHAPTER 441 PREVENTIVE TREATMENTS FOR MIGRAINE Patients with an increasing frequency of migraine attacks or with attacks that are either unresponsive or poorly responsive to abortive treatments are good candidates for preventive agents. In general, a preventive medication should be considered in patients with four or more migraine days a month. Significant side effects are associated with the use of many agents; furthermore, determination of dose can be difficult because the recommended doses have been derived for conditions other than migraine. The mechanism of action of older medicines is unclear; it seems likely that the brain sensitivity that underlies migraine is modified. Patients are usually started on a low dose of a chosen treatment; the dose is then gradually increased, up to a reasonable maximum, to achieve clinical benefit. Migraine and Other Primary Headache Disorders Treatments that have the capacity to stabilize migraine are listed in Table 441-6. Most treatments must be taken daily, and there is usually a lag of 2–12 weeks before an effect is seen. The drugs that have been approved by the FDA for the preventive treatment of migraine include propranolol, timolol, sodium valproate, topi­ ramate, eptinezumab, erenumab, fremanezumab, galcanezumab, rimegepant, and atogepant. In addition, a number of other drugs appear to display preventive efficacy. This group includes amitripty­ line, candesartan, nortriptyline, flunarizine, phenelzine, and cypro­ heptadine. Placebo-controlled trials of onabotulinum toxin type A in episodic migraine were negative, whereas, overall, placebocontrolled trials in chronic migraine were positive. The FDA has approved a range of neuromodulation approaches for the preventive treatment of migraine (Table 441-6). They offer a well-tolerated, effective option for patients. Phenelzine is a monoamine oxidase inhibitor (MAOI); therefore, tyramine-containing foods, decon­ gestants, and meperidine are contraindicated, and it is reserved for only very recalcitrant cases. Methysergide is now of historical interest only because it is no longer manufactured. Melatonin has been reported to be useful, with controlled trial evidence, but is not approved for this indication in the United States. The probability of success with any one of the antimigraine drugs is ~40–50%. Many patients are managed adequately with well-tolerated doses of candesartan, propranolol, amitriptyline, topiramate, or valproate. As data on fetal developmental issues have arisen, both topiramate and valproate are now considered less attractive for use in females during reproductive years. If these agents fail or produce unacceptable side effects, neuromodulation approaches can be used (Table 441-6). Once effective stabilization is achieved, the drug is continued for ~6–12 months and then slowly tapered, assuming the patient agrees, to assess the continued need. Many patients are able to discontinue medication and experience fewer and milder attacks for long periods. The advent of CGRP monoclonal antibodies and CGRP receptor antagonists has sig­ nificantly changed the landscape of preventive treatment; with the combination of efficacy that is often within the first month and excellent tolerability, expectations of outcomes have changed. TABLE 441-6  Preventive Treatments in Migrainea DRUG DOSE SELECTED SIDE EFFECTS Beta blocker   Propranolol   Metoprolol 40–120 mg bid 25–100 mg bid Antidepressants   Amitriptyline 10–75 mg at night Drowsiness   Dosulepin 25–75 mg at night   Nortriptyline 25–75 mg at night Note: Some patients may only need a total dose of 10 mg, although generally 1–1.5 mg/kg body weight is required.   Venlafaxine 75–150 mg/d Anticonvulsants   Topiramate 25–200 mg/d Paresthesias PART 13 Neurologic Disorders   Valproate 400–600 mg bid Drowsiness Serotonergic drugs   Pizotifenb 0.5–2 mg qd Weight gain CGRP pathway blockers   Eptinezumab   Erenumab   Fremanezumab   Galcanezumab 100 or 300 mg IV every 12 weeks 70 or 140 mg SC monthly 225 mg monthly or 675 mg q3 months, SC 240 mg loading then 120 mg monthly, SC   Rimegepant   Atogepant 75 mg every other day 10, 30, or 60 mg once daily Other classes   Flunarizineb 5–15 mg qd Drowsiness   Candesartan 4–24 mg daily Dizziness   Memantine 5–20 mg daily Dizziness, tiredness   Melatonin 3–12 mg nightly Drowsiness Neuromodulation   Single-pulse transcranial magnetic stimulation (sTMS)   Noninvasive vagus nerve stimulation (nVNS)   Remote electrical neuromodulation (REN)   Transcutaneous supraorbital nerve stimulation 4–24 pulses per day 120-s treatments 2–3 times daily 45 min every other day 20 min daily Chronic migraine   Onabotulinum toxin type A 155 U Loss of brow furrow No convincing evidence from controlled trials   Verapamil Controlled trials demonstrate no effect   Nimodipine   Clonidine   Selective serotonin reuptake inhibitors: fluoxetine aCommonly used preventives are listed with typical doses and common side effects. Not all listed medicines are approved by the U.S. Food and Drug Administration; local regulations and guidelines should be consulted. bNot available in the United States. Reduced energy Tiredness Postural symptoms Contraindicated in asthma Cognitive symptoms Weight loss Glaucoma Caution with nephrolithiasis Weight gain Tremor Hair loss Fetal abnormalities Hematologic or liver abnormalities Nasopharyngitis Nasopharyngitis, constipation Injection site reactions Nasopharyngitis Nausea abdominal pain/dyspepsia Constipation, nausea Weight gain Depression Parkinsonism Lightheadedness Tingling Tinnitus Site discomfort, irritation or pain Muscle twitching Well-tolerated; some local sensory symptoms Local paresthesia ■ ■TENSION-TYPE HEADACHE Clinical Features  The term tension-type headache is commonly used to describe a chronic head-pain syndrome characterized by bilateral tight, bandlike discomfort. The pain typically builds slowly, fluctuates in severity, and may persist more or less continuously for many days. The headache may be episodic or chronic (present >15 days per month). A useful clinical approach is to diagnose TTH in patients whose headaches are completely without accompanying features such as nausea, vomiting, photophobia, phonophobia, osmophobia, throbbing, and aggravation with movement. Such an approach neatly separates migraine, which has one or more of these features and is the main dif­ ferential diagnosis, from TTH. The International Headache Society’s main definition of TTH allows an admixture of nausea, photophobia, or phonophobia in various combinations, although the appendix defi­ nition does not; this illustrates the difficulty in distinguishing these two clinical entities. In clinical practice, using the appendix definition to dichotomize patients on the basis of the presence of associated features (migraine) and the absence of associated features (TTH) is highly rec­ ommended. Indeed, patients whose headaches fit the TTH phenotype and who have migraine at other times, along with a family history of migraine, migrainous illnesses of childhood, or typical migraine triggers to their migraine attacks, may be biologically different from those who have TTH headache with none of the features. TTH may be infrequent (episodic) or occur on 15 days or more a month (chronic). Pathophysiology  The pathophysiology of TTH is incompletely understood. It seems likely that TTH is due to a primary disorder of central nervous system pain modulation alone, unlike migraine, which involves a more generalized disturbance of sensory modulation. Data suggest a genetic contribution to TTH, but this may not be a valid finding: given the current diagnostic criteria, the studies undoubtedly included many migraine patients. The name tension-type headache implies that pain is a product of nervous tension, but there is no clear evidence for tension as an etiology. Muscle contraction has been TABLE 441-7  Clinical Features of the Trigeminal Autonomic Cephalalgias CLUSTER HEADACHE PAROXYSMAL HEMICRANIA SUNCT/SUNA Gender M > F F = M F ~ M Pain   Type Stabbing, boring Throbbing, boring, stabbing Burning, stabbing, sharp   Severity Excruciating Excruciating Severe to excruciating   Site Orbit, temple Orbit, temple Periorbital Attack frequency 1/alternate day–8/d 1–20/d (>5/d for more than half the time) 3–200/d Duration of attack 15–180 min 2–30 min 5–240 s Autonomic features Yes Yes Yes (prominent conjunctival injection and lacrimation)a Migrainous featuresb Yes Yes Yes Alcohol trigger Yes No No Cutaneous triggers No No Yes Indomethacin effect — Yesc — Abortive treatment Sumatriptan injection or nasal spray Zolmitriptan nasal spray Oxygen nVNSc Preventive treatment Verapamil Galcanezumab Topiramate Melatonin Lithium Gabapentin aIf conjunctival injection and tearing are not present, consider SUNA. bNausea, photophobia, or phonophobia; photophobia and phonophobia are typically unilateral on the side of the pain. cNoninvasive vagus nerve stimulation is U.S. Food and Drug Administration approved in episodic cluster headache dIndicates complete response to indomethacin. Abbreviations: nVNS, non-invasive vagus nerve stimulation; SUNA, short-lasting unilateral neuralgiform headache attacks with cranial autonomic features; SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing. considered to be a feature that distinguishes TTH from migraine, but there appear to be no differences in contraction between the two head­ ache types. In primary care, <10% of patients presenting with headache over 3 months or more without any neurologic symptoms or signs have tension-type headache; >90% have migraine. TREATMENT Tension-Type Headache The pain of TTH can generally be managed with simple analgesics such as acetaminophen, aspirin, or NSAIDs. Behavioral approaches including relaxation can also be effective. Clinical studies have demonstrated that triptans in pure TTH are not helpful, although triptans are effective in apparent TTH when the patient also has migraine. For chronic TTH, amitriptyline is the only proven treat­ ment (Table 441-6); other tricyclics, selective serotonin reuptake inhibitors, and the benzodiazepines have not been shown to be effective. There is no evidence for the efficacy of acupuncture. Placebo-controlled trials of onabotulinum toxin type A in chronic TTH were negative. CHAPTER 441 ■ ■TRIGEMINAL AUTONOMIC CEPHALALGIAS, INCLUDING CLUSTER HEADACHE The TACs describe a grouping of primary headache disorders including cluster headache, paroxysmal hemicrania (PH), SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing)/SUNA (short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms), and hemicrania continua (Table 441-1). TACs are characterized by relatively short-lasting attacks of head pain associated with lateralized cranial autonomic symptoms, such as lacrimation, conjunctival injection, aural fullness, or nasal con­ gestion (Table 441-7). Pain is usually severe and may occur more than once a day. Because of the associated nasal congestion or rhinorrhea, patients are often misdiagnosed with “sinus headache” and treated with decongestants, which are ineffective. Migraine and Other Primary Headache Disorders No effective treatment Lidocaine (IV) Indomethacind Lamotrigine nVNS Topiramate TACs must be differentiated from short-lasting headaches that do not have prominent cranial autonomic syndromes, notably trigeminal neuralgia (TN), primary stabbing headache, and hypnic headache. The cycling pattern and length, frequency, and timing of attacks are useful in classifying patients. Patients with TACs should be considered, if clinically indicated, to undergo pituitary imaging and pituitary func­ tion tests because there is an excess of TAC presentations in clinical practice in patients with pituitary tumor–related headache, particularly prolactin and growth hormone secreting tumors. Cluster Headache  Cluster headache is a relatively rare form of primary headache, although nonetheless a common condition, with a population frequency of ~0.1%. The pain is deep, usually retroorbital, often excruciating in intensity, nonfluctuating, and explosive in qual­ ity. A core feature of cluster headache is periodicity. Usually one of the daily attacks of pain recurs at about the same hour each day for the duration of a cluster bout. The typical cluster headache patient has daily bouts of one to two attacks of relatively short-duration unilateral pain for 8–10 weeks a year; this is usually followed by a pain-free inter­ val that averages a little less than 1 year. Cluster headache is character­ ized as chronic when there is <3 months of sustained remission without treatment. Patients are generally perfectly well between episodes. Onset of attacks is nocturnal in about 50% of patients, and men are affected three times more often than women. Patients with cluster headache tend to move about during attacks, pacing, rocking, or rubbing their head for relief; some may even become aggressive during attacks. This is in sharp contrast to patients with migraine, who prefer to remain motionless during attacks. PART 13 Neurologic Disorders Cluster headache is associated with ipsilateral symptoms of cra­ nial parasympathetic autonomic activation: conjunctival injection or lacrimation, aural fullness, rhinorrhea or nasal congestion, or cranial sympathetic dysfunction such as ptosis. The sympathetic deficit is peripheral and likely to be due to parasympathetic activation with injury to ascending sympathetic fibers surrounding a dilated carotid artery as it passes into the cranial cavity. When present, photophobia and phonophobia are more likely to be unilateral and on the same side of the pain, rather than bilateral, in contrast to migraine. This phenom­ enon of unilateral photophobia/phonophobia is characteristic of TACs. Cluster headache is likely to be a disorder involving central pacemaker neurons and neurons in the posterior hypothalamic region (Fig. 441-3). TREATMENT Cluster Headache The most satisfactory treatment is the administration of drugs to prevent cluster attacks until the bout is over. However, treatment of acute attacks is required for all cluster headache patients at some time. ACUTE ATTACK TREATMENT Cluster headache attacks peak rapidly, and thus a treatment with rapid onset is required. Many patients with acute cluster headache respond very well to oxygen inhalation. This should be given as 100% oxygen at 10–12 L/min for 15–20 min. It appears that high flow and high oxygen content are important, thus ultra-high flow with a demand valve may be a better option for some patients. Sumatriptan 6 mg SC is rapid in onset and will usually shorten an attack to 10–15 min; where available, 3 or 4 mg SC can also be effec­ tive; there is no evidence of tachyphylaxis. Sumatriptan (20 mg) and zolmitriptan (5 mg) nasal sprays are both effective in acute cluster headache, offering a useful option for patients who may not wish to self-inject daily. nVNS is FDA cleared for the acute treatment of attacks in episodic cluster headache using three 2-min stimulation cycles applied consecutively at the onset of headache on the side of pain; this may be repeated after 9 min. Oral sumatriptan is not effective for prevention or for acute treatment of cluster headache. PREVENTIVE TREATMENTS (TABLE 441-8) The choice of a preventive treatment in cluster headache depends in part on the length of the bout. Patients with long bouts or those TABLE 441-8  Preventive Management of Cluster Headache SHORT-TERM PREVENTION LONG-TERM PREVENTION EPISODIC CLUSTER HEADACHE AND PROLONGED CHRONIC CLUSTER HEADACHE EPISODIC CLUSTER HEADACHE Prednisone 1 mg/kg up to 60 mg qd, tapering over 21 days Verapamil 160–960 mg/d Galcanezumab 300 mg SC Greater occipital nerve injection (local anesthetic and corticosteroids) Verapamil 160–960 mg/d nVNS 6–24 stimulations/d Melatonina 9–12 mg/d Topiramatea 100–400 mg/d Lithium 400–800 mg/d Abbreviations: nVNS, noninvasive vagus nerve stimulation. with chronic cluster headache require medicines that are safe when taken for long periods. For patients with relatively short bouts, limited courses of oral glucocorticoids can be very use­ ful. A 10-day course of prednisone, beginning at 60 mg daily for 7 days and followed by a rapid taper, may interrupt the pain bout for many patients. Greater occipital nerve injection with lidocaine and corticosteroids has been shown to be effective in randomized controlled trials, with a benefit that lasts up to 6–8 weeks. The CGRP monoclonal antibody galcanezumab has been approved by the FDA for treatment of episodic cluster headache; it reduces attack frequency, is well tolerated, and is often an effec­ tive option. Most experts favor verapamil as the first-line preventive treat­ ment for patients with chronic cluster headache or with prolonged bouts. While verapamil compares favorably with lithium in practice, some patients require verapamil doses far in excess of those admin­ istered for cardiac disorders. The initial dose range is 40–80 mg twice daily; effective doses may be as high as 960 mg/d. Side effects such as constipation, leg swelling, or gingival hyperplasia can be problematic. Of paramount concern, however, is the cardiovascular safety of verapamil, particularly at high doses. Verapamil can cause heart block by slowing conduction in the atrioventricular node, a condition that can be monitored by following the PR interval on a standard electrocardiogram (ECG). Approximately 20% of patients treated with verapamil develop ECG abnormalities, which can be observed with doses as low as 240 mg/d; these abnormalities can worsen over time in patients on stable doses. A baseline ECG is recommended for all patients. The ECG is repeated 10 days after a dose change in patients whose dose is being increased above 240 mg daily. Dose increases are usually made in 80-mg increments. For patients on long-term verapamil, ECG monitoring every 6 months is advised. NEUROMODULATION THERAPY When medical therapies fail in chronic cluster headache, neuro­ modulation strategies can be used. Sphenopalatine ganglion (SPG) stimulation with an implanted battery-free stimulator has been shown in randomized controlled trials to be effective in aborting attacks and reducing their frequency over time. nVNS compares favorably with standard-of-care in open-label experience. Similarly, occipital nerve stimulation has been used open label and appears to be beneficial. Deep-brain stimulation of the region of the posterior hypothalamic gray matter is successful in about 50% of patients treated, although its risk-versus-benefit ratio makes it inappropriate before all other less invasive options have been explored. ■ ■PAROXYSMAL HEMICRANIA Paroxysmal hemicrania (PH) is characterized by frequent unilateral, severe, short-lasting episodes of headache. Like cluster headache, the pain tends to be retroorbital but may be experienced all over the head and is associated with cranial autonomic phenomena such as lacrima­ tion and nasal congestion. Patients with remissions are said to have episodic PH, whereas those with the nonremitting form are said to have chronic PH. The essential features of PH are unilateral very severe pain; short-lasting attacks (2–45 min); very frequent attacks (usually >5 a day); marked autonomic features ipsilateral to the pain; rapid course (<72 h); and excellent response to indomethacin. In contrast to cluster headache, which predominantly affects males, the male-to-female ratio in PH is close to 1:1. Indomethacin (25–75 mg tid), which can completely suppress attacks of PH, is the treatment of choice. Although therapy may be complicated by indomethacin-induced gastrointestinal side effects, currently there are no consistently effective alternatives. Topiramate is helpful in some cases. nVNS can be very effective in PH. Melatonin may be indomethacin-sparing in some patients. Verapamil, an effective treatment for cluster headache, does not appear to be useful for PH. In occasional patients, PH can coexist with TN (PH-tic syndrome); similar to cluster-tic syndrome, each component may require separate treatment. Secondary PH has been reported with lesions in the region of the sella turcica, including arteriovenous malformation, cavernous sinus meningioma, pituitary pathology, and epidermoid tumors. Secondary PH is more likely if the patient requires high doses (>200 mg/d) of indomethacin. In patients with apparent bilateral PH, raised cerebro­ spinal fluid (CSF) pressure should be suspected. It is important to note that indomethacin reduces CSF pressure. When a diagnosis of PH is considered, magnetic resonance imaging (MRI) is indicated to exclude a pituitary lesion. ■ ■SUNCT/SUNA SUNCT is a rare primary headache syndrome characterized by severe, unilateral orbital or temporal pain that is stabbing or throbbing in quality. Diagnosis requires at least 20 attacks, lasting for 5–240 s; ipsilateral conjunctival injection and lacrimation should be present. In some patients, conjunctival injection or lacrimation is missing, and the diagnosis of SUNA can be made. Diagnosis  The pain of SUNCT/SUNA is unilateral and may be located anywhere in the head. Three basic patterns can be seen: single stabs, which are usually short-lived; groups of stabs; or a longer attack comprising many stabs between which the pain does not completely resolve, thus giving a “saw-tooth” phenomenon with attacks lasting many minutes. Each pattern may be seen in the context of an under­ lying continuous head pain. Characteristics that lead to a suspected diagnosis of SUNCT are the cutaneous (or other) triggers of attacks, a lack of refractory period to triggering between attacks, and the lack of a response to indomethacin. Apart from trigeminal sensory disturbance, the neurologic examination is normal in primary SUNCT/SUNA. The diagnosis of SUNCT/SUNA is often confused with TN, par­ ticularly in first-division TN (Chap. 452). Minimal or no cranial auto­ nomic symptoms and a clear refractory period to triggering indicate a diagnosis of TN. Secondary (Symptomatic) SUNCT  SUNCT can be seen with posterior fossa or pituitary lesions. All patients with SUNCT/SUNA should be evaluated with pituitary function tests and a brain MRI with pituitary views. TREATMENT SUNCT/SUNA ABORTIVE THERAPY Therapy of acute attacks is not a useful concept in SUNCT/SUNA because the attacks are of such short duration. However, IV lido­ caine, which arrests the symptoms, can be used in hospitalized patients. PREVENTIVE THERAPY Long-term prevention to minimize disability and hospitalization is the goal of treatment. The most effective treatment for prevention is lamotrigine, 200–400 mg/d. Topiramate and gabapentin may also be effective. Carbamazepine, 400–500 mg/d, has been reported by patients to offer modest benefit. Surgical approaches such as microvascular decompression or destructive trigeminal procedures are seldom useful and often produce long-term complications. Greater occipital nerve injection has produced limited benefit in some patients. nVNS may be use­ ful. Occipital nerve stimulation is probably helpful in a subgroup of these patients. For intractable cases, short-term prevention with IV lidocaine can be effective. ■ ■HEMICRANIA CONTINUA The essential features of hemicrania continua are moderate and con­ tinuous unilateral pain associated with fluctuations of severe pain; complete resolution of pain with indomethacin; and exacerbations that may be associated with cranial autonomic features, including conjunc­ tival injection, lacrimation, and photophobia on the affected side. The age of onset ranges from 10 to 70 years; women are affected twice as often as men. The cause is unknown. CHAPTER 441 TREATMENT Hemicrania Continua Treatment consists of indomethacin; other NSAIDs appear to be of little or no benefit. The IM injection of 100 mg of indomethacin has been proposed as a diagnostic tool, and administration with a placebo injection in a blinded fashion can be very useful diagnosti­ cally. Alternatively, a trial of oral indomethacin, starting with 25 mg tid, then 50 mg tid, and then 75 mg tid, can be given. Up to 2 weeks at the maximal dose may be necessary to assess whether a dose has a useful effect. Topiramate can be helpful in some patients. nVNS can be very useful in these patients. Melatonin can be useful as an indomethacin-sparing agent. Occipital nerve stimulation probably has a role in patients with hemicrania continua who are unable to tolerate indomethacin. Migraine and Other Primary Headache Disorders ■ ■OTHER PRIMARY HEADACHE DISORDERS Primary Cough Headache  Primary cough (Valsalva maneuver) headache is a generalized headache that begins suddenly, lasts for seconds or several minutes, sometimes up to a few hours, and is pre­ cipitated by coughing; it is preventable by avoiding coughing or other precipitating events, which can include sneezing, straining, laughing, or stooping. In all patients with this syndrome, serious etiologies must be excluded before a diagnosis of “benign” primary cough headache can be established. A Chiari malformation or any lesion causing obstruction of CSF pathways or displacing cerebral structures can be the cause of the head pain. Other conditions that can present with cough or exertional headache as the initial symptom include cerebral aneurysm, carotid stenosis, and vertebrobasilar disease. Benign cough headache can resemble benign exertional headache (below); patients with the former condition are typically older. TREATMENT Primary Cough Headache Indomethacin 25–50 mg two to three times daily is the treatment of choice. Some patients with cough headache obtain complete cessation of their attacks with lumbar puncture; this is a simple option when compared to prolonged use of indomethacin, and it is effective in about one-third of patients. The mechanism of this response is unclear. Primary Exercise Headache  Primary exercise headache has features resembling both cough headache and migraine. It may be precipitated by any form of exercise; it often has the pulsatile quality of migraine. The pain lasts <48 h, is bilateral, and is often throbbing at onset; migrainous features may develop in patients susceptible to migraine. The duration tends to be shorter in adolescents than in older adults. Primary exercise headache can be prevented by avoiding exces­ sive exertion, particularly in hot weather or at high altitude. The mechanism of primary exercise headache is unclear. Acute venous distension likely explains one syndrome—the acute onset of headache with straining and breath holding, as in weightlifter’s headache. Because exercise can trigger headache in a number of seri­ ous underlying conditions (Chap. 17), these must be considered in patients with exercise headache. Pain from angina may be referred to the head, probably by central connections of vagal afferents, and may present as exercise headache (cardiac cephalgia). The link to exercise is the main clinical clue that headache is of cardiac origin. Pheochromo­ cytoma may occasionally cause exercise headache. Intracranial lesions and stenosis of the carotid arteries are other possible etiologies. TREATMENT Primary Exercise Headache Exercise regimens should begin modestly and progress gradu­ ally to higher levels of intensity. Indomethacin at daily doses from 25–150 mg is generally effective in benign exertional headache. Indomethacin (50 mg), a gepant-rimegepant (75 mg orally) or ubrogepant (100 mg orally), ergotamine (1 mg orally), and dihy­ droergotamine (2 mg by nasal spray) are useful short-term pre­ ventive measures. PART 13 Neurologic Disorders Primary Headache Associated with Sexual Activity  Three types of sex headache are reported: a dull bilateral ache in the head and neck that intensifies as sexual excitement increases; a sudden, severe, explosive headache occurring at orgasm; and a postural headache developing after coitus. The latter arises from vigorous sexual activity and is a form of low CSF pressure headache and thus not a primary headache disorder (Chap. 17). Headaches developing at the time of orgasm are not always benign; 5–12% of cases of subarachnoid hemor­ rhage are precipitated by sexual intercourse. Sex headache is reported by men more often than women and may occur at any time during the years of sexual activity. It may appear on several occasions in succes­ sion and then not trouble the patient again, even without an obvious change in sexual activity. In patients who stop sexual activity when headache is first noticed, the pain may subside within a period of 5 min to 2 h. In about half of patients, sex headache will subside within 6 months. Most patients with sex headache do not have exercise or cough headache; this clinical paradox is generally a marker of primary sex headache. Migraine is probably more common in patients with sex headache. TREATMENT Primary Sex Headache Benign sex headaches recur irregularly and infrequently. Manage­ ment can often be limited to reassurance and advice about ceasing sexual activity if a mild, warning headache develops. Propranolol can be used to prevent headache that recurs regularly or frequently, but the dosage required varies from 40–200 mg/d. An alterna­ tive is the calcium channel–blocking agent diltiazem, 60 mg tid. Indomethacin (25–50 mg), a gepant-rimegepant (75 mg orally) or ubrogepant (100 mg orally), or frovatriptan (2.5 mg), taken 30–45 min prior to sexual activity can also be helpful. Primary Thunderclap Headache  Sudden onset of severe head­ ache may occur in the absence of any known provocation. The differential diagnosis includes the sentinel bleed of an intracranial aneurysm, reversible cerebral vasoconstriction syndrome (RCVS), cervicocephalic arterial dissection, and cerebral venous thrombosis. Headaches of explosive onset may also be caused by the ingestion of sympathomimetic drugs or of tyramine-containing foods in a patient who is taking MAOIs, or they may be a symptom of pheochromo­ cytoma. Whether thunderclap headache can be the presentation of an unruptured cerebral aneurysm is uncertain; some experts believe that RCVS is the cause of most or all cases of otherwise undiagnosed thunderclap headache. When neuroimaging studies and lumbar puncture exclude subarachnoid hemorrhage, patients with thunder­ clap headache usually do very well over the long term. In one study of patients whose computed tomography (CT) scans and CSF findings were negative, ~15% had recurrent episodes of thunderclap headache, and nearly half subsequently developed migraine or TTH. The first presentation of any sudden-onset severe headache should be diligently investigated with neuroimaging (CT or, when pos­ sible, MRI with MR angiography) and CSF examination. In the presence of posterior leukoencephalopathy, the differential diagnosis includes cerebral angiitis, posterior reversible encephalopathy syn­ drome (PRES), drug toxicity (cyclosporine, intrathecal methotrexate/ cytarabine, pseudoephedrine, or cocaine), posttransfusion effects, and postpartum angiopathy. Treatment with nimodipine may be helpful, although the vasoconstriction often resolves spontaneously. Cold-Stimulus Headache  This refers to head pain triggered by application or ingestion/inhalation of something cold. It is brought on quickly and typically resolves within 10–30 min of the stimulus being removed. It is best recognized as “brain-freeze” headache or ice-cream headache when due to ingestion. Although cold may be uncomfortable at some level for many people, it is the reliable, severe, and somewhat prolonged nature of these pains that set them apart. The transient receptor potential cation subfamily M member 8 (TRPM8) channel, a known cold-temperature sensor, may be a mediator of this syndrome. Naproxen 500 mg taken 30 min prior to exposure can be helpful for this problem. External Pressure Headache  External pressure from compres­ sion or traction on the head can produce a pain that may have some generalized component, although the pain is largely focused around the site of the pressure. It typically resolves within an hour of the stimu­ lus being removed. Examples of stimuli include helmets, swimming goggles, or very long ponytails. Treatment is to recognize the problem and remove the stimulus. Primary Stabbing Headache  The essential features of primary stabbing headache are stabbing pain confined to the head or, rarely, the face, lasting from 1 to many seconds and occurring as a single stab or a series of stabs; absence of associated cranial autonomic features; absence of cutaneous triggering of attacks; and a pattern of recurrence at irregular intervals (hours to days). When present in adolescents, primary stabbing headache may be a presenting and very troublesome problem for the patient. The pains have been variously described as “ice-pick pains” or “jabs and jolts.” They are more common in patients with other primary headaches, such as migraine, the TACs, and hemi­ crania continua. A key clinical feature is an irregular cadence compared to the regular cadence of the throbbing or pounding that characterizes migraine. TREATMENT Primary Stabbing Headache The response of primary stabbing headache to indomethacin (25–50 mg two to three times daily) is usually excellent. As a general rule, the symptoms wax and wane, and after a period of control on indomethacin, it is appropriate to withdraw treatment and observe the outcome. Nummular Headache  Nummular headache is felt as a round or elliptical discomfort that is fixed in place, ranges in size from 1–6 cm, and may be continuous or intermittent. Uncommonly, it may be multifocal. It may be episodic but is more often continuous during exacerbations. Accompanying the pain there may be a local sensory disturbance, such as allodynia or hypesthesia. Local dermatologic or bony lesions need to be excluded by examination and investigation. This condition can be difficult to treat when present in isolation; # 12 - 442 Alzheimer’s Disease ### 442 Alzheimer’s Disease tricyclics, such as amitriptyline, or anticonvulsants, such as topira­ mate or valproate, are most often tried. This phenotype can be seen in combination with migraine and the TACs, in which cases treatment of the primary headache disorder is often effective for the nummular headache as well. Hypnic Headache  This headache syndrome typically begins a few hours after sleep onset. The headaches last from 15–30 min and are typically moderately severe and generalized, although they may be unilateral and can be throbbing. Patients may report falling back to sleep only to be awakened by a further attack a few hours later; up to three repetitions of this pattern occur through the night. Daytime naps can also precipitate head pain. Most patients are female, and the onset is usually after age 60 years. Headaches are typically bilateral but may be unilateral. Photophobia, phonophobia, and nausea are usually absent. The major secondary consideration in this headache type is poorly controlled hypertension; 24-h blood pressure monitoring is recommended to detect this treatable condition. TREATMENT Hypnic Headache Patients with hypnic headache generally respond to a bedtime dose of lithium carbonate (200–600 mg). One to two cups of coffee, or caffeine 60 mg orally, at bedtime may be effective in approximately one-third of patients. Reports suggest that verapamil, 160 mg; flu­ narizine, 5 mg nightly; or indomethacin, 25–75 mg nightly, can be effective. New Daily Persistent Headache  Primary new daily persistent headache (NDPH) occurs in both men and women. It can be of the migrainous type, with features of migraine, or it can be featureless, appearing as new-onset TTH. Those with migrainous features are the most common form and include unilateral headache and throbbing pain; each feature is present in about one-third of patients. Nausea, photophobia, and/or phonophobia occur in about half of patients. Some patients have a previous history of migraine. NDPH may be more common in adolescents. Treatment of migrainous-type primary NDPH consists of using the preventive therapies effective in migraine (see above). Featureless NDPH is one of the primary headache disor­ ders most refractory to treatment. Standard preventive therapies can be offered but are often ineffective. The secondary NDPHs are discussed elsewhere (Chap. 17). ■ ■FURTHER READING Buse DC et al: Demographics, headache features, and comorbidity profiles in relation to headache frequency in people with migraine: Results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache 60:2340, 2020. Charles A, Pozo-Rosich P: Targeting calcitonin gene-related pep­ tide: A new era in migraine therapy. Lancet 394:1765, 2019. Cittadini E, Goadsby PJ: Hemicrania continua: A clinical study of 39 patients with diagnostic implications. Brain 133:1973, 2010. Cittadini E et al: Paroxysmal hemicrania: A prospective clinical study of thirty-one cases. Brain 131:1142, 2008. de Boer I et al: Advance in genetics of migraine. Curr Opin Neurol 32:413, 2019. Ferrari MD et al: Migraine. Nat Prim 8:2, 2022. Goadsby PJ et al: Pathophysiology of migraine: A disorder of sensory processing. Physiol Rev 97:553, 2017. Schankin CJ et al: “Visual snow”: A disorder distinct from persistent migraine aura. Brain 137:1419, 2014. Wei DY, Goadsby PJ: Cluster headache pathophysiology: Insights from current and emerging treatments. Nat Rev Neurol 17:308, 2021. Weng H et al: Phenotypic and treatment outcome data on SUNCT and SUNA, including a randomised placebo-controlled trial. Cephalalgia 38:1554, 2018. Gil D. Rabinovici, Peter A. Ljubenkov, William W. Seeley, Bruce L. Miller Alzheimer’s Disease ALZHEIMER’S DISEASE Approximately 55 million people across the world are living with dementia. Alzheimer’s disease (AD) is the most common cause of dementia, contributing to an estimated 60–70% of all cases. Total U.S. health care costs related to dementia care are estimated at $360 billion in 2024, translating into an average of ~$25,000 per patient. Further­ more, the emotional toll for family members and caregivers is immea­ surable. AD can manifest as early as the third decade of life, but it is the most common neuropathology contributing to dementia in the elderly. Patients most often present with an insidious loss of episodic memory followed by a slowly progressive dementia. In typical amnestic AD, brain atrophy begins in the medial temporal lobes before spreading to inferior temporal, lateral and medial parietal, and dorsolateral frontal cortices. Microscopically, there are widespread neuritic plaques con­ taining amyloid beta (Aβ), neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau filaments, and Aβ accumulation in blood vessel walls in cortex and leptomeninges (see “Pathology,” below). The identification of causative mutations and susceptibility genes for AD has provided a foundation for rapid progress in understanding the biological basis of the disorder. The major genetic risk factor for AD is the ε4 allele of the apolipoprotein E (ApoE) gene. Carrying one ε4 allele increases the risk for AD by two- to threefold in women, whereas car­ rying two alleles increases the risk 10- to 15-fold in both sexes. Rapid progress in the development of imaging, cerebrospinal fluid (CSF), and plasma biomarkers of Aβ and phosphorylated tau has enabled detec­ tion of AD pathologic hallmarks in living people, opening the door to early detection and intervention with biologically specific therapies. CHAPTER 442 Alzheimer’s Disease ■ ■CLINICAL MANIFESTATIONS The cognitive changes of AD tend to follow a characteristic pattern, beginning with memory impairment and progressing to deficits in executive, language, and visuospatial functions. Yet, ~20% of patients with AD present with nonmemory complaints such as word-finding, organizational, or navigational difficulty. In other patients, visual processing dysfunction (referred to as posterior cortical atrophy syn­ drome) or a progressive “logopenic” aphasia characterized by difficul­ ties with naming and repetition is the primary manifestation of AD for years before progressing to involve memory and other cognitive domains. Still other patients may present with an asymmetric akineticrigid-dystonic (“corticobasal”) syndrome or a dysexecutive/behavioral (i.e., “frontal” variant of AD). Depression, social withdrawal, and anxi­ ety occur in early disease stages and may represent a prodrome before cognitive symptoms are apparent. In early stages of typical amnestic AD, the memory loss may go unrecognized or be ascribed to benign forgetfulness of aging. The term subjective cognitive decline refers to self-perceived worsening in mem­ ory or other cognitive abilities that may not be noticeable to others or apparent on formal neuropsychological testing. Once the memory loss becomes noticeable to the patient and spouse and is confirmed on standardized memory tests, the term mild cognitive impairment (MCI) is often used. This construct provides useful prognostic information because ~50% of patients with MCI (roughly 12% per year) will prog­ ress to the dementia stage over 4 years. Increasingly, the MCI construct is being replaced by the notion of “early symptomatic AD” to signify that AD is considered the underlying disease (based on clinical or bio­ marker evidence) in a patient who remains functionally compensated. Even earlier in the course, “preclinical AD” refers to a person with bio­ marker evidence of amyloid pathology (with or without tau pathology) in the absence of symptoms. It is estimated that preclinical biomarker changes may precede clinical symptoms by 20 years or more, creating a window of opportunity for early-stage treatment and prevention trials. Emerging evidence suggests that partial and sometimes general­ ized seizures herald AD and can occur even prior to dementia onset, especially in younger patients and those with autosomal dominant AD-causing mutations. Eventually with AD, the cognitive problems begin to interfere with daily activities, such as keeping track of finances, following instructions on the job, driving, shopping, and housekeeping. Some patients are unaware of these difficulties (anosognosia), but most remain acutely attuned to their deficits in early disease stages. Changes in environment (travel, relocation, hospitalization) tend to destabilize the patient. Over time, patients become lost on walks or while driving. Social graces, routine behavior, and superficial conversation may be surprisingly intact, even into the later stages of the illness. In the middle stages of AD, the patient is unable to work, is easily lost and confused, and requires daily supervision. Language becomes impaired—first naming, then comprehension, and finally fluency. Word-finding difficulties and circumlocution can be evident in the early stages, even when formal testing demonstrates intact naming and fluency. Apraxia emerges, manifesting as trouble performing learned sequential motor tasks such as using utensils or appliances. Visuospa­ tial deficits begin to interfere with dressing, eating, or even walking, and patients fail to solve simple puzzles or copy geometric figures. Simple calculations and clock reading become difficult in parallel. PART 13 Neurologic Disorders In the late stages, some persons remain ambulatory, wandering aimlessly. Loss of judgment and reasoning is inevitable. Delusions are prevalent and usually simple, with common themes of theft, infidelity, or misidentification. Disinhibition and uncharacteristic belligerence may occur and alternate with passivity and withdrawal. Sleep-wake patterns are disrupted, and nighttime wandering becomes disturbing to the household. Some patients develop a shuffling gait with generalized muscle rigidity associated with slowness and awkwardness of move­ ment. Patients often look parkinsonian (Chap. 446) but rarely have a high-amplitude, low-frequency tremor at rest. There is a strong overlap between dementia with Lewy bodies (DLB) (Chap. 445) and AD, and some AD patients develop more classical parkinsonian features. In the end stages, patients with AD become rigid, mute, incontinent, and bedridden, and need help with eating, dressing, and toileting. Hyperactive tendon reflexes and myoclonic jerks (sudden brief con­ tractions of various muscles or the whole body) may occur spontane­ ously or in response to physical or auditory stimulation. Often death results from malnutrition, secondary infections, pulmonary emboli, heart disease, or, most commonly, aspiration. The typical duration of symptomatic AD is 8–10 years, but the course ranges from 1 to 25 years. For unknown reasons, some patients with AD show a steady decline in function while others have prolonged plateaus without major deterioration. An increased risk for seizures is also increasingly recognized as a feature of AD; different seizure types (both generalized and focal onset) have been reported, and these occur more frequently as the disease progresses. ■ ■DIAGNOSIS See also “Other Causes of Dementia,” below, and the general discus­ sion of dementia presented in Chap. 31. Early in the disease course, other etiologies of dementia should be excluded (see Tables 31-1, 31-3, and 31-4). Slowly progressive decline in memory and orientation, normal results on systemic laboratory tests, and a magnetic resonance imaging (MRI) or computed tomography (CT) scan showing only distributed or posteriorly predominant cortical and hippocampal atrophy (see below) are suggestive of AD. A clinical diagnosis of AD reached after careful evaluation is confirmed at autopsy ~70–80% of the time, with misdi­ agnosed cases usually resulting from limbic-predominant age-related TDP-43 encephalopathy (LATE) with or without hippocampal sclero­ sis, primary age-related tauopathy (PART), Lewy body disease (LBD), vascular pathology, or frontotemporal lobar degeneration (FTLD; Chap. 443). Simple clinical clues are useful in the differential diagnosis. Early prominent gait disturbance with only mild memory loss suggests vascular dementia or, rarely, normal pressure hydrocephalus (NPH), discussed later. Resting tremor with stooped posture, bradykinesia, and masked facies suggest PD (Chap. 446) or DLB (Chap. 445). When dementia occurs after a well-established diagnosis of PD, PD dementia (PDD) is usually the correct diagnosis, but many patients with this diagnosis will show a mixture of AD and LBD at autopsy. The early appearance of parkinsonian features in association with fluctuating alertness, visual hallucinations, or delusional misidentification sug­ gests DLB. Chronic alcoholism should prompt the search for vitamin deficiency. Loss of joint position and vibration sensibility accompanied by Babinski signs suggests vitamin B12 deficiency, especially in a patient with a history of autoimmune disease, small bowel resection or irradia­ tion, or veganism (Chap. 104). Early onset of a focal seizure suggests a metastatic or primary brain neoplasm (Chap. 95). Previous or ongoing depression raises suspicion for depression-related cognitive impair­ ment, although significant cognitive changes with depression is com­ mon and AD and DLB can feature a prodrome of depression or anxiety. A history of treatment for insomnia, anxiety, psychiatric disturbance, or epilepsy suggests chronic drug intoxication. Rapid progression over a few weeks or months associated with rigidity and myoclonus suggests Creutzfeldt-Jakob disease (CJD) (Chap. 449). Prominent behavioral changes with intact navigation and focal anterior-predominant atro­ phy on brain imaging are typical of FTD. A positive family history of dementia suggests either one of the familial forms of AD or one of the other genetic disorders associated with dementia, such as FTD (Chap. 443), Huntington’s disease (HD) (Chap. 447), prion disease (Chap. 449), or rare hereditary ataxias (Chap. 450). Electroencephalogram (EEG) is usually normal or shows nonspe­ cific slowing; prolonged EEG can be used to seek out intermittent nonconvulsive seizures. Structural neuroimaging studies (CT and MRI) do not show a single specific pattern with AD and may be normal early in the disease. As AD progresses, more distributed but usually posterior-predominant cortical atrophy becomes apparent, along with atrophy of the medial temporal memory structures (see Fig. 31-1). The main purpose of structural imaging is to exclude other disorders, such as primary and secondary neoplasms, vascular dementia, diffuse white matter disease, and normal-pressure hydrocephalus (NPH). Imaging also helps to dis­ tinguish AD from other degenerative disorders, such as frontotemporal dementia (FTD) (Chap. 443) or the prion disorder CJD (Chap. 449), which feature imaging patterns that are different from AD. Functional imaging studies, such as fluorodeoxyglucose (FDG) positron emission tomography (PET), reveal hypometabolism in the posterior temporalparietal cortex in AD (see Fig. 31-1). Amyloid PET imaging (e.g., with radiotracers [11C]PIB, [18F]flo­ rbetapir, [18F]florbetaben, or [18F]flutemetamol) confirms the pres­ ence of neuritic and diffuse Aβ plaques throughout the neocortex (Fig. 442-1). [18F]florbetapir, [18F]florbetaben, and [18F]flutemetamol are approved for clinical use in the United States and other countries. Although amyloid PET binding is detected in AD, ~25% of cognitively unimpaired older individuals also have positive scans, thought to rep­ resent preclinical disease and an increase in the risk of converting to clinical AD. Similarly, dementia due to a non-AD disorder can be the underlying etiology in a patient who tests positively on amyloid PET due to comorbid AD pathology. Amyloid PET ligands also bind to vas­ cular Aβ deposits in cerebral amyloid angiopathy (CAA) (Chap. 439). Therefore, clinical use of amyloid PET should be restricted to specific scenarios in which knowledge of amyloid status is expected to impact diagnosis and change management. For example, a negative amyloid PET scan in a patient with dementia makes an AD diagnosis unlikely. Conversely, a positive PET scan can be used to establish eligibility for novel amyloid-lowering therapies in a patient who meets the clinical criteria for treatment (see below). Tau PET radiotracers (e.g., [18F]flortaucipir, [18F]MK-6240, [18F] PI-2620) bind to the paired helical filaments that form neurofibril­ lary tangles and are primarily available in the research setting. [18F] Flortaucipir is also approved for clinical use in the United States “to estimate the density and distribution of aggregated tau neurofibrillary tangles in adult patients with cognitive impairment who are being evaluated for AD.” The pattern of binding is largely consistent with FIGURE 442-1  Molecular imaging of Alzheimer’s disease pathophysiology in an 81-year-old with mild Alzheimer’s disease. A. Aβ positron emission tomography (PET) with [11C]PIB reveals extensive radiotracer retention in neocortex, consistent with the known distribution of amyloid plaques. B. Tau PET with [18F]FTP shows asymmetric uptake predominantly in the left temporal cortex, consistent with intermediate-stage neurofibrillary tangles. Tracer uptake in midbrain and basal ganglia represents “off-target” (non-tau-related) tracer retention. C. Fluorodeoxyglucose (FDG)-PET reveals reduced tracer uptake in left greater than right temporal and parietal cortex, indicative of decreased synaptic activity. The pattern of hypometabolism corresponds more closely to the pattern of tau than amyloid deposition. A–C. Axial brain slices are shown in neurologic orientation. L, left; R, right; SUVR, standardized uptake value ratio, a quantitative measure of PET radiotracer retention. Braak neuropathologic staging of neurofibrillary tangles, with early retention in medial temporal regions, followed by spread into tempo­ roparietal and cingulate cortices, dorsolateral prefrontal regions, and ultimately, primary sensory and motor areas. However, tau PET signal lags behind neuropathologic staging of tangles due to limited sensitiv­ ity, and completely negative tau PET does not rule out early neurofi­ brillary pathology (Braak stages I–III). Notably, tau PET radiotracers developed to detect AD-related tau aggregation have limited utility in detecting aggregated tau in non-AD tauopathies (e.g., progressive supranuclear palsy [PSP], cortical basal degeneration [CBD], chronic traumatic encephalopathy [CTE]). Routine spinal fluid examination is generally normal, but CSF reductions in Aβ42 levels and the Aβ42/Aβ40 ratio correlate with amy­ loid deposition, and increases in phosphorylated tau (at residue 181 or 217; p-Tau181 or p-Tau217) detect AD-related changes in tau phosphorylation and secretion. On the other hand, increases in total tau levels represent a nonspecific finding seen in AD but also in other causes of neurodegeneration. Several CSF AD biomarker assays are now approved for clinical use in the United States and other countries. Decreases in the Aβ42/Aβ40 ratio or increases in the p-Tau181/Aβ42 ratio show higher agreement with amyloid PET results or AD neuropathol­ ogy than any single CSF analyte. Increase in the microtubule-binding region (MTBR) of tau containing the residue 243 (MTBR-tau243) is an experimental biomarker (not yet available in clinical practice) that bet­ ter correlates with neurofibrillary tangles and tau PET binding. In recent years, there has been significant progress in the develop­ ment of plasma measurements of Aβ  and phosphorylated tau with ultra-sensitive immunoassays or mass spectrometry. These bloodbased AD biomarkers are entering the clinical arena and will undoubt­ edly improve access, scalability, and cost-effectiveness of AD biomarker testing in diverse practice settings. Similar to CSF, decreases in the plasma Aβ42/Aβ40 ratio and increases in plasma p-Tau181, p-Tau217, or p-Tau231 show high concordance with positive amyloid PET scans and AD neuropathology at autopsy. In conjunction with a clinical evaluation, plasma assays may be sufficient to establish the diagnosis CHAPTER 442 Alzheimer’s Disease of AD for certain use cases, with the highest-performing assays show­ ing comparable diagnostic performance to CSF biomarkers in detect­ ing AD neuropathology. It is important to note that concentrations of Aβ and p-Tau in blood can be impacted by medical comorbidities (e.g., reduced creatinine clearance, elevated body mass index), which may lead to false-positive or false-negative results, particularly if values are near the test’s threshold. While positive AD imaging or fluid biomarkers are highly predic­ tive of underlying AD neuropathology, the question of whether AD represents a primary or contributing cause to an individual patient’s clinical presentation is not always straightforward. For example, in a patient who presents at a relatively young age with classical AD symptoms, compatible MRI changes, and positive CSF or amyloid PET, it is highly likely that AD neuropathology is the primary cause of cognitive decline. In an elderly patient with the same clinical profile, however, AD is still likely to be contributing to impairment, although a contribution of other non-AD co-pathologies is also likely. In the case of a patient who presents with classical FTD and positive AD biomarkers, FTLD pathology may be the primary cause of impairment, with the positive AD biomarkers indicating incidental preclinical AD. Conversely, a patient who presents with a clinical syndrome suggest­ ing AD but with negative AD biomarkers is likely to have a non-AD neuropathology as the primary cause of impairment. In older patients, age-related conditions that selectively target the medial temporal lobes, such as LATE or PART, can mimic AD clinically, and these should be high on the list of diagnostic possibilities in biomarker-negative indi­ viduals presenting with a progressive amnestic dementia. The proliferation of AD biomarkers has led to a movement to rede­ fine AD on purely biological grounds, based solely on positivity of AD biomarkers and independent of the clinical syndrome. In the Revised Criteria for Diagnosis and Staging of AD proposed by the Alzheimer’s Association, amyloid PET, CSF/plasma Aβ,  and p-Tau measures are considered “core 1 biomarkers” that are necessary and sufficient for the diagnosis of AD, irrespective of clinical symptoms. Tau PET is designated a “core 2” biomarker to be used for biomarker-based disease PART 13 Neurologic Disorders staging. Clinical staging is performed independent of biomarkers based on the level of functional impairment, spanning the range from asymp­ tomatic “preclinical” AD to severe dementia. ■ ■EPIDEMIOLOGY The most important risk factors for AD are increasing age and a positive family history. In the United States, ~10% of people over age 65 have AD, including 3% of people age 65–74, 17% of people age 75–84, and 32% of people age 85 and older. A positive family history of demen­ tia suggests a genetic contribution to AD, which is usually attributable to the apolipoprotein E (ApoE) ε4 risk allele. Autosomal dominant inheritance occurs in only 1–2% of patients and is typically accompa­ nied by a multigenerational history of early-onset dementia. Female sex is a risk factor independent of the greater longevity of females, and women who carry a single Apo ε4 allele are more susceptible than are male ε4 carriers. A history of mild-to-severe traumatic brain injury increases the risk for AD. AD is more common in groups with low edu­ cational attainment, but education influences test-taking ability, and it is clear that AD can affect persons of all intellectual levels. One study found that the capacity to express complex written language in early adulthood correlated with a decreased risk for AD. Similarly, illiteracy and low educational attainment are risk factors for dementia. Numer­ ous environmental factors, including aluminum, mercury, and viruses, have been proposed as causes of AD, but rigorous studies have failed to demonstrate a significant role for any of these exposures. Similarly, several studies suggest that the use of nonsteroidal anti-inflammatory agents is associated with a decreased risk of AD, but this risk has not been confirmed in large prospective studies. Vascular disease, and stroke in particular, seems to lower the threshold for the clinical expres­ sion of AD. Also, in many patients with AD, amyloid angiopathy can lead to microhemorrhages, large lobar hemorrhages, ischemic infarc­ tions most often in the subcortical white matter, or in rare cases an inflammatory leukoencephalopathy. Diabetes increases the risk of AD threefold. Elevated homocysteine and cholesterol levels; hypertension; obesity; hearing loss; tobacco use; diminished serum levels of folic acid; low dietary intake of fruits, vegetables, and red wine; sleep disorders; low levels of exercise; and air pollution exposure are all being explored as potential risk factors for dementia in general and AD in particular. ■ ■PATHOLOGY At autopsy, the earliest and most severe degeneration is usually found in the medial temporal lobe (entorhinal/perirhinal cortex and hippo­ campus), inferolateral temporal cortex, and nucleus basalis of Meynert. The characteristic microscopic findings are neuritic plaques and NFTs (Fig. 442-2). These lesions accumulate in small numbers during nor­ mal brain aging but dominate the picture in AD. The overall burden of AD neuropathologic changes can be graded based on the topography of Aβ plaques, the density of neuritic plaques, and the spatial extent of NFTs present. Increasing evidence suggests that soluble amyloid spe­ cies called oligomers may cause cellular dysfunction and represent the early toxic molecule in AD. Eventually, further amyloid polymerization and fibril formation lead to neuritic plaques, which contain a central core of amyloid, proteoglycans, ApoE, α-antichymotrypsin, and other proteins. Aβ is a protein of 39–42 amino acids that is derived pro­ teolytically from a larger transmembrane protein, amyloid precursor protein (APP), when APP is cleaved by β and γ secretases (Fig. 442-3). The normal function of the Aβ peptides is uncertain. APP has neuro­ trophic and neuroprotective properties. The plaque core is surrounded by a halo, which contains dystrophic, tau-immunoreactive neurites and activated microglia. The accumulation of Aβ in cerebral arterioles is termed amyloid angiopathy. NFTs are composed of silver-staining neu­ ronal cytoplasmic fibrils composed of abnormally phosphorylated tau protein; they appear as paired helical filaments by electron microscopy. Tau binds to and stabilizes microtubules, supporting axonal transport of organelles, glycoproteins, neurotransmitters, and other important cargoes throughout the neuron. Once hyperphosphorylated, tau can no longer bind properly to microtubules and redistributes from the axon to throughout the neuronal cytoplasm and distal dendrites, compromising function. Other theories emphasize that abnormal conformations of tau induce misfolding of native (unfolded) tau into pathologic conformations and that this prion-like templating process is responsible for tau spreading (Chap. 435). Finally, patients with AD often show comorbid LBD, TDP-43, or vascular pathology. Most pre­ vailing rodent models of AD involve expression of mutant transgenes that leads to Aβ42 accumulation in the absence of tauopathy. Even in these models, diminishing neuronal tau ameliorates cognitive defi­ cits and nonconvulsive seizures while Aβ42 continues to accumulate, A B FIGURE 442-2  Neuropathology of Alzheimer’s disease. A. Early neurofibrillary degeneration, consisting of neurofibrillary tangles and neuropil threads, preferentially affects the medial temporal lobes, especially the stellate pyramidal neurons that compose the layer 2 islands of entorhinal cortex, as shown using Gallyas silver staining. B. Higher magnification view reveals the fibrillar nature of tangles (arrows) and the complex structure of neuritic plaques (arrowheads), whose major component is Aβ (inset shows immunohistochemistry for Aβ). Scale bars are 500 μM in A, 50 μM in B, and 20 μM in B inset. Step 1: Cleavage by either α or β secretase APP β α Cell membrane γ β Secretase product α Secretase product Step 2: Cleavage by γ secretase P3 Aβ40 Aβ42 Nontoxic Nontoxic Toxic Amyloidogenic FIGURE 442-3  Amyloid precursor protein (APP) is catabolized by α, β, and γ secretases. A key initial step is the digestion by either β secretase (BASE) or α secretase (ADAM10 or ADAM17 [TACE]), producing smaller nontoxic products. Cleavage of the β secretase product by γ secretase (Step 2) results in either the toxic Aβ42 or the nontoxic Aβ40 peptide; cleavage of the α secretase product by γ secretase produces the nontoxic P3 peptide. Excess production of Aβ42 is a key initiator of cellular damage in Alzheimer’s disease (AD). Therapeutics for AD have focused on attempts to reduce accumulation of Aβ42 by antagonizing β or γ secretases, promoting α secretase, or clearing Aβ42 that has already formed by use of specific antibodies. raising hope for tau-lowering therapies in humans. Biochemically, AD is associated with a decrease in the cortical levels of several proteins and neurotransmitters, especially acetylcholine, its synthetic enzyme choline acetyltransferase, and nicotinic cholinergic receptors. Reduc­ tion of acetylcholine reflects degeneration of cholinergic neurons in the nucleus basalis of Meynert, located just below the thalamus and adja­ cent to the third ventricle, that project throughout the cortex. There is also noradrenergic and serotonergic depletion due to degeneration of upper brainstem nuclei such as the locus coeruleus (norepinephrine) and dorsal raphe (serotonin), where tau-immunoreactive neuronal cytoplasmic inclusions can be identified in early adult life, even in individuals lacking entorhinal cortex NFTs. ■ ■GENETIC CONSIDERATIONS Several genes play an important role in the pathogenesis of AD. One is the APP gene on chromosome 21. Adults with trisomy 21 (Down’s syndrome) consistently develop the typical neuropatho­ logic hallmarks of AD if they survive beyond age 40 years, and many develop a progressive dementia superimposed on their baseline defi­ cits. The extra dose of the APP gene on chromosome 21 is the initiating cause of AD in adult Down’s syndrome and results in excess cerebral amyloid production. Supporting this hypothesis, some families with early-age-of-onset familial AD (FAD) have point mutations in APP. Although very rare, these families were the first examples of singlegene autosomal dominant transmission of AD. Investigation of large families with multigenerational FAD led to the discovery of two additional AD-causing genes, the presenilins. Presenilin-1 (PSEN-1) is on chromosome 14 and encodes presenilin-1 protein (also known as S182). Mutations in this gene cause an earlyage-of-onset AD, with onset typically before age 60 and often before age 50, transmitted in an autosomal dominant, highly penetrant fashion. More than 100 different mutations have been found in the PSEN-1 gene in families from a wide range of ethnic backgrounds. Pre­ senilin-2 (PSEN-2) is on chromosome 1 and encodes the presenilin-2 protein (also known as STM2). A mutation in the PSEN-2 gene was first found in a group of American families with Volga German eth­ nic background. Mutations in PSEN-1 are much more common than those in PSEN-2. The presenilins are highly homologous and encode similar proteins that at first appeared to have seven transmembrane domains (hence the designation STM), but subsequent studies have suggested eight such domains, with a ninth submembrane region. Both presenilins are cytoplasmic neuronal proteins that are widely expressed throughout the nervous system. They are homologous to a cell-trafficking protein, sel 12, found in the nematode Caenorhabditis elegans. Prior to symptom onset, patients with mutations in the prese­ nilin genes have elevated CSF levels of Aβ42, and in cell culture, PSEN-1 mutations produce increased Aβ42. PSEN-1 is involved in the cleavage of APP at the γ secretase site, and mutations in either gene (PSEN-1 or APP) may disturb γ secretase cleavage. Mutations in PSEN-1 are the most common cause of early-age-of-onset FAD, representing 40–70% of all cases. Mutations in PSEN-1 tend to produce AD with an earlier age of onset (mean onset 45 years) and a shorter, more rapidly progres­ sive course (mean duration 6–7 years) than mutations in PSEN-2 (mean onset 53 years; duration 11 years). Although some carriers of PSEN-2 mutations have had onset of dementia after the age of 70, mutations in the presenilins rarely lead to late-age-of-onset AD. Clinical genetic testing for these uncommon mutations is available but likely to be revealing only in early-age-of-onset FAD and should be performed in association with formal genetic counseling. CHAPTER 442 The Apoε gene on chromosome 19 is involved in the pathogenesis of AD. The protein product, ApoE, participates in cholesterol transport (Chap. 419), and the gene has three alleles: ε2, ε3, and ε4. The Apo ε4 allele confers increased risk of AD in the general population, including sporadic and late-age-of-onset familial forms. Approximately 24–30% of the nondemented white population has at least one ε4 allele (12–15% allele frequency), and ~2% are ε4/ε4 homozygotes. Among patients with AD, 40–65% have at least one ε4 allele, a highly significant eleva­ tion compared with controls. The increased risk of AD associated with a single ε4 allele is approximately three times higher than in ε4 noncar­ riers (and higher in female than male heterozygotes), while the risk in ε4 homozygotes is 10–15 times higher than in ε4 noncarriers. The risk of AD in Apo ε4 carriers also varies by racial and ethnic background, with increased risk in East Asians and decreased risk in African Americans and Hispanics compared to whites. Additionally, many patients with AD have no ε4 allele, and ε4 carriers may never develop AD. Therefore, ε4 is neither necessary nor sufficient to cause AD. Nev­ ertheless, the Apo ε4 allele represents the most important genetic risk factor for sporadic AD and acts as a dose-dependent disease modifier, with each Apo ε4 allele associated with an approximately 10-year ear­ lier age of onset. The association between Apo ε4 and AD is strongest in patients between the ages of 60 and 85 and is weaker in younger patients and in the very old. The precise mechanisms through which Apo ε4 confers AD risk or hastens onset remain unclear, but ε4 leads to less efficient amyloid clearance and production of toxic fragments from cleavage of the molecule. Apo ε can be identified in neuritic plaques and may also be involved in neurofibrillary tangle formation, because it binds to tau protein. Interestingly, carriers of a point muta­ tion in Apo ε3, termed the Christchurch mutation, may be protective against tau aggregation and dementia despite having amyloid plaques. Apo ε4 decreases neurite outgrowth in dorsal root ganglion neuronal cultures, perhaps indicating a deleterious role in the brain’s response to injury. Increasing evidence suggests that the ε2 allele may reduce AD risk. The ε4 allele is also associated with increased risk for CAA, DLB, and vascular dementia, while its association with FTD is uncertain. Some evidence suggests that ε4 may worsen the expression of non-AD neurodegenerative disorders, as well as following head trauma and other brain injuries. Use of Apo ε4 testing in AD diagnosis remains controversial because its predictive value remains unclear and many individuals with the ε4 allele will never develop dementia. However, clinical Apo ε4 testing is recommended for patients who are being evaluated for treatment with anti-Aβ monoclonal antibodies in order to determine their risk of adverse effects (see below). ApoE genotyping is available in some straight-to-consumer genetic testing platforms. Alzheimer’s Disease Additional genes are also likely to be involved in AD, especially as minor risk alleles for sporadic forms of the disease. Genome-wide asso­ ciation studies have identified >40 additional common genetic variants that, individually, have small (i.e., odds ratios ~1.1–1.2 or 0.8–0.9) impact on the risk of AD. Implicated genes converge in biological path­ ways related to innate immunity, lipid metabolism, and synaptic func­ tion. Examples include the clusterin (CLU), phosphatidylinositol-binding clathrin assembly protein (PICALM), and complement component (3b/4b) receptor 1 (CR1) genes, among others. CLU may play a role in synapse turnover, PICALM participates in clathrin-mediated endocytosis, and CR1 may be involved in amyloid clearance or synapse loss through the complement pathway. TREM2 is a gene involved with inflammation that increases the likelihood of dementia. Homozygous mutation carriers develop a frontal dementia with bone cysts (Nasu-Hakola disease), whereas heterozygotes are predisposed to the development of AD. TREM2 risk alleles are rare but have strong effects, with odds ratios estimated at 3–4 for developing clinical AD. Polygenic hazard scores that integrate the presence of multiple risk and protective alleles may be useful in predicting an individual’s lifetime risk of developing AD. The vast majority of AD genetic studies have focused on white populations of European descent, and much less is known about the genetics of AD in nonwhite populations. TREATMENT Alzheimer’s Disease PART 13 Neurologic Disorders The management of AD requires a multidomain approach that includes neurotransmitter-based therapies to manage symptoms, emerging molecular therapies that target AD pathophysiology with the goal of slowing disease progression and clinical decline, and ongoing patient and caregiver education. NEUROTRANSMITTER-BASED THERAPIES Donepezil (target dose, 10 mg daily), rivastigmine (target dose, 6 mg twice daily or 9.5-mg patch daily), galantamine (target dose, 24 mg daily, extended-release), and memantine (target dose, 10 mg twice daily) are approved by the U.S. Food and Drug Administration (FDA) for the treatment of AD. Dose escalations for each of these medications must be carried out over 4–6 weeks to minimize side effects. The pharmacologic action of donepezil, rivastigmine, and galantamine is inhibition of the cholinesterases, primarily acetylcholinesterase, with a resulting increase in cerebral acetylcholine levels. Memantine appears to act by blocking overexcited N-methyl-d-aspartate (NMDA) glutamate receptors. Double-blind, placebo-controlled, crossover studies with cholinesterase inhibitors (in mild-to-severe AD dementia) and memantine (in moderateto-severe AD dementia) have shown them to be associated with modestly improved caregiver ratings of patients’ functioning and with an apparent decreased rate of decline in cognitive test scores over periods of up to 3 years. The average patient on an anticholinesterase inhibitor maintains their mini-mental state examination (MMSE) score for close to a year, whereas a placebo-treated patient declines 2–3 points over the same time period. Memantine, used in conjunction with cholinesterase inhibitors or by itself, slows cognitive deterioration and decreases caregiver burden for patients with moderate to severe AD, but is not approved for mild AD. Neither cholinesterase inhibitors nor memantine have proven efficacious in patients with MCI, though the clinical trials lacked biomarkers at the time, and in retrospect likely included a mix of patients with AD and non-AD-related memory impairment. Cholinesterase inhibitors are easy to administer, and their major side effects are gastrointestinal symptoms (nausea, diarrhea, cramps), altered sleep with unpleasant or vivid dreams, bradycardia (usually benign), and muscle cramps. Potential side effects associated with memantine include constipation, dizziness, headache, and somnolence. A common approach to AD drug therapy is to initiate a cholinesterase inhibitor for a patient diagnosed with mild AD dementia and to add memantine when patients enter the moderate stage of disease. Cholinesterase inhibitors may also be effective in treating delusions and hallucinations, while memantine can reduce agitation. THERAPIES TARGETING AMYLOID-b A novel class of antiamyloid monoclonal antibodies has recently been approved for treatment of early clinical stages of AD. These drugs promote clearance of target Aβ epitopes, substantially lower amyloid plaque burden on amyloid PET, and comprise the first class of disease-modifying therapies to receive FDA approval for treatment of AD. Lecanemab (which targets Aβ protofibrils) and donanemab (which targets a pyroglutamate form of Aβ in plaques) are fully FDA approved for clinical use in early-stage AD based on evidence of clinical efficacy in phase 3, double-blinded, randomized, placebo-controlled clinical trials. Lecanemab is delivered as an intravenous infusion every 2 weeks, while donanemab is administered intravenously monthly. A third antibody, aducanumab, was the first to receive accelerated FDA approval based on reduction of amyloid PET signal, but evidence of clinical efficacy was ambiguous, and ultimately this drug has been removed from clinical use. All three of these antibodies lead to robust reductions in amyloid burden as measured by PET. Interestingly, drug trials of Aβ-targeting antibodies that showed less robust amyloid lowering on PET (e.g., solanezumab, crenezumab, gantenerumab) did not find a clinical benefit. Antiamyloid antibody therapy is currently restricted to patients with MCI or mild dementia and biomarker confirmation of Aβ pathology by PET or CSF. Clinical trials are underway for cognitively unimpaired individuals with biomarker evidence of Aβ pathology (i.e., preclinical AD). Patients with clinical features suggestive of non-AD causes of cognitive decline were excluded from the pivotal clinical trials and should not be treated, regardless of biomarker status. In Clarity-AD, a phase 3, randomized, placebo-controlled trial of lecanemab in patients with early symptomatic AD, patients who received lecanemab for 18 months experienced an average 27% slowing in their rate of clinical decline compared to placebo, as measured by change in the Clinical Dementia Rating Scale sum of boxes score (CDR-SB), a clinical scale that measures cognition and function and was the study’s primary outcome. Similar slowing of decline was reported on all secondary cognitive and functional outcomes. In TRAILBLAZER-ALZ2, a phase 3, randomized, placebocontrolled trial of donanemab in early symptomatic AD, patients on active treatment showed 22% slowing on the integrated Alzheimer Disease Rating Scale (iADRS; primary outcome) and 28% slowing on the CDR-SB (secondary outcome) over 76 weeks compared to placebo, with similar effects on all other secondary clinical endpoints. Patients in TRAILBLAZER-ALZ2 were stratified by tau PET at baseline, with patients with low-medium tau PET at trial entry showing the greatest clinical benefit (35% slowing on iADRS, 36% slowing on CDR-SB), suggesting that amyloid lowering may particularly benefit patients in earlier stages of tau spread. The duration of treatment was titrated based on amyloid PET response, with patients switched from donanemab to placebo when complete amyloid clearance was seen on PET. These findings suggest that limited-duration treatment until PET clearance may be sufficient to derive a robust clinical response. Given these results, future clinical practice may leverage baseline biomarkers of tau burden to identify patients more likely to benefit from antiamyloid therapy, whereas longitudinal biomarkers of Aβ burden may help to define the necessary duration of therapy. Antiamyloid antibodies are associated with significant potential side effects, including infusion reactions and a form of secondary brain inflammation and hemorrhage, collectively referred to as amyloid-related imaging abnormalities (ARIA) (Fig. 442-4). Rates of infusion reactions in the active treatment arms of the phase 3 trials were 26% for lecanemab and 9% for donanemab. ARIA-E manifests as focal areas of edema or sulcal effusions, detected by T2/fluid-attenuated inversion recovery (FLAIR) hyperintensities on MRI. ARIA-H typically manifests as microbleeds or superficial siderosis detected by gradient echo (GRE) or susceptibility-weighted imaging (SWI) MRI sequences, although lobar hemorrhages can rarely occur. Both ARIA-E and ARIA-H are thought to be related to CAA. Spontaneous ARIA-H occurs frequently in AD, but spontaneous ARIA-E (also known as inflammatory CAA) occurs very rarely in lieu of antiamyloid therapies. In the phase 3 trials, overall rates of ARIA-E were 13% for lecanemab and 24% for donanemab, whereas ARIA-H rates were 17% for lecanemab and 31% for donanemab. Approximately 75% of ARIA cases were asymptomatic and detected on safety MRI scans conducted throughout the study. When present, Radiographic Staging of ARIA-H Radiographic Staging of ARIA-E (Right) (Left) Mild ARIA-E FLAIR hyperintensity confined to sulcus and/or cortex/subcortex white matter in one location <5 cm A B Moderate ARIA-E FLAIR hyperintensity 5 to 10 cm in single greatest dimension, or more than 1 site of involvement, each measuring <10 cm FLAIR SWI C Severe ARIA-E FLAIR hyperintensity measuring >10 cm with associated gyral swelling and sulcal effacement. One or more separate/independent sites of involvement may be noted. FLAIR T2* FIGURE 442-4  Radiographic staging of amyloid-related imaging abnormalities (ARIAs). A. Axial fluid-attenuated inversion recovery (FLAIR) image depicting radiographically mild ARIA-E in an asymptomatic patient receiving lecanemab treatment. Cortical edema and adjacent sulcal effacement are present in a right superior frontal region with <5 cm of involvement. B. Axial susceptibility-weighted imaging (SWI) depicting radiographically mild ARIA-H (including right anterior cingulate and right parietal lobar microhemorrhages) in an asymptomatic patient receiving lecanemab. C–D. Axial FLAIR and T2* sequence images depicting radiographically severe ARIA-E and radiographically severe ARIA-H, respectively, in a patient presenting with focal neurologic symptoms localized to the left occipital lobe during aducanumab treatment. FLAIR imaging reveals multiple regions of cortical edema, with adjacent subcortical edema and sulcal effacement. T2* reveals multiple regions of cortical siderosis, including in bilateral frontal and posterior regions of concomitant ARIA-E, as well as numerous lobar microhemorrhages. ARIA symptoms are typically mild and nonspecific (e.g., headache, dizziness, greater confusion). However, severe symptoms, including seizures, stroke-like episodes, malignant hypertension, and (very rarely) death can occur. The risk of ARIA increases with each copy of the Apo ε4 allele and is highest in Apo ε4 homozygotes. Apo ε4 homozygotes are also at increased risk of symptomatic, severe, and recurrent ARIA, leading the FDA to issue a box warning for ε4 homozygotes in the prescribing information for both lecanemab and donanemab. Clinical Apo ε genotyping is recommended prior to initiating anti-Aβ antibody therapy to adequately inform shared decision-making about treatment risks and benefits. In a clinical setting, uncontrolled hypertension, radiographic evidence of extensive CAA (>4 brain microhemorrhages or ≥1 region of cortical siderosis), and other factors that may increase ARIA risk are regarded as contraindications for antiamyloid anti­ bodies. Limited data are available about the safety of anticoagulants in the context of anti-Aβ therapy, with the concern that anticoagu­ lation may increase the risk of ARIA-H. Expert recommendations suggest excluding patients on anticoagulants from treatment until more safety data are available. Patients treated with a single anti­ platelet agent do not appear to be at higher risk for ARIA. Patients treated with lecanemab or donanemab should be moni­ tored for ARIA with multiple surveillance MRIs during the first 6–12 months of treatment, following the schedule recommended by the FDA in the prescribing information. T2/FLAIR and GRE/ SWI sequences should be performed, and patients should ideally be imaged longitudinally on the same MRI scanner and sequences to allow optimal comparisons between time points. An urgent MRI should be performed whenever ARIA is clinically suspected based on symptoms. The severity of ARIA is graded based on radiographic criteria, as well as the presence and severity of clinical Mild ARIA-H Includes one or more of the following: • ≤4 new incident microhemorrhages • 1 new focal area of superficial siderosis Moderate ARIA-H Includes one or more of the following: • 5 to 9 new incident microhemorrhage • 12 focal areas of superficial siderosis CHAPTER 442 D Severe ARIA-H Alzheimer’s Disease Includes one or more of the following: • 10 or more microhemorrhages • >2 focal areas of superficial siderosis • ≥1 macrohemorrhage(s) (≥10 cm) symptoms. Patients can be treated safely through asymptomatic and radiographically mild ARIA, provided MRI scans are performed monthly to monitor evolution. Symptomatic or radiographically moderate to severe ARIA should lead to temporary suspension of treatment until ARIA-E resolves and ARIA-H stabilizes. Permanent cessation of treatment is recommended if symptoms are severe, ARIA has recurred more than twice, ARIA-H has led to macrohe­ morrhage or >10 additional microhemorrhages since treatment ini­ tiation, or more than one area of superficial siderosis has emerged. Cases of catastrophic, multifocal brain hemorrhages due to severe ARIA-E and ARIA-H leading to death have been reported in patients receiving antiamyloid antibody therapy while being treated with thrombolytic medications (e.g., tissue plasminogen activa­ tor) for acute stroke. When presenting with stroke-like symptoms, patients receiving anti-Aβ monoclonal antibodies should receive an immediate MRI to differentiate acute stroke from ARIA. Until more data are available, treatment with lecanemab or donanemab should therefore be considered a contraindication to peripheral thrombolysis. It is current practice at our institution to restrict use of antiamy­ loid monoclonal antibodies to patients with biomarker-confirmed Aβ pathology and early symptomatic disease, including MCI or mild AD dementia, who are not expected to require anticoagulant therapy. We corroborate interpretation of Aβ biomarkers and scru­ tinize baseline brain MRI for disqualifying lesions that may increase risk of ARIA and intracerebral hemorrhage, such as radiographic evidence of extensive CAA. All patients must know their ApoE allele status and understand their associated ARIA risk before start­ ing treatment. Apo ε4 homozygous patients may elect to pursue therapy at our institution after careful consideration of their ARIA risk, although several institutions do prohibit or carefully restrict use in Apo ε4 homozygous patients. Finally, and consistent with consensus clinical practice, all patients who receive therapy must undergo regular MRI safety screening to rule out ARIA. PATIENT AND CAREGIVER EDUCATION Building rapport with the patient, family members, and other care­ givers is essential. In the early stages of AD, memory aids such as notebooks and posted daily reminders can be helpful. Family mem­ bers should emphasize activities that are pleasant while curtailing those that increase stress on the patient. Kitchens, bathrooms, stair­ ways, and bedrooms need to be made safe, and eventually, patients will need to stop driving. Patients can be encouraged to engage in lifestyle modifications that may be protective against aging and neurodegeneration, such as physical, cognitive, and social activity; vascular risk factor modification; healthy sleep habits; and dietary modifications (e.g., Mediterranean or Dietary Approaches to Stop Hypertension diets). Loss of independence and change of environ­ ment may worsen confusion, agitation, and anger. Communication and repeated calm reassurance are necessary. Caregiver “burnout” is common, often resulting in nursing home placement of the patient or new health problems for the caregiver. Respite breaks for the caregiver help to maintain a successful long-term thera­ peutic milieu. Use of adult day care centers can be helpful. Local and national support groups, such as the Alzheimer’s Association and the Family Caregiver Alliance, are valuable resources. Internet access to these resources has become available to clinicians and families in recent years. PART 13 Neurologic Disorders ADDITIONAL THERAPIES Mild to moderate depression is common in the early stages of AD and may respond to antidepressants or cholinesterase inhibitors. Selective serotonin reuptake inhibitors (SSRIs) are commonly used due to their low anticholinergic side effects (e.g., escitalopram, tar­ get dose, 5–10 mg daily). Seizures can be treated with levetiracetam unless the patient had a different regimen that was effective prior to the onset of AD. Agitation, insomnia, hallucinations, and bel­ ligerence are especially troublesome characteristics of some AD patients, and these behaviors can lead to nursing home placement. The newer generation of atypical antipsychotics, such as risperi­ done, quetiapine, and olanzapine, are being used in low doses to treat these neuropsychiatric symptoms. Brexpiprazole, an atypical antipsychotic that acts on noradrenergic, serotonergic, and dopa­ minergic neurotransmitter systems, is the only drug to receive FDA approval for treatment of agitation in AD, based on a 12-week, double-blinded, randomized, placebo-controlled trial. The few con­ trolled studies comparing drugs against behavioral intervention in the treatment of agitation suggest mild efficacy with significant side effects related to sleep, gait, and cardiovascular complications, including an increased risk of death. Antipsychotics carry a black box FDA warning for use in elderly patients with dementia and thus should be prescribed only with caution; however, careful, daily, non­ pharmacologic behavior management is often not available, ren­ dering medications necessary for some patients. Medications with strong anticholinergic effects should be vigilantly avoided, includ­ ing prescription and over-the-counter sleep aids (e.g., diphenhydr­ amine) or incontinence therapies (e.g., oxybutynin). Several commonly used medications and supplements, includ­ ing estrogen hormone replacement therapy, statins, vitamin E, and ginkgo biloba, appeared to be associated with a decreased risk of AD in epidemiologic or observational studies but did not show efficacy in prospective, randomized, double-blinded, placebo-con­ trolled trials. Many vitamins and dietary supplements are marketed directly to consumers as “memory enhancing” or protective against AD without clinical evidence. Patients and families may come across anecdotal reports of “miraculous” responses to aggressive treatments such as anti-interferon intrathecal infusions, intrave­ nous immunoglobulin, antibiotics (purportedly to treat Lyme dis­ ease or another questionable infection), metal chelation, and stem cell therapies, but there is no scientific evidence to support use of any of these approaches to treating AD and significant concern for harm. EXPERIMENTAL THERAPIES The design of AD clinical trials has been transformed by the avail­ ability of PET, CSF, and more recently blood-based biomarkers of Aβ and tau. Many trials now require biomarker evidence of AD for trial inclusion. Biomarkers help assess target engagement (e.g., changes in Aβ biomarkers in an antiamyloid trial) or modifica­ tion of downstream disease pathophysiology (e.g., changes in tau biomarkers in an antiamyloid trial), with the pivotal trials leading to approval of lecanemab and donanemab being emblematic of this novel approach. Increasingly, many trials have shifted toward enrolling patients in the asymptomatic (preclinical) or very early symptomatic stages of AD, using positive biomarkers as the primary inclusion criterion. Primary (biomarker negative) and secondary (biomarker positive but no symptoms) prevention trials are under­ way in autosomal dominant mutation carriers, Apo ε4 homozy­ gotes, and even in the normally aging population. Active vaccination against Aβ is another approach that aims to promote immune-mediated clearance of amyloid pathology. The first Aβ42 vaccine trial in humans was aborted after a minority of patients developed meningoencephalitis, but subsequent trials with less immunogenic formulations have shown more favorable safety profiles. Oral drugs that inhibit β and γ secretase reduce the cleavage of APP to Aβ42 and showed promise in ameliorating pathology and behavioral changes in AD transgenic mice. Unfortunately, placebo-controlled trials failed to show clinical efficacy, and trials of β secretase inhibitors, in particular, found significant worsening of cognition in treated patients versus placebo, although fortu­ nately, this effect proved transient after discontinuing the drug. It is unclear whether toxicity of β and γ secretase inhibitors was directly related to changes in Aβ metabolism or to “off-target” drug effects. Monoclonal antibodies directed against phosphorylated tau are in earlier stages of development. These antibodies aim to prevent the transsynaptic spread of tau and have proven effective in tau transgenic mice. Safety profiles in human studies have proven favorable thus far, but clinical results have been lacking. Lower­ ing of tau expression via antisense oligonucleotides (ASOs) or small interfering RNA is a compelling therapeutic strategy that rescues most elements of the AD phenotype in AD transgenic mice. A recent phase 1 trial of the tau-targeting ASO MAPTRX, delivered intrathecally, showed the treatment to be well tolerated, with significant lowering of tau biomarkers in CSF and PET. A phase 2 clinical trial is currently underway. Additional therapeutic approaches targeting tau include active immunization; inhibition of tau phosphorylation, acetylation, and aggregation; and microtubule stabilization. Other druggable pathways represented in the AD drug development pipeline include those targeting neuroinflammation, metabolism/bioenergetics, synaptic plasticity, neuroprotection, and neurotransmitter-based cognitive enhancement or treatment of neuropsychiatric symptoms. A general approach to the symptomatic management of dementia is presented in Chap. 31. OTHER CAUSES OF DEMENTIA FTD (Chap. 443), vascular dementia (Chap. 444), DLB (Chap. 445), and prion diseases (Chap. 449) are covered in dedicated chapters. Prion diseases such as CJD are rare neurodegenerative conditions (prevalence ~1 per million) that produce dementia. CJD is a rapidly progressive disorder associated with dementia, focal cortical signs, rigidity, and myoclonus, causing death <1 year after first symptoms appear. The rapidity of progression seen with CJD is uncommon in AD so that the distinction between the two disorders is usually straightforward, although AD can on occasion present as a rap­ idly progressive dementia. In general, CBD (Chap. 443) and DLB (Chap. 445), more rapid degenerative dementias with prominent movement abnormalities, are more likely to be mistaken for CJD. The differential diagnosis for CJD includes other rapidly progres­ sive dementing conditions such as viral or bacterial encephalitides, Hashimoto’s encephalopathy, central nervous system (CNS) vasculitis, lymphoma, or paraneoplastic/autoimmune syndromes (Chap. 99). The markedly abnormal periodic complexes on EEG and cortical ribboning and basal ganglia hyperintensities on diffusion-weighted imaging or FLAIR MRI are diagnostic features of CJD, although rarely, prolonged focal or generalized seizures can produce a similar imaging appearance. Huntington’s disease (HD) (Chap. 447) is an autosomal dominant degenerative brain disorder. HD clinical hallmarks include chorea, behavioral disturbance, and executive impairment. Symptoms typi­ cally begin in the fourth or fifth decade, but there is a wide range, from childhood to >70 years. Memory is frequently not impaired until late in the disease, but attention, judgment, self-awareness, and executive functions are often deficient at an early stage. Depression, apathy, social withdrawal, irritability, and intermittent disinhibition are com­ mon. Delusions and obsessive-compulsive behavior may occur. Disease duration is variable but typically lasts ~15 years. NPH is a relatively uncommon but treatable syndrome. The clinical, physiologic, and neuroimaging characteristics of NPH must be care­ fully distinguished from those of other dementias associated with gait impairment. Historically, many patients treated for NPH have suffered from other dementias, particularly AD, vascular dementia, DLB, and PSP (Chap. 443). For NPH, the clinical triad includes an abnormal gait (ataxic or apractic), dementia (usually mild to moderate, with an emphasis on executive impairment), and urinary urgency or inconti­ nence. Neuroimaging reveals enlarged lateral ventricles (hydrocepha­ lus) with little or no cortical atrophy, although the sylvian fissures may appear propped open (so-called “boxcarring”), which can be mistaken for perisylvian atrophy. Crowding of dorsal frontal-parietal gyri helps distinguish NPH from other movement disorders, such as PSP and CBD, in which dorsal atrophy with sulcal widening is common. NPH is a communicating hydrocephalus with a patent aqueduct of Sylvius (see Fig. 31-3), in contrast to aqueductal stenosis, in which the aqueduct is small. Lumbar puncture opening pressure falls in the high-normal range, and the CSF protein, glucose, and cell counts are normal. NPH may be caused by obstruction to normal CSF flow over the cerebral convexities and delayed resorption into the venous system. The indo­ lent nature of the process results in enlarged lateral ventricles with rela­ tively little increase in CSF pressure. Presumed edema, stretching, and distortion of subfrontal white matter tracts may lead to clinical symp­ toms, but the precise underlying pathophysiology remains unclear. Some patients provide a history of conditions that produce meningeal scarring (blocking CSF resorption) such as previous meningitis, sub­ arachnoid hemorrhage, or head trauma. Others with longstanding but asymptomatic congenital hydrocephalus may have adult-onset dete­ rioration in gait or memory that is confused with NPH. In contrast to AD, the patient with NPH complains of an early and prominent gait disturbance without cortical atrophy on CT or MRI. Numerous attempts to improve NPH diagnosis with various spe­ cial studies and predict the success of ventricular shunting have been undertaken. These tests include radionuclide cisternography (showing a delay in CSF absorption over the convexity) and various efforts to monitor and alter CSF flow dynamics, including a constant-pressure infusion test. None has proven to be specific or consistently useful. A transient improvement in gait or cognition may follow lumbar punc­ ture (or serial punctures) with removal of 30–50 mL of CSF, but this finding has also not proved to be consistently predictive of postshunt improvement. Perhaps the most reliable strategy is a period of close inpatient evaluation before, during, and after lumbar CSF drainage. Occasionally, when a patient with AD presents with gait impairment (at times due to comorbid subfrontal vascular injury) and absent or only mild cortical atrophy on CT or MRI, distinguishing NPH from AD can be challenging. Hippocampal atrophy on MRI favors AD, whereas a characteristic “magnetic” gait with external hip rotation, low foot clearance, and short strides, along with prominent truncal sway or instability, favors NPH. The diagnosis of NPH should be avoided when hydrocephalus is not detected on imaging studies, even if the symptoms otherwise fit. Thirty to fifty percent of patients identified by careful diagnosis as having NPH will improve with ventricular shunting. Gait may improve more than cognition, but many reported failures to improve cognitively may have resulted from comorbid AD. Importantly, the presence of positive CSF AD biomarkers or amyloid PET is associated with lower likelihood of response to shunting. Shortlasting improvement is common. Patients should be carefully selected for shunting, because subdural hematoma, infection, and shunt failure are known complications and can be a cause for early nursing home placement in an elderly patient with previously mild dementia. Intracranial hypotension, sometimes called sagging brain syndrome, is a disorder caused by low CSF pressure, leading to downward pres­ sure on the subcortical structures and disruption of cerebral function. It presents in a variable manner with headache, often exacerbated by coughing or a Valsalva maneuver or by moving from lying to stand­ ing. Other common symptoms include dizziness, vomiting, disruption of sleep-wake cycles, and sometimes a progressive behavioral variant FTD-like syndrome (Chap. 443). Although sometimes idiopathic, this syndrome can be caused by CSF leaks secondary to lumbar puncture, head trauma, or spinal cord arachnoid cysts. Treatment consists of finding and patching the CSF leak. CHAPTER 442 Dementia can accompany chronic alcoholism (Chap. 464) and may result from associated malnutrition, especially of B vitamins, par­ ticularly thiamine. Other poorly defined aspects of chronic alcohol­ ism may, however, also produce cerebral damage. A rare idiopathic syndrome of dementia and seizures with degeneration of the corpus callosum has been reported primarily in male Italian red wine drinkers (Marchiafava-Bignami disease). Alzheimer’s Disease Thiamine (vitamin B1) deficiency causes Wernicke’s encephalopa­ thy (Chap. 318). The clinical presentation is usually a malnourished patient (frequently but not necessarily alcoholic) with confusion, ataxia, and diplopia resulting from inflammation and necrosis of peri­ ventricular midline structures, including dorsomedial thalamus, mam­ millary bodies, midline cerebellum, periaqueductal gray matter, and trochlear and abducens nuclei. Damage to the dorsomedial thalamus correlates most closely with the memory loss. Prompt administration of parenteral thiamine (100 mg intravenously for 3 days followed by daily oral dosage) may reverse the disease if given within the first days of symptom onset. Prolonged untreated thiamine deficiency can result in an irreversible and profound amnestic syndrome (Korsakoff’s syndrome) or even death. In Korsakoff’s syndrome, the patient is unable to recall new informa­ tion despite normal immediate memory, attention span, and level of consciousness. Memory for new events is seriously impaired, whereas knowledge acquired prior to the illness remains relatively intact. Patients are easily confused, disoriented, and cannot store information for more than a few minutes. Superficially, they may be conversant, engaging, and able to perform simple tasks and follow immediate com­ mands. Confabulation is common, although not always present. There is no specific treatment because the previous thiamine deficiency has produced irreversible damage to the medial thalamic nuclei and mam­ millary bodies. Mammillary body atrophy may be visible on MRI in the chronic phase (see Fig. 318-6). Vitamin B12 deficiency, as can occur in pernicious anemia, causes a megaloblastic anemia and may also damage the nervous system (Chaps. 104 and 453). Neurologically, it most commonly produces a spinal cord syndrome (myelopathy) affecting the posterior columns (loss of vibration and position sense) and corticospinal tracts (hyper­ active tendon reflexes with Babinski signs); it also damages peripheral nerves (neuropathy), resulting in sensory loss with depressed tendon reflexes. Damage to myelinated axons may also cause dementia. The mechanism of neurologic damage is unclear but may be related to a deficiency of S-adenosyl methionine (required for methylation of myelin phospholipids) due to reduced methionine synthase activity or accumulation of methylmalonate, homocysteine, and propionate, providing abnormal substrates for fatty acid synthesis in myelin. Use of histamine blockers or metformin, vegan diets, autoimmunity against gastric parietal cells, and various causes of malabsorption are the typical causes for vitamin B12 deficiency. The neurologic sequelae of vitamin B12 deficiency may occur in the absence of hematologic mani­ festations, making it critical to avoid using the complete blood count (CBC) and blood smear as a substitute for measuring B12 blood levels. Treatment with parenteral vitamin B12 (1000 μg intramuscularly daily for a week, weekly for a month, and monthly for life for pernicious anemia) stops progression of the disease if instituted promptly, but complete reversal of advanced nervous system damage will not occur. Deficiency of nicotinic acid (pellagra) is associated with skin rash over sun-exposed areas, glossitis, and angular stomatitis (Chap. 344). Severe dietary deficiency of nicotinic acid along with other B vitamins such as pyridoxine may result in spastic paraparesis, peripheral neu­ ropathy, fatigue, irritability, and dementia. This syndrome has been seen in prisoners of war and in concentration camps but should be con­ sidered in any malnourished individual. Low serum folate levels appear to be a rough index of malnutrition, but isolated folate deficiency has not been proved as a specific cause of dementia. CNS infections usually cause delirium and other acute neurologic syndromes. However, some chronic CNS infections, particularly those associated with chronic meningitis (Chap. 144), may produce a dementing illness. The possibility of chronic infectious menin­ gitis should be suspected in patients presenting with a dementia or behavioral syndrome, who also have headache, meningismus, cranial neuropathy, and/or radiculopathy. Between 20 and 30% of patients in the advanced stages of HIV infection become demented (Chap. 208). Cardinal features include psychomotor retardation, apa­ thy, and impaired memory. This syndrome may result from secondary opportunistic infections but can also be caused by direct infection of CNS neurons with HIV. Neurosyphilis (Chap. 187) was a common cause of dementia in the preantibiotic era; it is now uncommon but can still be encountered in patients with multiple sex partners, particularly among patients with HIV. Characteristic CSF changes consist of pleo­ cytosis, increased protein, and a positive Venereal Disease Research Laboratory (VDRL) test. The recent SARS-CoV-2 pandemic was associated in some individuals with persistent postrecovery changes in memory, executive, and other cognitive functions; responsible mechanisms might include effects of inflammation, multiorgan system failure, or virus-associated vascular injury. PART 13 Neurologic Disorders Primary and metastatic neoplasms of the CNS (Chap. 95) usually produce focal neurologic findings and seizures rather than dementia, but if tumor growth begins in the frontal or temporal lobes, the initial manifestations may be memory loss or behavioral changes. An auto­ immune, sometimes paraneoplastic, syndrome of dementia associated with occult carcinoma (often small-cell lung cancer) is termed limbic encephalitis. In this syndrome, confusion, agitation, seizures, poor memory, emotional changes, and frank dementia may occur. Paraneo­ plastic encephalitis associated with NMDA receptor antibodies presents as a progressive psychiatric disorder with memory loss and seizures; affected patients are often young women with ovarian teratoma. Autoimmune etiologies also include antibodies targeting leucine-rich glioma-inactivated 1 (LGI1; faciobrachial dystonic seizures); contactin- associated protein-like 2 (Caspr2; insomnia, ataxia, myotonia); and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor (limbic encephalitis with relapses), among others (Chap. 99). A nonconvulsive seizure disorder (Chap. 436) may underlie a syn­ drome of confusion, clouding of consciousness, and garbled speech. Often, psychiatric disease is suspected, but an EEG demonstrates the epileptic nature of the illness. If recurrent or persistent, the condition may be termed complex partial status epilepticus. The cognitive dis­ turbance often responds to anticonvulsant therapy. The etiology may be previous small strokes or head trauma; some cases are idiopathic. Nonconvulsive temporal lobe seizures can also emerge early in the course of AD. It is important to recognize systemic diseases that indirectly affect the brain and produce chronic confusion or dementia. Such conditions include hypothyroidism; vasculitis; and hepatic, renal, or pulmonary disease. Hepatic encephalopathy may begin with irritability and confu­ sion and slowly progress to agitation, lethargy, and coma. Isolated vasculitis of the CNS (CNS granulomatous angiitis) (Chaps. 375 and 438) occasionally causes a chronic encephalopathy associated with confusion, disorientation, and clouding of conscious­ ness. Headache is common, and strokes and cranial neuropathies may occur. Brain imaging studies may be normal or nonspecifically abnormal. CSF analysis reveals a mild pleocytosis or protein eleva­ tion. Cerebral angiography can show multifocal stenoses involving medium-caliber vessels, but some patients have only small-vessel disease that is not revealed on angiography. The angiographic appear­ ance is not specific and may be mimicked by atherosclerosis, infec­ tion, or other causes of vascular disease. Brain or meningeal biopsy demonstrates endothelial cell proliferation and mononuclear infil­ trates within blood vessel walls. The prognosis is often poor, although the disorder may remit spontaneously. Some patients respond to glucocorticoids or chemotherapy. Chronic metal exposure represents a rare cause of dementia. The key to diagnosis is to elicit a history of exposure at work or home. Chronic lead poisoning from inadequately fire-glazed pottery has been reported. Fatigue, depression, and confusion may be associated with episodic abdominal pain and peripheral neuropathy. Gray lead lines appear in the gums, usually accompanied by an anemia with basophilic stippling of red blood cells. The clinical presentation can resemble that of acute intermittent porphyria (Chap. 428), including elevated levels of urine porphyrins as a result of the inhibition of δ-aminolevulinic acid dehydrase. The treatment is chelation therapy with agents such as ethylenediamine tetraacetic acid (EDTA). Chronic mercury poisoning produces dementia, peripheral neuropathy, ataxia, and tremulousness that may progress to a cerebellar intention tremor or choreoathetosis. The confusion and memory loss of chronic arsenic intoxication is also associated with nausea, weight loss, peripheral neuropathy, pigmenta­ tion and scaling of the skin, and transverse white lines of the fingernails (Mees’ lines). Treatment is chelation therapy with dimercaprol (BAL). Aluminum poisoning is rare but was documented with the dialysis dementia syndrome, in which water used during renal dialysis was contaminated with excessive amounts of aluminum. This poisoning resulted in a progressive encephalopathy associated with confusion, nonfluent aphasia, memory loss, agitation, and, later, lethargy and stupor. Speech arrest and myoclonic jerks were common and associ­ ated with severe and generalized EEG changes. The condition has been eliminated by the use of deionized water for dialysis. Recurrent head trauma in professional athletes may lead to a dementia previously referred to as “punch-drunk” syndrome or dementia pugilistica but now known as chronic traumatic encepha­ lopathy (CTE) to signify its relevance to contact sport athletes other than boxers (Chap. 454). The symptoms can be progressive, beginning late in an athlete’s career or, more often, after retirement. Early in the course, a personality change occurs, associated with social instability, explosive rage, and sometimes paranoia and delusions. Later, memory loss progresses to full-blown dementia, often associated with parkin­ sonian signs and ataxia or intention tremor. At autopsy, the cerebral cortex shows tau-immunoreactive NFTs that are more prominent than amyloid plaques (which are usually diffuse or absent rather than neu­ ritic). NFTs and tau-positive reactive astrocytes are often clustered in the depths of cortical sulci and in a perivascular distribution. TDP-43 inclusions have also been reported, highlighting the overlap with the FTD spectrum (Chap. 443). Loss of neurons in the substantia nigra is a variable feature, and some with TDP-43 inclusions also develop motor neuron disease (MND) (Chap. 448). Chronic subdural hematoma (Chap. 454) is also occasionally associated with dementia, often in the context of underlying cortical atrophy from conditions such as AD or HD. Transient global amnesia (TGA) is characterized by the sudden onset of a severe episodic memory deficit, usually occurring in persons aged >50 years. Often the amnesia occurs in the setting of an emotional stimulus or physical exertion. During the attack, the individual is alert and communicative, general cognition seems intact, and there are no other neurologic signs or symptoms. The patient may seem confused and repeatedly ask about their location in place and time. The ability to form new memories returns after a period of hours, and the individual returns to normal with no recall for the period of the attack. Frequently no cause is determined, but cerebrovascular disease, epilepsy (7% in # 13 - 443 Frontotemporal Dementia ### 443 Frontotemporal Dementia one study), migraine, or cardiac arrhythmias have all been implicated. Approximately one-quarter of patients experience recurrent attacks. Rare instances of permanent memory loss have been reported in patients with TGA-like spells, usually representing ischemic infarction of the hippocampus or dorsomedial thalamic nucleus bilaterally. Sei­ zure activity due to AD should always be suspected in this syndrome. The ALS/parkinsonian/dementia complex of Guam is a rare degen­ erative disease that has occurred in the Chamorro natives on the island of Guam. Individuals may have any combination of parkinsonian fea­ tures, dementia, and MND. The most characteristic pathologic features are the presence of NFTs in degenerating neurons of the cortex and substantia nigra and loss of motor neurons in the spinal cord, although recent reanalysis has shown that some patients with this illness also show coexisting TDP-43 pathology. Epidemiologic evidence supports a possible environmental cause, such as exposure to a neurotoxin or an infectious agent with a long latency period. One interesting but unproven candidate neurotoxin is the seed of the false palm tree, which Guamanians traditionally used to make flour. The amyotrophic lateral sclerosis (ALS) syndrome is no longer present in Guam, but a dement­ ing illness with rigidity continues to be seen. Rarely, adult-onset leukodystrophies, lysosomal storage diseases, and other genetic disorders can present as a dementia in middle to late life. Metachromatic leukodystrophy (MLD) causes a progres­ sive psychiatric or dementia syndrome associated with an extensive, confluent frontal white matter abnormality. MLD is diagnosed by measuring reduced arylsulfatase A enzyme activity in peripheral white blood cells. Adult-onset presentations of adrenoleukodystrophy have been reported in female carriers, and these patients often feature spinal cord and posterior white matter involvement. Adrenoleuko­ dystrophy is diagnosed by demonstrating increased levels of plasma very-long-chain fatty acids. CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is another genetic syndrome associated with white matter disease, often frontally and temporally predominant. Diagnosis is made with skin biopsy, which shows osmophilic granules in arterioles, or increasingly through genetic testing for mutations in Notch 3. The neuronal ceroid lipofuscinoses are a genetically heterogeneous group of disorders asso­ ciated with myoclonus, seizures, vision loss, and progressive dementia. Diagnosis is made by finding eosinophilic curvilinear inclusions within white blood cells or neuronal tissue. Psychogenic amnesia for personally important memories can be seen. Whether this results from deliberate avoidance of unpleasant memories, outright malingering, or unconscious repression remains unknown and probably depends on the patient. Event-specific amnesia is more likely to occur after violent crimes such as homicide of a close relative or friend or sexual abuse. It may develop in association with severe drug or alcohol intoxication and sometimes with schizophrenia. More prolonged psychogenic amnesia occurs in fugue states that also commonly follow severe emotional stress. The patient with a fugue state suffers from a sudden loss of personal identity and may be found wandering far from home. In contrast to neurologic amnesia, fugue states are associated with amnesia for personal identity and events closely associated with the personal past. At the same time, memory for other recent events and the ability to learn and use new information are pre­ served. The episodes usually last hours or days and occasionally weeks or months while the patient takes on a new identity. On recovery, there is a residual amnesia gap for the period of the fugue. Very rarely does selective loss of autobiographic information reflect a focal injury to the brain areas involved with these functions. Psychiatric diseases may mimic dementia. Severely depressed or anxious individuals may appear demented, a phenomenon sometimes called pseudodementia. Memory and language are usually intact when carefully tested, and a significant memory disturbance usually suggests an underlying dementia, even if the patient is depressed. Patients in this condition may feel confused and unable to accomplish routine tasks. Vegetative symptoms, such as insomnia, lack of energy, poor appetite, and concern with bowel function, are common. Onset is often more abrupt, and the psychosocial milieu may suggest prominent reasons for depression. Such patients respond to treatment of the underlying psychiatric illness. Schizophrenia is usually not difficult to distinguish from dementia, but occasionally the distinction can be problematic. Schizophrenia generally has a much earlier age of onset (second and third decades) than most dementing illnesses and is associated with intact memory. The delusions and hallucinations of schizophrenia are usually more complex, bizarre, and threatening than those of demen­ tia. Some chronic schizophrenics develop an unexplained progressive dementia late in life that is not related to AD. Conversely, FTD, HD, vascular dementia, DLB, AD, or leukoencephalopathy can begin with schizophrenia-like features, leading to the misdiagnosis of a psychiatric condition. Later age of onset, significant deficits on cognitive testing, or the presence of abnormal neuroimaging suggest a degenerative condi­ tion. Memory loss may also be part of a conversion disorder. In this situ­ ation, patients commonly complain bitterly of memory loss, but careful cognitive testing either does not confirm the deficits or demonstrates inconsistent or unusual patterns of cognitive problems. The patient’s behavior and “wrong” answers to questions often indicate that they understand the question and know the correct answer. CHAPTER 443 Clouding of cognition by chronic drug or medication use, often pre­ scribed by physicians, is an important cause of dementia. Sedatives, tranquilizers, and analgesics used to treat insomnia, pain, anxiety, or agitation may cause confusion, memory loss, and lethargy, especially in the elderly. Discontinuation of the offending medication often improves mentation. Frontotemporal Dementia ■ ■FURTHER READING Andrews SJ et al: Interpretation of risk loci from genome-wide asso­ ciation studies of Alzheimer’s disease. Lancet Neurol 19:326, 2020. Belloy ME et al: A quarter century of APOE and Alzheimer’s disease: Progress to date and the path forward. Neuron 101:820, 2019. Cummings J et al: Progress in pharmacologic management of neu­ ropsychiatric syndromes in neurodegenerative disorders: A review. JAMA Neurol 81:645, 2024. Graff-Radford J et al: New insights into atypical Alzheimer’s disease in the era of biomarkers. Lancet Neurol 20:222, 2021. Jack CR et al: Revised criteria for the diagnosis and staging of Alzheimer’s disease. Nat Med 30:2121, 2024. Schindler SE et al: Acceptable performance of blood biomarker tests of amyloid pathology: Recommendations from the Global CEO Ini­ tiative on Alzheimer’s Disease. Nat Rev Neurol 20:426, 2024. Sims JR et al: Donanemab in early symptomatic Alzheimer disease: The TRAILBLAZER-ALZ 2 randomized clinical trial. JAMA 330:512, 2023. Van Dyck CH et al: Lecanemab in early Alzheimer’s disease. N Engl J Med 388:9, 2023. William W. Seeley, Bruce L. Miller Frontotemporal Dementia Frontotemporal dementia (FTD) refers to a group of clinical syndromes united by their links to underlying frontotemporal lobar degenera­ tion (FTLD) pathology. FTD, like the other major neurodegenerative diseases, is considered a disease of abnormal protein aggregation, with either tau or transactive response DNA-binding protein of 43 kDa (TDP-43) implicated in most cases. FTD most often begins in the fifth to seventh decades of life and is nearly as prevalent as Alzheimer’s disease (AD) in this age group. Early studies suggested that FTD may be more common in men than women; however, more recent reports cast doubt on this finding. Although a family history of dementia is common, autosomal dominant inheritance is seen in only 10–20% of all FTD cases. ■ ■CLINICAL MANIFESTATIONS Familial and sporadic forms of FTLD present with remarkable clinical heterogeneity. Three core clinical syndromes have been described (Fig. 443-1). In the behavioral variant (bvFTD), the most common FTD syn­ drome, social and emotional dysfunction manifests as apathy, disinhibi­ tion, compulsivity, loss of empathy, and overeating, often but not always accompanied by deficits in executive control. Two forms of primary progressive aphasia (PPA), the semantic and nonfluent/agrammatic variants, are commonly due to FTLD and are included under the FTD umbrella. In the semantic variant, patients slowly lose the ability to decode word, object, person-specific, and emotion meaning, whereas patients with the nonfluent/agrammatic variant develop profound inability to produce words, often with prominent motor speech impair­ ment. Any of these three clinical syndromes, but most often bvFTD, may be accompanied by motor neuron disease (MND) (Chap. 448), in which case the term FTD-MND is applied. In addition, the corticobasal syndrome (CBS) and progressive supranuclear palsy–Richardson syn­ drome (PSP-RS) can be considered part of the FTD clinical spectrum. Furthermore, patients may evolve from any of the major syndromes described above to have prominent features of another syndrome. PART 13 Neurologic Disorders Findings at the bedside are dictated by the anatomic localization of the disorder. Degeneration with atrophy occurs in the medial and orbital frontal cortex and anterior insula in bvFTD; the anterior tem­ poral region in semantic variant PPA; and the opercular frontal and precentral gyrus of the dominant hemisphere in nonfluent/agrammatic PPA. Typically, parietal functions such as visuospatial processing and arithmetic calculations are unaffected even late in the FTD syndromes. Many patients with nonfluent aphasia or bvFTD later develop aspects of PSP-RS as disease spreads into subcortical or brainstem structures or CBS-like features appear as disease moves into perirolandic cortices. ■ ■GENETIC CONSIDERATIONS Autosomal dominant forms of FTD can result from mutations in C9orf72 (chromosome 9), GRN (chromosome 17), and MAPT (chromosome 17) genes. A hexanucleotide (GGGGCC) expan­ sion in a noncoding exon of C9ORF72 is the most common genetic cause of familial or sporadic FTD (usually presenting as bvFTD with or without MND) and amyotrophic lateral sclerosis (ALS). The expansion is associated with C9orf72 haploinsufficiency, nuclear mRNA foci con­ taining transcribed portions of the expansion and other mRNAs, neu­ ronal cytoplasmic inclusions containing dipeptide repeat proteins translated from the repeat mRNA, and TDP-43 neuronal cytoplasmic and glial inclusions. The pathogenic significance of these various fea­ tures is a topic of vigorous investigation. MAPT mutations lead to a change in the alternate splicing of tau or cause loss of function in the FIGURE 443-1  Three major frontotemporal dementia (FTD) clinical syndromes. Coronal magnetic resonance imaging sections from representative patients with behavioral variant FTD (left) and the semantic (center) and nonfluent/ agrammatic (right) variants of primary progressive aphasia (PPA). Areas of early and severe atrophy in each syndrome are highlighted (white arrowheads). The behavioral variant features anterior cingulate and frontoinsular atrophy, spreading to orbital and dorsolateral prefrontal cortex. Semantic variant PPA shows prominent temporopolar atrophy, more often on the left. Nonfluent/agrammatic variant PPA is associated with dominant frontal opercular and dorsal insula degeneration. tau molecule, thereby altering microtubule binding. With GRN, muta­ tions in the coding sequence of the gene encoding progranulin protein result in mRNA degradation due to nonsense-mediated decay, leading to a ~50% reduction in circulating progranulin protein levels. Intrigu­ ingly, homozygous GRN mutations cause neuronal ceroid lipofuscino­ sis, focusing investigators on the lysosome as a site of molecular dysfunction in GRN-related FTD. Progranulin is a growth factor that binds to tumor necrosis factor (TNF) and sortilin receptors and partici­ pates in tissue repair and tumor growth. How progranulin mutations lead to FTD remains unknown, but the most likely mechanisms include lysosomal dysfunction and neuroinflammation. Often, MAPT and GRN mutations are associated with parkinsonian features, whereas ALS is rare. Infrequently, mutations in the valosin-containing protein (VCP, chromosome 9), TANK binding kinase 1 (TBK-1), T cell– restricted intracellular antigen-1 (TIA1), and charged multivesicular body protein 2b (CHMP2b, chromosome 3) genes also lead to autoso­ mal dominant familial FTD. Mutations in the TARDBP (encoding TDP-43) and FUS (encoding fused in sarcoma [FUS]) genes (see below) cause familial ALS, sometimes in association with an FTD syn­ drome, although a few patients presenting with FTD alone have been reported. ■ ■NEUROPATHOLOGY The pathological hallmark of FTLD is a focal atrophy of frontal, insular, and/or temporal cortex, which can be visualized with neuroimaging studies (Fig. 443-1) and is often profound at autopsy. Neuroimaging studies suggest that atrophy often begins focally in one hemisphere before spreading to anatomically interconnected cortical and subcorti­ cal regions. Loss of cortical serotonergic innervation is seen in many patients. In contrast to AD, the cholinergic system is relatively spared in FTD, which accounts for the poor efficacy of acetylcholinesterase inhibitors in this group. Although early studies suggested that 15–30% of patients with FTD showed underlying AD at autopsy, progressive refinement in clinical diagnosis has improved prediction accuracy, and most patients diagnosed with FTD at a dementia clinic will show underlying FTLD pathology. Microscopic findings seen across all patients with FTLD include gliosis, microvacuolation, and neuronal loss, but the disease is subtyped according to the protein composition of neuronal and glial inclusions, which contain either tau or TDP-43 in ~90% of patients, with the remaining ~10% showing inclusions containing the FET fam­ ily of proteins (FUS, Ewing sarcoma protein, TAF-15) (Fig. 443-2). ■ ■PATHOGENESIS In FTLD-tau, the toxicity and spreading capacity of misfolded tau are critical for the pathogenesis of inherited and sporadic tauopathies, although loss of tau microtubule stabilizing function may also play a role. In recent years, the distinctive structures of the misfolded tau in each FTLD tauopathy have been resolved using cryo-electron microscopy, opening up new approaches to diagnosis and treatment. TDP-43 and FET family proteins in contrast, are RNA/DNA binding proteins whose roles in neuronal function are still being actively investigated. TDP-43 is a master regulator of gene expression, and loss of TDP-43 function results in mis-splicing events leading to mRNA degradation (via nonsense-mediated decay) or aber­ rant transcripts that give rise to stable but dysfunctional peptides. One key role of TDP-43 and FET family proteins may be the chaperoning of mRNAs to the distal neuron for activity-dependent translation within dendritic spines. Because these proteins also form intra­ cellular aggregates and produce similar anatomic progression, protein toxicity and spreading may also factor heavily bvFTD svPPA nfvPPA FTD-MND CBS PSP-RS Frontotemporal lobar degeneration (FTLD) FTLD-tau FTLD-TDP FTLD-FET FTLD-3 CHMP2B Pick’s 3R tau CBD 4R tau PSP 4R tau aFTLD-U BIBD Type A (PGRN) (C9ORF72) FTDP-17 MAPT Other: CTE, AGD, MST, GGT Type D VCP FIGURE 443-2  Frontotemporal dementia syndromes are united by underlying frontotemporal lobar degeneration pathology, which can be divided according to the presence of tau, TDP-43, or FUS-containing inclusions in neurons and glia. Correlations between clinical syndromes and major molecular classes are shown with colored shading. Despite improvements in clinical syndromic diagnosis, a small percentage of patients with some frontotemporal dementia syndromes will show Alzheimer’s disease neuropathology at autopsy (gray shading). aFTLD-U, atypical frontotemporal lobar degeneration with ubiquitin-positive inclusions; AGD, argyrophilic grain disease; BIBD, basophilic inclusion body disease; bvFTD, behavioral variant frontotemporal dementia; CBD, corticobasal degeneration; CBS, corticobasal syndrome; CTE, chronic traumatic encephalopathy; FET, FUS, Ewing sarcoma protein, TAF-15 family of proteins; FTD-MND, frontotemporal dementia with motor neuron disease; FTDP-17, frontotemporal dementia with parkinsonism linked to chromosome 17; FUS, fused in sarcoma; GGT, globular glial tauopathy; MST, multisystem tauopathy; nfvPPA, nonfluent/ agrammatic variant primary progressive aphasia; NIBD, neurofilament inclusion body disease; NIFID, neuronal intermediate filament inclusion disease; PSP, progressive supranuclear palsy; PSP-RS, progressive supranuclear palsy–Richardson syndrome; svPPA, semantic variant primary progressive aphasia; Type U, unclassifiable type. in the pathogenesis of FTLD-TDP and FTLD-FET. As with tau, the ultrastructural characteristics of the TDP-43 and FET family protein misfolding events are now being actively characterized, with each pathologically recognized morphological subtype corresponding to a disease-specific fold. Increasingly, misfolded proteins in neurodegenerative disease are recognized as having “prion-like” or “corruptive” properties in that they can template the misfolding of their natively folded (or unfolded) protein counterparts, a process that creates exponential amplification of protein misfolding within a cell and may promote transcellular and even transsynaptic protein propagation between cells. This hypothesis could provide a unifying explanation for the stereotypical and network-rooted patterns of disease spread observed in each syndrome (Chap. 435). Although the term Pick’s disease was once used to describe a pro­ gressive degenerative disorder characterized by selective involvement of the anterior frontal and temporal neocortex and pathologically by intraneuronal cytoplasmic inclusions (Pick bodies), it is now used only in reference to a specific FTLD-tau histopathologic subtype. Classical Pick bodies are argyrophilic, staining positively with the Bielschowsky silver method (but not with the Gallyas method) and also with immunostaining for hyperphosphorylated tau. Recognition of the three FTLD major molecular classes has allowed delineation of distinct FTLD subtypes within each class. These subtypes, based on the morphology and distribution of the neuronal and glial inclusions (Fig. 443-3), account for the vast majority of patients, and some sub­ types show strong clinical or genetic associations (Fig. 443-2). Despite this progress, clinical features do not allow reliable prediction of the underlying FTLD subtype, or even the major molecular class, for all clinical syndromes. Molecular positron emission tomography (PET) imaging with ligands chosen to bind misfolded tau protein shows promise, but to date, these ligands only show robust and specific bind­ ing to AD-related misfolded tau. Because FTLD-tau and FTLD-TDP account for 90% of FTLD patients, the ability to detect pathologic tau (or TDP-43) protein deposition in vivo would greatly improve predic­ tion accuracy, especially when amyloid PET imaging is negative. ■ ■TREATMENT Caregivers for patients with FTD carry a heavy burden, especially when the illness disrupts core emotional and personality functions of the loved one. Treatment is symptomatic, and there are currently no thera­ pies known to slow progression or improve symptoms. Many of the Alzheimer’s disease Type B (C9ORF72) Type C CHAPTER 443 NIFID/ NIBD FUS NOS FUS Type U (C9ORF72) (TARDBP) Frontotemporal Dementia behaviors that may accompany FTD, such as depression, hyperorality, compulsions, and irritability, can be ameliorated with antidepressants, especially selective serotonin reuptake inhibitors (SSRIs). Because FTD is often accompanied by parkinsonism, antipsychotics, which can exacerbate this problem, must be used with caution. Experimental therapeutics, most targeting genetic forms of FTD, have just begun to enter clinical trials, but to date, no disease-modifying treatments have shown efficacy. A general approach to the symptomatic management of dementia is presented in Chap. 31. ■ ■PROGRESSIVE SUPRANUCLEAR PALSY SYNDROME PSP-RS is a degenerative disorder that involves the brainstem, basal ganglia, diencephalon, and selected areas of cortex. Clinically, PSPRS begins with falls and executive dysfunction or subtle personality changes (such as mental rigidity, impulsivity, or apathy). Shortly thereafter, a progressive oculomotor syndrome ensues that begins with square wave jerks, followed by slowed saccades (vertical worse than horizontal) before resulting in progressive supranuclear oph­ thalmoparesis. Dysarthria, dysphagia, and symmetric axial rigidity can be prominent features that emerge at any point in the illness. A stiff, unstable posture with hyperextension of the neck and a slow, jerky, toppling gait are characteristic. Frequent unexplained and sometimes spectacular falls are common secondary to a combination of axial rigidity, inability to look down, and impaired judgment. Even once patients have severely limited voluntary eye movements, they retain oculocephalic reflexes (demonstrated using a vertical doll’s head maneuver); thus, the oculomotor disorder is supranuclear. The dementia overlaps with bvFTD, featuring apathy, frontal-executive dysfunction, poor judgment, slowed thought processes, impaired verbal fluency, and difficulty with sequential actions and shifting from one task to another. These features are common at presentation and often precede the motor syndrome. Some patients with a pathologic diagnosis of PSP begin with a nonfluent aphasia or motor speech dis­ order and progress to classical PSP-RS. Response to l-dopa is limited or absent; no other treatments exist. Death occurs within 5–10 years of onset. Like Pick’s disease, increasingly the term PSP is used to refer to a specific histopathologic entity within the FTLD-tau class. In PSP, accu­ mulation of hyperphosphorylated 4-repeat tau is seen within neurons and glia. Tau neuronal inclusions often appear tangle-like and may be large, spherical (“globose”), and coarse in subcortical and brainstem A B C PART 13 Neurologic Disorders D E F FIGURE 443-3  Neuropathology in frontotemporal lobar degeneration (FTLD). FTLD-tau (A–C) and FTLD-TDP (D–F) account for >90% of patients with FTLD, and immunohistochemistry reveals characteristic lesions in each of the major histopathologic subtypes within each class: A. Pick bodies in Pick’s disease; B. a tufted astrocyte in progressive supranuclear palsy; C. an astrocytic plaque in corticobasal degeneration; D. small compact or crescentic neuronal cytoplasmic inclusions and short, thin neuropil threads in FTLD-TDP, type A; E. diffuse/granular neuronal cytoplasmic inclusions (with a relative paucity of neuropil threads) in FTLD-TDP, type B; and F. long, tortuous dystrophic neurites in FTLD-TDP, type C. TDP can be seen within the nucleus in neurons lacking inclusions but mislocalizes to the cytoplasm and forms inclusions in FTLD-TDP. Immunostains are 3-repeat tau (A), phospho-tau (B and C), and TDP-43 (D–F). Sections are counterstained with hematoxylin. Scale bar applies to all panels and represents 50 μm in A, B, C, and E and 100 μm in D and F. structures. The most prominent involvement is in the subthalamic nucleus, globus pallidus, substantia nigra, periaqueductal gray, tectum, oculomotor nuclei, pontine nuclei, and dentate nucleus of cerebellum. Neocortical tangle-like inclusions, like those in AD, often take on a more flame-shaped morphology, but the tau folds in AD and PSP are distinct. Prominent tau-positive glial inclusions are an essential feature of PSP. Tufted astrocytes in the neocortex or striatum are the signature lesion (Fig. 443-3). Coiled oligodendroglial inclusions (“coiled bodies”) are common but nonspecific. Most patients with PSP-RS show PSP at autopsy, although small numbers will show another tauopathy (corti­ cobasal degeneration [CBD] or globular glial tauopathy, or FTLD with a MAPT mutation; Fig. 443-2). In addition to its overlap with FTD and CBS (see below), PSP is often confused with idiopathic Parkinson’s disease (PD). Although elderly patients with PD may have restricted upgaze, they do not develop downgaze paresis or other abnormalities of voluntary eye movements typical of PSP. Dementia ultimately occurs in most patients with PD, often due to the emergence of a full-blown dementia with Lewy bodies (DLB)-like syndrome or comorbid AD-type dementia. Furthermore, the behavioral syndromes seen with DLB differ from PSP (see below). Dementia in PD becomes more likely with increasing age, increasing severity of extrapyramidal signs, long disease duration, and the pres­ ence of depression. Patients with PD who develop dementia also show cortical atrophy on brain imaging. Neuropathologically, there may be AD-related changes in the cortex or Lewy body disease (LBD)-related α-synuclein inclusions in both the limbic system and cerebral cortex. DLB and PD are discussed in Chaps. 445 and 446, respectively. ■ ■CORTICOBASAL SYNDROME CBS is a slowly progressive dementia-movement disorder associated with severe degeneration in the perirolandic cortex and basal ganglia (substantia nigra and striatopallidum). Patients typically present with asymmetric rigidity, dystonia, myoclonus, and apraxia that render a progressively incapacitated limb, at times associated with alien limb phenomena in which the limb exhibits unintended motor actions such as grasping, groping, drifting, or undoing. Eventually CBS becomes bilateral and leads to dysarthria, slow gait, action tremor, and a frontalpredominant dementia. Whereas CBS refers to the clinical syndrome, CBD refers to a specific histopathologic FTLD-tau entity (Fig. 443-2). Although CBS was once thought to be pathognomonic for CBD, increasingly it has been recognized that CBS can be due to CBD, PSP, FTLD-TDP, and AD, with the latter accounting for up to 30% of CBS in some series. In CBD, the microscopic features include ballooned, achromatic, tau-positive neurons; astrocytic plaques (Fig. 443-3); and other dystrophic glial tau pathomorphologies that overlap with those seen in PSP. Most specifically, CBD features a severe tauopathy bur­ den in the subcortical white matter, consisting of axonal threads and oligodendroglial coiled bodies. As shown in Fig. 443-2, patients with bvFTD, nonfluent/agrammatic PPA, and PSP-RS may also show CBD at autopsy, emphasizing the importance of distinguishing clinical and pathologic constructs and terminology. Treatment of CBS remains symptomatic; no disease-modifying therapies are available. ■ ■FURTHER READING Boeve BF et al: Advances and controversies in frontotemporal dementia: Diagnosis, biomarkers, and therapeutic considerations. Lancet Neurol 21:258, 2022. Creekmore BC et al: Neurodegenerative disease tauopathies. Annu Rev Pathol 19:345, 2024. Irwin DJ et al: Frontotemporal lobar degeneration: Defining pheno­ typic diversity through personalized medicine. Acta Neuropathol 129:469, 2015. Roberson ED: Mouse models of frontotemporal dementia. Ann Neurol 72:837, 2012. Seeley WW: Behavioral variant frontotemporal dementia. Continuum (Minneap Minn) 25:76, 2019. # 14 - 444 Vascular Dementia ### 444 Vascular Dementia Steven M. Greenberg, William W. Seeley Vascular Dementia The term vascular dementia has traditionally been used to describe a subset of dementia cases due primarily to one or more symptomatic strokes. Considered as such, vascular dementia is usually ranked the second most frequent cause of dementia, exceeded only by Alzheimer’s disease (Chap. 442), and is especially common in populations with limited access to medical care, where vascular risk factors are under­ treated. More recently, this relatively narrow definition of vascular dementia has been substantially broadened to encompass the full impact of cerebrovascular disease on age-related cognitive decline. The term vascular contributions to cognitive impairment and dementia (VCID) reflects the observation that pathologic changes involving the cerebral vasculature are highly prevalent in the elderly and contribute to cognitive impairment, whether occurring in isolation or—more commonly—in conjunction with other neurodegenerative processes. The concept of VCID is one facet of the contemporary understanding of age-related cognitive decline as due to cumulative effects of distinct and overlapping neuropathologic changes. Multifactorial or “mixed” dementias appear to be more prevalent than single-etiology dementias and thus represent the rule rather than the exception. Symptomatic stroke and asymptomatic vascular lesions, most com­ monly detected with brain magnetic resonance imaging (MRI) scans, both contribute importantly to cognitive impairment. At least some cognitive impairment is present in approximately half of stroke sur­ vivors and progressively increases with longer periods of follow-up. Population-based studies also demonstrate substantially increased risk of cognitive impairment among individuals without symptomatic stroke but with MRI evidence of cerebrovascular disease. The high risk for subsequent cognitive impairment or dementia conferred by MRI markers of otherwise silent vascular brain injury highlights the cumu­ lative impact of small distributed brain injuries—often associated with small-vessel brain disease—on compromising brain function. Further support for this framework comes from the correlation of cognitive performance during life with postmortem neuropathology. Analysis of large community-based samples demonstrates independent contri­ butions to cognitive dysfunction and decline from both grossly vis­ ible infarcts and pathologic markers of overall cerebrovascular disease severity such as atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy scores. The Religious Orders Study and Memory and Aging Project analysis of 1079 community-based participants, for example, found each of these cerebrovascular entities to be moderate to severe in >30% of postmortem brains and, when present, to each account for ~20% of an individual’s premortem cognitive decline. Recent epidemiologic evidence of a decline in age-adjusted dementia incidence hints at the potential public impact of improving vascular health. The population-based Framingham Study reported 5-year age- and sex-adjusted cumulative hazard rates for dementia of 3.6 per 100 persons during the late 1970s to early 1980s, 2.8 in the late 1980s to early 1990s, 2.2 in the late 1990s to early 2000s, and 2.0 in the late 2000s to early 2010s. These time intervals coincide with parallel trends in hypertension control and stroke prevention, though the associations do not prove causation. Evidence supporting a potential causative effect of blood pressure control came from the SPRINT-MIND trial target­ ing systolic blood pressure (SBP) of <120 mmHg versus 140 mmHg in hypertensive individuals aged ≥50 years. The study ended prematurely because of effective prevention of cardiovascular outcomes in the lower SBP target group but nonetheless demonstrated that SBP reduction reduced rates of mild cognitive impairment (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.69–0.95) and combined mild cogni­ tive impairment or probable dementia (HR, 0.85; 95% CI, 0.74–0.97), although not dementia alone (HR, 0.83; 95% CI, 0.67–1.04). It is nota­ ble that both these studies measured all-cause cognitive impairment rather than just a vascular dementia subset, underlining the potential importance of VCID as a target for dementia prevention. ■ ■GLOBAL CONSIDERATIONS A review of data from across the globe indicates good evidence for vari­ ability in vascular dementia. Intracranial atherosclerosis, for example, is higher in Asians, Hispanics, and American blacks than it is in European and American whites, while whites may have more extracranial dis­ ease. The causes of these disparities remain under investigation but likely include access to health care, lifestyle factors such as diet, and possible genetic influences. ■ ■SUBTYPES OF CEREBROVASCULAR DISEASE ASSOCIATED WITH VCID Large Cerebral Strokes  Symptomatic strokes, whether ischemic (Chap. 438) or hemorrhagic (Chap. 439), reflect irreversible injury to discrete areas of cerebral cortex, subcortical white matter, or other subcortical and infratentorial structures and produce cognitive impair­ ment as a function of their size and location. Rare individual infarcts in specific strategic locations such as thalamus, medial temporal cortex, anterior corpus callosum, or dominant-side angular gyrus can suffi­ ciently impair episodic memory and functional skills to meet memorybased criteria for dementia. More commonly, strokes occur outside these strategic territories and affect various other aspects of cognition such as executive function, processing speed, and visuospatial perfor­ mance that fall under the broader VCID concept. Multiple strokes and larger volumes of infarcted territory are associated with a higher likeli­ hood of poststroke cognitive dysfunction. CHAPTER 444 Vascular Dementia Stroke patients who make good cognitive recovery nonetheless demonstrate accelerated poststroke cognitive decline. Communitybased individuals in the longitudinal Reasons for Geographic and Racial Differences in Stroke study, for example, changed trajectory from an average prestroke cognitive gain of 0.021 points/year to post­ stroke cognitive loss of –0.035 points/year on the six-item screener global cognitive function scale. Mechanisms for poststroke cognitive decline likely include ongoing effects of the cerebrovascular disease that gave rise to the index stroke as well as loss of cognitive reserve that makes the brain less resilient to any additional age-related disorders. Cerebral Small-Vessel Disease  Diseases of the brain’s small ves­ sels (Chap. 438) can also cause symptomatic ischemic or hemorrhagic stroke but are more often clinically asymptomatic and recognized only during evaluation for cognitive decline or other symptoms. The two common age-related cerebral small-vessel pathologies are arteriolo­ sclerosis and cerebral amyloid angiopathy. Arteriolosclerosis represents thickening of arterioles due to infiltration of plasma proteins into the vessel wall. The primary risk factors for this process are age, hyper­ tension, and diabetes mellitus. Cerebrovascular arteriolosclerosis can present as a cause of ischemic or hemorrhagic symptomatic stroke, both most commonly centered in territories supplied by deep penetrat­ ing vessels such as thalamus, basal ganglia, or brainstem. Cerebral amy­ loid angiopathy is defined by deposition of the β-amyloid peptide in the walls of small cerebral arteries, arterioles, and capillaries, with conse­ quent loss of normal wall structure. Its primary risk factor is advancing age. Cerebral amyloid angiopathy is most often recognized symptom­ atically as a cause of intracerebral hemorrhage (Chap. 439), commonly located in cerebral cortex, subcortical white matter (collectively known as lobar hemorrhages), or the cerebral convexity subarachnoid space. This small-vessel pathology also appears to confer increased risk for the adverse amyloid-related imaging abnormalities (ARIA) associ­ ated with recently approved immunotherapies for Alzheimer’s disease (Chap. 442). The distinction between the deep penetrating territories most commonly affected by arteriolosclerosis and superficial lobar brain regions affected by cerebral amyloid angiopathy often allows the two small-vessel diseases to be radiographically distinguished. Despite differences in their underlying pathogenic mechanisms, the two cerebral small-vessel diseases produce a similar range of ischemic and hemorrhagic brain lesions detectable by histopathology at autopsy or MRI scan during life (Fig. 444-1). Small (lacunar) infarcts are a common feature of arteriolosclerosis and less commonly of cerebral amyloid angiopathy. Chronic lacunar infarcts can appear on MRI fluidattenuated inversion recovery (FLAIR) sequences as a hyperintense rim surrounding a hypointense cavitated core with diameters typically B A PART 13 Neurologic Disorders D FIGURE 444-1  Magnetic resonance imaging (MRI) markers of cerebral small vessel disease. A. Lacunar infarct: fluid-attenuated inversion recovery (FLAIR) sequence showing hyperintense rim surrounding a hypointense cavitated core in the left thalamus (arrowhead). B. Acute microinfarct: diffusion-weighted sequence showing small hyperintense lesion in the left centrum semiovale (arrowhead). C. Cerebral microbleeds in deep penetrating brain region: T2*-weighted sequence showing multiple small hypointense lesions in the pons (arrowheads). D. Cerebral microbleeds in lobar brain regions: T2*-weighted sequence showing multiple small hypointense lesions lobar brain regions (arrowheads). E. White matter hyperintensities: FLAIR sequence showing confluent diffuse hyperintensities in white matter. 3–15 mm (Fig. 444-1A), but this characteristic appearance evolves in only a subset of small infarctions, and many cannot be readily identi­ fied in the chronic stage. Microinfarcts <3 mm are characteristic of both small-vessel diseases. They are substantially more numerous than lacunar infarcts but less easily visualized. Acute microinfarcts may be visible as punctate hyperintensities on diffusion-weighted MRI images (Fig. 433-1B), whereas a small subset of chronic microinfarcts is detectable on high-resolution T2-weighted MRI sequences as hyper­ intense lesions in the cerebral cortex. Cerebral microbleeds are less numerous than lacunes or microinfarcts but readily detected in their chronic stage because of the paramagnetic effects of iron products. These appear as round hypointense lesions on T2∗-weighted MRI, pri­ marily in deep penetrating brain regions if caused by arteriolosclerosis (Fig. 444-1C) or lobar regions if caused by cerebral amyloid angiopathy (Fig. 444-1D). Other MRI markers of small-vessel disease identify diffuse injury of the white matter. White matter hyperintensities on T2-weighted or FLAIR MRI sequences (Fig. 444-1E) are an almost ubiquitous feature of aging. Although these lesions are readily visible on clinical MRI, they represent a nonspecific marker of white matter gliosis, demyelination, or increased water content. Extremely severe diffuse white matter vas­ cular injury is commonly referred to as Binswanger’s disease or subcor­ tical arteriosclerotic encephalopathy, recognized as a clinical syndrome with gradual cognitive deterioration and notable white matter changes of small-vessel ischemic disease. On neuroimaging, a progressive confluent subcortical and periventricular white matter disease is seen C E (see Fig. 31-2), with hypoperfusion and hypometabolism. More subtle alterations in white matter structure can be sensitively and quantita­ tively detected by diffusion tensor MRI (Chap. 434) as increased water diffusivity or decreased diffusion directionality. Diffusion tensor mea­ sures of white matter structural integrity show a consistent association with cognitive performance and gait speed, reflecting the central role of disconnection of key brain networks in mediating the effects of cere­ bral small-vessel disease. These diffusion tensor–based methods often require complex processing and are typically used in research rather than clinical settings. A relatively simple diffusion tensor–based metric defined by the peak width of the skeletonized mean diffusivity (PSMD) histogram has emerged as a candidate method for quantifying white matter disconnection. Functional MRI measurement of cerebrovascu­ lar reactivity to physiologic stimuli is generally not performed in clini­ cal practice, but it may become abnormal decades before appearance of structural brain injury and therefore represents a promising outcome marker for identifying disease-modifying interventions aimed to slow or prevent vascular brain injury. Role of Accompanying Brain Pathologies  The concept of VCID posits that large strokes and small-vessel disease often occur in combination with neurodegenerative brain diseases, most commonly Alzheimer’s disease (Chap. 442). Many clinicopathologic correlation studies have established that the co-occurrence of cerebrovascular and neurodegenerative lesions produces more cognitive and functional impairment than expected from the effects of each disease mechanism # 15 - 445 Dementia with Lewy Bodies ### 445 Dementia with Lewy Bodies considered independently. Interactions between cerebrovascular and neurodegenerative processes may also contribute to dementia. Such interactions might involve loss of blood-brain barrier integrity (pos­ sibly allowing brain penetration of neurotoxic or inflammatory agents) and impaired clearance of β-amyloid or other pathogenic molecules from the brain (postulated to occur along perivascular drainage path­ ways driven by physiologic vascular motion). APPROACH TO THE PATIENT Vascular Dementia Identifying vascular contributors to a patient’s cognitive impair­ ment can clarify the etiologic diagnosis and point to specific interventions aimed at slowing progression. Clinical evaluation is focused on identifying vascular risk factors (hypertension, diabetes mellitus, dyslipidemia, tobacco use, atrial fibrillation, coronary artery disease, or peripheral vascular disease), history of prior symptoms of stroke or transient ischemic attack, and family history of early stroke or vascular disease. Although stepwise progression and certain cognitive deficits such as loss of executive function are particularly suggestive, most individuals with VCID follow the more typical pattern of gradual progression of impaired episodic memory. The mainstay for detection and subtyping of cerebrovascular disease is brain MRI. The MRI should include FLAIR, diffusionweighed, and T2∗-weighted sequences to detect the range of lesions noted above: large and small chronic infarcts, acute microinfarcts, microbleeds, and white matter hyperintensities. Vessel imaging studies such as computed tomography or magnetic resonance angi­ ography are not required for initial evaluation of cognitive impair­ ment, though they may be useful for determining the cause of any macroscopic infarcts that are identified. Genetic testing for rare hereditary forms of VCID such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (Chap. 438) or hereditary cerebral amyloid angiopathy can be considered for cases in which there is a particularly young onset, positive family history, or suggestive neuroimaging, but is otherwise unnecessary. TREATMENT Vascular Dementia Very few trials have addressed the optimal treatment for individuals with asymptomatic large- or small-vessel cerebrovascular disease, leaving uncertainty as to whether to follow primary or secondary stroke prevention guidelines. At a minimum, treatment should assiduously follow primary stroke prevention guidelines. The American Heart Association recommends the prudent approach for vascular health of managing blood pressure, controlling choles­ terol, reducing blood sugar, maintaining an active lifestyle, adhering to a heart-healthy diet, losing weight, discontinuing tobacco, and getting healthy sleep (Life’s Essential 8, https://www.heart.org/en/ healthy-living/healthy-lifestyle/lifes-essential-8). Blood pressure tar­ gets are <140/90 mmHg for all individuals and <130/80 mmHg for those with estimated 10-year cardiovascular disease risk ≥10%, which likely applies to many individuals with imaging evidence of asymptomatic brain infarcts or advanced small-vessel disease. The usefulness of other treatments for secondary stroke prevention such as antiplatelet or statin therapy has not been established for asymp­ tomatic infarcts. These agents are reasonable to consider, however, when the imaging appearance suggests embolic or large-vesselrelated strokes. All individuals with asymptomatic infarcts should be screened for atrial fibrillation, and those with embolic-appearing infarcts can be considered for prolonged cardiac monitoring. Simi­ larly, patients with infarcts in the territories of large arteries should be considered for vascular imaging. The few trials of symptomatic medications for cognitive impair­ ment due to vascular etiologies have suggested modest cognitive benefits comparable to those found in Alzheimer’s disease patients. Therefore, it may be reasonable in VCID to consider agents such as the cholinesterase inhibitors donepezil, rivastigmine, or galan­ tamine for mild to moderate cognitive impairment and high-dose donepezil or the N-methyl-d-aspartate receptor antagonist meman­ tine for moderate to severe impairment (Chap. 442). A shared decision-making approach in considering these medications is use­ ful, given their relatively small impact on daily function. ■ ■FURTHER READING Boyle PA et al: Person-specific contribution of neuropathologies to cognitive loss in old age. Ann Neurol 83:74, 2018. Corriveau RA et al: The science of vascular contributions to cogni­ tive impairment and dementia (VCID): A framework for advancing research priorities in the cerebrovascular biology of cognitive decline. Cell Mol Neurobiol 36:281, 2016. Dichgans M, Leys D: Vascular cognitive impairment. Circ Res CHAPTER 445 120:573, 2017. Düering M et al: Neuroimaging standards for research into small ves­ sel disease-advances since 2013. Lancet Neurol 22:602, 2023. Greenberg SM et al: Cerebral amyloid angiopathy and Alzheimer dis­ ease: One peptide, two pathways. Nat Rev Neurol 16:30, 2020. Levine DA et al: Trajectory of cognitive decline after incident stroke. Dementia with Lewy Bodies JAMA 314:41, 2015. Smith EE et al: Prevention of stroke in patients with silent cerebro­ vascular disease: A scientific statement for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 48:e44, 2017. Snowdon DA et al: Brain infarction and the clinical expression of Alzheimer disease. The Nun Study. JAMA 277:813, 1997. Vermeer SE et al: Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 348:1215, 2003. Irene Litvan, William W. Seeley, Bruce L. Miller Dementia with Lewy Bodies Lewy body disease (LBD), manifesting as Parkinson’s disease dementia (PDD) or dementia with Lewy bodies (DLB), is the second most com­ mon cause of neurodegenerative dementia, after Alzheimer’s disease (AD) (Chap. 442). Approximately 10% of patients with Parkinson’s disease (PD) develop PDD per year, with the majority of PD patients developing PDD over time. The incidence of DLB is ~7 per 100,000 person-years. The prevalence of both PDD and DLB increases with aging, and both affect men more often than women. The development of increasingly useful biomarkers for PD and DLB is making possible new operational definitions, classifications, and staging for these disor­ ders, and these are likely to continue to evolve over time. CLINICAL MANIFESTATIONS Most investigators conceptualize PDD and DLB as points on a spec­ trum of LBD pathology. Cognitively, PDD and DLB usually manifest with severe executive, attentional, and visuospatial deficits but pre­ served episodic memory. Cognitive decline in LBD affects performance of daily living activities beyond other PD symptoms. Early psychosis including well-formed visual hallucinations, fluctuating cognition, rapid eye movement sleep behavior disorder (RBD), and parkinson­ ism are the main diagnostic features in DLB. The sense of a presence behind the person may precede well-formed hallucinations. Delusions are less frequent than hallucinations and are usually related to mis­ identification, infidelity, theft, or persecution. Fluctuating attention and concentration are other characteristic features. Minor day-to-day variation in cognitive functioning is common across dementias, but in DLB, these fluctuations can be marked, with short periods of confusion or severe lethargy that may rapidly resolve. Patients with PDD and DLB are highly sensitive to infectious or metabolic disturbances. The first manifestation of DLB in some patients is delirium, often precipitated by an infection, new medicine, or other systemic disturbance. Parkin­ sonism in DLB is usually associated with early postural instability and can present early or later in the course. RBD is a characteristic, often prodromal, feature. Normally, dreaming is accompanied by skeletal muscle paralysis, but patients with RBD enact dreams, often violently, leading to injuries to themselves or their bed partners. Both PDD and DLB may be accompanied or preceded by anosmia, constipation, RBD, depression, and anxiety. The symptom profile in DLB and PDD can provide clues for the differential diagnosis at the clinic. Clinically, the time interval between parkinsonism and dementia differentiates PDD and DLB. PDD presents in patients with long-standing PD, who manifest dementia often with visual hallucinations, fluctuating attention or alertness, and RBD. On the other hand, when the dementia and the neuropsychiatric symptoms precede or co-emerge with the parkinsonism, the patient is diagnosed with DLB. Patients with DLB, more frequently than those with PDD, also have AD co-pathology, making the prediction of underlying pathol­ ogy challenging for clinicians. Episodic memory disturbance points to the diagnosis of comorbid AD. Orthostatic hypotension that can lead to syncopal events, erectile dysfunction, and constipation can be present early in DLB, at times making it challenging to differentiate DLB from multiple system atrophy (MSA). In MSA, the autonomic disturbances occur early and are usually more severe than in DLB, and cognition is relatively preserved. Anosmia is also more characteristic of LBD than MSA. Skin biopsy and serum with biomarkers for α-synuclein oligomers, a major component of Lewy bodies, have shown potential for differentiating PD from MSA, and if validated for clinical use, this type of test may also differentiate DLB or PDD from MSA in the future. PART 13 Neurologic Disorders ■ ■PRODROMAL PHASE Both DLB and PDD have a prodromal phase where patients have a mild cognitive impairment (MCI), with cognitive deficits that do not have a substantial impact on daily life. PD-MCI is characterized by def­ icits in executive, attention, and visuospatial disturbances, but can also present with an amnestic or multiple-domain MCI. Prodromal DLB is characterized by similar cognitive disturbances but is also associated with either hallucinations unrelated to medications, RBD, fluctuations in attention, or parkinsonism. It is at times challenging to differentiate prodromal MCI-DLB and PD-MCI when the major features are RBD and parkinsonism, for which the term prodromal MCI–Lewy body (MCI-LB) was recently proposed. RBD may precede the development of an LBD-related syndrome by many years, usually evolving into either PD or DLB. The clinical profile and several biomarkers can help differentiate MCI due to LBD versus AD pathology (Table 445-1). PATHOLOGY The key neuropathologic feature in LBD is the presence of Lewy bod­ ies and Lewy neurites throughout specific brainstem nuclei, substan­ tia nigra, amygdala, cingulate gyrus, and, ultimately, the neocortex. Lewy bodies are intraneuronal cytoplasmic inclusions that stain with periodic acid–Schiff (PAS) and ubiquitin but are now identified with antibodies to the presynaptic protein α-synuclein. Lewy bodies are composed of straight neurofilaments 7–20 nm long with surrounding amorphous material and contain epitopes recognized by antibodies against phosphorylated and nonphosphorylated neurofilament pro­ teins, ubiquitin, and α-synuclein. The presence of α-synuclein aggre­ gates in neurons and glia in PDD and DLB molecularly classifies these diseases as synucleinopathies. In general, neuronal and synaptic loss, rather than Lewy pathology per se, best predicts the clinical deficits. Formal criteria identify three stages of progression: (1) brainstem predominant; (2) transitional limbic; and (3) diffuse neocortical. TABLE 445-1  Distinguishing MCI Due to Lewy Body Disease or Alzheimer’s Disease CLINICAL FEATURES PRODROMAL MCI-LB PATHOLOGY PRODROMAL MCI-AD PATHOLOGY MCI MCI usually affecting executive, attention, and/or visuospatial functions MCI with impaired memory and semantic naming Fluctuating cognition with variations in attention Frequent and severe Rare or not severe Sleep REM sleep behavior disorder Insomnia, frequent awakenings Recurrent visual hallucinations Frequent Rare Biomarkers Polysomnogram REM sleep behavior disorder without atonia Normal CSF Decreased CSF α-synuclein by RT-QuIC Decreased CSF β-amyloid and increased phospho-tau. This can now be performed in blood. MRI Atrophy of the amygdala Atrophy of the parahippocampal/ hippocampal areas 18F-deoxyglucose PET scan Hypometabolism in occipital lobe and increased in posterior cingulate (cingulate island sign) Hypometabolism in parietotemporal lobes Amyloid PET scan Normal, unless associated with AD Abnormal parietotemporal areas MIBG myocardial scintigraphy Postganglionic sympathetic denervation Normal DAT scan or PET dopamine scan Reduced dopamine transporter in the basal ganglia, particularly putamen Normal Abbreviations: AD, Alzheimer’s disease; CSF, cerebrospinal fluid; DAT, dopamine transporter; LB, Lewy bodies; MCI, mild cognitive impairment; MIBG, metaiodobenzylguanidine; MRI, magnetic resonance imaging; PET, positron emission tomography; REM, rapid eye movement; RT-QuIC, real-time quaking-induced conversion. Importantly, healthy older individuals may also show isolated scattered Lewy body pathology in the substantia nigra, amygdala, or olfactory bulb. Pathologic studies have shown that PD usually starts in the enteric nervous system and spreads through the vagus nerve to the heart, lower brainstem, substantia nigra, limbic system, and lastly the cerebral cortex. PD may also begin in the olfactory bulb and spread through olfactory system connections or start independently in enteric and olfactory bulb areas. Evidence from human anatomic pathology and animal models suggests that LBD may similarly propagate via a prionlike mechanism. Abnormally folded α-synuclein aggregates propagate transneuronally following connection pathways of the nervous system. This pathologic propagation from the periphery to the brain correlates with the evolution of clinical symptoms; PD usually manifests first with nonmotor features characterized by constipation and/or hypos­ mia, followed by anxiety, depression, RBD, parkinsonism, and lastly dementia. PDD is manifested clinically when limbic and cortical areas are involved. A profound cholinergic deficit, owing to basal forebrain and pedun­ culopontine nucleus involvement, is present in most patients with DLB and may be associated with the characteristic fluctuations, inattention, and visual hallucinations. Adrenergic deficits from locus coeruleus involvement further undermine arousal and alerting. PATHOGENESIS Both genes and environmental factors are thought to contribute to the development of LBD. The presence of α-synuclein aggregates in Lewy bodies led to the discovery of α-synuclein duplications and # 16 - 446 Parkinson’s Disease ### 446 Parkinson’s Disease triplications that manifest clinically as PD or DLB. There are multiple genes associated with PD, but mutations of glucocerebrosidase (GBA) particularly lead to PDD or DLB presentations (Chap. 446). The origins of LBD in gastrointestinal and olfactory areas suggest that environmental toxins acting on a susceptible genetic background may contribute to LBD pathogenesis (a “double-hit” hypothesis). Sev­ eral toxins have been associated with PD (Chap. 446), but epidemio­ logic studies of risk factors in DLB remain inconclusive. LABORATORY FEATURES In patients presenting with cognitive disturbances, it is always neces­ sary to rule out treatable causes of dementia such as drugs, infections, or metabolic disturbances (Chap. 31). Magnetic resonance imaging (MRI) of the brain can be helpful to rule out vascular parkinsonism or subdural hematomas, or support the diagnosis of other disorders such as MSA (i.e., pontine “hot-cross buns” sign; see Fig. 451-6). The biomarkers that can help diagnose LBD include the following: a polysomnogram showing RBD without atonia, seed amplification assays (SAAs) to detect αSyn in cerebrospinal fluid (CSF), demonstrating skin deposition of α-synuclein, iodine-123-meta-iodobenzylguanidine (MIBG) cardiac scintigraphy showing cardiac postganglionic sympathetic denervation, and dopamine transporter imaging using single-photon emission computed tomography (SPECT) or positron emission tomog­ raphy (PET) or, if associated with AD, increased CSF or blood levels of phospho-tau217 or phospho-tau181 (Table 445-1). TREATMENT Dementia with Lewy Bodies Although there are currently no disease-modifying agents to pre­ vent, slow, or cure LBD-related dementias, several symptomatic treatments are available. By addressing the substantial cholinergic deficit in DLB, cholinesterase inhibitors such as rivastigmine (target dose 6 mg twice daily or 9.5 mg patch daily) or donepezil (target dose 10 mg daily) often improve cognition, reduce hallucinosis, and stabilize delusional symptoms. The atypical antipsychotic pima­ vanserin is frequently helpful to treat the psychosis and does not worsen parkinsonism; it is approved by the U.S. Food and Drug Administration (FDA) for patients with PDD and is often used off-label for DLB. Pimavanserin (34 mg daily) is a selective inverse agonist of the serotonin 5-HT2A receptor that does not block dopa­ mine receptors but carries an FDA warning regarding an increase in risk of death, especially in older patients. Low-dose clozapine (begin at 6.25 mg, increasing up to 25 mg, daily) is also effective for treating hallucinations and delusions, but requires frequent blood draws due to the risk of agranulocytosis. Patients with LBD are sensitive to dopaminergic medications, which must be carefully titrated; tolerability may be improved with concomitant use of a cholinesterase inhibitor. Patients with DLB should not be exposed to typical neuroleptics, which can lead to a neuroleptic malignant syndrome and death, or anticholinergics or dopamine agonists that can exacerbate their symptoms. RBD usually responds to melatonin, requiring at times 20 mg/d. If melatonin is not effective, clonazepam, gabapentin, or codeine can be used with caution due to the possibility of worsening cogni­ tion or falls. Antidepressants, especially those with strong anxiolytic properties (escitalopram, paroxetine, duloxetine, or venlafaxine; see Chap. 463), are often necessary for mood and anxiety symptoms. Orthostatic hypotension may require treatment with nonpharma­ cologic measures (diet high in salt and liquids, a 30° elevation of the head of the bed) or pharmacologic therapies (i.e., fludrocortisone, midodrine, droxidopa). Physical therapy can maximize motor func­ tion and protect against fall-related injury. Home safety assessments and transfer instruction should also be provided. Education for patients and caregivers and social worker support are also impor­ tant. Therefore, the care of patients with LBD requires a multidis­ ciplinary approach. An experimental treatment that aims to slow down the progres­ sion of the disease is neflamapimod, which targets the synapse and showed promising results in initial phase 2a studies, findings that await confirmation. The majority of caregivers for individuals with DLB are women, often spouses, who frequently experience high levels of burden and depression. The severity of behavioral symptoms, sleep dis­ turbances, and autonomic symptoms in the person with DLB is associated with higher caregiver burden, leading to a poorer quality of life for the caregiver. The most commonly reported caregiver concerns include the inability to plan for the future, prioritizing the needs of the person with DLB over their own, and worry about the person with DLB becoming too dependent on the caregiver, among others. Overall, caregivers expressed satisfaction with the support provided by the medical team, but they reported the lowest satisfac­ tion with information about disease progression and the sharing of information among medical team members. Clinicians can address caregiver needs by providing support resources, educating caregiv­ ers about DLB, and developing management strategies for the range of troubling symptoms experienced by patients. CHAPTER 446 ■ ■FURTHER READING Diaz-Galvan P et al: Plasma biomarkers of Alzheimer’s disease in Parkinson’s Disease the continuum of dementia with Lewy bodies. Alzheimers Dement 20:2485, 2024. Emre M et al: Clinical diagnostic criteria for dementia associated with Parkinson’s disease. Mov Disord 22:1689, 2007. Litvan I et al: Diagnostic criteria for mild cognitive impairment in Parkinson’s disease: Movement Disorder Society Task Force guide­ lines. Mov Disord 27:349, 2012. Mckeith IG et al: Diagnosis and management of dementia with Lewy bodies: Fourth consensus report of the DLB Consortium. Neurology 89:88, 2017. Mckeith IG et al: Research criteria for the diagnosis of prodromal dementia with Lewy bodies. Neurology 94:743, 2020. Okuzumi A et al: Propagative α-synuclein seeds as serum biomarkers for synucleinopathies. Nat Med 29:1448, 2023. Rossi M et al: Ultrasensitive RT-QuIC assay with high sensitivity and specificity for Lewy body-associated synucleinopathies. Acta Neuropathol 140:49, 2020. Sonni I et al: Clinical validity of presynaptic dopaminergic imaging with 123I-ioflupane and noradrenergic imaging with 123I-MIBG in the differential diagnosis between Alzheimer’s disease and dementia with Lewy bodies in the context of a structured 5-phase development framework. Neurobiol Aging 52:228, 2017. C. Warren Olanow*, Anthony H. V. Schapira, Christine Klein Parkinson’s Disease PARKINSON’S DISEASE AND RELATED DISORDERS Parkinson’s disease (PD) is the second most common age-related neurodegenerative disease, exceeded only by Alzheimer’s disease (AD). Its cardinal clinical features were first described by the English physi­ cian James Parkinson in 1817. James Parkinson was a general physician who captured the essence of this condition based on a visual inspection *Deceased. of a mere handful of patients, several of whom he only observed walk­ ing on the street and did not formally examine. It is estimated that the number of people with PD worldwide is ~10.8 million, and this number is expected to double within 20 years based on the aging of the population. The mean age of onset of PD is about 60 years, and the lifetime risk is ~3% for men and 2% for women. The frequency of PD increases with age, but cases can be seen in individuals in their twenties and even younger, particularly when associated with a pathogenic gene mutation. Clinically, PD is characterized by bradykinesia (slowing), rest tremor, rigidity (stiffness), and gait dysfunction with postural insta­ bility. These are known as the classical or “cardinal” features of PD. Additional clinical features can include freezing of gait, speech dif­ ficulty, swallowing impairment, and a series of nonmotor features that include autonomic disturbances, sensory alterations, mood disorders, sleep disorders, and cognitive impairment/dementia (see Table 446-1 and discussion below). Pathologically, the hallmark features of PD are degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc), reduced striatal dopamine, and intraneuronal proteinaceous inclu­ sions in cell bodies and axons that stain for α-synuclein (known as Lewy bodies and Lewy neurites; collectively as Lewy pathology) (Fig. 446-1). While interest has focused on the dopamine system, neuronal degeneration with Lewy pathology can also affect cholin­ ergic neurons of the nucleus basalis of Meynert (NBM), norepineph­ rine neurons of the locus coeruleus (LC), serotonin neurons in the raphe nuclei of the brainstem, and neurons of the olfactory system, cerebral hemispheres, spinal cord, and peripheral autonomic nervous PART 13 Neurologic Disorders A B FIGURE 446-1  Pathologic specimens from a patient with Parkinson’s disease (PD) compared to a normal control demonstrating (A) reduction of pigment in SNc in PD (right) versus control (left), (B) reduced numbers of cells in SNc in PD (right) compared to control (left), and (C) Lewy bodies (arrows) within melanized dopamine neurons in PD. SNc, substantia nigra pars compacta. TABLE 446-1  Clinical Features of Parkinson’s Disease CARDINAL MOTOR FEATURES OTHER MOTOR FEATURES NONMOTOR FEATURES Bradykinesia Rest tremor Rigidity Postural instability Micrographia Masked facies (hypomimia) Reduced eye blinking Drooling Soft voice (hypophonia) Dysphagia Freezing Falling Anosmia Sensory disturbances (e.g., pain, hyposmia) Mood disorders (e.g., depression, anxiety, apathy) Sleep disturbances (e.g., fragmented sleep, RBD) Autonomic disturbances   Orthostatic hypotension   Gastrointestinal disturbances   Genitourinal disturbances   Sexual dysfunction Cognitive impairment/dementia Abbreviation: RBD, rapid eye movement sleep behavior disorder. system. This “nondopaminergic” pathology is likely responsible for the nonmotor clinical features listed above and in Table 446-1. It has been postulated that in some cases Lewy pathology can begin in the periph­ eral autonomic nervous system, gastrointestinal (GI) tract, olfactory system, or dorsal motor nucleus of the vagus nerve and then spread in a predictable and sequential manner to affect the SNc and cerebral hemi­ spheres (Braak staging). These studies suggest that the classic degen­ eration of SNc dopamine neurons and the cardinal motor features of PD may develop at a mid-stage of the illness. Indeed, epidemiologic C TABLE 446-2  Differential Diagnosis of Parkinsonism Parkinson’s disease   Sporadic   Genetic PD with dementia/dementia with Lewy bodies Atypical parkinsonism   Multiple-system atrophy (MSA)     Cerebellar type (MSA-c)     Parkinson type (MSA-p) Progressive supranuclear palsy     Parkinsonian variant     Richardson variant Corticobasal syndrome   Secondary parkinsonism   Drug-induced   Tumor   Infection   Vascular   Normal-pressure hydrocephalus   Trauma   Liver failure   Toxins (e.g., carbon monoxide, manganese, MPTP, cyanide, hexane, methanol, carbon disulfide) Abbreviation: MPTP, 1-methyl-4-phenyl-1,2,5,6-tetrahydropyridine. studies suggest that clinical symptoms reflecting early involvement of nondopaminergic neurons such as constipation, anosmia, rapid eye movement (REM) behavior sleep disorder, and cardiac denervation can precede the onset of the classic motor features of PD by several years if not decades. Originally it was considered that these represent risk factors for developing PD, but based on pathological findings, it is now considered likely that they represent an early premotor form of the disease. These observations have led to the notion of “body-first” and “brain-first” forms of PD based on whether pathology initially develops in the brain or periphery. Efforts are underway to accurately define the premotor stage of PD with high sensitivity and specificity. This will be of particular importance when a neuroprotective therapy becomes available as it will be desirable to initiate a disease-modifying treatment at the earliest stage of the disease possible. Recently, two new classifications have been developed aimed at defining the early stages of PD based on biological research criteria. The first stages PD based on neuronal α-synuclein accumulation. The second takes into account α-synuclein deposition, but also the distribution of neurodegen­ eration and pathogenic variants in known PD-causative genes. ■ ■DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS Parkinsonism is a term that is used to define a syndrome manifest by bradykinesia with rigidity and/or tremor. The differential diagnosis includes PD, atypical parkinsonisms such as multiple-system atrophy (MSA) and progressive supranuclear palsy (PSP), secondary parkinson­ ism, and parkinsonism associated with other neurodegenerative condi­ tions in which parkinsonian features are present (see Table 446-2 and discussion below). These conditions affect the basal ganglia, a group of subcortical nuclei that include the striatum (putamen and caudate nucleus), subthalamic nucleus (STN), globus pallidus pars externa (GPe), globus pallidus pars interna (GPi), and the SNc (Fig. 446-2). They differ, however, in the precise site of involvement within the basal Striatum (Putamen and Caudate) Globus Pallidus Globus Pallidus SNc A B FIGURE 446-2  Basal ganglia nuclei. Schematic (A) and postmortem (B) coronal sections illustrating the various components of the basal ganglia. SNc, substantia nigra pars compacta; STN, subthalamic nucleus. Other neurodegenerative disorders associated with parkinsonism   Wilson’s disease   Huntington’s disease   Neurodegeneration with brain iron accumulation   SCA 3 (spinocerebellar ataxia)   Fragile X–associated ataxia-tremor-parkinsonism   Prion diseases   X-linked dystonia-parkinsonism   Alzheimer’s disease with parkinsonism   Dopa-responsive dystonia CHAPTER 446 ganglia, the specific pathologic characteristics, and the clinical picture. Among the different forms of parkinsonism, PD is the most common (~75% of cases). Historically, PD was diagnosed based on the presence of two of three parkinsonian features (tremor, rigidity, bradykinesia). However, postmortem studies found a 24% error rate when diagnosis was based solely on these criteria. Clinicopathologic correlation studies subsequently determined that parkinsonism (bradykinesia and rigid­ ity) associated with rest tremor, asymmetry of motor impairment, and a good response to levodopa is much more likely to predict the correct pathologic diagnosis. With these revised criteria (known as the U.K. Brain Bank Criteria), a clinical diagnosis of PD could be confirmed pathologically in >90% of patients. Imaging of the dopamine system and new biomarkers (see below) further increase diagnostic accuracy. The International Parkinson’s Disease and Movement Disorder Society (MDS) has proposed revised clinical criteria for PD (known as the MDS Clinical Diagnostic Criteria for Parkinson’s disease), which are thought to increase diagnostic accuracy even further, particularly in early cases where levodopa has not yet been introduced. While motor parkinsonism has been retained as the core feature of the disease, in these criteria, the specific diagnosis of PD relies on three additional categories of diagnostic features: supportive criteria (features that increase confidence in the diagnosis of PD), absolute exclusion criteria, and red flags (which must be counterbalanced by supportive criteria to permit a diagnosis of PD). Utilizing these criteria, two levels of certainty have been delineated: clinically established PD and clinically probable PD (see Berg et al. in “Further Reading”). Parkinson’s Disease Imaging of the brain dopamine system can be helpful in diagnos­ ing PD and is performed using positron emission tomography (PET) or single-photon emission computed tomography (SPECT). These studies typically show reduced and asymmetric uptake in the stria­ tum, particularly in the posterior putamen with relative sparing of the caudate nucleus (Fig. 446-3). These findings reflect the degeneration Striatum Globus Pallidus STN SNc A PART 13 Neurologic Disorders B FIGURE 446-3  [11C]Dihydrotetrabenazine positron emission tomography (a marker of VMAT2) in healthy control (A) and Parkinson’s disease (B) patient. Note the reduced striatal uptake of tracer, which is most pronounced in the posterior putamen and tends to be asymmetric. (Courtesy of Dr. Jon Stoessl.) of nigrostriatal dopaminergic neurons and the loss of their striatal terminals. Imaging is useful in patients where there is diagnostic uncertainty (e.g., early-stage disease, essential tremor, dystonic tremor, psychogenic tremor) or in research studies in order to ensure diagnos­ tic accuracy, but it is not routinely required in clinical practice. This may change in the future when a disease-modifying therapy becomes available and it becomes critically important to make a correct diagno­ sis as early as possible. There is also some evidence suggesting that a diagnosis of PD, and even prodromal PD, may be made based on the presence of increased iron in the SNc using transcranial sonography or special magnetic resonance imaging (MRI) protocols. There have been intensive efforts to image α-synuclein in the brain but, in con­ trast to beta-amyloid or tau imaging in Alzheimer’s disease, this has proven difficult as most of the abnormal α-synuclein protein is located within cells. This makes it difficult to develop a marker that binds to α-synuclein and that can be detected with imaging. There has been a longstanding interest in developing a biomarker for PD that could aid in diagnosis, differentiate PD from other parkinsonian conditions, potentially assess the effects of a putative disease-modifying therapy, and be used as an endpoint in clinical trials. Considerable interest has focused on detecting abnormal α-synuclein deposits in cerebrospinal fluid (CSF), blood, muscle, and other tissues, but results to date have been inconsistent. The development of the α-synuclein seeding amplification assay (SAA) has provided a novel means to support a clinical diagnosis of PD. The SAA was developed for use on CSF and skin and provides a binary result indicating the presence or absence of endogenous α-synuclein sufficient to result in aggregation upon addition of α-synuclein “seeds.” This assay has very high sensitivity and specificity and is able to distinguish PD from other parkinsonisms. At present, the test has been primarily applied in a research setting, but the development of a blood-based assay may extend its use into a clinical role. This assay also has the potential to permit diagnosis in early-stage and even prodromal PD. Genetic testing can be helpful for establishing a diagnosis but is not routinely employed as monogenic forms of PD are relatively uncom­ mon and account for only 5% of cases, although this increases to 15% when pathogenic variants in the strongest known risk gene, glucocer­ ebrosidase (GBA1), are included (see discussion below), and this num­ ber may increase as more knowledge is acquired. A genetic form of PD should be considered in patients with a strong positive family history, early age of onset (<40 years), and a particular ethnic background (see below), and in research studies. Genetic variants of GBA1 are the most common genetic association with PD. They are present in ~10% of PD patients and in 25% of Ashkenazi PD patients. However, only ~20–30% of people with GBA1 variants will develop PD, and PD risk is correlated with the severity of the variant effect. Pathogenic variants in the LRRK2 gene have also attracted particular interest as they are responsible for ~3% of typical sporadic cases of the disease. LRRK2 mutations are a particularly common cause of PD (~25%) in Ashkenazi Jews and North African Berber Arabs; however, there is considerable variability in penetrance, and ~40–50% of carriers never develop clinical features of PD. Interestingly, some PD cases associated with LRRK2 mutations and other genetic causes have been described without Lewy bodies. Genetic testing is of particular interest for identifying at-risk individuals in a research setting and for defining enriched populations for clinical trials of therapies directed at a pathogenic mutation or pathway. Atypical, Secondary, and Other Forms of Parkinsonism  Atypical parkinsonism refers to a group of neurodegenerative condi­ tions that are usually associated with more widespread pathology than found in PD (e.g., degeneration potentially involving the striatum, globus pallidus, cerebellum, and brainstem as well as the SNc). These conditions include MSA (Chap. 451), PSP (Chap. 443), and cortico­ basal syndrome (CBS) (Chap. 443). As a group, they tend to present with parkinsonism (rigidity and bradykinesia) but manifest clinical differences from PD, reflecting their different pathologies. Clinical fea­ tures that typically differ from classical PD include early involvement of speech and gait, absence of rest tremor, lack of motor asymmetry, poor or no response to levodopa, and a more aggressive clinical course. They can be difficult to distinguish from PD in the early stages where levodopa has not yet been tried and in some cases that show a modest benefit from levodopa, but the diagnosis usually becomes clear as the disease evolves over time. Neuroimaging of the dopamine system is usually not helpful, as striatal dopamine depletion can be seen in both PD and atypical parkinsonism. By contrast, metabolic imaging of the basal ganglia/ thalamus network (using 2-F-deoxyglucose) may be helpful, showing a pattern of decreased activity in the GPi with increased activity in the thalamus, the reverse of what is seen in PD. MSA manifests as a combination of the atypical parkinsonian features described above, as well as varying degrees of cerebellar and autonomic features. Clinical syndromes can be divided into a predomi­ nantly parkinsonian (MSA-p), cerebellar (MSA-c), and more rarely, a primary autonomic form. Clinically, MSA is suspected when a patient has features of atypical parkinsonism in conjunction with cerebellar signs and/or prominent autonomic dysfunction, usually orthostatic hypotension and a poor or absent response to levodopa (Chap. 451). The use of biomarkers (e.g., SAA) has increased the accuracy of diag­ nosis in the early stages of the disease, and the rate of progression is typically more aggressive than in classic PD. Pathologically, MSA is characterized by degeneration of the SNc, striatum, cerebellum, and inferior olivary nuclei coupled with characteristic glial cytoplasmic inclusions (GCIs) that stain positively for α-synuclein aggregates (Lewy bodies), which accumulate in oligodendrocytes rather than in SNc neurons as in PD. MRI can show pathologic iron accumulation in the striatum on T2-weighted scans, high signal change in the region of the external surface of the putamen (putaminal rim) in MSA-p, or cerebellar and brainstem atrophy (the pontine “hot cross bun” sign [Fig. 451-6]) in MSA-c. There is currently no established evidence for any gene mutation or genetic risk factor for MSA, and no specific treatment exists. PSP is characterized by the features noted above coupled with slow ocular saccades, eyelid apraxia, and restricted vertical eye movements with impairment of downward gaze. Patients frequently experience hyperextension of the neck with early gait disturbance and falls. In later stages, speech and swallowing difficulty and cognitive impairment may become evident. Two clinical forms of PSP have been identified: a “Parkinson” form that can closely resembles PD in the early stages and can include a positive response to levodopa, and the more classic “Richardson” form that is characterized by the features described above with little or no response to levodopa. MRI may reveal a characteristic atrophy of the midbrain with relative preservation of the pons on mid­ sagittal images (the so-called “hummingbird sign”). Pathologically, PSP is characterized by degeneration of the SNc, striatum, STN, midline thalamic nuclei, and pallidum, coupled with neurofibrillary tangles and inclusions that stain for the tau protein. Mutations in the MAPT gene encoding the tau protein have been detected in some familial cases. CBS is a relatively uncommon condition that usually presents with asymmetric dystonic contractions, and clumsiness of one hand coupled with cortical sensory disturbances manifest as apraxia, agnosia, focal limb myoclonus, or alien limb phenomenon (where the limb assumes a position in space without the patient being aware of its location or recognizing that the limb belongs to them). Dementia may occur at any stage of the disease. Both cortical and basal ganglia features are required to make this diagnosis. MRI frequently shows asymmetric cortical atrophy, but this must be carefully sought and may not be obvious on casual inspection. Pathologic findings include achromatic neuronal degeneration with tau deposits. Considerable overlap may occur both clinically and pathologically between CBS and PSP, and they may be difficult to distinguish without pathologic confirmation. Secondary parkinsonisms occur as a consequence of other etiologic factors such as drugs, stroke, tumor, infection, or toxins (e.g., carbon monoxide, manganese) that cause basal ganglia dysfunction. Clinical features reflect the region of the basal ganglia that has been damaged. For example, strokes or tumors that affect the SNc may have a clini­ cal picture that is very similar to PD, whereas toxins such as carbon monoxide or manganese that damage the globus pallidus more closely resemble atypical parkinsonism and have a poor response to levodopa. Dopamine-blocking agents such as neuroleptics are the most common cause of secondary parkinsonism. These drugs are most widely used in psychiatry, but physicians should be aware that drugs such as metoclo­ pramide, which are primarily used to treat GI problems, are also neuro­ leptic agents and may induce secondary parkinsonism. These drugs can also cause acute and tardive dyskinesias (see Chap. 447). Other drugs that can cause secondary parkinsonism include tetrabenazine, calcium channel blockers (flunarizine, cinnarizine), amiodarone, and lithium. Parkinsonism can also be seen as a feature of dopa-responsive dysto­ nia (DRD), a condition that typically results from pathogenic variants in the GTP-cyclohydrolase 1 gene, which lead to a defect in a cofactor for tyrosine hydroxylase with impairment in the manufacture of dopa and dopamine. While it typically presents as dystonia (Chap. 447), it can present as a biochemically based form of parkinsonism (due to reduced synthesis of dopamine) closely resembling PD. DRD patients respond to levodopa, but abnormalities on fluorodopa PET (FD-PET) are typically not seen, nor are drug-induced dyskinesias, reflecting a biochemical abnormality without degeneration of the underlying anatomic structures. DRD should be considered in individuals aged <20  years who present with parkinsonism, particularly if there are dystonic features. Finally, parkinsonism can be seen as a feature of a variety of other neurodegenerative disorders such as Wilson’s disease (Chaps. 427 and 447), Huntington’s disease (especially the juvenile form known as the Westphal variant) (Chap. 447), certain spinocerebellar ataxias (Chap. 450), and neurodegenerative disorders with brain iron accumu­ lation such as pantothenate kinase (PANK)–associated neurodegenera­ tion (formerly known as Hallervorden-Spatz disease). It is particularly important to rule out Wilson’s disease, as progression can be prevented with the use of copper chelators. TABLE 446-3  Features Suggesting an Atypical or Secondary Cause of Parkinsonism ALTERNATIVE DIAGNOSIS TO CONSIDER SYMPTOMS/SIGNS History Early speech and gait impairment (lack of tremor, lack of motor asymmetry, early falls) Atypical parkinsonism Exposure to neuroleptics Drug-induced parkinsonism Onset prior to age 40 years Genetic form of PD, Wilson’s disease, DRD Liver disease Wilson’s disease, non-Wilsonian hepatolenticular degeneration Hallucinations and dementia which precede the development of PD features Dementia with Lewy bodies CHAPTER 446 Diplopia, impaired vertical gaze PSP Poor or no response to an adequate trial of levodopa Atypical or secondary parkinsonism Physical Examination Dementia as first or early feature Dementia with Lewy bodies Prominent orthostatic hypotension MSA Parkinson’s Disease Prominent cerebellar signs MSA-c Slow saccades with impaired downgaze PSP High-frequency (6–10 Hz) symmetric postural tremor with a prominent kinetic component Essential tremor Abbreviations: DRD, dopa-responsive dystonia; MSA-c, multiple-system atrophy– cerebellar type; MSA-p, multiple-system atrophy–Parkinson’s type; PD, Parkinson’s disease; PSP, progressive supranuclear palsy. Some features that suggest that parkinsonism might be due to a condition other than classic PD are shown in Table 446-3. ■ ■ETIOLOGY AND PATHOGENESIS Most PD cases occur sporadically and are of unknown cause. Gene mutations (see below) are the only known causes of PD and may be found even in seemingly sporadic cases. Twin studies performed several decades ago suggested that environmental factors may play an important role in patients with an age of onset ≥50 years, with genetic factors being more important in younger-onset patients. However, the demonstration of genetic variants (e.g., LRRK2 and GBA1) causing later onset PD shows that certain monogenic forms can manifest as late as in the eighth or ninth decade. With the advent of new sequenc­ ing technologies (long-read sequencing), numerous monogenic causes of late-onset neurodegenerative diseases have recently been identi­ fied, such as intronic repeat expansions in the FGF14 gene causing late-onset ataxia (Chap. 450), and it is conceivable that additional monogenic forms of PD will also be identified with this technology. In addition, it is likely that genetic factors could modify age at onset and severity of both genetic and nongenetic forms of PD. The environmental hypothesis received some support in the 1980s with the demonstration that MPTP (1-methyl-4-phenyl-1,2,5,6tetrahydropyridine), a by-product of the illicit manufacture of a heroin-like drug, caused a PD syndrome in addicts in northern Cali­ fornia. MPTP is transported into the central nervous system, where it is oxidized to form MPP+, a mitochondrial toxin that is selectively taken up by, and damages, dopamine neurons, but typically without the formation of Lewy bodies. Importantly, MPTP or MPTP-like com­ pounds have not been linked to sporadic PD. Epidemiologic studies have reported an increased risk of developing PD in association with exposure to pesticides, solvents, rural living, farming, and drinking well water, but study results have been inconsistent. Additionally, doz­ ens of other associations have also been reported in individual studies. To date, no environmental factor has yet been proven to be a cause of PD. Some possible protective factors have also been identified in epidemiologic studies, including caffeine, cigarette smoking, intake of nonsteroidal anti-inflammatory drugs, and calcium channel blockers. The validity of these findings and the responsible mechanism remain to be established. Large studies show that about 15% of PD cases are familial in ori­ gin, and mutations in several PD-linked genes have been identified (Table 446-4). While uncommon pathogenic variants in PD genes (i.e., mutations) have been shown to be causative of PD or to contribute to PD risk, a plethora of common genetic variants—alone or in combina­ tion as part of polygenic risk scores—are associated with an increased risk of developing PD. These include variants in the SNCA, LRRK2, MAPT, and GBA1 genes and may be ethnicity-specific, such as a strong risk variant confined to the African or African-admixed population. It has been proposed that many cases of PD may be due to a “double hit” involving an interaction between (1) one or more genetic risk factors that induce susceptibility and (2) exposure to a toxic environmental factor that may induce epigenetic or somatic DNA alterations or has the potential to directly damage the dopaminergic system. In this scenario, two factors (or more) are required for PD to ensue, while the presence of either one alone is not sufficient to cause the disease. While the “double-hit” hypothesis is of interest, there is no direct evidence for its support at this time. Furthermore, even if a genetic or environmen­ tal risk factor doubles the risk of developing PD, this only results in a lifetime risk of 4–6% or lower, and thus cannot presently be used for individual patient counseling. PART 13 Neurologic Disorders Thus, the bulk of accumulating evidence suggests that genetic fac­ tors play an important role in both familial and “sporadic” forms of PD, while the role of environmental factors remains unsettled. Although TABLE 446-4  Confirmed Genetic Causes of Parkinson’s Disease (PD) with a Clinical Presentation Similar to Idiopathic PDa DESIGNATIONa AND REFERENCE GENEREVIEWS AND OMIM REFERENCE CLINICAL CLUESB COMMENTS Dominantly Inherited PD PARK-SNCA GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 168601 Median AAO: 46 years (range 19–77 years); 25th/75th percentile: 36/54 years. Gene duplications cause classical PD. Most missense mutations and triplications cause early-onset, severe parkinsonism with prominent cognitive dysfunction PARK-LRRK2 GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1208/ OMIM 607060 Median AAO: 56 years (range 20–95 years); 25th/75th percentile: 47/64 years. Clinically typical PD with slightly slower progression PARK-VPS35 GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 616710 Median AAO: 52 years (range 26–75 years); 25th/75th percentile: 45/61 years. Clinically typical PD PARK-CHCHD2 GeneReviews N/A OMIM 614203 Likely clinically typical PD. Systematic MDSGene review not yet available PARK-RAB32 GeneReviews N/A OMIM 612906 (disease link not yet included) Likely clinically typical PD, possibly more frequent dementia. Systematic MDSGene review not yet available PARK-GBA1 GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 168600/606463 Clinically overall typical PD; however, faster progression and greater risk of cognitive impairment. Systematic MDSGene review not yet available Recessively Inherited PD PARK-PRKN GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1155/ OMIM 600116 Median AAO: 31 years (range 3–81 years); 25th/75th percentile: 23/38 years. Often presents with dystonia, typically in a leg PARK-PINK1 GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 605909 Median AAO: 32 years (range 9–67 years); 25th/75th percentile: 24/40 years. Prominent psychiatric features have been described in several families PARK-PARK7 GeneReviews http://www.ncbi.nlm.nih.gov/books/NBK1223/ OMIM 606324 Median AAO: 27 years (range 15–40 years); 25th/75th percentile: 22/34 aAccording to the recommendations of the International Parkinson’s and Movement Disorder Society (C Marras et al: Mov Disord 31:436, 2016; and L Lange et al: Mov Disord 37:905, 2022). bAdapted from MDSGene (www.mdsgene.org). Abbreviations: AAO, age at onset; N/A, not applicable; OMIM, Online Mendelian Inheritance in Man; PD, Parkinson’s disease. mutations in PD genes identified to date cause only a minority of cases of PD, they have been very helpful in pointing to specific targets, pathways, and molecular mechanisms that are likely to be central to the neurodegenerative process in the sporadic form of the disease. Detailed clinical and genetic features of monogenic PD are available in the MDSGene database (www.mdsgene.org). The α-synuclein gene (SNCA) was the first to be linked to PD and is also the most intensely investigated with respect to causative mutations, risk variants, function, and role in the etiopathogenesis of PD. Shared clinical features of patients with SNCA mutations include earlier age of disease onset than in nongenetic PD, a faster progression of motor signs that are mostly levodopa-responsive, early occurrence of motor fluctuations, and presence of prominent nonmotor features, particularly cognitive impairment. Importantly, duplication or triplica­ tion of the wild-type SNCA gene also causes PD, with triplication car­ riers being more severely affected than carriers of duplications. These findings indicate that increased production of the normal protein alone can cause PD. Intriguingly, α-synuclein constitutes the major component of Lewy bodies, implicating the protein in sporadic forms of PD as well (Fig. 446-1). In a remarkable study, Lewy pathology was discovered to have developed in healthy embryonic dopamine neurons that had been implanted into the striatum of PD patients, suggesting that the abnormal protein had transferred from affected cells to healthy unaffected dopamine neurons. Based on these findings, it has been proposed that the α-synuclein protein may be a prion and PD a prion disorder (Chaps. 435 and 449). In this model, α-synuclein can misfold Very rare form of PD, α-synuclein protein main component of Lewy bodies, the pathological hallmark of PD  Most common known genetic form of PD  Very rare form of PD  Very rare form of PD, predominantly found in Asia  Most recently found form of PD. All currently identified patients and families carry the same founder pathogenic variant  Strongest known genetic risk factor for PD; incomplete penetrance  Most common early-onset form of genetic PD. Protein name: Parkin  Clinically very similar to PARK-PRKN but much rarer  Clinically very similar to PARK-PRKN and PARK-PINK1, but rarest of all forms. Protein name: DJ-1 to form β-rich sheets, join to form toxic oligomers and aggregates, polymerize to form amyloid plaques (i.e., Lewy bodies), and cause neurodegeneration with spread to unaffected neurons. Indeed, injec­ tion of purified α-synuclein fibrils into the striatum of both transgenic and wild-type rodents produced Lewy pathology in host neurons, neu­ rodegeneration, behavioral abnormalities, and spread of α-synuclein pathology to anatomically connected sites. Further support for this hypothesis comes from the demonstration that inoculation into the striatum of homogenates derived from human Lewy bodies induces dopamine cell degeneration and widespread Lewy pathology in mice and primates. Evidence also suggests that in some cases α-synuclein pathology might begin peripherally within the GI tract and spread by way of the vagus nerve to the lower brainstem (dorsal motor nucleus of the vagus) and ultimately to the SNc to cause the motor features of PD (the Braak hypothesis). There is also interest in the possibility that the gut microbiome in PD patients can cause inflammatory changes that promote α-synuclein misfolding with spread to the brain via the vagus nerve. The gut-brain axis might therefore offer a mechanism by which α-synuclein pathology could spread to the brain and cause PD. The prion hypothesis for PD represents an exciting, although still unproven, line of investigation. Multiple lines of evidence support the concept that neuroprotective therapies for PD might be developed based on inhibiting the accumula­ tion or accelerating the removal of toxic forms of α-synuclein, knock­ ing down levels of host SNCA to prevent their misfolding, preventing the spread of misfolded SNCA, or blocking the templating phenom­ enon whereby misfolded α-synuclein promotes misfolding of the native protein in a prion-like chain reaction. Numerous studies testing dif­ ferent approaches to targeting α-synuclein are ongoing. Interestingly, postmortem studies in PD patients who had undergone a transplant procedure observed that inflammation with activated microglia at the transplant site preceded the development of α-synuclein aggregates by many years. This suggests the possibility that a chronic inflammatory milieu could promote misfolding of host α-synuclein, leading to neuro­ degeneration; to date, however, immune-based approaches to clearing α-synuclein have not been successful in PD. Pathogenic variants of the GBA1 gene represent the most important risk factor in terms of both the development of PD and its severity. GBA encodes the enzyme glucocerebrosidase (GCase), which pro­ motes lysosomal function and enhances the clearance of misfolded α-synuclein. The identification of GBA1 as a risk for PD resulted from the clinical observation that patients with Gaucher’s disease (GD) and their relatives show features of parkinsonism more frequently than would be expected. This clinical observation led to the discovery that literally hundreds of variants in GBA1 confer risk for the develop­ ment of PD. Experimentally, it has been shown that reduced levels of GCase activity due to GBA variants impair lysosomal function, resulting in the accumulation of α-synuclein. Conversely, the accumu­ lation of α-synuclein leads to inhibition of lysosomal function and a further reduction in levels of GCase by interfering with endoplasmic reticulum-to-Golgi trafficking. Thus, there is a vicious cycle in which decreased GCase activity leads to the accumulation of α-synuclein, and increased levels of α-synuclein lead to impairment in lysosomal func­ tion. In this regard, it is noteworthy that lysosomal function is impaired and levels of GCase are reduced in patients with sporadic PD, and not just in those with GBA1 variants. These findings suggest that this molecular pathway may not only apply to patients with a GBA1 vari­ ants but also to patients with sporadic PD or other synucleinopathies who have normal wild-type GBA1 alleles. Some studies suggest that patients with certain GBA1 variants (e.g., L444P) have a faster rate of progression and an increased frequency of cognitive impairment. Drug and gene-based therapies that enhance GCase activity and promote lysosomal function are currently being tested in the clinic as putative neuroprotective therapies. Multiple LRRK2 pathogenic mutations have also been clearly linked to PD; p.G2019S is the most common, possibly due to a founder effect in the Ashkenazi Jewish and North African Arab populations. Pathogenic variants in LRRK2 account for 2–41% of familial PD cases (depending on the specific population) and are also found in apparently sporadic cases, albeit at a lower rate. More than 200 variants have been reported. Recently developed functional assays testing acti­ vation of kinase activity as a gain-of-function effect help distinguish causative variants from those of uncertain significance. The phenotype of LRRK2 p.G2019S mutations is largely indistinguishable from that of sporadic PD, although tremor appears to be more common and disease progression is slightly slower than in idiopathic PD. The penetrance of LRRK2 pathogenic variants is incomplete (30–74% depending on the ethnic group), and patients tend to run a more benign course, with less cognitive impairment than seen in idiopathic PD. The mechanism responsible for cell death with this mutation is likely due to enhanced kinase activity with altered phosphorylation of target proteins (includ­ ing autophosphorylation) with possible impairment of lysosomal function. In laboratory models, kinase inhibitors can block toxicity associated with LRRK2 pathogenic variants. Accordingly, there has been interest in developing drugs directed at this target. However, nonselective kinase inhibitors are potentially toxic to the lungs and kidneys. Fortunately, LRRK2 inhibitors have now been developed that have good preclinical safety and are currently being tested in PD populations with and without pathogenic LRRK2 variants. There has been particular interest in c-Abl inhibitors, which target the tyrosine residue on α-synuclein protein and potentially prevent conversion to a toxic species. A pathogenic variant in RAB32 has been identified as a novel form of dominantly inherited PD with incomplete penetrance. Interestingly, LRRK2 and RAB32 interact directly, thus representing another potentially druggable target. CHAPTER 446 Parkinson’s Disease Pathogenic variants in PRKN, PINK1, and PARK7 have also been identified as a cause of PD. PRKN mutations are the most common and the major cause of autosomal recessive early-onset PD, accounting for up to 77% of juvenile PD patients, with an age of onset <20 years, and for 10–20% of early-onset PD patients in general. The disease is slowly progressive, responds well to antiparkinsonian treatment, and is com­ monly complicated by dystonia, but rarely by dementia. Pathologically, neurodegeneration tends to be restricted to the SNc and LC in patients with PRKN mutations, and Lewy bodies are only present in ~20% of the brains. The reason for these differences from classic PD is not known but may be related to the fact that parkin is a ubiquitin ligase and ubiquitination of damaged proteins is required for their clearance and possibly for their incorporation into Lewy bodies. The clinical phenotypes linked to pathogenic variants in PRKN, PINK1, and PRK7 are indistinguishable from one another. Parkin and PINK1 proteins are involved in cell protection mechanisms related to the turnover and clearance of damaged mitochondria (mitophagy). Indeed, mutations in Parkin and PINK1 cause mitochondrial dysfunction in transgenic animals that can be corrected with overexpression of parkin. Improv­ ing mitochondrial function is another attractive therapeutic target as postmortem studies in PD patients show a defect in complex I of the respiratory chain in SNc neurons. Several factors have been implicated in the pathogenesis of cell death in PD, including oxidative stress, inflammation, excitotoxicity, mitochondrial dysfunction, and lysosomal/proteasomal dysfunction. Inflammation and altered immunity have also been implicated as potentially key factors in the degenerative process. Genetic studies demonstrate an association of PD with the class II human leukocyte antigen (HLA) gene DRB1 (variants of which are associated with either protection or risk for PD) and findings in monogenic forms of PD demonstrating a role of inflammation and the immune sys­ tem. As noted above, this is supported by pathologic studies dem­ onstrating that inflammation occurs years before the accumulation of α-synuclein aggregates in transplanted patients, suggesting that inflammation plays a triggering role. Altered immunity has also been suggested by studies showing that autoreactive T cells recognizing peptides derived from α-synuclein are present in PD patients. Further, drugs such as sargramostim that upregulate T-regulatory cells have shown positive results in studies in animal models, and early studies in PD patients are underway. Whatever the pathogenic mechanism, cell death appears to occur, at least in part, by way of a signal-mediated apoptotic or “suicidal” process. Each of these mechanisms offers a potential target for putative neuroprotective drugs; however, clinical Etiology Oxidative stress Protein aggregation Excitotoxicity Inflammation Mitochondrial dysfunction PART 13 Neurologic Disorders Cell death FIGURE 446-4  Schematic representation of how pathogenetic factors implicated in Parkinson’s disease interact in a network manner, ultimately leading to cell death. This figure illustrates how interference with any one of these factors may not necessarily stop the cell death cascade. (Reproduced with permission from CW Olanow: The pathogenesis of cell death in Parkinson’s disease. Movement Disorders 22:S-335, 2007.) studies to date have not conclusively demonstrated a benefit using therapies directed against any of these targets. Moreover, it is not clear which of these factors is primary, if they are the same in all cases or specific to individual subgroups, if they act by way of a network such that multiple insults are required for neurodegeneration to ensue, or if the findings discovered to date merely represent epiphenomena unrelated to the true cause of cell death that still remains undiscovered (Fig. 446-4). It is anticipated that a better understanding of the pathways involved in the etiology and pathogenesis of cell death in PD will permit the development of more relevant animal models and better-defined tar­ gets for the development of neuroprotective drugs. Normal PD Dyskinesia Cortex Putamen SNc SNc SNc GPe GPe VL STN STN GPi SNr PPN A B C FIGURE 446-5  Basal ganglia organization. Classic model of the organization of the basal ganglia in the normal (A), Parkinson’s disease (PD) (B), and levodopa-induced dyskinesia (C) state. Inhibitory connections are shown as blue arrows and excitatory connections as red arrows. The striatum is the major input region and receives its input from the motor regions of the cerebral cortex. The GPi and SNr are the major output regions, and they project to the thalamocortical and brainstem motor regions. The striatum and GPi/SNr are connected by direct and indirect striatal pathways whose neurons are D1- and D2-bearing, respectively. This model predicts that parkinsonism results from decreased dopamine inhibition of the indirect pathway, leading to increased neuronal firing in the STN and GPi with inhibition of thalamocortical firing. These observations suggested that lesions or DBS of these targets might provide antiparkinsonian benefit. The model also predicts that dyskinesia results from decreased firing of the output regions, resulting in excessive cortical activation by the thalamus. This component of the model is not completely correct because lesions of the GPi ameliorate rather than increase dyskinesia in PD, suggesting that firing frequency is just one of the components that lead to the development of dyskinesia and that other components of the neuronal firing pattern such as pauses and bursts are also important. DBS, deep brain stimulation; GPe, external segment of the globus pallidus; GPi, internal segment of the globus pallidus; PPN, pedunculopontine nucleus; SNc, substantia nigra, pars compacta; SNr, substantia nigra, pars reticulata; STN, subthalamic nucleus; VL, ventrolateral thalamus. (Derived from JA Obeso et al: Trends Neurosci 23:S8, 2000.) ■ ■PATHOPHYSIOLOGY OF PD The classic model of the organization of the basal ganglia in the normal and PD states is provided in Fig. 446-5. With respect to motor function, a series of neuronal circuits with multiple feedback and feedforward loops link the basal ganglia nuclei with correspond­ ing cortical and brainstem motor regions in a somatotopic manner. The striatum is the major input region of the basal ganglia, whereas the GPi and substantia nigra (SNr) are the major output regions. The input and output regions are connected via direct and indirect pathways that have reciprocal effects on basal ganglia activity and motor function. The output of the basal ganglia provides inhibitory (GABAergic) tone to modulate excitatory thalamic and brainstem neurons that, in turn, connect to motor systems in the cerebral cortex and spinal cord that control motor function. An increase in neuronal activity in the output regions of the basal ganglia (GPi/SNr) is associated with reduced thalamic activity and poverty of move­ ment or parkinsonism, while decreased output results in movement facilitation. Dopaminergic projections from SNc neurons serve to modulate neuronal firing (in both directions) and thus to stabilize the basal ganglia network. Normal dopamine innervation thus serves to facilitate the selection of the desired movement and suppression or rejection of unwanted movements. Cortical loops integrating the cortex and the basal ganglia are thought to also play an important role in regulating other systems, such as behavioral, emotional, and cognitive functions. In PD, dopamine denervation with loss of dopaminergic tone leads to increased firing of neurons in the STN and GPi, excessive inhibition of the thalamus, reduced activation of cortical motor systems, and the development of parkinsonian features (Fig. 446-5). The current role of surgery in the treatment of PD is based on this model, which predicted that lesions or high-frequency stimulation of the STN or GPi might reduce their inhibition of thalamocortical pathways and thus improve PD features. This model has not proven to be as valuable in under­ standing dyskinesia where benefits are also seen with lesions in these regions (see below) and where it is now thought that that dyskinesia arises from altered firing patterns and not just firing frequency. Cortex Cortex Cortex Putamen Putamen DA DA GPe VL VL STN GPi GPi SNr SNr PPN PPN ■ ■COVID-19 AND PD SARS-CoV-2 viral infection can worsen PD features and off time. In addition, having PD increases the risks of complications and death rate associated with having a SARS-CoV-2 infection. Interestingly, it has been shown that the SARS-CoV-2 virus can enter the brain and cause inflammation with microglial activation, and new-onset cases of PD have been reported following infection. In this regard, it raises similarities to PD cases associated with the influenza A epidemic in 1918. Home confinement due to the risks of acquiring SARS-CoV-2 infection has also altered conduct of clinical trials in PD patients and promoted “remote” clinical trials in which patients are evaluated online rather than in person. With validation of the reliability of this approach, it is likely that remote clinical trials will be increasingly employed in routine clinical trials of PD patients. TREATMENT Parkinson’s Disease LEVODOPA Since its introduction in the late 1960s, levodopa has been the main­ stay of therapy for PD. Experiments in the late 1950s by Carlsson and colleagues demonstrated that blocking dopamine uptake with reser­ pine caused rabbits to become parkinsonian; this could be reversed with the dopamine precursor levodopa. Subsequently, Hornykiewicz demonstrated a dopamine deficiency in the striatum of PD patients and suggested the potential benefit of dopamine replacement ther­ apy. Dopamine does not cross the blood-brain barrier (BBB), so clinical trials were initiated with levodopa, the precursor of dopa­ mine. Studies over the course of the next decade confirmed the value of levodopa and revolutionized the treatment of PD. Levodopa is routinely administered in combination with a peripheral decarboxylase inhibitor to prevent its peripheral metab­ olism to dopamine and the development of nausea, vomiting, and orthostatic hypotension due to activation of dopamine receptors in the area postrema (the nausea and vomiting center) that are not protected by the BBB. In the United States, levodopa is combined with the decarboxylase inhibitor carbidopa (Sinemet), whereas in many other countries, it is combined with benserazide (Madopar). Levodopa plus a decarboxylase inhibitor is also available in a meth­ ylated formulation, a controlled-release formulation (Sinemet CR or Madopar HP), and in combination with a catechol-O-methyl­ transferase (COMT) inhibitor (Stalevo). A long-acting formulation of levodopa (Rytary), a levodopa-carbidopa intestinal gel adminis­ tered continuously by intra-intestinal infusion, continuous subcu­ taneous infusions of a levodopa formulation, and an inhaled form of levodopa that is absorbed through the pulmonary alveoli are also now available (see below). Levodopa remains the most effective symptomatic treatment for PD and the gold standard against which new therapies are compared. Early PD Dyskinesia threshold Clinical effect Clinical effect Response threshold Time (h) ↑Levodopa Time (h) ↑Levodopa • Long-duration motor response • Low incidence of dyskinesias • Short-duration motor response • “On” time may be associated with dyskinesias FIGURE 446-6  Changes in motor response associated with chronic levodopa treatment. Levodopa-induced motor complications. Schematic illustration of the gradual shortening of the duration of a beneficial motor response to levodopa (wearing off) and the appearance of dyskinesias complicating “on” time. PD, Parkinson’s disease. No current medical or surgical treatment provides antiparkinsonian benefits superior to what can be achieved with levodopa. Levodopa benefits the classic motor features of PD, prolongs independence and employability, improves quality of life, and increases life span. Indeed, levodopa also benefits some “nondopaminergic” features such as anxiety, depression, and sweating. Almost all PD patients experience improvement, and failure to respond to an adequate trial of levodopa should cause the diagnosis to be questioned. There are important limitations of levodopa therapy. Acute dopaminergic side effects include nausea, vomiting, and orthostatic hypotension. These are usually transient and can generally be avoided by starting with low doses and gradual up-titration. If they persist, they can be treated with additional doses of a peripheral decarboxylase inhibitor (e.g., carbidopa) or administered with food or a peripheral dopamine-blocking agent such as domperidone (not available in the United States). As the disease continues to progress, features such as falling, freezing, autonomic dysfunction, sleep disorders, and dementia may emerge that are not adequately controlled by levodopa. Indeed, these nondopaminergic features (especially falls and dementia) are the primary source of disability and the main reason for hospitalization and nursing home place­ ment for patients with advanced PD in the levodopa era. CHAPTER 446 Parkinson’s Disease The major concern with levodopa is that chronic treatment with ongoing disease progression is associated in most patients with the development of motor complications. Motor complica­ tions consist of fluctuations in motor response (“on” episodes when the drug is working and “off” episodes when Parkinsonian features return as the drug wears off) and involuntary movements known as dyskinesias, which typically complicate “on” periods (Fig. 446-6). When patients initially take levodopa, benefits are long-lasting (many hours and to some degree even weeks—the “long-duration” response) even though the drug has a relatively short half-life (60–90 min). With continued treatment, however, the duration of benefit following an individual dose becomes pro­ gressively shorter until benefits approach the half-life of the drug. This loss of benefit is known as the wearing-off effect. Some patients may also experience a rapid and unpredictable switch from the on to the off state known as the on-off phenomenon. In advanced cases, because of variability in the bioavailability of standard oral levodopa, the response to an individual dose of levodopa may be variable and unpredictable with the patient experiencing a full-on response, a partial-on response, a delay in turning on (delayed-on), or no response at all (no-on). Peak-dose dyskinesias occur at the time of levodopa peak plasma concentration and maximal clinical benefit. They are usually choreiform but can manifest as dystonic movements, myoclonus, or other movement disorders. They are not troublesome when mild but can be disabling when severe and can limit the ability to use higher doses of levodopa to better control PD motor features. In more advanced states, patients may cycle between “on” periods complicated by disabling dyskinesias Moderate PD Advanced PD Dyskinesia threshold Dyskinesia threshold Clinical effect Response threshold Response threshold Time (h) ↑Levodopa • Short-duration motor response • “On” time consistently associated with dyskinesias and “off” periods in which they suffer from severe parkinson­ ism and painful dystonic postures. Patients may also experience “diphasic dyskinesias,” which occur with lower plasma levodopa levels and manifest as the levodopa dose begins to take effect and again as it wears off. These dyskinesias typically consist of transient, stereotypic, rhythmic movements that predominantly involve the lower extremities asymmetrically and are frequently associated with parkinsonism in other body regions. They can be relieved by increasing the dose of levodopa (although higher doses may induce peak-dose dyskinesia) and disappear as the concentration declines. Long-term double-blind studies show that the risk of developing motor complications can be minimized by using the lowest dose of levodopa that provides satisfactory benefit and through the use of polypharmacy to avoid the need for raising the dose of levodopa. The precise cause of levodopa-induced motor complications is not known. They are more likely to occur in younger individuals, with the use of higher doses of levodopa, in females, and in those with more severe disease. The classic model of the basal ganglia has been useful for understanding the origin of motor features in PD, as noted above, but has proven less valuable for understanding levodopa-induced dyskinesias (Fig. 446-5). The model predicts that dopamine replacement might excessively inhibit the pallidal out­ put system, thereby leading to increased thalamocortical activity, enhanced stimulation of cortical motor regions, and the develop­ ment of dyskinesia. However, lesions of the pallidum that dramati­ cally reduce its output are associated with amelioration rather than induction of dyskinesia as would be suggested by the classic model. It is now thought that dyskinesia results from alterations in the GPi/ SNr neuronal firing pattern (pauses, bursts, synchrony, etc.) and not simply the firing frequency alone. This leads to the transmission of “misinformation” from pallidum to thalamus/cortex, which along with firing frequency contributes to the development of dyskinesia. Surgical or ultrasound lesions or high-frequency stimulation tar­ geted at the GPi or STN presumably ameliorate dyskinesia by inter­ fering with (blocking or masking) this abnormal neuronal activity and preventing the transfer of misinformation to motor systems. PART 13 Neurologic Disorders A number of studies suggest that motor complications develop in response to nonphysiologic levodopa replacement. Striatal dopa­ mine levels are normally maintained at a relatively constant level. In PD, where dopamine neurons and terminals have degenerated, striatal dopamine levels are dependent on the peripheral availability of levodopa. Intermittent oral doses of levodopa result in fluctuating plasma levels because of the short half-life of the drug and variability in the transit of the drug from the stomach to the jejunum where it is absorbed. These fluctuations are also reflected in the brain and result in striatal dopamine receptors being exposed to alternating pathologically high and low concentrations of dopamine. This in turn has been shown to induce molecular alterations in striatal neurons, neurophysiologic changes in pallidal output neurons, and ultimately the development of motor complications. It has been hypothesized that more continuous delivery of levodopa might be more physiologic and prevent the development or reduce the fre­ quency of motor complications. Indeed, double-blind studies in PD patients have demonstrated that continuous intraintestinal infusion of levodopa/carbidopa and continuous subcutaneous infusion of apomorphine or levodopa are associated with significant improve­ ment in “off” time and in “on” time without troublesome dyskinesia, compared with intermittent doses of standard oral levodopa. These benefits are superior to those observed in placebo-controlled stud­ ies with other dopaminergic agents. Intestinal infusion of levodopa is approved in the United States and Europe (Duodopa, Duopa). The treatment can, however, be complicated by potentially serious adverse events related to the surgical procedure, problems related to the tubing, and the inconvenience of having to wear an infusion system. Continuous subcutaneous delivery of levodopa or apomor­ phine avoids the need for a surgical procedure but is associated with a high frequency of cutaneous lesions and still requires wearing the inconvenient pump system. These are approved in Europe but not yet in the United States. Behavioral complications can also be associated with levodopa treatment. A dopamine dysregulation syndrome has been described where patients have a craving for levodopa and take frequent and unnecessary doses of the drug in an addictive manner. (In this regard, it is noteworthy that cocaine binds to the dopamine uptake receptor.) PD patients taking high doses of levodopa can also develop purposeless, stereotyped behaviors such as the assem­ bly and disassembly or collection and sorting of objects. This is known as punding, a term taken from the Swedish description of the meaningless behaviors seen in chronic amphetamine users. Hypersexuality and other impulse-control disorders are occasion­ ally encountered with levodopa but are more commonly seen with dopamine agonists. Finally, because levodopa undergoes oxidative metabolism and has the potential to generate toxic free radicals, there has been con­ cern that independent of the drug’s ability to provide symptomatic benefits, it might accelerate neuronal degeneration. Alternatively, as levodopa improves long-term outcomes in comparison to the pre-levodopa era, it has been suggested that by restoring striatal dopamine, levodopa has the potential to have a disease-modifying or neuroprotective effect. Neither of these hypotheses has been established. A recent delayed start study (explained below) showed neither beneficial nor deleterious effects of levodopa on the rate of clinical progression. Thus, it is generally recommended that levodopa be used solely based on its potential to provide symptom­ atic benefits balanced by the risk of inducing motor complications and other side effects. DOPAMINE AGONISTS Dopamine agonists are a diverse group of drugs that act directly on dopamine receptors. Unlike levodopa, they do not require meta­ bolic conversion to an active product and do not undergo oxidative metabolism. Initial dopamine agonists were ergot derivatives (e.g., bromocriptine, pergolide) and were associated with potentially seri­ ous ergot-related side effects such as cardiac valvular damage and pulmonary fibrosis. They have largely been replaced by a second generation of non-ergot dopamine agonists (e.g., pramipexole, ropinirole, rotigotine). In general, dopamine agonists do not have comparable efficacy to levodopa. They were initially introduced as adjuncts to levodopa to enhance motor function and reduce “off” time in fluctuating patients. Subsequently, it was shown that dopa­ mine agonists are less prone than levodopa to induce dyskinesia, possibly because they are relatively long acting in comparison to levodopa. For this reason, many physicians initiated therapy with a dopamine agonist, particularly in younger patients who are more prone to develop motor complications, although supplemental levodopa is eventually required in virtually all patients. This view has been tempered by the recognition that dopamine agonists are associated with potentially serious adverse effects such as unwanted sleep episodes and impulse control disorders (see below). Both ropinirole and pramipexole are available as orally administered immediate (three times a day) and extended-release (once a day) formulations. Rotigotine is administered as a once-daily transder­ mal patch and may be useful in managing surgical patients who are not able to be treated with an oral therapy. Apomorphine is the one dopamine agonist with efficacy thought to be comparable to levodopa, but it must be administered parenterally as it is rapidly and extensively metabolized if taken orally. It has a short half-life and duration of activity (45 min). It can be administered by subcu­ taneous injection as a rescue agent for the treatment of severe “off” episodes but can also be administered by continuous subcutaneous infusion where it has been shown to reduce both “off” time and dyskinesia in advanced patients. A sublingual bilayer formulation of apomorphine has been approved as a rapid and reliable therapy for individual “off” periods that avoids the need for a subcutaneous (SC) injection (see below). Dopamine agonist use is associated with a variety of side effects. Acute side effects are primarily dopaminergic and include nau­ sea, vomiting, and orthostatic hypotension. These can usually be avoided or minimized by starting with low doses and slowly uptitrating over weeks. Side effects associated with chronic use include hallucinations, cognitive impairment, and leg edema. Sedation with sudden unintended episodes of falling asleep that can occur in dan­ gerous situations, such as while driving a motor vehicle, have been reported. Patients should be informed about this potential problem and should not drive when tired. Dopamine agonists can also be associated with impulse-control disorders, including pathologic gambling, hypersexuality, and compulsive eating and shopping. Patients should be advised of these risks and specifically questioned for their occurrence at follow-up examinations. The precise cause of these problems, and why they appear to occur more frequently with dopamine agonists than levodopa, remains to be resolved, but differential effects on reward systems associated with dopamine and alterations in the ventral striatum and orbitofrontal regions have been implicated. In general, chronic side effects are doserelated and can be avoided or minimized with lower doses. Injec­ tions of apomorphine can be complicated by skin lesions at sites of administration, which can be minimized by proper cleaning and alternating the injection sites. The sublingual bilayer formulation of apomorphine can be associated with oropharyngeal side effects, but these are generally mild and resolve either spontaneously or with treatment withdrawal. A selective D1 agonist has been developed and shown to have mild antiparkinsonian effects but not greater than those seen with other available dopamine agonists. MAO-B INHIBITORS Inhibitors of monoamine oxidase type B (MAO-B) block cen­ tral dopamine MAO-B-oxidative metabolism and thereby increase synaptic concentrations of the neurotransmitter. Selegiline and rasagiline are relatively selective suicide inhibitors of the MAO-B isoform of the enzyme. Clinically, these agents provide antiparkin­ sonian benefits when used as monotherapy in early disease stages and reduced “off” time when used as an adjunct to levodopa in patients with motor fluctuations. MAO-B inhibitors are generally safe and well tolerated. They may increase dyskinesia in levodopatreated patients, but this can usually be controlled by down-titrating the dose of levodopa. Inhibition of the MAO-A isoform prevents metabolism of tyramine in the gut, leading to a potentially fatal hypertensive reaction known as a “cheese effect” because it can be precipitated by foods rich in tyramine such as some cheeses, aged meats, and red wine. Currently available MAO-B inhibitors are selective, do not functionally inhibit the MAO-A enzyme, and are not associated with a cheese effect with doses used in clinical prac­ tice. There are theoretical risks of a serotonin reaction in patients receiving concomitant selective serotonin reuptake inhibitor (SSRI) antidepressants, but these are rarely encountered. Safinamide is a reversible and selective MAO-B inhibitor that has been approved as an adjunct to levodopa for treating advanced PD patients with motor fluctuations. The drug also acts to block activated sodium channels and inhibit glutamate release and therefore has the poten­ tial to provide antidyskinetic as well as ant-parkinsonian effects. Interest in MAO-B inhibitors has also focused on their potential to have disease-modifying effects (see below). COMT INHIBITORS When levodopa is administered with a decarboxylase inhibitor, it is primarily metabolized in the periphery by the COMT enzyme. Inhibitors of COMT block its peripheral metabolism, increase the elimination half-life of levodopa, and enhance its brain availability. Combining levodopa with a COMT inhibitor reduces “off” time and prolongs “on” time in fluctuating patients while enhancing motor scores. The COMT inhibitors tolcapone and entacapone have been available for more than a decade; tolcapone is administered three times daily, while entacapone is administered in combination with each dose of levodopa. Opicapone, a long-acting COMT inhibitor that only requires once-daily administration, has more recently been approved in both Europe and the United States. A combination tab­ let of levodopa, carbidopa, and entacapone (Stalevo) is also available. Side effects of COMT inhibitors are primarily dopaminer­ gic (nausea, vomiting, increased dyskinesia) and can usually be controlled by down-titrating the dose of levodopa by 20–30% if required. Severe diarrhea has been described with tolcapone, and to a lesser degree with entacapone, and necessitates stopping the medication in 5–10% of individuals. Rare cases of fatal hepatic tox­ icity have been reported with tolcapone. It is still used because it is the most effective of the COMT inhibitors, but periodic monitoring of liver function is required. Liver problems have not been encoun­ tered with entacapone or opicapone. Discoloration of urine can be seen with COMT inhibitors due to accumulation of a metabolite, but it is of no clinical concern. It has been proposed that initiating levodopa in combination with a COMT inhibitor to enhance its elimination half-life could provide more continuous levodopa delivery and reduce the risk of motor complications (see below). While this result has been demonstrated in a preclinical MPTP model of PD, and continuous infusion reduces both “off” time and dyskinesia in advanced PD patients, no benefit of initiating levodopa with a COMT inhibitor compared to levodopa alone was detected in early PD patients in the STRIDE-PD study. This may have been because the combina­ tion was not administered at frequent enough intervals to provide continuous levodopa availability. For now, the main value of COMT inhibitors continues to be as an adjunct to levodopa. CHAPTER 446 Parkinson’s Disease OTHER MEDICAL THERAPIES Adenosine A2A receptor antagonists are a class of drugs that inhibit A2A receptors that form heterodimers with D2 dopamine receptors on medium spiny striatal D2-bearing neurons of the indirect path­ way. Blockade of A2A receptors decreases the excessive activation of the indirect pathway in PD and theoretically restores balance in the basal ganglia–thalamocortical circuit, providing a dopaminergic effect without the need to increase levodopa doses and activate D1-receptor-bearing neurons that comprise the direct pathway. Three A2A antagonists have been studied in PD, but development in two has been discontinued: preladenant because it failed in phase 3 studies and tozadenant because of agranulocytosis in a few patients. Istradefylline is the only agent that is currently approved for use. Clinical trials in advanced PD patients showed improve­ ment in “off” time comparable to other available agents but not in dyskinesia. The drug is generally well tolerated, with adverse events similar to dopaminergic agents. Interestingly, caffeine is a potent A2A antagonist, and epidemiologic studies suggest that drinking coffee is associated with a reduced frequency of PD. This has raised the question as to whether this class of agent might be neuroprotec­ tive, but this has not been established in clinical trials. Amantadine was originally introduced as an antiviral agent, but the drug was observed to also have antiparkinsonian effects, likely due to antagonism of the N-methyl-d-aspartate (NMDA) recep­ tor. While some physicians use amantadine in patients with early disease for its mild symptomatic effects, it is most widely used as an antidyskinesia agent in patients with advanced PD. Indeed, it is the only oral agent demonstrated in controlled studies to reduce dyskinesia without worsening parkinsonian features (indeed, motor benefits have been reported to be improved). Cognitive impairment is a major concern, particularly with high doses. Other side effects include livedo reticularis and weight gain. Amantadine should always be discontinued gradually because patients can experience withdrawal-like symptoms. An extended-release formulation of amantadine has also been developed. Central-acting anticholinergic drugs such as trihexyphenidyl and benztropine were used historically for the treatment of PD, but they lost favor with the introduction of levodopa. Their major clinical effect is on tremor, although it is not certain that this benefit is supe­ rior to what can be obtained with agents such as levodopa and dopa­ mine agonists. Still, they can be helpful in individual patients with severe tremor. Their use is limited particularly in the elderly, due to their propensity to induce a variety of side effects, including urinary dysfunction, glaucoma, and particularly cognitive impairment. TABLE 446-5  Drugs Commonly Used for Treatment of Parkinson’s Diseasea AGENT AVAILABLE DOSAGES TYPICAL DOSING Levodopaa       Carbidopa/levodopa 10/100, 25/100, 25/250 mg 200–1000 mg levodopa/day   Benserazide/levodopa 25/100, 50/200 mg     Carbidopa/levodopa CR 25/100, 50/200 mg     Benserazide/levodopa 25/200, 25/250 mg   MDS   Parcopa 10/100, 25/100, 25/250 mg     Rytary (carbidopa/ 23.75/95, 36.25/145, 48.75/195, 61.25/245 12.5/50/200, 18.75/75/200, 25/100/200, 31.25/125/200, 37.5/150/200, 50/200/200 mg See conversion tables levodopa)   Carbidopa/levodopa/ entacapone PART 13 Neurologic Disorders Dopamine agonists       Pramipexole 0.125, 0.25, 0.5, 1.0, 1.5 mg 0.25–1.0 mg tid   Pramipexole ER 0.375, 0.75, 1.5. 3.0, 4.5 mg 1–3 mg/d   Ropinirole 0.25, 0.5, 1.0, 3.0 mg 6–24 mg/d   Ropinirole XL 2, 4, 6, 8 mg 6–24 mg/d   Rotigotine patch 2-, 4-, 6-, 8-mg patches 4–24 mg/d   Apomorphine SC 2–8 mg 2–8 mg COMT inhibitors       Entacapone 200 mg 200 mg with each levodopa dose   Tolcapone   Opicapone 100, 200 mg 50 mg 100–200 mg tid 50 mg HS MAO-B inhibitors       Selegiline 5 mg 5 mg bid   Rasagiline   Safinamide 0.5, 1.0 mg 100 mg 1 mg QAM 100 mg QAM On-demand therapy for off periods   Inhaled levodopa   Apomorphine sublingual     5–40 mg     Up to 5 doses per day Up to 5 doses per day strip Others   A2A antagonist—   20, 40 mg    20 or 40 mg/d Istradefylline   Amantadine—immediate, 100–400 mg extended-release aTreatment should be individualized. Generally, drugs should be started in low doses and titrated to optimal dose. Note: Drugs should not be withdrawn abruptly but should be gradually lowered or removed as appropriate. Abbreviations: COMT, catechol-O-methyltransferase; MAO-B, monoamine oxidase type B; QAM, every morning. The anticonvulsant zonisamide has also been shown to have mild antiparkinsonian effects and is approved for use in Japan. Its mechanism of action is unknown. Several classes of drugs are cur­ rently being investigated in an attempt to enhance antiparkinsonian effects, reduce “off” time, and treat or prevent dyskinesia. These include a selective inhibitor of the GPR6 receptor, which is local­ ized to D2-bearing striatal neurons, and a selective antagonist of the D3 receptor. A list of the major drugs and available dosage strengths currently available to treat PD is provided in Table 446-5. CONTINUOUS DOPAMINERGIC DELIVERY As noted above, there is evidence suggesting that motor complica­ tions are related to nonphysiologic restoration of brain DA with intermittent oral doses of short-acting levodopa formulations. To overcome these problems, several approaches have been developed to deliver levodopa in a more continuous manner. These include continuous intraintestinal and continuous subcutaneous delivery. Each of these has been shown to provide more stable plasma levodopa levels than intermittent doses of standard levodopa and to be associated with reduced “off” time and increased “on” time with­ out troublesome dyskinesia. Similar results have also been seen with continuous subcutaneous delivery of apomorphine, as well as con­ tinuous oral delivery using a small intraoral micropump attached to a retainer. Attempts continue to develop an oral formulation of levodopa that can provide relatively continuous plasma levodopa levels and avoid a surgical procedure with resulting risk for cutane­ ous nodules and abscesses and the need to wear an inconvenient and cumbersome infusion pump. ON-DEMAND THERAPIES FOR OFF PERIODS Despite all available therapies including continuous delivery, many patients still experience “off” periods. Off periods can be disabling for patients, placing them at risk for falling and choking. As noted above, taking an additional levodopa tablet does not reliably treat individual off episodes, and some patients may continue in the off state for hours despite a levodopa dose. This inability to reliably and rapidly treat off episodes causes many patients to become depressed, withdrawn, and unwilling to participate in social or business activities. Three therapies have now been approved as specific on-demand treatments for off periods: inhaled levodopa, subcutaneous injection of apomorphine, and sublingual apomor­ phine. Each of these is fast acting, avoids the variable bioavailability seen with standard oral levodopa, and provides a predictable return to the on state. NEUROPROTECTION Despite the many therapeutic agents available for the symptomatic treatment of PD, patients continue to progress and to develop intol­ erable disability. A neuroprotective or disease-modifying therapy that slows or stops disease progression remains the major unmet therapeutic need. Some trials have shown positive results (e.g., selegiline, rasagiline, pramipexole, ropinirole) consistent with a disease-modifying effect. However, it has not been possible to determine with certainty if the positive results were due to neu­ roprotection with slowing of disease progression or confounding symptomatic or pharmacologic effects that mask disease progres­ sion. Interest has focused on selegiline and rasagiline, as MPTP toxicity can be prevented experimentally by coadministration of an MAO-B inhibitor. These agents block the oxidative conversion of MPTP to the pyridinium ion MPP+ that is taken up by and selec­ tively damages dopamine neurons. MAO-B inhibitors also have the potential to block the oxidative metabolism of dopamine and prevent oxidative stress. In addition, both selegiline and rasagiline incorporate a propargyl ring within their molecular structure that provides antiapoptotic effects in laboratory models. In the classic DATATOP study, selegiline delayed the time until the emergence of disability necessitating the introduction of levodopa in untreated PD patients. However, it could not be defini­ tively determined whether this benefit was due to a neuroprotective effect that slowed disease progression or a symptomatic effect that merely masked ongoing neurodegeneration. The ADAGIO study tested the putative neuroprotective effects of rasagiline using a two-period delayed-start design. In the first period, patients are randomized to treatment with the active drug or placebo. In the second period, patients in both groups receive the active treat­ ment. If early treatment provides an enduring benefit that cannot be achieved with delayed treatment, the result is consistent with a disease-modifying effect. In ADAGIO, early treatment with rasagi­ line 1 mg/d provided significant benefits that could not be achieved when treatment with the same drug was initiated at a later time point, consistent with a disease-modifying effect. However, this benefit was not seen with the 2-mg dose, and it did not receive regu­ latory approval for this indication. The reason the 2-mg dose failed remains uncertain, but many physicians use rasagiline in early-stage patients based on its potential to have neuroprotective effects. Neuroprotective therapies that prevent the formation or accu­ mulation of toxic α-synuclein species, inhibit LRRK2, or enhance GCase are currently being studied. GLP-1 agonists, developed for use in diabetes, have also shown some promise based on antiinflammatory and pro-mitochondrial actions, but results in doubleblind studies have been inconsistent. SURGICAL TREATMENT Surgical treatments for PD have been used for more than a century. Lesions were initially placed in the motor cortex and improved tremor but were associated with motor deficits, and this approach was abandoned. Subsequently, it was appreciated that lesions placed into the ventral intermediate (VIM) nucleus of the thala­ mus reduced contralateral tremor without inducing hemiparesis, but these lesions did not meaningfully help other more disabling features of PD. In the 1990s, it was shown that lesions placed in the posteroventral portion of the GPi (motor territory) improved rigid­ ity and bradykinesia as well as tremor. Importantly, pallidotomy was also associated with marked improvement in contralateral dyskinesia. This procedure gained favor with greater understanding of the pathophysiology of PD (see above). However, this proce­ dure is not optimal because PD affects both sides of the body and bilateral lesions are associated with side effects such as dysphagia, dysarthria, and impaired cognition. Lesions of the STN are also associated with antiparkinsonian benefit and reduced levodopa requirement, but there is a concern about the risk of hemiballismus, and this procedure is not commonly performed. Most surgical procedures for PD performed today use deep brain stimulation (DBS). Here, an electrode is placed into the target area and connected to a stimulator inserted subcutaneously over the chest wall. DBS simulates the effects of a lesion without needing to make a brain lesion. The precise mechanism whereby DBS works is not fully understood but may act by disrupting the abnormal neu­ rophysiological signals that are associated with PD and motor com­ plications. The stimulation variables can be adjusted with respect to electrode configuration, voltage, frequency, and pulse duration in order to maximize benefit and minimize adverse side effects. The procedure does not require making a lesion in the brain and is thus suitable for performing bilateral procedures with relative safety. In cases where there are no benefits or with intolerable side effects, stimulation can be stopped and the system removed. DBS for PD is primarily used to target the STN or the GPi. It provides antiparkinsonian benefits, particularly with respect to tremor, and reduces both “off” time and dyskinesias but does not provide antiparkinsonian benefits that are superior to levodopa. The procedure is thus primarily indicated for patients who suffer disability from severe tremor or from levodopa-induced motor complications that cannot be satisfactorily controlled with drug adjustments. Side effects can result from the surgical procedure (hemorrhage, infarction, infection), the DBS system (infection, lead break, lead displacement, skin ulceration), or the stimulation itself (ocular and speech abnormalities, muscle twitches, paresthesias, depression, and rarely suicide). Results of DBS of the STN and GPi are comparable, but GPi stimulation may be associated with a reduced frequency of depression. Although not all PD patients are candidates, the procedure can be profoundly beneficial for the appropriate patient. Long-term studies demonstrate continued benefits with respect to the dopaminergic features of PD, but DBS does not prevent the development of nondopaminergic features, which continue to evolve as the disease progresses and are a source of disability. Studies continue to evaluate the optimal way to use DBS (e.g., low- vs high-frequency stimulation, closed loop systems, adaptive approaches). Trials of DBS in early PD patients show ben­ efits that may be superior to best medical therapy, but this must be weighed against the cost of the procedure and the risk of side effects in patients who might otherwise be well controlled with relatively safe medical therapies for many years especially if used correctly (see below). Additionally, the PD landscape is changing with the availability of on-demand therapies for treating off periods and the likelihood that future therapies may provide continuous levodopa availability with a reduced risk of motor complications. Controlled studies comparing DBS to other therapies aimed at improving motor function without causing dyskinesia, such as continuous intraintestinal or SC levodopa infusions, remain to be performed. The utility of DBS may also be reduced in the future if new medi­ cal therapies are developed that provide the benefits of levodopa without motor complications. New targets for DBS are also being actively explored directed at gait dysfunction, depression, and cog­ nitive impairment, as well as “smart” closed-loop devices that sense the patient’s need for stimulation (Chap. 500). MRI-guided ultrasound is also now being used to target critical regions such as the GPi or STN in PD patients with motor compli­ cations in a relatively noninvasive manner that avoids the needs for a surgical procedure. Preliminary results suggest good target local­ ization and safety. Ultrasound has also been used to interrupt the BBB in a specific location, which might facilitate access to the brain for therapies that otherwise might not cross the BBB. CHAPTER 446 OTHER EXPERIMENTAL THERAPIES FOR PD These include cell-based therapies (e.g., transplantation of dopa­ mine neurons derived from stem cells), gene therapies, and trophic factors. Transplant strategies are based on the concept of implant­ ing dopaminergic cells into the striatum to replace degenerating SNc dopamine neurons. Fetal nigral mesencephalic cells have been demonstrated to survive implantation, re-innervate the striatum in an organotypic manner, and restore motor function in PD models. However, two double-blind studies failed to show significant benefit of fetal nigral transplantation in comparison to a sham operation. Grafting of fetal nigral cells is associated with a previously unrec­ ognized form of dyskinesia (graft-induced dyskinesia) that persists after lowering or even stopping levodopa. This has been postulated to be related to suboptimal release of dopamine from grafted cells, leading to a sustained form of diphasic dyskinesia. In addition, there is evidence that, after many years, transplanted healthy embryonic dopamine neurons from unrelated donors develop PD pathology and become dysfunctional, suggesting transfer of α-synuclein from affected to unaffected neurons in a prion-like manner (see discus­ sion above). There are also concerns about immune reactions to the injection of foreign tissue. Stem cells, and specifically autologous induced pluripotent stem (IPS) cells derived from the recipient, may overcome problems related to immune reactions and physi­ ologic integration, but many of the concerns listed above still apply. To date, stem cells have not yet been properly tested in double-blind studies and bear the additional theoretical concern of malignant transformation and other unanticipated side effects. Importantly, it is not clear how replacing dopamine cells alone will improve the nondopaminergic features of PD such as falling and dementia, which are the major sources of disability for patients with advanced disease. While there remains a need for scientifically based studies to evaluate the potential role of cell-based therapies in PD, there is no basis for treating PD patients with stem cells in nonresearch studies, as is being marketed in some countries. Parkinson’s Disease Trophic factors are a series of proteins that enhance neuronal growth and potentially could restore function to damaged neurons. Based on laboratory studies, several different trophic factors appear to have beneficial effects on dopamine neurons, and glial-derived neurotrophic factor (GDNF) and neurturin have attracted particu­ lar attention as possible therapies for PD. However, double-blind trials of intraventricular and intraputaminal infusions of GDNF failed to benefit PD patients, possibly because of inadequate deliv­ ery of the trophic molecule to the target region. Gene therapy offers the potential of providing long-term expression of a therapeutic protein with a single procedure. Gene therapy involves placing the nucleic acid of a therapeutic protein into a viral vector that can then be taken up and incorporated into the genome of host cells and then synthesized and released on a continual basis. The AAV2 virus has been most often used as the vector because it does not promote an inflammatory response, is not incorporated into the host genome, does not induce insertional mutagenesis, and is associated with long-lasting transgene expression. AAV2 delivery of the trophic factor neurturin (a member of the GDNF family) showed promis­ ing results in open-label trials but also failed in double-blind trials, even when injected into both the putamen and the SNc. Nonethe­ less, long-term postmortem studies have demonstrated transgene survival with biological effects as long as 10 years after treatment. However, the degree of putaminal coverage was very small, and it is likely that much higher gene doses will be required if this type of therapy is to provide clinically meaningful results. Gene delivery is also being explored as a means of deliver­ ing aromatic amino acid decarboxylase with or without tyrosine hydroxylase into the striatum to facilitate the conversion of orally administered levodopa to dopamine. Animal studies suggest that this approach can provide antiparkinsonian benefits with reduced motor complications; clinical trials in PD patients are underway. Gene therapy is also being studied as a way to enhance GBA1 and the gene product GCase in an attempt to promote lysosomal clear­ ance of misfolded α-synuclein protein. PART 13 Neurologic Disorders Importantly, no clinically significant adverse events have been encountered in gene therapy studies directed at the central ner­ vous system to date, but there remains a risk of unanticipated side effects including mutagenesis. Further, it is not clear how current approaches directed at the dopamine system, even if successful, will address the nondopaminergic features of the illness. MANAGEMENT OF NONMOTOR AND NONDOPAMINERGIC FEATURES OF PD Although PD treatment has primarily focused on the dopaminergic features of the illness, management of the nondopaminergic fea­ tures should not be ignored. Some nonmotor features benefit from dopaminergic drugs. For example, problems such as anxiety, panic attacks, depression, pain, sweating, sensory problems, freezing, and constipation all tend to be worse during “off” periods and have been reported to improve with better dopaminergic control. Recent studies with light therapy suggest that exposure to the specific light frequencies can restore a more normal circadian rhythm (which is altered in PD) and provide both motor and nonmotor benefits, particularly with respect to sleep and mood. Approximately 50% of PD patients suffer depression during the course of the disease, and depression is frequently underdiag­ nosed and undertreated. Antidepressants should not be withheld, particularly for patients with major depression, although dopami­ nergic agents such as pramipexole may prove helpful for treating both depression and PD motor features. Anxiety is also a common problem, and if not adequately controlled with antiparkinsonian therapies, it can be treated with short-acting benzodiazepines. Psychosis can be a problem for some PD patients and is often a harbinger of developing dementia. In contrast to AD, hallucinations in PD patients are typically visual, formed, and nonthreatening. Importantly, they can be associated with the use of dopaminergic drugs and may limit the use of these agents required for satisfactory motor control. Initial management is to withdraw agents that are less effective than levodopa, such as anticholinergics, amantadine, and dopamine agonists, followed by lowering the dose of levodopa if possible. Psychosis in PD often responds to low doses of atypical neu­ roleptics and may permit higher doses of levodopa to be tolerated. Clozapine is an effective drug, but it can be associated with agranu­ locytosis, and regular monitoring is required. Quetiapine avoids these problems, but it has not been established to be effective in placebo-controlled trials. Pimavanserin (Nuplazid) differs from other atypical neuroleptics in that it is an inverse agonist and antagonist of the serotonin 5-HT2A receptor. It has been shown to be effective in short-term double-blind trials but has only mild efficacy (although it can be very effective in individual patients) and has been reported to be associated with QT prolongation and death in elderly patients. Dementia in PD (PDD) is common, ultimately affecting as many as 80% of patients. Its frequency increases with aging and, in contrast to AD, primarily affects executive functions and attention, with relative sparing of language, memory, and calculation domains. When dementia precedes or develops within 1 year after onset of motor dysfunction, it is by convention referred to as dementia with Lewy bodies (DLB; Chap. 445). Interestingly, if dementia develops in a PD patient after 12 months, it is referred to as PD dementia, although it is not clear that these represent different disease entities. These patients are particularly prone to experience hallucinations and diurnal fluctuations. Pathologically, DLB is characterized by Lewy bodies distributed throughout the cerebral cortex (especially the hippocampus and amygdala) and is more likely to be associated with AD pathology. It is notable that variants of the GBA1 gene are a significant risk factor for both PD and DLB. Mild cognitive impairment (MCI) frequently precedes the onset of dementia and is a more reliable index of impending dementia than in the general population as it occurs in the setting of a neurodegenerative disor­ der. Indeed, many PD patients demonstrate abnormalities in cogni­ tive testing even at the earliest stages of the disease despite having no overt clinical dysfunction. Drugs used to treat PD can worsen cognitive function and should be stopped or reduced to try and pro­ vide a compromise between antiparkinsonian benefit and preserved cognitive function. Drugs are usually discontinued in the follow­ ing sequence: anticholinergics, amantadine, dopamine agonists, COMT inhibitors, and MAO-B inhibitors. Eventually, patients with cognitive impairment should be managed with the lowest dose of standard levodopa that provides meaningful antiparkinsonian effects and does not worsen mental function. Anticholinesterase agents such as memantine and cholinesterase inhibitors such as riv­ astigmine improve measures of cognitive function and can improve attention in PD, but do not improve cognition or quality of life in any meaningful way. More effective therapies that treat or prevent dementia are a critical unmet need in the therapy of PD. Autonomic disturbances are common and frequently require attention. Orthostatic hypotension can be problematic and con­ tribute to falling. Initial treatment should include adding salt to the diet and elevating the head of the bed to prevent overnight sodium natriuresis. Low doses of fludrocortisone (Florinef) or midodrine provide control for most cases. The norepinephrine precursor 3-0-methylDOPS (Droxidopa) has been shown to provide mild but transient benefits for patients with orthostatic hypotension. Vasopressin and erythropoietin can be used in more severe or refractory cases. If orthostatic hypotension is prominent in early parkinsonian cases, a diagnosis of MSA should be considered (Chap. 451). Sexual dysfunction may be helped with sildenafil or tadalafil. Urinary problems, especially in males, should be treated in consultation with a urologist to exclude prostate problems. Anti­ cholinergic agents, such as oxybutynin (Ditropan), may be helpful. Constipation can be a very important problem for PD patients. Mild laxatives or enemas can be useful, but physicians should first ensure that patients are drinking adequate amounts of fluid and consuming a diet rich in bulk with green leafy vegetables and bran. Agents that promote GI motility can also be helpful. Several studies are evaluating the effect on constipation of agents that interfere with inflammation and α-synuclein misfolding in the GI tract. Sleep disturbances are common in PD patients, with many expe­ riencing fragmented sleep with excess daytime sleepiness. These can be severe and result in sudden-onset sleep episodes that may occur in dangerous situations such as while driving a car. These problems tend to be exaggerated by dopamine agonists, particularly in high doses. These problems may relate to alterations in circadian rhythm associated with degeneration in melanopsin-containing neurons in the retina and cells of the suprachiasmatic nucleus, which occur in PD patients. Recent studies suggest that both motor and nonmotor features may be improved with light therapy using specific wavelengths that restore circadian rhythm in PD patients. Restless leg syndrome, sleep apnea, and other sleep disorders also occur with increased frequency in PD and should be treated as appropriate. REM behavior disorder (RBD) is a syndrome com­ posed of violent movements and vocalizations during REM sleep, possibly representing acting out of dreams due to a failure of motor inhibition that typically accompanies REM sleep (Chap. 33). Many PD patients have a history of RBD preceding the onset of the classic motor features of PD by many years, and most cases of RBD even­ tually go on to develop an α-synucleinopathy (PD or MSA). Low doses of clonazepam (0.5–1 mg at bedtime) are usually effective in controlling this problem. Consultation with a sleep specialist and polysomnography may be necessary to identify and optimally treat sleep problems. Excess daytime sleepiness can be problematic for PD patients, and therapies such as sodium oxybate (Xyrem) that are effective in narcolepsy are currently being evaluated in PD NONPHARMACOLOGIC THERAPY Gait dysfunction with falling is an important cause of disability in PD. Dopaminergic therapies may be of help for patients whose gait is worse in “off” time, but there are currently no specific therapies for gait dysfunction. Canes and walkers may become necessary to increase stability and reduce the risk of falling. An effective therapy for gait impairment is an important unmet need in PD. Freezing, where patients suddenly become stuck in place for sec­ onds to minutes as if their feet were glued to the ground, is another important problem and a major cause of falling. Freezing may occur during “on” or “off” periods. Freezing during “off” periods may respond to dopaminergic therapies, but there are no specific treatments for “on” period freezing and the mechanism is not well understood. Some patients will respond to sensory cues such as marching in place, singing a song, or stepping over an imaginary line or obstacle. Speech impairment is another source of disability for many advanced PD patients. Speech therapy programs may be helpful, but benefits are generally limited and transient. Exercise has been shown to help maintain and even improve function for PD patients, and active and passive exercises with full range of motion reduce the risk of arthritis and frozen joints. Some laboratory studies suggest the possibility that exercise might also have neuroprotective effects, but this has not been confirmed in PD patients. Exercise is generally recommended for all PD patients. It is less clear that any specific type of physical therapy or exercise program, such as tai chi or dance, offers any specific advantage. It is important for patients to maintain social and intellectual activities to the extent possible. Education, assistance with financial planning, social services, and attention to home safety are important elements of the overall care plan. Information is available through numerous PD foundations and on the web but should be reviewed with physi­ cians to ensure accuracy. The needs of the caregiver should not be neglected. Caring for a person with PD involves a substantial work effort, and there is an increased incidence of depression among caregivers. Support groups for patients and caregivers may be useful. CURRENT MANAGEMENT OF PD The management of PD should be tailored to the needs of the individual patient, and there is no single treatment approach that is universally accepted and applicable to all individuals. Clearly, if an agent could be demonstrated to have disease-modifying effects, it should be initiated at the time of diagnosis or even in the premotor stage once that can be diagnosed with confidence. Recent studies suggest that striatal dopamine terminal degeneration may be com­ plete within 4 years of diagnosis and thus limit the potential benefit of a therapy started after that time, even if it has been shown to have protective effects. Epidemiologic and pathologic studies sug­ gest that constipation, RBD, and anosmia may represent premotor features of PD and, along with imaging of the dopamine system and biomarkers (see above), could permit diagnosis and the initiation of a disease-modifying therapy prior to the onset of the classical motor features of the disease. However, no therapy has yet been conclusively proven to be a disease-modifying agent, although as noted above, rasagiline 1 mg/d met all three prespecified primary endpoints consistent with such a benefit. For now, physicians must use their judgment in deciding whether or not to introduce a drug such as rasagiline for its possible disease-modifying effects based on available preclinical and clinical information. The next important issue to address is when to initiate symp­ tomatic therapy and which agent to use. Several studies suggest that it may be best to start therapy at the time of diagnosis in order to preserve beneficial compensatory mechanisms and possibly provide functional benefits with improved quality of life even in the early stage of the disease. Levodopa remains the most effec­ tive symptomatic therapy for PD, and the American Academy of Neurology recommends starting it immediately using low doses (≤400 mg/d), as motor complications have now clearly been shown to be dose-related. Other experts, however, prefer to delay intro­ duction of levodopa treatment, particularly in younger patients, in order to reduce the risk of inducing motor complications. An alternate approach is to begin with am MAO-B inhibitor and/or a dopamine agonist and reserve levodopa for later stages when these drugs no longer provide satisfactory control. In making this deci­ sion, the patient’s age, degree of disability, and the side effect profile of the drug must all be considered. In patients with more severe dis­ ability, the elderly, and those with cognitive impairment, significant comorbidities, or uncertain diagnosis, most physicians would initi­ ate therapy with levodopa. A new pill that combines very low doses of rasagiline and pramipexole in extended-release formulations has been developed that provides clinical benefits comparable to highdose pramipexole in higher doses but without sleep-related and dopaminergic side effects. As such, it could represent an alternative to levodopa as initial therapy for PD. CHAPTER 446 Parkinson’s Disease Regardless of initial choice, most patients ultimately benefit from polypharmacy (a combination of levodopa, an MAO-B inhibi­ tor, and a dopamine agonist) in order to minimize the total daily levodopa dose and reduce the risk of motor complications. While it is important to use low doses of each agent to reduce the risk of side effects, patients should not be denied levodopa when they cannot be adequately controlled with alternative medications. It is also important to discuss the risks and benefits of the different therapeutic options with patients so that they have informed opin­ ions as to whether they wish to start therapy early and, if so, which drug to start. If motor complications develop, patients can initially be treated by adjusting the frequency and dose of levodopa or by combining lower doses of levodopa with a dopamine agonist, a COMT inhibi­ tor, or an MAO-B inhibitor. An A2A antagonist such as istrade­ fylline is an additional therapy that can be used for treating off periods. Amantadine is the only drug that has been demonstrated to treat dyskinesia without worsening parkinsonism, but benefits may decline over time and there are important side effects related to cognitive function particularly with higher doses. On-demand therapies such as subcutaneous apomorphine, inhaled levodopa, and sublingual apomorphine can be used to treat individual off periods and can delay the need for surgery in some patients. In advanced cases where patients suffer motor complications that can­ not be adequately controlled with medical therapies, it may be nec­ essary to consider a surgical procedure such as DBS or a continuous dopaminergic therapy such as Duodopa or subcutaneous infusion of levodopa or apomorphine, but as described above, these proce­ dures have their own set of complications. The use of DBS in early PD patients has been advocated by some, but there is considerable skepticism about this approach considering the costs and potential side effects, when inexpensive, well-tolerated, and effective medical alternatives are available. Continuous intraintestinal infusion of levodopa/carbidopa intestinal gel (Duodopa) offers similar ben­ efits to DBS, but also requires a surgical intervention with poten­ tially serious complications. Continuous subcutaneous infusion of levodopa or apomorphine does not require surgery but is associ­ ated with potentially troublesome skin nodules and abscesses and requires wearing an inconvenient infusion pump during the course of the day and potentially around the clock. Comparative studies of these approaches are awaited. There are ongoing efforts aimed at developing a long-acting formulation of levodopa that mirrors the pharmacokinetic properties of a levodopa infusion. Such a formu­ lation might provide all of the benefits of levodopa without motor # 17 - 447 Tremor, Chorea, and Other Movement Disorders ### 447 Tremor, Chorea, and Other Movement Disorders Parkinson’s disease Nonpharmacologic intervention Pharmacologic intervention Neuroprotection —? Rasagiline Functional disability No Yes PART 13 Neurologic Disorders Dopamine agonists MAO-B inhibitor Levodopa Combination therapy Levodopa/dopamine agonist/COMT Inhibitor/MAO-B Inhibitor Surgery/CDS FIGURE 446-7  Treatment options for the management of Parkinson’s disease (PD). Decision points include: (1) Introduction of a neuroprotective therapy: no drug has been established to have or is currently approved for neuroprotection or disease modification, but there are several agents that have this potential based on laboratory and preliminary clinical studies (e.g., rasagiline 1 mg/d). (2) When to initiate symptomatic therapy: There is a trend toward initiating therapy at the time of diagnosis or early in the course of the disease because patients may have some disability even at an early stage, and there is the possibility that early treatment may preserve beneficial compensatory mechanisms; however, some experts recommend waiting until there is functional disability before initiating therapy. (3) What therapy to initiate: many experts favor starting with low doses of levodopa particularly in the elderly and those with more advanced disease. A monoamine oxidase type B (MAO-B) inhibitor may be preferred in mildly affected patients because of their good safety profile and the potential for a disease-modifying effect. Some prefer dopamine agonists for younger patients with functionally significant disability as they have a reduced risk of inducing motor complications. All patients eventually require levodopa, but it is generally recommended to employ polypharmacy using low doses of multiple drugs to avoid side effects associated with high doses of any one agent and minimize the risks of levodopa-induced motor complications. (4) Management of motor complications: motor complications are typically approached with combination therapy to try and reduce dyskinesia and enhance the “on” time. When medical therapies cannot provide satisfactory control, surgical therapies such as deep brain stimulation (DBS) or continuous infusion of levodopa/carbidopa or apomorphine can be considered. (5) Nonpharmacologic approaches: interventions such as exercise, education, and support should be considered throughout the course of the disease. CDS, continuous dopaminergic stimulation; COMT, catechol-O-methyltransferase. (Reproduced with permission CW Olanow et al: Neurology 72:S1, 2009.) complications and avoid the need for polypharmacy and surgical intervention. Treatment for the nonmotor features of PD should be instituted as deemed appropriate, and exercise therapy is recom­ mended for all patients. A decision tree that considers the various treatment options and decision points for the management of PD is provided in Fig. 446-7. ■ ■FURTHER READING Balestrino R, Schapira AHV: Parkinson disease. Eur J Neurol 27:27, 2020. Ben-Shlomo Y et al: The epidemiology of Parkinson’s disease. Lancet 403:283, 2024. Berg D et al: MDS research criteria for prodromal Parkinson’s disease. Mov Disord 12:1600, 2015. Blauwendraat C et al: The genetic architecture of Parkinson’s disease. Lancet Neurol 19:170, 2020. Bloem BR et al: Parkinson’s disease. Lancet 397:2284, 2021. Marras C et al: Nomenclature of genetic movement disorders: Rec­ ommendations of the International Parkinson and Movement Disor­ der Society task force. Mov Disord 32:724, 2017. Morris HR et al: The pathogenesis of Parkinson’s disease. Lancet 403:293, 2024. Obeso JA et al: Past, present and future of Parkinson’s disease: A special essay on the 200th Anniversary of the Shaking Palsy. Mov Disord 32:1264, 2017. Postuma RB et al: MDS clinical diagnostic criteria for Parkinson’s disease. Mov Disord 12:1591, 2015. Schapira AHV et al: Non-motor features of Parkinson disease. Nat Rev Neurosci 18:446, 2017. Siderowf A et al: Assessment of heterogeneity among participants in the Parkinson’s Progression Markers Initiative cohort using alphasynuclein seed amplification: A cross-sectional study. Lancet Neurol 22:407, 2023. Tremor, Chorea, and Other Movement Disorders C. Warren Olanow*, Christine Klein HYPERKINETIC MOVEMENT DISORDERS Hyperkinetic movement disorders are characterized by involuntary movements unaccompanied by weakness. The major clinical features are summarized in Table 447-1. The term is somewhat arbitrary and potentially misleading as hypokinetic disorders such as Parkinson’s disease (PD) are often accompanied by tremor, while hyperkinetic disorders such as dystonia may be manifest as slow or restricted move­ ment because of severe muscle contractions. Nonetheless, the terms continue to be used by convention. The major hyperkinetic movement disorders and the diseases with which they are associated are consid­ ered in this section. TREMOR ■ ■CLINICAL FEATURES Tremor is defined as an involuntary, rhythmic, oscillatory movement of a body part with alternating contraction of agonist and antagonist muscles. It can be most prominent at rest (rest tremor), on assuming a posture (postural tremor), on actively reaching for a target (kinetic or intention tremor), or on carrying out a movement (action tremor). Tremor may also be characterized based on its distribution, frequency, amplitude, and related neurologic dysfunction. Tremor is classified along two axes: Axis 1 covers the clinical characteristics and histori­ cal features (age at onset, family history, temporal evolution), tremor characteristics (body distribution, activation condition), associated signs (systemic, neurologic), and laboratory tests (electrophysiology, imaging). Axis 2 relates to the etiology of the tremor and distinguishes genetic, secondary, or idiopathic origins. Essential tremor (ET) is characterized by a tremor that typically occurs while trying to sustain a posture and/or an action tremor that is noted when reaching toward a target. This contrasts with the resting tremor of PD (Chap. 446), which is characterized by a predominant resting tremor and is less pronounced with action. Cerebellar dys­ function is characterized by a kinetic tremor (brought out by trying to touch an object) and is usually associated with hypotonia and past pointing. Healthy individuals can have a physiologic tremor that typically manifests as a mild, high-frequency (10–12 Hz), postural, or *Deceased. TABLE 447-1  Hyperkinetic Movement Disorders Tremor Rhythmic oscillation of a body part due to intermittent muscle contractions Dystonia Involuntary, patterned, sustained, or repeated muscle contractions often associated with twisting movements and abnormal posture Athetosis Slow, distal, writhing, involuntary movements with a propensity to affect the arms and hands (this represents a form of dystonia with increased mobility) Chorea Rapid, semi-purposeful, graceful, dance-like nonpatterned involuntary movements involving distal or proximal muscle groups. When the movements are of large amplitude and predominant proximal distribution, the term ballism is used. Myoclonus Sudden, brief (<100 ms), jerk-like, arrhythmic muscle twitches Tic Brief, repeated, stereotyped muscle contractions that can often be suppressed for a short time. These can be simple and involve a single muscle group or complex and affect a range of motor activities. action tremor typically affecting the upper extremities. This tremor is usually of no clinical consequence and often is only appreciated with an accelerometer or under stress. An enhanced physiologic tremor (EPT) can be seen in up to 10% of the population and tends to occur in asso­ ciation with lifting a weight, anxiety, fatigue, a metabolic disturbance (e.g., hyperthyroidism, electrolyte abnormalities), drugs (e.g., valpro­ ate, lithium), or toxins (e.g., caffeine, smoking, alcohol). Treatment is initially directed at control of any underlying disorder, and if necessary, it can often be improved with a beta blocker. ■ ■ESSENTIAL TREMOR ET is the most common movement disorder, affecting ~1% of the population and 5% of those over 60 years (an estimated 5–10 million persons in the United States or Western Europe). It can present in childhood but dramatically increases in prevalence in those aged >70 years. ET is characterized by a high-frequency tremor (6–10 Hz) that predominantly affects the upper extremities. The tremor is most often manifest as a postural or action tremor and, in severe cases, can interfere with functions such as eating and drinking. It is typically bilat­ eral and symmetric but may begin on one side and remain asymmetric. Patients with severe ET can have an intention tremor with overshoot and slowness of movement, along with mild ataxia, suggesting the possibility of a cerebellar origin. Tremor involves the head in ~30% of cases, voice in ~20%, tongue in ~20%, face/jaw in ~10%, and lower limbs in ~10%. Multiple body parts are involved in ~50% of cases. The tremor is characteristically improved by alcohol and worsened by stress. Usually, the neurologic examination is normal aside from tremor, but subtle impairment of coordination or tandem walking may be present, and disturbances of hearing, cognition, personality, mood, and olfaction have been described. The differential diagnosis includes dystonic tremor (see below) or PD. PD can usually be differentiated from ET because the former tends to be present primarily at rest and to be suppressed by a voluntary action. Further, PD is typically associated with bradykinesia with progressive slowing of sequential movements (sequence effect), rigidity, gait, postural instability, and other parkinso­ nian features. However, the examiner should be aware that PD patients may have a postural tremor and ET patients may develop a rest tremor, but these typically only begin after a latency of a few seconds (emergent tremor). In contrast to the micrographia of PD, ET patients have rela­ tively large handwriting with evidence of tremor in writing samples. The examiner must be careful to identify tremor when assessing tone in order to distinguish the interruption of movement associated with tremor from the cogwheel rigidity found in PD. ■ ■ETIOLOGY AND PATHOPHYSIOLOGY The etiology and pathophysiology of ET are not known. Approximately 50% of ET patients have a positive family history with an autosomal dominant pattern of inheritance. Linkage studies have detected pos­ sible loci in large ET families. Expansion of a GGC repeat in the human-specific NOTCH2NLC gene has been found to be associated with ET, but no independently confirmed causative gene has been identified to date. It is likely that there are several as yet undiscovered genes underlying ET that have thus far escaped detection because of the heterogeneity of the syndrome and the high frequency of ET in the population, likely resulting in a large number of phenocopies (i.e., fam­ ily members with a similar clinical syndrome but not carrying the same causative mutation). The cerebellum and inferior olives have been implicated as possible sites of an altered “tremor pacemaker” based on the presence of cerebellar signs in ~10% of ET patients, as well as increased metabolic activity and blood flow in these regions in some patients. Some pathologic studies have described cerebellar pathology with a loss of Purkinje cells and axonal torpedoes, suggesting a neuro­ degenerative disease, but these findings remain controversial, and the precise pathologic correlate of ET remains to be defined. Interest has also focused on the possibility that ET is caused by degeneration of GABAergic cerebellar neurons with defects in neurotransmission. It is likely that multiple causes of ET will ultimately be identified. CHAPTER 447 ■ ■TREATMENT Many cases are mild, do not cause any functional impairment, and require no treatment other than reassurance. Occasionally, tremor can be severe and interfere with eating, writing, and activities of daily living. This is more likely to occur as the patient ages and is often associated with a reduction in tremor frequency. Beta blockers and primidone are the standard drug therapies for ET and are useful in ~50% of cases. Propranolol (20–120 mg daily, given in divided doses) is usually effective at relatively low doses, but higher doses may be needed in some patients. The drug is contraindicated in patients with bradycardia or asthma. Hand tremor tends to be most improved, while head tremor is often refractory. Primidone can be helpful but should be started at low doses (12.5 mg) and gradually increased as necessary (125–250 mg three times daily) to avoid sedation, nausea, and dizzi­ ness. Benefits have also been reported with gabapentin and topiramate, but these drugs have not been widely employed. Botulinum toxin injections may be helpful for limb or voice tremor, but treatment can be associated with muscle weakness. Surgical therapies targeting the ventro-intermediate (VIM) nucleus of the thalamus can be very effec­ tive for severe and drug-resistant cases. More recently, focal ultrasound (a procedure that does not require surgery) has also been shown to be an effective therapy against tremor in some cases of ET. Tremor, Chorea, and Other Movement Disorders DYSTONIA ■ ■CLINICAL FEATURES Dystonia is a movement disorder characterized by sustained or inter­ mittent synchronous muscle contractions of agonist and antagonist muscles causing abnormal, often repetitive, painful movements and postures. Dystonic movements are typically patterned and twisting and may be associated with a “dystonic” tremor. This tremor can usu­ ally be distinguished from ET as the tremor is most pronounced when the body part is moved in the direction of the dystonia and relieved when the body part is moved in the direction opposite to the dysto­ nia. Dystonia can range from minor contractions affecting only an individual muscle group (focal) to severe and disabling contractions with involvement of multiple muscle groups (i.e., multifocal, seg­ mental, or generalized). Nonmotor features such as pain, depression, anxiety, and impaired sleep can be associated with, or even precede onset of, the dystonia. The frequency of dystonia is estimated to be about 30 per 100,000 but is likely to be higher because many cases are not recognized or correctly diagnosed. Dystonia is often brought out by voluntary movements (action dystonia) and can extend to involve other muscle groups and body regions not required for the intended action (overflow contractions). Dystonia can be aggravated by stress and fatigue and attenuated by relaxation and sensory tricks such as touching the affected body part (geste antagoniste). Historically, dystonia has been described as primary or secondary. However, because of a confusing and not always congruent combina­ tion of phenotypic and etiologic features, the older terms are no longer TABLE 447-2  Monogenic Forms of Isolated and Combined Dystonia DESIGNATION AND PHENOTYPIC SUBGROUP ADDITIONAL DISTINGUISHING FEATURES FORM OF DYSTONIA GENE TOR1A DYT-TOR1A Childhood or adolescent onset, generalized AD Isolateda           KMT2B DYT-KMT2B Early onset, generalized, mild syndromic features AD THAP1 DYT-THAP1 Adolescent onset, cranial or generalized AD ANO3 DYT-ANO3 Adult onset, focal or segmental AD GNAL DYT-GNAL Mostly adult onset, focal or segmental AD VPS16 DYT-VPS16 Frequent cervical and laryngeal dystonia AD or AR EIF2AK2 DYT-EIF2AK2 Childhood or adolescent onset, focal to generalized AD or AR   PRKRA DYT-PRKRA Generalized AR   HPCA DYT-HPCA Childhood onset AR   AOPEP DYT-AOPEP Frequent cervical and laryngeal dystonia AR Combinedb Dystonia plus parkinsonism  GCH1 DYT-GCH1 Dopa-responsive AD   TAF1 DYT-TAF1 Neurodegeneration XL PART 13 Neurologic Disorders     ATP1A3 DYT-ATP1A3 Rapid onset AD   Dystonia plus myoclonus  SGCE DYT-SGCE Alcohol responsive AD   KCTD17 DYT-KCTD17 Childhood onset AD aKMT2B pathogenic variants may present with mild syndromic features. bSelected examples. Abbreviations: AD, autosomal dominant; AR, autosomal recessive; XL, X-linked. recommended. A Movement Disorder Society Task Force recom­ mended classifying dystonia along the same axes as ET: clinical and etiologic. On clinical grounds, dystonia can be categorized by age of onset (infancy, childhood, adolescence, early and late adulthood), body distribution (focal, segmental, multifocal, and generalized), temporal pattern (static or progressive, action-specific [diurnal and paroxys­ mal]), and association with additional features. Clinical description along these lines enables formulating specific dystonia syndromes (e.g., early-onset generalized isolated dystonia). From an etiologic point of view, dystonia primarily reflects genetic abnormalities, although occasionally it may be secondary to other causes, such as trauma and stroke. Genetic features used for classification include mode of inheritance or identification of a specific pathogenic gene variant. More than 200 genes have been linked to different types of dystonia, primarily childhood-onset and generalized forms. These include forms in which dystonia is the only disease manifestation with the exception of tremor (“isolated dystonia”) and forms in which dystonia co-occurs with another movement disorder such as parkinsonism, myoclonus, or other neurologic and/or nonneurologic manifestations (“combined dystonia”) and may not even be the dominant clinical feature. This group represents the most heterogeneous class in terms of clinical expression. A list of confirmed monogenic mutations associated with isolated or combined dystonias is provided in Table 447-2. ■ ■ISOLATED DYSTONIAS Focal, Multifocal, and Segmental Dystonia  Adult-onset, focal dystonia is by far the most frequent form of isolated dystonia. Women are affected about twice as often as men, with the exception of writer’s cramp, which occurs more frequently in men than in women. Focal dystonia typically presents in the fourth to sixth decade. The major clinical phenotypes are: (1) Cervical dystonia—dystonic contractions of neck muscles causing the head to deviate to one side (laterocollis), twist (torticollis), move in a forward direction (anterocollis), or move in a backward direction (retrocollis). Muscle contractions can be painful and occasionally can be complicated by a secondary cervical radicu­ lopathy and even myelopathy. (2) Blepharospasm—dystonic contrac­ tion of the eyelids resulting in increased blinking and eye closure that can interfere with reading, watching television, working on a com­ puter, and driving. This can sometimes be so severe as to cause func­ tional blindness. (3)  Oromandibular dystonia (OMD)—contractions of muscles of the lower face, lips, tongue, and jaw (opening or clos­ ing). Meige’s syndrome is a combination of OMD and blepharospasm that predominantly affects women aged >60 years. (4) Spasmodic MODE OF INHERITANCE dysphonia—dystonic contractions of the vocal cords during phonation, causing impaired speech. Most cases affect the adductor muscles and cause speech to have a choking or strained quality. Less commonly, the abductors are affected, leading to speech with a breathy or whispering quality. (5) Limb dystonias—these can be present in either arms or legs and are often brought out by task-specific activities such as handwrit­ ing (writer’s cramp), playing a musical instrument (musician’s cramp), or putting in golf (the yips). The vast majority of patients with focal dystonia have cervical dystonia (~40%) or blepharospasm (~15%). Focal hand or leg dystonia (~10%), musician’s dystonia (~3%), spas­ modic dysphonia (~2%), and OMD (~1%) are much less common. Focal dystonias can extend to involve other body regions (~30% of cases) and are frequently misdiagnosed as psychiatric or orthopedic in origin. Their cause is usually not known. They are rarely mono­ genic (~1%); autoimmunity and trauma have been suggested as other possible etiologies. Focal dystonias are often associated with a highfrequency tremor that can resemble ET. Dystonic tremor can usually be distinguished from ET because it tends to occur in the direction of the dystonic contraction and disappears when the dystonia is relieved (i.e., turning the head in the opposite direction of the dystonia). Generalized Dystonia   Generalized dystonia is often hereditary and, unlike focal dystonia, typically has an age of onset in childhood or adolescence. There are currently at least 10 well-established genes that, when mutated, can cause mostly isolated, segmental or generalized dystonia: ANO3, AOPEP, EIF2AK2, GNAL, HPCA, KMT2B, PRKRA, THAP1, TOR1A, and VPS16. The AOPEP, HPCA, and PRKRA patho­ genic mutations are recessively inherited, while others (e.g., EIF2AK2 and VPS16) can be either dominantly or recessively inherited. Accord­ ing to the recommendations of the International Parkinson’s Disease and Movement Disorder Society, monogenic forms of dystonia are classified according to the absence or presence of accompanying additional clinical features and preceded by a “DYT” prefix, e.g., DYT-TOR1A. Mutations in the TOR1A gene (torsin family 1 member A—formerly known as the DYT1 gene) are the most common cause of early-onset generalized dystonia. The first, and currently the only, clearly estab­ lished mutation is a 3-base pair deletion in the TOR1A gene. The mutation is frequently found among Ashkenazi Jewish patients due to a founder effect. Mutation carriers usually present with dystonia in an extremity in childhood that later progresses to affect other body parts, but the face and neck are typically spared. Rare carriers of two mutated alleles have been described and are characterized by a severe neurode­ velopmental syndrome and arthrogryposis. Missense mutations in KMT2B (lysine methyltransferase 2B) are another relatively frequent cause of early-onset generalized dystonia, which may be accompanied by other syndromic features, including intellectual disability, microcephaly, psychiatric features, dysmorphia, or skin lesions. The majority of the mutations occur de novo. KMT2B mutations may account for up to 10% of early-onset generalized dysto­ nia, but further validation is warranted, and placement into the group of isolated versus complex dystonias is currently under debate. Mutations in the THAP1 gene (THAP domain containing apoptosisassociated protein 1) have been linked to adolescent-onset dystonia with mixed phenotype. About 100 different mutations have been reported in THAP1. Mutations typically manifest with dysphonia or writer’s cramp beginning in late childhood or adolescence. Over the course of the disease, dystonia can spread to other body parts with prominent craniocervical involvement. While DYT-Tor1A and DYTKMT2B typically respond well to deep brain stimulation (DBS) of the globus pallidus internus bilaterally, the DBS response is much more variable in carriers of pathogenic variants in the THAP1 gene. Mutations in the ANO3 gene (anoctamin 3) were first reported in patients with predominantly craniocervical dystonia with a broad range of ages of onset. While a large number of missense variants can be found in healthy individuals, a pathogenic role of ANO3 mutations has been confirmed by the description of additional families with dys­ tonia and myoclonic jerks. Mutations in the GNAL gene (guanine nucleotide-binding protein subunit alpha L) are a rare cause of cervical or cranial dystonia, with a few patients developing generalized dystonia. The mean age of onset is in the thirties. Pathogenic variants in the VPS16 gene can be inherited in a recessive or dominant fashion, with the latter mode of inheritance being more common. Currently, >30 carriers of ~20 different, often truncating, heterozygous pathogenic variants have been described. The median age of onset is 14 years. Dystonia tends to generalize and is typically isolated, although more complex phenotypes have also been described. Pathogenic missense variants in EIF2AK2, coding for the eukaryotic translation initiation factor 2-alpha kinase 2, cause dystonia with a median age at onset of 6 years and onset often in the limbs followed by generalization. There is a recurrent missense variant (p.Gly130Arg) in most patients. The EIF2AK2 protein is one of the kinases responsible for eIF2a phosphorylation and is thus linked to the same pathway as PRKRA. The vast majority of PRKRA mutation carriers develop a generalized dystonia, frequently with laryngeal involvement. Likewise, all patients described to carry HPCA mutations are characterized by generalized dystonia with childhood onset. The median age at onset of carriers of recessively inherited, bial­ lelic, and typically truncating pathogenic variants in the AOPEP gene is 20 years, with frequent onset in the hands. Most patients progress to isolated, generalized dystonia. ■ ■COMBINED DYSTONIAS A number of other well-established genes have been described that are associated with combined forms of dystonia in which dystonia occurs in conjunction with a different movement disorder (e.g., parkinsonism or myoclonus) or with other neurologic and/or nonneurologic features. Dopa-responsive dystonia (DRD; also known as Segawa syndrome) is caused by mutations in the GCH1 gene (GTP cyclohydrolase-1) that encodes for the rate-limiting enzyme in the biosynthesis of dopamine via the biopterin pathway. It manifests as a childhood-onset form of dystonia with diurnal fluctuations, and it is important to recognize as the condition dramatically responds to low doses of levodopa. Parkinsonism can be a major or even the only finding, and there may be a presynaptic dopaminergic deficit as evidenced by single-photon emission computed tomography. Younger patients are frequently misdiagnosed as having cerebral palsy, mistaking dystonia for spastic­ ity, and it is important that young-onset forms of dystonia should be tested with levodopa to exclude the possibility of DRD. To date, >100 different mutations have been reported with a penetrance of ~50% and incidence considerably higher in women compared to men. Recessively inherited (biallelic) mutations in GCH1 result in a much more severe clinical phenotype with developmental delay and infantile onset. Due to the enzymatic defect in the levodopa biosynthesis, there is a life­ long and dramatic response to levodopa therapy. Importantly, since dopamine terminals do not degenerate and the dopamine neuronal network is anatomically preserved, fluctuations in dopamine levels can be avoided, and accordingly, these patients do not develop dyskinesia with chronic levodopa treatment. X-linked dystonia-parkinsonism (Lubag) presents with a combined form of dystonia and parkinsonism that is found exclusively in patients of Filipino origin due to a founder effect that seems to be fully pen­ etrant. The typical presentation is a focal (cranial) dystonia that rapidly generalizes and, after 5–10 years, is gradually replaced by a form of L-dopa-unresponsive parkinsonism. A retrotransposon insertion in the TAF1 (TATA-box binding protein associated factor 1) gene is the cause of the disease. Sixty-five percent of the age-at-onset variability is explained by the variable length of a hexameric repeat expansion within the retrotransposon and genotypes at three single-nucleotide polymorphisms in the MSH3 and PMS1 genes acting as age-at-onset modifiers. CHAPTER 447 Mutations in the ATP1A3 (ATPase Na+/K+ transporting subunit alpha 3) gene present with a characteristic, sudden-onset dystonia, usually in adolescence or young adulthood, often triggered by high fever, physi­ cal exertion, or emotional stress. Dystonic symptoms frequently show a rostrocaudal gradient with a strong involvement of the bulbar region, often accompanied by parkinsonian features such as bradykinesia. In addition, mutations in ATP1A3 have been linked to a variety of clini­ cal syndromes (pleiotropy), including epileptic or hemiplegic attacks, ataxia, cognitive decline, and other neurologic disorders, often with a more severe course and an earlier age at onset. Tremor, Chorea, and Other Movement Disorders Myoclonic-dystonia is characterized by action-induced, alcoholresponsive myoclonic jerks predominantly involving the upper body half. Onset is usually in childhood or adolescence. Many individuals also develop psychiatric features such as depression, anxiety-related disorders, and alcohol dependence. The disorder is primarily related to mutations in the SGCE gene (sarcoglycan epsilon), which codes for the ε member of the sarcoglycan family. About 80 different mutations have been reported in SGCE, including deletions of the entire gene. The latter type of mutation often also involves loss of adjacent genes, leading to additional clinical features such as joint problems. SGCE mutations are incompletely penetrant and only manifest when inher­ ited from the father due to the epigenetic effect of maternal imprinting of SGCE. KCTD17 mutations are another recently identified cause of myoclonus-dystonia. A number of additional monogenic causes have been suggested for isolated and combined forms of dystonia but still await independent confirmation. Table 447-2 provides a list of the confirmed monogenic forms of isolated and combined dystonias. Diagnostic Considerations  In the largest group of combined dystonias, dystonia is a part of a more complex syndrome that is char­ acterized by multiple different clinical manifestations of the disease. Most frequently, they are hereditary, such as Wilson’s disease (WD), Lesch-Nyhan syndrome, corticobasal ganglionic disorders, and a variety of other neurologic, neurometabolic, neurodevelopmental, and mitochondrial disorders. Dystonia may also develop as a consequence of drugs or toxins. Drug-induced dystonia may be acute or chronic and is most commonly seen with neuroleptic drugs or after chronic levodopa treatment in PD patients. Dystonia can also be observed following discrete lesions in the striatum (e.g., caudate/putamen) and occasionally in the globus pallidus, thalamus, cortex, or brainstem due to infarction, hemorrhage anoxia, trauma, tumor, infection, or toxins such as manganese or carbon monoxide. In these cases, dystonia often assumes a segmental distribution but may be generalized when lesions are bilateral or widespread. More rarely, dystonia can develop follow­ ing peripheral nerve injury and be associated with features of complex regional pain syndrome (Chap. 19). A psychogenic origin is respon­ sible for some cases of dystonia; these typically present with fixed, immobile dystonic postures (see below). ■ ■PATHOPHYSIOLOGY OF DYSTONIA Even in cases with a known dystonia gene mutation, the pathophysi­ ologic basis of dystonia is not completely known. Physiologically, dys­ tonia is characterized by co-contracting synchronous bursts of agonist and antagonist muscle groups with recruitment of muscle groups that are not required for a given movement (overflow). Dystonia is char­ acterized by derangement of the basic physiologic principle of action selection, leading to abnormal recruitment of inappropriate muscles for a given action with inadequate inhibition of this undesired motor activity. Loss of surround inhibition is observed at multiple levels of the motor system (e.g., cortex, brainstem, spinal cord), accompanied by increased cortical excitability and reorganization. Attention has focused on the basal ganglia as the site of origin of most types of dystonia, as there are alterations in blood flow and metabolism in these structures. Further, lesions of the basal ganglia (particularly the putamen) can induce dystonia, and surgical ablation or DBS of specific regions of the globus pallidus may ameliorate dystonia. The dopa­ mine system has been specifically implicated because dopaminergic therapies can both induce and treat some forms of dystonia in different circumstances. However, no specific pathology has been consistently identified that underlies dystonia. PART 13 Neurologic Disorders TREATMENT Dystonia Treatment of acute dystonia should include the immediate with­ drawal of any precipitating agent. A variety of drug therapies may be beneficial including diphenhydramine, benztropine, benzodiaz­ epines, or dopamine agonists. Treatment of chronic dystonia is for the most part symptomatic except in rare cases where correction of a primary underlying con­ dition is possible. WD should be ruled out, particularly in young patients with dystonia. Levodopa should be tried in all cases of childhood-onset dystonia to test for DRD. High-dose anticholin­ ergics (e.g., trihexyphenidyl 20–120 mg/d) may be beneficial in children, but adults can rarely tolerate high doses because of side effects related to cognitive impairment and hallucinations. Oral baclofen (20–120 mg) may also be helpful, but benefits, if present at all, are usually modest, and side effects of sedation, weakness, and memory loss can be problematic. Intrathecal infusion of baclofen is more likely to be useful, particularly for leg and trunk dystonia, but benefits are frequently not sustained, and complications can be serious and include infection, seizures, and coma. Tetrabenazine is another consideration; the usual starting dose is 12.5 mg/d and the average treating dose is 25–75 mg/d, but its use may be limited by sedation and the development of parkinsonism. Parkinsonian side effects can be minimized with deuterated tetrabenazine (discussed below). Neuroleptics can both improve and induce dystonia, but they are typically not recommended because of their potential to induce parkinsonism and other movement disorders, including tar­ dive dystonia. Clonazepam and diazepam are sometimes effective. Botulinum toxin is the preferred treatment for patients with focal and segmental dystonia, particularly where involvement is limited to small muscle groups such as in blepharospasm, torticollis, and spasmodic dysphonia. Botulinum toxin acts by blocking the release of acetylcholine at the neuromuscular junction, leading to reduced dystonic muscle contractions. However, treatment with botulinum toxin can be complicated by excessive weakness that can be trouble­ some, particularly if injections involve the neck and swallowing muscles. No systemic side effects are encountered with the doses typically used, but benefits are transient, and repeat injections are typically required at 2- to 4-month intervals. Some patients fail to respond after having experienced an initial benefit. This has been attributed to the development of neutralizing antibodies, but improper muscle selection, injection technique, and inadequate dose should be excluded. A new long-acting formulation of botu­ linum toxin (daxibotulinumtoxinA-l) that provides benefits for up to 6 months has recently been approved in the United States for the treatment of cervical dystonia. Surgical therapy is a consideration for patients with severe gener­ alized dystonia who are not responsive to other treatments. Periph­ eral procedures such as rhizotomy and myotomy were used in the past to treat cervical dystonia but are now rarely employed. DBS of the pallidum can provide dramatic benefits for some patients with various forms of hereditary and nonhereditary generalized dysto­ nia. This represents a major therapeutic advance because previously there was no consistently effective therapy, especially for patients with generalized dystonia and severe disability. Benefits tend to be obtained with a lower frequency of stimulation than used in PD or ET and often occur only after a relatively long latency (weeks to months). Better results are typically obtained in younger patients with shorter disease duration and in those with certain monogenic forms, such as DYT-Tor1A. DBS may also be valuable for patients with focal and secondary dystonias, although results are less consis­ tent. Neurophysiologic studies suggest that DBS acts by suppressing theta oscillations in the basal ganglia network that correlate with the dystonia. Adverse effects of DBS in dystonia patients include pares­ thesia, dysarthria, gait disturbance, and mood change. Dyskinesia can occur with stimulation of the subthalamic nucleus (STN), while bradykinesia and impaired coordination have been reported with stimulation of the globus pallidus pars interna (GPi). Focal ultra­ sound is being assessed as a possible alternative to surgical therapy. Supportive treatments such as physical therapy and education should be a part of the treatment regimen for all types of dystonia. Physicians should be aware of dystonic storm, a rare but poten­ tially fatal condition that can occur in response to a stress situation such as a surgical procedure or a systemic infection in patients with preexisting dystonia. It consists of the acute onset of generalized and persistent dystonic contractions that can involve the vocal cords or laryngeal muscles leading to airway obstruction. Patients may experience rhabdomyolysis with renal failure and should be managed in an intensive care unit with airway protection if required. Treatment can be instituted with one or a combination of anticholinergics, diphenhydramine, baclofen, benzodiazepines, and dopaminergic agents. In severe cases, anesthesia with muscle paralysis may be required. CHOREAS ■ ■HUNTINGTON’S DISEASE Huntington’s disease (HD) is a progressive, fatal, highly penetrant autosomal dominant disorder characterized by motor, behavioral, ocu­ lomotor, and cognitive dysfunction. The disease is named for George Huntington, a family physician who described cases on Long Island, New York, in the nineteenth century. Onset is typically between the ages of 25 and 45 years (range, 3–70 years) with a prevalence of 2–8 cases per 100,000 and an average age at death of 60 years. It is prevalent in Europe, North America, South America, and Australia but is rare in African blacks and Asians. HD is characterized by rapid, nonpat­ terned, semi-purposeful, involuntary choreiform movements, and for this reason was formerly referred to as Huntington’s chorea. However, dysarthria, gait disturbance, parkinsonism, oculomotor abnormalities, behavioral disturbance, and cognitive impairment with dementia are also common clinical features. Thus, the condition is currently referred to as Huntington’s disease. In the early stages, chorea tends to be focal or segmental but progresses over time to involve multiple body regions. With advancing disease, there tends to be a reduction in chorea and the emergence of dystonia, rigidity, bradykinesia, and myoclonus. Functional decline is often predicted by progressive weight loss despite adequate calorie intake. In younger patients (~10% of cases), HD can present as an akinetic-rigid parkinsonian syndrome known as the West­ phal variant. Eye movement abnormalities may be an early manifesta­ tion of HD. These include slowed and reduced amplitude saccades with intrusions in smooth pursuit movements and impaired convergence. HD patients eventually develop behavioral and cognitive disturbances, and the majority progress to dementia. Depression with suicidal ten­ dencies, aggressive behavior, and psychosis can be prominent features. HD patients may also develop non-insulin-dependent diabetes mellitus A B FIGURE 447-1  Huntington’s disease. A. Coronal fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging shows enlargement of the lateral ventricles reflecting typical atrophy (arrows). B. Axial FLAIR image demonstrates abnormal high signal in the caudate and putamen (arrows). and neuroendocrine abnormalities (e.g., hypothalamic dysfunction). A clinical diagnosis of HD can be strongly suspected in cases of chorea with a positive family history, but genetic testing provides the ultimate confirmation of the diagnosis. The disease predominantly affects the striatum but progresses to involve the cerebral cortex and other brain regions. Progressive atrophy of the head of the caudate nucleus, which forms the lateral margin of the lateral ventricles, can be readily visualized on magnetic resonance imaging (MRI) (Fig. 447-1), but the putamen can be equally or even more severely affected. More diffuse cortical atrophy can be seen in the middle and late stages of the disease. Supportive studies include reduced metabolic activity in the caudate nucleus and putamen and reduced brain metabolites on magnetic resonance spectroscopy. Genetic testing can be used to confirm the diagnosis and to detect atrisk individuals in the family, but it must be performed in conjunction with trained counselors because advising patients of positive results can worsen depression and even generate suicidal reactions. Indeed, genetic counseling is a requirement in some regions. The neuropa­ thology of HD consists of prominent neuronal loss and gliosis in the caudate nucleus and putamen; similar changes can also be widespread in the cerebral cortex. Intraneuronal inclusions containing aggregates of ubiquitin and the mutant protein huntingtin are found in the nuclei of some affected neurons. In anticipation of developing neuroprotective therapies, an inten­ sive effort has been made to define the earliest stage of HD. Subtle motor impairment, cognitive alterations, and imaging changes can be detected in at-risk individuals who later develop the manifest form of the disease. Defining the rate of progression of these features is paramount for future studies of putative disease-modifying therapies designed to slow the rate of disease progression and the development of cumulative disability. ■ ■ETIOLOGY HD is caused by a mutation in which there is an increase in the num­ ber of polyglutamine (CAG) repeats (>40) in the coding sequence of the Huntingtin gene located on the short arm of chromosome 4. The larger the number of repeats, the earlier the disease is manifest. Inter­ mediate forms of the disease with 36–39 repeats are described in some patients, typically with less severe clinical involvement and reduced penetrance (i.e., not every mutation carrier develops the disease). These clinic-genetic observations have recently been incorporated into a new research classification of HD. Carriers of a fully penetrant (>40 repeats) allele are defined as having stage 0 HD, irrespective of their affected status. These developments are meant to facilitate the inclu­ sion of at-risk individuals or those in the earliest disease stages into clinical trials. CHAPTER 447 Tremor, Chorea, and Other Movement Disorders Expansion of repeat length tends to occur, particularly in males, with subsequent generations having larger numbers of repeats and earlier age of disease onset, a phenomenon referred to as anticipation. There is also evidence of postnatal somatic gene expansion that occurs over time as well as genetic modifiers of disease progression, for exam­ ple, in the FAN1 and MSH3 genes, the latter overlapping with X-linked dystonia-parkinsonism. New-onset gene expansion in patients with no family history is rare. The Huntingtin gene encodes the highly conserved cytoplasmic pro­ tein huntingtin (HTT), which is widely distributed in neurons through­ out the central nervous system (CNS). Mutated HTT RNA is toxic and disrupts transcription, impairs immune and mitochondrial function, and is aberrantly modified posttranslationally. Genome-wide asso­ ciation studies have nominated DNA repair pathways as modifiers of somatic instability and disease course in HD. Fragments of the mutant HTT can also be toxic, possibly by translocating into the nucleus and interfering with transcriptional regulation of proteins. Neuronal inclusions found in affected regions in HD may represent a protective mechanism aimed at segregating and facilitating the clearance of these toxic proteins. There is also interest in the possibility that the accumula­ tion and aggregation of toxic proteins in HD, like Alzheimer’s disease (Chap. 442) and PD (Chap. 446), may be critical to the disease process and reflect a prion-like disorder (Chap. 449; see also Chap. 435). Models of HD with striatal pathology can be induced in multiple trans­ genic animals that express the mutant gene and by excitotoxic agents such as kainic acid and 3-nitropropionic acid, which promote calcium entry into the cell and cytotoxicity. These relevant animal models can be helpful in assessing potential therapeutic agents. Interestingly, when correcting the neurotransmitter deficit present in HD mice in the very first week of life, disease development can be prevented. TREATMENT Huntington’s Disease Although the gene for HD was identified >30 years ago, there is still no disease-modifying therapy for this disorder, and clinically mean­ ingful symptomatic treatment is limited. Current treatment involves a multidisciplinary approach, with medical, neuropsychiatric, and social approaches, as well as genetic counseling for patients and their families. Dopamine-blocking agents such as tetrabenazine and val­ benazine have been approved to treat the choreiform movements but can be associated with secondary parkinsonism as an adverse event. Deuterated tetrabenazine (Austedo) and a long-acting version of deuterated tetrabenazine have also been approved as treatments for chorea in HD. Deuteration interferes with the metabolism of tetrabenazine and avoids the high maximum concentration (Cmax), which is thought to contribute to adverse effects. In clinical trials, deuterated tetrabenazine has been shown to have fewer dose-related side effects and less parkinsonism than tetrabenazine and, therefore, can be administered in higher doses with potentially superior clini­ cal benefits. Neuroleptics are generally not recommended because of their potential to induce other troubling movement disorders and because HD chorea tends to be self-limited and is usually not disabling. These drugs may be used, however, in patients with severe and disabling chorea. There are currently no therapies approved for treating the more disabling motor features of HD, but large-scale platform studies are ongoing, which are assessing a variety of differ­ ent therapeutic approaches using a common placebo group. Depres­ sion and anxiety can be major problems, and patients should be treated with appropriate antidepressant and antianxiety drugs and monitored for mania and suicidal ideations. Psychosis can be treated with atypical antipsychotics such as clozapine (50–600 mg/d), que­ tiapine (50–600 mg/d), and risperidone (2–8 mg/d). PART 13 Neurologic Disorders A neuroprotective therapy that slows or stops disease progres­ sion is the major unmet medical need. Some strategies are designed to reduce the formation or accumulation of mutant HTT. These largely focus on inhibiting mRNA synthesis either by blocking transcription (zinc finger motif protein), preventing posttranscrip­ tional processes, promoting early mRNA degradation (antisense oligonucleotides [ASO]), or inhibiting translation with short inter­ fering RNA. The most advanced of these experimental therapeu­ tic approaches investigated intrathecal administration of an ASO in patients with early HD in a randomized, placebo-controlled, double-blind clinical trial. While a dose-dependent reduction in concentrations of mutant HTT was observed and there were no side effects, the study was terminated early because no clinical benefit was detected. Drugs that enhance mitochondrial func­ tion and increase the clearance of defective mitochondria are also being tested as possible disease-modifying therapies. Other inves­ tigative approaches include immunotherapy, dietary supplements (resveratrol), lipid-lowering medication (fenofibrate), anaplerotic therapy (triheptanoin), and DBS of the GPi. A promising therapy is the sigma 1 receptor agonist pridopidine. Various clinical trials have suggested that the drug may provide benefit with respect to total motor function and total functional capacity, particularly in patients with relatively mild disease. Double-blind studies are cur­ rently underway. Preliminary clinical trials testing cell-based thera­ pies (stem cells and fetal striatal cells) have been initiated, aimed at replacing damaged striatal neurons, but efficacy and safety of these procedures have not yet been determined. Experimentally, there is great interest in the potential of using CRISPR (gene editing) techniques to target and destroy or prevent the formation of mutant Huntingtin RNA and to reduce accumulation of the abnormal pro­ tein. Numerous other molecular and gene-based approaches are being evaluated to interfere with the formation and promote the clearance of the toxic protein, and many clinical studies are antici­ pated to begin within the next few years. HUNTINGTON’S DISEASE–LIKE DISORDERS A group of rare inherited conditions that can mimic HD, designated HD-like (HDL) disorders, have also been identified. HDL-1, -2, and -4 are autosomal dominant conditions that typically present in adult­ hood. HDL-3 is recessively inherited, presents in early childhood, and differs markedly from HD and the other HDLs. HDL-1 is due to expansion of an octapeptide repeat in PRNP, the gene encoding the prion protein (Chap. 449). Thus, HDL-1 is properly considered a prion disease. Patients exhibit onset of personality change in the third or fourth decade, followed by chorea, rigidity, myoclonus, ataxia, and epilepsy. HDL-2 manifests in the third or fourth decade with a variety of movement disorders, including chorea, dystonia, or parkinsonism, and dementia. Most patients are of African descent. Acanthocytosis can sometimes be seen in these patients, and this condition must be distinguished from neuroacanthocytosis (below). HDL-2 is caused by an abnormally expanded CTG/CAG trinucleotide repeat expansion in the junctophilin-3 (JPH3) gene. The pathology of HDL-2 consists of intranuclear inclusions immunoreactive for ubiquitin and expanded polyglutamine repeats. HDL-4, the most common condition in this group, is caused by expansion of trinucleotide repeats in TBP, the gene that encodes the TATA box-binding protein involved in regulat­ ing transcription; this condition is identical to spinocerebellar ataxia (SCA) 17 (Chap. 450), and most patients present with ataxia rather than chorea. Like in HD, a certain range of repeat expansions in the TBP gene is associated with reduced penetrance, whereby penetrance was recently identified to be full when a variant in the Stub1 gene is present in conjunction with the repeat expansion. Mutations of the C9Orf72 gene associated with frontotemporal dementia and amyo­ trophic lateral sclerosis (Chaps. 443 and 448) have also been reported in some individuals with an HDL phenotype. ■ ■OTHER CHOREAS Chorea can be seen in a number of other disorders related to genetic mutations or other disease states. Among the hereditary forms of childhood-onset chorea, mutations in the NKX2-1 gene cause a benign hereditary chorea. Mutations in the ADCY5 (adenylate cyclase 5) gene are an increasingly recognized and relatively common cause of childhood-onset chorea, often in combina­ tion with dystonia and developmental delay. Characteristic perioral movements are a hallmark of the disorder. Notably, patients respond well to caffeine. Chorea-acanthocytosis (neuroacanthocytosis) is a progressive and typically fatal autosomal recessive disorder that is characterized by chorea coupled with red cell abnormalities on peripheral blood smear (acanthocytes). The chorea can be severe and associated with selfmutilating behavior, dystonia, tics, seizures, and a polyneuropathy. Mutations in the VPS13A gene encoding chorein have been described. A phenotypically similar X-linked form of the disorder has been described in older individuals who have reactivity with Kell blood group antigens (McLeod syndrome). A benign hereditary chorea of childhood (BHC1) due to mutations in the gene for thyroid transcrip­ tion factor 1 and a late-onset benign senile chorea (BHC2) have also been reported. It is important to do genetic testing in these patients to ensure that they do not have HD. Chorea may also occur in association with a variety of infections and degenerative disorders as well as vascular diseases and hypo- and hyperglycemia. Sydenham’s chorea (originally called St. Vitus’s dance) is more common in females and is typically seen in childhood (5–15  years). It often develops in association with prior exposure to group A streptococcal infection (Chap. 153) and is thought to be autoimmune in nature. It is characterized by the acute onset of choreiform movements and behavioral disturbances. With the reduc­ tion in the incidence of rheumatic fever, the incidence of Sydenham’s chorea has fallen, but it can still be seen in developing countries. The chorea generally responds to dopamine-blocking agents, valproic acid, and carbamazepine, and is usually self-limited. Treatment is gener­ ally restricted to those with severe chorea. Chorea may recur in later life, particularly in association with pregnancy (chorea gravidarum) or treatment with sex hormones. Several reports have documented cases of chorea associated with N-methyl-d-aspartate (NMDA) recep­ tor antibody–positive encephalitis, following herpes simplex virus encephalitis, and in paraneoplastic syndromes associated with antiCRMP-5 or anti-Hu antibodies (Chap.  99). Systemic lupus erythe­ matosus (Chap. 368) is the most common systemic disorder that is associated with chorea. The chorea may last for only a few days but can be long-lasting and persist for years. Chorea can also be seen with hyperthyroidism, autoimmune disorders including Sjögren’s syn­ drome, infectious disorders including HIV, metabolic alterations, and polycythemia rubra vera. Chorea has been described following openheart surgery in the pediatric population. It may also occur in associa­ tion with many medications (especially anticonvulsants, cocaine, CNS stimulants, estrogens, and lithium). In particular, chorea is commonly seen as a side effect of chronic levodopa treatment in patients with PD (Chap. 446). ■ ■BALLISM/HEMIBALLISMUS Ballism is a violent form of choreiform movement composed of wild, flinging, large-amplitude movements most frequently affecting proxi­ mal limb muscles on one side of the body (hemiballism). The move­ ments may only affect one limb (monoballism) or, more exceptionally, both upper or lower limbs (paraballism). The movements may be so severe as to cause exhaustion, dehydration, local injury, and, in extreme cases, death. Fortunately, dopamine-blocking drugs can be very help­ ful, and importantly, hemiballismus is usually self-limiting and tends to resolve spontaneously after weeks or months. The most common cause is a partial lesion (infarct or hemorrhage) in the STN, but in 30–40% of cases, the lesion is found in the putamen, thalamus, or parietal cortex. In extreme cases, pallidotomy or DBS of the GPi can be effective and abolish the involuntary movements. Interestingly, surgically induced lesions and DBS of the STN in PD patients are usually not associated with hemiballismus. TICS A tic is a brief, rapid, recurrent, stereotyped and seemingly purpose­ less motor contraction. Motor tics can be simple, with movement only affecting an individual muscle group (e.g., blinking, twitching of the nose, jerking of the neck), or complex, with coordinated involvement of multiple muscle groups (e.g., jumping, sniffing, head banging, and echopraxia [mimicking movements]). Phonic (or vocal) tics can also be simple (e.g., grunting) or complex (e.g., echolalia [repeating other people’s words], palilalia [repeating one’s own words], and coprolalia [expression of obscene words]). Patients may also experience sensory tics, composed of unpleasant focal sensations in the face, head, or neck. These can be mild and of little clinical consequence or severe and dis­ abling. Tics may present in adulthood and can be seen in association with a variety of disorders, including PD, HD, trauma, dystonia, drugs (e.g., levodopa, neuroleptics), and toxins. TOURETTE’S SYNDROME Tourette’s syndrome (TS) is a neurobehavioral disorder named after the French neurologist Georges Gilles de la Tourette. It predominantly affects males, and the prevalence is estimated to be 0.03–1.6%, but it is likely that many mild cases do not come to medical attention. TS is characterized by multiple motor tics, often accompanied by vocaliza­ tions (phonic tics). Patients characteristically can voluntarily suppress tics for short periods of time but then experience an irresistible urge to express them. Tics vary in intensity and may be absent for days or weeks only to recur, occasionally in a different pattern. Tics tend to present between ages 2 and 15 years (mean 7 years) and often lessen or even disappear in adulthood, particularly in males. Associated behavioral disturbances include anxiety, depression, attention-deficit hyperactivity disorder (ADHD), and obsessive-compulsive disorder. Patients may experience personality disorders, self-destructive behav­ iors, difficulties in school, and impaired interpersonal relationships. Etiology and Pathophysiology  TS has a high heritability and is thus thought to be a genetic disorder, but no specific monogenic cause has yet been identified. Current evidence supports a complex inheritance pattern with an important contribution of de novo, likely gene-disrupting variants. Genome-wide linkage studies have suggested Slit, Trk-like 1, and histidine decarboxylase (HDC) genes as conferring genetic risk for TS. The risk of a family with one affected child having a second one with TS is ~25%. The pathophysiology of TS is not known, but alterations in dopamine neurotransmission, opioids, and secondmessenger systems have been proposed. TREATMENT Tics and Tourette’s Syndrome There is no cure for tics or TS. Patients with mild disease often only require education and counseling (for themselves and family mem­ bers). In a high proportion of patients, the severity of tics wanes in adult life, becoming less of a medical problem, thus arguing for conservative management if possible during the first decades of life. Drug treatment to help control tics is indicated when the tics are disabling and interfere with quality of life and social interactions. Therapy is individualized, and few treatment regimens have been properly evaluated in double-blind trials. Some physicians use the α-agonist clonidine, starting at low doses and gradually increas­ ing the dose and frequency until satisfactory control is achieved. Guanfacine (0.5–2 mg/d) is an α-agonist that is preferred by some because it only requires once-daily dosing. Other physicians prefer to use neuroleptics, but treatment can be complicated by tardive dyskinesia and weight gain. Atypical neuroleptics are usually used initially (risperidone, olanzapine, ziprasidone) because they are thought to be associated with a reduced risk of tardive dyskinesia. If they are not effective, low doses of classical neuroleptics such as hal­ operidol, fluphenazine, pimozide, or tiapride can be tried because the risk of tardive dyskinesia in young people is relatively low. Tet­ rabenazine and deuterated tetrabenazine may be recommended but are associated with depression. The dopamine D1 antagonist ecopi­ pam was reported to provide benefits without serious side effects in a controlled trial of short duration in TS. Antiepileptic drugs such as topiramate may provide benefit for some patients. Botulinum toxin injections can be effective in controlling focal tics that involve small muscle groups. There is also interest in the potential value of a wrist device that delivers electrical pulses and has been reported to reduce the frequency and severity of tics in an open-label study. The potential value of closed-loop DBS targeting the anterior portion of the internal capsule, the GPi, or the thalamus is currently being explored for severely affected patients. A large-scale public database and registry for DBS in TS has been established. Behavioral fea­ tures, and particularly anxiety and compulsions, can be a disabling feature of TS and should be treated as appropriate. Behavioral and speech therapies are also occasionally employed but have not been formally tested. ADHD medications such as methylphenidate are sometimes used to increase attention and concentration but may also exacerbate tics. CHAPTER 447 Tremor, Chorea, and Other Movement Disorders MYOCLONUS Myoclonus is a brief, rapid (<100 ms), shock-like, jerky movement consisting of single or repetitive muscle discharges that can occur with or without a pattern and with a variable frequency. Myoclonic jerks can be focal, multifocal, segmental, or generalized and can occur sponta­ neously, in association with voluntary movement (action myoclonus), or in response to an external stimulus (reflex myoclonus). Myoclonic jerks can be severe and interfere with normal movement or benign and of no clinical consequence, as is commonly observed in normal people who can experience myoclonic jerks when waking up or falling asleep (hypnagogic jerks). Negative myoclonus consists of a brief loss of muscle activity (e.g., asterixis in hepatic failure). Palatal myoclonus (or palatal tremor) involves contractions of the soft palate and may be associated with an audible click that can be disturbing to the patient and family members. This is usually idiopathic and benign but can be related to a lesion in the cerebellum or brainstem. Myoclonus may also occur consequent to injury to a peripheral or cranial nerve (e.g., hemifacial spasm). Myoclonic jerks differ from tics in that they are typically not repetitive, are not suppressible, and can severely interfere with normal voluntary movement. They can be associated with abnormal neuronal discharges in cortical, subcortical, brainstem, or spinal cord regions, particularly in cases related to hypoxemia (especially following cardiac arrest), encephalopathy, and neurodegeneration. Reversible myoclonus can be seen with metabolic disturbances (renal failure, electrolyte imbalance, hypocalcemia), toxins, and many medications. Hereditary myoclonus syndromes can be grouped into three classes based on clini­ cal features: prominent myoclonus, prominent myoclonus combined with another prominent movement disorder, and disorders that usually present with other phenotypes but can also manifest as a prominent myoclonus syndrome. An additional movement disorder is seen in nearly all myoclonus syndromes, most commonly ataxia or dystonia. Furthermore, cognitive decline and epilepsy are present in the majority of patients. The frequent association with epilepsy suggests that a brief epileptic-like discharge could underlie myoclonus in some situations. Myoclonic epilepsy is a disorder comprised of myoclonus and epi­ lepsy. It can be associated with other focal neurologic deficits, has a variable but progressive course, and may ultimately be fatal. The most common form of action myoclonus of cortical origin with general­ ized epilepsy is myoclonic epilepsy or Unverricht-Lundborg disease (EPM-1). Ataxia may also be a feature. This is an autosomal recessive disease caused by pathogenic variants in the CSBT gene. Other causes are Lafora body epilepsy or progressive myoclonic epilepsy (PME2) caused by mutations in the EPM2A or NHLRC1 genes. Neuronal ceroid lipofuscinosis (Batten’s disease) is another consideration. In patients with less severe or absent epilepsy, mitochondrial disorders and neurodegenerative disorders affecting the cerebellum (i.e., SCAs) should be considered. Essential myoclonus is a relatively benign familial condition characterized by multifocal, very brief, lightninglike movements that are frequently alcohol sensitive. Mutations in the epsilon-sarcoglycan gene have been associated with myoclonus seen in association with dystonia (myoclonus-dystonia). PART 13 Neurologic Disorders The precise cause of myoclonus is not known but, in some cases, is thought to be due to overexcitability or impaired inhibition of cortical or peripheral nerve stimuli related to a particular movement. Imaging studies are seeking to define the altered connectivity in neuronal cir­ cuits that underlies myoclonus. TREATMENT Myoclonus Treatment primarily consists of managing the underlying condition or removing an offending agent. Pharmacologic therapy involves one or a combination of GABAergic agents such as valproic acid (800–3000 mg/d), piracetam (8–20 g/d), clonazepam (2–15 mg/d), levetiracetam (1000–3000 mg/d), or primidone (500–1000 mg/d). Treatment may be associated with striking clinical improvement in chronic cases in which a cortical origin for the myoclonic dis­ charges has been identified (e.g., postanoxic myoclonus, progressive myoclonic epilepsy). In some cases, combinations of drugs may prove helpful. The serotonin precursor 5-hydroxytryptophan (plus carbidopa) may be useful in cases of postanoxic myoclonus. DBS can be highly effective in myoclonus-dystonia. Botulinum toxin has been used successfully in some patients with focal myoclonus, palatal myoclonus, and hemifacial spasm. Some patients with hemi­ facial spasm have also been reported to benefit from neurosurgical decompression of the involved facial nerve. DRUG-INDUCED MOVEMENT DISORDERS This important group of movement disorders is primarily associated with drugs that block dopamine receptors (neuroleptics) or central dopaminergic transmission. These drugs are widely used in psychiatry, but it is important to appreciate that drugs used in the treatment of nausea or vomiting (e.g., prochlorperazine [Compazine]) or gastro­ esophageal disorders (e.g., metoclopramide [Reglan]) are neurolep­ tic agents and can cause these disorders. Hyperkinetic movement disorders secondary to neuroleptic drugs can be divided into those that present acutely, subacutely, or after prolonged exposure (tardive syndromes). Dopamine-blocking drugs can also be associated with a reversible parkinsonian syndrome for which anticholinergics are often concomitantly prescribed, but these drugs are not effective antiparkinsonian agents and are associated with cognitive side effects, and there is concern that such treatment might actually increase the risk of developing a tardive syndrome. ■ ■ACUTE Dystonia is the most common acute hyperkinetic drug reaction (see above). It is typically generalized in children and focal in adults (e.g., blepharospasm, torticollis, or OMD). The reaction can develop within minutes of exposure and can be successfully treated in most cases with parenteral administration of anticholinergics (benztropine), diphenhydramine, benzodiazepines (lorazepam, clonazepam, or diaz­ epam), or dopamine agonists. The abrupt onset of severe spasms may occasionally be confused with a seizure; however, there is no loss of consciousness, and no automatisms, electroencephalogram abnormali­ ties, or postictal features typical of epilepsy. The acute onset of chorea, stereotypic behavior, and tics may also be seen, particularly following exposure to CNS stimulants such as methylphenidate, cocaine, or amphetamines. In rare cases, the airway may be affected and must be protected. ■ ■SUBACUTE Akathisia is the most common reaction in this category. Akathisia consists of motor restlessness with a need to move that is alleviated by movement. It is most frequently associated with use of neuroleptic drugs and generally starts within 2 weeks of initiating therapy. It can also be seen with calcium channel blockers, antiemetics, cocaine, and sedatives. The cause is not known but is thought to relate to blocking the dopaminergic system. Therapy consists of lowering the dose or removing the offending agent. When this is not possible, symptoms may be ameliorated with benzodiazepines, anticholinergics, beta blockers, or dopamine agonists. Treatment is generally effective, but in chronic cases, it may become associated with anxiety, depression, and even suicide. ■ ■TARDIVE SYNDROMES These disorders develop months to years after initiation of a neu­ roleptic agent. Tardive dyskinesias (TD) are most common and typically present with choreiform movements involving the mouth, lips, and tongue. In severe cases, the trunk, limbs, and respiratory muscles may also be affected. In approximately one-third of patients, TDs remit within 3 months of stopping the drug, and most patients gradually improve over the course of several years. However, abnor­ mal movements may also develop, persist, or worsen after stopping the offending agent. The movements are often mild and more upset­ ting to the family than to the patient, but in some cases, they can be severe and disabling, particularly in the context of an underlying psychiatric disorder. Second-generation or atypical antipsychotics (e.g., clozapine, risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole) are thought to be associated with a lower risk of causing TD in comparison to traditional antipsychotics, although they do not eliminate this risk. Younger patients have a lower risk of developing neuroleptic-induced TD, whereas the elderly, females, and those with underlying organic cerebral dysfunction are at greater risk. Chronic neuroleptic use is associated with increased risk of TD, and the U.S. Food and Drug Administration has specifically warned that use of metoclopramide for >12 weeks increases the risk of TD. Because TD can be permanent and resistant to treatment, antipsychotics should be used judiciously and atypical neuroleptics should be the preferred agent whenever possible, although there are now questions as to the risk of TD with atypical neuroleptics as well. In all patients on these agents, the need for continued use should be regularly evaluated. The cause of TD is not known with certainty, but it is thought to be related to hypersensitivity of dopamine receptors following the use of dopa­ mine D2–blocking agents. This concept is based on observations that acute discontinuation can lead to accentuation of TD, while higher doses of these agents or the introduction of more potent neuroleptics can alleviate symptoms (at least transiently). Another hypothesis is that structural changes at the receptor level due to toxic effects of the neuroleptic may be causative. It has also been suggested that there may be a genetic predisposition in individuals who develop TD. Treatment primarily consists of tapering and withdrawal of the offending agent. If the patient is receiving a traditional antipsychotic, and withdrawal is not possible, replacement with an atypical antipsy­ chotic (e.g., clozapine) should be tried. Abrupt cessation of a neurolep­ tic should be avoided because acute withdrawal can induce worsening. TD can persist after withdrawal of antipsychotics and can be difficult to treat. Tetrabenazine, a vesicular monoamine transporter type 2 (VMAT-2) inhibitor that blocks storage of dopamine, has been used to treat TD but is short-acting and is associated with a dose-related new onset or worsening of parkinsonian features. Valbenazine, an ester of tetrabenazine, has been approved for the treatment of tardive dyskinesia in a dose of 80 mg/d based on efficacy in double-blind trials, but it is associated with sleepiness and QT prolongation. Deuterated tetrabenazine has also been approved for this indication. Deuteration provides a longer half-life with lower Cmax, reducing risk of parkinso­ nian side effects. It can be individually titrated and permits the use of higher doses with lower risk of side effects. In open-label studies, benefits have also been reported with valproic acid (750–3000 mg/d), anticholinergics, and botulinum toxin injections. Other approaches include baclofen (40–80 mg/d) and clonazepam (1–8 mg/d). In some refractory cases, pallidal DBS may be an option. Chronic neuroleptic exposure can also be associated with a tardive dystonia, with preferential involvement of axial muscles and charac­ teristic rocking movements of the trunk and pelvis. Gray coloration of skin can be a clue that the patient is receiving a neuroleptic in patients for whom the cause of the dystonia is not obvious. Tardive dystonia can be more troublesome than tardive dyskinesia and frequently persists despite stopping medication. Valproic acid, anticholinergics, and botulinum toxin may occasionally be beneficial, but patients are frequently refractory to medical therapy. Tardive akathisia, tardive TS, and tardive tremor syndromes are rare but may also occur after chronic neuroleptic exposure. Neuroleptic medications can also be associated with a neuroleptic malignant syndrome (NMS). NMS is characterized by the acute or subacute onset of muscle rigidity, elevated temperature, altered mental status, hyperthermia, tachycardia, labile blood pressure, and renal fail­ ure with markedly elevated creatine kinase levels. Symptoms typically evolve within days or weeks after initiating the drug. NMS can also be precipitated by the abrupt withdrawal of dopaminergic medications in PD patients. Treatment involves immediate cessation of the offending antipsychotic drug and the introduction of a dopaminergic agent (e.g., a dopamine agonist or levodopa), dantrolene, or a benzodiazepine. In very severe cases, when oral intake is not possible, a patch (delivering rotigotine subcutaneously) or an infusion pump (delivering apomor­ phine or levodopa subcutaneously) may be required. Treatment may need to be undertaken in an intensive care setting and include sup­ portive measures such as control of body temperature (antipyretics and cooling blankets), hydration, electrolyte replacement, and control of renal function and blood pressure. Drugs that have serotonin-like activity (tryptophan, MDMA or “ecstasy,” meperidine) or that block serotonin reuptake can induce a rare, but potentially fatal, serotonin syndrome that is characterized by confusion, hyperthermia, tachycardia, and coma, as well as rigidity, ataxia, and tremor. Myoclonus is often a prominent feature, in contrast to NMS, which it resembles in other respects. Patients can be managed with propranolol, diazepam, diphenhydramine, chlorpromazine, or cyproheptadine, as well as supportive measures. A variety of other drugs can be associated with hyperkinetic move­ ment disorders. Some examples include phenytoin (chorea, dystonia, tremor, myoclonus), carbamazepine (tics and dystonia), tricyclic antidepressants (dyskinesias, tremor, myoclonus), fluoxetine (myoclo­ nus, chorea, dystonia), oral contraceptives (dyskinesia), β-adrenergics (tremor), buspirone (akathisia, dyskinesias, myoclonus), digoxin, cimetidine, diazoxide, lithium, methadone, and fentanyl (dyskinesias). And as described in an earlier chapter (Chap. 446), treatment of PD with levodopa can be associated with dyskinetic movements; these are typically choreiform, but dystonia and myoclonus may also occur. PAROXYSMAL DYSKINESIAS Paroxysmal dyskinesias are a group of rare disorders characterized by episodic, brief involuntary movements that can manifest as various types of hyperkinetic movements, including chorea, dystonia, tremor, myoclonus, and ballism. There are three main types: (1) paroxysmal kinesigenic dyskinesia (PKD), where the involuntary movements are triggered by sudden movement; (2) paroxysmal nonkinesigenic dyski­ nesias (PNKD), where the attacks are not induced by movement; and (3) rare cases of paroxysmal exertion-induced dyskinesia (PED), where attacks are induced by prolonged exercise. PKDs are characterized by brief, self-limited attacks induced by the onset of movement such as running but also occasionally by unex­ pected sound or photic stimulation. Attacks may affect one side of the body, last seconds to minutes at a time, and recur several times a day. They usually manifest as a mixed hyperkinetic movement disor­ der with dystonic posturing of a limb, ballismus, and chorea, which may also become generalized. PKD is most commonly familial with an autosomal dominant pattern of inheritance and mutations in the proline-rich transmembrane protein 2 (PRRT2) gene but may also occur secondary to various brain disorders such as multiple sclerosis or hyperglycemia. PKD is more frequent in males (4:1), and the onset is typically in the first or second decade of life. About 70% report sensory symptoms such as tingling or numbness of the affected limb preceding the attack by a few milliseconds. The evolution is relatively benign, and there is a trend toward resolution of the attacks over time. Treatment with low-dose anticonvulsant therapy such as carbamazepine or phe­ nytoin is advised when the attacks are frequent and interfere with daily life activities and is effective in ~80% of patients. Some clinical features of PKD (abrupt and short-lasting attacks preceded by an “aura”), the association with true seizure episodes, and its favorable response to anticonvulsant drugs have led to speculation that it is epileptic in ori­ gin, but this has not been established. CHAPTER 447 Tremor, Chorea, and Other Movement Disorders PNKD involves attacks of generalized dyskinesias precipitated by alcohol, caffeine, stress, or fatigue. In comparison to PKD, the epi­ sodes have a relatively longer duration (minutes to hours) and are less frequent (one to three per day). PNKD is inherited as an autosomal dominant condition with high (~80%) but incomplete penetrance. A missense mutation in the myofibrillogenesis regulator (PNKD) gene has been identified in several families. Recognition of the condition and elimination of the underlying precipitating factors, where possible, are the first priorities. Tetrabenazine, neuroleptics, dopamine-blocking agents, propranolol, clonazepam, and baclofen may be helpful. Treat­ ment may not be required if the condition is mild and self-limited. Most patients with PNKD do not benefit from anticonvulsant drugs, but these should be tried, and some may respond to clonazepam or other benzodiazepines. PED is characterized by a combination of chorea, athetosis, and dystonia in excessively exercised body regions, with the legs being most frequently affected. They are frequently familial. A single attack lasts from a few minutes to an hour and occurs after prolonged physi­ cal exercise. In addition to the movement disorder, several patients have other disease manifestations between episodes such as epilepsy, hemolytic anemia, and migraine. The SLC2A1 (solute carrier family 2 member 1) gene, previously linked to GLUT1 (glucose transporter of the blood-brain barrier) deficiency syndrome, can also cause parox­ ysmal PED. Treatment includes avoiding prolonged physical exercise. Whereas anticonvulsants and most medications are typically not effec­ tive, a ketogenic diet may be an effective therapeutic option. Other (rare) forms of paroxysmal dyskinesia are caused by pathogenic variants in the ECHS1, GLDC, KCNMA1, SCN8A, and TMEM151A genes. RESTLESS LEGS SYNDROME Restless legs syndrome (RLS) is a neurologic disorder that affects ~10% of the adult population (it is rare in Asians). It was first described in the seventeenth century by the English physician Thomas Willis but has only recently been appreciated to be a bona fide movement disorder. The four core symptoms required for diagnosis are an urge to move the legs usually caused or accompanied by an unpleasant sensation in the legs; symptoms that begin or worsen with rest; partial or complete relief by movement; and worsening during the evening or night. Symptoms are often mild but can cause significant morbidity in some individuals. Symptoms most commonly begin in the legs but can spread to, or even begin in, the upper limbs. The unpleasant sensation is often described as a creepy-crawly feeling, paresthesia, or burning. In ~80% of patients, RLS is associated with periodic leg movements (PLMs) during sleep and occasionally while awake. These involuntary move­ ments are usually brief, lasting no more than a few seconds, and recur every 5–90 s. The restlessness and PLMs are a major cause of sleep disturbance, leading to poor-quality sleep and daytime sleepi­ ness. RLS is also commonly associated with depression, anxiety, and hypertension. The mean age of onset in familial forms is in the third decade, although pediatric cases are recognized. The severity of symptoms is variable. Secondary RLS may be associated with pregnancy or a range of underlying disorders, including anemia, ferritin deficiency, renal failure, and peripheral neuropathy. There is an association with abnormalities of iron metabolism, possibly because low iron can result in reduced dopamine levels. Diagnosis is made on clinical grounds but can be supported by polysomnography and the demonstration of PLMs. Recent studies suggest that age, sex, and genetic markers can be used to accurately predict who is likely to develop RLS in 90% of cases. The neurologic examination is normal. Secondary causes of RLS should be excluded, and ferritin levels, glucose, and renal func­ tion should be measured. The pathogenesis is thought to be associated with an alteration in dopamine function, which may be peripheral or central, but this has not been specifically defined. Primary RLS is often familial and has a strong genetic component; however, no causative gene has yet been identified. Genome association studies have identi­ fied >150 variants associated with RLS risk, with the strongest candi­ dates in the PTPRD, BTBD9, and MEIS1 genes. Interestingly no genetic linkage to iron has been identified. PART 13 Neurologic Disorders Most RLS sufferers have mild symptoms that do not require specific treatment. General measures to improve sleep hygiene and quality should be attempted first. If symptoms remain intrusive, low doses of dopamine agonists, e.g., pramipexole (0.25–0.5 mg), ropinirole (1–2 mg), or patch rotigotine (2–3 mg), taken 1–2 h before bedtime are generally effective. Levodopa may also be effective but is more likely to be associated with augmentation (spread and worsening of symptoms and emergence during the day) or rebound (reappearance sometimes with worsening of symptoms at a time related to the drug’s short halflife). Augmentation can also be seen with chronic use of drugs such as dopamine agonists, particularly if higher doses are employed. Other drugs that have been reported to be effective in individual cases include anticonvulsants, analgesics, and opiates, but these are not commonly employed. Tonic motor activation (TOMAC) is a nonpharmacologic approach to RLS that has not responded to drug therapy and has recently been approved in the United States. The treatment involves electrical stimulation of the peroneal nerves during the night and is reported to be effective and to improve sleep quality. Management of secondary RLS should be directed to correcting the underlying disor­ der (e.g., iron replacement for anemia). OTHER DISORDERS THAT MAY PRESENT WITH A COMBINATION OF PARKINSONISM AND HYPERKINETIC MOVEMENTS ■ ■WILSON’S DISEASE (SEE ALSO CHAP. 427) Wilson’s disease (WD) is an inherited autosomal recessive disorder of copper metabolism that produces neurologic, psychiatric, and liver manifestations, alone or in combination. It is caused by mutations in the ATP7B gene encoding a P-type ATPase. The disease was first described by the English neurologist Kinnier Wilson at the beginning of the twentieth century, although at around the same time, the Ger­ man physicians Kayser and Fleischer separately noted the characteris­ tic association of corneal pigmentation (Kayser-Fleischer rings) along with hepatic and neurologic features. WD has a worldwide prevalence of ~1 in 30,000, with a mutation carrier frequency of 1 in 90. About half of WD patients (especially younger patients) present with liver abnormalities. The remainder present with neurologic disease (with or without underlying liver abnormalities), and a small proportion have hematologic or psychiatric problems at disease onset. Neurologic onset usually manifests in the second decade with tremor, rigidity, and dystonia. The tremor is usually in the upper limbs, bilateral, and asymmetric. Tremor can be on intention or occasionally at rest, and in advanced disease can take on a wing-beating character­ istic (a flapping movement when the arms are held outstretched with the fingers opposed). Other features can include parkinsonism with bradykinesia, dystonia (particularly facial grimacing), dysarthria, and dysphagia. More than half of those with neurologic features have a his­ tory of psychiatric disturbances, including depression, mood swings, and overt psychosis. Kayser-Fleischer (KF) rings are seen in virtually all patients with neurologic features and 80% of those with hepatic pre­ sentations. KF rings represent the deposition of copper in Descemet’s membrane around the cornea. They consist of a characteristic grayish rim or circle at the limbus of the cornea and are best detected by slitlamp examination. Neuropathologic examination is characterized by neurodegeneration and astrogliosis in the basal ganglia, particularly in the striatum. WD should always be considered in the differential diagnosis of a movement disorder, particularly when arising in the first decades of life. Low levels of blood copper and ceruloplasmin and high levels of urinary copper may be present, but normal levels do not exclude the diagnosis. Brain imaging usually reveals generalized brain atrophy in established cases, and ~50% have signal hypointensity in the caudate head, puta­ men, globus pallidus, substantia nigra, and red nucleus on T2-weighted MRI scans. However, the correlation of imaging changes with clinical features is not good. Liver biopsy with demonstration of high copper levels and genetic testing remain the gold standard for diagnosis. In the absence of treatment, the course is progressive and leads to severe neurologic dysfunction and early death in most patients, although a small proportion experience a relatively benign course. Treatment is directed at reducing tissue copper levels and maintenance therapy to prevent reaccumulation. There is no clear consensus on optimal treatment, and patients should be managed in a unit with expertise in treating this disease. Penicillamine is frequently used to increase copper excretion but may lead to a worsening of symptoms in the initial stages of therapy. Side effects are common and can to some degree be attenuated by co-administration of pyridoxine. Tetrathiomolybdate blocks the absorption of copper and can be used instead of penicillamine. Trientine tetrahydrochloride and zinc are useful drugs for maintenance therapy. Effective treatment can reverse the neurologic features in most patients, particularly when started early. However, some patients may still progress, especially those with hepatocerebral disease. KF rings tend to decrease after 3–6 months and disappear by 2 years. Adherence to maintenance therapy is a major challenge in long-term care. Patients with advanced hepatic disease may require a liver transplant, and the potential role of organ-specific chelation therapy is under investigation. Gene therapy studies that involve an infusion of a working copy of the ATP7B gene into the liver are being investigated clinically, while preclinical studies are testing the novel chelator methanobactin. ■ ■NEURODEGENERATION WITH BRAIN IRON ACCUMULATION Neurodegeneration with brain iron accumulation (NBIA) represents a group of inherited disorders characterized by iron accumulation in the basal ganglia. Clinically, they can manifest as a progressive neurologic disorder with a variety of clinical features including parkinsonism, dystonia, neuropsychiatric abnormalities, and retinal degeneration. Cognitive disorders and cerebellar dysfunction may also be seen. Pre­ sentation is usually in childhood, but adult cases have been described. Multiple genes have been identified. Pantothenate kinase-associated neurodegeneration (PKAN), formerly known as Hallervordan-Spatz disease, is caused by a mutation in the PANK2 gene and is the most common form of NBIA, accounting for ~50% of cases. Onset is usu­ ally in early childhood and is manifest as a combination of dystonia, parkinsonism, and spasticity. MRI shows a characteristic low signal abnormality in the center of the globus pallidus on T2-weighted scans caused by iron accumulation and known as the “eye of the tiger” sign. Numerous other gene mutations have been described associated with iron accumulation, including PLA2G6, C19orf12, FA2H, ATP13A2, WDR45, FTL, CP, COASY, and DCAF17. One must be cautious, however, not to assume that all cases with iron accumulation in the basal ganglia represent an NBIA because iron accumulation in some basal ganglia regions is normal, and excess iron accumulation may occur in the basal ganglia as a nonspecific secondary consequence of # 18 - 448 Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases ### 448 Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases neurodegeneration unrelated to a defect in iron metabolism. There are no specific treatments; iron binding may help slow progression, but this has not been established. FUNCTIONAL (PSYCHOGENIC) DISORDERS Virtually all movement disorders including tremor, tics, dystonia, myoclonus, chorea, ballism, and parkinsonism can be psychogenic in origin. The term functional neurologic symptom disorder (FND)/ conversion disorder has been suggested to replace the term psychogenic disorder in order to remove the criterion of psychological stress as a prerequisite for diagnosis; however, the terminology remains contro­ versial and both terms are used. A diagnosis can be made by identi­ fying neurologic signs that are specific to FNDs without reliance on psychological stressors or suggestive historical clues. Tremor affecting the upper limbs is the most common psychogenic movement disorder. Psychogenic movements can result from a somatoform or conversion disorder, malingering (e.g., seeking financial gain), or a factitious disorder (e.g., seeking psychological gain) (Chap. 463). Functional movement disorders are relatively common (estimated at 2–3% of patients seen in a movement disorder clinic), more frequent in women, disabling for the patient and family, and expensive for society. Clinical features suggesting a functional or psychogenic movement disorder include an acute onset with a pattern of abnormal movement that is inconsistent with the phenotype of a known movement disorder. Diag­ nosis is based on the nonorganic quality of the movement, the absence of findings of an organic disease process, and positive features that spe­ cifically point to a functional illness such as variability and distractibil­ ity. For example, in a functional tremor disorder, the magnitude of the tremor is increased with attention and diminishes or even disappears when the patient is distracted by being asked to perform a different task or is unaware that he or she is being observed. This is the opposite of what is seen with an organic tremor where the magnitude of tremor is increased with distraction and tends to be reduced when observed. Other positive features suggesting a psychogenic problem include vari­ able tremor frequency, entrainment of the tremor frequency with the frequency of a designated movement in the contralateral limb such as tapping, and a response to placebo interventions. Associated features can include nonanatomic sensory findings, give-way weakness, astasiaabasia (an odd, gyrating gait or posture) (Chap. 28), and multiple somatic complaints with no underlying pathology (somatoform disor­ der). Comorbid psychiatric problems such as anxiety, depression, and emotional trauma may be present but are not necessary for the diagno­ sis, which is why some prefer to call the movement disorder functional rather than psychogenic. Functional movement disorders typically occur as an isolated entity but may be seen in association with an underlying organic problem. The diagnosis can usually be made based on history and clinical features alone, and unnecessary tests or medi­ cations can be avoided. If there are underlying psychiatric problems, they should be identified and treated, but as noted, many patients with functional movement disorders have no obvious psychiatric pathology. Treatment of FND starts with explaining the diagnosis to the patient in a nonthreatening manner, but many are resistant to accepting this diag­ nosis. Psychological therapies (especially cognitive-behavioral) are the method of choice. An increasing role of physiotherapy has also recently been recognized, and a recent trial of physiotherapy and cognitivebehavioral therapy in combination was found to effectively improve symptoms in nearly half of patients. Comorbid depression, anxiety, and pain may be treated pharmacologically. Patients with hypochondriasis, factitious disorders, and malingering have a poor prognosis. ■ ■FURTHER READING Baumgartner AJ et al: Novel targets in deep brain stimulation for movement disorders. Neurosurg Rev 45:2593, 2022. Bhatia KP et al: Tremor Task Force of the International Parkinson and Movement Disorder Society. Mov Disord 33:75, 2018. Billnitzer A, Jankovic J: Current management of tics and Tourette syndrome: Behavioral, pharmacologic, and surgical treatments. Neu­ rotherapeutics 17:1681, 2020. Elias WJ, Shah BB: Essential tremor. JAMA 332:418, 2024. Espay AJ et al: Current concepts in diagnosis and treatment of func­ tional neurological disorders. JAMA Neurol 75:1132, 2018. Lange LM et al: Nomenclature of Genetic Movement Disorders: Recommendations of the International Parkinson and Movement Disorder Society Task Force—An update. Mov Disord 37:905, 2022. Macias-Garcia D et al: Combined physiotherapy and cognitive behavioral therapy for functional movement disorders: A random­ ized clinical trial. JAMA Neurol 81:966, 2024. Mestre TA: Recent advances in the therapeutic development for Hun­ tington disease. Parkinsonism Relat Disord 59:125, 2019. Tabrizi SJ et al: Potential disease-modifying therapies for Huntington’s disease: Lessons learned and future opportunities. Lancet Neurol 21:645, 2022. Thomsen M et al: Genetics and pathogenesis of dystonia. Annu Rev Pathol 19:99, 2024. CHAPTER 448 Robert H. Brown, Jr. Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases AMYOTROPHIC LATERAL SCLEROSIS Amyotrophic later sclerosis (ALS) is the most common progressive motor neuron disease. It is a prime example of a neurodegenerative disease and is arguably the most devastating of the neurodegenera­ tive disorders. ■ ■PATHOLOGY The pathologic hallmark of motor neuron degenerative disorders is death of lower motor neurons (consisting of anterior horn cells in the spinal cord and their brainstem homologues innervating bulbar muscles) and upper, or corticospinal, motor neurons (originating in layer five of the motor cortex and descending via the pyramidal tract to synapse with lower motor neurons, either directly or indirectly via interneurons) (Chap. 26). Although at its onset ALS may involve selec­ tive loss of function of only upper or lower motor neurons, it ultimately causes progressive loss of both categories of motor neurons. Indeed, in the absence of clear involvement of both motor neuron types, the diagnosis of ALS is questionable. In a subset of cases, ALS arises concurrently with frontotemporal dementia (Chap. 443); in these instances, there is degeneration of frontotemporal cortical neurons and corresponding cortical atrophy. Other motor neuron diseases involve only particular subsets of motor neurons (Tables 448-1 and 448-2). Thus, in bulbar palsy and spinal muscular atrophy (SMA, predominantly in children) and pro­ gressive muscular atrophy (PMA, in adults), the lower motor neurons of brainstem and spinal cord, respectively, are most severely involved. By contrast, pseudobulbar palsy, primary lateral sclerosis (PLS), and hereditary spastic paraplegia (HSP) affect only upper motor neurons innervating the brainstem and spinal cord. In each of these diseases, the affected motor neurons undergo shrinkage, often with accumulation of the pigmented lipid (lipofuscin) that normally develops in these cells with advancing age. In ALS, the motor neuron cytoskeleton is typically affected early in the illness. Focal enlargements are frequent in proximal motor axons; ultrastruc­ turally, these “spheroids” are composed of accumulations of neuro­ filaments and other proteins. Commonly in both sporadic and familial ALS, the affected neurons demonstrate ubiquitin-positive aggregates, often associated with the protein TDP43 (see below). Also seen is TABLE 448-1  Etiology of Motor Neuron Disorders DIAGNOSTIC CATEGORY INVESTIGATION Structural lesions   Parasagittal or foramen magnum MRI scan of head (including foramen magnum and cervical spine) tumors   Cervical spondylosis   Chiari malformation of syrinx   Spinal cord arteriovenous malformation Infections   Bacterial—tetanus, Lyme   Viral—poliomyelitis, herpes zoster   Retroviral—myelopathy CSF exam, culture Lyme titer Antiviral antibody HTLV-1 titers Intoxications, physical agents   Toxins—lead, aluminum, others   Drugs—strychnine, phenytoin   Electric short, x-irradiation 24-h urine for heavy metals Serum lead level PART 13 Neurologic Disorders Immunologic mechanisms   Plasma cell dyscrasias   Autoimmune polyradiculopathy   Motor neuropathy with conduction Complete blood counta Sedimentation ratea Total proteina Anti-GM1 antibodiesa block   Paraneoplastic   Paracarcinomatous Anti-Hu antibody MRI scan, bone marrow biopsy Metabolic   Hypoglycemia   Hyperparathyroidism   Hyperthyroidism   Deficiency of folate, vitamin B12, Fasting blood sugara Routine chemistries including calciuma PTH Thyroid functiona Vitamin B12, vitamin E, folatea vitamin E   Malabsorption   Deficiency of copper, zinc   Mitochondrial dysfunction Serum zinc, coppera 24-h stool fat, carotene, prothrombin time Fasting lactate, pyruvate, ammonia Consider mtDNA Hyperlipidemia Lipid electrophoresis Hyperglycinuria Urine and serum amino acids CSF amino acids Hereditary disorders   C9orf72   Superoxide dismutase   TDP43   FUS/TLS   Androgen receptor defect WBC DNA for mutational analysis (Kennedy’s disease) aShould be obtained in all cases. Abbreviations: CSF, cerebrospinal fluid; FUS/TLS, fused in sarcoma/translocated in liposarcoma; HTLV-1, human T-cell lymphotropic virus; MRI, magnetic resonance imaging; PTH, parathyroid; WBC, white blood cell. proliferation of astroglia and microglia, the inevitable accompaniment of all degenerative processes in the central nervous system (CNS). The death of the peripheral motor neurons in the brainstem and spinal cord leads to denervation and atrophy of the corresponding muscle fibers. Histochemical and electrophysiologic evidence indicates that in the early phases of the illness denervated muscle can be rein­ nervated by sprouting of nearby distal motor nerve terminals, although reinnervation in this disease is considerably less extensive than in most other disorders affecting motor neurons (e.g., poliomyelitis, peripheral neuropathy). As denervation progresses, muscle atrophy is readily recognized in muscle biopsies and on clinical examination. This is the basis for the term amyotrophy. The loss of cortical motor neurons results in thinning of the corticospinal tracts that travel via the inter­ nal capsule (Fig. 448-1) and pyramidal tracts in the brainstem to the lateral and anterior white matter columns of the spinal cord. The loss of fibers in the lateral columns and resulting fibrillary gliosis impart a particular firmness (lateral sclerosis). A remarkable feature of the TABLE 448-2  Sporadic Motor Neuron Diseases CHRONIC ENTITY Upper and lower motor neuron Amyotrophic lateral sclerosis Predominantly upper motor neuron Primary lateral sclerosis Predominantly lower motor neuron Multifocal motor neuropathy with conduction block   Motor neuropathy with paraproteinemia or cancer   Motor predominant peripheral neuropathies Other   Associated with other neurodegenerative disorders   Secondary motor neuron disorders (see Table 448-1)   Acute   Poliomyelitis   Herpes zoster   Coxsackie virus   West Nile virus   disease is the selectivity of neuronal cell death. By light microscopy, the entire sensory apparatus and cerebellar structures that control the coordination of movement remain intact. Except in cases of fronto­ temporal dementia, the components of the brain required for cognitive processing are also preserved. However, immunostaining indicates that neurons bearing ubiquitin, a marker for degeneration, are also detected in nonmotor systems. Moreover, studies of glucose metabolism in the illness also indicate that there is neuronal dysfunction outside of the motor system. Pathologic studies reveal proliferation of microglial cells and astrocytes in affected regions; in some cases, this phenomenon, designated neuroinflammation, can be visualized using positron emis­ sion tomography (PET) scanning for ligands that are recognized by activated microglia. Within the motor system, there is some selectivity FIGURE 448-1  Amyotrophic lateral sclerosis. Axial T2-weighted magnetic resonance imaging (MRI) scan through the lateral ventricles of the brain reveals abnormal high signal intensity within the corticospinal tracts (arrows). This MRI feature represents an increase in water content in myelin tracts undergoing Wallerian degeneration secondary to cortical motor neuronal loss. This finding is commonly present in ALS but can also be seen in AIDS-related encephalopathy, infarction, or other disease processes that produce corticospinal neuronal loss in a symmetric fashion. of involvement. Thus, motor neurons required for ocular motility remain unaffected, as do the parasympathetic neurons in the sacral spinal cord (the nucleus of Onufrowicz, or Onuf) that innervate the sphincters of the bowel and bladder. ■ ■CLINICAL MANIFESTATIONS The manifestations of ALS are somewhat variable depending on whether corticospinal neurons or lower motor neurons in the brain­ stem and spinal cord are more prominently involved. With lower motor neuron dysfunction and early denervation, typically the first evidence of the disease is insidiously developing asymmetric weakness, usually first evident distally in one of the limbs. A detailed history often discloses recent development of cramping with volitional movements, typically in the early hours of the morning (e.g., while stretching in bed). Weakness caused by denervation is associated with progressive wasting and atrophy of muscles and, particularly early in the illness, spontaneous twitching of motor units, or fasciculations. In the hands, a preponderance of extensor over flexor weakness is common. When the initial denervation involves bulbar rather than limb muscles, the problem at onset is difficulty with chewing, swallowing, and move­ ments of the face and tongue. Rarely, early involvement of the muscles of respiration may lead to death before the disease is far advanced elsewhere. With prominent corticospinal involvement, there is hyper­ activity of the muscle-stretch reflexes (tendon jerks) and, often, spastic resistance to passive movements of the affected limbs. Patients with significant reflex hyperactivity complain of muscle stiffness often out of proportion to weakness. Degeneration of the corticobulbar projections innervating the brainstem results in dysarthria and exaggeration of the motor expressions of emotion. The latter leads to involuntary excess in weeping or laughing (pseudobulbar affect). Virtually any muscle group may be the first to show signs of dis­ ease, but, as time passes, more and more muscles become involved until ultimately the disorder takes on a symmetric distribution in all regions. It is characteristic of ALS that, regardless of whether the initial disease involves upper or lower motor neurons, both will eventually be implicated. Even in the late stages of the illness, sensory, bowel and bladder, and cognitive functions are preserved. Even when there is severe brainstem disease, ocular motility is spared until the very late stages of the illness. As noted, in some cases (particularly those that are familial), ALS develops concurrently with frontotemporal dementia, characterized by early behavioral abnormalities with prominent behav­ ioral features indicative of frontal lobe dysfunction. A committee of the World Federation of Neurology has established diagnostic guidelines for ALS. Essential for the diagnosis is simulta­ neous upper and lower motor neuron involvement with progressive weakness and the exclusion of all alternative diagnoses. The disorder is ranked as “definite” ALS when three or four of the following are involved: bulbar, cervical, thoracic, and lumbosacral motor neurons. When two sites are involved, the diagnosis is “probable,” and when only one site is implicated, the diagnosis is “possible.” An exception is made for those who have progressive upper and lower motor neuron signs at only one site and a mutation in the gene encoding superoxide dismutase (SOD1; see below). It is now recognized that another clinical manifestation in most cases of ALS is the presence in cerebrospinal fluid (CSF) and serum of markers of neurodegeneration, such as elevated levels of neurofilament light chains (Nfl) or phosphorylated neurofilament heavy chains; some markers of inflammation (e.g., monocyte chemoattractant protein 1) are also elevated. Higher levels of serum or CSF Nfl are correlated with more aggressive disease and more rapid disease progression. Accord­ ingly, these CSF biomarkers are increasingly used as endpoints in clinical trials. ■ ■EPIDEMIOLOGY The illness is relentlessly progressive, leading to death from respiratory paralysis; the median survival is from 3 to 5 years. There are very rare reports of stabilization or even regression of ALS. In most societies, there is an incidence of 1–3 per 100,000 and a prevalence of 3–5 per 100,000. It is striking that about 1 in 500 deaths in North America and Western Europe (and probably elsewhere) are due to ALS; this finding predicts that >500,000 individuals now alive in the United States will die of ALS. Several endemic foci of higher prevalence exist in the western Pacific (e.g., in specific regions of Guam or Papua New Guinea). In the United States and Europe, men are somewhat more fre­ quently affected than women. Epidemiologic studies have incriminated risk factors for this disease including exposure to pesticides and insec­ ticides, silica, smoking, and possibly service in the military. Although ALS is overwhelmingly a sporadic disorder, some 10% of cases are inherited as an autosomal dominant trait. ■ ■FAMILIAL ALS Several forms of selective motor neuron disease are inheritable (Table 448-3). Familial ALS (FALS) involves both corticospinal and lower motor neurons. Apart from its inheritance as an autosomal dominant trait, it is clinically indistinguishable from sporadic ALS. Genetic studies have identified mutations in multiple genes, includ­ ing those encoding the protein C9orf72 (open reading frame 72 on chromosome  9), cytosolic enzyme SOD1 (superoxide dismutase), the RNA binding proteins TDP43 (encoded by the TAR DNA bind­ ing protein gene), and fused in sarcoma/translocated in liposarcoma (FUS/TLS), as the most common causes of FALS. Mutations in C9orf72 account for ~45–50% of FALS and perhaps 5–10% of sporadic ALS cases. Mutations in SOD1 explain another 20% of cases of FALS, whereas TDP43 and FUS/TLS each represent about 5% of familial cases. Mutations in several other genes (e.g., NEK1, optineurin, TBK1, KIF5A, TUBA4, and PFN11) each cause ~1% of cases. CHAPTER 448 Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases Rare mutations in other genes are also clearly implicated in ALS-like diseases. Thus, a familial, dominantly inherited motor disorder that in some individuals closely mimics the ALS phenotype arises from mutations in a gene that encodes a vesicle-binding protein. Mutations in senataxin, a helicase, cause an early-adult-onset, slowly evolving ALS variant. Kennedy’s syndrome is an X-linked, adult-onset disorder that may mimic ALS, as described below. Tau gene mutations usually underlie frontotemporal dementia but in some instances may be asso­ ciated with prominent motor neuron findings. Genetic analyses are also beginning to illuminate the pathogenesis of some childhood-onset motor neuron diseases. For example, a slowly disabling degenerative, predominantly upper motor neuron disease that starts in the first decade is caused by mutations in a gene that expresses a novel signaling molecule with properties of a guanineexchange factor, termed alsin. ■ ■DIFFERENTIAL DIAGNOSIS Because ALS is currently untreatable, it is imperative that poten­ tially remediable causes of motor neuron dysfunction be excluded (Table 448-1). This is particularly true in cases that are atypical by virtue of (1) restriction to either upper or lower motor neurons, (2) involvement of neurons other than motor neurons, and (3) evidence of motor neuronal conduction block on electrophysiologic testing. Com­ pression of the cervical spinal cord or cervicomedullary junction from tumors in the cervical regions or at the foramen magnum or from cer­ vical spondylosis with osteophytes projecting into the vertebral canal can produce weakness, wasting, and fasciculations in the upper limbs and spasticity in the legs, closely resembling ALS. The absence of cranial nerve involvement may be helpful in differentiation, although some foramen magnum lesions may compress the twelfth cranial (hypoglossal) nerve, with resulting paralysis of the tongue. Absence of pain or of sensory changes, normal bowel and bladder function, normal radiologic studies of the spine, and normal CSF all favor ALS. Where doubt exists, magnetic resonance imaging (MRI) scans and possibly contrast myelography should be performed to visualize the cervical spinal cord. Another important entity in the differential diagnosis of ALS is multifocal motor neuropathy with conduction block (MMCB), discussed below. A diffuse, lower motor axonal neuropathy mimicking ALS sometimes evolves in association with hematopoietic disorders such as lymphoma or multiple myeloma. In this clinical setting, the presence of an M-component in serum should prompt consideration of a bone TABLE 448-3  Genetic Motor Neuron Diseases GENE SYMBOL GENE NAME INHERITANCE DISEASE I. Selected Upper and Lower Motor Neurons (Familial ALS) + Frontotemporal Dementia (FTD) ALS/ALS-FTD C9ORF72 Chromosome 9 open reading frame 72 AD 45% (6–10% SALS) Adult Regulates vesicle trafficking ALS SOD1 Cu/Zn superoxide dismutase 1 AD 20% (2% SALS) Adult Protein antioxidant   ALS/ALS-FTD TARDBP TAR DNA binding protein AD 5% Adult DNA, RNA binding   ALS/ALS-FTD FUS/TLS Fused in sarcoma/ translocated in liposarcoma AD 5% Adult DNA, RNA binding   ALS/ALS-FTD CCNF E3 ubiquitin ligase cyclin F AD 2% Adult Mediates ubiquitination ALS NEK1 NMA-related kinase AR 2% Adult Microtubules, nuclear transport PART 13 Neurologic Disorders ALS/ALS-FTD TBK1 Tank binding kinase 1 AD 2% Adult Regulates autophagy, inflammation ALS KIF5A Kinesin family member 5A AD 1–2% Early adult Microtubule motor CMT ALS PFN1 Profilin 1 AD ~1% Adult Involved in actin polymerization ALS/ALS-FTD OPTN Optineurin AD/AR ~1% Adult Attenuates NF-κB   ALS SPG11 Spastic paraplegia 11 AR ~1% Adult Vesicle trafficking Spastic paraplegia ALS SETX Senataxin AD ~1% Late juvenile DNA helicase Late childhood onset ALS/ALS-FTD VCP Valosin-containing protein AD ~ 1% Adult ATPase Paget’s, myopathy ALS-FTD UBQLN2 Ubiquilin 2 XR <1% Adult or juvenile ALS-FTD CHMP2B Chromatin modifying protein 2B AD <1% Adult Chromatin binding protein ALS-FTD MAPT Microtubule Associated Protein Tau AD <1% Adult Cytoskeletal protein Usually causes only FTD ALS2 ALS2 Alsin AR <1% Juvenile GEF signaling Corticobulbar/ corticospinal may mimic PLS ALS-FTD CHMP2B Chromatin modifying protein 2B AD <1% Adult Chromatin binding protein II. Lower Motor Neurons Spinal muscular atrophies SMN Survival motor neuron AR 1/10,000 live births Infancy RNA metabolism   GM2-gangliosidosis                 1. Sandhoff’s disease HEXB Hexosaminidase B AR   Childhood Ganglioside recycling     2. AB variant GM2A GM2-activator protein AR   Childhood Ganglioside recycling     3. Adult Tay-Sachs HEXA Hexosaminidase A AR   Childhood Ganglioside recycling   disease X-linked spinobulbar muscular atrophy AR Androgen receptor XR   Adult Nuclear signaling   III. Upper Motor Neuron (Selected HSPs)   SPG3A ATL1 Atlastin AD 10% AD FSP Childhood GTPase—vesicle recycling   SPG4 SPAST Spastin AD 50–60% AD FSP Early adulthood ATPase family—   SPG10 KIF5A Kinesin heavy chain isoform 5A AD 10% AD FSP Second–third decade   SPG31 REEP1 Receptor Expression Enhancing Protein 1 AD 10% AD FSP Early Mitochondrial protein Rarely, amyotrophy   SPG5 CYP7B1 Cytochrome P450 AR 5–10% AR FSP Variable Degrades endogenous substances   SPG7 SPG7 Paraplegin AR 5–10% AR FSP Variable Mitochondrial protein Rarely, optic atrophy, ataxia, rarely PLS U.S. FREQUENCY % FALS USUAL ONSET PROTEIN FUNCTION UNUSUAL FEATURES May also be associated with parkinsonism, PLS         Protein degradation         Some sensory loss microtubule associate Motor-associated protein ± Peripheral neuropathy, retardation Sensory loss (Continued) TABLE 448-3  Genetic Motor Neuron Diseases (Continued) GENE SYMBOL GENE NAME INHERITANCE DISEASE   SPG11 SPG11 Spatacsin AR 20–70% AR FSP depends on ethnicity   SPG2 PLP Proteolipid protein XR <1% Early childhood Myelin protein Sometimes multiple CNS features Adrenoleukodystrophy ALDP Adrenoleukodystrophy protein XR <1% Early adulthood ATP binding Abbreviations: AD, autosomal dominant; ALS, amyotrophic lateral sclerosis; AR, autosomal recessive; CNS, central nervous system; CMT, Charcot-Marie-Tooth; BSCL2, Bernadelli-Seip congenital lipodystrophy 2B; FALS, familial amyotrophic lateral sclerosis; FSP, familial spastic paraplegia; FUS/TLS, fused in sarcoma/translocated in liposarcoma; GEF, guanidine nucleotide exchange factor; HSP, hereditary spastic paraplegia; NF-κB, nuclear factor-κB; PLS, primary lateral sclerosis; SALS, sporadic amyotrophic lateral sclerosis; TDP43, Tar DNA binding protein 43 kd; XR, X-linked recessive. marrow biopsy. Lyme disease (Chap. 191) may also cause an axonal, lower motor neuropathy, although typically with intense proximal limb pain and a CSF pleocytosis. Other treatable disorders that occasionally mimic ALS are chronic lead poisoning and thyrotoxicosis. These disorders may be suggested by the patient’s social or occupational history or by unusual clini­ cal features. When the family history is positive, disorders involving the genes encoding C9orf72, cytosolic SOD1, TDP43, FUS/TLS, and adult hexosaminidase A or α-glucosidase deficiency (Chap. 429) must be excluded. These are readily identified by appropriate laboratory tests; importantly, panels for simultaneous analysis of multiple ALS and frontotemporal dementia (FTD) genes are now commercially available. Benign fasciculations are occasionally a source of concern because on inspection they resemble the fascicular twitchings that accompany motor neuron degeneration. The absence of weakness, atrophy, or denervation phenomena on electrophysiologic examina­ tion usually excludes ALS or other serious neurologic disease. Patients who have recovered from poliomyelitis may experience a delayed deterioration of motor neurons that presents clinically with progres­ sive weakness, atrophy, and fasciculations. Its cause is unknown, but it is thought to reflect sublethal prior injury to motor neurons by poliovirus (Chap. 210). Rarely, ALS develops concurrently with features indicative of more widespread neurodegeneration. Neuropsychological testing may detect subtle cognitive impairment in ~15% of cases that clinically are purely ALS; these cognitive deficits worsen with disease progression. Impor­ tantly, one often encounters the combination of ALS and FTD in indi­ viduals who harbor C9orf72 mutations. The simultaneous occurrence of these disorders reflects shared embryologic origins and transcription factor expression in corticospinal motor neurons and neurons impli­ cated in FTD (von Economo neurons). Overall, up to 40% of FTD cases harbor mutations in the C9orf72 gene. Beyond C9orf72, several other ALS genes can trigger both ALS and FTD (see Table 448-3). As another example of an atypical phenotype, prominent amyotrophy has been described as a dominantly inherited disorder in individuals with bizarre behavior and a movement disorder suggestive of parkinsonism; many such cases have now been ascribed to mutations that alter the expression of tau protein in the brain (Chap. 443). An ALS-like disor­ der has also been described in some individuals with chronic traumatic encephalopathy (Chap. 454), associated with deposition of TDP43 and neurofibrillary tangles in motor neurons. ■ ■PATHOGENESIS The cause of sporadic ALS is not well defined, in part because there is no animal model for this form of ALS. Strikingly, motor neurons derived from stem cells of individuals with sporadic ALS can display diminished viability, suggesting that heritable factors play a role. Several mechanisms that impair motor neuron viability have been elucidated in rodents that harbor transgenes with mutant SOD1, pro­ filin-1, or C9orf72. One may loosely group the genetic causes of ALS into three categories. In one group, the primary problem is inherent U.S. FREQUENCY % FALS USUAL ONSET PROTEIN FUNCTION UNUSUAL FEATURES Predominantly childhood Cytosolic,? membrane-associated Some sensory loss, thin corpus callosum; may mimic ALS (ALS5) Possible adrenal insufficiency, CNS inflammation transporter protein CHAPTER 448 instability of the mutant proteins, with subsequent perturbations in protein degradation (SOD1, ubiquilin-1 and 2, p62). In the second category, the causative mutant genes perturb RNA processing, trans­ port, and metabolism (C9orf73, TDP43, FUS). In the case of C9orf72, the molecular pathology is an expansion of an intronic hexanucleo­ tide repeat (-GGGGCC-) beyond an upper normal of 30 repeats to hundreds or even thousands of repeats. As observed in other intronic repeat disorders such as myotonic dystrophy (Chap. 460) and spi­ nocerebellar atrophy type 8 (Chap. 450), the expanded intronic repeats generate expanded RNA repeats that form intranuclear foci and may confer toxicity by sequestering transcription factors or by undergoing noncanonical protein translation across all possible reading frames of the expanded RNA tracts. Importantly, the latter process generates lengthy dipeptides that are detected in the spinal fluid and are a unique biomarker for C9orf72 ALS. TDP43 and FUS are multifunctional proteins that bind RNA and DNA and shuttle between the nucleus and the cytoplasm, playing multiple roles in the control of cell proliferation, DNA repair and transcription, and gene translation, both in the cytoplasm and locally in dendritic spines in response to electrical activity. How mutations in FUS/TLS provoke motor neuron cell death is not clear, although this may represent loss of function of FUS/TLS in the nucleus or an acquired, toxic function of the mutant proteins in the cytosol. In the third group of ALS genes, the primary problem is defective axonal cytoskeleton and transport (dynactin, profilin-1). It is striking that variants in other genes influ­ ence survival in ALS but not ALS susceptibility. Intermediate-length polyglutamine-coding expansions (-CAG-) in the gene ataxin-2 confer increased ALS susceptibility; suppression of ataxin-2 expres­ sion extends survival in transgenic ALS mice. Beyond the upstream, primary defects, it is also evident that the ultimate neuronal cell death process is complex, involving multiple cellular processes acting in diverse components of the motor neuron (dendrites, cell body, axons, neuromuscular junction) to accelerate cell death. These include but are not limited to excitotoxicity, defective autophagy, impairment of axonal transport, oxidative stress, activation of endoplasmic reticu­ lum stress and the unfolded protein response, and mitochondrial dysfunction. In addition, the hexanucleotide expansions that cause C9orf72 ALS disrupt nucleocytoplasmic transport; the importance of this observation is underscored by the finding that mutations in the gene encoding GLE1, a protein that mediates mRNA export, cause an aggressive, infantile motor neuron disease. Amyotrophic Lateral Sclerosis and Other Motor Neuron Diseases Multiple studies have convincingly demonstrated that proliferating, activated nonneuronal cells such as microglia and astrocytes impor­ tantly influence the disease course, at least in ALS-transgenic mice. A striking additional finding in ALS and most neurodegenerative dis­ orders is that miscreant proteins arising from gene defects in familial forms of these diseases are often implicated in sporadic forms of the same disorder. For example, some reports propose that nonheritable, posttranslational modifications in SOD1 are pathogenic in sporadic ALS; indeed, SOD1 aggregates are sometimes observed in spinal cord in sporadic ALS without SOD1 mutations. TREATMENT Amyotrophic Lateral Sclerosis No treatment arrests the underlying pathologic process in ALS. The drug riluzole (100 mg/d) was approved for ALS because it produces a modest lengthening of survival. In one trial, the survival rate at 18 months with riluzole was similar to placebo at 15 months. The mechanism of this effect is not known with certainty; riluzole may reduce excitotoxicity by diminishing glutamate release. Riluzole is generally well tolerated; nausea, dizziness, weight loss, and elevated liver enzymes occur occasionally. A second drug, edaravone, has also been approved by the U.S. Food and Drug Administration (FDA) based on a single 6-month study in a highly selected ALS population that demonstrated a modest reduction in the trajectory of worsening on an ALS disability scale; survival was not included as an endpoint. This drug, which is believed to act as an antioxidant, was initially administered via recurring monthly 10-day series of daily intravenous infusions. A formulation for oral use is now available. PART 13 Neurologic Disorders Interventions such as antisense oligonucleotides (ASO) and microRNAs that diminish expression of mutant SOD1 protein prolong survival in transgenic-ALS rodent models and are also now under investigation in SOD1-mediated ALS. Tofersen, an ASO that suppresses SOD1 expression following intrathecal delivery, is now FDA approved for SOD1-mediated ALS. Pilot studies of an ASO targeting FUS/TLS have also been promising. Pathophysi­ ologic studies of cell lines and animal models incorporating mutant SOD1, C9orf72, and other ALS genes have disclosed diverse targets for therapy; consequently, multiple therapies are presently in clini­ cal trials for ALS including experimental trials of small molecules, mesenchymal stem cells, and immunosuppression. In the absence of a primary therapy for ALS, a variety of reha­ bilitative aids may substantially assist ALS patients. Foot-drop splints facilitate ambulation by obviating the need for excessive hip flexion and by preventing tripping on a floppy foot. Fingerextension splints can potentiate grip. Respiratory support may be life-sustaining. For patients electing against long-term ventilation by tracheostomy, positive-pressure ventilation by mouth or nose provides transient (weeks to months) relief from hypercarbia and hypoxia. Also extremely beneficial for some patients is a respiratory device (cough assist machine) that produces an artificial cough. This is highly effective in clearing airways and preventing aspira­ tion pneumonia. When bulbar disease prevents normal chewing and swallowing, gastrostomy is uniformly helpful, restoring nor­ mal nutrition and hydration. Fortunately, an increasing variety of speech synthesizers are now available to augment speech when there is advanced bulbar palsy. These facilitate oral communication and may be effective for telephone use. In contrast to ALS, several of the disorders (Tables 448-1 and 448-3) that bear some clinical resemblance to ALS are treatable. For this reason, a careful search for causes of secondary motor neuron disease is warranted. OTHER MOTOR NEURON DISEASES ■ ■SELECTED LOWER MOTOR NEURON DISORDERS In these motor neuron diseases, the peripheral motor neurons are affected without evidence of involvement of the corticospinal motor system (Tables 448-1, 448-2, and 448-3). X-Linked Spinobulbar Muscular Atrophy (Kennedy’s Disease)  This is an X-linked lower motor neuron disorder in which progressive weakness and wasting of limb and bulbar muscles begins in males in mid-adult life and is conjoined with androgen insensitivity mani­ fested by gynecomastia and reduced fertility (Chap. 403). In addition to gynecomastia, which may be subtle, two findings distinguishing this disorder from ALS are the absence of signs of pyramidal tract disease (spasticity) and the presence of a subtle sensory neuropathy in some patients. The underlying molecular defect is an expanded trinucleotide repeat (CAG) in the first exon of the androgen receptor gene on the X chromosome. An inverse correlation appears to exist between the number of CAG repeats and the age of onset of the disease. Adult Tay-Sachs Disease  Several reports have described adultonset, predominantly lower motor neuropathies arising from defi­ ciency of the enzyme β-hexosaminidase (hex A). These tend to be distinguishable from ALS because they are very slowly progressive and in some cases may have been symptomatic for years; dysarthria and radiographically evident cerebellar atrophy may be prominent. In rare cases, spasticity may also be present, although it is generally absent (Chap. 429). Spinal Muscular Atrophy  The SMAs are a family of selective lower motor neuron diseases of early onset. Despite some pheno­ typic variability (largely in age of onset), the defect in the majority of families with SMA is loss of a protein (SMN, for survival motor neuron) that is important in the formation and trafficking of RNA complexes across the nuclear membrane. Neuropathologically, these disorders are characterized by extensive loss of large motor neurons; muscle biopsy reveals evidence of denervation atrophy. Several clini­ cal forms exist. Infantile SMA (SMA I, Werdnig-Hoffmann disease) has the earliest onset and most rapidly fatal course. In some instances, it is apparent even before birth, as indicated by decreased fetal move­ ments late in the third trimester. Though alert, afflicted infants are weak and floppy (hypotonic) and lack muscle-stretch reflexes. Death generally ensues within the first year of life. Chronic childhood SMA (SMA II) begins later in childhood and evolves with a more slowly progressive course. Juvenile SMA (SMA III, Kugelberg-Welander disease) manifests during late childhood and runs a slow, indolent course. Unlike most denervating diseases, in this chronic disorder, weakness is greatest in the proximal muscles; indeed, the pattern of clinical weakness can suggest a primary myopathy such as limbgirdle dystrophy. Electrophysiologic and muscle biopsy evidence of denervation distinguish SMA III from the myopathic syndromes. Remarkably, two treatments have shown dramatic benefit in infan­ tile SMA. One, nusinersen, now an approved therapy, entails admin­ istering small oligonucleotides that alter mRNA splicing of one of the SMN genes, generating sufficient normal SMN protein to pro­ vide clinical benefit (including prolonged survival). The other treat­ ment uses systemically administered adeno-associated virus (AAV) to deliver the missing SMN gene to motor neurons and other cells. Multifocal Motor Neuropathy with Conduction Block  In this disorder, lower motor neuron function is regionally and chroni­ cally disrupted by focal blocks in conduction. Many cases have ele­ vated serum titers of mono- and polyclonal antibodies to ganglioside GM1; it is hypothesized that the antibodies produce selective, focal, paranodal demyelination of motor neurons. MMCB is not typically associated with corticospinal signs. In contrast with ALS, MMCB may respond dramatically to therapy such as IV immunoglobulin or chemotherapy; thus, it is imperative that MMCB be excluded when considering a diagnosis of ALS. Other Forms of Lower Motor Neuron Disease  In individual families, other syndromes characterized by selective lower motor neuron dysfunction in an SMA-like pattern have been described. There are rare X-linked and autosomal dominant forms of apparent SMA. There is an ALS variant of juvenile onset, the Fazio-Londe syndrome, that involves mainly the musculature innervated by the brainstem. A component of lower motor neuron dysfunction is also found in degenerative disorders such as Machado-Joseph disease and the related olivopontocerebellar degenerations (Chap. 450). Finally, a group of lower motor neuron disorders, sometimes mim­ icking Charcot-Marie-Tooth disease, and sometimes spinal muscular atrophy, are caused by mutations in the enzymes (tRNA synthetases) that charge tRNA with specific amino acids, an early step in protein synthesis. # 19 - 449 Prion Diseases ### 449 Prion Diseases ■ ■SELECTED DISORDERS OF THE UPPER MOTOR NEURON Primary Lateral Sclerosis  This rare disorder arises sporadi­ cally in adults in mid-to-late life. Clinically, PLS is characterized by progressive spastic weakness of the limbs, preceded or followed by spastic dysarthria and dysphagia, indicating combined involve­ ment of the corticospinal and corticobulbar tracts. Fasciculations, amyotrophy, and sensory changes are absent; neither electromyog­ raphy nor muscle biopsy shows denervation. On neuropathologic examination, there is selective loss of the large pyramidal cells in the precentral gyrus and degeneration of the corticospinal and corticobulbar projections. The peripheral motor neurons and other neuronal systems are spared. The course of PLS is usually indolent; infrequently, there is conversion to a more aggressive course with lower motor neuron degeneration as in ALS. Early in its course, PLS raises the question of multiple sclerosis, other demyelinating dis­ eases, or adult-onset spastic paraplegia as diagnostic considerations (Chap. 455). A myelopathy suggestive of PLS is infrequently seen with infection with the retrovirus human T-cell lymphotropic virus 1 (HTLV-1) (Chap. 453). The clinical course and laboratory testing will distinguish these possibilities. Hereditary Spastic Paraplegia  In its pure form, HSP is usu­ ally transmitted as an autosomal trait; most adult-onset cases are dominantly inherited. There are >80 genetic types of HSP for which causative mutations in >60 genes have been identified. Table 448-3 lists more commonly identified genetic types of HSP. Symptoms usually begin in the third or fourth decade of life, presenting as progressive spastic weakness beginning in the lower extremities; however, there are variants with onset so early that the differential diagnosis includes cerebral palsy. HSP typically has a long survival, presumably because respiratory function is spared. Late in the illness, there may be urinary urgency and incontinence and sometimes fecal incontinence; sexual function tends to be preserved. In pure forms of HSP, the spastic leg weakness is often accompanied by posterior column (vibration and position) abnormalities and distur­ bance of bowel and bladder function. Some family members may have spasticity without clinical symptoms. By contrast, particularly when recessively inherited, HSP may have complex or complicated forms in which altered corticospinal and dorsal column function is accompanied by significant involvement of other regions of the nervous system, including amyotrophy, intellectual disability, optic atrophy, and sensory neuropathy. Neuropathologically, in HSP, there is degeneration of the cortico­ spinal tracts, which appear nearly normal in the brainstem but show increasing atrophy at more caudal levels in the spinal cord; in effect, this pathologic picture is of a dying-back or distal axonopathy of long neuronal fibers within the CNS. Defects at numerous loci underlie both dominantly and recessively inherited forms of HSP (Table 448-3). The gene most commonly implicated in dominantly inherited HSP is spastin, which encodes a microtubule interacting protein. The most common childhood-onset dominant form arises from mutations in the atlastin gene. An infantile-onset form of X-linked, recessive HSP arises from mutations in the gene for myelin proteolipid protein. This is an example of rather striking allelic variation, as most other mutations in the same gene cause not HSP but Pelizaeus-Merzbacher disease, a widespread disorder of CNS myelin. Another recessive variant is caused by defects in the paraplegin gene. Paraplegin has homology to metalloproteases that are important in mitochondrial function in yeast. A slowly progressive, adult-onset X-linked progressive spastic paraly­ sis designated adrenomyeloneuropathy is caused by mutations in the ABCD1 gene; these cases are associated with elevated serum levels of very-long-chain fatty acids (Chap. 453). ■ ■FURTHER READING Akçimen F et al: Amyotrophic lateral sclerosis: Translating genetic discoveries into therapies. Nat Rev Genetics 44:642, 2023. Baryshnikov VA et al: Antisense oligonucleotide silencing of FUS expression as as therapeutic approach in amyotrophic lateral sclero­ sis. Nat Med 28(1):104, 2022. Brown RH, Al-Chalabi A: Review article: Amyotrophic lateral scle­ rosis. N Engl J Med 377:162, 2017. Chio A et al: Cognitive impairment across ALS clinical stages in a population cohort. Neurology 93:e984, 2018. Finkel RS et al: Treatment of infantile-onset spinal muscular atrophy with nusinersin: A phase 2, open-label, dose-escalation study. Lancet 388:3017, 2016. Gendron TF et al: Poly(GP) proteins are a useful pharmacodynamic marker for C9ORF72-associated amyotrophic lateral sclerosis. Sci Transl Med 9:pii:eaai7866, 2017. Miller TM et al: Trial of antisense oligonucleotide tofersen for ALS. N Engl J Med 387:1099, 2022. Mueller C et al: SOD1 suppression with adeno-associated virus and CHAPTER 449 microRNA in familial ALS. N Engl J Med 383:151, 2020. Schüle R et al: Hereditary spastic paraplegia: Clinicogenetic lessons from 608 patients. Ann Neurol 79:646, 2016. Shahim P et al: Neurofilaments in sporadic and familial amyotrophic lateral sclerosis: A systematic review and meta-analysis. Genes 15:496, 2024. Taylor JP et al: Decoding ALS: From genes to mechanism. Nature Prion Diseases 539:197, 2016. Van Damme P, Robberecht W: STING-induced inflammation—A novel therapeutic target in ALS? N Engl J Med 384:765, 2021. Visser AE et al: Multicentre, population-based, case-control study of particulates, combustion products and amyotrophic lateral sclerosis risk. J Neurol Neurosurg Psychiatry 90:854, 2019. ■ ■WEBSITES Several websites provide valuable information on ALS including those offered by the Muscular Dystrophy Association (www.mdausa.org), the Amyotrophic Lateral Sclerosis Association (www.alsa.org), the World Federation of Neurology and the Neuromuscular Unit at Washing­ ton University in St. Louis (www.neuro.wustl.edu), and the Northeast Amyotrophic Lateral Sclerosis Consortium (www.neals.org). Stanley B. Prusiner, Michael D. Geschwind Prion Diseases Prions are proteins that adopt alternative conformations, which become self-propagating. Some prions cause degeneration of the cen­ tral nervous system (CNS). Once relegated to causing a group of rare CNS disorders, such as Creutzfeldt-Jakob disease (CJD), increasing evidence argues that prions also cause more common neurodegenera­ tive diseases (NDs) including Alzheimer’s disease (AD) and Parkinson’s disease (PD). While CJD is caused by the accumulation of PrPSc prions (Table 449-1), α-synuclein prions cause multiple system atrophy (MSA) (Chap. 451). Infectious MSA prions have been recovered from human brain samples stored in formalin for up to 20 years. Similar resistance to formalin was demonstrated for brain samples from sheep with scrapie. Increasing data suggest that Aβ and tau prions together may cause AD, α-synuclein prions PD in addition to MSA, and tau prions frontotemporal lobar degeneration (FTLD). CJD typically pres­ ents as a rapidly progressive dementia accompanied by other motor abnormalities and behavioral changes. The illness is relentlessly pro­ gressive and generally causes death within ~7 months from onset. Most patients with sporadic CJD (sCJD) are between 50 and 75 years of age, although patients as young as 12 and as old as 96 have been described. TABLE 449-1  Glossary of PrP Prion Terminology Prion Proteinaceous infectious particle that lacks nucleic acid. Prions are composed entirely of alternatively folded proteins that undergo self-propagation. Distinct strains of prions exhibit different biologic properties, which are epigenetically heritable. PrP prions cause scrapie in sheep and goats, mad cow disease, and related neurodegenerative diseases of humans such as Creutzfeldt-Jakob disease (CJD). PrPSc Disease-causing Scrapie isoform of the prion protein. This protein is the only identifiable macromolecule in purified preparations of scrapie prions. PrPC Cellular isoform of the prion protein. PrPC is the precursor of PrPSc. PrP 27-30 A fragment of PrPSc, generated by truncation of the NH2-terminus by limited digestion with proteinase K. PrP 27-30 retains prion infectivity and polymerizes into amyloid. PRNP PrP gene located on human chromosome 20. Prion rod An aggregate of prions composed largely of PrP 27-30 molecules. Created by detergent extraction and limited proteolysis of PrPSc. Morphologically and histochemically indistinguishable from many amyloids. PART 13 Neurologic Disorders PrP amyloid Amyloid containing PrP in the brains of animals or humans with prion disease; often accumulates as plaques. The potential role of prions in the pathogenesis of NDs is reviewed in Chap. 435. CJD is one malady in a group of disorders caused by prions com­ posed of the human prion protein (PrP). PrP prions reproduce by binding to the normal, cellular isoform of the prion protein (PrPC) and stimulating conversion of PrPC into the disease-causing isoform PrPSc. PrPC is rich in α-helix and has little β-structure, whereas PrPSc has less α-helix and a high amount of β-structure. The α-to-β structural transi­ tion in PrP is the fundamental event underlying this group of prion diseases. Four new concepts have emerged from studies of PrP prions: (1) Prions are the only known transmissible pathogens that are devoid of nucleic acid; all other infectious agents possess genomes composed of either RNA or DNA that direct the synthesis of their progeny. (2)  Prion diseases may manifest as infectious, genetic, or sporadic disorders; no other group of illnesses with a single etiology presents with such a wide spectrum of clinical manifestations. (3) Prion diseases result from the accumulation of PrPSc, the conformation of which dif­ fers substantially from that of its precursor, PrPC. (4) Distinct strains of prions exhibit different biologic properties, which are epigeneti­ cally inherited. In other words, PrPSc can exist in a variety of different conformations, many of which seem to specify disease phenotypes. How a specific conformation of a PrPSc molecule is imparted to PrPC during prion replication to produce nascent PrPSc with the same conformation is not well understood. Additionally, it is unclear what factors determine where in the CNS a particular PrPSc molecule will be created. SPECTRUM OF PrP PRION DISEASES The sporadic form of CJD is the most common PrP prion disorder in humans. sCJD accounts for ~85% of all cases of human PrP prion disease, and genetic prion diseases account for 10–15% of all cases (Table 449-2). Genetic prion diseases were historically divided into three forms: familial CJD (fCJD), Gerstmann-Sträussler-Scheinker (GSS) disease, and fatal familial insomnia (FFI). All dominantly inher­ ited PrP prion diseases are caused by mutations in the PrP gene. Although infectious PrP prion diseases account for <1% of all cases and infection does not seem to play an important role in the natural history of these illnesses, the transmissibility of PrP prions is an impor­ tant biologic feature. Kuru of the Fore people of Papua New Guinea resulted from the consumption of brains from dead relatives during ritualistic cannibalism. After the cessation of this practice in the late 1950s, kuru nearly disappeared, with the exception of a few recent patients exhibiting incubation periods of >50 years. Iatrogenic CJD (iCJD) results from the accidental inoculation of patients with prions TABLE 449-2  The PrP Prion Diseases DISEASE HOST MECHANISM OF PATHOGENESIS Human Kuru Fore people Infection through ritualistic cannibalism iCJD Humans Infection from prion-contaminated hGH, dura mater grafts, etc. vCJD Humans Infection from bovine prions fCJD Humans Germline mutations in PRNP GSS Humans Germline mutations in PRNP FFI Humans Germline mutation in PRNP (D178N, M129) sCJD Humans Somatic mutation or spontaneous conversion of PrPC into PrPSc? sFI Humans Somatic mutation or spontaneous conversion of PrPC into PrPSc? Animal Scrapie Sheep, goats Infection in genetically susceptible sheep and goats BSE Cattle Infection with prion-contaminated MBM TME Mink Infection with prions from sheep or cattle CWD Mule deer, elk, or moose Unknown FSE Cats Infection with prion-contaminated beef Exotic ungulate encephalopathy Greater kudu, nyala, or oryx Infection with prion-contaminated MBM Abbreviations: BSE, bovine spongiform encephalopathy; CJD, CreutzfeldtJakob disease; CWD, chronic wasting disease; fCJD, familial Creutzfeldt-Jakob disease; FFI, fatal familial insomnia; FSE, feline spongiform encephalopathy; GSS, Gerstmann-Sträussler-Scheinker disease; hGH, human growth hormone; iCJD, iatrogenic Creutzfeldt-Jakob disease; MBM, meat and bone meal; sCJD, sporadic Creutzfeldt-Jakob disease; sFI, sporadic fatal insomnia; TME, transmissible mink encephalopathy; vCJD, variant Creutzfeldt-Jakob disease. through medical procedures such as cadaver-derived dura mater grafts and human pituitary hormones. Variant CJD (vCJD) that mostly occurs in teenagers and young adults in Europe, predominantly the United Kingdom and France, is the result of exposure to tainted beef from cattle with bovine spongiform encephalopathy (BSE). Although occasional cases of iCJD still occur, this form of CJD is currently on the decline due to public health measures aimed at preventing the spread of PrP prions. More than seven diseases of animals are caused by prions (Table 449-2). Scrapie of sheep and goats is the prototypic PrP prion disease. Mink encephalopathy, BSE, feline spongiform encephalopathy, exotic ungulate encephalopathy, and nonhuman primate prion dis­ ease are all thought to occur after the consumption of prion-infected foodstuffs. The BSE epidemic emerged in Britain in the late 1980s and was shown to be due to industrial cannibalism. Whether BSE began as a sporadic case of BSE in a cow or started with scrapie in sheep is unknown. The origin of chronic wasting disease (CWD), a prion dis­ ease endemic in deer and elk in regions of North America, and more recently identified in isolated populations in Scandinavia and Korea, is uncertain. In contrast to other prion diseases, CWD is highly transmis­ sible among cervids. Bodily excretions, such as feces, urine, and saliva, from asymptomatic, infected cervids contain prions that are likely to be responsible for the spread of CWD. Notably, mink are carnivores and mink encephalopathy is spread from one animal to another. ■ ■EPIDEMIOLOGY CJD is found throughout the world. The incidence of sCJD is ~1–2 cases per million population, although a person’s lifetime risk of dying from CJD is ~1 in 5000 to 6000 deaths. Because sCJD is an agedependent ND, its incidence is expected to increase steadily as older segments of populations in developed and developing countries con­ tinue to expand. Although many geographic clusters of CJD have been reported, each has been shown to segregate with a PrP gene mutation and/or included misdiagnoses. Attempts to identify common exposure to some etiologic agent have been unsuccessful for both the sporadic and familial cases. Ingestion of scrapie-infected sheep or goats as a cause of CJD in humans has not been demonstrated, and epidemiologic studies do not support this, although speculation about this potential route of infection continues. Whether PrP prion disease in deer, elk, or moose has passed to cows, sheep, or directly to humans remains unknown. Studies with mice modified to carry the human PRNP gene demonstrate that oral infection with CWD prions can occur, but the process is inefficient compared to intracerebral inoculation. The U.S. Centers for Disease Control and Prevention (CDC) conducts surveil­ lance of CJD in the United States to ascertain the number and type of cases annually. Because up to 90% of culled deer in some game herds have been shown to harbor CWD prions, the CDC also has a study fol­ lowing deer hunters to determine if they have an increased rate of prion disease and whether it is a novel prion disorder. ■ ■PATHOGENESIS The human PrP prion diseases were initially classified as NDs of unknown etiology. Even though the familial nature of GSS and a subset of CJD cases was well described, the significance of this observation became more obscure with the transmission of GSS and CJD to ani­ mals since genetic NDs were not considered transmissible. With the transmission of kuru and CJD to nonhuman primates, investigators began to view these diseases as infectious CNS illnesses caused by slow viruses. Eventually, the true cause of GSS and a minority of CJD cases became clear with the discovery in 1989 of mutations in the PRNP gene of these familial patients. The prion concept explains how a single dis­ ease can manifest as sporadic, heritable (i.e., genetic), and infectious. Moreover, the hallmark of all PrP prion diseases, whether sporadic, dominantly inherited, or acquired by infection, is that they involve the aberrant folding of the PrP protein. A major feature that distinguishes PrP prions from viruses is the finding that both the normal and disease-causing PrP isoforms are encoded by a chromosomal gene. In humans, the PrP gene is desig­ nated PRNP and is located on the short arm of chromosome 20. Lim­ ited proteolysis of PrPSc produces a smaller, protease-resistant molecule of ~142 amino acids designated PrP 27-30, whereas PrPC is completely hydrolyzed under the same conditions (Fig. 449-1). PrP 27-30 polymer­ izes into prion rods that are morphologically indistinguishable from the filaments that aggregate to form PrP amyloid plaques in the CNS. This discovery raised the possibility that many other NDs might be caused by different proteins, all of which can fold into prions. Prion Strains  Distinct strains of PrP prions exhibit different bio­ logic properties, which are epigenetically heritable. The existence of prion strains raised the question of how heritable biologic informa­ tion can be enciphered in a molecule other than nucleic acid. Various strains of PrP prions have been defined by incubation times, distribu­ tion of neuronal vacuolation (i.e., spongiform change) on neuropathol­ ogy, and stabilities of PrPSc to denaturation. Subsequently, the patterns of PrPSc deposition were found to correlate with the neuroanatomic PrP Polypeptide CHO CHO GPI S S PrPC 209 amino acids PrPSc 209 amino acids PrP 27-30 ~142 amino acids Codon FIGURE 449-1  PrP prion protein isoforms. Bar diagram of Syrian hamster PrP, which consists of 254 amino acids. After processing of the NH2 and COOH termini, both PrPC and PrPSc consist of 209 residues. After limited proteolysis, the NH2 terminus of PrPSc is truncated to form PrP 27-30 composed of ~142 amino acids. CHO, N-linked sugars; GPI, glycosylphosphatidylinositol anchor attachment site; S–S, disulfide bond. location and pattern of vacuolation, and these patterns were also used to characterize prion strains. Persuasive evidence that strain-specific information is enciphered in the tertiary structure of PrPSc comes from transmission of two different inherited human prion diseases to mice expressing a chimeric human– mouse PrP transgene. In most forms of fCJD and the majority of sCJD cases, the protease-resistant fragment of PrPSc after deglycosylation has a molecular mass of 21 kDa (i.e., type 1 prions), whereas in FFI, and a minority of sCJD cases, it is 19 kDa (type 2 prions) (Table 449-3). This difference in molecular mass was shown to be due to different sites of proteolytic cleavage at the NH2 termini of the two human PrPSc molecules, reflecting different tertiary structures. These distinct con­ formations were not unexpected because the amino acid sequences of the PrP fragments differ. Extracts from the brains of patients with FFI transmitted disease to the mice expressing the chimeric human–mouse PrP transgene and resulted in the formation of 19-kDa PrPSc, whereas brain extracts from patients with fCJD and sCJD harboring 21-kDa PrPSc resulted in 21-kDa PrPSc in mice expressing the same transgene. On second passage, these differences were maintained, demonstrating that chimeric PrPSc can exist in two different conformations as demon­ strated by the sizes of the protease-resistant fragments, even though the amino acid sequence of PrPSc is invariant. CHAPTER 449 Prion Diseases This analysis was extended when patients with sporadic fatal insom­ nia (sFI) were identified. Although they did not carry a PRNP muta­ tion, the patients demonstrated a clinical and pathologic phenotype that was indistinguishable from that of patients with FFI. Furthermore, 19-kDa PrPSc was found in their brains, and on passage of sFI prion disease to mice expressing the chimeric human–mouse PrP transgene, 19-kDa PrPSc was also found. These findings indicate that the disease phenotype is dictated by the conformation of PrPSc and not the amino acid sequence. PrPSc acts as a template for the conversion of PrPC into nascent PrPSc. On the passage of prions into mice expressing a chimeric hamster–mouse PrP transgene, a change in the conformation of PrPSc was accompanied by the emergence of a new strain of prions. Many new strains of prions were generated using recombinant PrP (recPrP) produced in bacteria; recPrP was polymerized into amy­ loid fibrils to make “synthetic prions,” which were inoculated into transgenic mice overexpressing high levels of wild-type mouse PrPC. Approximately 500 days later, the mice died of prion disease. The incu­ bation times (i.e., time to clinical disease onset) of the “synthetic prions” in mice were dependent on the conditions used for polymerization of the amyloid fibrils, which affected the stability of those amyloid fibrils. Highly stable amyloids gave rise to stable prions with long incubation times; low-stability amyloids led to prions with short incubation times. Amyloids of intermediate stability gave rise to prions with intermediate stabilities and intermediate incubation times. Such findings are consis­ tent with earlier studies showing that the incubation times of synthetic and naturally occurring prions are directly proportional to the stability of the prion. Species Barrier  Studies on the role of the primary and tertiary structures of PrP in the transmission of prion disease have provided new insights into the pathogenesis of these maladies. The amino acid sequence of PrP encodes the species of the prion, and the prion derives its PrPSc sequence from the last mammal in which it was passaged. While the primary structure (i.e., amino acid sequence) of PrP is likely to be the most important or even the sole determinant of the tertiary structure of PrPC, PrPSc seems to function as a template in determining the tertiary structure of nascent PrPSc molecules as they are formed from PrPC. In turn, prion diversity appears to be enciphered in the conformation of PrPSc, and thus prion strains seem to represent differ­ ent conformers of PrPSc. In general, transmission of PrP prion disease from one species to another is inefficient, in that not all intracerebrally inoculated animals develop disease, and those that fall ill do so only after long incubation times that can approach the natural life span of the animal. This “spe­ cies barrier” to transmission is correlated with the degree of similarity between the amino acid sequences of PrPC in the inoculated host and of PrPSc in the inoculum. The importance of sequence similarity between TABLE 449-3  Distinct Prion Strains Generated in Humans with Inherited Prion Diseases and Transmitted to Transgenic Micea INOCULUM HOST SPECIES HOST PrP GENOTYPE INCUBATION TIME [DAYS ± SEM] (n/n0) PrPSc (kDa) None Human FFI(D178N, M129)   FFI Mouse Tg(MHu2M) 206 ± 7 (7/7) FFI → Tg(MHu2M) Mouse Tg(MHu2M) 136 ± 1 (6/6) None Human fCJD(E200K)   fCJD Mouse Tg(MHu2M) 170 ± 2 (10/10) fCJD → Tg(MHu2M) Mouse Tg(MHu2M) 167 ± 3 (15/15) aTg(MHu2M) mice express a chimeric mouse–human PrP gene. Notes: Clinicopathologic phenotype is determined by the conformation of PrPSc in accord with the results of the transmission of human prions from patients with FFI to transgenic mice. Abbreviations: fCJD, familial Creutzfeldt-Jakob disease; FFI, fatal familial insomnia; SEM, standard error of the mean. the host and donor PrP argues that PrPC directly interacts with PrPSc in the prion conversion process. PART 13 Neurologic Disorders SPORADIC AND INHERITED PrP PRION DISEASES Several different scenarios might explain the initiation of sporadic prion disease: (1) A somatic mutation in a single cell may be the cause and thus follow a path similar to that for germline mutations in inherited disease. In this situation, the primary structure of PrPC made from the mutated gene would be more susceptible to misfolding into PrPSc. This mutant PrPSc then must be capable of targeting wild-type PrPC, a process known to be possible for some mutations (i.e., high penetrance) but less likely for others (low penetrance). (2) The activa­ tion energy barrier separating wild-type PrPC from PrPSc, preventing conversion to PrPSc, could be crossed on rare occasions in the context of a population. Most individuals would be spared, but presentations in older persons who have had more time for this conversion to occur would be seen. (3) PrPSc may be present at low levels in some normal cells, where it performs an important, but yet unknown, function. The level of PrPSc in such cells is hypothesized to be sufficiently low as not to be detected by routine bioassay. In some altered metabolic states, the cellular mechanisms for clearing PrPSc might become compromised, and the rate of PrPSc formation would then begin to exceed the capacity of the cell to clear it. The third possible mechanism is attractive because it suggests that PrPSc is not simply a misfolded protein, as proposed for the first and second mechanisms, but that it is an alternatively folded molecule with a function. Moreover, the multitude of conformational states that PrPSc can adopt, as described above, raises the possibility that PrPSc or another protein might function in a process such as shortterm memory where information storage is thought to occur in the absence of new protein synthesis. More than 40 different mutations resulting in nonconservative substitutions in the human PRNP gene have been found to segregate with inherited human prion diseases. Missense mutations, a dele­ tion, expansions in the octapeptide repeat region of the gene, called octapeptide repeat insertions (OPRIs), and stop codon mutations are responsible for genetic forms of prion disease. Although phenotypes may vary dramatically, even within families, specific phenotypes observed with certain mutations appear to cause fCJD. More than 20 missense variants—including substitutions at codons 102, 105, 117, 198, and 217, and mid to longer OPRIs—cause the GSS form of PrP prion disease, with prominent parkinsonism and/or cerebellar features and typically onset of dementia later in the course. Regarding OPRI mutations, the normal human PrP sequence contains an unstable section in the N-terminal region comprised of five repeats—a nine-amino-acid sequence or nonapeptide (R1) fol­ lowed by four octapeptide repeats (R2, R2, R3, R4), which includes two tandem R2 domains. Insertions from 2 to 12 extra octapeptide repeats cause variable phenotypes including conditions indistinguishable from sCJD, GSS-like presentations, and even a slowly progressive dementing illness of many years’ duration to an early-age-of-onset disorder that is similar to AD. A mutation at codon 178 that results in substitution of asparagine for aspartic acid generally causes FFI if methionine is encoded at codon 129 on the same allele. In contrast, a typical CJD phenotype generally occurs when there is a valine at codon 129 of the same allele. Stop codon (nonsense) mutations are rare and cause a range of phenotypes, including some with a prolonged course of years to decades, GSS- or AD-like presentations, autonomic and sensory peripheral nervous system involvement, chronic gastrointestinal upset, and extensive PrPSc amyloid deposits. ■ ■HUMAN PRNP GENE POLYMORPHISMS Polymorphisms influence the susceptibility to sporadic, genetic, and acquired forms of PrP prion disease. The methionine [M] or valine [V] polymorphism at codon 129 of human PRNP not only modulates the age of onset of some genetic prion diseases but also can affect the clinical phenotype. Sporadic CJD can be divided into six different molecular subtypes, based on the combination of codon 129 poly­ morphism (MM, MV, or VV) and the prion type (1 or 2), with each subtype having a particular clinical and pathological presentation. MM1/MV1 subtypes are the most common (~40–70% of cases) and usually have the most prototypic form of sCJD with rapidly progres­ sive dementia, ataxia, and myoclonus and a mean survival of ~4–7 months. The VV2 subtype represents ~15% of sCJD cases, usually starts with ataxia, and has a similar survival as MM1/MV1. The MV2 subtype represents ~10% of cases and has a longer mean survival of ~17 months. The vast majority of MV2 cases are a form with kuru plaques in the cerebellum, called MV2K, which are clinically similar to VV2 (i.e., early ataxia) but have a slower progression and longer survival. A minority of MV2 cases are of a cortical subtype called MV2-cortical (MV2C) with significant vacuolation (spongiform change) surrounded by perivacuolar PrPSc staining in all cortical lay­ ers and are usually without kuru plaques or cerebellar involvement. The MV2C cases present as a slowly progressive cognitive/dementia syndrome with motor symptoms occurring late in the disease course. The MM2 subtype represents ~4% of sCJD cases, has a mean survival of ~15.5 months, and is divided about equally into two subtypes: MM2-thalamic (MM2T, also called sFI) and MM2-cortical (MM2C). MM2T is clinicopathologically nearly identical to FFI (see below), whereas MM2C presents similarly to MV2C with a relatively slow progressive dementia and has a mean age of onset in the 50s, about a decade younger than most sCJD. VV1 is the least common subtype, representing ~1% of cases, presenting as a progressive dementia with a mean age of onset in the mid to late 40s, about two decades earlier than most other sCJD subtypes. Substitution of the basic residue lysine for glutamine at position 218 in mouse PrP produced dominant-negative inhibition of prion replica­ tion in transgenic mice. This same lysine substituted for glutamine at position 219 in human PrP has been found in 12% of the Japanese population, a group that appears to be resistant to prion disease. Dominant-negative inhibition of prion replication was also found with substitution of the basic residue arginine at position 171; sheep with arginine were resistant to scrapie prions but were susceptible to BSE prions that were inoculated intracerebrally. A very interesting poly­ morphism at codon 127 in PRNP was identified among longtime sur­ vivors of the kuru epidemic in the Fore people of Papua New Guinea, which when expressed in transgenic mice with humanized PRNP prevented the animals from acquiring prion disease. ACQUIRED (TRANSMITTED) PrP PRION DISEASES ■ ■IATROGENIC CJD Accidental transmission of CJD to humans through medical proce­ dures (i.e., iatrogenic) appears to have occurred with cadaver-derived human pituitary hormones, dura mater grafts, and corneal trans­ plants, as well as through contaminated electroencephalogram (EEG) electrode implantation and possibly through other neurosurgical procedures. Corneas from donors with unsuspected CJD have been transplanted to apparently healthy recipients who developed CJD after variable incubation periods. Two other cases arose due to contamina­ tion during epilepsy surgery from depth EEG electrodes previously used in a patient who unknowingly had CJD; these electrodes were subsequently implanted in a chimpanzee, causing CJD 18 months later. Surgical procedures may have resulted in other accidental inocula­ tions of patients with prions, presumably because some instrument or apparatus in the operating theater became contaminated when a CJD patient underwent surgery. Although the epidemiology of these studies is highly suggestive, no proof for such episodes exists. Dura Mater Grafts  More than 200 cases of CJD after implanta­ tion of dura mater grafts (dCJD) have been recorded. Dura mater is normally collected from cadavers, mass sterilized in a heated vat, freeze-dried, and prepared for use in a variety of surgical procedures. Unfortunately, some of the donor cadavers unknowingly had prion disease. All but possibly two of the grafts appear to have been acquired from a single manufacturer. More than two-thirds of the cases occurred in Japan. Patients with dCJD usually present with cerebellar ataxia, visual symptoms, and dementia and have a mean incubation period of 12 years (range 1.3–30 years). Two subtypes of dCJD have been identi­ fied in Japan, a type with PrPSc plaques and a type without plaques (synaptic PrPSc). Human Growth Hormone and Pituitary Gonadotropin Therapy  The transmission of CJD prions from contaminated human growth hormone (hGH) preparations derived from human pituitaries has been responsible for fatal cerebellar disorders with dementia in >200 patients ranging in age from 5 to 42 years, most occurring in France, the United Kingdom, and the United States. These patients received injections of hGH every 2–4 days for ~2–12 years. If it is thought that these patients developed CJD from injections of prion-contaminated hGH preparations, the possible incubation periods range from 4 to 30 years. Recombinant hGH is now exclusively used therapeutically so that possible contamination with prions is no longer an issue. Four cases of CJD also occurred in women in Australia receiving human pituitary gonadotropin, with incubation periods of 12–16 years. Notably, there is some evidence that deceased patients who received hGH early in life may have inadvertently received Aβ prions also, which can lead to amyloid and even tau pathology. Whether iatrogenic propagation of Aβ or tau prions in the human CNS led to an ND, such as AD or cerebral amyloid angiopathy (CAA), in these patients is still controversial. ■ ■VARIANT CJD The restricted geographic occurrence and chronology of vCJD raised the possibility that BSE prions had been transmitted to humans through the consumption of tainted beef. More than 200 cases of vCJD have occurred, with >90% of these in Britain. Variant CJD has also been reported in people either living in or originating from France, Ireland, Italy, the Netherlands, Portugal, Spain, Saudi Arabia, the United States, Canada, and Japan. For some of these patients, such as those from North America, evidence suggests they acquired the disease while living or traveling outside their home country. The steady decline in the number of vCJD cases over the past decade argues that there will not be a prion disease epidemic in Europe, similar to those seen for BSE and kuru. What is certain is that PrP-prion-tainted meat should be prevented from entering the human food supply. The most compelling evidence that vCJD is caused by BSE prions was obtained from experiments in mice expressing the bovine PrP transgene. Both BSE and vCJD prions were efficiently transmitted to these transgenic mice and with similar incubation periods. In contrast to sCJD prions, vCJD prions did not transmit disease efficiently to mice expressing a chimeric human–mouse PrP transgene. Earlier stud­ ies with nontransgenic mice suggested that vCJD and BSE might be derived from the same source because both inocula transmitted disease with similar but very long incubation periods. Attempts to determine the origin of BSE and vCJD prions have relied on passaging studies in mice, some of which are described above, as well as studies of the conformation and glycosylation of PrPSc. One scenario suggests that a particular conformation of bovine PrPSc was selected for heat resistance during the rendering process and was then reselected multiple times as cattle infected by ingesting prion-contaminated meat and bone meal (MBM) were slaughtered and their offal rendered into more MBM. Variant CJD cases have virtually disappeared with protec­ tion of the beef supply in Europe. Interestingly, almost all of the ~238 cases of vCJD reported as of 2024 have been homozygous for methionine (MM) at codon 129 in PRNP. However, two cases (one probable and one definite) were codon 129 MV, which is the most common codon 129 polymorphism in most of the world. This finding raises the concern that persons with this polymorphism might have a longer incubation period and that another rise in cases might still occur. Of particular concern is that four known (and a fifth possible) secondary cases of vCJD infec­ tion occurred from blood product transfusions. These persons received blood components (non-leukodepleted red blood cells [RBCs] in the four known cases and factor X in the fifth case) from asymptomatic donors who later developed vCJD infection. The second of four RBC recipients did not die from vCJD but was found to have vCJD prions in the lymphoreticular system. The RBC donors did not develop vCJD infection until ~1.5–3.3 years after donation, and the incubation period for recipients of RBCs ranged from 5 to 8.5 years. Thus, vCJD is the only form of human prion disease proven to be transmissible by blood. Further evidence of the transmissibility of vCJD is that among the two most recent cases of vCJD identified, one in France and one in Italy, both had laboratory exposure to BSE-infected brain tissue. The French patient accidentally stabbed herself with forceps being used on frozen brain sections from a transgenic mouse overexpressing human PrP and inoculated with BSE. She developed symptoms 7.5 years later at age 31 and died from definite vCJD after 19 months in 2019. The last reported case of vCJD worldwide was in France in 2021, and the prior two cases occurred in the United Kingdom in 2013 and 2016. CHAPTER 449 Prion Diseases ■ ■NEUROPATHOLOGY Frequently, the brains of patients with CJD have no recognizable abnormalities on gross examination. Patients who survive for several years have variable degrees of cerebral atrophy. On light microscopy, the pathologic hallmarks of CJD are spon­ giform degeneration (vacuolation), neuronal loss, and astrocytic gliosis. The lack of an inflammatory response in CJD and other prion diseases is an important pathologic feature of these degenerative dis­ orders. Spongiform degeneration is characterized by many 1- to 5-μm vacuoles in the neuropil between nerve cell bodies. Generally, the vacuolation occurs in the cerebral cortex, putamen, caudate nucleus, thalamus, and molecular layer of the cerebellum. Astrocytic gliosis is a constant but nonspecific feature of PrP prion diseases. Widespread proliferation of fibrous astrocytes is found throughout the gray matter of brains infected with CJD prions. Astrocytic processes filled with glial filaments form extensive networks. The degree and location of these pathologic hallmarks vary depending on the type of human prion disease, including between sCJD subtypes described above. Amyloid plaques have been found in ~10% of CJD cases. Purified CJD prions from humans and animals exhibit the ultrastructural and histochemical characteristics of amyloid when treated with detergents during limited proteolysis. On first passage of samples from some human Japanese CJD cases into mice, amyloid plaques were found. These plaques stain with antibodies raised against PrP, demonstrating that the amyloid is composed of PrP. The amyloid plaques of GSS disease are morphologically distinct from those seen in kuru or scrapie. GSS plaques consist of a central dense core of amyloid surrounded by smaller globules of amyloid. Ultrastructurally, they consist of a radiating fibrillar network of amy­ loid fibrils, with scant or no neuritic degeneration. The plaques can be distributed throughout the brain but are most frequently found in the cerebellum. They are often located adjacent to blood vessels. Congo­ philic angiopathy has been noted in some cases of GSS disease. In vCJD, a characteristic feature is the presence of “florid plaques.” These are composed of a central core of PrP amyloid, surrounded by vacuoles in a pattern suggesting petals on a flower. ■ ■CLINICAL FEATURES Nonspecific prodromal symptoms occur in approximately a third of patients with CJD and may include fatigue, sleep disturbance, weight loss, headache, anxiety, vertigo, malaise, and ill-defined pain. Most patients with CJD present with cognitive and/or motor deficits. Behavioral and psychiatric symptoms, such as depression, anxiety, irritability, apathy, insomnia, appetite changes, psychosis, and visual hallucinations, are very common and often early features. These deficits usually progress over weeks or months to a state of profound dementia characterized by memory loss, impaired judgment, and a decline in virtually all aspects of intellectual function. A minority of patients present early with either isolated visual impairment or cere­ bellar gait and coordination deficits, referred to as the Heidenhain and Brownell-Oppenheim variants, respectively. Frequently, the cerebellar deficits are rapidly followed by progressive dementia. Visual problems often begin with blurred vision and diminished acuity, rapidly fol­ lowed by dementia. Patients with early visual deficits often have a faster decline overall. PART 13 Neurologic Disorders Motor symptoms and signs other than cerebellar ataxia include extrapyramidal dysfunction manifested as rigidity, masklike facies, dystonia, myoclonus, or less commonly choreoathetoid movements and pyramidal signs (usually mild and not actual weakness). Some uncommon features include seizures (usually major motor), hypo­ esthesia, supranuclear gaze palsy, motor neuron disease, or dysauto­ nomic signs such as changes in body temperature and sweating. Most patients with the most common subtype of CJD will eventually develop myoclonus. Unlike other involuntary movements, myoclonus usually persists during sleep. Startle myoclonus elicited by loud sounds, bright lights, or a person or object suddenly appearing in a patient’s visual field is frequent. It is important to stress that myoclonus is nei­ ther specific nor confined to CJD and tends to occur later in the course of CJD. Dementia with myoclonus can also be due to AD (Chap. 442), dementia with Lewy bodies (Chap. 445), corticobasal degeneration (Chap. 443), cryptococcal encephalitis (Chap. 221), or the myoclonic epilepsy disorder Unverricht-Lundborg disease (Chap. 436). Clinical Course  Most patients with sCJD and most types of fCJD live ~6–12 months after the onset of clinical signs and symptoms. Life expectancies can be longer, up to a few years, for less common sCJD subtypes, and some mutations causing genetic prion disease can have durations of a decade or longer. ■ ■DIAGNOSIS The constellation of a rapid onset of cognitive impairment over weeks to months, with myoclonus and other motor symptoms, and typical mag­ netic resonance imaging (MRI) findings (see below) in an afebrile 60- to 70-year-old patient generally indicates CJD—most commonly sCJD. Variations in the typical course appear in genetic and transmitted (i.e., acquired) forms of the disease. As noted above, most mutations causing fCJD have a slightly earlier mean age of onset, although usu­ ally an otherwise similar clinical and radiologic presentation as sCJD. In GSS, cerebellar ataxia is usually a prominent and presenting feature, with dementia occurring late in the disease course. GSS also presents earlier than sCJD (mean age ~43 years) and usually progresses more slowly, leading to death ~5 years after symptom onset. FFI is typically characterized by insomnia and dysautonomia; dementia occurs only in the terminal phase of the illness; survival is typically <2 years and sometimes just a few months. Variant CJD has a different clinical course from most other prion diseases, with an early psychiatric prodrome (most commonly depres­ sion, anxiety, apathy, withdrawal, and/or delusions) that persists for several months prior to the appearance of other neurologic symptoms including cerebellar ataxia, painful sensory symptoms, a movement disorder (often myoclonus, dystonia, and/or chorea), and cognitive impairment progressing to dementia. The mean age of onset for vCJD is 28 years (median 26, range 12–74), with the majority of patients being <55 years old. ■ ■LABORATORY TESTS The only highly specific diagnostic tests for CJD and other human PrP prion diseases measure PrPSc. The most widely used method involves limited proteolysis that generates PrP 27-30, which is detected by immunoassay after denaturation. In humans, the diagnosis of CJD can be established by brain biopsy if PrPSc is detected, although with cur­ rent ancillary testing available, biopsy is rarely indicated. Because PrPSc is not uniformly distributed throughout the CNS, the absence of PrPSc in a limited sample such as a biopsy does not rule out prion disease. The use of reverse templated quake-induced conversion assay (RTQuIC; see below), a method for amplifying prions into amyloid fibrils and detecting them with thioflavin fluorescence, has greatly increased the sensitivity of brain biopsy. If no attempt is made to measure or detect PrPSc but pathologic changes typical of CJD are seen in a brain biopsy, then the diagnosis is reasonably secure. Brain MRI has become an important diagnostic tool for prion dis­ eases, especially CJD, and can help distinguish CJD from most other conditions. The first reported MRI findings were on T2-weighted MRI and were hyperintensities in the striatum (caudate and puta­ men) and less commonly in the thalamus (depending on the type of prion disease). Subsequently, with fluid-attenuated inversion recovery (FLAIR) sequences, hyperintensity of the cortex (cortical ribboning) could also be seen. Diffusion MRI, with a combination of diffusionweighted imaging (DWI) and attenuation deficient coefficient (ADC) sequences, greatly improved sensitivity and specificity (to mid to high 90th percentile) of MRI for prion disease, showing hyperintensity (i.e., brightness or high signal) on DWI with corresponding hypointensity (i.e., darkness or low signal) on ADC in the cortex (cortical ribboning) and striatum and less commonly in the thalamus and/or cerebellum (Fig. 449-2). This abnormal signal on DWI and ADC is due to reduced or restricted diffusion of water molecules in these brain regions sec­ ondary to vacuolation. DWI and FLAIR MRI, however, often show areas of artifactual hyperintensity, particularly in regions where there is air adjacent to brain tissue, such as near sinuses. The true abnormal signal of reduced or restricted diffusion can be distinguished from artifact by (1) acquiring the diffusion MRI in multiple planes (e.g., axial and coronal), (2) looking for corresponding hypointensity in the cor­ tex or deep nuclei on ADC, and/or increasing the degree of diffusion weighting. T2, FLAIR, and diffusion MRI are often normal, however, particularly in GSS, FFI, sFI, and in some rare genetic prion diseases such as those due to stop-codon mutations. Any prion disease with a long duration (e.g., >1–2 years) often will show nonspecific atrophy on brain MRI or head computed tomography (CT). To a limited extent, the pattern of these MRI abnormalities can also help determine the subtype of sCJD present. For example, MRI findings in the MM1/MV1 subtype are typically located in the cortex (i.e., cortical ribboning) and deep nuclei (striatum +/– thalamus), MV2K and VV2 involve deep nuclei, and MM2/MV2C are predominantly cortical. These abnor­ malities may be unilateral or bilateral; when they are bilateral, they may be symmetric or asymmetric. The pattern and type of MRI abnor­ malities in CJD are not seen with other NDs but can overlap with viral encephalitis, paraneoplastic/autoimmune encephalopathy syndromes, metabolic disorders, or seizures. To establish the diagnosis of either sCJD or familial prion disease, sequencing the PRNP gene must be performed. Finding the wild-type PRNP gene sequence permits the diagnosis of sCJD if there is no history to suggest infection from an exogenous source of prions. The identifi­ cation of a mutation in the PRNP gene sequence that encodes a non­ conservative amino acid substitution argues for familial prion disease. A B C FIGURE 449-2  Brain magnetic resonance imaging (MRI) in a 72-year-old patient with sporadic Creutzfeldt-Jakob disease, MM1 subtype (classic subtype), showing axial (A) fluid-attenuated inversion recovery (FLAIR), (B) diffusion-weighted imaging (DWI), and (C) attenuation deficient coefficient (ADC) sequences at three different levels. There is cortical ribboning indicating restricted diffusion in the left much greater than right temporal (solid white arrow), occipital (solid white arrow), parietal (solid white arrow), insular (no arrow), and posterior cingulate cortices (dashed arrows). There is also restricted diffusion in the left greater than the right caudate head (arrowheads). The corresponding hypointensity (very dark) areas on the ADC sequence confirm that the hyperintensity (bright) areas on DWI and FLAIR are regions of reduced diffusion, not artifacts. Note that the abnormalities are best seen on DWI sequences. Images are radiologic orientation (right side of image is left side of brain). General cerebrospinal fluid (CSF) laboratory testing (i.e., cell count, protein, glucose) is nearly always normal, except that mild and non­ specific protein elevation and, rarely, mild pleocytosis can be seen in a minority of cases. The first CSF surrogate biomarker used in clinical practice and still incorporated in several diagnostic criteria for sCJD is the 14-3-3 protein, which is elevated in many forms of brain cell injury. Although newer enzyme-linked immunosorbent assays (ELISAs) quantitatively measuring the 14-3-3γ isoform have improved sensitiv­ ity and specificity, this test is still less accurate diagnostically than some other biomarkers. The sensitivity of 14-3-3 ELISAs in sCJD ranges from ~60% to almost 90% depending on the sCJD subtype (highest in MM1/MV1), whereas the range of specificity has been reported to be as low as 40% to as high as 96% depending on the controls used, making its utility questionable. The level of total tau protein (t-tau), a microtubule-associated protein expressed in neurons and glia, is ele­ vated in the CSF in many conditions associated with brain cell injury. ELISAs measuring t-tau appear to have a sensitivity and a specificity in the low to mid 90%, which is clinically superior to 14-3-3; however, there is no consensus at this time regarding the best t-tau ELISA or cutoff that should be used to support a diagnosis of sCJD. Assays that amplify PrPSc into amyloid PrPSc fibrils and detect the fibrils by adding thioflavin, which binds amyloid and fluoresces, have greatly enhanced premortem diagnosis of human prion diseases. The first such assay developed was the protein misfolding cyclic ampli­ fication (PMCA), which was modified into the more user-friendly CHAPTER 449 Prion Diseases RT-QuIC assay that is now widely used in clinical practice but still primarily performed at national prion surveillance centers. The sen­ sitivity and specificity of the current CSF RT-QuIC assay (i.e., second generation) for sCJD are about 90–95% and 98–99%, respectively. The advantage of PMCA and RT-QuIC is that they detect prions; however, false positives for RT-QuIC do occur, and as noted by the sensitivity, upward of 10% of sCJD cases are negative for RT-QuIC. As with other surrogate biomarkers, RT-QuIC is less sensitive for some uncommon sCJD subtypes, for several genetic prion diseases (i.e., GSS and other slower progressing forms), and particularly for vCJD. In contrast, PMCA seems to be more sensitive when applied to CSF and possibly blood and urine from patients with vCJD, but this test is not available for clinical practice in most countries. Improved methods to detect prions in blood, urine, skin, and even tears will be welcomed. EEG can be useful in the diagnosis of CJD, particularly when other ancillary tests are unrevealing, although only ~60% of patients (mostly with the MM1/MV1 subtype of sCJD) show the typical pattern of peri­ odic sharp wave complexes (PSWCs). PSWCs are usually repetitive, high-voltage, bi- or triphasic sharp discharges that normally appear quite late in the clinical course. Even when PSWCs are seen, they may be transient and might require serial EEGs to detect. During the early phase of CJD, the EEG is usually normal or shows only scattered theta and even delta slow wave activity. The presence of these stereotyped periodic bursts of PSWCs, <200 ms in duration and occurring every 1–2 s, makes the diagnosis of CJD very likely. These discharges are fre­ quently but not always symmetric; there may be a one-sided predomi­ nance in amplitude. As CJD progresses, normal background rhythms become fragmentary and slower. ■ ■DIFFERENTIAL DIAGNOSIS Many conditions mimic CJD, including various NDs, autoimmune/ paraneoplastic encephalopathies or ataxias, infections, and even psy­ chiatric conditions. Dementia with Lewy bodies (DLB) (Chap. 445) is one of the most common disorders to be mistaken for CJD, particularly when there is a phase of the illness with a fast decline. It can present rarely in a subacute fashion with delirium, myoclonus, and extrapy­ ramidal features. Other NDs to consider include AD, frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, ceroid lipofuscinosis, and myoclonic epilepsy with Lafora bodies. Usually when these diseases are mistaken for CJD, they have a more slowly progressive and perhaps subtle onset over a few years and then a sudden decline, which makes clinicians consider CJD. A thorough history of the earliest features of the illness—obtained through speak­ ing with friends, family members, or coworkers—often reveals a slower onset over a few years with a more recent rapid decline, suggesting a non-CJD etiology. There have been, however, rapidly progressive cases of AD with a course of <3 years from first symptom onset, often with ataxia, myoclonus, and other symptoms similar to those seen in CJD. Many of these cases have elevated CSF biomarkers such as 14-3-3. The absence of abnormalities on diffusion MRI (i.e., DWI and ADC) will almost always distinguish these conditions from CJD. CSF RT-QuIC, if positive, can also be helpful. PART 13 Neurologic Disorders Several autoantibody-mediated autoimmune encephalopathies (AEs) (Chap. 99), such as anti-LGI1 (leucine-rich glioma inactivated 1), anti-Crmp5 (collapsin response-mediator protein-5 or anti-CV2), and anti-AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor) antibody-mediated AEs, can have significant clinical overlap with CJD. Detection of autoantibodies in the serum and/or CSF, depending on the specific antibody-mediated syndrome, and the absence of brain MRI and CSF prion-specific biomarkers can help distinguish these cases from CJD. In AE with seizures, however, brain MRI may show diffusion MRI abnormalities similar to those in CJD, though this is rare, and these abnormalities disappear soon after sei­ zures are treated. In contrast, these MRI abnormalities generally persist in CJD, except in very long-lived cases. Intracranial vasculitides (Chap. 375) may produce nearly all the symptoms and signs associated with CJD, sometimes without systemic abnormalities. Myoclonus is uncommon with cerebral vasculitis, but focal seizures may confuse the diagnosis. Prominent headache, absence of myoclonus, stepwise change in deficits, abnormal CSF, and focal white matter change on MRI or angiographic abnormalities all favor vasculitis. Other diseases that can simulate CJD include neurosyphilis (Chap. 187), AIDS dementia complex (Chap. 208), progressive multifocal leukoencephalopathy (Chap. 142), subacute sclerosing panencephalitis, progressive rubella panencephalitis, herpes simplex encephalitis (Chap. 142), diffuse intracranial tumor (gliomatosis cerebri; Chap. 95), anoxic encephalopathy, dialysis dementia, uremia, hepatic encephalopathy, and lithium or bismuth intoxication. Fever, elevated sedimentation rate, leukocytosis in blood, or a pleocytosis in CSF should alert the physician to another etiology that explains the patient’s CNS dysfunction, although there are rare cases of CJD in which mild CSF pleocytosis or mild elevation in IgG index or oligoclonal bands are observed. ■ ■CARE OF CJD PATIENTS There are no disease-modifying treatments for prion diseases, and treatment is symptomatic. Although CJD is communicable, the likelihood of transmission from one patient to another is remote. The risk of accidental inocula­ tion by aerosols is minuscule; nonetheless, procedures producing aero­ sols should be performed in certified biosafety cabinets. Biosafety level 2 practices, containment equipment, and facilities are recommended by the CDC and the National Institutes of Health. The primary concern in caring for patients with CJD is the inadvertent infection of health­ care workers by needle and stab wounds, although with the possible exception of vCJD (as noted above) in which blood transfusions appear to carry some minimal risk for transmission. When caring for patients with prion disease, standard universal precautions used in the clinical setting (e.g., gloves, gowns, and/or eye protection) are recommended when handling bodily fluids (e.g., blood, urine, and feces). Electroen­ cephalographic and electromyographic needles should not be reused after studies on patients with CJD have been performed. Autopsies on patients whose clinical diagnosis is CJD can be per­ formed with minimal risk to pathologists or other morgue employees if proper prion-specific precautions are followed. Standard microbio­ logic practices outlined here, along with specific recommendations for decontamination, are generally adequate precautions for the care of patients with CJD and the handling of infected specimens. ■ ■DECONTAMINATION OF CJD PRIONS Prions are generally resistant to commonly used inactivation procedures, and there is some disagreement about the optimal conditions for ster­ ilization. Some investigators recommend treating CJD-contaminated materials once with 1 N NaOH at room temperature, but we believe this procedure may be inadequate for sterilization. Autoclaving at 134°C for 5 h or treatment with 2 N NaOH for several hours is recommended for sterilization of prions. The term sterilization implies complete destruc­ tion of prions; any residual infectivity can be hazardous. Transgenic mouse studies show that sCJD prions bound to stainless-steel surfaces are resistant to inactivation by autoclaving at 134°C for 2 h; exposure of bound prions to an acidic detergent solution prior to autoclaving rendered prions susceptible to inactivation. Recent studies show that α-synuclein prions in brain homogenates prepared from MSA patients bind to stainless-steel wires and that the bound prions can be transmit­ ted to transgenic mice expressing mutant human α-synuclein. Prion precaution protocols should be used for any patient with known or suspected CJD who is undergoing a surgical procedure that has a high risk of exposure to prions (e.g., neurosurgery). In such protocols, procedures should be implemented to reduce exposure of operating room staff and to isolate surgical equipment until the diag­ nosis has been definitively determined. If the patient is known to have prion disease, the equipment should be destroyed if possible or, if not possible, then thoroughly cleansed to eliminate risk of prion exposure. Importantly, as human prions appear to be more resistant than many animal prions to denaturation, particularly when bound to metal, prion removal methods used in the clinical setting should be based on data from studies using human prions. ■ ■PREVENTION AND THERAPEUTICS There is no known effective therapy for preventing or treating CJD. The finding that phenothiazines and acridines inhibit PrPSc formation in cultured cells led to clinical studies of quinacrine in CJD patients. Unfortunately, quinacrine failed to slow the rate of cognitive decline in CJD, possibly because therapeutic concentrations of quinacrine were not achieved in the brain. Although inhibition of the P-glycoprotein (Pgp) transport system resulted in substantially increased quinacrine levels in the brains of mice, the prion incubation times were not extended by treatment with the drug. Whether such an approach can be used to treat CJD remains to be established. Like the acridines, anti-PrP antibodies have been shown to elimi­ nate PrPSc from cultured cells. Additionally, such antibodies in mice, either administered by injection or produced from a transgene, have been shown to prevent prion disease when prions are introduced by a peripheral route, such as intraperitoneal inoculation. Unfortunately, the antibodies were ineffective in mice inoculated intracerebrally with prions. Several drugs, including pentosan polysulfate as well as por­ phyrin and phenylhydrazine derivatives, delay the onset of disease in animals inoculated intracerebrally with prions if the drugs are given intracerebrally beginning soon after inoculation. New treatment trials are underway and, based on animal models, hold promise even when treatment is begun close to symptom onset. # 20 - 450 Ataxic Disorders ### 450 Ataxic Disorders The best method to treat human prion diseases may be by reducing PrP, the substrate for PrPSc, rather than trying to directly reduce or eliminate PrPSc. The lifespan of mice is normal when PrPC is reduced or even eliminated; when PRNP is knocked out, mice live a normal span of time with minimal deficits detected, aside from a mild neuropathy. Identification of adults hemizygous for PRNP suggests that humans can also live with reduced levels of PrPC. Currently, antisense oligo­ nucleotides (ASOs) against PrPC are being tested in symptomatic prion disease. One advantage of treatment methods reducing PrPC is that if they are effective, they should work for all strains and types of human prion disease, as the method is independent of the form of PrPSc that is pathogenic in a given individual. ■ ■FURTHER READING Aoyagi A et al: Aβ and tau prion-like activities decline with longevity in the Alzheimer’s disease human brain. Sci Transl Med 11:eaat8462, 2019. Bizzi A et al: Subtype diagnosis of sporadic Creutzfeldt-Jakob disease with diffusion magnetic resonance imaging. Ann Neurol 89:560, 2021. Collinge J: Mammalian prions and their wider relevance in neurode­ generative diseases. Nature 539:217, 2016. Geschwind MD: Prion diseases. Continuum (Minneap Minn) 21:1612, 2015. Hermann P et al: Biomarkers and diagnostic guidelines for sporadic Creutzfeldt-Jakob disease. Lancet Neurol 20:235, 2021. Jucker M, Walker LC: Evidence for iatrogenic transmission of Alzheimer’s disease. Nat Med 30:344, 2024. Kraus A et al: High-resolution structure and strain comparison of infectious mammalian prions. Mol Cell 81:4540, 2021. Prusiner SB (ed): Prion Biology. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 2017. Prusiner SB (ed): Prion Diseases. Cold Spring Harbor, NY, Cold Spring Harbor Laboratory Press, 2017. Prusiner SB et al: Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc Natl Acad Sci USA 112:E5308, 2015. Staffaroni AM et al: Neuroimaging in dementia. Semin Neurol 37:510, 2017. Roger N. Rosenberg, Vikram G. Shakkottai Ataxic Disorders APPROACH TO THE PATIENT Ataxic Disorders Symptoms and signs of ataxia consist of gait impairment, unclear (“scanning”) speech, visual blurring due to nystagmus, hand inco­ ordination, and tremor with movement. These result from the involvement of the cerebellum and its afferent and efferent path­ ways, including the spinocerebellar pathways, and the frontopon­ tocerebellar pathway originating in the rostral frontal lobe. True cerebellar ataxia must be distinguished from ataxia associated with vestibular nerve or labyrinthine disease, as the latter results in a disorder of gait associated with a significant degree of dizziness, light-headedness, or the perception of movement (Chap. 24). True cerebellar ataxia is devoid of these vertiginous complaints and is clearly an unsteady gait due to imbalance. Sensory disturbances can also on occasion simulate the imbalance of cerebellar disease; with sensory ataxia, imbalance dramatically worsens when visual input is removed (Romberg sign). Rarely, weakness of proximal leg muscles mimics cerebellar disease. In the patient who presents with ataxia, the rate and pattern of the development of cerebellar symptoms help to narrow the diagnostic possibilities (Table 450-1). A gradual and progressive increase in symptoms with bilateral and symmetric involvement suggests a genetic, metabolic, immune, or toxic etiol­ ogy. Conversely, focal, unilateral symptoms with headache and impaired level of consciousness accompanied by ipsilateral cranial nerve palsies and contralateral weakness imply a space-occupying cerebellar lesion. SYMMETRIC ATAXIA Progressive and symmetric ataxia can be classified with respect to onset as acute (over hours or days), subacute (weeks or months), or chronic (months to years). Acute and reversible ataxias include those caused by intoxication with alcohol, phenytoin, lithium, barbiturates, and other drugs. Intoxication caused by toluene expo­ sure, gasoline sniffing, glue sniffing, spray painting, or exposure to methyl mercury or bismuth are additional causes of acute or subacute ataxia, as is treatment with cytotoxic chemotherapeutic drugs such as fluorouracil and paclitaxel. Patients with a postinfec­ tious syndrome (especially after varicella) may develop gait ataxia and mild dysarthria, both of which are reversible (Chap. 456). Rare infectious causes of acquired ataxia include poliovirus, coxsackievi­ rus, echovirus, Epstein-Barr virus, toxoplasmosis, Legionella, and Lyme disease. CHAPTER 450 Ataxic Disorders The subacute development of ataxia of gait over weeks to months (degeneration of the cerebellar vermis) may be due to the com­ bined effects of alcoholism and malnutrition, particularly with deficiencies of vitamins B1 and B12. Hyponatremia has also been associated with ataxia. Paraneoplastic cerebellar ataxia is associated with a number of different tumors (and autoantibodies) such as breast and ovarian cancers (anti-Yo), small-cell lung cancer (antiPQ-type voltage-gated calcium channel), and Hodgkin’s disease (anti-Tr) (Chap. 99). Another paraneoplastic syndrome associated with myoclonus and opsoclonus occurs with breast (anti-Ri) and lung cancers and neuroblastoma. For all of these paraneoplastic ataxias, the neurologic syndrome may be the presenting symp­ tom of the cancer. Autoantibody-associated cerebellar syndromes also occur without a cancer association. The most common is a progressive ataxic syndrome affecting speech and gait associated with serum anti-glutamic acid decarboxylase (GAD65) antibodies (Chap. 99). Another immune-mediated progressive ataxia is asso­ ciated with antigliadin (and antiendomysium) antibodies and the human leukocyte antigen (HLA) DQB1*0201 haplotype; in some affected patients, biopsy of the small intestine reveals villus atrophy consistent with gluten-sensitive enteropathy (Chap. 336). Finally, subacute progressive ataxia may be caused by a prion disorder, especially when an infectious etiology, such as transmission from contaminated human growth hormone, is responsible (Chap. 449). Chronic symmetric gait ataxia suggests an inherited ataxia (dis­ cussed below), a metabolic disorder, or a chronic infection. Hypo­ thyroidism must always be considered as a readily treatable and reversible form of gait ataxia. Infectious diseases that can present with ataxia are meningovascular syphilis and tabes dorsalis due to degeneration of the posterior columns and spinocerebellar path­ ways in the spinal cord. FOCAL ATAXIA Acute focal ataxia commonly results from cerebrovascular disease, usually ischemic infarction or cerebellar hemorrhage. These lesions typically produce cerebellar symptoms ipsilateral to the injured cerebellum and may be associated with an impaired level of con­ sciousness due to brainstem compression and increased intracra­ nial pressure; ipsilateral pontine signs, including sixth and seventh nerve palsies, may be present. Focal and worsening signs of acute ataxia should also prompt consideration of a posterior fossa subdu­ ral hematoma, bacterial abscess, or primary or metastatic cerebellar TABLE 450-1  Etiology of Cerebellar Ataxia SYMMETRIC AND PROGRESSIVE SIGNS FOCAL AND IPSILATERAL CEREBELLAR SIGNS SUBACUTE (DAYS TO WEEKS) CHRONIC (MONTHS TO YEARS) ACUTE (HOURS TO DAYS) ACUTE (HOURS TO DAYS) Intoxication: alcohol, lithium, phenytoin, barbiturates (positive history and toxicology screen) Acute viral cerebellitis (CSF supportive of acute viral infection) Postinfection syndrome Intoxication: mercury, solvents, gasoline, glue Cytotoxic chemotherapeutic drugs Alcoholic-nutritional (vitamin B1 and B12 deficiency) Lyme disease Paraneoplastic syndrome Antigliadin antibody syndrome Hypothyroidism Inherited diseases Tabes dorsalis (tertiary syphilis) Phenytoin toxicity Amiodarone Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging. PART 13 Neurologic Disorders tumor. Computed tomography (CT) or magnetic resonance imag­ ing (MRI) studies will reveal clinically significant processes of this type. Many of these lesions represent true neurologic emergencies, as sudden herniation, either rostrally through the tentorium or caudal herniation of cerebellar tonsils through the foramen mag­ num, can occur and is usually devastating. Acute surgical decom­ pression may be required (Chap. 318). Lymphoma or progressive multifocal leukoencephalopathy (PML) in a patient with AIDS may present with an acute or subacute focal cerebellar syndrome. Chronic etiologies of progressive ataxia include multiple sclerosis (Chap. 455) and congenital lesions such as a Chiari malformation (Chap. 453) or a congenital cyst of the posterior fossa (DandyWalker syndrome). THE INHERITED ATAXIAS Inherited ataxias may show autosomal dominant, autosomal recessive, or maternal (mitochondrial) modes of inheritance. A genomic classifi­ cation (Table 450-2)1 has now largely superseded previous ones based on clinical expression alone. Although the clinical manifestations and neuropathologic findings of cerebellar disease dominate the clinical picture, there may also be characteristic changes in the basal ganglia, brainstem, spinal cord, optic nerves, retina, and peripheral nerves. In large families with dominantly inherited ataxias, many gradations are observed from purely cerebellar manifestations to mixed cerebellar and brainstem disorders, cerebel­ lar and basal ganglia syndromes, and spinal cord or peripheral nerve disease. Rarely, dementia is present as well. The clinical picture may be homogeneous within a family with dominantly inherited ataxia, but sometimes most affected family members show one characteristic syndrome, while one or several members have an entirely different phenotype. ■ ■AUTOSOMAL DOMINANT ATAXIAS The autosomal spinocerebellar ataxias (SCAs) include SCA types 1 through 50, dentatorubropallidoluysian atrophy (DRPLA), and epi­ sodic ataxia (EA) types 1 to 7 (Table 450-2). SCA1, SCA2, SCA3 (Machado-Joseph disease [MJD]), SCA6, SCA7, and SCA17 are caused by CAG triplet repeat expansions in different genes. SCA8 is due to an untranslated CTG repeat expansion, SCA12 is linked to an untranslated CAG repeat, and SCA10 is caused by an untranslated pentanucleotide repeat. The clinical phenotypes of these SCAs overlap. The genotype has become the gold standard for diagnosis and clas­ sification. CAG encodes glutamine, and these expanded CAG triplet repeat expansions result in expanded polyglutamine proteins, termed ataxins, that produce a toxic gain of function with autosomal dominant inheritance. Although the phenotype is variable for any given disease gene, a pattern of neuronal loss with gliosis is produced that is relatively unique for each ataxia. Immunohistochemical and biochemical studies 1Table 450-2 can be found online at accessmedicine.com. SUBACUTE (DAYS TO WEEKS) CHRONIC (MONTHS TO YEARS) Vascular: cerebellar infarction, hemorrhage, or subdural hematoma Infectious: cerebellar abscess (mass lesion on MRI/CT, history in support of lesion) Neoplastic: cerebellar glioma or metastatic tumor (positive for neoplasm on MRI/CT) Demyelinating: multiple sclerosis (history, CSF, and MRI are consistent) AIDS-related multifocal leukoencephalopathy (positive HIV test and CD4+ cell count for AIDS) Stable gliosis secondary to vascular lesion or demyelinating plaque (stable lesion on MRI/ CT older than several months) Congenital lesion: Chiari or DandyWalker malformations (malformation noted on MRI/CT) have shown cytoplasmic (SCA2), neuronal (SCA1, MJD, SCA7), and nucleolar (SCA7) accumulation of the specific mutant polyglutaminecontaining ataxin proteins. Expanded polyglutamine ataxins with more than ~40 glutamines are potentially toxic to neurons for a variety of reasons including the following: high levels of gene expression for the mutant polyglutamine ataxin in affected neurons; conformational change of the aggregated protein to a β-pleated structure; abnormal transport of the ataxin into the nucleus (SCA1, MJD, SCA7); binding to other polyglutamine proteins, including the TATA-binding transcrip­ tion protein and the CREB-binding protein, impairing their functions; altering the efficiency of the ubiquitin-proteasome system of protein turnover; and inducing neuronal apoptosis. An earlier age of onset (anticipation) and more aggressive disease in subsequent generations are due to further expansion of the CAG triplet repeat and increased polyglutamine number in the mutant ataxin. The most common disor­ ders are discussed below. ■ ■SCA1 SCA1 was previously referred to as olivopontocerebellar atrophy, but genomic data have shown that that entity represents several different genotypes with overlapping clinical features. Symptoms and Signs  SCA1 is characterized by the development in early- or middle-adult life of progressive cerebellar ataxia of the trunk and limbs, impairment of equilibrium and gait, slowness of voluntary movements, scanning speech, nystagmoid eye movements, and oscillatory tremor of the head and trunk. Dysarthria, dysphagia, and oculomotor and facial palsies may also occur. Extrapyramidal symptoms include rigidity, an immobile face, and parkinsonian tremor. The reflexes are usually normal, but knee and ankle jerks may be lost, and extensor plantar responses may occur. Dementia may be noted but is usually mild. Impairment of sphincter function is common, with urinary and sometimes fecal incontinence. Cerebellar and brainstem atrophy are evident on MRI (Fig. 450-1). Marked shrinkage of the ventral half of the pons, disappearance of the olivary eminence on the ventral surface of the medulla, and atrophy of the cerebellum are evident on gross postmortem inspection of the brain. Variable loss of Purkinje cells, reduced numbers of cells in the molecular and granular layer, demyelination of the middle cerebellar peduncle and the cerebellar hemispheres, and severe loss of cells in the pontine nuclei and olives are found on histologic examination. Degenerative changes in the striatum, especially the putamen, and loss of the pigmented cells of the substantia nigra may be found in cases with extrapyramidal features. More widespread degeneration in the central nervous system (CNS), including involvement of the posterior columns and the spinocerebellar fibers, is often present. ■ ■GENETIC CONSIDERATIONS SCA1 encodes a gene product, called ataxin-1, that regulates tran­ scriptional repression with various nuclear factors. As a protein that can bind RNA, ataxin-1 may also regulate gene transcription posttranslationally. The mutant allele has 40 CAG repeats located FIGURE 450-1  Sagittal magnetic resonance imaging (MRI) of the brain of a 60-yearold man with gait ataxia and dysarthria due to spinocerebellar ataxia type 1 (SCA1), illustrating cerebellar atrophy (arrows). (Reproduced with permission from RN Rosenberg, P Khemani, in RN Rosenberg, JM Pascual [eds]: Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease, 5th ed. London, Elsevier, 2015.) within the coding region, whereas alleles from unaffected individuals have ≤36 repeats. A few patients with 38–40 CAG repeats have been described. There is a direct correlation between a larger number of repeats and a younger age of onset for SCA1. Juvenile patients have higher numbers of repeats, and anticipation is present in subsequent generations. Transgenic mice carrying SCA1 developed ataxia and Purkinje cell pathology. Leucine-rich acidic nuclear protein localiza­ tion, but not aggregation, of ataxin-1 appears to be required for cell death initiated by the mutant protein. ■ ■SCA2 Symptoms and Signs  Another clinical phenotype, SCA2, has been described in patients from Cuba and India. Cuban patients probably are descendants of a common ancestor, and the population may be the largest homogeneous group of patients with ataxia described. The age of onset ranges from 2 to 65 years, and there is considerable clinical variability within families. Although neuropathologic and clinical find­ ings are compatible with a diagnosis of SCA1, including slow saccadic eye movements, ataxia, dysarthria, parkinsonian rigidity, optic disc pallor, mild spasticity, and retinal degeneration, SCA2 is a unique form of cerebellar degenerative disease. ■ ■GENETIC CONSIDERATIONS The gene in SCA2 families also contains CAG repeat expansions coding for a polyglutamine-containing protein, ataxin-2. Normal alleles contain 15–32 repeats; mutant alleles have 35–77 repeats. Ataxin-2 has recently been shown to assemble with polyribosomes. Ataxin-2 is also an important risk factor for sporadic amyotrophic lat­ eral sclerosis (ALS). ■ ■MACHADO-JOSEPH DISEASE/SCA3 MJD was first described among the Portuguese and their descendants in New England and California. Subsequently, MJD has been found in families from Portugal, Australia, Brazil, Canada, China, England, France, India, Israel, Italy, Japan, Spain, Taiwan, and the United States. In most populations, it is the most common autosomal dominant ataxia. Symptoms and Signs  MJD has been classified into three clinical types. In type I MJD (ALS-parkinsonism-dystonia type), neurologic deficits appear in the first two decades and involve weakness and spas­ ticity of extremities, especially the legs, often with dystonia of the face, neck, trunk, and extremities. Patellar and ankle clonus are common, as are extensor plantar responses. The gait is slow and stiff, with a slightly broadened base and lurching from side to side; this gait results from spasticity, not true ataxia. There is no truncal titubation. Pharyngeal weakness and spasticity cause difficulty with speech and swallowing. Of note is the prominence of horizontal and vertical nystagmus, loss of fast saccadic eye movements, hypermetric and hypometric saccades, and impairment of upward vertical gaze. Facial fasciculations, facial myokymia, lingual fasciculations without atrophy, ophthalmoparesis, and ocular prominence are common early manifestations. In type II MJD (ataxic type), true cerebellar deficits of dysarthria and gait and extremity ataxia begin in the second to fourth decades along with corticospinal and extrapyramidal deficits of spasticity, rigidity, and dystonia. Type II is the most common form of MJD. Ophthalmoparesis, upward vertical gaze deficits, and facial and lingual fasciculations are also present. Type II MJD can be distinguished from the clinically similar disorders SCA1 and SCA2. Type III MJD (ataxic-amyotrophic type) presents in the fifth to seventh decades with a pancerebellar disorder that includes dysarthria and gait and extremity ataxia. Distal sensory loss involving pain, touch, vibration, and position senses and distal atrophy are prominent, indi­ cating the presence of peripheral neuropathy. The deep tendon reflexes are depressed to absent, and there are no corticospinal or extrapyra­ midal findings. CHAPTER 450 The mean age of onset of symptoms in MJD is 25 years. Neurologic deficits invariably progress and lead to death from debilitation within 15 years of onset, especially in patients with types I and II disease. Usu­ ally, patients retain full intellectual function. Ataxic Disorders The major pathologic findings are variable loss of neurons and glial replacement in the corpus striatum and severe loss of neurons in the pars compacta of the substantia nigra. A moderate loss of neurons occurs in the dentate nucleus of the cerebellum and in the red nucleus. Purkinje cell loss and granule cell loss occur in the cerebellar cortex. Cell loss also occurs in the dentate nucleus and in the cranial nerve motor nuclei. Sparing of the inferior olives distinguishes MJD from other dominantly inherited ataxias. ■ ■GENETIC CONSIDERATIONS The gene for MJD maps to 14q24.3-q32. Unstable CAG repeat expansions are present in the MJD gene coding for a polygluta­ mine-containing protein named ataxin-3, or MJD-ataxin. An earlier age of onset is associated with longer repeats. Alleles from nor­ mal individuals have between 12 and 37 CAG repeats, whereas MJD alleles have 60–84 CAG repeats. Polyglutamine-containing aggregates of ataxin-3 (MJD-ataxin) have been described in neuronal nuclei undergoing degeneration. MJD-ataxin codes for a ubiquitin protease, which is inactive due to expanded polyglutamines. Proteosome func­ tion is impaired, resulting in altered clearance of proteins and cerebel­ lar neuronal loss. ■ ■SCA6 Genomic screening for CAG repeats in other families with autosomal dominant ataxia and vibratory and proprioceptive sensory loss have yielded another locus. Of interest is that different mutations in the same gene for the α1A voltage-dependent calcium channel subunit (CACNLIA4; also referred to as the CACNA1A gene) at 19p13 result in different clinical disorders. CAG repeat expansions (21–27 in patients; 4–16 triplets in normal individuals) result in late-onset progressive ataxia with cerebellar degeneration. Missense mutations in this gene result in familial hemiplegic migraine. Nonsense mutations resulting in termination of protein synthesis of the gene product yield heredi­ tary paroxysmal cerebellar ataxia or EA. Some patients with familial hemiplegic migraine develop progressive ataxia and also have cerebel­ lar atrophy. ■ ■SCA7 This disorder is distinguished from all other SCAs by the presence of retinal pigmentary degeneration. The visual abnormalities first appear as blue-yellow color blindness and proceed to frank visual loss with macular degeneration. In almost all other respects, SCA7 resembles several other SCAs in which ataxia is accompanied by various non­ cerebellar findings, including ophthalmoparesis and extensor plantar responses. The genetic defect is an expanded CAG repeat in the SCA7 gene at 3p14-p21.1. The expanded repeat size in SCA7 is highly vari­ able. Consistent with this, the severity of clinical findings varies from essentially asymptomatic to mild late-onset symptoms to severe, aggressive disease in childhood with rapid progression. Marked antici­ pation has been recorded, especially with paternal transmission. The disease protein, ataxin-7, forms aggregates in nuclei of affected neu­ rons, as has also been described for SCA1 and SCA3/MJD. Ataxin-7 is a subunit of GCN5, a histone acetyltransferase-containing complex. ■ ■SCA8 This form of ataxia is caused by a CTG repeat expansion in an untrans­ lated region of a gene on chromosome 13q21. There is marked mater­ nal bias in transmission, perhaps reflecting contractions of the repeat during spermatogenesis. The mutation is not fully penetrant. Symp­ toms include slowly progressive dysarthria and gait ataxia beginning at ~40 years of age with a range between 20 and 65 years. Other features include nystagmus, leg spasticity, and reduced vibratory sensation. Severely affected individuals are nonambulatory by the fourth to sixth decades. MRI shows cerebellar atrophy. The mechanism of disease may involve a dominant “toxic” effect occurring at the RNA level, as occurs in myotonic dystrophy. PART 13 Neurologic Disorders ■ ■SCA27B SCA27B is a recently discovered entity, resulting from an intronic GAA repeat expansion in the FGF14 gene, and is one of the most common late-onset inherited ataxias. SCA27B occurs with a median age of onset of 60 years and presents as a relatively pure cerebellar ataxia with episodic symptoms at the disease onset. Other clinical features include afferent sensory deficits and dysautonomia. Cognitive impairment is infrequent. Both the episodic symptoms and symptom severity of ataxia appear to improve with 4-aminopyridine, although randomized clinical trials have not yet been performed in this population. ■ ■DENTATORUBROPALLIDOLUYSIAN ATROPHY DRPLA has a variable presentation that may include progressive ataxia, choreoathetosis, dystonia, seizures, myoclonus, and dementia. DRPLA is due to unstable CAG triplet repeats in the open reading frame of a gene named atrophin located on chromosome 12p12-ter. Larger expan­ sions are found in patients with earlier onset. The number of repeats is 49 in patients with DRPLA and ≤26 in normal individuals. Anticipa­ tion occurs in successive generations, with earlier onset of disease in association with an increasing CAG repeat number in children who inherit the disease from their father. One well-characterized family in North Carolina has a phenotypic variant known as the Haw River syn­ drome, now recognized to be due to the DRPLA mutation. ■ ■EPISODIC ATAXIA EA types 1 and 2 are two rare dominantly inherited disorders that have been mapped to chromosomes 12p (a potassium channel gene, KCNA1, Phe249Leu mutation) for type 1 and 19p for type 2. Patients with EA-1 have brief episodes of ataxia with myokymia and nystagmus that last only minutes. Startle, sudden change in posture, and exercise can induce episodes. Acetazolamide or anticonvulsants may be thera­ peutic. Patients with EA-2 have episodes of ataxia with nystagmus that can last for hours or days. Stress, exercise, or excessive fatigue may be precipitants. Acetazolamide may be therapeutic and can reverse the relative intracellular alkalosis detected by magnetic resonance spec­ troscopy. Stop codon, nonsense mutations causing EA-2 have been found in the CACNA1A gene, encoding the α1A voltage-dependent calcium channel subunit (see “SCA6,” above). ■ ■AUTOSOMAL RECESSIVE ATAXIAS Friedreich’s Ataxia  This is the most common form of inherited ataxia, composing one-half of all hereditary ataxias. It can occur in a classic form or in association with a genetically determined vitamin E deficiency syndrome; the two forms are clinically indistinguishable. SYMPTOMS AND SIGNS  Friedreich’s ataxia presents before 25 years of age with progressive staggering gait, frequent falling, and titubation. The lower extremities are more severely involved than the upper ones. Dysarthria occasionally is the presenting symptom; rarely, progressive scoliosis, foot deformity, nystagmus, or cardiopathy is the initial sign. The neurologic examination reveals nystagmus, loss of fast saccadic eye movements, truncal titubation, dysarthria, dysmetria, and ataxia of trunk and limb movements. Extensor plantar responses (with normal tone in trunk and extremities), absence of deep tendon reflexes, and weakness (greater distally than proximally) are usually found. Loss of vibratory and proprioceptive sensation occurs. The median age of death is 35 years. Women have a significantly better prognosis than men. Cardiac involvement occurs in 90% of patients. Cardiomegaly, sym­ metric hypertrophy, murmurs, and conduction defects are reported. Moderate intellectual disability or psychiatric syndromes are present in a small percentage of patients. A high incidence (20%) of diabetes mellitus is found and is associated with insulin resistance and pancre­ atic β-cell dysfunction. Musculoskeletal deformities are common and include pes cavus, pes equinovarus, and scoliosis. MRI of the spinal cord shows atrophy (Fig. 450-2). The primary sites of pathology are the spinal cord, dorsal root ganglion cells, and the peripheral nerves. Slight atrophy of the cerebel­ lum and cerebral gyri may occur. Sclerosis and degeneration occur predominantly in the spinocerebellar tracts, lateral corticospinal tracts, and posterior columns. Degeneration of the glossopharyngeal, vagus, hypoglossal, and deep cerebellar nuclei is described. The cerebral cor­ tex is histologically normal except for loss of Betz cells in the precentral gyri. The peripheral nerves are extensively involved, with a loss of large myelinated fibers. Cardiac pathology consists of myocytic hypertrophy and fibrosis, focal vascular fibromuscular dysplasia with subintimal or medial deposition of periodic acid-Schiff (PAS)-positive material, myocytopathy with unusual pleomorphic nuclei, and focal degenera­ tion of nerves and cardiac ganglia. ■ ■GENETIC CONSIDERATIONS The classic form of Friedreich’s ataxia has been mapped to 9q13q21.1, and the mutant gene, frataxin, contains expanded GAA triplet repeats in the first intron. There is homozygosity for expanded GAA repeats in >95% of patients. Normal persons have 7–22 GAA repeats, and patients have 200–900 GAA repeats. A more varied clinical syndrome has been described in compound heterozy­ gotes who have one copy of the GAA expansion and the other copy a point mutation in the frataxin gene. When the point mutation is located in the region of the gene that encodes the amino-terminal half of frataxin, the phenotype is milder, often consisting of a spastic gait, retained or exaggerated reflexes, no dysarthria, and mild or absent ataxia. Patients with Friedreich’s ataxia have undetectable or extremely low levels of frataxin mRNA, as compared with carriers and unrelated FIGURE 450-2  Sagittal magnetic resonance imaging (MRI) of the brain and spinal cord of a patient with Friedreich’s ataxia, demonstrating spinal cord atrophy. (Reproduced with permission from RN Rosenberg, P Khemani, in RN Rosenberg, JM Pascual [eds]: Rosenberg’s Molecular and Genetic Basis of Neurological and Psychiatric Disease, 5th ed. London, Elsevier, 2015.) individuals; thus, disease appears to be caused by a loss of expression of the frataxin protein. Frataxin is a mitochondrial protein involved in iron homeostasis. Mitochondrial iron accumulation due to loss of the iron transporter coded by the mutant frataxin gene results in a deficiency in iron/sulfur clusters containing mitochondrial enzymes, decreased ATP production, and accumulation of iron in the heart. Excess oxidized iron results in turn in the oxidation of cellular compo­ nents and irreversible cell injury. Two forms of hereditary ataxia associated with abnormalities in the interactions of vitamin E (α-tocopherol) with very-low-density lipo­ protein (VLDL) have been delineated. These are abetalipoproteinemia (Bassen-Kornzweig syndrome) and ataxia with vitamin E deficiency (AVED). Abetalipoproteinemia is caused by mutations in the gene coding for the larger subunit of the microsomal triglyceride transfer protein (MTP). Defects in MTP result in impairment of formation and secretion of VLDL in liver. This defect results in a deficiency of delivery of vitamin E to tissues, including the central and peripheral nervous system, as VLDL is the transport molecule for vitamin E and other fat-soluble substitutes. AVED is due to mutations in the gene for α-tocopherol transfer protein (α-TTP). These patients have an impaired ability to bind vitamin E into the VLDL produced and secreted by the liver, resulting in a deficiency of vitamin E in periph­ eral tissues. Hence, either absence of VLDL (abetalipoproteinemia) or impaired binding of vitamin E to VLDL (AVED) causes an ataxic syn­ drome. Once again, a genotype classification has proved to be essential in sorting out the various forms of the Friedreich’s disease syndrome, which may be clinically indistinguishable. RFC1-Related CANVAS Syndrome  Biallelic intronic AAGGG repeat expansions in the replication factor C subunit 1 (RFC1) gene are the cause of late-onset ataxia, particularly if associated with sensory neuronopathy and bilateral vestibular areflexia (CANVAS syndrome). A chronic unexplained cough is often associated with and may precede the onset of neurologic symptoms. Ataxia Telangiectasia  •  SYMPTOMS AND SIGNS  Patients with ataxia telangiectasia (AT) present in the first decade of life with pro­ gressive telangiectatic lesions associated with deficits in cerebellar function and nystagmus. The neurologic manifestations correspond to those in Friedreich’s disease, which should be included in the differ­ ential diagnosis. Truncal and limb ataxia, dysarthria, extensor plantar responses, myoclonic jerks, areflexia, and distal sensory deficits may develop. There is a high incidence of recurrent pulmonary infections and neoplasms of the lymphatic and reticuloendothelial system in patients with AT. Thymic hypoplasia with cellular and humoral (IgA and IgG2) immunodeficiencies, premature aging, and endocrine disorders such as type 1 diabetes mellitus are described. There is an increased incidence of lymphomas, Hodgkin’s disease, acute T-cell leukemias, and breast cancer. The most striking neuropathologic changes include loss of Purkinje, granule, and basket cells in the cerebellar cortex as well as of neurons in the deep cerebellar nuclei. The inferior olives of the medulla may also have neuronal loss. There is a loss of anterior horn neurons in the spinal cord and of dorsal root ganglion cells associated with posterior column spinal cord demyelination. A poorly developed or absent thy­ mus gland is the most consistent defect of the lymphoid system. ■ ■GENETIC CONSIDERATIONS The gene for AT (the ATM gene) at 11q22-23 encodes a protein that is similar to several yeast and mammalian phosphatidylinositol-3′ kinases involved in mitogenic signal transduction, meiotic recombina­ tion, and cell cycle control. Defective DNA repair in AT fibroblasts exposed to ultraviolet light has been demonstrated. The discovery of ATM permits early diagnosis and identification of heterozygotes who are at risk for cancer (e.g., breast cancer). Elevated serum alphafetoprotein and immunoglobulin deficiency are noted. ■ ■MITOCHONDRIAL ATAXIAS Spinocerebellar syndromes have been identified with mutations in mitochondrial DNA (mtDNA). Thirty pathogenic mtDNA point mutations and 60 different types of mtDNA deletions are known, sev­ eral of which cause or are associated with ataxia (Chap. 460). TREATMENT Ataxic Disorders The most important goal in management of patients with ataxia is to identify treatable disease entities. Mass lesions must be recog­ nized promptly and treated appropriately. Autoimmune paraneo­ plastic disorders can often be identified by the clinical patterns of disease that they produce, measurement of specific autoanti­ bodies, and uncovering the primary cancer; these disorders are often refractory to therapy, but some patients improve following removal of the tumor or immunotherapy (Chap. 99). Ataxia with antigliadin antibodies and gluten-sensitive enteropathy may improve with a gluten-free diet. Malabsorption syndromes lead­ ing to vitamin E deficiency may lead to ataxia. The vitamin E deficiency form of Friedreich’s ataxia must be considered, and serum vitamin E levels measured. Vitamin E therapy is indi­ cated for these rare patients. Vitamin B1 and B12 levels in serum should be measured, and the vitamins administered to patients having deficient levels. Hypothyroidism is easily treated. The cerebrospinal fluid should be tested for a syphilitic infection in patients with progressive ataxia and other features of tabes dor­ salis. Similarly, antibody titers for Lyme disease and Legionella should be measured and appropriate antibiotic therapy should be instituted in antibody-positive patients. Aminoacidopathies, leukodystrophies, urea-cycle abnormalities, and mitochondrial encephalomyopathies may produce ataxia, and some dietary or metabolic therapies are available for these disorders. The deleteri­ ous effects of phenytoin and alcohol on the cerebellum are well known, and these exposures should be avoided in patients with ataxia of any cause. CHAPTER 450 Ataxic Disorders There is no proven therapy for any of the autosomal dominant ataxias (SCA1 to SCA43). Omaveloxolone, a NRF2 agonist, is the only U.S. Food and Drug Administration–approved agent for Friedreich’s ataxia. NRF2 is a transcription factor that regulates gene transcripts involved in mitochondrial energy production and addresses the root cause of mitochondrial dysfunction in Fried­ reich’s ataxia. Iron chelators and antioxidant drugs are potentially harmful in Friedreich’s patients because they may increase heart muscle injury. Acetazolamide can reduce the duration of symptoms of EA. At present, identification of an at-risk person’s genotype, together with appropriate family and genetic counseling, can reduce the incidence of these cerebellar syndromes in future generations (Chap. 480). ■ ■GENETIC DIAGNOSTIC LABORATORIES 1. Baylor College of Medicine; Houston, Texas, 1-713-798-6522 http://www.bcm.edu/genetics/index.cfm?pmid=21387 2. The University of Chicago Genetic Services Laboratories https://dnatesting.uchicago.edu   3. GeneDx http://www.genedx.com   4. Transgenomic, 1-877-274-9432 http://www.transgenomic.com/labs/neurology   ■ ■GLOBAL FEATURES Ataxias with autosomal dominant, autosomal recessive, X-linked, or mitochondrial forms of inheritance are present on a worldwide basis. MJD (SCA3) (autosomal dominant) and Friedreich’s ataxia (autosomal recessive) are the most common types in most populations. Genetic markers are now commercially available to precisely identify the genetic mutation for correct diagnosis and also for family planning. Early detection of asymptomatic preclinical disease can reduce or eliminate the inherited form of ataxia in some families on a global, worldwide basis. # 21 - 451 Disorders of the Autonomic Nervous System ### 451 Disorders of the Autonomic Nervous System ■ ■FURTHER READING Anheim M et al: The autosomal recessive cerebellar ataxias. N Engl J Med 16:636, 2012. Cortese A et al: Biallelic expansion of an intronic repeat in RFC1 is a common cause of late-onset ataxia. Nat Genet 51:649, 2019. Jacobi H et al: Long-term disease progression in spinocerebellar ataxia types 1, 2, 3, and 6: A longitudinal cohort study. Lancet Neurol 14:1101, 2015. Lynch DR et al: Omaveloxolone for the treatment of Friedreich ataxia: Clinical trial results and practical considerations. Expert Rev Neu­ rother 24:251, 2024. Paulson HL et al: Polyglutamine spinocerebellar ataxias—from genes to potential therapy. Nat Rev Neurosci 18:613; 2017. Pellerin D et al: Deep intronic FGF14 GAA repeat expansion in lateonset cerebellar ataxia. N Engl J Med 388:128, 2023. PART 13 Neurologic Disorders Safwan S. Jaradeh Disorders of the Autonomic Nervous System The autonomic nervous system (ANS) has a large central nervous sys­ tem (CNS) organization and an extensive peripheral nervous system (PNS) network that innervates and influences all organ systems. As such, it is important in securing normal homeostasis. The ANS has three major components: parasympathetic, sympathetic, and enteric. The parasympathetic component has mainly a craniosacral localiza­ tion (brainstem and sacral cord), while the sympathetic component has mainly a thoracolumbar localization (first thoracic to second lumbar segments). ANS neurons of these components project thinly myelin­ ated fibers to autonomic ganglia, where they synapse with postgangli­ onic, mainly unmyelinated fibers that innervate the respective target organs. The enteric nervous system (ENS) has its own set of autonomic neurons and neurotransmitters but is heavily regulated by the central and peripheral autonomic nervous systems. The ANS also sensitizes endocrine organs to the effect of hormones, influencing how hormonal balances may affect neurologic diseases. The classification of autonomic dysfunction (or dysautonomia) can be based on the impaired component (sympathetic, parasympathetic, or enteric), but a more practical clinical approach is based on organ specificity: heart, blood vessels, sweat glands, pupils, gastrointestinal, and genitourinary, either in isolation or in any potential combination. The time course of the development of dysautonomia (acute, subacute, or chronic; progressive or static) is especially useful in the differential etiologic diagnosis. The ANS functions as a reflex circuit, using the sensory and sen­ sorial feedback from the organs to modulate the ANS output and maintain homeostasis. This requires exquisite integration of the cen­ tral ANS, peripheral ANS, and target organs. In the CNS, autonomic circuits operate at several levels: cerebral supratentorial, cerebral infratentorial, and spinal. Supratentorial areas include the insular cor­ tex, prefrontal cortex, limbic lobe located on the medial surface of the cerebral hemispheres, hypothalamus, and hypothalamic-pituitary axis. Infratentorial areas are mainly the nucleus tractus solitaries (NTS), dorsal motor nucleus of the vagus (DMV) and nucleus ambiguous (NA). Spinal areas are in the intermediate lateral horns (IML) of the spinal cord gray matter between the first thoracic segment and the fourth sacral segment. Descending CNS information to the brainstem and IML allows the CNS to modulate autonomic activity. Peripheral, visceral, spinal, and brainstem afferent information conveyed to the CNS is also important in influencing autonomic function in health and disease. ANS dysfunction may explain many symptoms related to the aging process and various degenerative neurologic disorders, such as Parkinson’s disease, multiple system atrophy, Lewy body disease, and pure autonomic failure. It features prominently in various autoimmune disorders, particularly autoimmune autonomic ganglionopathy and certain paraneoplastic disorders. ANS dysfunction in a more restricted form is present in various cyclical disorders such as migraine, cyclic vomiting, and other circadian rhythm disorders. It plays an important role in the genesis of various conditions of orthostatic intolerance (OI) including orthostatic hypotension (OH), postural orthostatic tachycar­ dia syndrome (POTS), and syncope. A detailed discussion of syncope can be found in Chap. 23. ANATOMIC, BIOCHEMICAL, AND PHARMACOLOGIC ORGANIZATION Connections between ANS centers in the cerebral cortex and brain­ stem coordinate autonomic outflow and their integration with emo­ tional and higher mental functions. The preganglionic parasympathetic neurons leave the CNS in the third, seventh, ninth, and tenth cranial nerves as well as the second to fourth sacral nerves. The preganglionic sympathetic neurons exit the spinal cord between the first thoracic and the second lumbar segments (Fig. 451-1). The autonomic ganglia reside outside the CNS. The sym­ pathetic ganglia are located in paravertebral and prevertebral ganglia, while the parasympathetic ganglia are located near, or sometimes within, the target organs. Responses to sympathetic and parasympa­ thetic stimulation are frequently antagonistic (Table 451-1), allowing fine-tuning of autonomic responses. In general, increased sympathetic activity leads to the “fight or flight” response, while parasympathetic activity leads to the “rest and digest” response. Biochemically, acetylcholine (ACh) is the preganglionic neurotrans­ mitter for both sympathetic and parasympathetic divisions of the ANS as well as the postganglionic neurotransmitter of the parasympathetic neurons; all preganglionic receptors are nicotinic, while postgangli­ onic receptors are muscarinic in type. Norepinephrine (NE) is the neurotransmitter of postganglionic sympathetic neurons, except for sympathetic cholinergic neurons innervating the eccrine sweat glands where the neurotransmitter is also ACh. As stated above, the ENS has a large number of neurons organized in plexuses. Meissner’s (submucosal) plexus, Auerbach’s (myenteric) and interstitial cells of Cajal (circular muscular) compose the majority of the ENS; they contain numerous neurotransmitters. Parasympathetic control of the gastrointestinal system is mediated through the cranio­ spinal nerves (vagus and S2–S4 nerves), while sympathetic control is mediated through the thoracolumbar (T1–L2) nerves. CLINICAL EVALUATION Disorders of the ANS are rather common and can occur with either CNS or PNS pathology that disrupts the afferent limb, CNS processing center, efferent limb, or any combination of these. It is also important to recognize that clinical manifestations can result from decreased function, overactivity, or dysregulation of autonomic circuits. The evaluation begins by taking an accurate and complete auto­ nomic medical history. The chief complaint and history of present illness should be sought from the patient, assisted by family members or significant others when necessary. Records from previous hospi­ talizations and test results are useful but cannot substitute for direct history taking. It is important to obtain the sequence of symptoms as accurately as possible. Antecedent events such as a viral illness or surgi­ cal procedure followed by subacute OI suggests an autoimmune cause, while a history of frequent fainting since childhood or adolescence favors a congenital or genetic condition. Therefore, a detailed family history is often essential, particularly in younger patients. In a patient with POTS, which occurs mainly in young women, it is important to ask privately about emotional or physical abuse in childhood. Physical deconditioning often exacerbates chronic OI and POTS. A prior his­ tory of irradiation to the neck in a patient with labile blood pressure and OI suggests arterial baroreflex failure due to injury to the carotid sinus baroreceptors. III Ciliary ganglion Eye VII IX X T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T11 T12 L1 L2 S2 S3 S4 Pelvic splanchnic nerve FIGURE 451-1  Schematic representation of the autonomic nervous system. (Reproduced with permission from R Snell: Clinical Neuroanatomy, 7th ed. Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 2009.) Like other medical histories, it is important to determine exac­ erbating and alleviating factors. In patients with OI, the positional nature of symptoms (standing vs supine or sitting) can be a key clue to diagnosis. Patients with neurogenic OH are often more symptomatic in the morning, after exercise particularly in the heat, or after eating a large meal, especially with alcohol. Patients with POTS may feel worse when standing in a warm shower and notice reddish or purplish feet Parasympathetic nerves Preganglionic fibers Postganglionic fibers Sympathetic nerves Preganglionic fibers Postganglionic fibers Lacrimal gland Submandibular and sublingual salivary glands CHAPTER 451 Otic g. Parotid gland Disorders of the Autonomic Nervous System Heart Lungs Celiac g. Stomach Small intestine Sup. mes. g. Suprarenal gland Kidney Renal g. Inf. mes. g. Colon Rectum Urinary bladder Sex organs in that situation. However, given the widespread autonomic network underlying many dysautonomic states, these conditions are often mul­ tisystemic, and specific symptoms can vary from day to day. A review of autonomic symptoms begins with questions about OI (lightheadedness, dizziness, orthostatic weakness or dyspnea, orthostatic neck and shoulder discomfort, orthostatic headache), a history of supine hypertension, unpredictable blood pressure swings, TABLE 451-1  Effects of Sympathetic and Parasympathetic Systems on Various Effector Organs   SYMPATHETIC PARASYMPATHETIC Pupil Pupillodilation (alpha) Pupilloconstriction Accommodation Decreased Increased Heart Positive chronotropic effect (beta) Positive inotropic effect (beta) Negative chronotropic effect Negative inotropic effect Arteries Vasoconstriction (alpha) Vasodilation (beta) Vasodilation Veins Vasoconstriction (alpha) Vasoconstriction (beta)   Tracheobronchial tree Bronchodilation (beta) Bronchoconstriction Increased bronchial gland secretions Gastrointestinal tract Decreased motility (beta) Contraction of sphincters (alpha) Increased motility Relaxation of sphincter PART 13 Neurologic Disorders Bladder Detrusor relaxation (beta) Contraction of sphincter (alpha) Detrusor contraction Relaxation of sphincter Salivary glands Scant, thick, viscid saliva (alpha) Copious, thin, watery saliva Skin Piloerection (cutis anserina) No piloerection Sweat glands Increased secretion (cholinergic) Decreased secretion Genitalia Ejaculation Ejaculation/Erection Adrenal medulla Catecholamine release   Glycogen Glycogenolysis (alpha and beta) Lipolysis (alpha and beta) Glycogen synthesis Source: Reproduced with permission from WW Campbell: The autonomic nervous system, in DeJong’s The Neurologic Examination, 8th ed. Wolters Kluwer, 2020. or syncopal episodes. Gastrointestinal symptoms may resemble those of irritable bowel syndrome (constipation, diarrhea, or both), but also constant nausea and bloating, unexplained vomiting, or dumping syn­ drome may be present, both in diabetics and in others. Genitourinary symptoms include dysuria, incontinence, urgency, and male erectile dysfunction. Sweating abnormalities (dry skin, excessive sweating) and body temperature changes reflect disordered thermoregulation and heat dissipation. Sicca syndrome may resemble that of Sjögren syndrome. Blurred vision from dark to light suggests slow, tonic pupil­ lary dilation. Pertinent nonautonomic symptoms such as acroparesthesias or burning feet (and hands) suggest an autonomic small-fiber neuropa­ thy. Impaired olfaction, impaired balance, abnormal movements, and abnormal sleep behavior (apnea, stridor, or excessive moving and talk­ ing during sleep known as dream enactment behavior) are red flags for a degenerative neurologic extrapyramidal disorder. A complete listing of all prescribed drugs, over-the-counter medica­ tions, herbal remedies, and dietary supplements is important because they can affect autonomic function and may produce unexpected adverse events. For instance, certain diet supplements have sympa­ thomimetic activity and cause unexpected hypertension, tachycardia, or both. Physical examination begins by obtaining full vital signs, including supine blood pressure and heart rate, followed by orthostatic blood pressure values at 1 and 3 min after rising from a seated position. An abnormal body temperature, either hyperthermia or hypothermia, may be a clue to a systemic or endocrine illness. Next comes the inspection of the limbs, looking for changes in the feet (pes cavus or planus), vasomotor color changes in the distal limbs, neuropathic foot or toe ulcers, scoliosis, chest deformity (pectus excavatum or carinii), hyper­ mobility, skin elasticity, arachnodactyly, an abnormal pattern of sweat­ ing or hair distribution, or angiokeratoma (Fabry’s disease). Head and neck evaluation begins with a careful pupillary examination in a dark room, looking for asymmetry, miosis, mydriasis, reaction to light and accommodation, and rate and symmetry of redilation. A high-arched palate is present in some patients with OI and Ehlers-Danlos syndrome (Chap. 425). The tongue’s appearance (smooth vs normal) and size (macroglossia suggests amyloidosis) should be noted. For patients in whom a neurologic cause is likely, a complete evalu­ ation of the cranial nerves, strength and muscle tone, reflexes, sensory function including small-fiber modalities (pinprick, temperature), cer­ ebellar function, and gait is important (Chap. 433). This may require a neurologic referral if the primary care physician is uncomfortable with the assessment. LOCALIZATION Once the history and examination are complete, an initial localization is usually possible, based on a working knowledge of the anatomy and pharmacology of ANS components. For example, parasympathetic dysfunction is mainly cholinergic. Patients will report dry mouth and constipation, urinary retention, and erectile failure in men. On the other hand, sympathetic dysfunction is mainly adrenergic (nor­ epinephrine, epinephrine, dopamine) and symptoms and signs of OI predominate, given the prominent effect of these neurotransmitters on cardiac function and vasomotor tone. These patients will report lightheadedness, dizziness, faintness, visual changes, and a need to sit down. Muscarinic dysfunction leads to reduced sweating, hyperthermia, reduced salivation and lacrimation (sicca syndrome), mydriasis with blurred vision, slow gastrointestinal motility, and urinary retention. Tachycardia and arrhythmias are less common. Some CNS symptoms such as delirium and hallucinations may occur. Adrenergic dysfunction presents with excessive sweating, vasomo­ tor changes, irritable bowel syndrome, dysuria and stress incontinence. Tachycardia and arrhythmias are common. Miosis or mydriasis may occur, usually without blurred vision. Some CNS symptoms are panic, anxiety, and mood disorders. Certain features favor preganglionic versus postganglionic localiza­ tion. Preganglionic disorders are more likely to cause body temperature dysregulation, syncope and POTS, sleep disturbances, and autonomic storms. Postganglionic disorders are more likely in the presence of acral pain, acral anhidrosis, severe OH, and severe gastrointestinal or urinary dysmotility. However, overlap may occur as some pathologic conditions involve both preganglionic and postganglionic systems; examples include autoimmune, paraneoplastic, and neurodegenerative disorders. LABORATORY EVALUATION Testing begins by obtaining basic blood tests (complete blood count with differential, comprehensive metabolic panel, erythrocyte sedi­ mentation rate). It is important to check iron, ferritin, vitamin B12, and vitamin D levels as well as folic acid. In patients with gastrointestinal distress, particularly with significant weight loss, measurement of vari­ ous nutritional factors and vitamins is important, including less com­ mon ones such as thiamine, vitamin B6, niacin, riboflavin, vitamin C, vitamin E, serum copper, coenzyme Q10, and carnitine levels. A search for endocrine disorders such as diabetes, thyroid disease, or disorders of adrenal cortical (cortisol) and medullary (catecholamine) function may be necessary, as well as 5-hydroxyindoleacetic acid (5-HIAA) to look for carcinoid tumors. In patients with small-fiber neuropathy and normal hemoglobin A1c, a 2-h glucose tolerance test is necessary, as glucose intolerance is a rather frequent cause of isolated small-fiber neuropathy in the absence of overt diabetes. In patients with OI, supine and upright catecholamine levels can provide useful information. In patients with central or preganglionic adrenergic dysautonomia, supine catecholamine levels tend to be normal but fail to rise significantly in the upright position; the normal healthy response is a doubling or greater. In patients with peripheral or postganglionic adrenergic dys­ autonomia, supine catecholamine levels tend to be low and also fail to rise significantly in the upright position. In some acquired autonomic disorders, rheumatologic test screen­ ing, particularly for Sjögren’s syndrome (Chap. 373), scleroderma (Chap. 372), and mixed connective tissue disease (Chap. 372), is use­ ful. If the bedside examination or autonomic testing shows evidence for a peripheral autonomic neuropathy, serum free light chains and protein electrophoresis to look for paraproteinemia is important, as it may be the sign of early primary amyloidosis (Chap. 117). In probable acquired autonomic disorders, serologic tests to check for autoimmune markers are indicated, including antibodies to the ganglionic ACh nicotinic receptor (see “Autoimmune Autonomic Ganglionopathy,” below), voltage-gated potassium and calcium P/Q channel, plexin, and glutamic acid decarboxylase (GAD). If a paraneoplastic etiology is suspected, testing for anti-Hu, anti-CRMP5, anti-amphiphysin, or other autoantibodies may also be indicated (Chap. 99). If there is a history of infection, appropriate serologic tests can be requested (e.g., HIV, Epstein-Barr virus, herpes simplex virus, varicella-zoster virus, cytomegalovirus). In young patients or those with a positive family history, testing for porphyria (Chap. 428) and Fabry’s disease (Chap. 429) is important, as these conditions are now treatable (Table 451-2). TABLE 451-2  Classification of Clinical Autonomic Disorders I. Autonomic Disorders with Brain Involvement A. Associated with multisystem degeneration 1. Multisystem degeneration: autonomic failure clinically prominent a. Multiple-system atrophy (MSA) b. Parkinson’s disease with autonomic failure c. Diffuse Lewy body disease with autonomic failure 2. Multisystem degeneration: autonomic failure clinically not usually prominent a. Parkinson’s disease without autonomic failure b. Other extrapyramidal disorders (inherited spinocerebellar atrophies, progressive supranuclear palsy, corticobasal degeneration, Machado-Joseph disease, fragile X syndrome [FXTAS]) B. Unassociated with multisystem degeneration (focal CNS disorders) 1. Disorders mainly due to cerebral cortex involvement a. Frontal cortex lesions causing urinary/bowel incontinence b. Focal seizures (temporal lobe or anterior cingulate) c. Cerebral infarction of the insula 2. Disorders of the limbic and paralimbic circuits a. Limbic encephalitis b. Autonomic seizures c. Shapiro’s syndrome (agenesis of corpus callosum, hyperhidrosis, hypothermia) II. Autonomic Disorders with Spinal Cord Involvement A. Traumatic quadriplegia B. Syringomyelia C. Subacute combined degeneration D. Multiple sclerosis and neuromyelitis optica III. Autonomic Neuropathies A. Acute/subacute autonomic neuropathies a. Subacute autoimmune autonomic ganglionopathy (AAG) b. Subacute paraneoplastic autonomic neuropathy c. Guillain-Barré syndrome d. Botulism e. Porphyria f. Drug-induced autonomic neuropathies—stimulants, drug withdrawal, vasoconstrictor, vasodilators, beta-receptor antagonists, beta-agonists g. Toxin-induced autonomic neuropathies h. Subacute cholinergic neuropathy Abbreviations: BP, blood pressure; CNS, central nervous system; HR, heart rate; OH, orthostatic hypotension; POTS, postural orthostatic tachycardia syndrome. AUTONOMIC EVALUATION TESTS The most commonly employed autonomic tests evaluate cardiovascu­ lar function. ■ ■HEART RATE VARIATION TO DEEP BREATHING This tests the parasympathetic cardiovascular reflexes mediated via the vagus nerve. The patient is instructed to breathe deeply at a rate of 6 breaths/min, and the acceleration and deceleration of the heart rate accompanying the inspiratory/expiratory cycle is calculated and averaged. The score is the average of the heart rate variability, or the expiratory to inspiratory ratio (Fig. 451-2). The ratio decreases gradu­ ally with age and is therefore age-corrected. ■ ■VALSALVA MANEUVER This test is performed in the supine position. The patient blows into a closed mouthpiece to increase the intrathoracic pressure by CHAPTER 451 3. Disorders of the hypothalamus a. Thiamine deficiency (Wernicke-Korsakoff syndrome) b. Diencephalic syndrome c. Neuroleptic malignant syndrome d. Serotonin syndrome e. Fatal familial insomnia Disorders of the Autonomic Nervous System f. Antidiuretic hormone (ADH) syndromes (diabetes insipidus, inappropriate ADH secretion) g. Disturbances of temperature regulation (hyperthermia, hypothermia) h. Disturbances of sexual function i. Disturbances of appetite j. Disturbances of BP/HR and gastric function k. Horner’s syndrome 4. Disorders of the brainstem and cerebellum a. Posterior fossa tumors b. Syringobulbia and Arnold-Chiari malformation c. Disorders of BP control (hypertension, hypotension) d. Cardiac arrhythmias e. Central sleep apnea f. Baroreflex failure g. Horner’s syndrome h. Vertebrobasilar and lateral medullary (Wallenberg’s) syndromes i. Brainstem encephalitis E. Amyotrophic lateral sclerosis (mild, late) F. Tetanus G. Stiff-person syndrome H. Spinal cord tumors B. Chronic peripheral autonomic neuropathies 1. Small fiber neuropathy, including cryptogenic sensory polyneuropathy (CSPN) 2. Combined sympathetic and parasympathetic failure a. Amyloid b. Diabetic autonomic neuropathy c. AAG (paraneoplastic and idiopathic) d. Sensory neuronopathy with autonomic failure e. Fabry’s disease f. Diabetic, uremic, or nutritional deficiency g. Familial dysautonomia (Riley-Day syndrome) h. Hereditary sensory and autonomic neuropathy i. HIV-related autonomic neuropathy j. Geriatric dysautonomia (age >80 years) 3. Disorders of orthostatic intolerance: OH; POTS; reflex syncope; prolonged bed rest; space flight; chronic fatigue Heart rate (Beats/Min) A 01:00 02:00 03:00 02:30 01:30 00:30 PART 13 Neurologic Disorders Heart rate (Beats/Min) 03:30 02:10 02:20 02:30 02:40 02:50 Time scale (Min:Sec) B FIGURE 451-2  Examples of normal (A) and reduced (B) heart rate variability to deep breathing. >40 mmHg for 15 s. During blowing, there is a decrease in venous return to the heart, leading to a fall in blood pressure and an associ­ ated compensatory tachycardia. Reduced blood pressure induces a compensatory peripheral sympathetic vasoconstriction in the lower extremities, which stops the blood pressure fall and reverses it close to baseline. Following release of the effort, blood pressure rises due to increased cardiac filling from the venous return, along with persistent sympathetic vasoconstriction. This leads to transient hypertension (an overshoot response) that stimulates the aortic and carotid barorecep­ tors leading to reflex bradycardia. The Valsalva ratio is the ratio of the higher to the lower heart rate and is a measure of the parasympathetic arm of the baroreflex. The magnitude of the drop in blood pressure, and of recovery in the overshoot phase, produces an adrenergic index score that, along with the blood pressure recovery time, is a marker of the sympathetic arm of the baroreflex (Fig. 451-3). The heart rate variation to deep breathing and the Valsalva ratio are diminished in most patients with autonomic failure, including diabetes and α-synuclein disorders and also in patients who take anticholinergic medications. ■ ■TILT TABLE TESTING This test of great value for patients with all syndromes of OI, with or without syncope. Many autonomic laboratories are equipped with spe­ cial devices and a finger cuff that enables the accurate reproduction of beat-to-beat arterial waveforms. The tilt test is an excellent test of sym­ pathetic vasomotor and cardiovascular innervation, as it detects OH in all its forms, as well as excessive orthostatic tachycardia (Fig. 451-4 ). When syncope occurs, testing allows differentiation between the vari­ ous types (i.e., vasovagal, vasodepressor, and cardiodepressor syncope). Tilt Table Testing for Recurrent Syncope  When an initial phase of tilt at an angle of 60–70° for 30–40 min is negative, pharma­ cologic provocation of syncope (with intravenous, sublingual, or spray nitroglycerin, or intravenous isoproterenol) can be used. This increases 03:00 03:10 03:20 the sensitivity of testing, at the expense of specificity (i.e., some patients with normal sympathetic function may also faint after administration of these drugs). ■ ■SUDOMOTOR FUNCTION TESTING Sweating is secondary to the release of ACh from sympathetic postgan­ glionic fibers. The quantitative sudomotor axon reflex test (QSART) measures regional ACh-induced sweating. The test is usually per­ formed at four different sites (forearm, proximal leg, distal leg, and foot) to provide information on both the extent and distribution of postganglionic sudomotor impairment (Fig. 451-5 ). A low or absent response indicates a lesion of the postganglionic sudomotor axon. If the equipment necessary to perform the test is not available, sym­ pathetic skin responses recorded from the foot and the hand using standard nerve conduction equipment can be used, although results obtained in this manner may be less sensitive and specific. As a gen­ eral rule, autonomic or small-fiber neuropathies often lead to reduced sweating in the feet. The thermoregulatory sweat test (TST) is a qualita­ tive measure of global sweat production in response to an elevation of body temperature under controlled conditions. An indicator powder dusted on the anterior surface of the forehead and body changes color with sweat production in a hot and humid chamber. The pattern of color change measures the integrity of both preganglionic and postgan­ glionic sudomotor functions. A postganglionic lesion is present if both QSART and TST show absent sweating. In a preganglionic lesion, the QSART is preserved but TST shows anhidrosis. ■ ■SKIN BIOPSY Skin biopsies are commonly performed to diagnose small-fiber neu­ ropathies. These consist of small punch biopsy specimens, often 2–4 mm in diameter, stained for special axonal markers. This allows the identification of epidermal nerve fiber density as well as sudomo­ tor innervation density. Patients often undergo biopsies from two to four sites, usually from the distal and proximal lower extremity as well Heart rate (Beats/Min) 09:00 10:00 10:15 10:30 09:15 09:30 09:45 Blood pressure (mmHg) 09:00 10:00 10:15 10:30 09:15 09:30 Time scale (Min:Sec) 09:45 A Heart rate (Beats/Min) 02:00 03:00 03:15 03:30 03:45 02:15 02:30 02:45 Blood pressure (mmHg) 02:00 03:00 03:15 03:30 03:45 02:15 02:30 02:45 B FIGURE 451-3  A. The tracing shows a normal Valsalva ratio and blood pressure response. B. A low Valsalva ratio and abnormal blood pressure response are illustrated. Expiratory pressure (mmHg) CHAPTER 451 Expiratory pressure (mmHg) Disorders of the Autonomic Nervous System Expiratory pressure (mmHg) Expiratory pressure (mmHg) Time scale (Min:Sec) Heart rate (Beats/Min) TU 20:00 15:00 PART 13 Neurologic Disorders Blood pressure (mmHg) TU 15:00 20:00 TD A Heart rate (Beats/Min) tu TU 10:00 15:00 Blood pressure (mmHg) tu 10:00 20:00 25:00 15:00 TD TU B FIGURE 451-4  Examples of abnormal tilt responses. In each panel, the first tracing represents the heart rate, while the second represents the systolic, mean, and diastolic blood pressure responses. A. Progressive orthostatic hypotension leading to syncope. B. Neurogenic orthostatic hypotension (orthostatic hypotension without an adequate increase in heart rate). Notice the baseline supine hypertension (systolic blood pressure of 175 mmHg) due to associated baroreflex impairment. C. Postural orthostatic tachycardia syndrome (POTS). Notice the dramatic increase of the heart rate by >50 beats/min after tilt upward. TD, tilt downward; TU, tilt upward. TD Time scale (Min:Sec) td TD 20:00 25:00 td Time scale (Min:Sec) Heart rate (Beats/Min) TU TU 15:00 Blood pressure (mmHg) TU TU 15:00 C FIGURE 451-4  (Continued) Sweat rate (nL/min) t.i.m ON 00:00 05:00 10:00 15:00 Sweat rate (nL/min) t.i.m ON 00:00 05:00 A FIGURE 451-5  A. Examples of normal (forearm, top tracing) and reduced (proximal leg, bottom tracing) quantitative sweat responses consistent with a mild, lengthdependent autonomic neuropathy. B. Normal (forearm, top tracing), reduced (proximal leg, middle tracing), and quasi-absent (distal leg, bottom tracing) quantitative sweat responses consistent with a length-dependent autonomic and small-fiber neuropathy. Tim ON, time when electrical stimulation is turned on to start iontophoresis of acetylcholine and induce sweating. 20:00 25:00 30:00 TD CHAPTER 451 Disorders of the Autonomic Nervous System 20:00 25:00 30:00 TD Time scale (Min:Sec) Forearm Prox Leg 10:00 15:00 Sweat Rate - Right Forearm Sweat rate (µL) 20:50 00:00 04:10 Time 08:20 12:30 16:40 Sweat Rate - Right Proximal Leg PART 13 Neurologic Disorders Sweat rate (µL) 20:50 00:00 04:10 Time 08:20 12:30 16:40 Sweat Rate - Right Distal Leg Sweat rate (µL) 20:50 00:00 04:10 Time 08:20 12:30 16:40 B FIGURE 451-5  (Continued) as the forearm. The reduction in the number of nerve fibers and the pattern of reduction assist in establishing the diagnosis but also pro­ vide a clue to the underlying etiology, particularly when the fiber loss is not length-dependent. Skin biopsies are also useful in diagnosing autonomic dysfunction secondary to synucleinopathies, as at least one specimen may demonstrate phosphorylated α-synuclein inclusions in postganglionic sympathetic adrenergic and cholinergic nerve fibers. In these cases, a more proximal biopsy obtained near the cervical paraspi­ nal region can be a helpful diagnostic tool if it shows accumulation of α-synuclein (see specific disorders below). If all testing remains unrevealing, it is reasonable to consider a fat aspirate biopsy to check for amyloidosis. SPECIFIC CONDITIONS OF ANS DYSFUNCTION ■ ■ORTHOSTATIC HYPOTENSION OH is a common disorder with many underlying conditions. It can be debilitating, leading to fatigue, falls, syncope, cognitive impairment, and end-organ damage. OH increases with advancing age and is com­ monly associated with a variety of general medical, neurologic, and primary autonomic disorders including diabetes, heart failure, kidney failure, and neurodegenerative and autoimmune diseases. Upon standing or with tilt testing, ~500–700 mL of blood shifts to peripheral venous vessels in the lower limbs and splanchnic bed, reduc­ ing venous return. In a healthy person, there is slight increase in heart rate and peripheral venoconstriction and arteriolar constriction that maintains systolic blood pressure (SBP) and increases slightly diastolic blood pressure (DBP). This normal response depends on interactions between multiple homeostatic systems, including baroreceptors, auto­ nomic afferents, central processing centers, autonomic efferents, and peripheral vascular sympathetic receptors. Classical OH is defined as a sustained reduction of SBP ≥20 mmHg or DBP ≥10 mmHg within 3 min of active standing or on a head-up tilt (HUT) test ≥60°. Variants of OH include smaller but symptom­ atic reductions in SBP when the supine SBP is low (90–100 mmHg) but drops well below this level with standing or tilt. In patients with hypertension, OH is defined as an orthostatic drop of SBP/DBP ≥30/15 mmHg. The prevalence of OH in the general population ranges from <5% below age 50 up to 20% above age 70. The diagnosis can be overlooked, as most patients are asymptomatic or have only minor symptoms. OH is associated with increased risk of falls, coronary heart disease, heart failure, stroke, and death. When the orthostatic compensatory heart rate (HR) increase exceeds 15 beats/min, OH is nonneurogenic. On the contrary, neurogenic OH is associated with a blunted compensatory HR increase of <15 beats/ min, provided there are no other possible explanations, such as cardio­ active medications or intrinsic cardiac rhythm disturbances preventing an orthostatic HR increase. A more accurate way to diagnose neuro­ genic OH (NOH) is by dividing the HR increase by the fall in SBP (ΔHR/ΔSBP), as this metric provides a marker of cardiac baroreflex gain. A ratio <0.5 beats/min/mmHg after 3 min of standing (or tilt) more accurately indicates NOH. NOH is characterized by inadequate release of peripheral norepinephrine leading to impaired systemic vascular tone. The distinction is important because patients with NOH have a greater risk of mortality, approaching 44% over 30 months of follow-up, and exceeding 60% over 10 years. Furthermore, NOH can be associated with supine hypertension in patients with baroreflex impairment or autonomic failure, particularly in neurodegenerative conditions. Clinical Presentation  OH symptoms result from decreased blood flow to the brain. The most common symptom is lightheadedness on standing. Patients may report other orthostatic symptoms, such as palpitations, flushing, or pallor. More severe OH may lead to fainting or near-fainting. Triggers include bed rest (explaining the common occurrence upon waking up in the morning), food ingestion (particu­ larly a large meal with alcohol), fever, heat, exercise, hyperventilation, medications, sepsis, or surgery. Aging, long periods of exercise, and intensification of antihypertensive treatment sometimes trigger the symptoms. Patients with underlying cardiac conditions (heart failure, chronotropic insufficiency) often have an added cardiogenic compo­ nent to their OH. However, in the absence of triggers, many patients with mild OH remain asymptomatic, as cerebral autoregulation can compensate for mild swings in blood pressure and blood flow. Remark­ ably, in cases of chronic OH, particularly NOH, symptoms may remain quite mild in the face of significant blood pressure decrements. Many patients with chronic OH have indirect symptoms. Instead of lightheadedness and near fainting, they may report dizziness (usu­ ally feeling wobbly, falling, or rarely vertigo), wooziness, or orthostatic imbalance. They may report fatigue and tiredness. Some may complain of generalized weakness after prolonged standing or walking. Some report neck and shoulder discomfort (coat hanger syndrome) second­ ary to hypoperfusion of the cervical paraspinal and trapezius muscles. In others, orthostatic dyspnea, known as platypnea, develops second­ ary to hypoperfusion of the lung apex. Myocardial hypoperfusion may cause orthostatic angina. A few patients also report orthostatic headache that may be mistaken as low-pressure cerebrospinal fluid headache. OH can be classified into four functional classes. In functional class I, patients are asymptomatic but may show symptoms of OH including syncope and falls. In functional class II, symptoms occur weekly or monthly, with mild to moderate limitation of daily living. In functional class III, symptoms are more severe and frequent and markedly limit daily activities. In functional class IV, severe symptoms are daily, lead­ ing to significant disability. Other OH variants include initial, delayed, and postprandial OH. Initial OH is an exaggerated, abrupt decrease in blood pressure (>40 mmHg SBP and >20 mmHg DBP) within 15–30 s upon stand­ ing due to transient mismatch between cardiac output and systemic vascular resistance. This condition occurs almost exclusively in young subjects (adolescents and young adults) but may also occur in older patients treated with antihypertensive drugs. The magnitude of the initial OH is often less with tilt than it is with active standing. In delayed OH, SBP often remains steady for the first 3–5 min and then begins to decrease. In some cases, delayed OH does not appear until after 10 min of tilt. While the primary etiology in such cases may be secondary to medications, it often denotes some type of autonomic dysfunction, such as autonomic neuropathy. Postprandial OH is a blood pressure drop after eating. OH often appears within 2 h of a larger meal, particularly if there is a highcarbohydrate load or alcohol ingestion. In these conditions, the meal produces gastric and esophageal distension and an increase in the splanchnic blood volume. It is more frequent in elderly patients with underlying neurologic conditions, particularly autonomic disorders. These patients sometimes faint after getting up from the dining table. When OH is accompanied by baroreflex impairment, as seen with autonomic neuropathies or degenerative autonomic disorders, it can be associated with supine hypertension. In these patients, supine SBP during sleep may be higher than when they wake up in the morning, a pattern known as reverse dipping. Supine hypertension is a particular risk factor for end-organ damage (kidney, cardiac, or cerebrovas­ cular). Over time, affected individuals develop alterations in the renin-angiotensin-aldosterone axis, leading to worse daytime OH by inducing pressure diuresis and volume loss during sleep. Management  Management of OH includes nonpharmacologic and pharmacologic measures. Nonpharmacologic measures are essential and may be sufficient in earlier stage I OH. However, the physician needs to ascertain whether the patient is actually asymptomatic and safe. This begins by addressing possible identifiable confounders, such as medications interfering with cardiovascular reflexes (e.g., diuretics, antihypertensives, tricyclic antidepressants, antipsychotics, dopamine agonists). Comorbidities can include iron deficiency, vitamin B12 and D deficiencies, and frailty. Increasing fluid intake up to 3 L/d and salt intake to 2 g up to 3 times a day can expand plasma and blood volume and often improve orthostatic tolerance. It is important to monitor the patient’s weight and blood pressure on this regimen. In some patients, it would be reasonable to check the 24-h urine sodium before and after initiation of the fluid and salt load. Other simple remedies include lower limb stockings applied before getting out of bed. An abdominal binder is also quite effective in reducing the amount of splanchnic blood pooling. Physical countermaneuvers, such as crossing the legs while standing, are also helpful. It is also prudent to recommend elevat­ ing the head of bed by up to 30° to prevent the recurrence of supine hypertension and decrease nocturia. CHAPTER 451 Disorders of the Autonomic Nervous System Pharmacologic agents are quite effective. Fludrocortisone is a min­ eralocorticoid that expands the plasma volume, in addition to having a mild α-agonist effect. The dose is 0.1–0.2 mg/d (sometimes up to 0.4 mg/d) taken usually once in the morning. Because of its long duration of effect, it is important to monitor for supine hypertension. By increasing fluid retention, it can predispose to pedal edema, a low potassium level, headaches, and occasional mood changes. For older patients who require treatment for several years or longer, it is also prudent to check their bone density intermittently. Midodrine is a direct agonist of α1-adrenoceptors. It is prudent to start at a dose of 2.5 mg 3 times daily and increase gradually up to 15 mg 3 times daily. Most patients respond to 7.5–10 mg TID. The drug’s onset of action is between 30 and 60 min, and its effect lasts up to 4 h. A usual schedule is to take it before getting out of bed, before lunch, and in mid-to-late afternoon, with the last dose usually before 6:00 p.m. to avoid nocturia and supine hypertension. Side effects include scalp tingling and goosebumps because of its stimulatory effect on pilomo­ tor nerve fibers and urinary urgency because of its stimulatory effect at the bladder neck. Pyridostigmine, a drug commonly used in myasthenia gravis, acts as a cholinesterase inhibitor and increases ganglionic transmission. Patients may be sensitive to the drug, so it is practical to start with 30 mg TID and increase gradually to 60 mg TID. It potentiates the effect of midodrine. It may cause abdominal cramps and diarrhea in susceptible patients. It is particularly beneficial for autonomic patients with OH and slow gastrointestinal motility. It does not promote supine hypertension, an advantage for this drug. Atomoxetine is a norepinephrine reuptake inhibitor that is useful as an adjuvant therapy. Most patients benefit from 18 mg in the morn­ ing. While some patients may need it midday to early afternoon, it is important to monitor for symptoms and signs of CNS stimulation such as anxiety and tremor. Droxidopa is the newest agent approved for treatment of NOH. It is a norepinephrine precursor. Treatment should start with 100 mg TID and be gradually increased to 400–600 mg TID. The medication improved orthostatic symptoms and decreased falls in PD patients. Supine hypertension remains an issue in most patients. Desmopressin increases water reabsorption and reduces urination. Low-dose oral administration or nasal spray can be useful in reducing the frequency of nocturia that often interrupts sleep. Patients should be monitored for hyponatremia. When patients with OH or NOH develop supine hypertension, it is important to revise their medications, monitor end-organ function, ensure elevation of the head of bed during sleep (30–45°), and use short-acting blood pressure–lowering drugs at bedtime. ■ ■POSTURAL ORTHOSTATIC TACHYCARDIA SYNDROME POTS is a common syndrome of chronic (>3 months) OI without sustained OH, accompanied by an increase in HR of ≥30 beats/min in adults (≥40 beats/min if under the age of 19 years) or an orthostatic HR >120 beats/min within 10 min of standing that subsides on sit­ ting or lying down. The symptoms reflect a combination of cerebral hypoperfusion (lightheadedness, blurred vision, cognitive decline, and brain fog) and sympathetic activation (palpitations, chest pain, and tremulousness). Near-syncope is common, but complete syncope is less frequent. The condition is four to five times more common in women, and most develop the syndrome between the ages of 15 and 45 years. Symptoms may flare up around menstrual cycles. PART 13 Neurologic Disorders POTS is often multifactorial, as the pathophysiology is heteroge­ neous: distal sympathetic denervation in the feet and legs with pre­ served cardiovascular sympathetic function (so-called neuropathic POTS), venous pooling, reduced cardiac function due to decondition­ ing, hypovolemia, altered baroreceptor regulation, increased sympa­ thetic activity, and rarely reduced parasympathetic activity may play a role. About half the cases follow a viral illness. Most prominent among these are Epstein-Barr virus, coronavirus, and enteroviral illnesses. The condition has increased since the COVID-19 pandemic; it is the leading manifestation of long COVID. Other POTS triggers include surgery, the postpartum period, puberty, pregnancy, concussion, and chronic emotional distress. Ehlers-Danlos syndrome is a significant predisposing condition, present in up to 25% of patients. When symp­ toms of POTS are prominent, patients become sedentary, exacerbating their deconditioning and leading to a vicious cycle with prolongation of the syndrome. In the chronic state, cardiovascular deconditioning becomes the common pathway. POTS comorbidities include migraine and various headache dis­ orders, symptoms of gastrointestinal dysmotility, chronic fatigue, fibromyalgia, gastrointestinal and bladder visceral pain, and sleep disturbances. Some patients report temperature intolerance, more to heat than cold, with impaired sweating (either increased or decreased). Patients often appear anxious in the clinic and have a tendency to be hypervigilant with respect to somatic symptoms, but the incidence of significant psychiatric disorders does not differ from that in the general population. Some patients report a new onset of various allergic symp­ toms (flushing, hives, and environmental and food allergies) suggestive of some type of mast cell activation syndrome. While there is no standardized approach to the diagnosis, it is important to rule out primary cardiac causes, including arrhythmias (POTS is a sinus rhythm disorder), as well as endocrine conditions that lead to sympathetic activation, such as pheochromocytoma and hyperthyroidism. In addition to routine complete blood count and electrolyte panel, it is important also to measure ferritin and vitamin D levels and correct these if low, as this helps the condition respond better to other treatments. Management has some similarities to the management of OH. Typically, it encourages the expansion of fluid volume with water (8–10 cups daily) and salt (6–8 g/d). Elastic stockings, waist high with 20–30 mmHg counterpressure, reduce venous pooling and improve venous return. Pharmacotherapy with low-dose fludrocortisone can be helpful. When symptoms of sympathetic overactivity are prominent, low doses of a beta blocker, increased gradually, can be helpful. These patients can be sensitive to beta blockers, so it is important to measure their blood pressure while on treatment; if it decreases, they would need a higher dose of fludrocortisone or the addition of a vasoactive drug such as midodrine. The latter is particularly useful in patients with neuropathic POTS, as it counteracts the significant peripheral vasodilation that is present. In patients with gastrointestinal hypomo­ tility, low-dose pyridostigmine can be helpful and may improve the patient’s fatigue as well. When tachycardia proves refractory to the above measures, low-dose ivabradine can also be tried. A graduated program of exercise to improve cardiac deconditioning is essential and often needs at least 6 months before significant benefit is obtained. Because of the orthostatic nature of the condition, exercise is better tolerated in the supine or sitting position (recumbent bike, rowing, swimming) and should involve a combination of aerobic cardiovascu­ lar training and resistance training primarily to the leg muscles. If the patient’s symptoms and tolerance improve after 3 months, exercise in the upright position (treadmill, elliptical) can be gradually advanced. ■ ■SYNUCLEINOPATHIES This group of disorders is secondary to the accumulation of phos­ phorylated α-synuclein in various parts of the ANS. They include mul­ tiple system atrophy (MSA), Parkinson’s disease (PD; Chap. 446) with autonomic failure, Dementia with Lewy bodies (DLB; Chap. 445), and primary autonomic failure (PAF). Pathologically, there are aggregates of misfolded α-synuclein in the CNS and PNS. Cardiovascular auto­ nomic denervation is more common in PD and PAF, whereas it tends to occur later in MSA and DLB. PAF is a sporadic peripheral autonomic degenerative disease that has clinical manifestations similar to those in other autonomic neu­ ropathies, such as diabetic autonomic neuropathy, and the autoim­ mune autonomic neuropathies. NOH is the prominent clinical feature and frequently associated with supine hypertension. After 5–10 years, a significant number of PAF patients develop a CNS synucleinopathy, particularly PD or DLB but also MSA. In addition to the presence of autonomic dysfunction, skin punch biopsy with immunohistochem­ istry staining can demonstrate small nerve fibers and intraneural α-synuclein deposition. MSA, or Shy-Drager syndrome, is a disorder that combines auto­ nomic failure and either parkinsonism (MSA-P) or a cerebellar syn­ drome (MSA-C). MSA is uncommon, with a prevalence estimated at 2–5 per 100,000 individuals. Onset is typically in the mid-fifties, men are slightly more affected than women, and most cases are sporadic. MSA generally progresses relentlessly to death 7–10 years after onset, but some patients may survive beyond 10 years. MSA-C is more com­ mon in Asian population, particularly in Japan, while MSA-P is the more common form in the rest of the world, including Western coun­ tries. A characteristic of the extrapyramidal parkinsonian phenotype is the relatively poor response to levodopa; when a response occurs, it tends to be transient. Rigidity dominates, while rest tremor is not prominent. Other distinguishing features that favor MSA-P over idio­ pathic PD is the early impairment of urinary control in both genders, early erectile dysfunction in men, symptomatic OH within 2 years of onset, preserved olfaction, and a lower frequency of gastrointestinal symptomatology, especially colonic hypomotility and constipation. Early autonomic dysfunction, early bladder dysfunction, female gen­ der, and rapid progression of disability imply a worse prognosis. Brain magnetic resonance imaging (MRI) can show iron deposition in the striatum in MSA-P, and cerebellar atrophy with a characteristic T2 hyperintense signal (“hot cross bun” sign) in the pons in MSA-C (Fig. 451-6). However, the typical MRI findings may be present only with advanced disease. Cardiac postganglionic adrenergic innervation, measured by the uptake of meta-iodobenzylguanidine (MIBG) on a radionuclear scan or fluorodopamine on positron emission tomogra­ phy, is usually intact in MSA, whereas it is low in the dysautonomias of PD, LBD, and PAF. The neuropathology of MSA shows neuronal loss and gliosis in many CNS regions, including the brainstem, cerebellum, striatum, and intermediolateral cell column of the thoracolumbar spi­ nal cord. The characteristic pathologic feature is the presence of glial cytoplasmic inclusions that stain positively for α-synuclein (early Lewy bodies) primarily in oligodendrocytes, in contrast to their neuronal localization in PD or LBD. Research has shown some transfer of these cytoplasmic inclusions from cell to cell, akin to that of a prion (Chap. 449). FIGURE 451-6  Multiple system atrophy, cerebellar type (MSA-C). Axial T2-weighted and FLAIR (fluid-attenuated inversion recovery) magnetic resonance images at the level of the pons demonstrate a characteristic cruciform hyperintense signal in the pons, the “hot cross bun” sign. This appearance is characteristic but not pathognomonic of MSA-C, as it can also be seen in some spinocerebellar atrophies and other neurodegenerative conditions affecting the brainstem. The images additionally demonstrate atrophy of the pons, bilateral middle cerebellar peduncles, and cerebellum. (Courtesy of Dr. Nancy Fischbein, Stanford University School of Medicine.) Management is symptomatic for NOH (see earlier section on OH), sleep disorders including laryngeal stridor, and gastrointestinal and urinary dysfunction. Gastrointestinal symptoms can be managed with frequent small meals, a soft diet, stool softeners, and bulk agents. Per­ sistent significant gastric and colonic hypomotility requires the admin­ istration of the newer motility stimulation drugs, such as prucalopride, linaclotide, plecanatide, or lubiprostone. Metoclopramide stimulates gastric emptying but should be used only as a short-term measure, if at all, because it worsens parkinsonism by blocking central dopamine receptors. Domperidone, a peripheral dopamine (D2 and D3) receptor antagonist, is also effective but is not U.S. Food and Drug Adminis­ tration approved for use in the United States because of its potential arrhythmogenic risk. Pharmacologic management of neurogenic blad­ der relies usually on muscarinic blockers to reduce bladder urgency. Oxybutynin is often a first-line agent, but increasing the dose may cause other antimuscarinic side effect such as dry mouth, dry eyes, and anhidrosis. More selective blockers (tolterodine, darifenacin, or solif­ enacin) produced fewer systemic side effects. Mirabegron and vibegron are selective β3-adrenergic agonists that reduces detrusor overactivity and are quite effective. A potential beneficial side effect is their gentle hypertensive effect that may help with OH management but may also require adjusting doses of other OH medications to avoid significant supine hypertension. Autonomic dysfunction also occurs in DLB (Chap. 445) with the severity usually intermediate between that of MSA and PD. In multiple sclerosis (MS; Chap. 455), autonomic complications reflect the CNS location of MS lesions (more common with brainstem and spinal cord demyelination) and generally worsen with disease duration and disability but are generally less severe than with synucleinopathies. ■ ■SPINAL CORD DISORDERS Spinal cord lesions may cause focal autonomic deficits dominated by OH, bowel dysfunction, and genitourinary dysfunction, as well as temperature dysregulation secondary to anhidrosis below the level of CHAPTER 451 Disorders of the Autonomic Nervous System the lesion. Quadriparesis predisposes to supine hypertension and OH after upward tilting. Autonomic dysreflexia is a dramatic blood pressure increase that occurs in response to irritation of the bladder, skin, or muscles. It usually follows traumatic spinal cord lesions above the T6 level, as lesions below T6 allow for compensatory splanchnic vasodila­ tion and a lesser likelihood of autonomic dysreflexia. The condition sometimes interferes with patient care, particularly when patients require urinary catheterization for distended bladder or rectal manage­ ment for constipation and fecal impaction. In addition to blood pres­ sure surges that may induce intracranial vasospasm or hemorrhage, other symptoms include facial flushing, headache, hypertension, pilo­ erection, and even cardiac arrhythmia. Sitting the patient up reduces excessive supine hypertension. Prophylactic clonidine can reduce the hypertension resulting from bladder or rectal stimulation. Disorders of the spinal cord are discussed in Chap. 453. ■ ■PERIPHERAL NERVE AND NEUROMUSCULAR TRANSMISSION DISORDERS Peripheral autonomic neuropathies are the most common cause of autonomic insufficiency. These complex disorders can impact cardio­ vascular, gastrointestinal, urogenital, and sudomotor systems. They affect small myelinated and unmyelinated fibers of the sympathetic and parasympathetic nerves and commonly occur in diabetes mel­ litus, amyloidosis, chronic alcoholism, porphyria, idiopathic smallfiber polyneuropathy, and Guillain-Barré syndrome. Neuromuscular junction disorders with autonomic involvement include botulism and Lambert-Eaton myasthenic syndrome (Chaps. 457–459). Diabetes Mellitus  Diabetes mellitus remains one of the leading causes of peripheral autonomic neuropathy. The presence of autonomic neuropathy increases the mortality rate of diabetes up to threefold, even after adjusting for other cardiovascular risk factors. The neuropathy risk correlates with the product of the patient’s hemoglobin A1c values and the duration of the diabetes. Early autonomic impairment is most often manifest as cardiovascular parasympathetic hypofunction. As diabetes progresses, sympathetic hypofunction follows, dominated by OH. The autonomic involvement also predicts other complications including cor­ onary artery disease, renal disease, stroke, and sleep apnea. It also plays a significant role in the gastrointestinal dysmotility, which may further complicate glycemic control. Improved glycemic control significantly reduces the long-term risk of autonomic cardiovascular neuropathy. Diabetes mellitus is discussed in Chaps. 415–417. Amyloidosis  Amyloidosis, both acquired primary (AL) and hered­ itary transthyretin (hATTR) types, leads to autonomic neuropathy. Patients usually present with a distal sensorimotor polyneuropathy accompanied by autonomic insufficiency, but an autonomic neuropa­ thy in isolation may also occur. A history of carpal tunnel syndrome is common. Postmortem studies reveal amyloid deposition in many organs, including two sites that contribute to autonomic failure: intra­ neural blood vessels and autonomic ganglia. For AL amyloidosis, the diagnosis is made by blood tests showing monoclonal gammopathy and elevated free light chains (with lambda more often than kappa being the culprit). For hATTR, If genetic testing for TTR mutations is negative, confirmation usually requires histologic diagnosis (abdomi­ nal fat pad, rectal mucosa, nerve/muscle biopsy, or myocardial biopsy in cases with cardiomyopathy) to search for amyloid deposits. Genebased treatments (either RNA silencing or antisense oligonucleotides) are effective for hATTR amyloidosis. Treatment for AL amyloidosis usually relies on chemotherapeutic drugs. Death is usually due to cardiac or renal involvement. Amyloidosis is discussed in Chap. 117. PART 13 Neurologic Disorders Alcoholic Neuropathy  Abnormalities in parasympathetic vagal and efferent sympathetic function are usually mild in alcoholic poly­ neuropathy. OH is usually due to brainstem involvement, rather than injury to the PNS. Impotence is a common symptom, but concurrent gonadal hormone abnormalities may play a role in this symptom. Clinical symptoms of autonomic failure generally appear only when the stocking-glove polyneuropathy is severe, and there may be coex­ isting ataxia or Wernicke’s encephalopathy (Chap. 318). Autonomic involvement may contribute to the high mortality rates associated with alcoholism. Alcohol use disorders are discussed in Chap. 464. Porphyria  Autonomic dysfunction occurs only in the hepatic por­ phyrias. It is documented in acute intermittent porphyria, but may also occur with variegate porphyria and hereditary coproporphyria. Sym­ pathetic overactivity dominates the clinical presentation. Autonomic symptoms include tachycardia, sweating, urinary retention, abdomi­ nal pain, nausea and vomiting, insomnia, hypertension, and (less commonly) hypotension. Often, patients have psychiatric symptoms dominated by anxiety, but depression and bipolar-like presentations may occur. Abnormal autonomic function can occur both during acute attacks and during remissions. Elevated catecholamine levels during acute attacks correlate with the degree of tachycardia and hypertension that is present. Porphyria is discussed in Chap. 428. Guillain-Barré Syndrome (GBS)  GBS often causes autonomic instability, more often but not exclusively in more severe cases. Car­ diovascular dysautonomia can be life-threatening, and gastrointestinal autonomic involvement, abnormal sweating, and pupillary dysfunction may also occur. The dysautonomia is secondary to the demyelination of the vagus and glossopharyngeal nerves and the preganglionic sympathetic white rami communicantes. In some cases, autonomic involvement outweighs other manifestations of the motor or sensory neuropathy. Acute autonomic and sensory neuropathy is a variant that spares the motor system and presents with NOH and varying degrees of sensory loss. The treatment is similar to that for GBS (IV immuno­ globulin or plasma exchange), but the prognosis is less favorable, with persistent sensory deficits and variable degrees of OH present in many patients. GBS is discussed in Chap. 458. Autoimmune Autonomic Ganglionopathy (AAG)  AAG is a rare form of dysautonomia. Approximately 100 Americans are diag­ nosed each year. It affects people of both sexes and all ages, although it is more common in women and in adults. Other names for this condition are acute pandysautonomia, idiopathic subacute autonomic neuropathy, and autoimmune autonomic neuropathy. It is typically associated with high titers of autoantibodies against the α3 subunit of the ganglionic acetylcholine nicotinic receptor (g-AChR α3). AAG often follows a triggering event: infection, surgery, autoimmunity, or malignancy in most patients. This condition is important to recognize because it is a treatable disorder. Symptoms mimic those caused by ganglion-blocking drugs without neuromuscular block, depending upon on which ANS division predominates. Ocular involvement leads to mydriasis and cycloplegia with blurred vision. Bronchial involve­ ment leads to bronchodilation. Gastrointestinal involvement leads to reduced motility and secretion. Genitourinary involvement leads to urinary retention and impaired erection and ejaculation. Cardiac involvement leads to mild tachycardia. Vascular involvement reduces sympathetic tone and produces postural hypotension. Involvement of salivary and sweat glands leads to dry mouth and impaired sweat­ ing. Symptoms of autonomic failure occur in various combinations: syncope and OH; labile blood pressure; gastrointestinal hypomotility; bladder hypomotility; pupillary dysfunction with Adie’s tonic pupil (slow reaction to light, bitter reaction to accommodation, slow relax­ ation afterward); dry mouth and eyes; and anhidrosis. Optic neuritis has also been reported in smokers with positive g-AChR α3 antibodies. Some patients with higher titers of AAG have a paraneoplastic form of the disease associated with small cell lung carcinoma, thy­ moma, or lymphoma (Chap. 99). Therefore, it is prudent to search for malignancy in the initial workup of AAG. Although no large studies have evaluated the efficacy of various treatments in AAG, IV immu­ noglobulin or plasmapheresis is generally used as first-line therapy, with glucocorticoids, rituximab, or mycophenolate mofetil, alone or in combination, used for nonresponders. Symptomatic treatment is of utmost importance, with attention to OI, gastrointestinal dysmotility, and genitourinary disturbances. Nonpharmacologic treatments such as exercise, increasing salt and fluid intake, compression stockings, and good sleep habits can also help. Seronegative Autoimmune Autonomic Neuropathy (SAAN)  SAAN is likely a seronegative variant of AAG, as this con­ dition presents with subacute autonomic disturbances similar to AAG. Pathology shows preferential involvement of small unmyelinated nerve fibers, with sparing of larger myelinated ones. The neuropathy follows a viral infection in about half of cases. Several cases have been associ­ ated with use of checkpoint inhibitors. About one-third of untreated patients improve over time. Management is similar to that for AAG, although some patients may respond better to glucocorticoids as firstline therapy. Botulism  Botulinum toxin binds presynaptically to cholinergic nerve terminals and blocks ACh release. This condition presents with motor paralysis and signs of cholinergic failure that include blurred vision, sluggishly reactive pupils, dry mouth, dry skin, reduced gastric and colonic motility, and urinary retention (Chap. 138). Chronic Idiopathic Anhidrosis  Chronic idiopathic anhidrosis is a rare condition in which patients present with heat intolerance but preserved vasomotor function. There is no associated somatic neuropathy. Some patients may have Adie’s tonic pupils as well (Ross syndrome). Acknowledgment Richard J. Barohn and John W. Engstrom contributed to this chapter in the prior edition and material from that chapter has been retained here. ■ ■FURTHER READING Campbell WW, Baron RJ: The autonomic nervous system, in DeJong’s The Neurologic Examination, 8th ed. WW Campbell, RJ Barohn (eds). Philadelphia, Wolters Kluwer, 2020. Cheshire WP: Autonomic history, examination and laboratory evalu­ ation. Continuum (Minneap Minn) 26:25, 2020. Donadio V et al: Phosphorylated α-synuclein in skin Schwann cells: A new biomarker for multiple system atrophy. Brain 146:1065, 2023. # 22 - 452 Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders ### 452 Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders Fedorowski A, Sutton R: Autonomic dysfunction and postural orthostatic tachycardia syndrome in postacute Covid 19 syndrome. Nat Rev Cardiol 20:281, 2023. Gibbons C et al: Cutaneous α-synuclein alpha signatures in patients with multiple system atrophy and Parkinson disease. Neurology 100:e1529, 2023. Gibbons CH et al: Skin biopsy in evaluation of autonomic disorders. Continuum (Minneap Minn) 26:200, 2020. Jaradeh SS, Prieto TE: Evaluation of the autonomic nervous system. Phys Med Rehabil Clin N Am 14:287, 2003. Lamotte G, Sandroni P: Updates from the diagnosis and treatment of peripheral autonomic neuropathies. Curr Neurol Neurosci Rep 12:823, 2022. Vernino S: Autoimmune autonomic disorders. Continuum (Minneap Minn) 26:44, 2020. Vanja C. Douglas, Stephen L. Hauser Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders The cranial nerves consist of 12 paired nerves that mediate variable combinations of motor, sensory, and autonomic functions. They are considered as a group because of their close anatomic relationship to the brainstem (Fig. 452-1) and to one another, and tendency to be involved together in a variety of disease states. Nine cranial nerves connect directly with brainstem nuclei; the exceptions are cranial nerves 1 (olfactory) and 2 (optic) that are more accurately considered fiber tracts of the brain, and cranial nerve 11 (spinal accessory) whose motor neurons reside largely in the upper cervical cord. Analogous to spinal nerves (Chap. 453), motor fibers of the cranial nerves have their origin in the brainstem or upper cervical cord, while sensory nerves are pseudounipolar, with ganglia outside the central nervous system and a synapse with second-order fibers in the brainstem. Symptoms and signs of cranial nerve pathology are common in internal medicine. They may develop in the context of a widespread neurologic disturbance, and in such situations, cranial nerve involve­ ment may represent the initial manifestation of the illness. In other disorders, involvement is largely restricted to one or several cranial nerves; these distinctive disorders are reviewed in this chapter. Disor­ ders of olfaction are discussed in Chap. 35, vision and ocular move­ ment in Chap. 34, hearing in Chap. 36, and vestibular function in Chap. 24. FACIAL PAIN OR NUMBNESS ■ ■ANATOMIC CONSIDERATIONS The trigeminal (fifth cranial) nerve supplies sensation to the skin of the face, anterior half of the head, and the nasal and oral mucosa (Fig. 452-2). The motor part innervates the muscles involved in chewing (including masseter, temporalis, and pterygoids) as well as the anterior belly of the digastric, mylohyoid, tensor veli palatini, and the tensor tympani (hear­ ing especially for high-pitched tones). It is the largest of the cranial nerves. It exits in the lateral midpons and traverses the middle cranial fossa to the semilunar (gasserian, trigeminal) ganglion in Meckel’s cave, where the nerve splits into three divisions (ophthalmic [V1], maxillary [V2], and mandibular [V3]). V1 and V2 traverse the cavernous sinus to exit in the superior orbital fissure and foramen rotundum; V3 exits through the foramen ovale. The trigeminal nerve is predominantly Frontal lobe Olfactory bulb and peduncle Pituitary gland Cranial nerves Mamillary bodies X IX VIII VII VI V IV III II Temporal lobe CHAPTER 452 Trigeminal ganglion Cerebellopontine angle Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders Cerebellum XII XI FIGURE 452-1  Ventral view of the brain, illustrating relationships between the 12 pairs of cranial nerves and the brainstem. (Adapted from SG Waxman: Clinical Neuroanatomy, 29th ed. http://www.accessmedicine.com.) sensory, and motor innervation is exclusively carried in V3. The cor­ nea is primarily innervated by V1, although an inferior crescent may be V2. Upon entering the pons, pain and temperature fibers descend ipsilaterally as far as the upper cervical spinal cord as the spinal tract of V, before synapsing with the spinal nucleus of V; this accounts for the facial numbness that can occur with spinal cord lesions above C2. In the brainstem, the spinal tract of V is also located adjacent to crossed ascending fibers of the spinothalamic tract, producing a “crossed” sen­ sory loss for pain and temperature (ipsilateral face, contralateral arm/ trunk/leg) with lesions of the lateral lower brainstem. CN V is also ensheathed by oligodendrocyte-derived, rather than Schwann cell– derived, myelin for up to 7 mm after it leaves the brainstem, unlike just a few millimeters for other cranial and spinal nerves; this may explain some instances of trigeminal neuralgia in multiple sclerosis (MS) (Chap. 455), a disorder of oligodendrocyte myelin. ■ ■TRIGEMINAL NEURALGIA (TIC DOULOUREUX) Clinical Manifestations  Trigeminal neuralgia is characterized by excruciating paroxysms of pain in the lips, gums, cheek, or chin and, very rarely, in the distribution of the ophthalmic division of the fifth nerve. The pain seldom lasts more than a few seconds or a minute or two but may be so intense that the patient winces, hence the term tic. The paroxysms, experienced as single jabs or clusters, tend to recur frequently, both day and night, for several weeks at a time. They may occur spontaneously or be brought on with movements of affected areas by speaking, chewing, or smiling. Another characteristic feature is the presence of trigger zones, typically on the face, lips, or tongue, that provoke attacks; patients may report that tactile stimuli—e.g., washing the face, brushing the teeth, or exposure to a draft of air— generate excruciating pain. An essential feature of trigeminal neural­ gia is that objective signs of sensory loss cannot be demonstrated on examination. Trigeminal neuralgia is relatively common, with an estimated annual incidence of 4–8 per 100,000 individuals. Middle-aged and KEY Ophthalmic (V1) Maxillary (V2) Mandibular (V3) Supraorbital nerve Anterior ethmoidal nerve Posterior ethmoidal nerve PART 13 Neurologic Disorders Frontal branch of frontal nerve Supratrochlear nerve Infratrochlear nerve Internal nasal rami Infraorbital nerve External nasal rami a m l ri a c l a l i x L Ma Nasal and labial rami of infraorbital nerve Anterior superior alveolar nerves n l ua ng Li ol ve al or eri Submandibular ganglion Inf Submandibular and sublingual glands Mental nerve FIGURE 452-2  The trigeminal nerve and its branches and sensory distribution on the face. The three major sensory divisions of the trigeminal nerve consist of the ophthalmic, maxillary, and mandibular nerves. (Reproduced with permission from Waxman SG: Clinical Neuroanatomy, 26th ed. New York, McGraw-Hill, 2009.) elderly persons are affected primarily, and ~60% of cases occur in women. Onset is typically sudden, and bouts tend to persist for weeks or months before remitting spontaneously. Remissions may be longlasting, but in most patients, the disorder ultimately recurs. Pathophysiology  Symptoms result from ectopic generation of action potentials in pain-sensitive afferent fibers of the fifth cranial nerve root just before it enters the lateral surface of the pons. Com­ pression or other pathology in the nerve leads to demyelination of large myelinated fibers that do not themselves carry pain sensation but become hyperexcitable and electrically coupled with smaller unmy­ elinated or poorly myelinated pain fibers in close proximity; this may explain why tactile stimuli, conveyed via the large myelinated fibers, can stimulate paroxysms of pain. Compression of the trigeminal nerve root by a blood vessel, most often the superior cerebellar artery or on occasion a tortuous vein, is believed to be the source of trigeminal neu­ ralgia in most patients. In cases of vascular compression, age-related C2 C3 C4 Frontal nerve Mesencephalic nucleus of V Ophthalmic nerve Semilunar ganglion Main sensory nucleus of V Main motor nucleus of V Nucleus of spinal tract of V Mandibular nerve Anterior and posterior deep temporal nerves (to temporal muscles) y r Pterygopalatine ganglion Otic ganglion Auriculotemporal nerve e v er Lateral pterygoid muscle Chorda tympani nerve e v er n ar Buccinator nerve Medial pterygoid muscle Masseter muscle Mylohyoid nerve Anterior belly of digastric muscle brain sagging and increased vascular thickness and tortuosity may explain the prevalence of trigeminal neuralgia in later life. Differential Diagnosis  Trigeminal neuralgia must be distin­ guished from other causes of face and head pain (Chap. 17) and from pain arising from diseases of the jaw, teeth, or sinuses. Pain from migraine or cluster headache tends to be deep-seated and steady, unlike the superficial stabbing quality of trigeminal neuralgia; rarely, cluster headache is associated with trigeminal neuralgia, a syndrome known as cluster-tic. Other rare, paroxysmal headache disorders such as short-lasting unilateral headache attacks with conjunctival injec­ tion and tearing, short-lasting unilateral headache attacks with cranial autonomic symptoms, and paroxysmal hemicrania (Chap. 441) are distinguished by the frequency and duration of attacks and associated autonomic symptoms. In temporal arteritis, superficial facial pain is present but is not typically shocklike, the patient frequently complains of myalgias and other systemic symptoms, and an elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) is usually present (Chap. 375). When trigeminal neuralgia develops in a young adult or is bilateral, MS is a key consideration, and in such cases, the cause is often a demyelinating plaque near the root entry zone of the fifth nerve in the pons, especially when there is evidence of superimposed facial sensory loss, which can be subtle. Cases that are secondary to mass lesions—such as aneurysms, neurofibromas, acoustic schwannomas, or meningiomas—usually produce objective signs of sensory loss in the trigeminal nerve distribution (trigeminal neuropathy, see below). Laboratory Evaluation  An ESR or CRP is indicated if temporal arteritis is suspected. Neuroimaging studies are often necessary to exclude secondary causes and help assess overlying vascular lesions in order to plan for decompression surgery. TREATMENT Trigeminal Neuralgia Drug therapy with carbamazepine is effective in ~50–75% of patients. Carbamazepine should be started as a single daily dose of 100 mg taken with food and increased gradually (by 100 mg daily in divided doses every 1–2 days) until substantial (>50%) pain relief is achieved. Most patients require a maintenance dose of 200 mg four times daily. Doses >1200 mg daily provide no additional benefit. Dizziness, imbalance, sedation, and rare cases of agranulocytosis are the most important side effects of carbamazepine. If treatment is effective, it is usually continued for 1 month and then tapered as tolerated. Oxcarbazepine (300–1200 mg bid) is an alternative to carbamazepine that has less bone marrow toxicity and probably is equally efficacious. If these agents are not well tolerated or are inef­ fective, phenytoin (300–400 mg daily) is another option. Lamotrigine (400 mg daily), baclofen (10–20 mg tid), or topiramate (50 mg bid) may also be tried. Gabapentin, up to 3600 mg daily in divided doses, may occasionally provide relief. If drug treatment fails, surgical therapy should be offered. The most widely used method is currently microvascular decompres­ sion to relieve pressure on the trigeminal nerve as it exits the pons. This procedure requires a suboccipital craniotomy. This proce­ dure appears to have a >70% efficacy rate and a low rate of pain recurrence in responders; the response is better for classic ticlike symptoms than for nonlancinating facial pains. High-resolution magnetic resonance angiography is useful preoperatively to visual­ ize the relationships between the fifth cranial nerve root and nearby blood vessels. Gamma knife radiosurgery of the trigeminal nerve root is also used for treatment and results in complete pain relief, sometimes delayed in onset, in approximately one-half of patients and a low risk of persistent facial numbness; the response is sometimes longlasting, but recurrent pain develops over 2–3 years in one-third of patients. Compared with surgical decompression, gamma knife surgery appears to be somewhat less effective but has few serious complications. Another procedure, radiofrequency thermal rhizotomy, creates a heat lesion of the trigeminal ganglion or nerve. Short-term relief is experienced by >95% of patients; long-term studies indicate that pain recurs in up to one-third of treated patients. Postoperatively, partial numbness of the face is common, masseter (jaw) weakness may occur especially following bilateral procedures, and corneal denervation with secondary keratitis can follow rhizotomy for firstdivision trigeminal neuralgia. Percutaneous balloon compression of the trigeminal ganglion is an alternative approach performed under general anesthesia that results in similar rates of short- and longterm pain relief and is also commonly complicated by ipsilateral facial numbness. ■ ■TRIGEMINAL NEUROPATHY A variety of diseases can affect the trigeminal nerve (Table 452-1). Most present with sensory loss on the face or with weakness of the jaw TABLE 452-1  Trigeminal Nerve Disorders Nuclear (Brainstem) Lesions Multiple sclerosis Stroke Syringobulbia Glioma Lymphoma Preganglionic Lesions Acoustic neuroma Meningioma Metastasis Chronic meningitis Cavernous carotid aneurysm Semilunar Ganglion Lesions CHAPTER 452 Trigeminal neuroma Herpes zoster Infection (spread from otitis media or mastoiditis) Cavernous Sinus Lesions (see Table 452-2) Peripheral Nerve Lesions Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders Tumor (e.g., nasopharyngeal carcinoma, squamous cell carcinoma, lymphoma) Trauma Guillain-Barré syndrome Sjögren’s syndrome Collagen-vascular diseases Sarcoidosis Leprosy Drugs (stilbamidine, trichloroethylene) Idiopathic trigeminal neuropathy muscles. Deviation of the jaw on opening indicates weakness of the pterygoids on the side to which the jaw deviates. Some cases are due to Sjögren’s syndrome or a collagen-vascular disease such as systemic lupus erythematosus, scleroderma, or mixed connective tissue disease. Among infectious causes, herpes zoster (acute or postherpetic) and lep­ rosy should be considered. Tumors of the middle cranial fossa (menin­ giomas), of the trigeminal nerve (schwannomas), or of the base of the skull (metastatic tumors) may cause a combination of motor and sen­ sory signs. Lesions in the cavernous sinus can affect the first and sec­ ond divisions of the trigeminal nerve, and lesions of the superior orbital fissure can affect the first (ophthalmic) division; the accompanying corneal anesthesia increases the risk of ulceration (neurokeratitis). Isolated sensory loss over the chin (mental neuropathy) can be the only manifestation of systemic malignancy. Rarely, an idiopathic form of trigeminal neuropathy is observed. It is characterized by numb­ ness and paresthesias, sometimes bilaterally, with loss of sensation in the territory of the trigeminal nerve but without weakness of the jaw. Gradual recovery is the rule. Tonic spasm of the masticatory muscles, known as trismus, is symptomatic of tetanus (Chap. 157) or may occur in patients treated with phenothiazines. FACIAL WEAKNESS ■ ■ANATOMIC CONSIDERATIONS (Fig. 452-3) The seventh cranial nerve supplies all the muscles con­ cerned with facial expression, as well as the stapedius, stylohyoid, and posterior belly of the digastric. The sensory and parasympathetic com­ ponents (the nervus intermedius) convey taste sensation from the ante­ rior two-thirds of the tongue, cutaneous impulses from the anterior wall of the external auditory canal, and preganglionic parasympathetic signals to the pterygopalatine and submandibular ganglia, stimulat­ ing lacrimation, rhinorrhea, and salivation. The cell bodies of pseu­ dounipolar sensory neurons lie in the geniculate ganglion. The motor nucleus of the seventh nerve lies anterior and lateral to the abducens nucleus. After leaving the pons, the seventh nerve enters the internal auditory meatus with the acoustic nerve. The nerve continues its course Superior salivatory nucleus Geniculate ganglion Trigeminal ganglion Motor nucleus VI n. V n. Motor nucleus VII n. Nucleus fasciculus solitarius C VII n. B A PART 13 Neurologic Disorders Fasciculus solitarius Chorda tympani Lingual nerve Submandibular gland Submandibular ganglion FIGURE 452-3  The facial nerve. A, B, and C denote lesions of the facial nerve at the stylomastoid foramen, distal and proximal to the geniculate ganglion, respectively. Green lines indicate the parasympathetic fibers, red line indicates motor fibers, and purple lines indicate visceral afferent fibers (taste). (Reproduced with permission from MB Carpenter: Core Text of Neuroanatomy, 2nd ed. Williams & Wilkins, 1978.) in its own bony channel, the facial canal, and exits from the skull via the stylomastoid foramen. It then passes through the parotid gland and subdivides to supply the facial muscles. A complete interruption of the facial nerve at the stylomastoid fora­ men paralyzes all muscles of facial expression. The corner of the mouth droops, the creases and skinfolds are effaced, the forehead is unfur­ rowed, and the eyelids will not close. Upon attempted closure of the lids, the eye on the paralyzed side rolls upward (Bell’s phenomenon). The lower lid sags and falls away from the conjunctiva, permitting tears to spill over the cheek. Food collects between the teeth and lips, and saliva may dribble from the corner of the mouth. The patient com­ plains of a heaviness or numbness in the face, but sensory loss is rarely demonstrable and taste is intact. If the lesion is in the middle-ear portion, taste is lost over the ante­ rior two-thirds of the tongue on the same side. If the nerve to the sta­ pedius is interrupted, there is hyperacusis (sensitivity to loud sounds). Lesions in the internal auditory meatus may affect the adjacent audi­ tory and vestibular nerves, causing deafness, tinnitus, or dizziness. Intrapontine lesions that paralyze the face usually affect the abducens nucleus as well, and often the corticospinal and sensory tracts. If the peripheral facial paralysis has existed for some time and recov­ ery of motor function is incomplete, a continuous diffuse contraction of facial muscles may appear. The palpebral fissure becomes narrowed, and the nasolabial fold deepens. Facial spasms, initiated by movements of the face, may develop (hemifacial spasm). Anomalous regeneration of seventh nerve fibers may result in other troublesome phenomena. If fibers originally connected with the orbicularis oculi come to innervate the orbicularis oris, closure of the lids may cause a retraction of the mouth (synkinesis), or if parasympathetic fibers originally connected with salivary glands later innervate the lacrimal gland, anomalous tear­ ing (“crocodile tears”) may occur with eating. Another facial synkinesia is triggered by jaw opening, causing closure of the eyelids on the side of the facial palsy (jaw-winking). ■ ■BELL’S PALSY The most common form of facial paralysis is Bell’s palsy. The annual incidence of this idiopathic disorder is ~25 per 100,000 annually, or Major superficial petrosal nerve Lacrimal gland Pterygopalatine ganglion To nasal and palatine glands Sublingual gland about 1 in 60 persons in a lifetime. Risk factors include pregnancy and diabetes mellitus. Clinical Manifestations  The onset of Bell’s palsy is fairly abrupt, with maximal weakness being attained by 48 h as a general rule. Pain behind the ear may precede the paralysis for a day or two. Taste sensa­ tion may be lost unilaterally, and hyperacusis may be present. In some cases, there is mild cerebrospinal fluid lymphocytosis. MRI may reveal swelling and uniform enhancement of the geniculate ganglion and facial nerve and, in some cases, entrapment of the swollen nerve in the temporal bone. Approximately 80% of patients recover within a few weeks or months. Electromyography may be of some prognostic value; evidence of denervation after 10 days indicates there has been axonal degeneration, that there will be a long delay (3 months as a rule) before regeneration occurs, and that it may be incomplete. The presence of incomplete paralysis in the first week is the most favorable prognostic sign. Recurrences are reported in ~7% of cases. Pathophysiology  In acute Bell’s palsy, there is inflammation of the facial nerve with mononuclear cells, consistent with an infectious or immune cause. Herpes simplex virus (HSV) type 1 DNA was fre­ quently detected in endoneurial fluid and posterior auricular muscle, suggesting that a reactivation of this virus in the geniculate ganglion may be responsible for most cases. Reactivation of varicella-zoster virus is associated with Bell’s palsy in up to one-third of cases and may represent the second most frequent cause. A variety of other viruses including SARS-CoV-2 have also been implicated less commonly, and Bell’s palsy can be observed in the setting of human immunodeficiency virus (HIV) seroconversion. Differential Diagnosis  There are many other causes of acute facial palsy that must be considered in the differential diagnosis of Bell’s palsy. Lyme disease can cause unilateral or bilateral facial palsies; in endemic areas, ≥10% of cases of facial palsy are likely due to infection with Borrelia burgdorferi (Chap. 191). Ramsay Hunt syndrome, caused by reactivation of herpes zoster in the geniculate ganglion, consists of a severe facial palsy associated with a vesicular eruption in the external auditory canal and sometimes in the pharynx and other parts of the A B FIGURE 452-4  Axial and coronal T1-weighted images after gadolinium with fat suppression demonstrate diffuse smooth linear enhancement of the left facial nerve, involving the genu, tympanic, and mastoid segments within the temporal bone (arrows), without evidence of mass lesion. Although highly suggestive of Bell’s palsy, similar findings may be seen with other etiologies such as Lyme disease, sarcoidosis, and perineural malignant spread. cranial integument; often the eighth cranial nerve is affected as well. Facial palsy that is often bilateral occurs in sarcoidosis (Chap. 379) and in Guillain-Barré syndrome (Chap. 458). Leprosy frequently involves the facial nerve, and facial neuropathy may also occur in diabetes mel­ litus, connective tissue diseases including Sjögren’s syndrome, and amy­ loidosis. The rare Melkersson-Rosenthal syndrome consists of recurrent facial paralysis; recurrent—and eventually permanent—facial (particu­ larly labial) edema; and, less constantly, plication of the tongue. Its cause is unknown. Acoustic neuromas frequently involve the facial nerve by local compression. Infarcts, demyelinating lesions of MS, and tumors are common pontine lesions that interrupt the facial nerve fibers; other signs of brainstem involvement are usually present. Tumors that invade the temporal bone (carotid body, cholesteatoma, dermoid) may produce a facial palsy, but the onset is insidious and the course progressive. Facial palsy after temporal bone fracture can present acutely or after a delay of several days; blunt head injury without temporal bone fracture may also trigger facial palsy. All these forms of nuclear or peripheral facial palsy must be dis­ tinguished from the supranuclear type. In the latter, the frontalis and orbicularis oculi muscles of the forehead are involved less than those of the lower part of the face, since the upper facial muscles are inner­ vated by corticobulbar pathways from both motor cortices, whereas the lower facial muscles are innervated only by the opposite hemisphere. In supranuclear lesions, there may be a dissociation of emotional and voluntary facial movements, and often some degree of paralysis of the arm and leg or an aphasia (in dominant-hemisphere lesions) is present. Laboratory Evaluation  The diagnosis of Bell’s palsy can usually be made clinically in patients with (1) a typical presentation, (2) no risk factors or preexisting symptoms for other causes of facial paralysis, (3) absence of cutaneous lesions of herpes zoster in the external ear canal, and (4) a normal neurologic examination apart from the facial nerve. Particular attention to the eighth cranial nerve, which courses near to the facial nerve in the pontomedullary junction and in the temporal bone, and to other cranial nerves is essential. In atypical or uncertain cases, an ESR or CRP, testing for diabetes mellitus, a Lyme titer, HIV serologies, angiotensin-converting enzyme and chest imaging studies for possible sarcoidosis, a lumbar puncture for possible Guillain-Barré syndrome, or MRI scanning may be indicated. MRI often shows swelling and enhancement of the facial nerve in idiopathic Bell’s palsy (Fig. 452-4). TREATMENT Bell’s Palsy Symptomatic measures include (1) the use of paper tape to depress the upper eyelid during sleep and prevent corneal drying, (2) arti­ ficial tears, and (3) massage of the weakened muscles. A course of glucocorticoids, given as prednisone 60–80 mg daily during the first CHAPTER 452 5 days and then tapered over the next 5 days, modestly shortens recovery and improves the functional outcome. Although large and well-controlled randomized trials found no added benefit of the antiviral agents valacyclovir (1000 mg daily for 5–7 days) or acyclovir (400 mg five times daily for 10 days) compared to gluco­ corticoids alone, either of these agents should be used if vesicular lesions are observed in the palate or external auditor canal. For patients with permanent paralysis from Bell’s palsy, a number of cosmetic surgical procedures have been used to restore a relatively symmetric appearance to the face. Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders ■ ■OTHER MOTOR DISORDERS OF THE FACE Hemifacial spasm consists of painless irregular involuntary contrac­ tions on one side of the face. Most cases appear related to vascular compression of the exiting facial nerve in the pons. Other cases develop as a sequela to Bell’s palsy or are secondary to compression and/or demyelination of the nerve by tumor, infection, or MS. Local injec­ tions of botulinum toxin into affected muscles can relieve spasms for 3–4 months, and the injections can be repeated. Refractory cases due to vascular compression usually respond to surgical decompression of the facial nerve. Anecdotal reports describe success using carbamaze­ pine, gabapentin, or baclofen. Blepharospasm is an involuntary recur­ rent spasm of both eyelids that usually occurs in elderly persons as an isolated phenomenon or with varying degrees of spasm of other facial muscles. Severe, persistent cases of blepharospasm can be treated by local injection of botulinum toxin into the orbicularis oculi. Clonaz­ epam, baclofen, and trihexyphenidyl have also been used to treat this disorder. Facial myokymia refers to a fine rippling activity of the facial muscles; it may be caused by MS or follow Guillain-Barré syndrome (Chap. 458). OTHER CRANIAL NERVE DISORDERS ■ ■GLOSSOPHARYNGEAL NEURALGIA The ninth cranial (glossopharyngeal) nerve (Fig. 452-5) conveys somatic sensation from the pharynx, middle ear, tympanic membrane, eustachian tube, and posterior third of the tongue to the spinal trigemi­ nal nucleus. It also relays taste from the posterior third of the tongue and information about blood pressure from baroreceptors in the carotid sinus to the nucleus solitarius, which also serves as the sensory nucleus for the vagus nerve. Motor function originates in the nucleus ambiguus and is limited to the stylopharyngeus muscle. Parasympa­ thetic fibers from the medullary inferior salivatory nucleus synapse in the otic ganglion with postganglionic fibers that innervate the parotid gland. Glossopharyngeal neuralgia resembles trigeminal neuralgia in many respects but is much less common. Sometimes it involves por­ tions of the tenth (vagus) nerve. The pain is intense and paroxysmal; it originates on one side of the throat, approximately in the tonsillar fossa. Inferior salivatory nucleus (parasympathetic) Petrous portion of temporal bone Ambiguus nucleus (motor) Nucleus of solitary tract (sensory) Superior or jugular ganglion Jugular foramen VII Petrous ganglion PART 13 Neurologic Disorders Communication with auricular branch of X Nodose ganglion X Superior cervical sympathetic ganglion Carotid body Sinus nerve Carotid sinus and nerve plexus Common carotid artery Sensory branches to soft palate, fauces, and tonsils Sympathetic root (vasomotor) IX (Sensory) Vagal root (motor and sensory) Pharyngeal plexus To muscles and mucous membrane of the pharynx and soft palate Taste and sensation to posterior third of tongue FIGURE 452-5  The ninth cranial (glossopharyngeal) nerve. FO, foramen ovale; FR, foramen rotundum; TP, tympanum plexus. (Reproduced with permission from SG Waxman: Clinical Neuroanatomy, 29th ed. New York, McGraw Hill, 2020.) In some cases, the pain is localized in the ear or may radiate from the throat to the ear because of involvement of the tympanic branch of the glossopharyngeal nerve. Spasms of pain may be initiated by swallowing or coughing. There is no demonstrable motor or sensory deficit. Cardiac symptoms—bradycardia or asystole, hypotension, and fainting— have been reported. Glossopharyngeal neuralgia can result from vascu­ lar compression, MS, or tumors, but many cases are idiopathic. Medical therapy is similar to that for trigeminal neuralgia, and carbamazepine is generally the first choice. If drug therapy is unsuccessful, surgical procedures—including microvascular decompression if vascular com­ pression is evident—or rhizotomy of glossopharyngeal and vagal fibers in the jugular bulb is frequently successful. ■ ■DYSPHAGIA AND DYSPHONIA The tenth cranial (vagus) nerve (Fig. 452-6) carries somatic sen­ sation from the posterior aspect of the external auditory canal, Geniculotympanic nerve Pterygopalatine ganglion Great petrosal nerve Nerve of the pterygoid canal Facial nerve Otic ganglion Parotid gland FO Small petrosal nerve FR TP Auditory tube (eustachian) Deep petrosal nerve (sympathetic) Tympanic nerve (of jacobson) to tympanic plexus Internal carotid artery Tympanic nerve (of jacobson) to tympanic plexus Parasympathetic nerves Styloglossus muscle Sensory nerves Communication with facial nerve Motor nerves Sympathetic nerves Stylopharyngeal muscle Tonsils laryngopharynx, superior larynx, and meninges of the posterior fossa to the spinal trigeminal nucleus, as well as taste from the epiglottis and pharynx and visceral sensation from chemoreceptors and barorecep­ tors in the aortic arch, heart, and gastrointestinal tract to the splenic flexure to the nucleus solitarius. The motor part originates in the nucleus ambiguous and innervates most muscles of the oropharynx and soft palate as well as all laryngeal muscles. Parasympathetic fibers originate in the dorsal motor nucleus of the vagus nerve and decrease the heart rate through action at the sinoatrial and atrioventricular nodes; others promote peristalsis and secretion of the alimentary tract from the esophagus to the splenic flexure. When the intracranial por­ tion of one vagus (tenth cranial) nerve is interrupted, the soft palate droops ipsilaterally and does not rise in phonation. There is loss of the gag reflex on the affected side, as well as of the “curtain movement” of the lateral wall of the pharynx, whereby the faucial pillars move medi­ ally as the palate rises in saying “ah.” The voice is hoarse and slightly Nucleus of solitary tract Nucleus of spinal tract of V Dorsal motor nucleus of vagus Ambiguus nucleus XI C1 Spinal roots of accessory nerve Superior laryngeal nerve Sternocleidomastoid muscle C5 Trapezius muscle Arytenoid, thyroarytenoid, and cricoarytenoid muscles Esophagus Glottis Right subclavian artery Cardiac nerves Cardiac plexus Pulmonary plexus Esophageal plexus Celiac plexus Liver Gallbladder Right kidney Small intestine FIGURE 452-6  The vagus nerve. J, jugular (superior) ganglion; N, nodose (inferior) ganglion. (Reproduced with permission from SG Waxman: Clinical Neuroanatomy, 29th ed. New York, McGraw Hill, 2020.) nasal, and the vocal cord lies immobile midway between abduction and adduction. Loss of sensation at the external auditory meatus and the posterior pinna may also be present. The vagus nerve may be involved at the meningeal level by neo­ plastic and infectious processes and within the medulla by tumors, vascular lesions (e.g., the lateral medullary syndrome), and motor neuron disease. The nerve may be involved by infection with varicellazoster virus. Injury to the vagus nerve in the carotid sheath can occur with carotid dissection or following endarterectomy. The pharyngeal branches of both vagal nerves may be affected in diphtheria; the voice has a nasal quality, and regurgitation of liquids through the nose occurs during swallowing. Polymyositis and dermatomyositis, which cause hoarseness and dysphagia by direct involvement of laryngeal and pha­ ryngeal muscles, may be confused with diseases of the vagus nerves. Dysphagia is also a symptom in some patients with myotonic dystro­ phy. Nonneurologic causes of dysphagia are discussed in Chap. 47. Meningeal branch to posterior fossa Auricular branch to posterior auricle and part of external meatus VII IX X J Muscles to palate and pharynx N Sensation to lower pharynx CHAPTER 452 Epiglottic and lingual rami Inferior pharyngeal constrictor Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders Cricothyroid muscle Right recurrent laryngeal nerve Left recurrent laryngeal nerve Left vagus nerve Aortic arch Diaphragm Stomach Spleen Pancreas Left kidney Sensory nerves Parasympathetic nerves Motor nerves The recurrent laryngeal nerves, especially the left, are most often damaged as a result of intrathoracic disease. Aneurysm of the aortic arch, an enlarged left atrium, and tumors of the mediastinum and bronchi are much more frequent causes of an isolated vocal cord palsy than are intracranial disorders. However, a substantial number of cases of recurrent laryngeal palsy remain idiopathic. When confronted with a case of laryngeal palsy, the physician must attempt to determine the site of the lesion. If it is intramedullary, there are usually other signs, such as ipsilateral cerebellar dysfunction, loss of pain and temperature sensation over the ipsilateral face and contra­ lateral arm and leg, and an ipsilateral Horner’s syndrome. If the lesion is extramedullary, the glossopharyngeal and spinal accessory nerves are frequently involved (jugular foramen syndrome). If it is extracranial in the posterior laterocondylar or retroparotid space, there may be a combination of ninth, tenth, eleventh, and twelfth cranial nerve palsies and Horner’s syndrome (Table 452-2). If there is no sensory loss over TABLE 452-2  Cranial Nerve Syndromes SITE CRANIAL NERVES USUAL CAUSE Orbital apex II, III, IV, first division V, VI Invasive fungal infections, amyloidosis, granulomatous disease Sphenoid fissure (superior orbital) III, IV, first division V, VI Invasive tumors of sphenoid bone; aneurysms Lateral wall of cavernous sinus III, IV, first division V, VI, often with proptosis Infection, thrombosis, aneurysm or fistula of cavernous sinus; invasive tumors from sinuses and sella turcica; benign granuloma responsive to glucocorticoids Retrosphenoid space II, III, IV, V, VI Large tumors of middle cranial fossa Apex of petrous bone V, VI Petrositis; tumors of petrous bone Internal auditory meatus VII, VIII Tumors of petrous bone (dermoids, etc.); infectious processes; acoustic neuroma PART 13 Neurologic Disorders Pontocerebellar angle V, VI, VII, VIII, and sometimes IX Acoustic neuroma; meningioma Jugular foramen IX, X, XI Tumors and aneurysms Posterior laterocondylar space IX, X, XI, XII Tumors of parotid gland and carotid body and metastatic tumors Posterior retroparotid space IX, X, XI, XII, and Horner’s syndrome Tumors of parotid gland, carotid body, lymph nodes; metastatic tumor; tuberculous adenitis the palate and pharynx and no palatal weakness or dysphagia, the lesion is below the origin of the pharyngeal branches, which leave the vagus nerve high in the cervical region; the usual site of disease is then the mediastinum. ■ ■NECK WEAKNESS The eleventh cranial nerve (spinal accessory) is a pure motor nerve arising from the nucleus ambiguus and the ventral horn of the spinal cord from C1–C6. The nerve travels superiorly through the fora­ men magnum and exits through the jugular foramen to innervate the ipsilateral sternocleidomastoid and trapezius muscles. Isolated involvement of the accessory (eleventh cranial) nerve can occur any­ where along its route, resulting in partial or complete paralysis of the sternocleidomastoid and trapezius muscles. Spinal accessory nerve palsy does not result in significant neck weakness because several other muscles also turn the head and flex the neck; therefore, detection of accessory nerve injury relies on palpating the absence of sternoclei­ domastoid contraction during head turning. Similarly, shoulder shrug is only slightly impacted by trapezius weakness, although the affected shoulder is lower at rest, scapular winging occurs, and the arm cannot abduct beyond 90°. Isolated spinal accessory nerve palsy is often iat­ rogenic due to neck surgery or jugular vein cannulation, or traumatic. An idiopathic form of accessory neuropathy, akin to Bell’s palsy, has been described, and it may be recurrent in some cases. Most but not all patients recover. ■ ■TONGUE PARALYSIS The twelfth cranial nerve (hypoglossal) supplies the ipsilateral muscles of the tongue. Nerve lesions cause the tongue to deviate toward the ipsilateral side during protrusion due to ipsilateral genioglossus weak­ ness, in addition to weakness of tongue movements toward the affected side to weakness of ipsilateral intrinsic tongue musculature. Atrophy and fasciculations of the tongue develop weeks to months after inter­ ruption of the nerve. The nucleus of the nerve or its fibers of exit may be involved by intramedullary lesions such as tumor, poliomyelitis, or most often motor neuron disease. Lesions of the basal meninges and the occipital bones (platybasia, invagination of occipital condyles, Paget’s disease) may compress the nerve in its extramedullary course or as it exits the skull in the hypoglossal canal. Isolated lesions of unknown cause can occur. MULTIPLE CRANIAL NERVE PALSIES When multiple cranial nerves are affected by a disease process, the clinical approach begins by determining whether the pathology lies within or outside of the brainstem. Lesions that lie on the surface of the brainstem are characterized by involvement of adjacent cranial nerves (often occurring in succession) and late and rather slight involvement of the long sensory and motor pathways and segmental structures lying within the brainstem. The opposite is true of primary lesions within the brainstem. Extramedullary lesions are more likely to cause bone erosion or enlargement of the foramens of exit of cranial nerves. By contrast, intramedullary lesions involving cranial nerves often produce a crossed sensory or motor paralysis (cranial nerve signs on one side of the body and tract signs on the opposite side). Involvement of multiple cranial nerves outside the brainstem is frequently the result of trauma, localized infections including varicellazoster virus, infectious and noninfectious (especially carcinomatous) causes of meningitis (Chaps. 143 and 144), granulomatous diseases such as granulomatosis with polyangiitis (Chap. 375), Behçet’s dis­ ease (Chap. 376), vascular disorders including those associated with diabetes, enlarging aneurysms, or locally infiltrating tumors. Among the tumors, nasopharyngeal cancers, lymphomas, neurofibromas, meningiomas, chordomas, cholesteatomas, carcinomas, and sarcomas have all been observed to involve a succession of lower cranial nerves. Owing to their anatomic relationships, the multiple cranial nerve palsies form a number of distinctive syndromes, listed in Table 452-2. Sarcoidosis (Chap. 379) is the cause of some cases of multiple cranial neuropathy; tuberculosis, the Chiari malformation, platybasia, and basilar invagination of the skull are additional causes. Cavernous sinus syndrome (Fig. 452-7) is a distinctive and fre­ quently life-threatening disorder. It often presents as orbital or facial pain; orbital swelling, chemosis due to occlusion of the ophthalmic veins; fever; oculomotor neuropathy affecting the third, fourth, and sixth cranial nerves; and trigeminal neuropathy affecting the ophthal­ mic (V1) and occasionally the maxillary (V2) divisions of the trigemi­ nal nerve. Cavernous sinus thrombosis, often secondary to infection from orbital cellulitis (frequently Staphylococcus aureus), a cutaneous source on the face, or sinusitis (especially with mucormycosis in diabetic patients), is the most frequent cause; other etiologies include aneurysm of the carotid artery, a carotid-cavernous fistula (orbital bruit may be present), meningioma, nasopharyngeal carcinoma, other tumors, or an idiopathic granulomatous disorder (Tolosa-Hunt syn­ drome, discussed below). The two cavernous sinuses directly commu­ nicate via intercavernous channels; thus, involvement on one side may extend to become bilateral. Early diagnosis is essential, especially when due to infection, and treatment depends on the underlying etiology. Ant. cerebral a. Int. carotid a. Ant. clinoid process Subarachnoid space Optic chiasm Oculomotor (III) n. Trochlear (IV) n. Hypophysis Ophthalmic (V1) n. Maxillary (V2) n. Sphenoid sinus Pia Arachnoid Dura Abducens (VI) n. FIGURE 452-7  Anatomy of the cavernous sinus in coronal section, illustrating the location of the cranial nerves in relation to the vascular sinus, internal carotid artery (which loops anteriorly to the section), and surrounding structures. # 23 - 453 Diseases of the Spinal Cord ### 453 Diseases of the Spinal Cord In infectious cases, prompt administration of broad-spectrum antibiotics, drainage of any abscess cavities, and identification of the offending organism are essential. Anticoagulant therapy may benefit cases of primary thrombosis. Repair or occlusion of the carotid artery may be required for treatment of fistulas or aneurysms. Tolosa-Hunt syndrome is characterized by onset, over days or a few weeks, of severe orbital pain with variable ophthalmoparesis and numbness of the upper face (V1 and V2 divisions of the tri­ geminal nerve) and by a dramatic clinical response to glucocorticoids. Although distinctive, the presentation can be mimicked by numerous other conditions that involve the cavernous sinus and orbit, includ­ ing sarcoid (Chap. 379), vasculitis (Chap. 375), IgG4-related disease (Chap. 380), lymphoma, and fungal infections. MRI can suggest the presence of granulomatous inflammation, but biopsy is sometimes required for diagnosis. A dramatic improvement in pain is usually evident within a few days; oral prednisone (60 mg daily) is usually con­ tinued for 2 weeks and then gradually tapered over a month, or longer if pain recurs. Occasionally an immunosuppressive medication, such as azathioprine or methotrexate, needs to be added to maintain an initial response to glucocorticoids. Lesions in the superior orbital fissure and orbital apex cause more prominent vision loss than those in the cavernous sinus due to com­ pression of the optic nerve; the second branch of the trigeminal nerve is usually spared. The cause is often an invasive fungal infection, frequently due to osseous erosion through the wall of the maxillary, sphenoid, or ethmoid sinuses. Infiltrative processes such as amyloi­ dosis, granulomatosis with polyarteritis, an idiopathic granulomatous inflammation similar to Tolosa-Hunt, and IgG4-related disease are additional causes. Biopsy is often necessary for diagnosis. As noted above, Guillain-Barré syndrome commonly affects the facial nerves bilaterally. In the Fisher variant of Guillain-Barré syn­ drome, oculomotor paresis occurs with ataxia and areflexia in the limbs (Chap. 458). Wernicke’s encephalopathy can cause a severe ophthalmoplegia combined with other brainstem signs (Chap. 318). Progressive bulbar palsy is a slowly progressive purely motor disor­ der affecting multiple cranial nerve nuclei. Weakness of the face, jaw, pharynx, neck, and tongue is usually present accompanied by atrophy and fasciculations. It is a form of motor neuron disease (Chap. 448). Pure motor syndromes without atrophy raise the question of myas­ thenia gravis (Chap. 459), and when rapidly evolving, Guillain-Barré syndrome, diphtheria, and poliomyelitis are additional considerations. Glossopharyngeal neuropathy in conjunction with vagus and acces­ sory nerve palsies may occur with herpes zoster infection or with a tumor or aneurysm in the posterior fossa or in the jugular foramen, through which all three nerves exit the skull. Hoarseness due to vocal cord paralysis, some difficulty in swallowing, deviation of the soft pal­ ate to the intact side, anesthesia of the posterior wall of the pharynx, and weakness of the upper part of the trapezius and sternocleidomas­ toid muscles make up jugular foramen syndrome. Paralysis of the vagus and hypoglossal nerves (Tapia syndrome) can rarely follow endotracheal intubation and has been reported during the COVID-19 pandemic; symptoms consist of dysphonia and tongue deviation and usually resolve within a few months. An idiopathic form of multiple cranial nerve involvement on one or both sides of the face is occasionally seen. The syndrome consists of a subacute onset of boring facial pain, followed by paralysis of motor cranial nerves. The clinical features overlap those of Tolosa-Hunt syndrome and appear to be due to idiopathic inflammation of the dura mater, which may be visualized by MRI. The syndrome is usually responsive to glucocorticoids. ■ ■FURTHER READING Abad S et al: IgG4-related disease in patients with idiopathic orbital inflammation syndrome: Data from the French SIOI prospective cohort. Acta Ophthalmol 97:e648, 2019. Bendsten L et al: European Academy of Neurology guideline on tri­ geminal neuralgia. Eur J Neurol 26:831, 2019. Gagyor I et al: Antiviral treatment of Bell’s palsy (idiopathic facial paralysis). Cochrane Database Syst Rev 9:CD001869, 2019. Gutierrez S et al: Lower cranial nerve syndromes: A review. Neuro­ surg Rev 44:1345, 2020. Madhok VB et al: Corticosteroids for Bell’s palsy (idiopathic facial paralysis). Cochrane Database Syst Rev 7:CD001942, 2016. Mullen E et al: Reappraising the Tolosa-Hunt syndrome diagnostic criteria: A case series. Headache 60:259, 2020. Rafati A et al: Association of SARS-CoV-2 vaccination or infection with Bell palsy: A systematic review and meta-analysis. JAMA Otolaryngol Head Neck Surg 149:493, 2023. Stephen L. Hauser Diseases of the Spinal Cord CHAPTER 453 Diseases of the Spinal Cord Diseases of the spinal cord are frequently devastating. They produce quadriplegia, paraplegia, and sensory deficits far beyond the damage they would inflict elsewhere in the nervous system because the spinal cord contains, in a small cross-sectional area, almost the entire motor output and sensory input of the trunk and limbs. Many spinal cord diseases are reversible if recognized and treated at an early stage (Table 453-1); thus, they are among the most critical of neurologic emergencies. Proper management requires the efficient use of diag­ nostic procedures, guided by knowledge of the anatomy and clinical features of spinal cord diseases. APPROACH TO THE PATIENT Spinal Cord Disease SPINAL CORD ANATOMY RELEVANT TO CLINICAL SIGNS The spinal cord is a thin, tubular extension of the central nervous system contained within the bony spinal canal. It originates at the medulla and continues caudally to the conus medullaris at the lumbar level; its fibrous extension, the filum terminale, terminates at the coccyx. The adult spinal cord is ~46 cm (18 in.) long, oval in shape, and enlarged in the cervical and lumbar regions, where neu­ rons that innervate the upper and lower extremities, respectively, are located. The white matter tracts containing ascending sensory and descending motor pathways are located peripherally, whereas nerve cell bodies are clustered in an inner region of gray matter shaped like a four-leaf clover that surrounds the central canal (ana­ tomically an extension of the fourth ventricle). The membranes that cover the spinal cord—the pia, arachnoid, and dura—are continu­ ous with those of the brain, and the cerebrospinal fluid is contained within the subarachnoid space between the pia and arachnoid. The spinal cord has 31 segments, each defined by an exit­ ing ventral motor root and entering dorsal sensory root. During embryologic development, growth of the cord lags behind that of the vertebral column, and the mature spinal cord ends at approxi­ mately the first lumbar vertebral body. The lower spinal nerves take an increasingly downward course to exit via intervertebral foramina. The first seven pairs of cervical spinal nerves exit above the same-numbered vertebral bodies, whereas all the subsequent nerves exit below the same-numbered vertebral bodies; this is because there are eight cervical spinal cord segments but only seven cervical vertebrae. The relationship between spinal cord segments and the corresponding vertebral bodies is shown in Table 453-2. These relationships assume particular importance for localization of lesions that cause spinal cord compression. Sensory loss below TABLE 453-1  Treatable Spinal Cord Disorders Compressive   Epidural, intradural, or intramedullary neoplasm   Epidural abscess   Epidural hemorrhage   Cervical spondylosis   Herniated disk   Posttraumatic compression by fractured or displaced vertebra or hemorrhage Vascular   Arteriovenous malformation and dural fistula   Antiphospholipid syndrome and other hypercoagulable states Inflammatory   Multiple sclerosis   Neuromyelitis optica   Sarcoidosis PART 13 Neurologic Disorders   Systemic immune-mediated disorders: SLE, Sjögren’s, Behcet’s disease, APL antibody syndrome, others vasculitis   Other CNS disorders: anti-MOG, anti-GFAP, paraneoplastic,a CLIPPERS, Erdheim-Chester Infectious   Viral: VZV, HSV-1 and -2, CMV, HIV, HTLV-1, others   Bacterial and mycobacterial: Borrelia, Listeria, syphilis, others   Mycoplasma pneumoniae   Parasitic: schistosomiasis, toxoplasmosis, cysticercosis Developmental   Syringomyelia   Meningomyelocele   Tethered cord syndrome Metabolic   Vitamin B12 deficiency (subacute combined degeneration)   Folate deficiency   Copper deficiency aIncluding anti-amphiphysin, CRMP-5, Hu. Abbreviations: CLIPPERS, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; CMV, cytomegalovirus; CNS, central nervous system; CRMP5, collapsin response mediator 5-IgG; GFAP, glial fibrillary acidic protein; HSV, herpes simplex virus; HTLV, human T-cell lymphotropic virus; MOG, myelin oligodendrocyte glycoprotein; SLE, systemic lupus erythematosus; VZV, varicella-zoster virus. the level of the umbilicus, for example, corresponds to pathology at the T10 cord segment, which is located adjacent to the seventh or eighth thoracic vertebral body (see Figs. 27-2 and 27-3). In addition, at every level, the main ascending and descending tracts are somatotopically organized with a laminated distribution that reflects the origin or destination of nerve fibers. Determining the Level of the Lesion  The presence of a horizon­ tally defined level below which sensory, motor, and autonomic function is impaired is the hallmark of a spinal cord lesion. This sensory level is sought by asking the patient to identify a pinprick or cold stimulus applied to the proximal legs and lower trunk and successively moved up toward the neck on each side. Sensory loss below this level is the result of damage to the spinothalamic tract on the opposite side, one to two segments higher in the case of a TABLE 453-2  Spinal Cord Levels Relative to the Vertebral Bodies SPINAL CORD LEVEL CORRESPONDING VERTEBRAL BODY Upper cervical Same as cord level Lower cervical 1 level higher Upper thoracic 2 levels higher Lower thoracic 2–3 levels higher Lumbar T10–T12 Sacral T12–L1 unilateral spinal cord lesion, and at the level of a bilateral lesion. The discrepancy in the level of a unilateral lesion is the result of the course of the second-order sensory fibers, which originate in the dorsal horn and ascend for one or two levels as they cross ante­ rior to the central canal to join the opposite spinothalamic tract. Lesions that transect the descending corticospinal and other motor tracts cause paraplegia or quadriplegia with heightened deep ten­ don reflexes, Babinski signs, and eventual spasticity (upper motor neuron syndrome). Transverse damage to the cord also produces autonomic disturbances consisting of absent sweating below the implicated cord level and bladder, bowel, and sexual dysfunction. The uppermost level of a spinal cord lesion can also be local­ ized by attention to the segmental signs corresponding to disturbed motor or sensory innervation by an individual cord segment. A band of altered sensation (hyperalgesia or hyperpathia) at the upper end of the sensory disturbance, fasciculations or atrophy in muscles innervated by one or several segments, or a muted or absent deep tendon reflex may be noted at this level. These signs also can occur with focal root or peripheral nerve disorders; thus, they are most useful when they occur together with signs of long-tract damage. With severe and acute transverse lesions, the limbs initially may be flaccid rather than spastic. This state of “spinal shock” lasts for several days, rarely for weeks, and may be mistaken for extensive damage to the anterior horn cells over many segments of the cord or for an acute polyneuropathy. The main features of transverse damage at each level of the spinal cord are summarized below. Cervical Cord  Upper cervical cord lesions produce quadriplegia and weakness of the diaphragm. The uppermost level of weakness and reflex loss with lesions at C5–C6 is in the biceps; at C7, in finger and wrist extensors and triceps; and at C8, finger and wrist flexion. Horner’s syndrome (miosis, ptosis, and facial hypohidrosis) may accompany a cervical cord lesion at any level. Thoracic Cord  Lesions here are localized by the sensory level on the trunk and, if present, by the site of midline back pain. Useful markers of the sensory level on the trunk are the nipples (T4) and umbilicus (T10). Leg weakness and disturbances of bladder and bowel function accompany the paralysis. Lesions at T9–T10 para­ lyze the lower—but not the upper—abdominal muscles, resulting in upward movement of the umbilicus when the abdominal wall contracts (Beevor’s sign). Lumbar Cord  Lesions at the L2–L4 spinal cord levels paralyze flexion and adduction of the thigh, weaken leg extension at the knee, and abolish the patellar reflex. Lesions at L5–S1 paralyze only movements of the foot and ankle, flexion at the knee, and extension of the thigh, and abolish the ankle jerks (S1). Sacral Cord/Conus Medullaris  The conus medullaris is the tapered caudal termination of the spinal cord, comprising the sacral and single coccygeal segments. The distinctive conus syndrome consists of bilateral saddle anesthesia (S3–S5), prominent bladder and bowel dysfunction (urinary retention and incontinence with lax anal tone), and impotence. The bulbocavernosus (S2–S4) and anal (S4–S5) reflexes are absent (Chap. 433). Muscle strength is largely preserved. By contrast, lesions of the cauda equina, the nerve roots derived from the lower cord, are characterized by low back and radicular pain, asymmetric leg weakness and sensory loss, variable areflexia in the lower extremities, and relative sparing of bowel and bladder function. Mass lesions in the lower spinal canal often produce a mixed clinical picture with elements of both cauda equina and conus medullaris syndromes. Special Patterns of Spinal Cord Disease  The location of the major ascending and descending pathways of the spinal cord are shown in Fig. 453-1. Most fiber tracts—including the posterior col­ umns and the spinocerebellar and pyramidal tracts—are situated on the side of the body they innervate. However, afferent fibers medi­ ating pain and temperature sensation ascend in the spinothalamic Posterior Columns (Joint Position, Vibration, Pressure) Fasciculus gracilis Fasciculus cuneatus Dorsal root Dorsal spinocerebellar tract C T L S Ventral spinocerebellar tract L/ S L/ S S L T C Lateral spinothalamic tract S L T C Pain, temperature Ventral reticulospinal tract Ventral root Ventral spinothalamic tract Pressure, touch (minor role) FIGURE 453-1  Transverse section through the spinal cord, composite representation, illustrating the principal ascending (left) and descending (right) pathways. The lateral and ventral spinothalamic tracts ascend contralateral to the side of the body that is innervated. In humans, the lateral corticospinal (pyramidal) tract is thought to lack strict somatotopic organization in the spinal cord. C, cervical; D, distal; E, extensors; F, flexors; L, lumbar; P, proximal; S, sacral; T, thoracic. tract contralateral to the side they supply. The anatomic configura­ tions of these tracts produce characteristic syndromes that provide clues to the underlying disease process. Brown-Sequard Hemicord Syndrome  This consists of ipsi­ lateral weakness (corticospinal tract) and loss of joint position and vibratory sense (posterior column), with contralateral loss of pain and temperature sense (spinothalamic tract) one or two levels below the lesion. Segmental signs, such as radicular pain, muscle atrophy, or loss of a deep tendon reflex, are unilateral. Partial forms are more common than the fully developed syndrome. Central Cord Syndrome  This syndrome results from selective damage to the gray matter nerve cells and crossing spinothalamic tracts surrounding the central canal. In the cervical cord, the central cord syndrome produces arm weakness out of proportion to leg weakness and a “dissociated” sensory loss, meaning loss of pain and temperature sensations over the shoulders, lower neck, and upper trunk (cape distribution), in contrast to preservation of light touch, joint position, and vibration sense in these regions. Spinal trauma, syringomyelia, and intrinsic cord tumors are the main causes. Anterior Cord Syndrome  Infarction of the cord is generally the result of occlusion or diminished flow in the anterior spinal artery. The result is bilateral tissue destruction at several contiguous levels that spares the posterior columns. All spinal cord functions—motor, sensory, and autonomic—are lost below the level of the lesion, with the striking exception of retained vibration and position sensation. Foramen Magnum Syndrome  Lesions in this area interrupt decussating pyramidal tract fibers destined for the legs, which cross caudal to those of the arms, resulting in weakness of the legs (cru­ ral paresis). Compressive lesions near the foramen magnum may produce weakness of the ipsilateral shoulder and arm followed by weakness of the ipsilateral leg, then the contralateral leg, and finally the contralateral arm, an “around-the-clock” pattern that may begin Anterior horn (motor neurons) Lateral corticospinal (pyramidal) tract Distal limb movements Rubrospinal tract Lateral reticulospinal tract P E D F CHAPTER 453 Vestibulospinal tract Axial and proximal limb movements Diseases of the Spinal Cord Tectospinal tract Ventral (uncrossed) corticospinal tract Distal limb movements (minor role) in any of the four limbs. There is typically suboccipital pain spread­ ing to the neck and shoulders. Intramedullary and Extramedullary Syndromes  It is useful to differentiate intramedullary processes, arising within the sub­ stance of the cord, from extramedullary ones that lie outside the cord and compress the spinal cord or its vascular supply. The differ­ entiating features are only relative and serve as clinical guides. With extramedullary lesions, radicular pain is often prominent, and there is early sacral sensory loss and spastic weakness in the legs with incontinence due to injury to the corresponding sensory and motor fibers in the spinothalamic and corticospinal tracts (Fig. 453-1). Intramedullary lesions tend to produce poorly localized burn­ ing pain rather than radicular pain and to spare sensation in the perineal and sacral areas (“sacral sparing”), reflecting the laminated configuration of the spinothalamic tract with sacral fibers outer­ most; corticospinal tract signs appear later. Regarding extramedul­ lary lesions, a further distinction is made between extradural and intradural masses, as the former are generally malignant and the latter benign (neurofibroma being a common cause). Consequently, a long duration of symptoms favors an intradural origin. ACUTE AND SUBACUTE SPINAL CORD DISEASES Symptoms of the cord diseases that evolve over days or weeks typically present as focal neck or back pain, followed by various combinations of paresthesias, sensory loss, motor weakness, and sphincter disturbance. There may be mild sensory symptoms only or a devastating functional transection of the cord. When paresthesias begin in the feet and then ascend, a polyneuropathy is often considered, and in such cases, the presence of bladder disturbances and a sharply demarcated spinal cord level provide important clues to the spinal cord origin of the disease. In severe and abrupt cases, areflexia reflecting spinal shock may be present, but hyperreflexia supervenes over days or weeks; persistent areflexic paralysis with a sensory level usually indicates necrosis over multiple segments of the spinal cord. APPROACH TO THE PATIENT Compressive and Noncompressive Myelopathy DISTINGUISHING COMPRESSIVE FROM NONCOMPRESSIVE MYELOPATHY The first priority is to exclude treatable compression of the cord by a mass lesion. The common causes are tumor, epidural abscess or hematoma, herniated disk, and spondylitic vertebral pathology. Epi­ dural compression due to malignancy or abscess often causes warn­ ing signs of neck or back pain, bladder disturbances, and sensory symptoms that precede the development of paralysis. Spinal sublux­ ation, hemorrhage, and noncompressive etiologies such as infarc­ tion are more likely to produce myelopathy without antecedent symptoms. Magnetic resonance imaging (MRI) with gadolinium, centered on the clinically suspected level, is the initial diagnostic procedure if it is available; it is often appropriate to image the entire spine (cervical through sacral regions) to search for additional clini­ cally silent lesions. Once compressive lesions have been excluded, noncompressive causes of acute myelopathy that are intrinsic to the cord are considered, primarily vascular, inflammatory, and infec­ tious etiologies. PART 13 Neurologic Disorders ■ ■COMPRESSIVE MYELOPATHIES Neoplastic Spinal Cord Compression  In adults, most neo­ plasms are epidural in origin, resulting from metastases to the adjacent vertebral column. The propensity of solid tumors to metastasize to the vertebral column probably reflects the high proportion of bone marrow located in the axial skeleton. Almost any malignant tumor can metasta­ size to the spinal column, with breast, lung, prostate, kidney, lymphoma, and myeloma being particularly frequent. The thoracic spinal column is most commonly involved; exceptions are metastases from prostate and ovarian cancer, which occur disproportionately in the sacral and lumbar vertebrae, probably from spread through Batson’s plexus, a network of veins along the anterior epidural space. Retroperitoneal neoplasms (especially lymphomas or sarcomas) enter the spinal canal laterally through the intervertebral foramina and produce radicular pain with signs of weakness that corresponds to the level of involved nerve roots. Pain is usually the initial symptom of spinal metastasis; it may be aching and localized or sharp and radiating in quality and typically worsens with movement, coughing, or sneezing and characteristi­ cally awakens patients at night. A recent onset of persistent back pain, particularly if in the thoracic spine (which is uncommonly involved by spondylosis), should prompt consideration of vertebral metasta­ sis. Rarely, pain is mild or absent. Plain radiographs of the spine and radionuclide bone scans have a limited role in diagnosis because they do not identify 15–20% of metastatic vertebral lesions and fail to detect paravertebral masses that reach the epidural space through the inter­ vertebral foramina. MRI provides excellent anatomic resolution of the extent of spinal tumors (Fig. 453-2) and is able to distinguish between malignant lesions and other masses—epidural abscess, tuberculoma, lipoma, or epidural hemorrhage, among others—that present in a simi­ lar fashion. Vertebral metastases are usually hypointense relative to a normal bone marrow signal on T1-weighted MRI; after the administra­ tion of gadolinium, contrast enhancement may deceptively “normalize” the appearance of the tumor by increasing its intensity to that of nor­ mal bone marrow. Infections of the spinal column (osteomyelitis and related disorders) are distinctive in that, unlike tumor, they often cross the disk space to involve the adjacent vertebral body. If spinal cord compression is suspected, imaging should be obtained promptly. If there are radicular symptoms but no evidence of myelopa­ thy, it may be safe to defer imaging for 24–48 h. Up to 40% of patients who present with cord compression at one level are found to have asymptomatic epidural metastases elsewhere; thus, imaging of the entire length of the spine is important to define the extent of disease. A B FIGURE 453-2  Epidural spinal cord compression due to breast carcinoma. Sagittal T1-weighted (A) and T2-weighted (B) magnetic resonance imaging scans through the cervicothoracic junction reveal an infiltrated and collapsed second thoracic vertebral body with posterior displacement and compression of the upper thoracic spinal cord. The low-intensity bone marrow signal in A signifies replacement by tumor. TREATMENT Neoplastic Spinal Cord Compression Proper management is based on multiple considerations, includ­ ing radiosensitivity of the primary tumor, extent of compression, prior therapy to the site, and stability of the spine. Treatment includes glucocorticoids to reduce cord edema, surgery and/or local radiotherapy (initiated as early as possible) to the symptomatic lesion, and specific therapy for the underlying tumor type. Gluco­ corticoids (typically dexamethasone, 10 mg intravenously) can be administered before an imaging study if there is clinical suspicion of cord compression and continued at a lower dose (4 mg every 6 h orally) until definitive treatment with radiotherapy and/or surgi­ cal decompression is completed. In one trial, initial management with surgery followed by radiotherapy was more effective than radiotherapy alone for patients with a single area of spinal cord compression by extradural tumor; however, patients with recur­ rent cord compression, brain metastases, radiosensitive tumors, or severe motor symptoms of >48 h in duration were excluded from this study. Stereotactic body radiotherapy, which delivers high doses of focused radiation, is preferred for radioresistant tumor types and for patients requiring re-irradiation. Biopsy of the epidural mass is unnecessary in patients with known primary cancer, but it is indicated if a history of underly­ ing cancer is lacking. Surgical treatment, either decompression by laminectomy or a spinal fixation procedure, is also indicated when signs of cord compression worsen despite radiotherapy; the maximum-tolerated dose of radiotherapy has been delivered previ­ ously to the site; a vertebral compression fracture or spinal instabil­ ity contributes to cord compression; or in cases of high-grade spinal cord compression from a radioresistant tumor. A good response to therapy can be expected in individuals who are ambulatory at presentation. Treatment usually prevents new weakness, and some recovery of motor function occurs in up to one-third of patients. Motor deficits (paraplegia or quadriplegia), once established for >12 h, do not usually improve, and beyond 48 h, the prognosis for substantial motor recovery is poor. Although most patients do not experience recurrences in the months fol­ lowing radiotherapy, with survival beyond 2 years, recurrence becomes increasingly likely and can be managed with additional radiotherapy. FIGURE 453-3  Magnetic resonance imaging of a thoracic meningioma. Coronal T1-weighted postcontrast image through the thoracic spinal cord demonstrates intense and uniform enhancement of a well-circumscribed extramedullary mass (arrows) that displaces the spinal cord to the left. In contrast to tumors of the epidural space, most intradural mass lesions are slow-growing and benign. Meningiomas and neurofibromas account for most of these, with occasional cases caused by chordoma, lipoma, dermoid, or sarcoma. Meningiomas (Fig. 453-3) are often located posterior to the thoracic cord or near the foramen magnum, although they can arise from the meninges anywhere along the spinal canal. Neurofibromas are benign tumors of the nerve sheath that typi­ cally arise from the posterior root; when multiple, neurofibromatosis is the likely etiology. Symptoms usually begin with radicular sensory symptoms followed by an asymmetric, progressive spinal cord syn­ drome. Therapy is surgical resection. Primary intramedullary tumors of the spinal cord are uncommon. They present as central cord or hemicord syndromes, often in the cervical region. There may be poorly localized burning pain in the extremities and sparing of sacral sensation. In adults, these lesions are ependymomas, hemangioblastomas, or low-grade astrocytomas (Fig. 453-4). Complete resection of an intramedullary ependymoma is often possible with microsurgical techniques. Debulking of an intra­ medullary astrocytoma can also be helpful, as these are often slowly growing lesions; the value of adjunctive radiotherapy and chemother­ apy is uncertain. Secondary (metastatic) intramedullary tumors also occur, especially in patients with advanced metastatic disease (Chap. 95), although these are not nearly as frequent as brain metastases. Spinal Epidural Abscess  Spinal epidural abscess presents with midline back or neck pain, fever, and progressive limb weakness. Prompt recognition of this distinctive process may prevent permanent sequelae. Aching pain is almost always present, either over the spine or in a radicular pattern. The duration of pain prior to presentation is generally ≤2 weeks but may on occasion be several months or longer. Fever is typically but not invariably present, accompanied by elevated white blood cell count, sedimentation rate, and C-reactive protein. As the abscess expands, further spinal cord damage results from venous congestion and thrombosis. Once weakness and other signs of myelopathy appear, progression may be rapid and irreversible. A more chronic sterile granulomatous form of abscess is also known, usually after treatment of an acute epidural infection. Risk factors include an impaired immune status (HIV, diabetes mel­ litus, renal failure, alcoholism, malignancy), intravenous drug abuse, CHAPTER 453 FIGURE 453-4  Magnetic resonance imaging of an intramedullary astrocytoma. Sagittal T1-weighted postcontrast image through the cervical spine demonstrates expansion of the upper cervical spine by a mass lesion emanating from within the spinal cord at the cervicomedullary junction. Irregular peripheral enhancement occurs within the mass (arrows). Diseases of the Spinal Cord and infections of the skin or other tissues. Two-thirds of epidural infections result from hematogenous spread of bacteria from the skin (furunculosis), soft tissue (pharyngeal or dental abscesses; sinusitis), or deep viscera (bacterial endocarditis). The remainder arises from direct extension of a local infection to the subdural space; examples of local predisposing conditions are vertebral osteomyelitis, decubitus ulcers, lumbar puncture, epidural anesthesia, or spinal surgery. Most cases are due to Staphylococcus aureus; gram-negative bacilli, Streptococcus, anaerobes, and fungi can also cause epidural abscesses. Methicillinresistant Staphylococcus aureus (MRSA) is an important consideration, and therapy should be tailored to this possibility. Tuberculosis from an adjacent vertebral source (Pott’s disease) remains an important cause in the developing world. MRI (Fig. 453-5) localizes the abscess and excludes other causes of myelopathy. Blood cultures are positive in more than half of cases, but direct aspiration of the abscess at surgery is often required for a A B FIGURE 453-5  Magnetic resonance (MR) imaging of a spinal epidural abscess due to tuberculosis. A. Sagittal T2-weighted free spin-echo MR sequence. A hypointense mass replaces the posterior elements of C3 and extends epidurally to compress the spinal cord (arrows). B. Sagittal T1-weighted image after contrast administration reveals a diffuse enhancement of the epidural process (arrows) with extension into the epidural space. microbiologic diagnosis. Lumbar puncture is only required if encepha­ lopathy or other clinical signs raise the question of associated menin­ gitis, a feature that is found in <25% of cases. The level of the puncture should be planned to minimize the risk of meningitis due to passage of the needle through infected tissue. A high cervical tap is sometimes the safest approach. Cerebrospinal fluid (CSF) abnormalities in epidural and subdural abscesses consist of pleocytosis with a preponderance of polymorphonuclear cells, an elevated protein level, and a reduced glucose level, but the responsible organism is not cultured unless there is associated meningitis. TREATMENT Spinal Epidural Abscess Treatment is by decompressive laminectomy with debridement combined with long-term antibiotic treatment. Surgical evacua­ tion prevents development of paralysis and may improve or reverse paralysis in evolution, but it is unlikely to improve fixed deficits more than several days in duration. Broad-spectrum antibiotics, typically vancomycin 15–20 mg/kg q12h (Staphylococcus including MRSA, Streptococcus), ceftriaxone 2 g q12h (gram-negative bacilli), and when indicated, metronidazole 30 mg/kg per day divided into q6h intervals (anaerobes), should be started empirically before sur­ gery and then modified on the basis of culture results; medication is generally continued for 6–8 weeks. If surgery is contraindicated or if there is a fixed paraplegia or quadriplegia that is unlikely to improve following surgery, long-term administration of systemic and oral antibiotics can be used; in such cases, the choice of antibiotics may be guided by results of blood cultures. Surgical management remains the treatment of choice unless the abscess is limited in size and causes few or no neurologic signs. PART 13 Neurologic Disorders With prompt diagnosis and treatment, up to two-thirds of patients experience significant recovery. Spinal Epidural Hematoma  Hemorrhage into the epidural (or subdural) space causes acute focal or radicular pain followed by vari­ able signs of a spinal cord or conus medullaris disorder. Therapeutic anticoagulation, trauma, tumor, or blood dyscrasias are predisposing conditions. Rare cases complicate lumbar puncture or epidural anes­ thesia. MRI and computed tomography (CT) confirm the clinical sus­ picion and can delineate the extent of the bleeding. Treatment consists of prompt reversal of any underlying clotting disorder and surgical decompression. Surgery may be followed by substantial recovery, espe­ cially in patients with some preservation of motor function preopera­ tively. Because of the risk of hemorrhage, lumbar puncture should be avoided whenever possible in patients with severe thrombocytopenia or other coagulopathies. Hematomyelia  Hemorrhage into the substance of the spinal cord is a rare result of trauma, intraparenchymal vascular malformation (see below), vasculitis due to polyarteritis nodosa or systemic lupus erythematosus (SLE), bleeding disorders, or a spinal cord neoplasm. Hematomyelia presents as an acute painful transverse myelopathy. With large lesions, extension into the subarachnoid space results in subarachnoid hemorrhage (Chap. 440). Diagnosis is by MRI or CT. Therapy is supportive, and surgical intervention is generally not useful. An exception is hematomyelia due to an underlying vascular malfor­ mation, for which spinal angiography and endovascular occlusion may be indicated, or surgery to evacuate the clot and remove the underlying vascular lesion. Acute Spondylytic Myelopathy  Of particular concern are hyperextension injuries in patients with underlying degenerative cervi­ cal spine disease (Chap. 19). The provoking stimulus may be obvious, such as a forward fall, or occur after seemingly innocuous low-impact movements of the neck. A preexisting stenotic spinal canal is often present, and “buckling” of the posterior ligamentum flavum (less com­ monly acute disk herniation or subluxation) is believed to produce the cord compression, sometimes with a central cord syndrome (see above) and involvement of the upper, more than lower, limbs. Deficits can be transient, resulting in a “concussion” of the spinal cord, or permanent. The more common syndrome of chronic spondylitic myelopathy is dis­ cussed below. ■ ■NONCOMPRESSIVE MYELOPATHIES Once a compressive etiology has been excluded as the cause of an acute myelopathy, the principal challenge is to distinguish vascular/ischemic from inflammatory/infectious causes. This is often not straightforward because clinical presentations can overlap. Moreover, findings that usually point to an inflammatory etiology—such as focal gadolinium enhancement on MRI scans or pleocytosis in the CSF—can also occur with spinal cord ischemia. Ischemia is likely in hyperacute presenta­ tions with back or neck pain and when an anterior pattern of spinal cord injury is identified on clinical examination or by MRI. By contrast, inflammation is more likely in cases that develop subacutely or when systemic symptoms, CSF oligoclonal bands, or multiple discrete spinal cord MRI lesions are present. The most frequent inflammatory causes of acute myelopathy are multiple sclerosis (MS); neuromyelitis optica (NMO); sarcoidosis; systemic inflammatory diseases such as SLE and Behcet’s disease; postinfectious or idiopathic transverse myelitis, which is presumed to be an immune condition related to acute disseminated encephalomyelitis (Chap. 456); and infectious (primarily viral) causes. The evaluation generally requires a lumbar puncture and a search for underlying systemic disease (Table 453-3). Spinal Cord Infarction  The cord is supplied by three arteries that course vertically over its surface: a single anterior spinal artery and paired posterior spinal arteries. The anterior spinal artery originates in paired branches of the vertebral arteries at the craniocervical junction and is fed by additional radicular vessels that arise at C6, at an upper thoracic level, and, most consistently, at T11–L2 (artery of Adamkie­ wicz). At each spinal cord segment, paired penetrating vessels branch from the anterior spinal artery to supply the anterior two-thirds of the TABLE 453-3  Considerations in the Evaluation of Myelopathy 1. MRI of spinal cord with and without contrast (exclude compressive causes). 2. CSF studies: Cell count, protein, glucose, IgG index/synthesis rate, oligoclonal bands, VDRL; Gram’s stain, acid-fast bacilli, and India ink stains; PCR for VZV, HSV-2, HSV-1, EBV, CMV, HHV-6, enteroviruses, HIV; antibody for HTLV-1, Borrelia burgdorferi, Mycoplasma pneumoniae, and Chlamydia pneumoniae; viral, bacterial, mycobacterial, and fungal cultures. 3. Blood studies for infection: HIV; RPR; IgG and IgM enterovirus antibody; IgM WNV, group B arbovirus, mumps, measles, rubella, Brucella melitensis, Chlamydia psittaci, Bartonella henselae, schistosomal antibody; PCR and antigen tests for SARS-CoV-2; cultures for B. melitensis. Also consider nasal/ pharyngeal/anal cultures for enteroviruses; stool O&P for Schistosoma ova. 4. Vascular causes: MRI, CT myelogram; spinal angiogram. 5. Multiple sclerosis: Brain MRI scan; evoked potentials. 6. Neuromyelitis optica and related disorders: Serum anti-aquaporin-4 antibody, anti-MOG antibody, anti-GFAP antibody. 7. Sarcoidosis: Serum angiotensin-converting enzyme; serum Ca; 24-h urine Ca; chest x-ray; chest CT; slit-lamp eye examination; total-body gallium scan; lymph node biopsy. 8. Systemic immune-mediated disorders: ESR; ANA; ENA; dsDNA; rheumatoid factor; anti-SSA; anti-SSB, complement levels; antiphospholipid and anticardiolipin antibodies; pANCA; antimicrosomal and antithyroglobulin antibodies; if Sjögren’s syndrome suspected, Schirmer test, salivary gland scintigraphy, and salivary/lacrimal gland biopsy. 9. Paraneoplastic disorders: Antibody for amphiphysin, CRMP5, Hu, others. 10. Other: vitamin B12, copper, zinc. Abbreviations: ANA, antinuclear antibodies; Ca, calcium; CMV, cytomegalovirus; CRMP5, collapsin response mediator 5-IgG; CSF, cerebrospinal fluid; CT, computed tomography; EBV, Epstein-Barr virus; ENA, epithelial neutrophil-activating peptide; ESR, erythrocyte sedimentation rate; GFAP, glial fibrillary acidic protein; HHV, human herpes virus; HSV, herpes simplex virus; HTLV, human T-cell leukemia/lymphoma virus; MOG, myelin oligodendrocyte glycoprotein; MRI, magnetic resonance imaging; O&P, ova and parasites; pANCA, perinuclear antineutrophilic cytoplasmic antibodies; PCR, polymerase chain reaction; RPR, rapid plasma reagin (test); VDRL, Venereal Disease Research Laboratory; VZV, varicella-zoster virus; WNV West Nile virus. cord; the posterior spinal arteries, which often become less distinct below the midthoracic level, supply the posterior columns. Spinal cord ischemia can occur at any level; however, the presence of the artery of Adamkiewicz below, and the anterior spinal artery circula­ tion above, creates a region of marginal blood flow in the upper tho­ racic segments. With hypotension or cross-clamping of the aorta, cord infarction typically occurs at the level of T3–T4 and also at boundary zones between the anterior and posterior spinal artery territories. The latter may result in a rapidly progressive syndrome over hours of weak­ ness and spasticity with little sensory change. Acute infarction in the territory of the anterior spinal artery pro­ duces paraplegia or quadriplegia, dissociated sensory loss affecting pain and temperature sense but sparing vibration and position sense, and loss of sphincter control (anterior cord syndrome). Onset may be sudden but more typically is progressive over minutes or a few hours, unlike stroke in the cerebral hemispheres. Sharp midline or radiating back pain localized to the area of ischemia is frequent. Areflexia due to spinal shock is often present initially; with time, hyperreflexia and spasticity appear. Less common is infarction in the territory of the posterior spinal arteries, resulting in loss of posterior column function either on one side or bilaterally. Causes of spinal cord infarction include aortic atherosclerosis, dis­ secting aortic aneurysm, vertebral artery occlusion or dissection in the neck, aortic surgery, or profound hypotension from any cause. Car­ diogenic emboli, vasculitis (Chap. 375), and collagen vascular disease (particularly SLE [Chap. 368], Sjögren’s syndrome [Chap. 373], and the antiphospholipid antibody syndrome [Chap. 369]) are other etiologies. Occasional cases develop from embolism of nucleus pulposus material into spinal vessels, usually from local spine trauma. A surfer’s myelopa­ thy, usually in the thoracic region, has been associated with prolonged back extension due to lifting the upper body off the board while wait­ ing for waves; it typically manifests as back pain followed by an anterior cord syndrome with progressive paralysis and loss of sphincter control and is likely vascular in origin. A few reports have also been associated with cocaine use, as well as with heroin. In a substantial number of cases, no cause can be found, and thromboembolism in arterial feeders is suspected. MRI may fail to demonstrate infarctions of the cord, especially in the first day, but often the imaging becomes abnormal at the affected level. MRI features suggestive of cord infarction include diffusionweighted restriction; longitudinally extensive anterior T2 signal bright­ ness on sagittal images (“pencil-like sign”); focal enhancement in the anterior horns; and paired areas of focal T2 hyperintensity in the anterior medial cord on axial images (“owl’s eyes”). When present, infarction of a vertebral body adjacent to the area of cord involvement is diagnostically helpful. With cord infarction due to presumed thromboembolism, acute anticoagulation is not indicated, with the possible exception of the unusual transient ischemic attack or incomplete infarction with a stut­ tering or progressive course. The antiphospholipid antibody syndrome is treated with anticoagulation (Chap. 369). Increasing systemic blood pressure to a mean arterial pressure of >90 mmHg, or lumbar drainage of spinal fluid, was reportedly helpful in a few published cases of cord infarction, but neither of these approaches has been studied system­ atically. Prognosis following spinal cord infarction is influenced by the severity of the deficits at presentation; patients with severe motor weakness and those with persistent areflexia usually do poorly, but in one large series, some improvement over time occurred in many patients, with more than half ultimately regaining some ambulation. Inflammatory and Immune Myelopathies (Myelitis)  This broad category includes MS, NMO, and postinfectious myelitis, as well as sarcoidosis, systemic autoimmune disease, and infections. In approximately one-quarter of cases of myelitis, no underlying cause can be identified. Some will later manifest additional symptoms of an immune-mediated disease. Transverse myelitis refers to a pattern of extensive spinal cord injury due to inflammation, clinically manifest as bilateral sensory symptoms, unilateral or bilateral weakness, and bladder and/or bowel disturbance. In most of the developed world, MS is the most common inflammatory cause of an acute myelitis, but involvement is usually partial and not transverse. Recurrent episodes of myelitis are usually due to one of the immune-mediated diseases or to infection with herpes simplex virus (HSV) type 2 (below). MULTIPLE SCLEROSIS  MS may present with acute myelitis, particu­ larly in individuals of Asian or African ancestry. In whites, MS attacks rarely cause a transverse myelopathy (i.e., attacks of bilateral sensory disturbances, unilateral or bilateral weakness, and bladder or bowel symptoms), but MS is among the most common causes of a partial cord syndrome. MRI findings in MS-associated myelitis typically consist of mild swelling of the cord and diffuse or multifocal “shoddy” areas of abnormal signal on T2-weighted sequences. Contrast enhance­ ment, indicating disruption in the blood-brain barrier associated with inflammation, is present in many acute cases. In one study 68% of patients presenting with partial myelitis developed MS after a mean follow-up of 4 years; risk factors for conversion to MS included age <40 years, inflammatory CSF, and more than three periventricular lesions on brain MRI. CHAPTER 453 Treatment of acute episodes of MS-associated myelitis consists of intravenous methylprednisolone (500 mg qd for 3 days) followed by oral prednisone (1 mg/kg per day for several weeks, then a gradual taper). A course of plasma exchange may be indicated for severe cases if glucocorticoids are ineffective. MS is discussed in Chap. 455. Diseases of the Spinal Cord NEUROMYELITIS OPTICA  NMO is an immune-mediated disorder consisting of a severe myelopathy that is typically longitudinally extensive, meaning that the lesion typically spans three or more ver­ tebral segments. NMO is associated with optic neuritis that is often bilateral and may precede or follow myelitis by weeks or months and also by brainstem and, in some cases, hypothalamic or focal cerebral white matter involvement. Recurrent myelitis without optic nerve or other involvement can also occur in NMO. CSF studies reveal a variable mononuclear pleocytosis of up to several hundred cells per microliter (higher than in typical MS) with occasional cases show­ ing polymorphonuclear predominant pattern; oligoclonal bands are present in <20% of NMO cases. Diagnostic serum autoantibodies against the water channel protein aquaporin-4 (AQP-4) are present in 90% of patients with NMO; in some AQP-4-negative cases, auto­ antibodies against the central nervous system (CNS) myelin protein myelin oligodendrocyte glycoprotein (MOG) are found. NMO is also associated with SLE (see below) as well as with other systemic autoim­ mune diseases; rare cases are paraneoplastic. Acute relapses of NMO are treated with glucocorticoids and, for severe or refractory cases, plasma exchange. Three monoclonal antibodies are now available for prophylactic treatment: eculizumab, a terminal complement inhibitor; inebilizumab, a B-cell depleter; and satralizumab, an interleukin (IL) 6 receptor blocker. Other options include off-label use of azathioprine, mycophenolate, or rituximab. Treatment for 5 years or longer is gener­ ally recommended. NMO is discussed in Chap. 456. SARCOIDOSIS  Sarcoid myelopathy may present as a slowly progressive or relapsing disorder. Clinically, sensory involvement often predomi­ nates. MRI may show edematous swelling of the spinal cord mimicking tumor and in some cases longitudinally extensive involvement resem­ bling NMO. Subpial gadolinium enhancement of active lesions, which may appear nodular, are typically located along the dorsal surface of the cord; on axial images, these dorsal lesions combined with enhance­ ment of the central canal can produce a characteristic “trident sign.” The typical CSF profile consists of a mild lymphocyte-predominant pleocytosis and elevated protein level; in a minority of cases, reduced glucose and oligoclonal bands are found. When present, the hypogly­ corrhachia can be helpful in distinguishing neurosarcoid from other noninfectious causes of myelitis. The diagnosis is particularly difficult when systemic manifestations of sarcoid are minor or absent (nearly 50% of cases) or when other typical neurologic manifestations of the disease, such as cranial neuropathy, hypothalamic involvement, or meningeal enhancement visualized by MRI, are lacking. A slit-lamp examination of the eye to search for uveitis, chest x-ray and CT to assess pulmonary involvement and mediastinal lymphadenopathy, serum or CSF angiotensin-converting enzyme (ACE; lacks specificity and values are elevated in only a minority of cases), serum calcium, and a gallium scan may assist in the diagnosis. Initial treatment is with high doses of glucocorticoids, which need to be administered long term and tapered slowly while monitoring resolution of clinical and MRI signs of active disease; relapses are managed with high-dose glucocorticoids plus a steroid-sparing immunosuppressant drug (typically mycopheno­ late mofetil, azathioprine, or methotrexate) or with the tumor necrosis factor α-inhibitor infliximab. Sarcoidosis is discussed in Chap. 379. SYSTEMIC IMMUNE-MEDIATED DISORDERS  Myelitis occurs in a small number of patients with SLE, many cases of which are associated with antibodies to AQP-4 and satisfy diagnostic criteria for NMO (discussed above). These patients are at high risk of developing future episodes of myelitis and/or optic neuritis. In others, the etiology of SLE-associated myelitis is uncertain. Antiphospholipid antibodies have been sug­ gested to play a role; however, the frequency of these antibodies is similar in SLE patients with and without myelitis. NMO-associated myelitis typically produces severe clinical disease, CSF pleocytosis with polymorphonuclear leukocytes, and an MRI pattern of central gray matter spinal cord involvement; in cases not due to NMO, less severe and more subacutely evolving clinical findings are often present, with milder CSF lymphocytic pleocytosis and MRI changes consistent with white matter involvement of the cord. In both forms, CSF oligoclonal bands are variable findings. There are no systematic trials of therapy for SLE myelitis, but based on limited data, patients with AQP-4 antibodies should be treated as for NMO (above), and in others, high-dose glu­ cocorticoids followed by cyclophosphamide have been recommended. Severe episodes that do not initially respond to glucocorticoids are often treated with a course of plasma exchange. Sjögren’s syndrome (Chap. 373) can also be associated with NMO and also with cases of chronic progressive myelopathy. Other immune-mediated myelitides include Behçet’s disease (Chap. 376), antiphospholipid antibody syn­ drome (Chap. 369), mixed connective tissue disease (Chap. 372), and vasculitis related to polyarteritis nodosa, perinuclear antineutrophilic cytoplasmic (pANCA) antibodies, or primary CNS vasculitis (Chap. 375). Occasional cases of myelitis, often accompanied by other manifestations that can include encephalitis or optic neuritis, have been associated with autoantibodies against glial fibrillary acidic pro­ tein (GFAP) (Chap. 456). Other rare etiologies are chronic lympho­ cytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) and Erdheim-Chester disease producing inflammatory mass-like lesions that can be intramedullary or extra­ axial and compressive. PART 13 Neurologic Disorders POSTINFECTIOUS MYELITIS  Many cases of myelitis, termed postinfec­ tious or postvaccinal, follow an infection or vaccination. Numerous organisms have been implicated, including Epstein-Barr virus (EBV), cytomegalovirus (CMV), and mycoplasma most frequently, with many others including influenza, measles, varicella, mumps, and yellow fever also described. Recently, vaccination (or active infection) with SARS-CoV-2 virus has been associated with a small number of cases of myelitis and NMO. As in the related disorder acute disseminated encephalomyelitis (Chap. 456), postinfectious myelitis often begins as the patient appears to be recovering from an acute febrile infection or in the subsequent days or weeks, but an infectious agent cannot be isolated from the nervous system or CSF. Serum anti-MOG antibodies are present acutely in some cases, especially in children. The presump­ tion is that the myelitis represents an autoimmune disorder triggered by infection and is not due to direct infection of the spinal cord. No randomized controlled trials of therapy exist; treatment is usually with glucocorticoids or, in fulminant cases, plasma exchange. ACUTE INFECTIOUS MYELITIS  Many viruses have been associated with an acute myelitis that is infectious in nature rather than postinfec­ tious. Nonetheless, the two processes are often difficult to distinguish. Herpes zoster is a well characterized agent of viral myelitis, with direct spread to the spinal cord from dorsal root ganglia, and HSV types 1 and 2, EBV, CMV, and rabies virus are other well-described causes. Zika virus has also been recognized as a cause of infectious myelitis, as has a rare association with monkeypox. HSV-2 (and less commonly HSV-1) produces a distinctive syndrome of recurrent sacral and cauda equina neuritis in association with outbreaks of genital herpes (Elsberg’s syndrome). Poliomyelitis is a prototypic viral myelitis that is more or less restricted to the anterior gray matter of the cord contain­ ing the spinal motoneurons. A polio-like syndrome can also be caused by a large number of enteroviruses (including enterovirus A-71 and coxsackie) and, importantly, by West Nile virus and other flaviviruses such as Japanese encephalitis. Beginning in 2012, cases of acute flaccid paralysis in children and adolescents have appeared associated with enterovirus A-71 and D-68 infection. Chronic viral myelitic infections, such as those due to HIV or human T-cell lymphotropic virus type 1 (HTLV-1), are discussed below. Bacterial and mycobacterial myelitis (most are essentially abscesses) are less common than viral causes and much less frequent than cerebral bacterial abscess. Almost any pathogenic species may be responsible, including Borrelia burgdorferi (Lyme disease), Listeria monocytogenes, Mycobacterium tuberculosis, and Treponema pallidum (syphilis). Myco­ plasma pneumoniae may be a cause of myelitis, but its status is uncer­ tain because many cases are more properly classified as postinfectious. Schistosomiasis (Chap. 241) is an important cause of parasitic myelitis in endemic areas. The process is intensely inflammatory and granulomatous, caused by a local response to tissue-digesting enzymes from the ova of the parasite, typically Schistosoma haematobium or Schistosoma mansoni. Toxoplasmosis (Chap. 235) can occasionally cause a focal myelopathy, and this diagnosis should especially be con­ sidered in patients with AIDS (Chap. 208). Cysticercosis (Chap. 242) is another consideration, although myelitis from this helminth is far less common than parenchymal brain or meningeal involvement. In cases of suspected viral myelitis, it may be appropriate to begin specific therapy pending laboratory confirmation. Herpes zoster, HSV, and EBV myelitis are treated with intravenous acyclovir (10 mg/kg q8h) or oral valacyclovir (2 g tid) for 10–14 days; CMV is treated with ganciclovir (5 mg/kg IV bid) plus foscarnet (60 mg/kg IV tid) or cido­ fovir (5 mg/kg per week for 2 weeks, then biweekly for two additional doses). High-Voltage Electrical Injury  Spinal cord injuries are promi­ nent following electrocution from lightning strikes or other accidental electrical exposures. The syndrome consists of transient weakness acutely (often with an altered sensorium and focal cerebral distur­ bances), sometimes followed several days or even weeks later by a myelopathy that can be severe and permanent. This is a rare injury type, and limited data incriminate a vascular pathology involving the anterior spinal artery and its branches in some cases. Therapy is supportive. CHRONIC MYELOPATHIES ■ ■SPONDYLOTIC MYELOPATHY Spondylotic myelopathy is the most common cause of myelopathy and of gait difficulty in the elderly, accounting for more than half of non­ traumatic spinal cord injuries in some series. Neck and shoulder pain with stiffness are early symptoms; impingement of bone and soft tissue overgrowth on nerve roots results in radicular arm pain, most often in a C5 or C6 distribution. Compression of the cervical cord, which occurs in fewer than one-third of cases, produces a slowly progressive spastic paraparesis, at times asymmetric and often accompanied by paresthesias in the feet and hands. Vibratory sense is diminished in the legs, there is a Romberg sign, and occasionally there is a sensory level for vibration or pinprick on the upper thorax. In some cases, cough­ ing or straining produces leg weakness or radiating arm or shoulder pain. Dermatomal sensory loss in the arms, atrophy of intrinsic hand muscles, increased deep-tendon reflexes in the legs, and extensor plan­ tar responses are common. Urinary urgency or incontinence occurs in advanced cases, but there are many alternative causes of these problems in older individuals. A tendon reflex in the arms is often diminished at some level, most often at the biceps (C5–C6). In individual cases, radicular, myelopathic, or combined signs may predominate. The diagnosis should always be considered in cases of progressive cervical myelopathy, paresthesias of the feet and hands, or wasting of the hands. Diagnosis is usually made by MRI and may be suspected from CT images; plain x-rays are less helpful. Extrinsic cord compression and deformation are appreciated on axial MRI views, and T2-weighted sequences may reveal areas of high signal intensity within the cord adjacent to the site of compression. A cervical collar may be helpful in milder cases, but the likelihood of progression of medically treated myelopathy is high, estimated at 8% over 1 year. Definitive therapy consists of surgical decompression, either posterior laminectomy or an anterior approach with resection of the protruded disk and bony material. Cervical spondylosis and related degenerative diseases of the upper spine are discussed in Chap. 19. ■ ■VASCULAR MALFORMATIONS OF THE CORD AND DURA Vascular malformations, comprising ~4% of all mass lesions of the cord and overlying dura, are treatable causes of progressive myelopathy. Most common are fistulas located within the dura or posteriorly along the surface of the cord. Most dural arteriovenous (AV) fistulas are located at or below the midthoracic level, usually consisting of a direct connection between a radicular feeding artery in the nerve root sleeve with dural veins. The typical presentation is a middle-aged man with a progressive myelopathy that worsens slowly or intermittently and may have periods of remission, sometimes mimicking MS. Acute deteriora­ tion due to hemorrhage into the spinal cord (hematomyelia) or sub­ arachnoid space may also occur but is rare. In many cases, progression results from local ischemia and edema due to venous congestion. Most patients have incomplete sensory, motor, and bladder disturbances. The motor disorder may predominate and produce a mixture of upper and restricted lower motor neuron signs, simulating amyotrophic lateral sclerosis (ALS). Pain over the dorsal spine, dysesthesias, or radicular pain may be present. Other symptoms suggestive of AV mal­ formation (AVM) or dural fistula include intermittent claudication; symptoms that change with posture, exertion, Valsalva maneuver, or menses; and fever. Less commonly, AVM disorders are intramedullary rather than dural. One unusual disorder is a progressive thoracic myelopathy with paraparesis developing over weeks or months, characterized pathologi­ cally by abnormally thick, hyalinized vessels within the cord (subacute necrotic myelopathy or Foix-Alajouanine syndrome). Spinal bruits are infrequent but may be sought at rest and after exercise in suspected cases. A vascular nevus on the overlying skin may indicate an underlying vascular malformation as occurs with KlippelTrenaunay-Weber syndrome. MR angiography and CT angiography can detect the draining vessels of many AVMs (Fig. 453-6). Definitive diagnosis requires selective spinal angiography, which defines the feed­ ing vessels and the extent of the malformation. Treatment is tailored to the anatomy and location of the lesion and generally consists of microsurgical resection, endovascular embolization of the major feed­ ing vessels, or a combination of the two approaches. ■ ■RETROVIRUS-ASSOCIATED MYELOPATHIES The myelopathy associated with HTLV-1, formerly called tropical spas­ tic paraparesis, is a slowly progressive spastic syndrome with variable sensory and bladder disturbance. Approximately half of patients have mild back or leg pain. The neurologic signs may be asymmetric, often lacking a well-defined sensory level; the only sign in the arms may be hyperreflexia after several years of illness. The onset is usually insidi­ ous, and the tempo of clinical progression occurs at a variable rate; in one study, median time for progression to cane-, walker-, or wheel­ chair-dependent state was 6, 13, and 21 years, respectively. Progres­ sion appears to be more rapid in older patients and those with higher viral loads. Diagnosis is made by demonstration of HTLV-1-specific antibody in serum by enzyme-linked immunosorbent assay (ELISA), confirmed by radioimmunoprecipitation or Western blot analysis. Especially in endemic areas, a finding of HTLV-1 seropositivity in a patient with myelopathy does not necessarily prove that HTLV-1 is causative. The CSF/serum antibody index may provide support by establishing intrathecal synthesis of antibodies, including oligoclonal antibodies, favoring HTVL-1 myelopathy over asymptomatic carriage. CHAPTER 453 FIGURE 453-6  Arteriovenous malformation. Sagittal magnetic resonance scans of the thoracic spinal cord: T2 fast spin-echo technique (left) and T1 postcontrast image (right). On the T2-weighted image (left), abnormally high signal intensity is noted in the central aspect of the spinal cord (arrowheads). Numerous punctate flow voids indent the dorsal and ventral spinal cord (arrow). These represent the abnormally dilated venous plexus supplied by a dural arteriovenous fistula. After contrast administration (right), multiple, serpentine, enhancing veins (arrows) on the ventral and dorsal aspect of the thoracic spinal cord are visualized, diagnostic of arteriovenous malformation. This patient was a 54-year-old man with a 4-year history of progressive paraparesis. Diseases of the Spinal Cord Measuring proviral DNA by polymerase chain reaction (PCR) in peripheral blood and CSF cells can be useful as an ancillary part of diagnosis. The pathogenesis of the myelopathy is uncertain. It could result from an immune response directed against HTLV-1 antigens in the nervous system or, alternatively, to secondary autoimmunity trig­ gered by the viral infection. There is no proven effective treatment. Based on limited evidence, systemic glucocorticoids, pulsed high-dose induction followed by low-dose chronic maintenance, can be tried, and mogamulizumab, a monoclonal antibody directed against CCR4, has been reported in one preliminary trial to slow progression and reduce neurologic disability in some recipients. A progressive myelopathy can also result from HIV infection (Chap. 208). It is characterized by vacuolar degeneration of the pos­ terior and lateral tracts, resembling subacute combined degeneration (see below). SYRINGOMYELIA Syringomyelia is a developmental cavity in the cervical cord that may enlarge and produce progressive myelopathy or may remain asymptomatic. Symptoms begin insidiously in adolescence or early adulthood, progress irregularly, and may undergo spontaneous arrest for several years. Many young patients acquire a cervical-thoracic scoliosis. More than half of all cases are associated with Chiari type 1 malformations in which the cerebellar tonsils protrude through the foramen magnum and into the cervical spinal canal. The pathophysi­ ology of syrinx expansion is controversial, but some interference with the normal flow of CSF seems likely, perhaps by the Chiari malfor­ mation. Acquired cavitations of the cord in areas of necrosis are also termed syrinx cavities; these follow trauma, myelitis, necrotic spinal cord tumors, and chronic arachnoiditis due to tuberculosis and other etiologies. The presentation is a central cord syndrome consisting of a regional dissociated sensory loss (loss of pain and temperature sensation with sparing of touch and vibration) and areflexic weakness in the upper limbs. The sensory deficit has a distribution that is “suspended” over the nape of the neck, shoulders, and upper arms (cape distribution) or in the hands. Most cases begin asymmetrically with unilateral sensory loss in the hands that leads to injuries and burns that are not PART 13 Neurologic Disorders FIGURE 453-7  Magnetic resonance imaging of syringomyelia associated with a Chiari malformation. Sagittal T1-weighted image through the cervical and upper thoracic spine demonstrates descent of the cerebellar tonsils below the level of the foramen magnum (black arrows). Within the substance of the cervical and thoracic spinal cord, a cerebrospinal fluid collection dilates the central canal (white arrows). appreciated by the patient. Muscle wasting in the lower neck, shoul­ ders, arms, and hands with asymmetric or absent reflexes in the arms reflects expansion of the cavity in the gray matter of the cord. As the cavity enlarges and compresses the long tracts, spasticity and weakness of the legs, bladder and bowel dysfunction, and Horner’s syndrome appear. Some patients develop facial numbness and sensory loss from damage to the descending tract of the trigeminal nerve (C2 level or above). In cases with Chiari malformations, cough-induced headache and neck, arm, or facial pain may be reported. Extension of the syrinx into the medulla, syringobulbia, causes palatal or vocal cord paralysis, dysarthria, horizontal or vertical nystagmus, episodic dizziness or ver­ tigo, and tongue weakness with atrophy. MRI accurately identifies developmental and acquired syrinx cavi­ ties and their associated spinal cord enlargement (Fig. 453-7). Images of the brain and the entire spinal cord should be obtained to delineate the full longitudinal extent of the syrinx, assess posterior fossa struc­ tures for the Chiari malformation, and determine whether hydro­ cephalus is present. TREATMENT Syringomyelia Surgical decompression is the treatment of choice, with mixed results reported in most series. The Chiari tonsillar herniation may be decompressed, generally by suboccipital craniectomy, upper cer­ vical laminectomy, and placement of a dural graft. Fourth ventricular outflow is reestablished by this procedure. If the syrinx cavity is large, some surgeons recommend direct decompression or drainage, but an added benefit of this procedure has not been demonstrated, and complications are common. Shunting of hydrocephalus, when pres­ ent, generally precedes any attempt to correct the syrinx. Surgery may stabilize the neurologic deficit, and some patients improve. Patients with few symptoms and signs from the syrinx do not require surgery and are followed by serial clinical and imaging examinations. Syrinx cavities secondary to trauma or infection, if symptomatic, can be treated with a decompression and drainage procedure in which a small shunt is inserted between the cavity and subarach­ noid space; alternatively, the cavity can be fenestrated. Cases due to intramedullary spinal cord tumor are generally managed by resec­ tion of the tumor. ■ ■CHRONIC MYELOPATHY OF MULTIPLE SCLEROSIS A chronic progressive myelopathy is the most frequent cause of dis­ ability in both primary progressive and secondary progressive forms of MS. Involvement is typically bilateral but asymmetric and produces motor, sensory, and bladder/bowel disturbances. Fixed motor disabil­ ity appears to result from extensive loss of axons in the corticospinal tracts. Diagnosis is facilitated by identification of earlier attacks such as optic neuritis. MRI, CSF, and evoked-response testing are confirma­ tory. Treatment with ocrelizumab, an anti-CD20 B-cell monoclonal antibody, is effective in patients with primary progressive MS, and disease-modifying therapy is also indicated in patients with secondary progressive MS who have clinical or MRI evidence of active disease. MS is discussed in Chap. 455. ■ ■SUBACUTE COMBINED DEGENERATION (VITAMIN B12 DEFICIENCY) This treatable myelopathy presents with subacute paresthesias in the hands and feet, loss of vibration and position sensation, and a progres­ sive spastic and ataxic weakness. Loss of reflexes due to an associated peripheral neuropathy in a patient who also has Babinski signs is a helpful diagnostic clue. Optic atrophy and irritability or other cogni­ tive changes may be prominent in advanced cases and are occasion­ ally the presenting symptoms. The myelopathy of subacute combined degeneration tends to be diffuse rather than focal; signs are generally symmetric and reflect predominant involvement of the posterior and lateral tracts, including Romberg sign. Causes include dietary defi­ ciency, especially in vegans, and gastric malabsorption syndromes including pernicious anemia (Chap. 104). The diagnosis is confirmed by the finding of macrocytic red blood cells, a low serum B12 concen­ tration, and elevated serum levels of homocysteine and methylmalonic acid. Treatment is by replacement therapy, beginning with 1000 μg of intramuscular vitamin B12 daily for 5–7 days and then continued as a once-weekly dose for 4–8 weeks and then as a monthly maintenance dose; oral maintenance with high doses of cyanocobalamin (1–2 mg daily) can also be used for maintenance, as small amounts of vitamin B12 are absorbed passively by the gut even in pernicious anemia. Two closely related conditions deserve mention here. The first is folate deficiency–associated myelopathy, now only rarely seen since widespread programs of dietary fortification with folate have been implemented. A second is due to inhalation with nitrous oxide (laugh­ ing gas), an irreversible inhibitor of vitamin B12, which also produces a myelopathy identical to subacute combined degeneration. Exposure to nitrous oxide may occur during dental or surgical procedures or from recreational inhalation (“doing whippets”). ■ ■HYPOCUPRIC MYELOPATHY This myelopathy is similar to subacute combined degeneration, except serum levels of B12 are normal. Low levels of serum copper are found, and often there is also a low level of serum ceruloplasmin. Some cases follow gastrointestinal procedures, particularly bariatric surgery, that result in impaired copper absorption; others have been associated with excess zinc from health food supplements or, in the past, zinccontaining denture creams, all of which impair copper absorption via induction of metallothionein, a copper-binding protein. Many cases are idiopathic. There is often a coexisting anemia. Improvement or at least stabilization may be expected with reconstitution of copper stores by oral supplementation (2 mg/d). ■ ■TABES DORSALIS The classic syphilitic syndromes of tabes dorsalis and meningovascular inflammation of the spinal cord are now less frequent than in the past but must be considered in the differential diagnosis of spinal cord dis­ orders. The characteristic symptoms of tabes are fleeting and repetitive lancinating pains, primarily in the legs or less often in the back, thorax, abdomen, arms, and face. Ataxia of the legs and gait due to loss of position sense occurs in half of patients. Paresthesias, bladder distur­ bances, and acute abdominal pain with vomiting (visceral crisis) occur in 15–30% of patients. The cardinal signs of tabes are loss of reflexes in the legs; impaired position and vibratory sense; Romberg sign; and, in almost all cases, bilateral Argyll Robertson pupils, which fail to constrict to light but accommodate. Diabetic polyradiculopathy may simulate this condition. Treatment of tabes dorsalis and other forms of neurosyphilis consists of penicillin G administered intravenously, or intramuscularly in combination with oral probenecid (Chap. 187). ■ ■HEREDITARY SPASTIC PARAPLEGIA Many cases of slowly progressive myelopathy are genetic in origin (Chap. 448). More than 90 different causative loci have been identi­ fied, including autosomal dominant, autosomal recessive, and X-linked forms. Especially for the recessive and X-linked forms, a family his­ tory of myelopathy may be lacking. Most patients present with almost imperceptibly progressive spasticity and weakness in the legs, usually but not always symmetrical. Sensory symptoms and signs are absent or mild, but sphincter disturbances may be present. In some families, additional neurologic signs are prominent, including nystagmus, ataxia, or optic atrophy. The onset may be as early as the first year of life or as late as middle adulthood. Only symptomatic therapies are available. PRIMARY LATERAL SCLEROSIS This is a mid- to late-life-onset degenerative disorder characterized by progressive spasticity with weakness, eventually accompanied by dysarthria and dysphonia; bladder symptoms occur in approximately half of patients. Sensory function is spared. The disorder resembles ALS and is considered a variant of the motor neuron degenerations, but without the characteristic lower motor neuron disturbance and with typically a slower progression. Some cases may represent late-onset cases of hereditary spastic paraplegia, particularly autosomal recessive or X-linked varieties in which a family history may be absent. (See also Chap. 448.) ■ ■ADRENOMYELONEUROPATHY This X-linked peroxisomal disorder is a variant of adrenoleukodystro­ phy (ALD). Most affected males have a history of adrenal insufficiency and then develop a progressive spastic (or ataxic) paraparesis begin­ ning in early or sometimes middle adulthood; some patients also have cerebral involvement and/or a mild peripheral neuropathy. Female heterozygotes may develop a slower, insidiously progressive spastic myelopathy beginning later in adulthood and without adrenal insuffi­ ciency. Diagnosis is usually made by demonstration of elevated levels of very-long-chain fatty acids in plasma and in cultured fibroblasts. The responsible gene encodes the adrenoleukodystrophy protein (ALDP), a peroxisomal membrane transporter involved in carrying long-chain fatty acids to peroxisomes for degradation. Corticosteroid replacement is indicated if hypoadrenalism is present. Allogeneic bone marrow transplantation has been successful in slowing progression of cogni­ tive decline in some patients with ALD treated early in their disease but appears to be ineffective for the myelopathy. A preliminary study of leriglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist, reported suggestive slowing of myelopathic signs in some patients, but the primary endpoint was not met. Nutritional supplements (Lorenzo’s oil) have also been attempted for this condition without evidence of efficacy. ■ ■CANCER-RELATED SYNDROMES Cancer-related causes of chronic myelopathy, besides the common neoplastic compressive myelopathy discussed earlier, include radia­ tion injury (Chap. 95) and a myelopathy resembling subacute com­ bined degeneration that can follow intrathecal administration of TABLE 453-4  Expected Neurologic Function Following Complete Cord Lesions LEVEL SELF-CARE TRANSFERS MAXIMUM MOBILITY High quadriplegia (C1–C4) Dependent on others; requires respiratory support Dependent on others Motorized wheelchair Low quadriplegia (C5–C8) Partially independent with adaptive equipment May be dependent or independent May use manual wheelchair, drive an automobile with adaptive equipment Paraplegia (below T1) Independent Independent Ambulates short distances with aids Source: Adapted from JF Ditunno, CS Formal: Chronic spinal cord injury. N Engl J Med 330:550, 1994. methotrexate (a folate antagonist). Rare paraneoplastic myelopathies are most often associated with lung cancer and anti-amphiphysin (also breast), anti-collapsin response mediator 5 (CRMP5) (also lymphoma), or anti-Hu antibodies (Chap. 99). Another uncommon lymphomaassociated paraneoplastic syndrome is a progressive flaccid paresis with destruction of anterior horn cells. NMO with AQP-4 antibodies (Chap. 456) can also rarely be paraneoplastic in origin. Several series have reported cases of myelopathy associated with use of checkpoint inhibitors in cancer treatment; some are associated with development of paraneoplastic or NMO antibodies. Metastases to the cord are prob­ ably more common than any of these disorders in patients with cancer. ■ ■OTHER CHRONIC MYELOPATHIES Tethered cord syndrome is a developmental disorder of the lower spinal cord and nerve roots that rarely presents in adulthood as low back pain accompanied by a progressive lower spinal cord and/or nerve root syndrome. Some patients have a leg or foot deformity indicating a longstanding process, and in others, a dimple, patch of hair, or sinus tract on the skin overlying the lower back is the clue to a congenital lesion. Diagnosis is made by MRI, which demonstrates a low-lying conus medullaris and thickened filum terminale. The MRI may also reveal diastematomyelia (division of the lower spinal cord into two halves), lipomas, cysts, or other congenital abnormalities of the lower spine coexisting with the tethered cord. Treatment is with surgical release. CHAPTER 453 Diseases of the Spinal Cord There are a number of rare toxic causes of spastic myelopathy, including lathyrism due to ingestion of chickpeas containing the exci­ totoxin β-N-oxalylamino-L-alanine (BOAA), seen primarily in the developing world or during famines, and Konzo due to ingestion of the cyanogen-containing casava plant found in sub-Saharan Africa. Often, a cause of intrinsic myelopathy can be identified only through periodic reassessment. REHABILITATION OF SPINAL CORD DISORDERS The prospects for recovery from an acute destructive spinal cord lesion fade after ~6 months. There are currently no effective means to promote repair of injured spinal cord tissue; promising but entirely experimental approaches include the use of factors that influence rein­ nervation by axons of the corticospinal tract, nerve and neural sheath graft bridges, forms of electrical stimulation at the site of injury, and the local introduction of stem cells. The disability associated with irreversible spinal cord damage is determined primarily by the level of the lesion and by whether the disturbance in function is complete or incomplete (Table 453-4). Even a complete high cervical cord lesion may be compatible with a productive life. The primary goals are devel­ opment of a rehabilitation plan framed by realistic expectations and attention to the neurologic, medical, and psychological complications that commonly arise. Many of the usual symptoms associated with medical illnesses, especially somatic and visceral pain, may be lacking because of the destruction of afferent pain pathways. Unexplained fever, worsening of spasticity, or deterioration in neurologic function should prompt a search for infection, thrombophlebitis, or an intraabdominal pathol­ ogy. The loss of normal thermoregulation and inability to maintain normal body temperature can produce recurrent fever (quadriplegic fever), although most episodes of fever are due to infection of the uri­ nary tract, lung, skin, or bone. Bladder dysfunction generally results from loss of supraspinal innervation of the detrusor muscle of the bladder wall and the # 24 - 454 Concussion and Other Traumatic Brain Injuries ### 454 Concussion and Other Traumatic Brain Injuries sphincter musculature. Detrusor spasticity is treated with anticholin­ ergic drugs (oxybutynin, 2.5–5 mg qid) or tricyclic antidepressants with anticholinergic properties (imipramine, 25–200 mg/d). Failure of the sphincter muscle to relax during bladder emptying (urinary dyssynergia) may be managed with the α-adrenergic blocking agent terazosin hydrochloride (1–2 mg tid or qid), with intermittent cath­ eterization, or, if that is not feasible, by use of a condom catheter in men or a permanent indwelling catheter. Surgical options include the creation of an artificial bladder by isolating a segment of intestine that can be catheterized intermittently (enterocystoplasty) or can drain continuously to an external appliance (urinary conduit). Bladder areflexia due to acute spinal shock or conus lesions is best treated by catheterization. Bowel regimens and disimpaction are necessary in many patients to ensure at least biweekly evacuation and avoid colonic distention or obstruction. Patients with acute cord injury are at risk for venous thrombosis and pulmonary embolism. Use of calf-compression devices and anticoagu­ lation with low-molecular-weight heparin are recommended. In cases of persistent paralysis, anticoagulation should probably be continued for 3 months. PART 13 Neurologic Disorders Prophylaxis against decubitus ulcers should involve frequent changes in position in a chair or bed, the use of special mattresses, and cushioning of areas where pressure sores often develop, such as the sacral prominence and heels. Early treatment of ulcers with care­ ful cleansing, surgical or enzyme debridement of necrotic tissue, and appropriate dressing and drainage may prevent infection of adjacent soft tissue or bone. Spasticity is aided by stretching exercises to maintain mobility of joints. Drug treatment is effective but may result in reduced function, as some patients depend on spasticity as an aid to stand, transfer, or walk. Baclofen (up to 240 mg/d in divided doses) is effective; it acts by facilitating γ-aminobutyric acid–mediated inhibition of motor reflex arcs. Diazepam acts by a similar mechanism and is useful for leg spasms that interrupt sleep (2–4 mg at bedtime). Tizanidine (2–8 mg tid), an α2 adrenergic agonist that increases presynaptic inhibition of motor neu­ rons, is another option. For nonambulatory patients, the direct muscle inhibitor dantrolene (25–100 mg qid) may be used, but it is potentially hepatotoxic. In refractory cases, intrathecal baclofen administered via an implanted pump, botulinum toxin injections, or dorsal rhizotomy may be required to control spasticity. Despite the loss of sensory function, many patients with spinal cord injury experience chronic pain sufficient to diminish their quality of life. Randomized controlled studies indicate that gabapentin or prega­ balin is useful in this setting. Epidural electrical stimulation and intra­ thecal infusion of pain medications have been tried with some success. Management of chronic pain is discussed in Chap. 14. A paroxysmal autonomic hyperreflexia may occur following lesions above the major splanchnic sympathetic outflow at T6. Headache, flushing, and diaphoresis above the level of the lesion, as well as hyper­ tension with bradycardia or tachycardia, are the major symptoms. The trigger is typically a noxious stimulus—for example, bladder or bowel distention, a urinary tract infection, or a decubitus ulcer—below the level of the cord lesion. Treatment consists of removal of offending stimuli; ganglionic blocking agents (mecamylamine, 2.5–5 mg) or other short-acting antihypertensive drugs are useful in some patients. Emerging neuro-therapeutic technologies, including rehabilitation robotics and brain-machine interfaces, offer real hope to advance prospects for full and productive lives in patients with disabling myelopathies (Chap. 500). ■ ■FURTHER READING Badhiwala JH et al: Degenerative cervical myelopathy—update and future directions. Nat Rev Neurol 16:108, 2020. Bradshaw MJ et al: Neurosarcoidosis: Pathophysiology, diagnosis, and treatment. Neurol Neuroimmunol Neuroinflamm 8:e1084, 2021. Garg RK et al: Spinal cord involvement in COVID-19: A review. J Spinal Cord Med 46:390, 2023. Gritsch D, Valencia-Sanchez C: Drug-related immune-mediated myelopathies. Front Neurol 13:1003270, 2022. Hassing LT et al: Nitrous-oxide-induced polyneuropathy and sub­ acute combined degeneration of the spine: Clinical and diagnostic characteristics in 70 patients, with focus on electrodiagnostic studies. Eur J Neurol 31:e16076, 2024. Holroyd KB, Berkowitz AL: Metabolic and toxic myelopathies. Continuum (Minneap Minn) 30:199, 2024. Jain S et al: Transverse myelitis associated with systemic lupus erythe­ matosus (SLE-TM): A review article. Lupus 32:1033, 2023. Kühl JS et al: Long-term outcomes of allogeneic haematopoietic stem cell transplantation for adult cerebral X-linked adrenoleukodystrophy. Brain 140:953, 2017. Montalvo M, Flanagan EP: Paraneoplastic/autoimmune myelopa­ thies. Handb Clin Neurol 200:193, 2024. Ropper AE, Ropper AH: Acute spinal cord compression. N Engl J Med 376:1358, 2017. Stenimahitis V et al: Long-term outcomes after periprocedural and spontaneous spinal cord infarctions: A population-based cohort study. Neurology 101:e114, 2023. Yáñez ML et al: Diagnosis and treatment of epidural metastases. Cancer 123:1106, 2017. Geoffrey T. Manley, Benjamin L. Brett, Michael McCrea Concussion and Other Traumatic Brain Injuries Traumatic brain injury (TBI) represents a significant global public health problem. In the United States, estimates of the frequency of TBI range between 2.5 and 4.8 million cases per year, depending on the study and methods used to define and include cases. Age-specific rates show a bimodal distribution, with highest risk in younger individuals and older adults. The most common mechanism of injury in the young is motor vehicle accidents and is more common in men, whereas in older adults, falls are the major cause of injury and are more likely to occur in women. Nonfatal TBI-related hospitalization rates are com­ parable across non-Hispanic white, non-Hispanic black, and Hispanic persons with age adjustment. TBI imposes substantial demands on health care systems. Worldwide, at least 10 million TBIs are serious enough to result in death or hospi­ talization, producing a global economic burden of $400 billion annu­ ally. In the United States, the estimated annual cost is >$76 billion. Due to advances in medical care and other factors, more people are surviving TBI than ever before. Brain injury accounts for more lost productivity at work among Americans than any other form of injury. An estimated 5.3 million Americans are living with significant disabili­ ties resulting from TBI that complicate their return to a full and pro­ ductive life. Increased media attention to military and sports-related TBI has highlighted the growing concern that injuries that were previ­ ously dismissed can have lifelong consequences for some individuals. Head injuries are so common that almost all physicians will be called upon to provide some aspect of immediate care or to see patients who are suffering from various sequelae. Patients and their families initially need education regarding the natural history of TBI along with treatment of acute symptoms such as headache. Continued follow-up is important to ensure that the sequelae experienced by some patients— such as the persistent postconcussion symptoms (PPCS) of headache, disturbances in balance, depression, and sleep disorder—are identified and treated appropriately. Effective management of TBI and its conse­ quences often requires a coordinated multidisciplinary care team. ■ ■DEFINITION AND CLASSIFICATION TBI is commonly defined as an alteration in brain function, or other evidence of brain pathology, caused by an external force, and character­ ized by the following: (1) any period of loss or decreased level of con­ sciousness (LOC), (2) any loss of memory for events immediately before (retrograde) or after (posttraumatic) the injury, (3) any neurologic deficits, and/or (4) any alteration in mental state at the time of injury. Evidence of TBI can include visual, neuroradiologic, or laboratory confirmation of damage to the brain, but TBI is more often diagnosed on the basis of acute clinical criteria. In addition to standard com­ puted tomography (CT) imaging and conventional clinical magnetic resonance imaging (MRI), advanced MRI imaging (functional MRI, cerebral blood flow, diffusion MRI) techniques show increasing sen­ sitivity, and it is likely that sensitive blood-based biomarkers will play an increasingly important role in the diagnosis and treatment of these patients (described below). Mechanisms of TBI  Common mechanisms of TBI include the head being struck by an object, the head striking an object, the brain undergoing an acceleration/deceleration movement, a foreign body penetrating the brain, or forces generated from events such as a blast or explosion. Unintentional falls and motor vehicle crashes have his­ torically been cited as the most common cause of TBI. All forms of transportation, however, are common causes of TBI, including motor­ cycle crashes, bicycle accidents, skateboarding, and pedestrian injuries. The other leading causes of TBI are falls, assaults, and sports, with var­ ied frequency across the lifespan. Certainly, there has been an increased focus on the high frequency of mild TBI (mTBI), often referred to as concussion, encountered by athletes participating in contact and colli­ sion sports at all competitive levels, as well as the potential short-term effects and long-term risks associated with sport-related concussion. Classification of TBI Severity  Numerous systems have been developed over the years to define and classify TBI severity along a con­ tinuum from mild to moderate to severe. These systems are usually most applicable to closed head injuries. In nearly all classification systems, TBI severity is graded based on acute injury characteristics rather than post­ acute injury status, as other factors can intervene to influence functional outcome. This can be problematic, as some patients with severe TBI will have a full recovery and some with mild TBI will be left with lifetime disability. Historically, the presence and duration of unconsciousness and amnesia have been the main points of distinction along the gra­ dient of TBI severity. Efforts to develop more advanced classification systems that incorporate patho-anatomical features reflecting biological response to injury, such as blood-based biomarkers, as well as socioen­ vironmental factors that may influence ultimate prognosis are currently underway. A recent working group convened by the National Institutes of Health has proposed a new framework for TBI characterization that includes clinical features, blood-based biomarkers, and imaging features, along with modifiers. As this more precise nomenclature is validated, it is anticipated that it will replace the current approach of characterizing patients based solely on their clinical exam and symptoms. The Glasgow Coma Scale (GCS) is the most recognized and widely used method for grading TBI severity. The GCS provides a practical indicator of gross neurologic status by assessing motor function, verbal responses, and the patient’s ability to open his or her eyes voluntarily or in response to external commands and stimuli. The grading is applied to the best response that can be elicited from the patient at the time of assessment, preferably before any paralyzing or sedating medication is administered or the patient is intubated, as these interventions con­ found interpretation of the score. The GCS assessment produces scores ranging from 3 to 15 (Table 454-1). Upon the 40th anniversary of the GCS in 2014, the wording for responses was revised, and recommendations were made to improve its utility. Importantly, individual patients are best described by the three components of the coma scale (eye, verbal, motor, e.g., E3V4M6); the derived total coma score (e.g., 13) is less informative and should only be used to characterize groups of patients. Several injury-classification systems have been developed to go beyond GCS score or acute injury characteristics and incorporate chief TABLE 454-1  Glasgow Coma Scale EYE OPENING (E)   VERBAL RESPONSE (V)   Spontaneous Oriented To speech Confused To pressure Words None Sounds None Best Motor Response (M) Obeying commands Localizing Normal flexion Abnormal flexion Extension None CHAPTER 454 Note: Revised GCS (2014). Source: Reproduced with permission from G Teasdale et al: The Glasgow Coma Scale at 40 years: Standing the test of time. Lancet Neurol 13:844, 2014. signs and symptoms in defining mTBI. The use of multiple severity indicators is intended to improve sensitivity in the detection of mTBI (GCS 13–15), while also taking into consideration traditional acute injury characteristics that have been presumed to predict outcome fol­ lowing mild and moderate brain injury. LOC and posttraumatic amne­ sia (PTA) remain the most common injury characteristics referenced in these classification systems. In the case of moderate (GCS 9–12) and severe (GCS 3–8) TBI, GCS score and the duration of LOC and PTA can be robust predictors of long-term outcome and morbidity. In cases of mTBI, however, while PTA and LOC are important indicators of acute injury, they are less predictive of eventual recovery time and outcome, particularly within sport-related concussion. Concussion and Other Traumatic Brain Injuries ■ ■TBI TYPES AND PATHOLOGIES Mild TBI (Concussion)  It is estimated that 70–90% of all treated TBIs are mild in severity based on traditional case definitions and acute injury characteristics, with most reported estimates in the order of 85%. The published figures likely underrepresent the true incidence of mTBI because of variable case definitions and heterogeneous methods. Moreover, because a subgroup of individuals with milder brain injuries does not seek medical attention, epidemiologic studies that depend on hospital-based data also underestimate the true incidence. In fact, it has been estimated that current data collection sources and methods may only capture one of every nine mTBI/concussions in the United States. The term concussion, while popular, is vague and is not based on widely accepted objective criteria, resulting in multiple definitions from various groups. There has been debate as to whether concussion is part of the TBI spectrum or a separate entity. The Concussion in Sports Group has concluded that “concussion is a traumatic brain injury” as part of the consensus statement definition of the injury. By firmly plac­ ing concussion in the spectrum of TBI, the underlying pathophysiologic processes common to all TBI presentations can now be considered together. CT imaging is often normal in this population. However, emerg­ ing evidence indicates that 3-tesla (3T) MRI scans with greater image resolution can identify pathology consistent with acute brain injury such as contusion and microhemorrhage. When patients with mTBI have CT and/or MRI abnormalities, they are often referred to as having complicated mTBI and are more likely to have an unfavorable outcome. SKULL FRACTURE, EXTRA-AXIAL HEMATOMA, CONTUSION, AND AXONAL INJURY ■ ■SKULL FRACTURE A blow to the skull that exceeds the elastic tolerance of the bone causes a fracture. Intracranial lesions accompany roughly two-thirds of skull fractures, and the presence of a fracture increases many-fold the chances of an underlying subdural or epidural hematoma. Con­ sequently, fractures are primarily markers of the site and severity of injury. If the underlying arachnoid membrane has been torn, fractures also provide potential pathways for entry of bacteria to the cerebrospi­ nal fluid (CSF) with a risk of meningitis and for leakage of CSF outward through the dura. If there is leakage of CSF, severe orthostatic headache results from lowered pressure in the spinal fluid compartment. Most fractures are linear and extend from the point of impact toward the base of the skull. Basilar skull fractures are often exten­ sions of adjacent linear fractures over the convexity of the skull but may occur independently owing to stresses on the floor of the middle cranial fossa or occiput. Basilar fractures are usually parallel to the petrous bone or along the sphenoid bone and directed toward the sella turcica and ethmoidal groove. Although most basilar fractures are uncomplicated, they can cause CSF leakage, pneumocephalus, and delayed cavernous-carotid fistulas. Hemotympanum (blood behind the tympanic membrane), ecchymosis over the mastoid process (Battle sign), and periorbital ecchymosis (“raccoon sign”) are clinical signs associated with basilar fractures. PART 13 Neurologic Disorders ■ ■EPIDURAL AND SUBDURAL HEMATOMAS Hemorrhages between the dura and skull (epidural) or beneath the dura (subdural) have characteristic clinical and imaging features. They are sometimes associated with underlying brain contusions and other injuries, often making it difficult to determine the relative contribution of each component to the clinical state. The mass effect of raised intra­ cranial pressure (ICP) caused by these hematomas can be life threaten­ ing, making it imperative to identify them rapidly by CT or MRI scan and to surgically remove them when appropriate. Epidural Hematoma (Fig. 454-1)  These highly dangerous lesions usually arise from an injury to a meningeal arterial vessel and evolve rapidly. They are often accompanied by a “lucid interval” of several minutes to hours prior to neurologic deterioration. They occur in up to 10% of cases of severe head injury but are less often associated with underlying cortical damage compared to subdural hematomas. Rapid surgical evacuation and ligation or cautery of the damaged ves­ sel, usually the middle meningeal artery that has been lacerated by an overlying skull fracture, is indicated. If recognized and treated rapidly, patients often have a favorable outcome. Acute Subdural Hematoma (Fig. 454-2)  Direct cranial trauma may be minor and is not always required for acute subdural hemor­ rhage to occur, especially in the elderly and those taking anticoagulant medications. Acceleration forces alone, as from whiplash, are some­ times sufficient to produce subdural hematoma. Up to one-third of patients have a lucid interval lasting minutes to hours before coma FIGURE 454-1  Acute epidural hematoma. The tightly attached dura is stripped from the inner table of the skull, producing a characteristic lenticular-shaped hemorrhage on noncontrast computed tomography scan. Epidural hematomas are usually caused by tearing of the middle meningeal artery following fracture of the temporal bone. FIGURE 454-2  Acute subdural hematoma. Noncontrast computed tomography scan reveals a hyperdense clot that has an irregular border with the brain and causes more horizontal displacement (mass effect) than might be expected from its thickness. The disproportionate mass effect is the result of the large rostral-caudal extent of these hematomas. Compare to Fig. 454-1. supervenes, but most are drowsy or comatose from the moment of injury. A unilateral headache and slightly enlarged pupil on the side of the hematoma are frequently, but not invariably, present. Small subdu­ ral hematomas may be asymptomatic and usually do not require surgi­ cal evacuation if they do not enlarge. Stupor or coma, hemiparesis, and unilateral pupillary enlargement are signs of larger hematomas. The bleeding that causes larger subdural hematomas is primarily venous in origin, although arterial bleeding sites are sometimes found at opera­ tion, and a few large hematomas have a purely arterial origin. In an acutely deteriorating patient, an emergency craniotomy is required. In contrast to epidural hematomas, there is significant morbidity and mortality associated with acute subdural hematomas that require surgery. Chronic Subdural Hematoma  A subacutely evolving syndrome due to subdural hematoma occurs days or weeks after injury with drowsiness, headache, confusion, or mild hemiparesis, usually in the elderly with age-related atrophy and often after only minor or unno­ ticed trauma. On imaging studies, chronic subdural hematomas appear as crescentic clots over the convexity of one or both hemispheres, most commonly in the frontotemporal region (Fig. 454-3). A history of trauma may or may not be elicited in relation to chronic subdural hematoma; the injury may have been trivial and forgotten, particularly in the elderly and those with clotting disorders. Headache is common FIGURE 454-3  Computed tomography scan of chronic bilateral subdural hematomas of different ages. The collections began as acute hematomas and have become hypodense in comparison to the adjacent brain after a period during which they were isodense and difficult to appreciate. Some areas of resolving blood are contained on the more recently formed collection on the left (arrows). but not invariable. Additional features that may appear weeks later include slowed thinking, vague change in personality, seizure, or a mild hemiparesis. The headache typically fluctuates in severity, some­ times with changes in head position. Drowsiness, inattentiveness, and incoherence of thought are generally more prominent than focal signs such as hemiparesis. Rarely, chronic hematomas cause brief episodes of hemiparesis or aphasia that are indistinguishable from transient ischemic attacks. CT without contrast initially shows a low-density mass over the convexity of the hemisphere. Between 2 and 6 weeks after the initial bleeding, the clot becomes isodense compared to adjacent brain and may be inapparent. Many subdural hematomas that are several weeks in age contain areas of blood and intermixed serous fluid. Infusion of contrast material demonstrates enhancement of the vascular fibrous capsule surrounding the collection. MRI reliably identifies both sub­ acute and chronic hematomas. Clinical observation coupled with serial imaging is a reasonable approach to patients with few symptoms and small chronic subdural collections that do not cause mass effect. Treatment with surgical evacuation through burr holes is usually successful, if a cranial drain is used postoperatively. The fibrous membranes that grow from the dura and encapsulate the collection may require removal with a craniotomy to prevent recurrent fluid accumulation. ■ ■TRAUMATIC SUBARACHNOID HEMORRHAGE Subarachnoid hemorrhage (SAH) is common in TBI. Rupture of small cortical arteries or veins can cause bleeding into the subarachnoid space. Traumatic SAH is often seen in the sulci and is frequently the only radiographic finding on CT following mild TBI. SAH occurs dif­ fusely after severe TBI and confers an increase in mortality. In mild TBI, SAH provides an objective imaging biomarker for TBI and, in some patients, is associated with unfavorable outcomes. ■ ■CONTUSION (FIG. 454-4) A surface bruise of the brain, or contusion, consists of varying degrees of petechial hemorrhage, edema, and tissue destruction. Contusions and deeper hemorrhages result from mechanical forces that displace and compress the hemispheres forcefully and by deceleration of the brain against the inner skull, either under a point of impact (coup lesion) or, as the brain swings back, in the antipolar area (contrecoup lesion). Trauma sufficient to cause prolonged unconsciousness usu­ ally produces some degree of contusion. Blunt deceleration impact, as occurs against an automobile dashboard or from falling forward onto a hard surface, causes contusions on the orbital surfaces of the frontal lobes and the anterior and basal portions of the temporal lobes. With lateral forces, as from impact on an automobile door frame, contusions are situated on the lateral convexity of the hemisphere. The clinical signs of contusion are determined by the location and size of the lesion; FIGURE 454-4  Traumatic cerebral contusion. Noncontrast computed tomography scan demonstrating a hyperdense hemorrhagic region in the anterior temporal lobe. often, there are no focal abnormalities with a routine neurologic exam, but these injured regions are later the sites of gliotic scars that may produce seizures. A hemiparesis or gaze preference is fairly typical of moderately sized contusions. Large bilateral contusions produce stupor with extensor posturing, while those limited to the frontal lobes cause a taciturn state. Contusions in the temporal lobe may cause delirium or an aggressive, combative syndrome. Torsional or shearing forces within the brain can cause hemorrhages of the basal ganglia and other deep regions. Large contusions and hemorrhages after minor trauma should raise concerns for coagulopathy due to an underlying disease or more commonly anticoagulant therapy. Acute contusions are easily visible on CT and MRI scans, appearing as inhomogeneous hyperdensities on CT and as hyperintensities on T2 and fluid-attenuated inversion recovery (FLAIR) MRI sequences; there is usually surrounding localized brain edema and some subarachnoid bleeding. Blood in the CSF due to trauma may provoke a mild inflam­ matory reaction. Over a few days, contusions acquire a surrounding contrast enhancement and edema that may be mistaken for tumor or abscess. CHAPTER 454 ■ ■AXONAL INJURY (FIG. 454-5) Traumatic axonal injury (TAI) is one of the most common injuries after TBI. There is disruption, or shearing, of axons at the time of impact, and this is associated with microhemorrhages. It occurs follow­ ing high-speed deceleration injuries, such as motor vehicle collisions (see Johnson et al, 2013, in Further Readings). The presence of four or more areas of TAI is called diffuse axonal injury (DAI) and, when widespread, has been proposed to explain persistent coma and the veg­ etative state after TBI (Chap. 30). Only severe TAI lesions that contain substantial blood are visualized by CT, usually in the corpus callosum and centrum semiovale. More commonly, the CT will be negative for TAI, but subsequent MRI, particularly gradient-echo or susceptibilityweighted imaging, will show hemosiderin deposits reflective of micro­ hemorrhages in addition to the axonal damage on diffusion sequences. Traditionally, TAI and DAI have been considered as sequelae much more likely to result from moderate and severe injuries. Accumulating evidence has demonstrated that diffuse white matter abnormalities purportedly reflective of axonal injury, such as changes in microstruc­ ture and neurite density, are quite common in mild TBI as well. The degree of these changes correlates with metrics of injury severity (e.g., symptom burden) and recovery duration. Concussion and Other Traumatic Brain Injuries ■ ■CRANIAL NERVE INJURIES The cranial nerves most often injured with TBI are the olfactory, optic, oculomotor, and trochlear nerves; the first and second branches of the trigeminal nerve; and the facial and auditory nerves. Anosmia and an apparent loss of taste (actually a loss of perception of aromatic flavors, FIGURE 454-5  Multiple small areas of hemorrhage and tissue disruption in the white matter of the frontal lobes on noncontrast computed tomography scan. These appear to reflect an extreme type of the diffuse axonal shearing lesions that occur with closed head injury. with retained elementary taste perception) occur in ~10% of persons with serious head injuries, particularly from falls on the back of the head. This is the result of displacement of the brain and shearing of the fine olfactory nerve filaments that course through the cribriform bone. At least partial recovery of olfactory and gustatory function is expected, but if bilateral anosmia persists for several months, the prognosis is poor. Partial optic nerve injuries from closed trauma result in blurring of vision, central or paracentral scotomas, or sector defects. Direct orbital injury may cause short-lived blurred vision for close objects due to reversible iridoplegia. Diplopia limited to downward gaze and cor­ rected when the head is tilted away from the side of the affected eye indi­ cates trochlear (fourth nerve) nerve damage. It occurs frequently as an isolated problem after minor head injury or may develop for unknown reasons after a delay of several days. Facial nerve injury caused by a basilar fracture is present immediately in up to 3% of severe injuries; it may also be delayed for 5–7 days. Fractures through the petrous bone, particularly the less common transverse type, are liable to produce facial palsy. Delayed facial palsy occurring up to a week after injury, the mechanism of which is unknown, has a good prognosis. Injury to the eighth cranial nerve from a fracture of the petrous bone causes loss of hearing, vertigo, and nystagmus immediately after injury. Deafness from eighth nerve injury is rare and must be distinguished from blood in the middle ear or disruption of the middle ear ossicles. Dizziness, tinnitus, and high-tone hearing loss occur from cochlear concussion. PART 13 Neurologic Disorders ■ ■SEIZURES Convulsions are surprisingly uncommon immediately after TBI, but a brief period of tonic extensor posturing or a few clonic movements of the limbs just after the moment of impact can occur. However, the corti­ cal scars that evolve from contusions are highly epileptogenic and may later manifest as seizures, even after many months or years (Chap. 436). The severity of injury roughly determines the risk of future seizures. It has been estimated that 17% of individuals with brain contusion, sub­ dural hematoma, or prolonged LOC will develop a seizure disorder and that this risk extends for an indefinite period of time, whereas the risk is ≤2% after mild injury. The majority of convulsions in the latter group occur within 5 years of injury but may be delayed for decades. Penetrat­ ing injuries have a much higher rate of subsequent epilepsy. CLINICAL SYNDROMES AND TREATMENT OF HEAD INJURY ■ ■CONCUSSION/MILD TBI The patient who has briefly lost consciousness or been stunned after a minor head injury usually becomes fully alert and attentive within minutes but may complain of headache, dizziness, faintness, nausea, a single episode of emesis, difficulty with concentration, a brief amnestic period, or slight blurring of vision. This typical concussion syndrome has a good prognosis with little risk of subsequent deterioration. Chil­ dren are particularly prone to drowsiness, vomiting, and irritability, symptoms that are sometimes delayed for several hours after apparently minor injuries. Vasovagal syncope that follows injury may cause undue concern. Generalized or frontal headache is common in the following days. It may be migrainous (throbbing and hemicranial) in nature or aching and bilateral. After several hours of observation, patients with minor injury may be accompanied home and observed for a day by a family member or friend, with written instructions to return if symp­ toms worsen. Persistent severe headache and repeated vomiting in the context of normal alertness and no focal neurologic signs is usually benign, but CT should be obtained and a longer period of observation is appro­ priate. The decision to perform imaging tests also depends on clinical signs that indicate that the impact was severe (e.g., persistent confu­ sion, repeated vomiting, palpable skull fracture); the presence of other serious bodily injuries, an underlying coagulopathy, or age >65 years; and on the degree of surveillance that can be anticipated after dis­ charge. Guidelines have also indicated that older age (>65 years), two or more episodes of vomiting, >30 min of retrograde or persis­ tent anterograde amnesia, seizure, and concurrent drug or alcohol intoxication are sensitive (but not specific) indicators of intracranial hemorrhage that justify CT scanning. Though not incorporated into conventional clinical practice guide­ lines, growing evidence suggests that MRI improves sensitivity for detection of small intracranial hemorrhages and other lesions in mild TBI patients, particular among those with negative findings on CT. Specifically, intracranial abnormalities are fairly common on MRI (27%) in CT-negative patients. Further, acute MRI findings have prog­ nostic utility in predicting recovery and outcome after mTBI/concus­ sion (e.g., risk of functional impairment, time to return to activity). Blood-based (serum and plasma) biomarkers of astrocyte damage/ astrogliosis (glial fibrillary acidic protein [GFAP]) and neuronal injury (ubiquitin carboxy-terminal hydrolase L1 [UCHL1]) also hold promise in improving detection and outcome prediction across the full spec­ trum of TBI. With development and regulatory approval of new rapid assay systems, these biomarkers can now be used for real-time pointof-care assessment; GFAP in particular has high discriminant ability to detect intracranial abnormalities, as well as potential to differentiate CT+, CT–/MRI+, and CT–/MRI– patients. Similar to MRI, emerging biomarkers appear to have not only diagnostic but also prognostic util­ ity in predicting the trajectory of recovery and functional impairments weeks and months after TBI. ■ ■SPORT-RELATED CONCUSSION Concussion is a frequent injury in contact and collision sports (e.g., football, hockey, wrestling) at all levels of participation, including youth sports. Head injury associated with sport and recreational activ­ ity accounts for 45% of TBI-related emergency department visits in children age 17 years and under. Over the last decade, data from the Centers for Disease Control and Prevention indicate a 27% decrease in emergency department visits for sport- and recreation-related TBI in the United States between 2012 and 2018, with a specific decline in contact sport–related visits by 32%. Given that national and state surveillance systems continue to report increased sport-related concus­ sion rates over the same time period, it could be inferred that diagnosis and management of sport-related concussion outside of the emergency department have increased. The natural history of clinical recovery following sport-related con­ cussion has been a subject of substantial ongoing research. Recent large prospective studies have reinforced earlier indications that the acute recovery is favorable. For example, a longitudinal study of over 34,000 collegiate athletes (1751 who experienced concussion) from 22 institu­ tions found that median time to symptom resolution was 6.4 days and median time for return to sport was 12.8 days. By 1 month after injury, 92% of athletes had experienced resolution of symptoms and 85% had been cleared to return to sport. Across several studies, postinjury symptom burden is the most robust predictor of recovery and risk of prolonged symptoms. Other injury/postinjury factors associated with longer return to sport time were continued play following injury and access to health care providers. Several other prospective studies have replicated that the overwhelming majority of athletes across ages (pediatric to adult) achieve a complete recovery in symptoms, cognitive functioning, postural stability, and other functional impairments over a period of 1–4 weeks following concussion. There continues to be a growing focus toward a more rapid return to activity and early rehabilitation following injury. Specifically, while experts agree that initial rest after injury is beneficial for recovery, extended inactivity beyond 5 days can be detrimental and increase risk for protracted recovery. Rather, active rehabilitation involv­ ing supervised subthreshold exercise has been shown to decrease the duration of symptoms and reduce risk of a protracted recovery. Cervicovestibular rehabilitation has been recently recommended for those who experience neck pain, dizziness, or headaches for >10 days after injury. Preliminary evidence suggests that earlier return to learn/school is associated with faster injury recovery, and there has been an increased focus on facilitating a faster and optimal return to learn/school through accommodations. This could include, but is not limited to, a shortened schedule or built-in breaks for fatigue, opportunity for a quiet work environment to prevent headaches or attentional difficulties, and setting expectations for course work to reduce anxiety, among other accommodations. Most patients (>90%) experience a full return to learn without accommodations by 10 days. There are a small, select percentage of athletes who remain symp­ tomatic or impaired on functional testing well beyond the window of recovery commonly reported in group studies. The greatest challenge arguably still facing sport medicine clinicians and public health experts is how to most effectively manage and reduce risk in this subset of athletes who do not follow the “typical” course of recovery. The precise likelihood that an athlete will not follow the typical course of rapid, spontaneous recovery and instead exhibit prolonged postconcussive symptoms or other functional impairments after concussion remains unclear. In addition to the injury-related or postinjury factors identi­ fied above, a preinjury mental health disorder, migraine, and prior concussion have been consistently associated with the potential for prolonged recovery. Following acute concussion, multimodal advanced neuroimaging has demonstrated a variety of changes, including decreased cerebral blood flow, increased global and local functional connectivity, and alterations in white matter microstructure reflecting axonal organiza­ tion. In general, these metrics correlate with measures of injury severity, and resolution of these changes tends to parallel clinical recovery. How­ ever, a number of studies have shown that slight changes on advanced multimodal imaging can persist even after symptoms have fully resolved, supporting the concept that the “tail” of neurobiologic recov­ ery may extend beyond the time course of apparent clinical recovery. In the current absence of adequate data, a commonsense approach to athletic concussion has been to remove the individual from play immediately and avoid contact sports for at least several days after a mild injury, and for a longer period if there are more severe injuries or if there are protracted neurologic symptoms such as headache and difficulty concentrating. No individual should return to play unless all concussion-related symptoms have resolved and an assessment has been made by a health care professional who has experience with treatment of concussion. Validated symptom inventories, such as the Rivermead Post-Concussion Symptom Questionnaire (Table 454-2), have been developed to aid clinicians with recording and quantifying the diverse range of physical, cogni­ tive, and behavioral symptoms that can occur following concussion. In addition to characterizing the constellation of acute symptoms and their severity, symptom inventories can be beneficial to track the course and resolution of symptoms through recovery. Differ­ entiating concussion-related symptoms from factors that may be also influencing endorsement (e.g., preinjury mood disorders) is an important component of managing recovery from sport-related concussion. Once cleared, the individual can then begin a gradu­ ated program of increasing activity. These guidelines are designed TABLE 454-2  Review of Concussion Symptoms PHYSICAL COGNITIVE BEHAVIORAL Headaches Forgetfulness or poor memory Being irritable, easily angered Dizziness Poor concentration Feeling depressed or tearful Nausea and/or vomiting Taking longer to think Feeling frustrated or impatient Noise sensitivity   Restlessness Sleep disturbance     Fatigue     Blurred vision     Light sensitivity     Double vision     Note: Items were adapted from the Rivermead Post-Concussion Symptom Questionnaire. Each item is rated on a 5-point Likert scale (0–4), as follows: 0 = Not experienced at all; 1 = No more of a problem now than preinjury; 2 = A mild problem; 3 = A moderate problem; 4 = A severe problem. Total scores can range from 0–64. in part to avoid a perpetuation of symptoms but also to prevent the rare second-impact syndrome, in which diffuse and fatal cerebral swelling follows a second minor head injury. ■ ■POSTCONCUSSIVE STATES There has been a recent paradigm shift from the term postconcussion syndrome (PCS) to persistent postconcussion symptoms (PPCS) in an effort to avoid classifying prolonged sequelae under a nonspecific diagnostic label and a shifting focus toward identifying and targeting treatment toward direct areas of persistent difficulty. PPCS following mild TBI could include symptoms of fatigue, dizziness, headache, and/ or difficulty in concentration. Management is difficult and generally requires identification and management of the specific problem or problems that are most troubling to the individual. A clear explanation and education around the symptoms that may follow concussion have been shown to reduce subsequent complaints. Care is taken to avoid prolonged use of drugs that produce dependence. Headache may ini­ tially be treated with acetaminophen and small doses of amitriptyline. Vestibular exercises (Chap. 24) and small doses of vestibular suppres­ sants such as promethazine (Phenergan) may be helpful when dizziness is the main problem. After mild or moderate injury, patients who have difficulty with memory or with complex cognitive tasks at work may be reassured to know that these problems usually improve over several months, and a reduced workload or other accommodations may be prescribed in the interim. For select cases, speech and language therapy intervention may be appropriate. CHAPTER 454 Concussion and Other Traumatic Brain Injuries For the vast majority of individuals with mTBI, symptoms of PPCS subside and resolve within a few weeks of injury. For a subset of indi­ viduals with mTBI, however, complaints of postconcussion symptoms persist beyond the expectation derived from TBI severity markers. Subtypes of PPCS have been proposed to improve characterization of specific symptoms or types of sequelae following mTBI. These include neurologic, cognitive, behavioral, or somatic complaints that continue beyond the acute and subacute periods, becoming chronic and often operationalized as persisting beyond 3 months. Although the overall risk of experiencing PPCS following mTBI is low, the frequency of mTBI patients who present in a clinical setting is believed to be higher. mTBI patients with PPCS frequently present to the outpatient clinics of primary care physicians, physiatrists, or neurologists seeking relief for lingering related symptoms. While some patients will have already received an initial medical workup to rule out a more serious brain injury during the acute phase, many patients will have had no prior contact with health care specialists. A medical workup ordered in the outpatient setting for PPCS-related complaints is typically unremark­ able for any identifiable neurologic cause to account for the persist­ ing symptoms reported by the patient. The development of uniform decision trees or “standard of care” treatment regimens for PPCS has been limited by the diversity of symptoms that patients experience, even within mTBI subgroups that have sustained very similar injury patterns. While some patients experience somatic symptoms, others complain of subjective cognitive or behavioral changes. Symptom inventories (Table 454-2) can be helpful in documenting the broad range of these symptoms and serve as a metric for improvement fol­ lowing symptom-based treatment. Active rehabilitation for the treatment of PPCS involving subthresh­ old exercise has increased in popularity over recent years and has gained empirical support for its effectiveness as a useful intervention for protracted recovery. PPCS are often influenced by diverse cognitive, emotional, medical, psychosocial, and motivational factors. Because of this complexity, treatments targeting persistent and refractory symptoms should be tailored to the needs and expectations of the individual patient, with referrals to specialists as needed for assistance with management of headache, neck and back pain, dizziness and vertigo, and other persist­ ing symptoms. A comprehensive review of concussion and persisting symptoms, presented in Table 454-2, allows for development of an individualized approach that leverages currently available treatment for those sequelae that are most bothersome to the patient (e.g., vestibu­ lar or cervicovestibular rehabilitation therapy for vertigo, melatonin for sleep disturbance). Patients are frequently referred to behavioral health providers such as neuropsychologists, rehabilitation psycholo­ gists, health psychologists, and/or psychiatrists for a variety of reasons, but particularly when they are experiencing persistent cognitive, emotional, or behavioral changes. Patients with mood disorders (e.g., depression), anxiety disorders (e.g., posttraumatic stress disorder), or adjustment reactions may benefit from psychiatric consultation for appropriate medication trials or from time-limited psychotherapy such as cognitive behavioral therapy. Due to the complexity of presentation and varying diagnostic cri­ teria, there are limited studies regarding overall prognosis of PPCS. However, treatment targeted to the individual’s specific persisting difficulties can improve functional outcomes and patient-rated quality of life. Further, collaborative care has been shown to improve out­ comes among patients experiencing PPCS. These improved outcomes are likely due to a multidisciplinary team’s ability to simultaneously address the diverse set of difficulties that can occur with PPCS. PART 13 Neurologic Disorders ■ ■INJURY OF INTERMEDIATE SEVERITY Patients who are not fully alert or have persistent confusion, behav­ ioral changes, extreme dizziness, or focal neurologic signs such as hemiparesis should be admitted to the hospital and undergo a cere­ bral imaging study. A cerebral contusion or hematoma will usually be found. Common syndromes include (1) delirium with a disinclina­ tion to be examined or moved, expletive speech, and resistance if dis­ turbed (anterior temporal lobe contusions); (2) a quiet, disinterested, slowed mental state (abulia) alternating with irascibility (inferior frontal and frontopolar contusions); (3) a focal deficit such as aphasia or mild hemiparesis (due to subdural hematoma or convexity contu­ sion or, less often, carotid artery dissection); (4) confusion and inat­ tention, poor performance on simple mental tasks, and fluctuating orientation (associated with several types of injuries, including those described above, and with medial frontal contusions and interhemi­ spheric subdural hematoma); (5) repetitive vomiting, nystagmus, drowsiness, and unsteadiness (labyrinthine concussion, but occasion­ ally due to a posterior fossa subdural hematoma or vertebral artery dissection); and (6) diabetes insipidus (damage to the median emi­ nence or pituitary stalk). Injuries of this degree can be complicated by drug or alcohol intoxication, and clinically inapparent cervical spine injury may be present. Blast injuries are often accompanied by rupture of the tympanic membranes. After surgical removal of hematomas, patients in this category improve over weeks to months. During the first week, the state of alertness, memory, and other cognitive functions often fluctuate, and agitation and somnolence are common. Behavioral changes tend to be worse at night, as with many other encephalopathies, and may be treated with small doses of antipsychotic medications. Subtle abnor­ malities of attention, intellect, spontaneity, and memory return toward normal weeks or months after the injury, sometimes abruptly. How­ ever, the full extent of recovery may not be realized for several years. Persistent cognitive problems are discussed below. ■ ■SEVERE INJURY Patients who are comatose from the moment of injury require imme­ diate neurologic attention and resuscitation. After intubation, with care taken to immobilize the cervical spine, the depth of coma, pupil­ lary size and reactivity, limb movements, and Babinski responses are assessed. As soon as vital functions permit and cervical spine x-rays and a CT scan have been obtained, the patient should be transported to a critical care unit. Hypoxia should be reversed, and normal saline used as the resuscitation fluid in preference to albumin. The finding of an epidural or subdural hematoma or large intracerebral hemorrhage is usually an indication for prompt surgery and intracranial decom­ pression in an otherwise salvageable patient. Measurement of ICP with a ventricular catheter or fiberoptic device in order to guide treat­ ment has been favored by many units but has not improved outcome. Similarly, induced hypothermia has shown no benefit. Hyperosmolar intravenous solutions are used in various regimens to limit intracranial pressure. Prophylactic antiepileptic medications are recommended for 7 days and should be discontinued unless there are multiple seizures after injury. Management of raised ICP, a frequent feature of severe head injury, is discussed in Chap. 318. Despite the improvement in mortality for severe TBI over the past few decades, a great deal of therapeutic nihilism persists in TBI. The common use of a 6-month outcome for TBI clinical studies reinforces this misconception. The recovery from severe TBI can take years. Fur­ thermore, the ability to predict long-term outcome is limited and fre­ quently incorrect. Best-practice guidelines recommend, in the absence of brain death, that aggressive therapy be instituted for at least 72 h in the acute injury period. ■ ■LONG-TERM OUTCOMES IN TBI Continued follow-up of prospective studies has increased awareness of TBI as a chronic condition with evolving changes and needs over sev­ eral years after injury. While the majority of individuals remain broadly stable, clinically meaningful improvement and decline across multiple domains (psychiatric, cognitive, and functional outcomes) have been observed from 2 to 7 years after injury, regardless of initial TBI severity. The direction of the changes beyond 1 year after injury can be variable (may decline and improve later, or vice versa). Collectively, this indicates that functional status remains dynamic beyond 1 year after injury, a conventionally considered plateau of recovery. Future investigation is required to better understand which factors are associated with improvement and decline beyond 1 year after injury. Regardless, there is growing awareness that TBI is an evolving condition that requires ongoing monitoring, rehabilitation, and support to address individual patient needs. Chronic difficulties associated with TBI (characterized above), as opposed to level of risk for Alzheimer’s disease and related demen­ tias (ADRD), is an important distinction in determining long-term outcomes of TBI. TBI (aggregated mild to severe) is associated with a 63–96% increased risk of all-cause dementia. The degree of risk for dementia ranges along the gradient of TBI severity (i.e., greatest risk among severe injuries). There is some evidence that repeated mTBI or sport-related concussions may be associated with elevated risk as well. To date, however, investigations have less reliably established mTBI as a robust risk factor for dementia, likely due to methodologic heterogene­ ity (e.g., use of different diagnostic criteria, exposure misclassification, self-report vs physician diagnoses of TBI or dementia). Though an identified risk factor for all-cause dementia, pathophysi­ ologic and epidemiologic factors that underlie the association between TBI and risk of specific neurodegenerative pathologies and dementia subtypes are not well understood. As a result, associations between TBI and clinical syndromes (e.g., Alzheimer’s disease, Parkinson’s dis­ ease, amyotrophic lateral sclerosis) or distinct neuropathologies (e.g., beta-amyloid, Lewy bodies, transactive response DNA-binding protein 43) have been inconsistently reported in the literature. In a large study involving clinical and neuropathologic data from three pooled prospec­ tive studies of community-based cohorts, a significant relationship was found between TBI with LOC >1 h and subsequent Parkinson’s disease diagnosis, progression rate of parkinsonism, and Lewy body accumu­ lation at postmortem examination. Positron emission tomography (PET) studies have allowed for in vivo investigation of neuropathologic deposition and have failed to consistently observe associations between remote TBI (mild through severe) and amyloid or tau deposition. Among former contact and collision sport athletes, exposure to repetitive head impacts (RHI) involving external blows that do not produce signs and symptoms of mTBI/concussion is common. The brains of these patients with substantial RHI exposure may display a characteristic deposition of tau protein in neurons located in the super­ ficial cortical layers and perivascular regions and particularly in the depths of sulci. This pattern has been defined as the pathognomonic lesion of chronic traumatic encephalopathy (CTE). The degree to which this neuropathologic finding is present in nonathlete populations with potential RHI exposure (e.g., former military service members and veterans, victims of intimate partner violence) is uncertain, although the prevalence was found to be low in a large autopsy study of military service members. # 25 - 455 Multiple Sclerosis ### 455 Multiple Sclerosis A variety of neurodegenerative pathologies are commonly found in the presence of CTE, adding to the complexity of diagnosis. Further­ more, the dynamic interplay between RHI and mTBI history is not well understood. While staging criteria for this neuropathologic entity have yet to be established, a consensus meeting to define the neuro­ pathologic criteria for CTE proposed an algorithm assessing CTE as “low” or “high” in severity. Overall, its contribution, if any, to late-life dementia and parkinsonism in former athletes, soldiers, or others who have sustained repeated concussive injuries is unknown. Research criteria for the clinical diagnosis of CTE have been pro­ posed. The criteria generally require substantial exposure to RHI, cog­ nitive impairment (primarily in the domains of episodic memory and executive function) and/or neurobehavioral dysregulation, progressive course, and the absence of an alternative explanation for symptoms. Multiple studies have suggested that these proposed criteria lack speci­ ficity (i.e., they are frequent in other conditions and non-CTE cases). As such, CTE remains a postmortem diagnosis. Investigations have not observed robust or consistent in vivo brain-related changes associated with years of contact sport/football exposure (a commonly used proxy measure for RHI) using advanced MRI, PET imaging, or blood-based biomarkers. For example, associa­ tions between years of participation and amyloid deposition or white matter hyperintensity volume have not been observed. Studies of brain morphometry (volumetric and structural changes) and tau deposition have been more variable, though evidence suggests that convention­ ally employed PET tracers and blood biomarkers may be limited in their specificity for CTE p-tau. Impairment of neuropsychological and neuropsychiatric function is most commonly observed in those with polypathology, particularly amyloid. Taken together, further study is required to better refine the clinical and postmortem diagnostic criteria of CTE, enhance clinicopathologic correlation, and ultimately improve patient care and management. CTE is also discussed in Chap. 435. ■ ■FURTHER READING Brett BL et al: Long-term multidomain patterns of change after trau­ matic brain injury: A TRACK-TBI LONG Study. Neurol 101:7, 2023. Johnson VE et al: Axonal pathology in traumatic brain injury. Exp Neurol 246:35, 2013. Kowalski R et al: Recovery of consciousness and functional outcome in moderate and severe traumatic brain injury. JAMA Neurol 78:548, 2021. McCrory P et al: Consensus statement on concussion in sport—the 5th international conference on concussion in sport held in Berlin, October 2016. Br J Sports Med 51:838, 2017. Mez J et al: Clinicopathological evaluation of chronic traumatic encephalopathy in players of American football. JAMA 318:360, 2017. Nelson L et al: Recovery after mild traumatic brain injury in patients presenting to US level I trauma centers: A Transforming Research and Clinical Knowledge in Traumatic Brain Injury (TRACK-TBI) study. JAMA Neurol 76:1049, 2019. Taylor CA et al: Traumatic brain injury-related emergency depart­ ment visits, hospitalizations, and deaths—United States, 2007 and 2013. MMWR Surveill Summ 66:1, 2017. Bruce A. C. Cree, Stephen L. Hauser Multiple Sclerosis Multiple sclerosis (MS) is an autoimmune disease of the central ner­ vous system (CNS) characterized by chronic inflammation, demyelin­ ation, gliosis (plaques or scarring), and neuronal loss; the course can be relapsing or progressive. MS plaques typically develop at different times and in different CNS locations (i.e., MS is said to be disseminated in time and space). One million individuals in the United States, and millions worldwide, are affected. The clinical course is extremely vari­ able, ranging from a relatively benign condition to a rapidly evolving and incapacitating disease requiring profound lifestyle adjustments. The past decade has seen tremendous progress in understanding basic disease mechanisms underlying MS and in developing highly effec­ tive therapies especially for the relapsing form of the disease. These advances have dramatically improved the long-term outcome for patients. ■ ■CLINICAL MANIFESTATIONS Onset is typically between 20 and 40 years (slightly later in men than in women), but the disease can present across the lifespan. Women are affected approximately three times more often than men. Early symptoms may be severe or seem so trivial that a patient may not seek medical attention for months or years. On occasion, MS lesions are located exclusively in noneloquent regions of the nervous system, and in such instances, clinical manifestations can be largely or entirely absent. Autopsy series identified MS in some individuals (~0.1% of cases) who were seemingly asymptomatic during life, and magnetic resonance imaging (MRI) scans obtained for unrelated reasons also showed evidence of asymptomatic MS, an incidental finding termed a radiologically isolated syndrome (RIS; see below). CHAPTER 455 Multiple Sclerosis Specific symptoms of MS are varied and reflect the location and severity of lesions within the CNS (Table 455-1). Moreover, neuro­ logic examination often reveals unexpected findings in addition to the anticipated ones. For example, a patient may present with symptoms in one leg but signs in both. Sensory symptoms include both paresthesias (e.g., tingling, prickling sensations, “pins and needles,” formications, or painful burning) and hypesthesia (e.g., reduced sensation, numbness, or a “dead” feeling). Unpleasant sensations (e.g., feelings that body parts are swollen, wet, raw, or tightly wrapped) are also common. Sensory impairment of the trunk and legs below a horizontal line on the torso (a sensory level) indicates that the spinal cord is the site of the disturbance. It is often accompanied by a bandlike sensation of tightness around the torso. Pain is a common symptom of MS, experienced by >50% of patients. Pain can occur anywhere on the body and can change locations over time. Optic neuritis (ON) presents as diminished visual acuity, dimness, or decreased color perception (desaturation) in the central field of vision. These symptoms can be mild or may progress to severe visual loss. Rarely, there is complete loss of light perception. Visual symptoms are generally monocular but may be bilateral. Periorbital pain (aggravated by eye movement) typically precedes or accompanies the visual loss. An afferent pupillary defect (Chap. 34) is usually present. Fundoscopic examination may be normal or reveal optic disc swelling (papillitis). Pallor of the optic disc (optic atrophy) commonly follows ON. Uveitis is uncommon and should raise the possibility of alternative diagnoses such as sarcoidosis or lymphoma. TABLE 455-1  Initial Symptoms of Multiple Sclerosis (MS) PERCENTAGE OF CASES SYMPTOM PERCENTAGE OF CASES SYMPTOM Sensory loss Lhermitte Optic neuritis Pain Weakness Dementia Paresthesias Visual loss Diplopia Facial palsy Ataxia Impotence Vertigo Myokymia Paroxysmal attacks Epilepsy Bladder Falling Source: Data from RJ Swingler, DA Compston: The morbidity of multiple sclerosis. Q J Med 83:325, 1992. Weakness of the limbs can manifest as loss of strength, speed, or dexterity; as fatigue; or as a disturbance of gait. Exercise-induced weakness is a characteristic symptom of MS. The weakness is of the upper motor neuron type (Chap. 26) and is usually accompanied by other pyramidal signs such as spasticity, hyperreflexia, and extensor plantar responses. Occasionally, a tendon reflex may be lost (simulating a peripheral nerve lesion) if an MS lesion disrupts the afferent reflex fibers in the spinal cord (see Fig. 26-2). Facial weakness due to a lesion in the pons may resemble idiopathic Bell’s palsy (Chap. 452). Unlike Bell’s palsy, facial weakness in MS is usually not associated with ipsilateral loss of taste sensation or retro­ auricular pain. Spasticity (Chap. 26) is commonly associated with spontaneous and movement-induced muscle spasms, especially in the legs. This can be accompanied by painful spasms interfering with ambulation, work, or self-care. Occasionally, spasticity provides support for the body weight during ambulation, and in these cases, treatment of spasticity may actually do more harm than good. PART 13 Neurologic Disorders Visual blurring in MS may result from ON or diplopia (double vision); if the symptom resolves when either eye is covered, the cause is diplopia. Diplopia may be caused by internuclear ophthalmoplegia (INO) or palsy of the sixth cranial nerve (rarely the third or fourth). An INO consists of impaired adduction of one eye due to a lesion in the ipsilateral medial longitudinal fasciculus (Chaps. 34 and V3). Prominent nystagmus is often observed in the abducting eye, along with a small skew deviation. A bilateral INO is particularly suggestive of MS. Other common gaze disturbances in MS include (1) a horizon­ tal gaze palsy, (2) a “one and a half” syndrome (horizontal gaze palsy plus an INO), and (3) acquired pendular nystagmus. Ataxia usually manifests as cerebellar tremors (Chap. 450). Ataxia may also involve the head and trunk or the voice, producing a charac­ teristic cerebellar dysarthria (scanning speech). Vertigo may appear suddenly from a brainstem lesion, superficially resembling acute labyrinthitis (Chap. 24). Hearing loss (Chap. 36) may also occur in MS but is uncommon. ■ ■ANCILLARY SYMPTOMS Paroxysmal symptoms are distinguished by their brief duration (10 s to 2 min), high frequency (5–40 episodes per day), lack of any altera­ tion of consciousness or change in background electroencephalogram during episodes, and a self-limited course (generally lasting weeks to months). They may be precipitated by hyperventilation or movement. Manifestations can include Lhermitte’s symptom; tonic contractions of a limb, face, or trunk (tonic seizures); paroxysmal dysarthria and ataxia; paroxysmal sensory disturbances; and several other less wellcharacterized syndromes. Paroxysmal symptoms probably result from spontaneous discharges arising at the edges of demyelinated plaques and spreading to adjacent white matter tracts. Lhermitte’s symptom is an electric shock–like sensation (typically induced by flexion or other movements of the neck) that radiates down the back into the legs. Rarely, it radiates into the arms. It is generally selflimited but may persist for years. Lhermitte’s symptom can also occur with other disorders of the cervical spinal cord (e.g., cervical spondylosis). Trigeminal neuralgia, hemifacial spasm, and glossopharyngeal neural­ gia (Chap. 452) can occur when the demyelinating lesion involves the root entry (or exit) zone of the fifth, seventh, and ninth cranial nerve, respectively. Trigeminal neuralgia (tic douloureux) is a very brief lanci­ nating facial pain often triggered by an afferent input from the face or teeth. Most cases of trigeminal neuralgia are not MS related; however, atypical features such as onset before age 50 years, bilateral symptoms, objective sensory loss, or nonparoxysmal pain should raise the pos­ sibility that MS could be responsible. Facial myokymia consists of either persistent rapid flickering con­ tractions of the facial musculature (especially the lower portion of the orbicularis oculus) or a contraction that slowly spreads across the face. It results from lesions of the corticobulbar tracts or brainstem course of the facial nerve. Heat sensitivity refers to neurologic symptoms produced by an elevation of the body’s core temperature. For example, unilateral visual blurring may occur during a hot shower or with physical exercise (Uhthoff’s symptom). It is also common for MS symptoms to worsen transiently, sometimes dramatically, during febrile illnesses. Such heatrelated symptoms probably result from transient conduction block. Bladder dysfunction is ultimately present in most MS patients. During normal reflex voiding, relaxation of the bladder sphincter (α-adrenergic innervation) is coordinated with contraction of the detrusor muscle in the bladder wall (muscarinic cholinergic innerva­ tion). Detrusor hyperreflexia, due to impairment of suprasegmental inhibition, causes urinary frequency, urgency, nocturia, and uncon­ trolled bladder emptying. Detrusor sphincter dyssynergia, due to loss of synchronization between detrusor and sphincter muscles, causes difficulty in initiating and/or stopping the urinary stream, producing hesitancy, urinary retention, overflow incontinence, and recurrent infection. Constipation occurs in some patients, especially with advanced disease. Fecal urgency or bowel incontinence is less common than urinary symptoms but can be socially debilitating. Sexual dysfunction may manifest as decreased libido, impaired geni­ tal sensation, impotence in men, and diminished vaginal lubrication or adductor spasms in women. Cognitive dysfunction is often mild when present, but can include memory loss; impaired attention; difficulties in executive functioning, memory, and problem solving; slowed information processing; and problems shifting between cognitive tasks. Euphoria (elevated mood) or emotional lability (pseudobulbar palsy) was once thought to be characteristic of MS but is actually relatively uncommon. Cognitive dysfunction sufficient to impair activities of daily living is rare. Depression, experienced by approximately half of patients, can be reactive, endogenous, or part of the illness itself and can contribute to fatigue. Fatigue (Chap. 25) is experienced by most MS patients and is the most common reason for work-related disability in MS. Fatigue can be exacerbated by elevated temperatures, depression, expending exceptional effort to accomplish basic activities of daily living, or sleep disturbances (e.g., from frequent nocturnal awakenings to urinate). DISEASE COURSE In the traditional model of MS, the disease was considered to have three principal clinical forms, designated relapsing-remitting, second­ ary progressive, and primary progressive. Relapses were thought to be caused by inflammation, while progression was the consequence of neurodegeneration. More recently, these categories were supplanted by a unitary view of the disease, in which inflammation and neurode­ generation are present in most patients throughout the disease course. The concept that all MS is a single disease is also supported by findings from genetics, epidemiology, immunology, and pathology. Nonethe­ less, from a clinical perspective, it is still often useful to apply the clas­ sical subtype scheme to assessment and management of patients. 1. Relapsing-remitting or bout onset MS (RRMS) accounts for 90% of MS cases and is characterized by discrete attacks of neurologic dys­ function that generally evolve over days to weeks (rarely over hours). In early MS, there is often substantial or complete recovery over the ensuing weeks to months. However, as attacks continue, recovery may be less evident. Between attacks, patients were earlier thought to be neurologically stable; however, it is now clear that most if not all patients with RRMS experience subtle “silent” progression even when relapse-free (Fig. 455-1). The category relapsing MS (RMS) is used to identify all relapsing patients, both RRMS as well as second­ ary progressive patients who continue to experience attacks. 2. Secondary progressive MS (SPMS) always begins as RRMS. At some point, however, the clinical course changes so that the patient expe­ riences progressive deterioration in function unassociated with acute attacks. SPMS produces a greater amount of fixed neurologic disability than RRMS. A practical definition for SPMS is a patient who has developed some level of permanent walking disability not due exclusively to relapses. The Extended Disability Status Score (EDSS) is a widely used measure of neurologic impairment in MS RELAPSING PHASE PREMONITORY PHASE PROGRESSIVE PHASE RIS CIS Relapsing MS Progressive MS NATURAL HISTORY/TRADITIONAL VIEW EDSS Relapses MRI Activity –5 –2 Onset Time (years) A PREMONITORY PHASE Neuroinflammation CURRENT TREATMENT ERA/MODERN VIEW START HIGH-EFFICACY TREATMENT EDSS Relapses MRI Activity –5 –2 Onset Time (years) B FIGURE 455-1  The clinical course of multiple sclerosis (MS) in the current treatment era. The top half of the figure illustrates the traditional view of the natural history of relapse-onset MS in the pretreatment era. During the relapsing phase, disability accumulation was thought to result from incomplete recovery from relapses, until relapseindependent disability, designated SPMS, supervened. In the bottom half of the figure, the “new” natural history of MS in the current treatment era is shown. With use of highly effective therapies, attacks are abolished in most patients, but insidious progression independent of relapse activity, termed “silent progression,” is now evident during the relapsing phase. CIS, clinically isolated syndrome; EDSS, Extended Disability Status Score; MRI, magnetic resonance imaging; RIS, radiologically isolated syndrome; SPMS, secondary progressive multiple sclerosis. (Table 455-2); an EDSS of 4 or greater, plus a Functional Status Scale (FSS) motor system score of 2 or greater, can support a diagnosis of SPMS. For a patient with RRMS, in the pretreatment era, the risk of developing SPMS was ~3% each year, meaning that the great major­ ity of RRMS would ultimately evolve into SPMS. However, more recent case series have indicated a much lower rate of evolution to SPMS, estimated at <1% each year, likely due to widespread use of increasingly effective therapies for MS. 3. Primary progressive MS (PPMS) accounts for ~10% of cases. These patients do not experience attacks but rather steadily decline in function from disease onset. Compared to RRMS, the sex distribu­ tion is more even, the disease begins later in life (mean age ~40 years), and disability develops faster relative to the onset of the first clinical symptom. As noted above, despite these differences PPMS appears Neuroinflammation Neurodegeneration CHAPTER 455 Multiple Sclerosis MS DISEASE CONTINUUM Neurodegeneration NATURAL HISTORY “Silent Progression” Progression Independent of Relapse Activity (PIRA) OBSERVED COURSE EXPECTED COURSE to represent the same underlying illness as RRMS and SPMS, and some PPMS patients experience relapses over the course of their ill­ ness. The term active progressive MS is used to categorize progressive MS patients (both SPMS and PPMS) who experience relapses or are found to have new lesions on serial MRI scans. Disability in MS is thought to accumulate as either a consequence of limited recovery following an acute relapse, a process also known as relapse associated worsening (RAW), or from presumed underlying neurodegeneration in the absence of clinical relapse, a process termed progression independent of relapsing activity (PIRA). Although RAW was once thought to be the primary driver of disability accumulation in RRMS, it is now clear that PIRA is the cause of disability accumula­ tion in RRMS, SPMS, and PPMS. That PIRA events can occur “silently,” TABLE 455-2  Scoring Systems for Multiple Sclerosis (MS) Expanded Disability Status Scale (EDSS) 0.0 = Normal neurologic examination (all grade 0 in functional status [FS]) 1.0 = No disability, minimal signs in one FS (i.e., grade 1) 1.5 = No disability, minimal signs in more than one FS (more than one grade 1) 2.0 = Minimal disability in one FS (one FS grade 2, others 0 or 1) 2.5 = Minimal disability in two FS (two FS grade 2, others 0 or 1) 3.0 = Moderate disability in one FS (one FS grade 3, others 0 or 1) or mild disability in three or four FS (three/four FS grade 2, others 0 or 1) although fully ambulatory 3.5 = Fully ambulatory but with moderate disability in one FS (one grade 3) and one or two FS grade 2; or two FS grade 3; or five FS grade 2 (others 0 or 1) 4.0 = Ambulatory without aid or rest for ~500 m 4.5 = Ambulatory without aid or rest for ~300 m 5.0 = Ambulatory without aid or rest for ~200 m PART 13 Neurologic Disorders Functional Status (FS) Score A. Pyramidal functions 0 = Normal 1 = Abnormal signs without disability 2 = Minimal disability 3 = Mild or moderate paraparesis or hemiparesis, or severe monoparesis 4 = Marked paraparesis or hemiparesis, moderate quadriparesis, or monoplegia 5 = Paraplegia, hemiplegia, or marked quadriparesis 6 = Quadriplegia B. Cerebellar functions 0 = Normal 1 = Abnormal signs without disability 2 = Mild ataxia 3 = Moderate truncal or limb ataxia 4 = Severe ataxia all limbs 5 = Unable to perform coordinated movements due to ataxia C. Brainstem functions 0 = Normal 1 = Signs only 2 = Moderate nystagmus or other mild disability 3 = Severe nystagmus, marked extraocular weakness, or moderate disability of other cranial nerves 4 = Marked dysarthria or other marked disability 5 = Inability to swallow or speak D. Sensory functions 0 = Normal 1 = Vibration or figure-writing decrease only, in 1 or 2 limbs 2 = Mild decrease in touch or pain or position sense, and/or moderate decrease in vibration in 1 or 2 limbs, or vibratory decrease alone in 3 or 4 limbs 3 = Moderate decrease in touch or pain or position sense, and/or essentially lost vibration in 1 or 2 limbs, or mild decrease in touch or pain, and/or moderate decrease in all proprioceptive tests in 3 or 4 limbs 4 = Marked decrease in touch or pain or loss of proprioception, alone or combined, in 1 or 2 limbs or moderate decrease in touch or pain and/or severe proprioceptive decrease in >2 limbs Source: Adapted from JF Kurtzke: Rating neurologic impairment in multiple sclerosis: An expanded disability status scale (EDSS). Neurology 33:1444, 1983. meaning so insidiously that neither the patient nor the provider rec­ ognizes their occurrence at the time of gradual worsening, raises the important question as to whether there is a meaningful distinction between RRMS and SPMS. If any confirmed PIRA event is considered to be indicative of SPMS, then the SPMS onset begins much earlier in the disease course when patients still experience relapses but have only accumulated relative minor disability. ■ ■EPIDEMIOLOGY Geographic gradients are consistently observed in MS, with the highest prevalence generally found in temperate zones; in tropical regions, the 5.5 = Ambulatory without aid or rest for ~100 m 6.0 = Unilateral assistance required to walk about 100 m with or without resting 6.5 = Constant bilateral assistance required to walk about 20 m without resting 7.0 = Unable to walk beyond about 5 m even with aid; essentially restricted to wheelchair; wheels self and transfers alone 7.5 = Unable to take more than a few steps; restricted to wheelchair; may need aid to transfer 8.0 = Essentially restricted to bed or chair or perambulated in wheelchair, but out of bed most of day; retains many self-care functions; generally has effective use of arms 8.5 = Essentially restricted to bed much of the day; has some effective use of arm(s); retains some self-care functions 9.0 = Helpless bed patient; can communicate and eat 9.5 = Totally helpless bed patient; unable to communicate or eat 10.0 = Death due to MS 5 = Loss (essentially) of sensation in 1 or 2 limbs or moderate decrease in touch or pain and/or loss of proprioception for most of the body below the head 6 = Sensation essentially lost below the head E. Bowel and bladder functions 0 = Normal 1 = Mild urinary hesitancy, urgency, or retention 2 = Moderate hesitancy, urgency, retention of bowel or bladder, or rare urinary incontinence 3 = Frequent urinary incontinence 4 = In need of almost constant catheterization 5 = Loss of bladder function 6 = Loss of bowel and bladder function F. Visual (or optic) functions 0 = Normal 1 = Scotoma with visual acuity (corrected) better than 20/30 2 = Worse eye with scotoma with maximal visual acuity (corrected) of 20/30 to 20/59 3 = Worse eye with large scotoma, or moderate decrease in fields, but with maximal visual acuity (corrected) of 20/60 to 20/99 4 = Worse eye with marked decrease of fields and maximal acuity (corrected) of 20/100 to 20/200; grade 3 plus maximal acuity of better eye of 20/60 or less 5 = Worse eye with maximal visual acuity (corrected) <20/200; grade 4 plus maximal acuity of better eye of ≤20/60 6 = Grade 5 plus maximal visual acuity of better eye of ≤20/60 G. Cerebral (or mental) functions 0 = Normal 1 = Mood alteration only (does not affect EDSS score) 2 = Mild decrease in mentation 3 = Moderate decrease in mentation 4 = Marked decrease in mentation 5 = Chronic brain syndrome—severe or incompetent prevalence is often 10-fold to 20-fold less. In addition, a north-south gradient was observed in numerous national and regional studies, with decreasing rates as one moves equatorially. The prevalence of MS also increased steadily in several regions around the world over the past half-century, presumably reflecting the impact of some environmental shift, improved diagnosis, and/or a longer lifespan. Moreover, this increase appears to have occurred to a greater degree in women than men and in nonwhite populations. In the United States, there is a slightly higher prevalence in white compared with black individuals, with lower estimates in Hispanics, followed by Asians. Multiple lines of evidence incriminate a role for infection with the Epstein-Barr virus (EBV) in MS. Individuals who have never been EBV infected (~5% of the population globally) have a very low MS risk, ~20-fold lower than in EBV-positive individuals, and a history of infectious mononucleosis (associated with initial exposure to EBV dur­ ing adolescence or later in life) increases risk more than twofold higher yet. Higher antibody titers to EBV nuclear antigens were repeatedly associated with MS risk, and studies from longitudinal biobank col­ lections showed that serologic conversion to EBV is a near-universal prerequisite for development of MS. Following primary EBV infection, a lifelong infection is established in most individuals, with latent EBV exclusively present in very small numbers (~1:10−6) of B lymphocytes. EBV-infected B cells were not consistently identified in the nervous system of MS patients. It is possible that ongoing lytic cycles by very few infected B cells residing within the CNS could produce bursts of inflammation and MS lesions; however, it is more likely that pathology could be triggered by B cell–mediated antigen presentation of EBV peptides that cross-react with MS autoantigens via molecular mimicry (see “Immunology,” below). A history of cigarette smoking is also associated with MS risk. Interestingly, in an animal model of MS, the lung was identified as a critical site for activation of pathogenic T lymphocytes responsible for autoimmune demyelination. Finally, vitamin D deficiency has been repeatedly associated with MS. Immunoregulatory effects of vitamin D could explain these appar­ ent relationships. Exposure of the skin to ultraviolet B (UVB) radiation from the sun is essential for the biosynthesis of vitamin D, and this endogenous production is the most important source of vitamin D in most individuals. A diet rich in fatty fish represents another source of vitamin D. At higher latitudes, the amount of UVB radiation reach­ ing the earth’s surface is often insufficient, particularly during winter months, and consequently, low serum levels of vitamin D are frequent in temperate zones. The common practice to avoid direct sun exposure and the widespread use of sunblock would be expected to exacerbate any population-wide vitamin D deficiency. GENETIC CONSIDERATIONS MS aggregates within some families, and adoption, half-sibling, twin, and spousal studies indicate that familial aggregation is primarily due to genetic factors. Importantly, family studies also support a contribution of environment, as fraternal twins of MS patients are at higher risk than nontwin siblings (Table 455-3). Susceptibility to MS is polygenic, with each gene contributing a rela­ tively small amount to overall risk. The strongest susceptibility signal genome-wide maps to the human leukocyte antigen (HLA)-DRB1 gene in the class II region of the major histocompatibility complex (MHC) and specifically to HLA-DRB1*1501 (formerly designated DR2), and this association accounts for ~10% of the disease risk. This HLA asso­ ciation, first described in the early 1970s, suggests that MS, at its core, is an autoimmune disease. Whole-genome association studies have iden­ tified >230 other MS susceptibility variants, each of which individually has only a very small effect on MS risk. Many of these MS-associated genes have known roles in the adaptive and innate immune system, for example, the genes for the interleukin (IL) 7 receptor (CD127), IL-2 receptor (CD25), and T-cell costimulatory molecule LFA-3 (CD58); some variants also influence susceptibility to other autoimmune dis­ eases in addition to MS. The variants identified so far all lack specificity TABLE 455-3  Risk of Developing Multiple Sclerosis (MS) 1 in 3 If an identical twin has MS 1 in 15 If a fraternal twin has MS 1 in 25 If a sibling has MS 1 in 50 If a parent or half-sibling has MS 1 in 100 If a first cousin has MS 1 in 1000 If a spouse has MS 1 in 1000 If no one in the family has MS and sensitivity for MS; thus, at present, they are not useful for diagnosis and have no meaningful effect on the clinical course of MS once it begins. For many years, identification of genes that influence disease expression was elusive, but recently, the first loci for MS severity were identified; unlike risk genes, these variants appear to operate in the nervous system rather than immune system, and one signal reaching genome-wide significance, located in the region of dysferlin and a zinc finger gene (ZNF638), confers a 7-year acceleration of progression to wheelchair-dependent status. PATHOGENESIS ■ ■PATHOLOGY Demyelination  New MS lesions begin with perivenular cuffing by inflammatory mononuclear cells, predominantly T cells and macro­ phages, which also infiltrate the surrounding white matter. At sites of inflammation, the blood-brain barrier (BBB) is disrupted, but unlike vasculitis, the vessel wall is preserved. At the leading edge of lesions, cytotoxic CD8 cells are found. Involvement of the humoral immune system is also evident; B lymphocytes infiltrate the nervous system, myelin-specific autoantibodies are present on degenerating myelin sheaths, and complement is activated. CHAPTER 455 Multiple Sclerosis Sharply demarcated areas of demyelination are the pathologic hallmark of MS lesions, and evidence of myelin degeneration is found at the earliest time points of tissue injury. Although relative sparing of axons is typical, partial or total axonal destruction can also occur, especially within highly inflammatory lesions. In some lesions, sur­ viving oligodendrocytes or those that differentiate from precursor cells partially remyelinate the surviving axons, producing so-called shadow plaques. However, in many lesions, oligodendrocyte precursor cells are present but fail to differentiate into mature myelin-producing cells. Therefore, promoting remyelination to protect axons remains an important therapeutic goal. As lesions evolve, there is prominent astro­ cytic proliferation (gliosis), and the term sclerosis refers to these gliotic plaques that have a rubbery or hardened texture at autopsy. Neurodegeneration  Cumulative axonal and neuronal loss is the most important contributor to irreversible neurologic disability and progressive symptoms. With paraplegia due to MS, as many as 70% of axons are ultimately lost from the lateral corticospinal (e.g., motor) tracts. Demyelination can reduce trophic support for axons, redistrib­ ute ion channels, and destabilize action potential membrane potentials. Axons can adapt initially to these injuries, but over time, distal and retrograde degeneration (“dying-back” axonopathy) occurs. Multiple pathologies appear to contribute to progressive symptoms. Chronic active plaques are preexisting white matter lesions that show evidence of persistent inflammation, progressive axonal loss, and gradual concentric expansion, with large numbers of microglial cells at the leading edge of enlarging lesions without BBB disruption. Also important is a primary injury to the cerebral cortex. Cortical plaques are frequent in MS but are generally not well visualized by MRI; these can extend upward from adjacent white matter lesions or may be located entirely within the cortex or underneath the pia. Ectopic lymphoid follicles are aggregates of B, T, and plasma cells located in the superficial meninges, especially overlying deep cortical sulci; similar clusters are also present in perivascular spaces. Ectopic lymphoid fol­ licles are associated with underlying demyelination and neuronal loss in the cerebral cortex, and diffusible factors from these lymphoid cells appear to mediate subpial cortical demyelination and neurodegenera­ tion. Cux2-positive neurons in layer 2 and 3 of the neocortex appear to be particularly vulnerable. Neuronal and axonal death may result from glutamate-mediated excitotoxicity, oxidative injury, iron accumulation, and/or mitochondrial failure. In relapsing MS, inflammation is characterized by focal perivenular infiltration of lymphocytes and monocytes, BBB disruption, and active demyelination. By contrast, inflammation in progressive MS is more diffuse, with widespread microglial proliferation across large areas of white matter, accompanied by infiltration of CD8 T cells and plasma­ blasts/plasma cells. Reduced myelin staining and axonal injury (“dirty white matter”) are associated with these chronic pathologies. Astro­ gliosis has long been known to be a prominent feature of MS pathol­ ogy, and activated astrocytes likely contribute directly to neuronal and myelin injury (Chap. 435). Ongoing inflammation occurs behind an intact BBB in many patients with progressive MS, possibly accounting for the failure of immunotherapies not capable of crossing the BBB to benefit patients with progressive MS. ■ ■IMMUNOLOGY An autoimmune response directed against components of CNS myelin, and perhaps other neural elements as well, remains the cornerstone of current concepts of MS pathogenesis. However, specific antigenic targets in MS have never been conclusively identified. B Lymphocytes and Antibodies  B cells are centrally involved in the development of demyelinating lesions, as evidenced by the efficacy of B cell–based treatments in all forms of MS (see “Treatment” below). Clonally restricted populations of activated, antigen-experienced, mem­ ory B cells and plasma cells are present in MS lesions, in meningeal lymphoid follicle-like structures overlying the cerebral cortex, and in cerebrospinal fluid (CSF). They produce the oligoclonal immunoglobu­ lins and increased antibody synthesis rates in the CSF long useful in the diagnosis of MS. Myelin-specific autoantibodies, some directed against an extracellular myelin protein, myelin oligodendrocyte glyco­ protein (MOG), have been detected bound to degenerating myelin in MS plaques. However, many more antibodies derived from these B cells appear to be directed against a diverse array of ubiquitous intracellular proteins seemingly unrelated to MS pathogenesis. Furthermore, the specific targets are different in each patient. Therefore, although these highly restricted CNS antibodies are characteristic of MS, their role in disease remains uncertain. PART 13 Neurologic Disorders More likely, the antigen-presenting cell (APC) function of B cells explains their role in MS pathogenesis. Fragments of self-peptides derived from HLA-DR2 proteins themselves were found to bind intact DRB1*1501 molecules on B cells and serve as antigens for presenta­ tion to T cells. Memory CD4+ T cells derived from CSF responded to these self-peptides bound to DR2 molecules, and in some cases, these self-peptides were cross-reactive with several myelin antigens, as well as proteins derived from EBV, Akkermansia muciniphila (a com­ mensal gut bacterium associated with dysbiosis in MS patients), and RAS guanyl-releasing protein 2 (RASGRP2), previously found to be a possible T-cell autoantigen in MS. Thus, MS-associated HLA proteins contain fragments that might trigger autoimmunity through molecular mimicry with viral, bacterial, or normal host antigens. Autoreactive T Lymphocytes  Autoreactive T cells may be trig­ gered and sustained via B-cell antigen presentation. Myelin basic protein (MBP), an intracellular protein involved in myelin compaction, is an important T-cell antigen in experimental allergic encephalomyelitis (EAE), a laboratory model for MS. Activated MBP-reactive T cells have been identified in the blood, in CSF, and within MS lesions. The MS-associated HLA-DRB1*1501 protein binds with high affinity to a fragment of MBP (spanning amino acids 89–96), potentially stimulat­ ing T-cell responses to this self-protein. Several different populations of proinflammatory T cells are likely to mediate autoimmunity in MS. T-helper type 1 (TH1) cells producing interferon γ (IFN-γ) are one key effector population; TH1 cytokines, including IL-2, tumor necrosis fac­ tor (TNF)-α, and IFN-γ, play key roles in activating and maintaining autoimmune responses, and TNF-α and IFN-γ may directly injure oligo­ dendrocytes or the myelin membrane. B cells from MS patients are also known to be high producers of TNF-α. As noted above, CD8 cytotoxic T cells are present at the active edges of expanding MS lesions, and acti­ vated CD8 cells also appear to be enriched for reactivity against myelin antigens in MS patients. Microglial Activation  Widespread microglial activation is a hall­ mark of progressive MS pathology. Activated microglia are found in cortical plaques in the absence of macrophage and leukocyte infiltrates. Some cortical plaques are found adjacent to sites of meningeal inflam­ mation in which tertiary lymphoid follicles are found. As discussed above, these meningeal lymphoid structures are a hallmark of MS pathology. Microglial activation in MS is thought to be triggered by proinflammatory B and T lymphocytes or in response to tissue injury signals via toll-like receptor signaling. Although once thought to exist in either proinflammatory or anti-inflammatory states, microglia are now understood to have varied and context-dependent transcriptional states. ■ ■PHYSIOLOGY Nerve conduction in myelinated axons occurs in a saltatory manner, with the nerve impulse jumping from one node of Ranvier to the next without depolarization of the axonal membrane underlying the myelin sheath between nodes (Fig. 455-2A). This produces faster conduction velocities (~70 m/s) than the slow velocities (~1 m/s) produced by continuous propagation in unmyelinated nerves. Conduction block occurs when the nerve impulse is unable to traverse the demyelinated segment. This can happen when the resting axon membrane becomes hyperpolarized due to exposure of voltage-dependent potassium chan­ nels that are normally buried underneath the myelin sheath. A tem­ porary conduction block often follows a demyelinating event before sodium channels (originally concentrated at the nodes) redistribute along the naked axon (Fig. 455-2B). This redistribution ultimately allows continuous propagation of nerve action potentials through the demyelinated segment. Conduction block may be incomplete, affecting high- but not low-frequency volleys of impulses. Variable conduction block can also occur with raised body temperature or metabolic altera­ tions. These factors may explain clinical fluctuations that vary from hour to hour or appear with fever or exercise. Conduction slowing occurs when the demyelinated segments of the axonal membrane are reorganized to support continuous (slow) nerve impulse propagation. DIAGNOSIS There is no single diagnostic test for MS. Diagnostic criteria for clini­ cally definite MS require two or more episodes of symptoms and two or more signs that reflect pathology in anatomically noncontiguous white matter tracts of the CNS (Table 455-4). Symptoms must last for >24 h and occur as distinct episodes separated by a month or more. In patients who have only one of the two required signs on neurologic examination, the second may be documented by abnormal tests such as MRI or evoked potentials (EPs). Similarly, in the most recent diagnos­ tic scheme, the second clinical event (in time) may be supported solely by MRI findings, consisting of either the development of new focal white matter lesions on MRI or the simultaneous presence of both an enhancing lesion and a nonenhancing lesion in an asymptomatic loca­ tion. In patients whose course is progressive from onset for ≥6 months Saltatory nerve impulse Myelin sheath Axon Node of Ranvier Na+ channels A Continuous nerve impulse Myelin sheath Myelin sheath Axon Na+ channels B FIGURE 455-2  Nerve conduction in myelinated and demyelinated axons. A. Saltatory nerve conduction in myelinated axons occurs with the nerve impulse jumping from one node of Ranvier to the next. Sodium channels (shown as breaks in the solid black line) are concentrated at the nodes where axonal depolarization occurs. B. Following demyelination, additional sodium channels are redistributed along the axon itself, thereby allowing continuous propagation of the nerve action potential despite the absence of myelin. TABLE 455-4  Diagnostic Criteria for Multiple Sclerosis (MS) CLINICAL PRESENTATION ADDITIONAL DATA NEEDED FOR MS DIAGNOSIS 2 or more attacks; objective clinical evidence of 2 or more lesions or objective clinical evidence of 1 lesion with reasonable historical evidence of a prior attack None 2 or more attacks; objective clinical evidence of 1 lesion Dissemination in space, demonstrated by ≥1 T2 lesion on MRI in at least 2 out of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) OR • Await a further clinical attack implicating a different CNS site 1 attack; objective clinical evidence of 2 or more lesions Dissemination in time, demonstrated by • Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time OR • A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan OR • Await a second clinical attack 1 attack; objective clinical evidence of 1 lesion (clinically isolated syndrome) Dissemination in space and time, demonstrated by: For dissemination in space • ≥1 T2 lesion in at least 2 out of 4 MS-typical regions of the CNS (periventricular, juxtacortical, infratentorial, or spinal cord) OR • Await a second clinical attack implicating a different CNS site AND • For dissemination in time • Simultaneous presence of asymptomatic gadolinium-enhancing and nonenhancing lesions at any time OR • A new T2 and/or gadolinium-enhancing lesion(s) on follow-up MRI, irrespective of its timing with reference to a baseline scan OR • Await a second clinical attack Insidious neurologic progression suggestive of MS (PPMS) 1 year of disease progression (retrospectively or prospectively determined) PLUS 2 out of the 3 following criteria: • Evidence for dissemination in space in the brain based on ≥1 T2+ lesions in the MS-characteristic periventricular, juxtacortical, or infratentorial regions • Evidence for dissemination in space in the spinal cord based on ≥2 T2+ lesions in the cord • Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated IgG index) Abbreviations: CNS, central nervous system; CSF, cerebrospinal fluid; MRI, magnetic resonance imaging; PPMS, primary progressive multiple sclerosis. Source: Reproduced with permission from AJ Thompson et al: Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17:162, 2018. without superimposed relapses, documentation of intrathecal IgG synthesis may be used to support a diagnosis of PPMS. DIAGNOSTIC TESTS ■ ■MAGNETIC RESONANCE IMAGING MRI has revolutionized the diagnosis and management of MS (Fig. 455-3); characteristic abnormalities are found in >95% of patients, although the majority of lesions visualized by MRI are asymptomatic. An increase in vascular permeability from a breakdown of the BBB is detected by leakage of intravenous gadolinium (Gd) into the parenchyma. Such leakage occurs early in the development of an MS lesion and serves as a marker of inflammation. Gd enhancement typically persists for <1 month, and the residual MS plaque remains visible indefinitely as a focal area of hyperintensity (a lesion) on T2-weighted images. Lesions are frequently oriented perpendicular to the ventricular surface, corresponding to a pattern of perivenous demyelination (Dawson’s fingers; Fig. 455-3B). Lesions are multifocal within the brain, brainstem, and spinal cord. Lesions >6 mm located in the corpus callosum, periventricular white matter, brainstem, cerebel­ lum, or spinal cord are particularly helpful diagnostically. Also useful diagnostically is a central vein sign within plaques visualized with susceptibility-weighted (such as T2*) sequences (Chap. 434). Criteria for the use of MRI in diagnosis of MS are shown in Table 455-4. Serial MRI studies in RRMS reveal that bursts of focal inflamma­ tory disease activity occur far more frequently than would have been predicted by the frequency of relapses. Thus, early in MS, most disease activity is clinically silent. CHAPTER 455 The total volume of T2-weighted signal abnormality (the “burden of disease”) shows a significant (albeit weak) correlation with clinical disability. Quantitative measures of brain and especially spinal cord atrophy provide evidence of diffuse tissue injury and correlate more strongly with measures of disability or progressive MS. Serial MRI studies also indicate that progressive brain atrophy occurs even in very early MS and continues throughout the disease course. Approximately one-third of T2-weighted lesions appear as hypointense lesions (black holes) on T1-weighted imaging. Black holes are markers of irreversible demyelination and axonal loss, although even this measure depends on the timing of the image acquisition (e.g., most acute Gd-enhancing T2 lesions are T1 dark, and in chronic lesions, there is progressive T1 darkening over time). Multiple Sclerosis ■ ■CEREBROSPINAL FLUID CSF changes in MS include a mononuclear cell pleocytosis and an increased level of intrathecally synthesized IgG. The total CSF protein is usually normal or only mildly elevated. Various formulas distinguish intrathecally synthesized IgG from IgG that entered the CNS passively from the serum. The CSF IgG index expresses the ratio of IgG to albumin in the CSF divided by the same ratio in the serum. The IgG synthesis rate uses serum and CSF IgG and albumin measurements to calculate the rate of CNS IgG synthesis. The measurement of oligoclo­ nal bands (OCBs) by agarose gel electrophoresis of the CSF assesses intrathecal production of specific IgG clones separated by differences in charge. Two or more discrete OCBs, not present in a paired serum sample, are found in >90% of patients with MS. OCBs may be absent at the onset of MS, and in individual patients, the number of bands may increase over time. A mild CSF pleocytosis (>5 cells/μL) is present in ~25% of cases, usually in young patients with RMS. A pleocytosis of >75 cells/μL, the presence of polymorphonuclear leukocytes, or a protein concentration >1 g/L (>100 mg/dL) in CSF should raise concern that the patient may not have MS. Because of its utility to rule in and also rule out MS, CSF examination is highly recommended as part of the routine MS workup, and especially when the diagnosis is uncertain. ■ ■EVOKED POTENTIALS EP testing assesses function in afferent (visual, auditory, and somato­ sensory) or efferent (motor) CNS pathways. EPs use computer averag­ ing to measure CNS electric potentials evoked by repetitive stimulation of selected peripheral nerves or of the brain. These tests provide the most information when the pathways studied are clinically uninvolved. For example, in a patient with a relapsing spinal cord syndrome with sensory deficits in the legs, an abnormal somatosensory EP following posterior tibial nerve stimulation provides little new information. By contrast, an abnormal visual EP in this circumstance would permit a diagnosis of clinically definite MS (Table 455-4). Abnormalities on one or more EP modalities occur in 80–90% of MS patients. EP abnormali­ ties are not specific to MS, although a marked delay in the latency of a PART 13 Neurologic Disorders specific EP component (as opposed to a reduced amplitude or distorted wave shape) suggests demyelination. DIFFERENTIAL DIAGNOSIS The possibility of an alternative diagnosis should always be considered (Table 455-5), particularly when (1) symptoms are localized exclu­ sively to the posterior fossa, craniocervical junction, or spinal cord; (2) the patient is <15 or >60 years of age; (3) the clinical course is pro­ gressive from onset; (4) the patient has never experienced visual, sen­ sory, or bladder symptoms; or (5) laboratory findings (e.g., MRI, CSF, or EPs) are atypical. Similarly, symptoms that are uncommon or rare in MS (e.g., aphasia, parkinsonism, chorea, isolated dementia, severe muscular atrophy, peripheral neuropathy, episodic loss of conscious­ ness, fever, headache, seizures, or coma) favor an alternative diagnosis. Diagnosis can be particularly difficult in patients with a rapid or explo­ sive (stroke-like) onset or those with mild symptoms and a normal neurologic examination. Rarely, intense inflammation and swelling may produce a mass lesion that mimics a primary or metastatic tumor. Disorders possibly mistaken for MS include neuromyelitis optica (NMO) and the more recently identified myelin oligodendrocyte protein-associated disease (MOGAD) and glial fibrillary acid pro­ tein (GFAP) disorders (Chap. 456); these should be considered in patients who present with bilateral and/or severe optic neuritis or severe transverse myelitis. With hyperacute or postinfectious presenta­ tions, another consideration is acute disseminated encephalomyelitis (ADEM; Chap. 456). Other possibilities include Sjögren’s syndrome, sarcoidosis, vascular disorders (antiphospholipid syndrome and vas­ culitis), rarely CNS lymphoma, and still more rarely infections such as syphilis or Lyme disease. The specific tests required to exclude alternative diagnoses will vary with each clinical situation; however, an erythrocyte sedimentation rate, serum B12 level, antinuclear antibodies, and treponemal antibody should probably be obtained in all patients with suspected MS. TREATMENT Therapy for MS can be divided into several categories: (1) treatment of acute attacks, (2) treatment with disease-modifying agents that reduce the biologic activity of MS, and (3) symptomatic therapy. Treatments that promote remyelination or neural repair do not currently exist, but several promising approaches are being actively investigated. A B C D FIGURE 455-3  Magnetic resonance imaging findings in multiple sclerosis (MS). A. Axial first-echo image from T2-weighted sequence demonstrates multiple bright signal abnormalities in white matter, typical for MS. B. Sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) image in which the high signal of cerebrospinal fluid (CSF) has been suppressed. CSF appears dark, whereas areas of brain edema or demyelination appear high in signal, as shown here in the corpus callosum (arrows). Lesions in the anterior corpus callosum are frequent in MS and rare in vascular disease. C. Sagittal T2-weighted fast spin echo image of the thoracic spine demonstrates a fusiform high-signal-intensity lesion in the midthoracic spinal cord. D. Sagittal T1-weighted image obtained after the intravenous administration of gadolinium diethylene triamine pentaacetic acid (DTPA) reveals focal areas of blood-brain barrier disruption, identified as high-signal-intensity regions (arrows). TABLE 455-5  Disorders That Can Mimic Multiple Sclerosis (MS) Acute disseminated encephalomyelitis (ADEM) Antiphospholipid antibody syndrome Behçet’s disease Cerebral autosomal-dominant arteriopathy, subcortical infarcts, and leukoencephalopathy (CADASIL) Congenital leukodystrophies (e.g., adrenoleukodystrophy, metachromatic leukodystrophy) Glial Fibrillary Acidic Protein (GFAP) Autoimmunity Human immunodeficiency virus (HIV) infection Ischemic optic neuropathy (arteritic and nonarteritic) Lyme disease Mitochondrial encephalopathy with lactic acidosis and stroke (MELAS) Myelin oligodendrocyte glycoprotein-associated disease (MOGAD) Neoplasms (e.g., lymphoma, glioma, meningioma) Neuromyelitis optica Sarcoidosis Sjögren’s syndrome Stroke and ischemic cerebrovascular disease Syphilis Systemic lupus erythematosus and related collagen vascular disorders Tropical spastic paraparesis (HTLV-1/2 infection) Vascular malformations (especially spinal dural AV fistulas) Vasculitis (primary CNS or other) Vitamin B12 deficiency Abbreviations: AV, arteriovenous; CNS, central nervous system; HTLV, human T-cell lymphotropic virus. As noted above, the EDSS is a widely used measure of neurologic impairment in MS (Table 455-2). Most patients with EDSS scores <3.5 walk normally and are generally not disabled; by contrast, patients with EDSS scores >4.0 have progressive MS (SPMS or PPMS), are gaitimpaired, and often are occupationally disabled. ■ ■ACUTE ATTACKS OR INITIAL DEMYELINATING EPISODES When patients experience acute deterioration, it is important to consider whether this change reflects new disease activity or a “pseu­ doexacerbation” resulting from an increase in ambient temperature, fever, or an infection. When the clinical change is thought to reflect a pseudoexacerbation, glucocorticoid treatment is inappropriate. Gluco­ corticoids are used to manage first attacks and exacerbations that are moderate to severe in severity. They provide short-term clinical benefit by reducing the degree and duration of attacks. Whether treatment provides any long-term benefit on the course of the illness is less clear. Therefore, mild attacks are often not treated. Physical and occupational therapy can help with mobility and manual dexterity. Glucocorticoid treatment is usually administered as intravenous methylprednisolone, 500–1000 mg/d for 3–5 days, either without a taper or followed by a course of oral prednisone beginning at a dose of 60–80 mg/d and gradually tapered over 2 weeks. Orally administered methylprednisolone, prednisone, or dexamethasone (in equivalent dosages) can be substituted for the intravenous portion of the therapy. Outpatient treatment is almost always possible. Side effects of short-term glucocorticoid therapy include fluid retention, potassium loss, weight gain, gastric disturbances, acne, and emotional lability. Concurrent use of a low-salt, potassium-rich diet and avoidance of potassium-wasting diuretics are advisable. Lithium carbonate (300 mg orally bid) may help manage emotional lability and insomnia associated with glucocorticoid therapy. Patients with a history of peptic ulcer disease may require cimetidine (400 mg bid) or ranitidine (150 mg bid). Proton pump inhibitors such as pantoprazole (40 mg orally bid) may reduce the likelihood of gastritis, especially when large doses are administered orally. Plasma exchange (five to seven exchanges: 40–60 mL/kg per exchange, every other day for 14 days) may benefit patients with fulminant attacks of demyelination that are unresponsive to glucocorticoids. ■ ■DISEASE-MODIFYING THERAPIES FOR MS RMS  More than a dozen immunomodulatory and immunosuppres­ sive agents are in use for treatment of RMS (Table 455-6). In phase 3 clinical trials, each was shown to reduce the frequency of clinical relapses and evolution of new brain MRI lesions. Each can also be used in SPMS patients who continue to experience attacks, both because SPMS can be difficult to distinguish from RRMS and because the available clinical trials, although not all definitive, suggest that such patients may sometimes derive therapeutic benefit. Moreover, regula­ tors now consider patients with recent relapses to be a “relapsing form of MS” (i.e., RMS), regardless of whether these patients previously had progressive disability independent from relapses. It is important to note that the relative efficacy of the different agents has not been directly tested in head-to-head studies and that cross-trial comparisons are inaccurate. However, given the increasingly complex landscape of therapeutics for MS, for convenience, the presentation of these agents was divided by an estimate of their relative (high, moderate, or modest) perceived level of efficacy. These are meant to serve as a general guide, with the caveat that considerable variance exists in practice patterns, as well as availability of these agents, in different parts of the world. CHAPTER 455 Multiple Sclerosis Therapy should be initiated in all patients diagnosed with RMS and those presenting with a first demyelinating event who are at high risk for MS (sometimes termed as a clinically isolated syndrome [CIS]). We favor use of the most highly effective disease-modifying therapies as first-line options for most patients. This recommendation is based on evidence from long-term prospective trials and real-world data indicating that initial treatment with highly effective agents provides outstanding control against relapsing disease, maximum protection against relapse-independent progression, and long-term outcomes, and is safe. We typically begin with an anti-CD20 B-cell-targeting drug (ocrelizumab, ofatumumab, or ublituximab) or, if these approved treat­ ments are unavailable, with rituximab or a biosimilar. In JCV-negative patients, we begin with the cell-trafficking inhibitor natalizumab. AntiCD20 agents are particularly attractive given their high level of efficacy, relative ease of use, favorable safety profile, and absence of rebound fol­ lowing discontinuation. For patients who prefer oral treatment, either an S1P modulator or a fumarate is also reasonable for first-line therapy. First-line treatment with high-efficacy therapy has supplanted the alternative approach in which a treatment of modest or moderate effectiveness was first used and therapy advanced to a more effec­ tive agent when breakthrough disease (evident clinically or by MRI) occurred. Older first-generation therapies, such as IFN-βor glatiramer acetate, are often continued in patients who are doing well on these agents but are less commonly used today for patients with new-onset MS. Irrespective of the agent used, a change in therapy may be required in patients with suboptimal responses, such as those experiencing relapses and/or active MRI scans while on treatment, or for adverse events that may be drug-related. Pregnancy-related management is discussed later in this chapter. Some patients, especially those with a mild initial RRMS course— e.g., a normal examination or minimal impairment (EDSS ≤2.5) and low disease activity by MRI—may initially decline therapy with a potent immunosuppressive drug. In these situations, either an oral (fumarates, S1P modulators, or teriflunomide) or injectable (IFN-β or glatiramer acetate) agent can be considered. The injectable agents (IFN-β and glatiramer acetate) have a superb long-term track record for safety but have a high nuisance factor due to the need for frequent injections, as well as bothersome side effects that reduce adherence. As noted above, multiple lines of evidence indicate that institution of effective therapy can improve the long-term outcome of MS, includ­ ing a prolongation of the time to reach disability outcomes (e.g., SPMS and requiring assistance to ambulate) and reduction in MS-related mortality. These benefits seem most conspicuous when treatment is begun early in the relapsing stage of the illness. It may be reasonable to delay initiating treatment in some patients with (1) normal neurologic TABLE 455-6  Disease-Modifying Therapies for Multiple Sclerosis CATEGORY AND MECHANISM OF ACTION GENERIC NAME (TRADE NAME) DOSE AND INTERVAL CHARACTERISTICS COMMENTS (USE, ADVERSE EFFECTS, ETC.) Highly Effective Anti-CD20 B cell MAbs: Depletes B lymphocytes, especially motile B cells in peripheral blood; B cells in lymphoid organs variably protected; plasma cells preserved Ocrelizumab (Ocrevus) 600-mg infusion q6 months (first dose given as two 300-mg infusions 14 days apart) Ofatumumab (Kesimpta) 20-mg subcutaneous injections monthly (after 3 weekly 20-mg loading doses) Ublituximab (Briumvi) 450-mg infusion q6 months (first dose given as 150-mg, followed 14 days later by 450-mg, infusions) Rituximab (Rituxan and biosimilars) 1000-mg infusion q6 months (dose used in phase 2 trial in RMS); some clinicians use 500 mg IV q6 months PART 13 Neurologic Disorders Natalizumab (Tysabri) 300-mg monthly infusion Humanized Hypersensitivity Rxns (<10%) including anaphylaxis; NAbs in ~6%; major risk is PML (0.4%); can be given safely only if serum antibodies to JC virus are absent (~50% of patients); repeat testing q6 months with ongoing treatment; risk of rebound disease activity after cessation Anti-α4 subunit of α4β1 integrin (adhesion molecule) MAb: Prevents lymphocytes from binding to endothelial cells and entering the CNS Anti-CD52 MAb: Depletes lymphocytes and monocytes Alemtuzumab (Lemtrada) 12 mg/m2 infusion for 5 consecutive days; a second 3-day course administered 1 year later Moderately Effective Sphingosine-1-phosphate (S1P) modulators: Prevents egress of lymphocytes from secondary lymphoid organs Pretreatment CBC, LFTs, ECG, eye exam required; vaccinate for VZV in seronegative patients Fingolimod (Gilenya) 0.5 mg oral once daily Binds to S1P1, S1P3, S1P4, and S1P5 receptors Ozanimod (Zeposia) 1 mg oral once daily S1P1- and S1P5-selective inhibitor (cardiac receptors are mostly S1P3 and only weakly engaged by ozanimod) Ponesimod (Ponvory) 20 mg oral once daily S1P1-selective modulator Up-titration regimen used to begin treatment; initial dose requires 4-h cardiac monitoring for patients with heart rate <55 beats/min Siponimod (Mayzent) Based on CYP2C9 genotype. 1 mg oral daily for pts with CYP2C9 1/*3 or 2/*3 Dose reduced in patients with the CYP2C9 *3/*3 genotype (<0.5% of the population) due to substantially elevated drug levels Fumarate: Immunomodulator; reduces proinflammatory and increases regulatory cytokines; inhibits degradation of Nrf2, increasing natural antioxidants Dimethyl fumarate (Tecfidera) 240 mg oral twice daily (halfdose for first 7 days) Diroximel fumarate (Vumerity) 262 mg oral twice daily Metabolized to active compound monomethyl fumarate 2-Chlorodeoxyadenosine: Lymphocytotoxic; possibly followed by reconstitution by nonpathogenic immune cells Cladribine (Mavenclad) Weight-based oral dosing (3.5 mg/kg) divided over 4–5 days, repeated 23–27 days later; a second identical course is administered 1 year later Humanized ADCC > complement Infusion reactions usually mild; outstanding efficacy and safety in longterm RMS extension trials; also approved for PPMS Fully human Complement > ADCC Advantage of home-based treatment; only very minor injection- related reactions Chimeric ADCC > Complement   Chimeric Complement > ADCC Formally tested only in preliminary (phase 2) study Long-lasting benefits but serious risks limit use; approval in United States only for patients who have failed at least two other drugs Multiple autoimmune complications including thyroid (~25%) and ITP (1–3%), malignancies, infection risk Heart block or bradycardia can occur with first dose; a 6-h period of initial observation with ECG monitoring required; LFT abnormalities, macular edema; rare VZV or cryptococcal infections; risk of rebound disease activity after cessation for all agents in this class Up-titration regimen used to begin treatment; first-dose monitoring not required for most patients S1P1- and S1P5-selective modulator Approved for SPMS with active disease (relapses or new focal MRI lesions); firstdose monitoring only for patients with sinus bradycardia, heart block, or prior myocardial infarction or heart failure Metabolized to active compound monomethyl fumarate Gastrointestinal side effects, flushing; these may improve over time; monitor for LFT abnormalities and for lymphopenia (which can persist after drug cessation); rare PML cases Similar side effect profile as dimethyl fumarate Purine analogue prodrug phosphorylated in lymphocytes and incorporated into DNA, triggering apoptosis; long-lasting Long-lasting benefits but use limited by risks of malignancy, teratogenicity, and infection including PML (Continued) TABLE 455-6  Disease-Modifying Therapies for Multiple Sclerosis CATEGORY AND MECHANISM OF ACTION GENERIC NAME (TRADE NAME) DOSE AND INTERVAL CHARACTERISTICS COMMENTS (USE, ADVERSE EFFECTS, ETC.) Modestly Effective Glatiramer acetate: Immunomodulator; reduces proinflammatory and increases regulatory cytokines; induces antigen-specific suppressor T cells; binds MHC molecules Glatiramer acetate (Copaxone) Subcutaneous injection 20 mg daily, or alternatively, 40 mg three times weekly Intramuscular injections 30 mg once weekly With all IFN preparations: flu-like symptoms (fever, chills, myalgias) common; managed with NSAIDs; mild lab abnormalities (LFTs, lymphopenia); rare cases of severe hepatotoxicity Interferon-β-1a (Rebif) Interferon (IFN)-β: Immunomodulator; reduces proinflammatory and increases regulatory cytokines; interferes with antigen presentation, T-cell proliferation, lymphocyte trafficking Interferon-β-1a (Avonex) Subcutaneous injections 44 mg three times per week Subcutaneous injections 250 mg every other day Interferon-β-1b (Betaseron or Extavia) Pegylated interferon-β-1a (Plegridy) Subcutaneous injections 125 mg every 14 days Teriflunomide: Antiinflammatory; limits proliferation of rapidly dividing B and T lymphocytes Teriflunomide (Aubagio) 14 mg oral daily Inhibits mitochondrial enzyme dihydro-orotate dehydrogenase involved in de novo pyrimidine synthesis; cytostatic rather than cytotoxic Abbreviations: ADCC, antibody-dependent cell-mediated cytotoxicity; CBC, complete blood count; CNS, central nervous system; ECG, electrocardiogram; ITP, immune thrombocytopenia; LFT, liver function test; MAbs, monoclonal antibodies; MHC, major histocompatibility complex; MRI, magnetic resonance imaging; NAb, neutralizing antibody; NSAID, nonsteroidal anti-inflammatory drug; PML, progressive multifocal leukoencephalopathy; PPMS, primary progressive multiple sclerosis; RMS, relapsing multiple sclerosis; Rxn, reaction; SPMS, secondary progressive multiple sclerosis; VZV, varicella-zoster virus. examinations, (2) a single attack or a low attack frequency, and (3) a low burden of disease as assessed by brain MRI. Untreated patients, however, should be followed closely with periodic brain MRI scans; the need for therapy is reassessed if scans reveal evidence of ongoing, subclinical disease. Finally, vitamin D deficiency should be corrected in all patients with MS, and generally this requires oral supplementa­ tion with vitamin D3, 4000 IU daily. Several clinical trials showed that supplementation with vitamin D in relapsing MS patients reduces MRI measures of disease activity and may also reduce the relapse frequency in patients actively treated with either IFN or glatiramer acetate. SPMS  For patients with active SPMS, either ocrelizumab or siponi­ mod is a reasonable first-line option. Ocrelizumab is approved for active SPMS despite not having been specifically studied in this patient population. Siponimod in a single pivotal study reduced the risk of progression in SPMS; however, subgroup analysis showed that patients with a relapse in the 2 years prior to treatment and those with contrastenhancing lesions on brain MRI received the most therapeutic benefit. Regulatory bodies also approved cladribine and ponesimod for active SPMS despite neither having been specifically studied in this MS subgroup. PPMS  Ocrelizumab was shown to reduce progression of clinical disability in PPMS by 25% and also improve other clinical and MRI markers of inflammatory and degenerative disease activity. Although the magnitude of the effect in PPMS is lower than in RMS, for the average patient with PPMS, these data translate to the expectation that >7 years of wheelchair-independent function is gained on aver­ age. Ocrelizumab is the only agent convincingly shown to modify the course of PPMS. ■ ■OTHER OFF-LABEL TREATMENT OPTIONS Autologous hematopoietic stem cell transplantation appears to be highly effective in reducing relapses and may improve disability in relapsing MS. It appears to be largely ineffective for patients with progressive MS. Stem cell transplantation also carries significant risk, however, includ­ ing toxicities from chemotherapy-conditioning regimens. Ongoing clinical trials should help to better position this procedure with respect to available pharmacologic interventions. (Continued) Synthetic random polypeptide of four amino acids (l-glutamic acid, l-lysine, l-alanine, Well tolerated; injection site reactions; ~15% of patients experience one (or less often more than one) episode of flushing, chest tightness, dyspnea, palpitations, anxiety l-tyrosine) Neutralizing antibodies in 2–10% (can decrease over time with all IFN preparations) Neutralizing antibodies in 15–25% Neutralizing antibodies in 30–40% CHAPTER 455 Pegylation increases half-life; neutralizing antibodies in <1% Hair thinning, gastrointestinal toxicity (nausea and diarrhea), rarely toxic epidermal necrolysis or Stevens-Johnson syndrome; long-lasting teratogenicity (elimination protocol with cholestyramine or activated charcoal) Multiple Sclerosis Intravenous immunoglobulin (IVIg), administered in monthly pulses (up to 1 g/kg) for up to 2 years, appears to reduce annual exacerbation rates. However, its use is limited because of its high cost, questions about optimal dose, and uncertainty about any impact on long-term disability. It can be considered when the risks of immunosuppression preclude use of other MS agents. Numerous clinical trials of promising experimental therapies are currently underway. These include studies testing higher doses of ocrelizumab; Bruton’s tyrosine kinase (BTK) inhibitors to selec­ tively deplete B cells, plasma cells, and microglia; CD19-targeted chimeric antigen receptor (CAR) T cells; and molecules to promote remyelination. THERAPIES TO AVOID Many purported treatments for MS have never been subjected to sci­ entific scrutiny. These include dietary therapies (e.g., the Swank diet, the Paleo diet, the Wahls diet), megadose vitamins, calcium orotate, bee stings, cow colostrum, hyperbaric oxygen, procarin (a combination of histamine and caffeine), chelation, acupuncture, acupressure, various Chinese herbal remedies, and removal of mercury-amalgam tooth fill­ ings, among others. Although infections with EBV, human herpesvirus (HHV) 6, or other agents are plausibly involved in MS, treatment with antiviral agents or antibiotics is not recommended. A chronic cere­ brospinal insufficiency (CCSVI) was proposed as a cause of MS, and surgical intervention with vascular repair was recommended; however, multiple studies failed to confirm the initial claims. A double-blind trial of high-dose biotin to improve disability in progressive forms of MS also found no benefit. Patients should avoid costly or potentially hazardous unproven treatments, many of which also lack biologic plausibility. SYMPTOMATIC THERAPIES For all patients, it is important to encourage attention to a healthy life­ style, including maintaining an optimistic outlook, a healthy diet, and regular exercise as tolerated (swimming is often well-tolerated because of the cooling effect of cold water). It is reasonable also to correct vitamin D deficiency with oral vitamin D and consider dietary supple­ mentation with long-chain fatty acids (such as omega-3 oil tablets) due to their mild immunomodulatory effects. Bladder dysfunction management is best guided by urodynamic testing because symptoms correlate poorly with the specific patho­ physiology, which can also change over time as the disease evolves. The underlying cause can be bladder hyperreflexia, atony, or dyssynergia between the detrusor and the external sphincter muscle. Detrusor hyperreflexia can be initially managed with evening fluid restriction or frequent voluntary voiding. If these methods fail, beta-3 adrenergic agonists such mirabegron (25–50 mg/d) and vibegron (75 mg/d) that relax bladder smooth muscle should be tried. Beta-3 adrenergic agonists are preferred over anticholinergic agents such as oxybutynin (5–15 mg/d), propantheline bromide (10–15 mg/d), tolterodine tartrate (2–4 mg/d), or solifenacin (5–10 mg/d) because anticholinergic side effects can worsen other MS symptoms includ­ ing cognitive dysfunction. Co-administration of pseudoephedrine (30–60 mg) with anticholinergics is sometimes beneficial. Detrusor muscle injections of botulinum toxin (e.g., onabotulinumtoxinA 200 IU) can be useful when anticholinergics are ineffective or produce side effects such as cognitive dysfunction or fatigue. PART 13 Neurologic Disorders An atonic bladder due to loss of reflex bladder wall contraction may respond to bethanechol (30–150 mg/d), and detrusor/sphincter dyssyn­ ergia may respond to phenoxybenzamine (10–20 mg/d) or terazosin hydrochloride (1–20 mg/d). However, both conditions often require catheterization. Urinary tract infections should be treated promptly. Patients with postvoid residual urine volumes >200 mL are predisposed to infec­ tions. Prevention by urine acidification (with cranberry juice or vitamin C) inhibits some bacteria. Prophylactic administration of anti­ biotics is sometimes necessary but may lead to colonization by resistant organisms. Intermittent catheterization may help to prevent recurrent infections and reduce overflow incontinence. Treatment of constipation includes high-fiber diets and fluids. Natu­ ral or other laxatives may help. Fecal incontinence may respond to a reduction in dietary fiber. Spasticity and spasms may improve with physical therapy, regular exercise, and stretching. Avoidance of triggers (e.g., infections, fecal impactions, bed sores) is extremely important. Effective medications include baclofen (20–120 mg/d), diazepam (2–40 mg/d), tizanidine (8–32 mg/d), dantrolene (25–400 mg/d), and cyclobenzaprine hydro­ chloride (10–60 mg/d). For severe spasticity, a baclofen pump (deliver­ ing medication directly into the CSF) can provide substantial relief. Weakness can sometimes be improved with the use of potassium channel blockers such as 4-aminopyridine (20 mg/d) and 3,4-diaminopyridine (40–80 mg/d), particularly in the setting where lowerextremity weakness interferes with the patient’s ability to ambulate. Extended-release 4-aminopyridine (10 mg twice daily) can be obtained either as dalfampridine (Ampyra) or through a compounding phar­ macy. The principal concern with the use of these agents is the possibil­ ity of inducing seizures at high doses. Ataxia/tremor is often intractable. Clonazepam (0.5–2 mg/d), primi­ done (50–250 mg/d), propranolol (40–200 mg/d), or ondansetron (8–16 mg/d) may help. Wrist weights occasionally reduce tremor in the arm or hand. Thalamotomy and deep-brain stimulation have been tried with mixed success. Pain is treated with anticonvulsants (gabapentin [300–3600 mg/d]; pregabalin [50–300 mg/d]; carbamazepine [100–1000 mg/d]; phenytoin [300–600 mg/d]); tricyclic antidepressants (amitrip­ tyline [25–100 mg/d], nortriptyline [25–100 mg/d], desipramine [100–300 mg/d]); serotonin-norepinephrine reuptake inhibitors (duloxetine [20–120 mg/d] or venlafaxine [75–225 mg/d]); or anti­ arrhythmics (mexiletine, 300–900 mg/d). If these approaches fail, patients should be referred to a comprehensive pain-management program. Depression should be actively treated. Useful drugs include the selective serotonin reuptake inhibitors (escitalopram [10–20 mg/d], fluoxetine [20–80 mg/d], or sertraline [50–200 mg/d]), tricyclic antide­ pressants (amitriptyline [25–150 mg/d], nortriptyline [25–150 mg/d], or desipramine [100–300 mg/d]) and mixed norepinephrine/sero­ tonin reuptake inhibitors (duloxetine [20–120 mg/d] or venlafaxine [75–225 mg/d]). Fatigue may improve with assistive devices, help in the home, or suc­ cessful management of spasticity. Careful attention to medications that could contribute to fatigue is often helpful. For example, patients who require anticholinergic medication for nocturia may benefit from dos­ ing at bedtime only. Excessive daytime somnolence caused by MS may respond to methylphenidate (5–25 mg/d), modafinil (100–400 mg/d), or armodafinil (150–250 mg/d). Cognitive problems may respond marginally to lisdexamfetamine (40 mg/d). Paroxysmal symptoms respond dramatically to low-dose anticonvul­ sants (acetazolamide [200–600 mg/d], carbamazepine [50–400 mg/d], phenytoin [50–300 mg/d], or gabapentin [600–1800 mg/d]). Heat sensitivity may respond to heat avoidance, air-conditioning, or cooling garments. Sexual dysfunction may be helped by lubricants to aid in genital stimulation and sexual arousal. Management of pain, spasticity, fatigue, and bladder/bowel dysfunction may also help. Sildenafil (50–100 mg), tadalafil (5–20 mg), or vardenafil (5–20 mg), taken 1–2 h before sex, are standard treatments for erectile dysfunction. PROGNOSIS Historically, most patients with MS ultimately experienced progres­ sive neurologic disability. In older studies conducted before diseasemodifying therapies for MS were available, 15 years after onset, only 20% of patients had no functional limitation, and between one-third and one-half of RMS patients progressed to SPMS and required assis­ tance with ambulation; furthermore, 25 years after onset, ~80% of MS patients reached this level of disability. Long-term studies from the early treatment era indicated clearly that prognosis had improved substantially, with a two- to threefold slowing of transition from RMS to SPMS. And currently with high-efficacy therapy widely available, the prognosis continues to improve; relapses are largely eliminated and relapse-independent progression has been further slowed. For example, the ocrelizumab extension trials revealed that after 10 years of continuous treatment, nearly 80% of patients with RMS experienced no disease worsening and more patients had improved than worsened, and in PPMS, more than one-third had experienced no worsening and more than 80% were still ambulatory. As noted above, the long-term course may improve further as highly efficacious agents are increas­ ingly employed early in the disease course. However, many patients with progressive MS still continue to worsen despite best available ther­ apy, and for these patients, more effective therapies are sorely needed. Natural history studies from the pretreatment era indicated that certain clinical features suggest a more favorable prognosis. These include ON or sensory symptoms at onset; fewer than two relapses in the first year of illness; and minimal impairment after 5 years. Predic­ tors of an early aggressive course of the illness include an older age at symptom onset, male gender, greater disability, and the appearance of motor signs during the first year of the illness. Importantly, some MS patients, estimated at <10%, have a benign variant of MS and never develop neurologic disability even when untreated. ■ ■PREGNANCY-RELATED ISSUES Pregnant MS patients experience fewer attacks during gestation (especially in the last trimester) but more attacks in the first 3 months postpartum. When considering the pregnancy year as a whole (i.e., 9 months of pregnancy plus 3 months postpartum), the overall disease course is unaffected. Disease-modifying therapy is generally discontin­ ued during pregnancy, and special care needs to be taken with agents (natalizumab and the S1P drugs) that have risk of rebound disease activity following discontinuation. Replacement of these agents with an anti-CD20 B-cell therapy such as ocrelizumab before conception appears to mitigate this risk and also provide long-lasting protection that extends throughout the pregnancy and immediate postpartum period. Intravenously administered B-cell therapies also provide an attractive management option for many patients contemplating preg­ nancy, and our practice is to advise patients to stop receiving infusions 3–4 months prior to attempting to conceive. Earlier studies raised con­ cerns that drugs used for fertility treatments might worsen MS disease A B C D FIGURE 455-4  Magnetic resonance imaging findings in variants of MS. A and B. Acute tumefactive MS. In A, a sagittal T2-weighted fluid-attenuated inversion recovery (FLAIR) image of a large solitary right parieto-occipital white matter lesion is shown, with effacement of overlying cortical sulci consistent with mass effect. In B, T1-weighted image obtained after the intravenous administration of gadolinium diethylene triamine pentaacetic acid (DTPA) reveals a large serpiginous area of blood-brain barrier disruption consistent with acute inflammation. C and D. Balo’s concentric sclerosis. In C, an axial T2-weighted sequence shows multiple areas of abnormal ovoid bright signal in the supratentorial white matter bilaterally; some lesions reveal concentric layers, typical of Balo’s concentric sclerosis. In D, T1-weighted magnetic resonance images after gadolinium demonstrate abnormal enhancement of all lesions with some lesions demonstrating concentric ring enhancement. activity, but more recent studies indicate that these produce little if any additional risk. CLINICAL VARIANTS OF MS Acute or fulminant MS (Marburg’s variant) is an aggressive demy­ elinating process that in some cases progresses inexorably to death within 1–2 years. Typically, there are no remissions. Marburg’s vari­ ant does not seem to follow infection or vaccination, and it is unclear whether this syndrome represents an extreme form of MS or another disease altogether. When an acute demyelinating syndrome pres­ ents as a solitary expansile lesion, a brain tumor is often suspected (Fig. 455-4A, B). Such cases are designated tumefactive MS, and a brain biopsy may be required to establish the diagnosis. Balo’s con­ centric sclerosis is another fulminant demyelinating syndrome char­ acterized by concentric brain or spinal cord lesions with alternating spheres of demyelination and remyelination (Fig. 455-4C, D). For these fulminant demyelinating states, no controlled trials of therapy exist; high-dose glucocorticoids and plasma exchange are often used, with uncertain benefit. ■ ■FURTHER READING Absinta M et al: Mechanisms underlying progression in multiple scle­ rosis. Curr Opin Neurol 33:277, 2020. CHAPTER 455 Multiple Sclerosis Bjornevik K et al: Epstein-Barr virus as a leading cause of multiple sclerosis: Mechanisms and implications. Nat Rev Neurol 19:160, 2023. Brown JWL et al: Association of initial disease-modifying therapy with later conversion to secondary progressive multiple sclerosis. JAMA 321:175, 2019. Cree BAC et al: Silent progression in disease activity-free relapsing multiple sclerosis. Ann Neurol 85:653, 2019. Graham EL et al: Practical considerations for managing pregnancy in patients with multiple sclerosis: Dispelling the myths. Neurol Clin Pract 14:e200253, 2024. Hauser SL et al: Safety of ocrelizumab in patients with relapsing and primary progressive multiple sclerosis. Neurology 97:e1546, 2021. International Multiple Sclerosis Genetics Consortium; Mul­ tiple MS Consortium: Locus for severity implicates CNS resilience in progression of multiple sclerosis. Nature 619:323, 2023. Kuhlmann T et al: Multiple sclerosis progression: Time for a new mechanism-driven framework. Lancet Neurol 22:78, 2023. Portaccio E et al: Progression is independent of relapse activity in early multiple sclerosis: A real-life cohort study. Brain 145:2796, 2022. Thompson AJ et al: Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17:162, 2018. Woo MS et al: The neuropathobiology of multiple sclerosis. Nat Rev Neurosci 25:493, 2024. # 26 - 456 Neuromyelitis Optica ### 456 Neuromyelitis Optica Bruce A. C. Cree, Stephen L. Hauser Neuromyelitis Optica Neuromyelitis optica (NMO) is an aggressive, antibody-mediated, inflammatory disorder characterized by recurrent attacks of optic neu­ ritis (ON) and myelitis; the more inclusive term NMO spectrum disor­ der (NMOSD) was proposed to incorporate individuals with partial forms and those with involvement of additional structures in the cen­ tral nervous system (Table 456-1). NMO is more frequent in women than men (9:1) and typically begins in adulthood (40-year mean age of onset) but can arise at any age. An important consideration, especially early in its presentation, is distinguishing between NMO and multiple sclerosis (MS; Chap 455). In patients with NMO, attacks of ON can be bilateral and produce severe vision loss (uncommon in MS); myelitis can be severe and transverse (rare in MS) and is typically longitudinally extensive (Fig. 456-1) involving three or more contiguous vertebral seg­ ments. In contrast to MS, progressive symptoms only rarely occur in NMO, and accumulation of disability is caused by attack-related injury. The brain magnetic resonance imaging (MRI) was earlier thought to PART 13 Neurologic Disorders TABLE 456-1  Diagnostic Criteria for Neuromyelitis Optica Spectrum Disorder (NMOSD) Diagnostic Criteria for NMOSD with AQP4-IgG 1. At least one core clinical characteristic 2. Positive test for AQP4-IgG using best available detection method (cell-based assay strongly recommended) 3. Exclusion of alternative diagnoses Diagnostic Criteria for NMOSD without AQP4-IgG or NMOSD with Unknown AQP4-IgG Status 1. At least two core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements: a. At least one core clinical characteristic must be optic neuritis, acute myelitis with LETM, or area postrema syndrome b. Dissemination in space (two or more different clinical characteristics) c. Fulfillment of additional MRI requirements, as applicable 2. Negative test for AQP4-IgG using best available detection method or testing unavailable 3. Exclusion of alternative diagnoses Core Clinical Characteristics 1. Optic neuritis 2. Acute myelitis 3. Area postrema syndrome: episode of otherwise unexplained hiccups or nausea or vomiting 4. Acute brainstem syndrome 5. Symptomatic narcolepsy or acute diencephalic clinical syndrome (hypothalamic dysfunction) with NMOSD-typical diencephalic MRI lesions 6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions Additional MRI Requirements for NMOSD without AQP4-IgG and NMOSD with Unknown AQP4-IgG Status 1. Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific white matter lesions, OR (b) optic nerve MRI with T2-hyperintense lesion of T1-weighted gadolinium-enhancing lesion extending over >1/2 optic nerve length or involving optic chiasm 2. Acute myelitis: requires associated intramedullary MRI lesion extending ≥3 contiguous segments (LETM) OR ≥3 contiguous segments of focal spinal cord atrophy in patients with history compatible with acute myelitis 3. Area postrema syndrome requires associated dorsal medulla/area postrema lesions 4. Acute brainstem syndrome requires periependymal brainstem lesions Abbreviations: AQP4, aquaporin-4; LETM, longitudinally extensive transverse myelitis; MRI, magnetic resonance imaging. Source: Reproduced with permission from DM Wingerchuk et al: International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85:177, 2015. be normal in NMO, but it is now recognized that in many cases brain lesions are present, including areas of nonspecific signal change as well as lesions associated with specific syndromes such as the area postrema in the lower medulla presenting as intractable hiccoughs or vomiting; the hypothalamus causing a sleep disorder or endocrinopathy; or the cerebral hemispheres producing focal symptoms, encephalopathy, or seizures. Large MRI lesions in the cerebral hemispheres can be asymp­ tomatic, sometimes have a “cloud-like” appearance, and unlike MS lesions, are often not destructive and can resolve completely. Spinal cord MRI lesions typically consist of focal enhancing areas of swelling and tissue destruction, extending over three or more spinal cord seg­ ments, and on axial sequences, these are centered on the gray matter of the cord. Cerebrospinal fluid (CSF) findings include pleocytosis greater than that observed in MS, with neutrophils and eosinophils present in many acute cases; oligoclonal bands (OCBs) are uncom­ mon, occurring in <20% of NMO patients. The pathology of NMO is a distinctive astrocytopathy with inflammation, loss of astrocytes, and an absence of staining of the water channel protein aquaporin-4 (AQP4) by immunohistochemistry, plus thickened blood vessel walls, demyelination, and deposition of antibody and complement. NMO is an autoimmune disease associated with a highly specific autoantibody directed against the water channel protein AQP4 that is present in the sera of ~90% of affected patients. AQP4 is localized to the foot processes of astrocytes in close apposition to endothelial surfaces, as well as at paranodal regions near nodes of Ranvier. Patho­ logic studies in NMO show loss of AQP4 associated with antibody and complement deposition and cytolysis of astrocytes within NMO lesions. It is likely that AQP4 antibodies are pathogenic because pas­ sive transfer of AQP4 antibodies into laboratory animals can repro­ duce histologic features of the disease. Both complement fixation and antibody-dependent cell-mediated cytotoxicity (ADCC) are thought to contribute to astrocyte injury. Proinflammatory T lymphocytes of the TH17 type recognize an immunodominant epitope of AQP4 and may also contribute to pathogenesis. Recent data have identified a population of B lymphocytes in the thymus that constitutively express AQP4 and interact with AQP4-specific T cells to produce antigenspecific tolerance; this interaction might be impaired in NMO. During acute attacks of myelitis, CSF levels of interleukin-6 (IL-6; a proinflam­ matory cytokine) and glial fibrillary acidic protein (GFAP; an astrocyte protein) are markedly elevated, consistent with active inflammation and astrocyte injury. Because of the high specificity of the antibody, its presence is diagnostic when found in conjunction with a typical clini­ cal presentation. Anti-AQP4 seropositive patients have a high risk for future attacks; more than half will relapse within 1 year if untreated. CLINICAL COURSE NMO is typically a recurrent disease; the course is monophasic in <10% of patients. Individuals who test negative for AQP4 antibodies are somewhat more likely to have a monophasic course. Untreated NMO is usually severely disabling over time; in one series, respiratory failure from cervical myelitis was present in one-third of patients, and 8 years after onset, 60% of patients were blind and more than half had permanent paralysis of one or more limbs. Observational data suggest that the long-term course of NMO has been substantially improved since the development of therapies to treat acute attacks and prevent relapses. The 5-year survival rate appears to have increased from 68–75% around 1999 to 91–98% as of 2017, a change presumably due to improved diagnosis and widespread use of immune-suppressing therapies. GLOBAL CONSIDERATIONS The incidence and prevalence of NMO shows considerable variation between populations and geographic regions, with prevalence esti­ mates that range from <1 to >4 per 100,000. Although NMO can occur in people of any ethnic background, individuals of Asian and African origin are disproportionately affected, with the highest reported preva­ lence in Martinique. Among white populations, MS (Chap. 455) is far more common than NMO. A B C E F FIGURE 456-1  Imaging findings in neuromyelitis optica: longitudinally extensive transverse myelitis, optic neuritis, and brainstem involvement. A. Sagittal fluid-attenuated inversion recovery (FLAIR) cervical spine MRI showing an area of increased signal change on T2-weighted imaging spanning more than three vertebral segments in length. B. Sagittal T1-weighted cervical spine MRI following gadolinium-diethylene triamine pentaacetic acid (DPTA) infusion showing enhancement. C and D. Axial and coronal brain MRI following gadolinium DPTA infusion shows enhancement of the right optic nerve. E. Axial brain MRI shows an area of hyperintense signal on T2-weighted imaging within the area postrema (arrow). F. Axial T1-weighted brain MRI following gadolinium-DPTA infusion shows punctate enhancement of the area postrema (arrow). Interestingly, when MS affects individuals of African or Asian ances­ try, there is a propensity for demyelinating lesions in some individu­ als to involve predominantly the optic nerve and spinal cord, an MS subtype termed opticospinal MS. Some patients with opticospinal MS are seropositive for AQP4 antibodies, indicating that they represent NMOSD. CHAPTER 456 Neuromyelitis Optica D ASSOCIATED CONDITIONS Up to 40% of NMO patients have a systemic autoimmune disorder, such as systemic lupus erythematosus, Sjögren’s syndrome, perinuclear antineutrophil cytoplasmic antibody (p-ANCA)–associated vasculitis, myasthenia gravis, Hashimoto’s thyroiditis, or mixed connective tissue disease. This is another feature distinct from MS; MS patients rarely have other comorbid autoimmune diseases other than hypothyroid­ ism. In some NMO cases, onset may be associated with acute infection with varicella-zoster virus, Epstein-Barr virus, HIV, or tuberculosis. Rare cases appear to be paraneoplastic and associated with breast, lung, or other cancers. TREATMENT Neuromyelitis Optica ACUTE ATTACKS Acute attacks are usually treated with high-dose glucocorticoids (e.g., methylprednisolone 1 g/d for 5–10 days followed by a predni­ sone taper). Plasma exchange (typically 5–7 exchanges of 1.5 plasma volumes/exchange) is used empirically for acute episodes that do not respond to glucocorticoids. PROPHYLAXIS AGAINST RELAPSES Given the unfavorable natural history of untreated NMO, pro­ phylaxis against relapses is recommended for nearly all patients. Four monoclonal antibody medications are approved for attack prevention in NMO: an anti-CD19 B-cell depleter (inebilizumab), an IL-6 receptor blocker (satralizumab), and two terminal comple­ ment inhibitors (eculizumab and ravulizumab) (Table 456-2). It is our general practice to begin therapy with either inebilizumab or satralizumab and to use complement inhibitors as second-line treat­ ment for nonresponders. None of the U.S. Food and Drug Admin­ istration–approved medications are approved for AQP4-negative patients, and in practice, obtaining these medications for sero­ negative patients is challenging from a payer perspective. In AQP4seronegative patients, the risk of a relapse is lower (approximately half of patients have only a single attack), and in these patients, our practice is to begin treatment with empiric therapies such as ritux­ imab or mycophenolate mofetil. Because AQP4-seronegative patients require involvement of both optic neuritis and longitudinally exten­ sive myelitis to meet criteria for seronegative NMOSD, the majority of AQP4-seronegative patients will have had more than one attack. Inebilizumab (Uplizna)  Inebilizumab is a humanized affinityoptimized, afucosylated monoclonal antibody that binds to the B-cell surface antigen CD19 and depletes a wide range of B cells including pre-B cells and some plasmablasts. Expression of CD19 starts at an earlier stage of B-cell development than CD20, and in contrast to CD20, which is absent from plasmablasts and mature plasma cells, CD19 is expressed on plasmablasts, as well as a pro­ portion of plasma cells in secondary lymphoid organs and bone marrow. In the pivotal clinical trial that included individuals both positive and negative for AQP4, inebilizumab reduced the time to the first attack by 77% compared to placebo (hazard ratio, 0.23; p <.0001). Inebilizumab-treated participants also had reduced rates of hospitalizations, disability worsening, and new MRI lesions. PART 13 Neurologic Disorders Inebilizumab is dosed as an initial 300-mg IV infusion followed 2 weeks later by a second 300-mg IV infusion, with subsequent doses of 300-mg infusions every 6 months thereafter. Inebilizumab is associated with a dose dependent decline in serum IgG levels and with neutropenia in some patients. TABLE 456-2  Attack Risk Reductions of Approved Neuromyelitis Optica Spectrum Disorder (NMOSD) Treatments RISK REDUCTION IN AQUAPORIN- 4–SEROPOSITIVE NMOSD Eculizumab (add-on to immune suppression) 94%, p <.001 Ravulizumab (add-on to immune suppression) 100%, p <.001 Inebilizumab (monotherapy) 78%, p = .01 Satralizumab (monotherapy) 77%, p <.001 Satralizumab (add-on to immune suppression) 74%, p = .001 Satralizumab (Enspryng)  Satralizumab is a monoclonal antibody that binds to the IL-6 receptor, blocking engagement of IL-6, a proinflammatory cytokine that is upregulated in the CSF during acute NMO attacks. Satralizumab was investigated in NMOSD in two registration trials: one as monotherapy and the other as add-on therapy. Both AQP4-seropositive and AQP4-seronegative partici­ pants were enrolled. In the monotherapy study, the risk of attack was reduced by 74% with satralizumab (p = .014), and in the add-on study, the risk of attack was reduced by 78% (p = .014). Although both studies recruited substantial numbers of AQP4-seronegative participants, there was no clinically meaningful impact of satrali­ zumab in seronegative participants. Satralizumab is administered as a loading dosage of 120 mg by subcutaneous injection at weeks 0, 2, and 4, followed by a main­ tenance dose of 120 mg every 4 weeks. Screening for hepatitis B virus, tuberculosis, and liver transaminase elevations is required before starting satralizumab. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) should be monitored during treatment for transaminase elevations and complete blood count (CBC) monitored for neutropenia. Satralizumab is also associated with weight gain; body weight increases of at least 7% from baseline occurred in 30% of satralizumab-treated participants compared to 8% of those treated with placebo. Eculizumab (Soliris)  The monoclonal antibody eculizumab binds with high affinity to the complement protein C5, inhibiting its cleavage into C5a and C5b and thereby preventing generation of the terminal complement attack complex C5b-9. Eculizumab was investigated as an add-on therapy in AQP4-seropositive NMO. The time to first attack was longer in patients treated with eculizumab compared to placebo (relative risk reduction, 94%; hazard ratio, 0.058; p <.0001) Eculizumab-treated patients also had a 96% rela­ tive reduction in the annualized attack rate, as well as dramatically reduced rates of hospitalizations and need for glucocorticoids or plasma exchange for acute attacks. Eculizumab is dosed as follows: 900 mg weekly for the first 4 weeks, followed by 1200 mg for the fifth dose 1 week later, and then 1200 mg every 2 weeks thereafter. Because of its toxicity profile, eculizumab is available only through a restricted program under a Risk Evaluation and Miti­ gation Strategy (REMS). Life-threatening and fatal meningococ­ cal infections have occurred (boxed warning). Eculizumab-treated patients must be immunized with meningococcal vaccines (Men­ ACWY two doses at least 8 weeks apart plus either MenB-4C [two doses at least 1 month apart] or MenB-FHbp [three doses over 6 months]) at least 2 weeks prior to administering the first dose unless the risks of delaying eculizumab therapy outweigh the risks of developing a meningococcal infection. The MenACWY vaccine requires revaccination every 5 years, and the MenB-4C/ MenB-FHbp requires a booster 1 year after vaccination and then every 2–3 years with ongoing treatment. Vaccination reduces, but does not eliminate, the risk of meningococcal infections. Eculi­ zumab-treated patients must be monitored closely for early signs of meningococcal infections and evaluated immediately if infection is suspected. Ravulizumab (Ultomiris)  Like eculizumab, ravulizumab is a termi­ nal complement inhibitor. Ravulizumab was developed using anti­ body recycling technology to increase its half-life, thereby allowing less frequent administration than its parent compound eculizumab. In a single-arm, open-label study of ravulizumab in NMOSD, ravulizumab-treated participants did not experience any attacks during 50 weeks of observation. A historical control arm from the eculizumab PREVENT clinical trial was used for comparison. Ravulizumab-treated patients also require vaccination for menin­ gococcal infections. It seems likely that ravulizumab produces even more potent complement inhibition than eculizumab, resulting in apparently greater efficacy but also a higher risk of meningococ­ cal infection. Ravulizumab is administered intravenously with a weight-based loading dose followed by maintenance dosing every 8 weeks. OTHER TREATMENTS Prior to the approval of disease-modifying therapies for NMO, sev­ eral empiric regimens were commonly used including mycopheno­ late mofetil (1000 mg bid); rituximab, a B-cell-depleting anti-CD20 monoclonal antibody (2 g IV every 6 months); or a combination of glucocorticoids (500 mg IV methylprednisolone daily for 5 days, then oral prednisone 1 mg/kg per day for 2 months, followed by slow taper) plus azathioprine (2 mg/kg per day started on week 3). Plasma cell–targeted therapy with anti–B-cell maturation anti­ gen (BCMA) chimeric antigen receptor (CAR) T cells has shown promise in an early clinical study of patients with NMOSD who failed to respond to other treatments. Importantly, some therapies with proven efficacy in MS do not appear to be useful for NMO. Available evidence suggests that interferon beta is ineffective and paradoxically may increase the risk of NMO relapses, and based on limited data, glatiramer acetate, fingolimod, natalizumab, and alemtuzumab also appear to be inef­ fective. These distinctions highlight the need for efficient diagnosis of NMO. MYELIN OLIGODENDROCYTE GLYCOPROTEIN ANTIBODY– ASSOCIATED DISEASE Although long considered to be a likely target for antibody-mediated demyelination, anti–myelin oligodendrocyte glycoprotein (MOG) antibodies detected by a cell-based assay that enables recognition of MOG epitopes in a lipid bilayer were only recently found to be associ­ ated with cases of acute disseminated encephalomyelitis (ADEM) in children and then with cases of AQP4-seronegative NMO. Further studies showed that patients who are seropositive for anti-MOG anti­ bodies are at risk for bilateral, synchronous optic neuritis and myelitis and meningoencephalitis (Table 456-3). A clinical feature that can help distinguish ON associated with MOG antibody–associated dis­ ease (MOGAD) from NMO or MS is the presence of papillitis seen by fundoscopy or orbital MRI, a finding that is common in MOGAD, rare in NMO, and variable but usually unilateral in MS. ON associated with MOGAD is typically longitudinally extensive on MRI, and brain MRI can be normal or show fluffy areas of increased signal change in TABLE 456-3  Diagnostic Criteria for Myelin Oligodendrocyte Glycoprotein Antibody–Associated Disease (MOGAD) Diagnostic Criteria for MOGAD 1. At least one core clinical event: Optic neuritis Myelitis ADEM Cerebral monofocal or polyfocal deficits Brainstem or cerebellar deficits Cerebral or cortical encephalitis often with seizures 2. Positive MOG IgG test (cell-based assay) Clear positive – no additional requirements Low positive, or positive without titer or CSF positive only – Must be AQP4 seronegative and have one or more of the following supporting features Supporting clinical or radiographic features: Optic neuritis – bilateral synchronous, >50% of length of optic nerve involvement, perineural optic nerve sheath enhancement, disc edema Myelitis – longitudinally extensive, central cord involvement or “H sign,” conus involvement Brain/brainstem/cerebellar – ill-defined lesions, deep gray matter involvement, cortical lesions with or without overlying meningeal enhancement 3. Exclusion of better diagnoses including MS Abbreviations: ADEM, acute disseminated encephalomyelitis; AQP4, aquaporin 4; CSF, cerebrospinal fluid; MOG, myelin oligodendrocyte glycoprotein; MS, multiple sclerosis. Source: Adapted from B Banwell et al: Lancet Neurol 22:268, 2023. white or gray matter structures, similar to NMO. MRI lesions that are typical for MS, including finger-like lesions oriented perpendicular to the ventricular surface (Dawson fingers) and T1 hypointense lesions, are uncommon. Spinal cord lesions can be longitudinally extensive or short and sometimes involve the conus medullaris. Demyelination associated with MOGAD is sometimes monophasic, as in ADEM, but can also be recurrent. The CSF may show a pleocytosis with occa­ sional neutrophils. Elevated intrathecal synthesis of gamma globulins is atypical: oligoclonal bands are present in only ~6–13% of cases. A small percentage of patients who present with syndromes suggestive of MOGAD but test negative (or only weakly positive) for serum antiMOG antibodies have detectable antibodies restricted to the CSF; thus, in these seronegative cases, CSF anti-MOG antibody testing should be pursued. The mechanism of central nervous system (CNS) injury in MOGAD is not established and could involve MOG-reactive cytotoxic T cells in addition to anti-MOG antibodies. Studies in MOG-induced experimental autoimmune encephalomyelitis, an animal model, sug­ gest that anti-MOG antibodies may opsonize traces of MOG protein in secondary lymphoid tissues, triggering a peripheral immune response against MOG. CHAPTER 456 Acute episodes are managed with high-dose glucocorticoids fol­ lowed by a prednisone taper and sometimes by plasmapheresis, as with NMO. Brain lesions associated with MOGAD often respond rapidly to treatment with glucocorticoids and may resolve entirely. Some patients experience disease recurrence following discontinuation of prednisone and can become glucocorticoid dependent. Clinical trials in MOGAD are underway with satralizumab (the IL-6 receptor blocker indi­ cated for AQP4-seropositive NMO) and rozanolixizumab (Rystiggo; a humanized monoclonal antibody that binds the neonatal Fc receptor). There are limited data on use of other immune-suppressing medica­ tions typically used in NMO. Off-label empiric treatments include daily prednisone, IV immunoglobulin, rituximab, and mycophenolate mofetil. Anti-MOG antibody titers appear to decline either spontane­ ously or in the setting of treatment. Neuromyelitis Optica GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP) AUTOIMMUNITY Autoimmunity against the astrocyte protein GFAP presents with a range of symptoms referable to meningismus, encephalitis, myelitis, and optic neuritis. Some cases follow a viral prodrome, and fever and headache are commonly present. The clinical syndrome can also include a move­ ment disorder reflecting involvement of deep gray matter structures. MRI shows characteristic patterns of gadolinium enhancement local­ ized to GFAP-enriched CNS regions including venous structures in a periventricular radial orientation, the leptomeninges, the periepen­ dymal spinal cord, and a striking serpiginous pattern involving brain parenchyma. Longitudinally extensive spinal cord involvement can also be present. These patterns share similarities with those observed in neurosarcoidosis, and their presence should prompt consideration for either condition. A lymphocytic pleocytosis is commonly present in the CSF. Antibodies against GFAP can be measured in the serum or CSF. GFAP autoimmunity is found as a paraneoplastic syndrome in ~25% of cases, most commonly associated with ovarian teratoma, and can coex­ ist with anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis or NMO. T cells are implicated in pathophysiology based on histopathol­ ogy and association with checkpoint inhibitor treatment for cancer or in the setting of HIV. GFAP autoimmunity is generally glucocorticoid responsive. Early recognition with prompt intervention is associated with more favorable outcomes. Relapses occur in ~20% of patients and require use of immune suppression therapy. ACUTE DISSEMINATED ENCEPHALOMYELITIS ADEM has a monophasic course and is often associated with an antecedent infection (postinfectious encephalomyelitis); historically, a small number of ADEM cases have followed immunization (post­ vaccinal encephalomyelitis). ADEM is far more common in children than adults, and many adult cases initially thought to represent ADEM subsequently experience late relapses qualifying as either MS or # 27 - SECTION 3 Nerve and Muscle Disorders ## SECTION 3 Nerve and Muscle Disorders another chronic inflammatory disorder such as vasculitis, sarcoidosis, or lymphoma. Many cases previously thought to represent ADEM are now recognized as MOGAD. The hallmark of ADEM is the presence of widely scattered foci of perivenular inflammation and demyelin­ ation that can involve both white matter and gray matter structures, in contrast to larger confluent white matter lesions typical of MS. In the most explosive form of ADEM, acute hemorrhagic leukoencephalitis, the lesions are vasculitic and hemorrhagic, and the clinical course is devastating. Postinfectious encephalomyelitis is most frequently associated with the viral exanthems of childhood. Infection with measles virus is the most common antecedent (1 in 1000 cases). Worldwide, measles encephalomyelitis is still common, although use of the live measles vaccine has dramatically reduced its incidence. In developed countries, ADEM is now most frequently associated with varicella (chickenpox) infections (1 in 4000–10,000 cases). It may also follow infection with rubella, mumps, influenza, parainfluenza, Epstein-Barr virus, human herpesvirus-6, HIV, dengue, Zika, other viruses, and Mycoplasma pneumoniae. Cases have also been described in association with SARSCoV-2 infection. Some patients may have a nonspecific upper respira­ tory infection or no known antecedent illness. Modern vaccines appear to pose no meaningful risk for ADEM; one large study (Vaccine Safety Datalink) of 24 different vaccines in >9 million individuals (64 million doses in total) revealed no excess risk for ADEM, with the possible exception of Tdap (tetanus, diphtheria, acellular pertussis) vaccine estimated at less than one case per million doses. PART 13 Neurologic Disorders All forms of ADEM presumably result from a cross-reactive immune response to the infectious agent that then triggers an inflam­ matory demyelinating response. Autoantibodies to MBP and other myelin antigens have been detected in the CSF from some patients with ADEM, and as noted above, ADEM cases with serum or CSF antibod­ ies against MOG are now considered to be MOGAD. ■ ■CLINICAL MANIFESTATIONS In severe cases, onset is abrupt and progression rapid (hours to days). In postinfectious ADEM, the neurologic syndrome generally begins late in the course of the viral illness as the exanthem is fading. Fever reappears, and headache, meningismus, and lethargy progressing to coma may develop. Seizures are common. Signs of disseminated neu­ rologic disease are consistently present (e.g., hemiparesis or quadripa­ resis, extensor plantar responses, lost or hyperactive tendon reflexes, sensory loss, and brainstem involvement). In ADEM due to chicken­ pox, cerebellar involvement is often conspicuous. CSF protein is mod­ estly elevated (0.5–1.5 g/L [50–150 mg/dL]). Lymphocytic pleocytosis, generally ≥200 cells/μL, occurs in 80% of patients. Occasional patients have higher counts or a mixed polymorphonuclear-lymphocytic pat­ tern during the initial days of the illness. Transient CSF oligoclonal banding was reported in a minority of cases. MRI usually reveals extensive changes in the brain and spinal cord, consisting of white matter hyperintensities on T2 and fluid-attenuated inversion recovery (FLAIR) sequences with gadolinium enhancement on T1-weighted sequences. ■ ■DIAGNOSIS The diagnosis is most reliably established when there is a history of a recent infectious illness. In severe cases with predominantly cerebral involvement, acute encephalitis due to infection with herpes simplex or other viruses including HIV may be difficult to exclude; other consid­ erations include hypercoagulable states including the antiphospholipid antibody syndrome, autoimmune (paraneoplastic) limbic encephalitis, vasculitis, sarcoidosis, primary CNS lymphoma, or metastatic cancer. An explosive presentation of MS can mimic ADEM, and especially in adults, it may not be possible to distinguish these conditions acutely. The simultaneous onset of disseminated symptoms and signs is com­ mon in ADEM and rare in MS. Similarly, meningismus, encephalopa­ thy (drowsiness, stupor or coma), and seizures suggest ADEM rather than MS. Unlike MS, in ADEM, optic nerve involvement is generally bilateral and transverse myelopathy complete. MRI findings that favor ADEM include extensive and relatively symmetric white matter abnormalities, basal ganglia or cortical gray matter lesions, and gado­ linium enhancement of all abnormal areas. In contrast, OCBs in the CSF are more common in MS. In one study of adult patients initially thought to have ADEM, 30% experienced additional relapses over a follow-up period of 3 years, and they were reclassified as having MS. Other patients initially classified as ADEM are subsequently found to have NMO, MOGAD, or GFAP autoimmunity. Occasional patients with “recurrent ADEM” have also been reported, especially children; however, it is not possible to distinguish this entity from atypical MS. Because of the clinical overlap at presentation between ADEM and MS, it is important that routine surveillance imaging be performed follow­ ing recovery from ADEM so that subclinical disease activity due to MS can be recognized and treatment for MS initiated. ■ ■TREATMENT Initial therapy is with high-dose glucocorticoids; depending on the response, treatment may need to be continued for 8 weeks. Patients who fail to respond within a few days may benefit from a course of plasma exchange or IV immunoglobulin. The prognosis reflects the severity of the underlying acute illness. In modern case series of pre­ sumptive ADEM in adults, mortality rates of 5–20% are reported, and many survivors have permanent neurologic sequelae. ■ ■FURTHER READING Banwell B et al: Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol 22:268, 2023. Baxter R et al: Acute demyelinating events following vaccines: A casecentered analysis. Clin Infect Dis 63:1456, 2016. Cacciaguerra L et al: Updates in NMOSD and MOGAD diagnosis and treatment: A tale of two central nervous system autoimmune inflammatory disorders. Neurol Clin 42:77, 2024. Cree BAC et al: Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): A double-blind, randomised placebo-controlled phase 2/3 trial. Lancet 394:1352, 2019. Hagbohm C et al: Clinical and neuroimaging phenotypes of autoim­ mune glial fibrillary acidic protein astrocytopathy: A systematic review and meta-analysis. Eur J Neurol 20:e16284, 2024. Pittock SJ et al: Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med 381:614, 2019. Qin C et al: Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity. Sci Immunol 9:eadj9730, 2024. Traboulsee A, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: A randomised, doubleblind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol 19:402, 2020. Wingerchuk DM et al: International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85:177, 2015. Section 3 Nerve and Muscle Disorders Anthony A. Amato, Richard J. Barohn Peripheral Neuropathy Peripheral nerves are composed of sensory, motor, and autonomic elements. Diseases can affect the cell body of a neuron or its periph­ eral processes, namely the axons or the encasing myelin sheaths. Most peripheral nerves are mixed and contain sensory and motor as well as autonomic fibers. Nerves can be subdivided into three major # 28 - 457 Peripheral Neuropathy ### 457 Peripheral Neuropathy another chronic inflammatory disorder such as vasculitis, sarcoidosis, or lymphoma. Many cases previously thought to represent ADEM are now recognized as MOGAD. The hallmark of ADEM is the presence of widely scattered foci of perivenular inflammation and demyelin­ ation that can involve both white matter and gray matter structures, in contrast to larger confluent white matter lesions typical of MS. In the most explosive form of ADEM, acute hemorrhagic leukoencephalitis, the lesions are vasculitic and hemorrhagic, and the clinical course is devastating. Postinfectious encephalomyelitis is most frequently associated with the viral exanthems of childhood. Infection with measles virus is the most common antecedent (1 in 1000 cases). Worldwide, measles encephalomyelitis is still common, although use of the live measles vaccine has dramatically reduced its incidence. In developed countries, ADEM is now most frequently associated with varicella (chickenpox) infections (1 in 4000–10,000 cases). It may also follow infection with rubella, mumps, influenza, parainfluenza, Epstein-Barr virus, human herpesvirus-6, HIV, dengue, Zika, other viruses, and Mycoplasma pneumoniae. Cases have also been described in association with SARSCoV-2 infection. Some patients may have a nonspecific upper respira­ tory infection or no known antecedent illness. Modern vaccines appear to pose no meaningful risk for ADEM; one large study (Vaccine Safety Datalink) of 24 different vaccines in >9 million individuals (64 million doses in total) revealed no excess risk for ADEM, with the possible exception of Tdap (tetanus, diphtheria, acellular pertussis) vaccine estimated at less than one case per million doses. PART 13 Neurologic Disorders All forms of ADEM presumably result from a cross-reactive immune response to the infectious agent that then triggers an inflam­ matory demyelinating response. Autoantibodies to MBP and other myelin antigens have been detected in the CSF from some patients with ADEM, and as noted above, ADEM cases with serum or CSF antibod­ ies against MOG are now considered to be MOGAD. ■ ■CLINICAL MANIFESTATIONS In severe cases, onset is abrupt and progression rapid (hours to days). In postinfectious ADEM, the neurologic syndrome generally begins late in the course of the viral illness as the exanthem is fading. Fever reappears, and headache, meningismus, and lethargy progressing to coma may develop. Seizures are common. Signs of disseminated neu­ rologic disease are consistently present (e.g., hemiparesis or quadripa­ resis, extensor plantar responses, lost or hyperactive tendon reflexes, sensory loss, and brainstem involvement). In ADEM due to chicken­ pox, cerebellar involvement is often conspicuous. CSF protein is mod­ estly elevated (0.5–1.5 g/L [50–150 mg/dL]). Lymphocytic pleocytosis, generally ≥200 cells/μL, occurs in 80% of patients. Occasional patients have higher counts or a mixed polymorphonuclear-lymphocytic pat­ tern during the initial days of the illness. Transient CSF oligoclonal banding was reported in a minority of cases. MRI usually reveals extensive changes in the brain and spinal cord, consisting of white matter hyperintensities on T2 and fluid-attenuated inversion recovery (FLAIR) sequences with gadolinium enhancement on T1-weighted sequences. ■ ■DIAGNOSIS The diagnosis is most reliably established when there is a history of a recent infectious illness. In severe cases with predominantly cerebral involvement, acute encephalitis due to infection with herpes simplex or other viruses including HIV may be difficult to exclude; other consid­ erations include hypercoagulable states including the antiphospholipid antibody syndrome, autoimmune (paraneoplastic) limbic encephalitis, vasculitis, sarcoidosis, primary CNS lymphoma, or metastatic cancer. An explosive presentation of MS can mimic ADEM, and especially in adults, it may not be possible to distinguish these conditions acutely. The simultaneous onset of disseminated symptoms and signs is com­ mon in ADEM and rare in MS. Similarly, meningismus, encephalopa­ thy (drowsiness, stupor or coma), and seizures suggest ADEM rather than MS. Unlike MS, in ADEM, optic nerve involvement is generally bilateral and transverse myelopathy complete. MRI findings that favor ADEM include extensive and relatively symmetric white matter abnormalities, basal ganglia or cortical gray matter lesions, and gado­ linium enhancement of all abnormal areas. In contrast, OCBs in the CSF are more common in MS. In one study of adult patients initially thought to have ADEM, 30% experienced additional relapses over a follow-up period of 3 years, and they were reclassified as having MS. Other patients initially classified as ADEM are subsequently found to have NMO, MOGAD, or GFAP autoimmunity. Occasional patients with “recurrent ADEM” have also been reported, especially children; however, it is not possible to distinguish this entity from atypical MS. Because of the clinical overlap at presentation between ADEM and MS, it is important that routine surveillance imaging be performed follow­ ing recovery from ADEM so that subclinical disease activity due to MS can be recognized and treatment for MS initiated. ■ ■TREATMENT Initial therapy is with high-dose glucocorticoids; depending on the response, treatment may need to be continued for 8 weeks. Patients who fail to respond within a few days may benefit from a course of plasma exchange or IV immunoglobulin. The prognosis reflects the severity of the underlying acute illness. In modern case series of pre­ sumptive ADEM in adults, mortality rates of 5–20% are reported, and many survivors have permanent neurologic sequelae. ■ ■FURTHER READING Banwell B et al: Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria. Lancet Neurol 22:268, 2023. Baxter R et al: Acute demyelinating events following vaccines: A casecentered analysis. Clin Infect Dis 63:1456, 2016. Cacciaguerra L et al: Updates in NMOSD and MOGAD diagnosis and treatment: A tale of two central nervous system autoimmune inflammatory disorders. Neurol Clin 42:77, 2024. Cree BAC et al: Inebilizumab for the treatment of neuromyelitis optica spectrum disorder (N-MOmentum): A double-blind, randomised placebo-controlled phase 2/3 trial. Lancet 394:1352, 2019. Hagbohm C et al: Clinical and neuroimaging phenotypes of autoim­ mune glial fibrillary acidic protein astrocytopathy: A systematic review and meta-analysis. Eur J Neurol 20:e16284, 2024. Pittock SJ et al: Eculizumab in aquaporin-4-positive neuromyelitis optica spectrum disorder. N Engl J Med 381:614, 2019. Qin C et al: Single-cell analysis of anti-BCMA CAR T cell therapy in patients with central nervous system autoimmunity. Sci Immunol 9:eadj9730, 2024. Traboulsee A, et al. Safety and efficacy of satralizumab monotherapy in neuromyelitis optica spectrum disorder: A randomised, doubleblind, multicentre, placebo-controlled phase 3 trial. Lancet Neurol 19:402, 2020. Wingerchuk DM et al: International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85:177, 2015. Section 3 Nerve and Muscle Disorders Anthony A. Amato, Richard J. Barohn Peripheral Neuropathy Peripheral nerves are composed of sensory, motor, and autonomic elements. Diseases can affect the cell body of a neuron or its periph­ eral processes, namely the axons or the encasing myelin sheaths. Most peripheral nerves are mixed and contain sensory and motor as well as autonomic fibers. Nerves can be subdivided into three major classes: large myelinated, small myelinated, and small unmyelin­ ated. Motor axons are usually large myelinated fibers that conduct rapidly (~50 m/s). Sensory fibers may be any of the three types. Large-diameter sensory fibers conduct proprioception and vibra­ tory sensation to the brain, while the smaller-diameter myelinated and unmyelinated fibers transmit pain and temperature sensation. Autonomic nerves are also small in diameter. Thus, peripheral neu­ ropathies can impair sensory, motor, or autonomic function, either singly or in combination. Peripheral neuropathies are further classi­ fied into those that primarily affect the cell body (e.g., neuronopathy or ganglionopathy), myelin (myelinopathy), and the axon (axonopa­ thy). These different classes of peripheral neuropathies have distinct clinical and electrophysiologic features. This chapter discusses the clinical approach to a patient suspected of having a peripheral neuropathy, as well as specific neuropathies, including hereditary and acquired neuropathies. The inflammatory neuropathies are discussed in Chap. 458. GENERAL APPROACH In approaching a patient with a neuropathy, the clinician has three main goals: (1) identify where the lesion is, (2) identify the cause, and (3) determine the proper treatment. The first goal is accomplished by obtaining a thorough history, neurologic examination, and electrodiag­ nostic and other laboratory studies (Fig. 457-1). While gathering this information, seven key questions are asked (Table 457-1), the answers to which help identify the pattern of involvement and the cause of the neuropathy (Table 457-2). Despite an extensive evaluation, in approximately half of patients, no etiology is ever found; these patients typically have a predominately sensory polyneuropathy and have been labeled as having idiopathic or cryptogenic sensory and sensorimotor polyneuropathy (CSPN). History and examination compatible with neuropathy? No Yes Mononeuropathy Mononeuropathy multiplex Polyneuropathy Evaluation of other disorder or reassurance and follow-up EDx EDx Axonal Demyelinating  with focal  conduction block Is the lesion axonal or demyelinating? Is entrapment or compression present? Is a contributing systemic disorder present? Consider vasculitis or other multifocal process Consider multifocal form of CIDP Decision on need for surgery (nerve repair, transposition, or release procedure) Possible nerve biopsy Test for paraprotein, HIV, Lyme disease Treatment appropriate for specific diagnosis If tests are negative, consider treatment for CIDP Treatment appropriate  for specific diagnosis FIGURE 457-1  Approach to the evaluation of peripheral neuropathies. CIDP, chronic inflammatory demyelinating polyradiculoneuropathy; EDx, electrodiagnostic; GBS, Guillain-Barré syndrome; IVIg, intravenous immunoglobulin. ■ ■INFORMATION FROM THE HISTORY AND PHYSICAL EXAMINATION: SEVEN KEY QUESTIONS (TABLE 457-1) 1. What Systems Are Involved?  It is important to determine if the patient’s symptoms and signs are motor, sensory, autonomic, or a combination of these. If the patient has only weakness without any evidence of sensory or autonomic dysfunction, a motor neuropathy, neuromuscular junction abnormality, or myopathy should be con­ sidered. Some peripheral neuropathies are associated with significant autonomic nervous system dysfunction. Symptoms of autonomic involvement include fainting spells or orthostatic lightheadedness; heat intolerance; or any bowel, bladder, or sexual dysfunction (Chap. 451). There will typically be an orthostatic fall in blood pressure without an appropriate increase in heart rate. Autonomic dysfunction in the absence of diabetes should alert the clinician to the possibility of amy­ loid polyneuropathy. Rarely, a pandysautonomic syndrome can be the only manifestation of a peripheral neuropathy without other motor or sensory findings. The majority of neuropathies are predominantly sensory in nature. CHAPTER 457 2. What Is the Distribution of Weakness?  Delineating the pattern of weakness, if present, is essential for diagnosis, and in this regard, two additional questions should be answered: (1) Does the weakness only involve the distal extremity, or is it both proximal and distal? and (2) Is the weakness focal and asymmetric, or is it sym­ metric? Symmetric proximal and distal weakness is the hallmark of acquired immune demyelinating polyneuropathies, both the acute form (Guillain-Barré syndrome [GBS]) and the chronic form (chronic inflammatory demyelinating polyneuropathy [CIDP]) (Chap. 458). The importance of finding symmetric proximal and distal weakness in a patient who presents with both motor and sensory symptoms cannot Peripheral Neuropathy Patient Complaint: ? Neuropathy EDx Axonal Demyelinating Chronic course (years) Uniform slowing,  chronic Nonuniform slowing, conduction block Subacute course (months) Review history for toxins; test for associated systemic disease or intoxication Test for paraprotein, if negative If chronic or subacute: CIDP If acute: GBS IVIg or plasmapheresis; supportive care including respiratory assistance Review family history; examine family members; genetic testing Treatment for CIDP; see Ch. 458 Genetic counseling if appropriate TABLE 457-1  Approach to Neuropathic Disorders: Seven Key Questions 1. What systems are involved? • Motor, sensory, autonomic, or combinations 2. What is the distribution of weakness? • Only distal versus proximal and distal • Focal/asymmetric versus symmetric 3. What is the nature of the sensory involvement? • Temperature loss or burning or stabbing pain (e.g., small fiber) • Vibratory or proprioceptive loss (e.g., large fiber) 4. Is there evidence of upper motor neuron involvement? • Without sensory loss • With sensory loss 5. What is the temporal evolution? • Acute (days to 4 weeks) • Subacute (4–8 weeks) • Chronic (>8 weeks) • Monophasic, progressive, or relapsing-remitting 6. Is there evidence for a hereditary neuropathy? PART 13 Neurologic Disorders • Family history of neuropathy • Lack of sensory symptoms despite sensory signs 7. Are there any associated medical conditions? • Cancer, diabetes mellitus, connective tissue disease or other autoimmune diseases, infection (e.g., HIV, Lyme disease, leprosy) • Medications including over-the-counter drugs that may cause a toxic neuropathy • Preceding events, drugs, toxins be overemphasized because this identifies the important subset of patients who may have a treatable acquired demyelinating neuropathic disorder (i.e., GBS or CIDP). Findings of an asymmetric or multifocal pattern of weakness narrow the differential diagnosis. Some neuropathic disorders may present with unilateral extremity weakness. In the absence of sensory symp­ toms and signs, such weakness evolving over weeks or months would be worrisome for motor neuron disease (e.g., amyotrophic lateral scle­ rosis [ALS]), but it would be important to exclude multifocal motor neuropathy that may be treatable (Chap. 458). In a patient presenting with asymmetric subacute or acute sensory and motor symptoms and signs, radiculopathies, plexopathies, compressive mononeuropathies, or multiple mononeuropathies (e.g., mononeuropathy multiplex) must be considered. ALS (Chap. 448) can produce prominent neck extensor weakness (head drop), tongue and pharyngeal weakness (dysarthria and dyspha­ gia), or shortness of breath. These focal symmetric weakness patterns can also be seen in neuromuscular junction disorders (myasthenia gravis, Lambert-Eaton myasthenic syndrome [LEMS] [Chap. 459]) and some myopathies, particularly isolated neck extensor myopathy (Chap. 460). 3. What Is the Nature of the Sensory Involvement?  The patient may have loss of sensation (numbness), altered sensation to touch (hyperpathia or allodynia), or uncomfortable spontaneous sen­ sations (tingling, burning, or aching) (Chap. 27). Neuropathic pain can be burning, dull, and poorly localized (protopathic pain), presumably transmitted by polymodal C nociceptor fibers, or sharp and lancinating (epicritic pain), relayed by A-delta fibers. If pain and temperature per­ ception are lost, while vibratory and position sense are preserved along with muscle strength, deep tendon reflexes, and normal nerve conduc­ tion studies (NCS), a small-fiber neuropathy is likely. The most likely causes of small-fiber neuropathies, when one is identified, are diabetes mellitus (DM) or glucose intolerance. Amyloid neuropathy should be considered as well in such cases, but most of these small-fiber neuropa­ thies remain idiopathic despite extensive evaluation. Severe proprioceptive loss also narrows the differential diagnosis. Affected patients will note imbalance, especially in the TABLE 457-2  Patterns of Neuropathic Disorders Pattern 1: Symmetric proximal and distal weakness with sensory loss   Consider: inflammatory demyelinating polyneuropathy (GBS and CIDP) Pattern 2: Symmetric distal sensory loss with or without distal weakness   Consider: cryptogenic or idiopathic sensory polyneuropathy (CSPN), diabetes mellitus and other metabolic disorders, drugs, toxins, familial (HSAN), CMT, amyloidosis, CANVAS, SORD neuropathy, and others Pattern 3: Asymmetric distal weakness with sensory loss   With involvement of multiple nerves     Consider: multifocal CIDP, vasculitis, cryoglobulinemia, amyloidosis, sarcoid, infectious (leprosy, Lyme, hepatitis B, C, or E, HIV, CMV), HNPP, tumor infiltration   With involvement of single nerves/regions     Consider: may be any of the above but also could be compressive mononeuropathy, plexopathy, or radiculopathy Pattern 4: Asymmetric proximal and distal weakness with sensory loss   Consider: polyradiculopathy or plexopathy due to diabetes mellitus, meningeal carcinomatosis or lymphomatosis, sarcoid, amyloid, hereditary plexopathy (HNPP, HNA), idiopathic Pattern 5: Asymmetric distal weakness without sensory loss   With upper motor neuron findings     Consider: motor neuron disease   Without upper motor neuron findings     Consider: progressive muscular atrophy, juvenile monomelic amyotrophy (Hirayama’s disease), multifocal motor neuropathy, multifocal acquired motor axonopathy Pattern 6: Symmetric sensory loss and distal areflexia with upper motor neuron findings   Consider: vitamin B12, vitamin E, and copper deficiency with combined system degeneration with peripheral neuropathy, chronic liver disease, hereditary leukodystrophies (e.g., adrenomyeloneuropathy), HSP-plus Pattern 7: Symmetric weakness without sensory loss   With proximal and distal weakness     Consider: SMA   With distal weakness     Consider: hereditary motor neuropathy (“distal” SMA) or atypical CMT Pattern 8: Focal midline proximal symmetric weakness   Neck extensor weakness     Consider: ALS   Bulbar weakness     Consider: ALS/PLS, isolated bulbar ALS (IBALS), Kennedy’s syndrome (X-linked, bulbospinal SMA), bulbar presentation GBS   Diaphragm weakness (SOB)     Consider: ALS Pattern 9: Asymmetric proprioceptive sensory loss without weakness   Consider causes of a sensory neuronopathy (ganglionopathy):   Cancer (paraneoplastic)   CANVAS   Sjögren’s syndrome   Idiopathic sensory neuronopathy (possible GBS variant)   Cisplatin and other chemotherapeutic agents   Vitamin B6 toxicity   HIV-related sensory neuronopathy Pattern 10: Autonomic symptoms and signs   Consider neuropathies associated with prominent autonomic dysfunction:   Hereditary sensory and autonomic neuropathy   Amyloidosis (familial and acquired)   Diabetes mellitus   GBS   Idiopathic pandysautonomia (may be a variant of GBS)   Porphyria   HIV-related autonomic neuropathy   Vincristine and other chemotherapeutic agents Abbreviations: ALS, amyotrophic lateral sclerosis; CIDP, chronic inflammatory demyelinating polyneuropathy; CANVAS, cerebellar ataxia, neuropathy, and vestibular areflexia syndrome; CMT, Charcot-Marie-Tooth disease; CMV, cytomegalovirus; GBS, Guillain-Barré syndrome; HIV, human immunodeficiency virus; HNA, hereditary neuralgic amyotrophy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory and autonomic neuropathy; HSP-plus, hereditary spastic paraplegia plus neuropathy; PLS, primary lateral sclerosis; SMA, spinal muscular atrophy; SOB, shortness of breath; SORD, sorbitol dehydrogenase deficiency. dark. A neurologic examination revealing a dramatic loss of pro­ prioception with vibration loss and normal strength should alert the clinician to consider a sensory neuronopathy/ganglionopathy (Pattern 9, Table 457-2). In particular, if this loss is asymmetric or affects the arms more than the legs, this pattern suggests a non-length-dependent process as seen in sensory neuronopathies. 4. Is There Evidence of Upper Motor Neuron Involvement?  If the patient presents with symmetric distal sensory symptoms and signs suggestive of a distal sensory neuropathy, but there is additional evidence of symmetric upper motor neuron involvement (Chap. 26), the physician should consider a combined system degeneration with neuropathy. The most common cause for this pattern is vitamin B12 deficiency, but other etiologies should also be considered (e.g., copper deficiency, human immunodeficiency virus [HIV] infection, severe hepatic disease, adrenomyeloneuropathy [AMN]), and hereditary spastic paraplegia plus a neuropathy. 5. What Is the Temporal Evolution?  It is important to deter­ mine the onset, duration, and evolution of symptoms and signs. Does the disease have an acute (days to 4 weeks), subacute (4–8 weeks), or chronic (>8 weeks) course? Is the course monophasic, progressive, or relapsing? Most neuropathies are insidious and slowly progressive in nature. Neuropathies with acute and subacute presentations include GBS, vasculitis, and radiculopathies related to diabetes or Lyme dis­ ease. A relapsing course can be present in CIDP and porphyria. 6. Is There Evidence for a Hereditary Neuropathy?  In patients with slowly progressive distal weakness over many years with few sensory symptoms yet significant sensory deficits on clinical exam­ ination, the clinician should consider a hereditary neuropathy (e.g., Charcot-Marie-Tooth disease [CMT]). On examination, the feet may show high or flat arches or hammer toes, and scoliosis may be present. In suspected cases, it may be necessary to perform neurologic and elec­ trophysiologic studies on family members in addition to the patient. 7. Does the Patient Have Any Other Medical Conditions?  It is important to inquire about associated medical conditions (e.g., DM, systemic lupus erythematosus [SLE]); preceding or concurrent infec­ tions (e.g. diarrheal illness preceding GBS); surgeries (e.g., gastric bypass and nutritional neuropathies); medications (toxic neuropathy), including over-the-counter vitamin preparations (B6); alcohol; dietary habits; and use of dentures (e.g., fixatives contain zinc that can lead to copper deficiency). ■ ■PATTERN RECOGNITION APPROACH TO NEUROPATHIC DISORDERS Based on the answers to the seven key questions, neuropathic disor­ ders can be classified into several patterns based on the distribution or pattern of sensory, motor, and autonomic involvement (Table 457-2). Each pattern has a limited differential diagnosis, and information from laboratory studies usually permits a final diagnosis to be established. ■ ■ELECTRODIAGNOSTIC STUDIES The electrodiagnostic (EDx) evaluation of patients with a suspected peripheral neuropathy consists of NCS and needle electromyography (EMG). In addition, studies of autonomic function can be valuable. The electrophysiologic data can confirm whether the neuropathic disorder is a mononeuropathy, multiple mononeuropathy (mononeu­ ropathy multiplex), radiculopathy, plexopathy, or generalized poly­ neuropathy. Similarly, EDx evaluation can ascertain whether the process involves only sensory fibers, motor fibers, autonomic fibers, or a combination of these. Finally, the electrophysiologic data can help distinguish axonopathies from myelinopathies as well as axonal degeneration secondary to ganglionopathies from the more common length-dependent axonopathies. NCS are most helpful in classifying a neuropathy as due to axonal degeneration or segmental demyelination (Table 457-3). In general, low-amplitude potentials with relatively preserved distal latencies, conduction velocities, and late potentials, along with fibrillations on needle EMG, suggest an axonal neuropathy. On the other hand, slow TABLE 457-3  Electrophysiologic Features: Axonal Degeneration versus Segmental Demyelination SEGMENTAL DEMYELINATION AXONAL DEGENERATION Motor Nerve Conduction Studies CMAP amplitude Decreased Normal (except with CB or distal dispersion) Distal latency Normal Prolonged Conduction velocity Normal Slow Conduction block Absent Present Temporal dispersion Absent Present F wave Normal or absent Prolonged or absent H reflex Normal or absent Prolonged or absent Sensory Nerve Conduction Studies CHAPTER 457 SNAP amplitude Decreased Normal or decreased Distal latency Normal Prolonged Conduction velocity Normal Slow Needle EMG Spontaneous activity Peripheral Neuropathy   Fibrillations Present Absent   Fasciculations Present Absent Motor unit potentials   Recruitment Decreased Decreased   Morphology Long duration, large amplitude, polyphasic (if there is reinnervation) Normal Abbreviations: CB, conduction block; CMAP, compound motor action potential; EMG, electromyography; SNAP, sensory nerve action potential. conduction velocities, prolonged distal latencies and late potentials, relatively preserved amplitudes, and the absence of fibrillations on needle EMG imply a primary demyelinating neuropathy. The presence of nonuniform slowing of conduction velocity, conduction block, or temporal dispersion further suggests an acquired demyelinating neu­ ropathy (e.g., GBS or CIDP) as opposed to a hereditary demyelinating neuropathy (e.g., CMT type 1). Autonomic studies are used to assess small myelinated (A-delta) or unmyelinated (C) nerve fiber involvement. Such testing includes heart rate response to deep breathing, heart rate and blood pressure response to both the Valsalva maneuver and tilt-table testing, and quantitative sudomotor axon reflex testing (Chap. 451). These studies are par­ ticularly useful in patients who have pure small-fiber neuropathy or autonomic neuropathy in which routine NCS are normal. ■ ■OTHER IMPORTANT LABORATORY INFORMATION In patients with generalized symmetric peripheral neuropathy, a stan­ dard laboratory evaluation should include a complete blood count, basic chemistries including serum electrolytes and tests of renal and hepatic function, fasting blood glucose (FBS), hemoglobin (Hb) A1c, thyroid function tests, B12, folate, erythrocyte sedimentation rate (ESR), rheumatoid factor, antinuclear antibodies (ANA), serum protein electrophoresis (SPEP) and immunoelectrophoresis or immunofixa­ tion, and free light chains in serum and urine. Quantification of the concentration of serum-free light chains and the kappa/lambda ratio is more sensitive than SPEP, immunoelectrophoresis, or immunofixation to detect a monoclonal gammopathy and therefore should be done if amyloidosis is suspected. A skeletal survey should be performed in patients with acquired demyelinating neuropathies and M-spikes to look for osteosclerotic or lytic lesions. Patients with monoclonal gam­ mopathy should also be referred to a hematologist for consideration of a bone marrow biopsy. An oral glucose tolerance test is indicated in patients with painful sensory neuropathies even if FBS and HbA1c are normal, as the test is abnormal in about one-third of such patients. In addition to the above tests, patients with a mononeuropathy multiplex pattern of involvement should have a vasculitis workup, including antineutrophil cytoplasmic antibodies (ANCAs), cryoglobulins, hepa­ titis serology, Western blot for Lyme disease, HIV, and occasionally a cytomegalovirus (CMV) titer. There are many autoantibody panels (various antiganglioside anti­ bodies) marketed for screening routine neuropathy patients for a treat­ able condition. These autoantibodies have no proven clinical utility or added benefit beyond the information obtained from a complete clinical examination and detailed EDx. A heavy metal screen is also not necessary as a screening procedure, unless there is a history of possible exposure or suggestive features on examination (e.g., severe painful sensorimotor and autonomic neuropathy and alopecia— thallium; severe painful sensorimotor neuropathy with or without gastrointestinal [GI] disturbance and Mee’s lines—arsenic; wrist or finger extensor weakness and anemia with basophilic stippling of red blood cells—lead). In patients with suspected GBS or CIDP, a lumbar puncture is indicated to look for an elevated cerebrospinal fluid (CSF) protein. In idiopathic cases of GBS and CIDP, CSF pleocytosis is usually absent. If cells are present, one should consider HIV infection, Lyme disease, sarcoidosis, or lymphomatous or leukemic infiltration of nerve roots. Recently, serum IgG4 antibodies to neurofascin and contactin-2 have been discovered in CIDP with severe sensory ataxia, tremor, and distal weakness (Chap. 458). These cases are difficult to treat with standard immunotherapies but may respond to rituximab. Some patients with GBS and CIDP have abnormal liver function tests. In these cases, it is important to also check for hepatitis B and C, HIV, CMV, and EpsteinBarr virus (EBV) infection. In patients with an axonal GBS (by EMG/ NCS) or those with a suspicious coinciding history (e.g., unexplained abdominal pain, psychiatric illness, significant autonomic dysfunc­ tion), it is reasonable to screen for porphyria. PART 13 Neurologic Disorders In patients with a severe sensory ataxia, a sensory ganglionopathy or neuronopathy should be considered. The most common causes of sensory ganglionopathies are Sjögren’s syndrome (Chap. 373) and a paraneoplastic neuropathy (Chap. 99). Neuropathy can be the initial manifestation of Sjögren’s syndrome. Thus, one should always inquire about dry eyes and mouth in patients with sensory signs and symptoms. Further, some patients can manifest sicca complex without other manifestations of Sjögren’s syndrome. Thus, patients with sen­ sory ataxia should be tested for antibodies to SS-A/Ro and SS-B/La, in addition to the routine ANA. To evaluate a possible paraneoplastic sensory ganglionopathy, antineuronal nuclear antibodies (e.g., anti-Hu antibodies) should be obtained. These antibodies are most commonly seen in patients with small-cell carcinoma of the lung but are also present with breast, ovarian, lymphoma, and other cancers. Impor­ tantly, the paraneoplastic neuropathy can precede the detection of the cancer, and detection of these autoantibodies should lead to a search for malignancy. ■ ■NERVE BIOPSIES Nerve biopsies are now rarely performed in the evaluation of neuropa­ thies. The primary indication for nerve biopsy is suspicion for amyloid neuropathy or vasculitis. In most instances, the abnormalities present on biopsies do not help distinguish one form of peripheral neuropathy from another (beyond what is already apparent by clinical examination and the NCS). Nerve biopsies should only be performed when the NCS are abnormal. The sural nerve is most commonly biopsied because it is a pure sensory nerve and biopsy will not result in loss of motor func­ tion. In suspected vasculitis, a combination biopsy of a superficial pero­ neal nerve (pure sensory) and the underlying peroneus brevis muscle obtained from a single small incision increases the diagnostic yield. Tissue can be analyzed to assess for evidence of inflammation, vasculi­ tis, or amyloid deposition. Semithin plastic sections, teased fiber prepa­ rations, and electron microscopy are used to assess the morphology of the nerve fibers and to distinguish axonopathies from myelinopathies. ■ ■SKIN BIOPSIES Skin biopsies are sometimes used to diagnose a small-fiber neuropathy. Following a punch biopsy of the skin in the distal lower extremity, immunologic staining can be used to measure the density of small unmyelinated fibers. The density of these nerve fibers is reduced in patients with small-fiber neuropathies in whom NCS and routine nerve biopsies are often normal. This technique may allow for an objective measurement in patients with mainly subjective symptoms. However, it often adds little to what one already knows from the clinical examina­ tion and EDx. SPECIFIC DISORDERS ■ ■HEREDITARY NEUROPATHIES CMT disease is the most common type of hereditary neuropathy (Pattern 2, Table 457-2). Rather than one disease, CMT is a syndrome of many genetically distinct disorders (Table 457-4). The various sub­ types of CMT are classified according to the nerve conduction veloci­ ties (NCVs) and predominant pathology (e.g., demyelination or axonal degeneration), inheritance pattern (autosomal dominant, autosomal recessive, or X-linked), and the specific mutated genes. Type 1 CMT (or CMT1) refers to inherited demyelinating sensorimotor neuropa­ thies, whereas the axonal sensory neuropathies are classified as CMT2. By definition, motor conduction velocities in the arms are slowed to <38 m/s in CMT1 and are >38 m/s in CMT2. However, most cases of CMT1 actually have motor NCVs between 20 and 25 m/s. CMT1 and CMT2 usually begin in childhood or early adult life; however, onset later in life can occur, particularly in CMT2. Both are inherited in an autosomal dominant fashion, with a few exceptions. There are no medical therapies for any of the CMTs, but physical and occupational therapy can be beneficial, as can bracing (e.g., ankle-foot orthotics for foot drop) and other orthotic devices. ■ ■CMT1 CMT1 is the most common form of hereditary neuropathy. Affected individuals usually present in the first to third decade of life with distal leg weakness (e.g., foot drop), although patients may remain asymp­ tomatic even late in life. People with CMT generally do not complain of numbness or tingling, which can be helpful in distinguishing CMT from acquired forms of neuropathy in which sensory symptoms usu­ ally predominate. Although usually asymptomatic, reduced sensation to all modalities is apparent on examination. Muscle stretch reflexes are unobtainable or reduced throughout. There is often atrophy of the muscles below the knee (particularly the anterior compartment), lead­ ing to so-called inverted champagne bottle legs. Motor NCVs are generally in the 20–25 m/s range. Nerve biopsies usually are not performed on patients suspected of having CMT1, because the diagnosis usually can be made by less invasive testing (e.g., NCS and genetic studies). However, when done, the biopsies reveal reduced numbers of myelinated nerve fibers with a predilection for loss of large-diameter fibers and Schwann cell proliferation around thinly or demyelinated fibers, forming so-called onion bulbs. CMT1A is the most common subtype of CMT1, representing 70% of cases, and is caused by a 1.5-megabase (Mb) duplication within chromo­ some 17p11.2-12 encoding the gene for peripheral myelin protein-22 (PMP-22). This results in patients having three copies of the PMP-22 gene rather than two. This protein accounts for 2–5% of myelin protein and is expressed in compact regions of the peripheral myelin sheath. Approximately 20% of patients with CMT1 have CMT1B, caused by mutations in the myelin protein zero (MPZ). CMT1B is for the most part clinically, electrophysiologically, and histologically indistinguish­ able from CMT1A. MPZ is an integral myelin protein and accounts for more than half of the myelin protein in peripheral nerves. Other forms of CMT1 are much less common and also indistinguishable from one another clinically and electrophysiologically (Table 457-4). ■ ■CMT2 CMT2 occurs approximately half as frequently as CMT1, and CMT2 tends to present later in life. Affected individuals usually become symp­ tomatic in the second decade; some cases present earlier in childhood, whereas others remain asymptomatic into late adult life. Clinically, CMT2 is for the most part indistinguishable from CMT1. NCS are helpful in this regard; in contrast to CMT1, the velocities are normal or TABLE 457-4  Classification of Charcot-Marie-Tooth Disease and Related Neuropathies NAME INHERITANCE GENE LOCATION GENE CMT1   CMT1A AD 17p11.2 PMP22 (usually duplication of gene)   CMT1B AD 1q21-23 MPZ   CMT1C AD 16p13.1-p12.3 LITAF   CMT1D AD 10q21.1-22.1 ERG2   CMT1E (with deafness) AD 17p11.2 PMP22 gene (usually point mutations)   CMT1F AD 8p13-21 NEFL   CMT1G AD 8q21 PMP22 HNPP AD 17p11.2 PMP22 (deletion of gene) CMT dominant-intermediate (CMTDI)   CMT-DIA AD 10q24.1-25.1 ?   CMT-DIB AD 19.p12-13.2 DNM2   CMT-DIC AD 1p35 YARS   CMT-DID   CMT-DIE   CMT-DIF   CMT-DIG AD AD AD AD CMT recessive-intermediate (CMT-RI)   CMT-RIA   CMT-RIB   CMT-RIC   CMT-RI D AR AR AR AR CMT2   CMT2A2 (allelic to HMSN VI with optic atrophy) AD 1p36.2 MFN2   CMT2B AD 3q13-q22 RAB7   CMT2B1 (allelic to LGMD 1B) AR 1q21.2 LMNA   CMT2B2 AR 19q13 PNKP   CMT2C (allelic to scapuloperoneal neuropathy) AD 12q23-24 TRPV4   CMT2D (allelic to distal SMA5)   CMT2DD AD AD   CMT2E (allelic to CMT1F)   CMT2EE AD AD   CMT2F AD 7q11-q21 HSPB1   CMT2G (allelic to CMT2P) AD 9q31.3-34.2 LRSAM1   CMT2I (allelic to CMT1B) AD 1q22 MPZ   CMT2J AD 1q22 MPZ   CMT2H, CMT2K (allelic to CMT4A) AD 8q13-q21 GDAP1   CMT2L (allelic to distal hereditary motor neuropathy AD 12q24 HSPB8 type 2)   CMT2M AD 16q22 DNM2   CMT2N AD 16q22.1 AARS   CMT2O AD 14q32.31 DYNC1H1   CMT2P AD and AR 9q31.3-34.2 LRSAM1   CMT2P-Okinawa (allelic to HSMN2P) AD 3q13-q14 TFG   CMT2Q   CMT2RCMT2S   CMT2T   CMT2U   CMT2V   CMT2W   CMT2X   CMT2Y   CMT2Z AD AD AD ADAD AD AD AD AD AD 1q21-23 MPZ CHAPTER 457 1q22 14q32.33 3q26 8p31 MPZ IFN-2 GNB4 NEFL Peripheral Neuropathy 8q21.1 6q23 1p36 12q24 GDAP1 KARS5 PLEKHG5 COX6A1 7p14 1p13 GARS1 ATP1A1 8p21 2p23 NEFL MPV17 10p14 4q 11q13.3 3q25.2 12q13 17q11 5q31 15q21.1 9p13 22q12 DHTKD1 TRIM2 IGHMBP2 MME MARS1 NAGLU HARS1 SPB11 VCP MORC2 (Continued) TABLE 457-4  Classification of Charcot-Marie-Tooth Disease and Related Neuropathies NAME INHERITANCE GENE LOCATION GENE CMT3 AD 17p11.2 PMP22   (Dejerine-Sottas disease, congenital hypomyelinating AD 1q21-23 MPZ neuropathy) AR 10q21.1-22.1 ERG2 AR 19q13 PRX CMT4   CMT4A AR 8q13-21.1 GDAP1   CMT4B1 AR 11q23 MTMR2   CMT4B2   CMT4B3 AR AR   CMT4C AR 5q23-33 SH3TC2   CMT4D (HMSN-Lom) AR 8q24 NDRG1   CMT4E (congenital hypomyelinating neuropathy) AR 10q21.3 ERG2 PART 13 Neurologic Disorders   CMT4F AR 19q13.1-13.3 PRX   CMT4G AR 10q23.2 HK1   CMT4H AR 12p11.21 FGD4   CMT4J   CMT4K AR AR CMTX (X-linked)   CMTX1   CMTX4   CMTX5   CMTX6 X-linked dominant X-linked recessive X-linked recessive X-linked dominant HSAN1A AD 9q22 SPTLC1 HSAN1C AD 14q24.3 SPTLC2 HSAN1D AD 14q21.3 ATL1 HSAN1E AD 19p13.2 DNMT1 HSAN1F AD 11q13.1 ATL3 HSAN2A AR 12p13.33 WNK1 HSAN2B AR 5p15.1 RETREG1 (FAM134B) HSAN2C AR 12q13.13 KIF1A HSAN2D AR 2q24.3 SCN9A HSAN3A (Riley-Day syndrome; hereditary dysautonomia) AR 9q21 ELP1 (IKBKAP) HSAN4 AR 3q NTRK1 HSAN5 AR 1p13.2 NGF HSAN6 AR 6p12.1 DST HSAN7 HSAN8 HSAN9 AD AR AR Others   HNA   SORD neuropathy (allelic to distal HMN8)   Hereditary neuropathy with neuromyotonia   CANVAS AD AR AR AR Abbreviations: AARS, alanyl-tRNA synthetase; AD, autosomal dominant; AR, autosomal recessive; ATL, atlastin; CANVAS, cerebellar ataxia, neuropathy, and vestibular areflexia syndrome; CMT, Charcot-Marie-Tooth; DNMT1, DNA methyltransferase 1; DYS, dystonin; DYNC1HI, cytoplasmic dynein 1 heavy chain 1; ELP1, elongator complex protein 1; ERG2, early growth response-2 protein; FAM134B, family with sequence similarity 134, member B; FIG4, FDG1-related F actin-binding protein; GDAP1, gangliosideinduced differentiation-associated protein-1; HK1, hexokinase 1; HMSN-P, hereditary motor and sensory neuropathy proximal; HNA, hereditary neuralgic amyotrophy; HNPP, hereditary neuropathy with liability to pressure palsies; HSAN, hereditary sensory and autonomic neuropathy; IFN2, inverted formin-2; IKBKAP, kB kinase complexassociated protein; LGMD, limb girdle muscular dystrophy; LITAF, lipopolysaccharide-induced tumor necrosis factor α factor; LRSAM1, E3 ubiquitin-protein ligase; MED25, mediator 25; MFN2, mitochondrial fusion protein mitofusin 2 gene; MPZ, myelin protein zero protein; MTMR2, myotubularin-related protein-2; NDRG1, N-myc downstream regulated 1; NGF, Beta-nerve growth factor; NTRK, 1trkA/NGF receptor; PMP-22, peripheral myelin protein-22; PRKWNK1, protein kinase, lysine deficient 1; PRPS1, phosphoribosylpyrophosphate synthetase 1; RAB7, Ras-related protein 7; RFC1, replication factor C subunit 1; SEPT9, septin 9; SH3TC2, SH3 domain and tetratricopeptide repeats 2; SMA, spinal muscular atrophy; SORD, sorbitol dehydrogenase; SPTLC, serine palmitoyltransferase long-chain base; TFG, TRK-fused gene; TrkA/NGF, tyrosine kinase A/nerve growth factor; tRNA, transfer ribonucleic acid; TRPV4, transient receptor potential cation channel, subfamily V, member 4; WNK1, WNK lysine deficient; YARS, tyrosyl-tRNA synthetase. Source: Modified from AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill, 2016, Table 11-1, pp. 265–266. (Continued) 11p15 22q13.33 SBF2 SBF1 6q21 9q34 FIG4 SURF1 Xq13 Xq26.1 Xq22.3 Xp22.11 GJB1 AIFM1 PRPS1 PDK3 3p22.2 9q34.12 14q32.31 SCN11A PRDM12 TECPR2 17q24 15q21.1 5q23.3 4p14 SEPT9 SORD HINT1 RFC1 only slightly slowed. The most common cause of CMT2 is a mutation in the gene for mitofusin 2 (MFN2), which accounts for ~20–30% of CMT2 cases overall. MFN2 localizes to the outer mitochondrial mem­ brane, where it regulates the mitochondrial network architecture by participating in mitochondrial fusion. The other genes associated with CMT2 are much less common (Table 457-4). ■ ■CMT DOMINANT AND RECESSIVE INTERMEDIATE In CMT dominant-intermediate (CMT-DI) and CMT recessiveintermediate (CMT-RI), the NCVs are faster than usually seen in CMT1 (e.g., >38 m/s) but slower than in CMT2 (Table 457-4). ■ ■CMT3 CMT3 was originally described by Dejerine and Sottas as a hereditary demyelinating sensorimotor polyneuropathy presenting in infancy or early childhood. Affected children are severely weak. Motor NCVs are markedly slowed, typically ≤5–10 m/s. Most cases of CMT3 are caused by point mutations in the genes for PMP-22, MPZ, or ERG-2, which are also the genes responsible for CMT1. The term CMT3 is no longer recommended, but rather, the neuropathy is classified as CMT1 if autosomal dominant or as CMT4 in cases of autosomal recessive inheritance. ■ ■CMT4 CMT4 is extremely rare and is characterized by a severe, childhoodonset sensorimotor polyneuropathy that is usually inherited in an autosomal recessive fashion. Electrophysiologic and histologic evalua­ tions can show demyelinating or axonal features. CMT4 is genetically heterogeneous (Table 457-4). ■ ■CMTX There are several forms of X-linked CMT, the most common type is CMTX1 (Table 457-4). This shares clinical features similar to CMT1 and CMT2, except that the neuropathy is much more severe in males than in females. CMT1X accounts for ~10–15% of CMT overall. Males usually present in the first two decades of life with atrophy and weak­ ness of the distal arms and legs, areflexia, pes cavus, and hammer toes. Obligate female carriers are frequently asymptomatic but can develop signs and symptoms of CMT. Onset in females is usually after the sec­ ond decade of life, and the neuropathy is milder in severity. NCS reveal features of both demyelination and axonal degeneration. In males, motor NCVs in the arms and legs are moderately slowed (in the low to mid 30-m/s range). About 50% of males with CMTX1 have motor NCVs between 15 and 35 m/s with ~80% of these falling between 25 and 35 m/s (intermediate slowing). In contrast, ~80% of females with CMTX1 have NCVs in the normal range and 20% have NCVs in the intermediate range. CMT1X is caused by mutations in GJB1, which encodes for gap junction protein-beta or connexin-32. Connexins are gap junction structural proteins that are important in cell-to-cell communication. Hereditary Neuropathy with Liability to Pressure Palsies (HNPP)  HNPP is an autosomal dominant disorder related to CMT1A. While CMT1A is usually associated with a 1.5-Mb duplica­ tion in chromosome 17p11.2 that results in an extra copy of the PMP22 gene, HNPP is caused by inheritance of the chromosome with the corresponding 1.5-Mb deletion of this segment, and thus, affected individuals have only one copy of the PMP-22 gene. Patients usually manifest in the second or third decade of life with painless numbness and weakness in the distribution of single peripheral nerves, although multiple mononeuropathies can occur (Pattern 3, Table 457-2). Symp­ tomatic mononeuropathy or multiple mononeuropathies are often precipitated by trivial compression of nerve(s) as can occur with wear­ ing a backpack, leaning on the elbows, or crossing one’s legs for even a short period of time. These pressure-related mononeuropathies may take weeks or months to resolve. In addition, some affected individuals manifest with a progressive or relapsing, generalized and symmetric, sensorimotor peripheral neuropathy that resembles CMT. Hereditary Neuralgic Amyotrophy (HNA)  HNA is an auto­ somal dominant disorder characterized by recurrent attacks of pain, weakness, and sensory loss in the distribution of the brachial plexus often beginning in childhood (Pattern 4, Table 457-2). These attacks are similar to those seen with idiopathic brachial plexitis (see below). Attacks may occur in the postpartum period, following surgery, or at other times of stress. Most patients recover over several weeks or months. Slightly dysmorphic features, including hypotelorism, epican­ thal folds, cleft palate, syndactyly, micrognathia, and facial asymmetry, are evident in some individuals. EDx demonstrate an axonal process. HNA is genetically heterogeneous but can be caused by mutations in septin 9 (SEPT9). Septins may be important in formation of the neu­ ronal cytoskeleton and have a role in cell division, but it is not known how mutations in SEPT9 lead to HNA. Hereditary Sensory and Autonomic Neuropathy (HSAN)  The HSANs are a very rare group of hereditary neu­ ropathies in which sensory and autonomic dysfunction predominates over muscle weakness, unlike CMT, in which motor findings are most prominent (Pattern 2, Table 457-2; Table 457-4). Nevertheless, affected individuals can develop motor weakness, and there can be overlap with CMT. There are no medical therapies available to treat these neuropathies, other than prevention and treatment of mutilating skin and bone lesions. CHAPTER 457 Peripheral Neuropathy Of the HSANs, only HSAN1 typically presents in adults. HSAN1 is the most common of the HSANs and is inherited in an autosomal dominant fashion. Affected individuals usually manifest in the second through fourth decades of life. HSAN1 is associated with the degen­ eration of small myelinated and unmyelinated nerve fibers leading to severe loss of pain and temperature sensation, deep dermal ulcerations, recurrent osteomyelitis, Charcot joints, bone loss, gross foot and hand deformities, and amputated digits. Although most people with HSAN1 do not complain of numbness, they often describe burning, aching, or lancinating pains. Autonomic neuropathy is not a prominent feature, but bladder dysfunction and reduced sweating in the feet may occur. HSAN1A, which is most common, is caused by mutations in the serine palmitoyltransferase long-chain base 1 (SPTLC1) gene. OTHER HEREDITARY NEUROPATHIES (TABLE 457-5) ■ ■SORBITAL DEHYDROGENASE DEFICIENCY WITH PERIPHERAL NEUROPATHY Sorbitol dehydrogenase deficiency with peripheral neuropathy (SORD) is a newly reported entity that is very important as it appears to be the most common autosomal recessive inherited form of neuropathy. It presents as a slowly progressive, length-dependent, axonal motor greater than sensory polyneuropathy or pure motor neuropathy. Age of onset is usually in the late teens. It is caused by pathogenic mutations in the SORD gene. SORD is the second enzyme of the two-step polyol pathway whereby glucose is metabolized into sorbitol, and then SORD oxidizes sorbitol into fructose. Sorbitol is a relatively nonmetabolizable sugar, and levels are markedly increased. ■ ■FABRY’S DISEASE Fabry’s disease (angiokeratoma corporis diffusum) is an X-linked dominant disorder. Although men are more commonly and severely affected, women can also manifest symptoms and signs of the disease. Angiokeratomas are reddish-purple maculopapular lesions that are usually found around the umbilicus, scrotum, inguinal region, and perineum. Burning or lancinating pain in the hands and feet often develops in males in late childhood or early adult life (Pattern 2, Table 457-2). However, the neuropathy is usually overshadowed by com­ plications arising from an associated premature atherosclerosis (e.g., hypertension, renal failure, cardiac disease, and stroke) that often lead to death by the fifth decade of life. Some patients also manifest primar­ ily with a dilated cardiomyopathy. Fabry’s disease is caused by mutations in the α-galactosidase gene that lead to the accumulation of ceramide trihexoside in nerves and TABLE 457-5  Rare Hereditary Neuropathies Hereditary Disorders of Lipid Metabolism Metachromatic leukodystrophy Krabbe’s disease (globoid cell leukodystrophy) Fabry’s disease Adrenoleukodystrophy/adrenomyeloneuropathy Refsum’s disease Tangier disease Cerebrotendinous xanthomatosis Hereditary Ataxias with Neuropathy CANVAS (cerebellar ataxia, neuropathy, and vestibular areflexia syndrome) Friedreich’s ataxia Vitamin E deficiency Spinocerebellar ataxia Abetalipoproteinemia (Bassen-Kornzweig disease) PART 13 Neurologic Disorders Disorders of Defective DNA Repair CANVAS Ataxia-telangiectasia Cockayne’s syndrome Giant Axonal Neuropathy Porphyria Acute intermittent porphyria (AIP) Hereditary coproporphyria (HCP) Variegate porphyria (VP) Familial Amyloid Polyneuropathy (FAP) Transthyretin-related Gelsolin-related Apolipoprotein A1-related Source: Modified from AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill, 2016, Table 12-1, p. 299. blood vessels. A decrease in α-galactosidase activity is evident in leukocytes and cultured fibroblasts. Glycolipid granules may be appre­ ciated in ganglion cells of the peripheral and sympathetic nervous sys­ tems and in perineurial cells. Enzyme replacement therapy (ERT) may improve the neuropathy if patients are treated early, before irreversible nerve fiber loss develops. Current U.S. Food and Drug Administra­ tion (FDA)-approved recombinant ERTs are agalsidase-α (Replagal; 0.2 mg/kg body weight) and agalsidase-β (Fabrazyme; 1 mg/kg body weight) and pegunigalsidase (Elfabrio), which are each given intrave­ nously every 2 weeks. In addition, migalastat is an oral pharmacologic chaperone that increases the enzyme activity of “amenable” mutations (defined as those mutations in the catalytic domain of the enzyme that lead to misfolding of the enzyme but otherwise would not signifi­ cantly impair its function). Such mutations occur in ~50% of patients. Migalastat had been shown to reduce left ventricular mass and stabi­ lize kidney function, but studies have not assessed if the neuropathy improves or stabilizes. ■ ■ADRENOLEUKODYSTROPHY/ ADRENOMYELONEUROPATHY Adrenoleukodystrophy (ALD) and AMN are allelic X-linked dominant disorders caused by mutations in the peroxisomal transmembrane ade­ nosine triphosphate-binding cassette (ABC) transporter gene. Patients with ALD manifest with central nervous system (CNS) abnormalities. However, ~30% of patients with mutations in this gene present with the AMN phenotype that typically manifests in the third to fifth decade of life as mild to moderate peripheral neuropathy combined with pro­ gressive spastic paraplegia (Pattern 6, Table 457-2) (Chap. 453). Rare patients present with an adult-onset spinocerebellar ataxia or only with adrenal insufficiency. EDx is suggestive of a primary axonopathy with secondary demy­ elination. Nerve biopsies demonstrate a loss of myelinated and unmyelinated nerve fibers with lamellar inclusions in the cytoplasm of Schwann cells. Very-long-chain fatty acid (VLCFA) levels (C24, C25, and C26) are increased in the urine. Laboratory evidence of adrenal insufficiency is evident in approximately two-thirds of patients. The diagnosis can be confirmed by genetic testing. Adrenal insufficiency is managed by replacement therapy; however, there is no proven effective therapy for the neurologic manifestations of ALD/AMN. Diets low in VLCFAs and supplemented with Lorenzo’s oil (erucic and oleic acids) reduce the levels of VLCFAs and increase the levels of C22 in serum, fibroblasts, and liver; however, several large, open-label trials of Lorenzo’s oil failed to demonstrate efficacy. Although allogeneic bone marrow transplantation and gene therapy have been successful in slowing progression of cognitive decline in some patients with ALD treated early in their disease, these approaches are ineffective for the myelopathy or neuropathy. ■ ■REFSUM’S DISEASE Refsum’s disease can manifest in infancy to early adulthood with the classic tetrad of (1) peripheral neuropathy, (2) retinitis pigmentosa, (3) cerebellar ataxia, and (4) elevated CSF protein concentration. Most affected individuals develop progressive distal sensory loss and weak­ ness in the legs leading to foot drop by their twenties (Pattern 2, Table 457-2). Subsequently, the proximal leg and arm muscles may become weak. Patients may also develop sensorineural hearing loss, cardiac conduction abnormalities, ichthyosis, and anosmia. Serum phytanic acid levels are elevated. Sensory and motor NCS reveal reduced amplitudes, prolonged latencies, and slowed conduc­ tion velocities. Nerve biopsy demonstrates a loss of myelinated nerve fibers, with remaining axons often thinly myelinated and associated with onion bulb formation. Refsum’s disease is genetically heterogeneous but autosomal reces­ sive in nature. Classical Refsum’s disease with childhood or early adult onset is caused by mutations in the gene that encodes for phytanoylCoA α-hydroxylase (PAHX). Less commonly, mutations in the gene encoding peroxin 7 receptor protein (PRX7) are responsible. These mutations lead to the accumulation of phytanic acid in the central and peripheral nervous systems. Treatment is removal of phytanic precur­ sors (phytols: fish oils, dairy products, and ruminant fats) from the diet. ■ ■TANGIER DISEASE Tangier disease is a rare autosomal recessive disorder that can present as (1) asymmetric multiple mononeuropathies, (2) a slowly progres­ sive symmetric polyneuropathy predominantly in the legs, or (3) a pseudo-syringomyelia pattern with dissociated sensory loss (i.e., abnormal pain/temperature perception but preserved position/vibra­ tion in the arms [Chap. 453]). The tonsils may appear swollen and yellowish-orange in color, and there may also be splenomegaly and lymphadenopathy. Tangier disease is caused by mutations in the ATP-binding cassette transporter 1 (ABC1) gene, which leads to markedly reduced levels of high-density lipoprotein (HDL) cholesterol levels, whereas triacylg­ lycerol levels are increased. Nerve biopsies reveal axonal degeneration with demyelination and remyelination. Electron microscopy demon­ strates abnormal accumulation of lipid in Schwann cells, particularly those encompassing unmyelinated and small myelinated nerves. There is no specific treatment. ■ ■PORPHYRIA Porphyria is a group of inherited disorders caused by defects in heme biosynthesis (Chap. 428). Three forms of porphyria are associated with peripheral neuropathy: acute intermittent porphyria (AIP), hereditary coproporphyria (HCP), and variegate porphyria (VP). The acute neurologic manifestations are similar in each, with the exception that a photosensitive rash is seen with HCP and VP but not in AIP. Attacks of porphyria can be precipitated by certain drugs (usually those metabolized by the P450 system), hormonal changes (e.g., pregnancy, menstrual cycle), and dietary restrictions. An acute attack of porphyria may begin with sharp abdominal pain. Subsequently, patients may develop agitation, hallucinations, or seizures. Several days later, back and extremity pain followed by weak­ ness ensues, mimicking GBS (Pattern 1, Table 457-2). Weakness can involve the arms or the legs and can be asymmetric, proximal, or distal in distribution, as well as affecting the face and bulbar musculature. Dysautonomia and signs of sympathetic overactivity are common (e.g., pupillary dilation, tachycardia, and hypertension). Constipation, urinary retention, and incontinence can also be seen. The CSF protein is typically normal or mildly elevated. Liver function tests and hematologic parameters are usually normal. Some patients are hyponatremic due to inappropriate secretion of antidi­ uretic hormone (Chap. 390). The urine may appear brownish in color secondary to the high concentration of porphyrin metabolites. Accu­ mulation of intermediary precursors of heme (i.e., d-aminolevulinic acid, porphobilinogen, uroporphobilinogen, coproporphyrinogen, and protoporphyrinogen) is found in urine. Specific enzyme activities can also be measured in erythrocytes and leukocytes. The primary abnor­ malities on EDx are marked reductions in compound motor action potential (CMAP) amplitudes and signs of active axonal degeneration on needle EMG. The porphyrias are inherited in an autosomal dominant fashion. AIP is associated with porphobilinogen deaminase deficiency, HCP is caused by defects in coproporphyrin oxidase, and VP is associated with protoporphyrinogen oxidase deficiency. The pathogenesis of the neuropathy is not completely understood. Treatment with glucose and hematin may reduce the accumulation of heme precursors. Intrave­ nous glucose is started at a rate of 10–20 g/h. If there is no improve­ ment within 24 h, intravenous hematin 2–5 mg/kg per day for 3–14 days should be administered. Givosiran is a small interfering RNA (siRNA) that neutralizes excess aminolevulinic acid (ALA) mRNA in hepatocytes for patients with recurrent attacks of acute intermittent porphyria. In clinical trials, givosiran 2.5 mg/kg subcutaneously per month led to reduced attack frequency, better daily pain scores for pain, improved quality of life, lower levels of urinary ALA and porpho­ bilinogen, and fewer days of hematin compared with placebo. ■ ■CEREBELLAR ATAXIA, NEUROPATHY, AND VESTIBULAR AREFLEXIA SYNDROME (CANVAS) Cerebellar ataxia, neuropathy, and vestibular areflexia syndrome (CANVAS) appears to be the most common cause of autosomal reces­ sive ataxia. It usually manifests in middle adult life with a sensory neuropathy/neuronopathy that progresses over the course of 10–15 years to cerebellar and vestibular dysfunction, as well as a dry cough. Examination reveals loss of large-fiber sensory modalities with a sen­ sory ataxia as well as cerebellar ataxia. The clinical spectrum is quite broad, however, and some patients manifest with upper and low motor neuron involvement (spasticity, brisk reflexes, muscle atrophy, and fas­ ciculations) similar to amyotrophic lateral sclerosis. CANVAS can also present with dysautonomia and features of parkinsonism. NCS reveal low-amplitude or absent sensory responses that are in a non-lengthdependent pattern, and EMG can show signs of active denervation and chronic reinnervation. Brain magnetic resonance imaging (MRI) scans can reveal cerebellar atrophy. Sural nerve biopsies have shown loss of large myelinated axons, and autopsy studies demonstrate degenera­ tion of the dorsal root ganglia and posterior columns. In most cases, CANVAS is associated with biallelic (AAGGG)n repeat expansions in the second intron of the replication factor complex subunit 1 (RFC1). The is a DNA polymerase accessory protein required for the coordi­ nated synthesis of both DNA strands during replication and after DNA damage. ■ ■FAMILIAL AMYLOID POLYNEUROPATHY Familial amyloid polyneuropathy (FAP) is phenotypically and geneti­ cally heterogeneous and is caused by mutations in the genes for transthyretin (TTR), apolipoprotein A1, or gelsolin (Chap. 117). The majority of patients with FAP have mutations in the TTR gene. Amy­ loid deposition may be evident in abdominal fat pad, rectal, or nerve biopsies. The clinical features, histopathology, and EDx reveal abnor­ malities consistent with a generalized or multifocal, predominantly axonal but occasionally demyelinating, polyneuropathy. Patients with TTR-related FAP usually develop insidious onset of numbness and painful paresthesias in the distal lower limbs in the third to fourth decade of life, although some patients develop the disorder later in life (Pattern 2, Table 457-2). Carpal tunnel syndrome (CTS) is common. Autonomic involvement can be severe, leading to postural hypotension, constipation or persistent diarrhea, erectile dysfunction, and impaired sweating (Pattern 10, Table 457-2). Amyloid deposition also occurs in the heart, kidneys, liver, and corneas. Patients usually die 10–15 years after the onset of symptoms from cardiac failure or complications from malnutrition. Because the liver produces much of the body’s TTR, liver transplantation has been used to treat FAP related to TTR mutations. Serum TTR levels decrease after transplantation, and improvement in clinical and EDx features has been reported. Both tafamidis meglumine (20 mg daily) and diflunisal (250 mg twice daily), which prevent misfolding and deposition of mutated TTR, appear to slow the rate of deterioration in patients with TTR-related FAP. Several forms of gene therapy are also now available. Random­ ized, placebo-controlled trials of antisense oligonucleotides, patisiran 0.3 mg/kg intravenous every 3 weeks, vutrisiran 25 mg subcutaneous every 3 months, and eplontersen 45 mg subcutaneous every 4 weeks, as well as the siRNA inotersen 300 mg subcutaneous weekly, have been shown to be effective in FAP related to TTR mutations. These drugs block expression of both mutant and wild-type TTR, reducing amyloid precursor protein synthesis. CHAPTER 457 Peripheral Neuropathy Patients with apolipoprotein A1–related FAP (Van Allen type) usu­ ally present in the fourth decade with numbness and painful dyses­ thesias in the distal limbs. Gradually, the symptoms progress, leading to proximal and distal weakness and atrophy. Although autonomic neuropathy is not severe, some patients develop diarrhea, constipa­ tion, or gastroparesis. Most patients die from systemic complications of amyloidosis (e.g., renal failure) 12–15 years after the onset of the neuropathy. Gelsolin-related amyloidosis (Finnish type) is characterized by the combination of lattice corneal dystrophy and multiple cranial neu­ ropathies that usually begin in the third decade of life. Over time, a mild generalized sensorimotor polyneuropathy develops. Autonomic dysfunction does not occur. ACQUIRED NEUROPATHIES ■ ■PRIMARY OR AL AMYLOIDOSIS (SEE CHAP. 117) Besides FAP, amyloidosis can also be acquired. In primary or AL amyloidosis, the abnormal protein deposition is composed of immuno­ globulin light chains. AL amyloidosis occurs in the setting of multiple myeloma (MM), Waldenström’s macroglobulinemia, lymphoma, other plasmacytomas, or lymphoproliferative disorders, or without any other identifiable disease. Approximately 30% of patients with AL primary amyloidosis pres­ ent with a polyneuropathy, most typically painful dysesthesias and burning sensations in the feet (Pattern 2, Table 457-2). However, the trunk can be involved, and some patients manifest with a mononeu­ ropathy multiplex pattern. CTS occurs in 25% of patients and may be the initial manifestation. The neuropathy is slowly progressive, and eventually, weakness develops along with large-fiber sensory loss. Most patients develop autonomic involvement with postural hypertension, syncope, bowel and bladder incontinence, constipation, impotence, and impaired sweating (Pattern 10, Table 457-2). Patients generally die from their systemic illness (renal failure, cardiac disease). The monoclonal protein may be composed of IgG, IgA, IgM, or only free light chain. Lambda (λ) is more common than κ light chain (>2:1) in AL amyloidosis. The CSF protein is often increased (with normal cell count), and thus, the neuropathy may be mistaken for CIDP (Chap. 458). Nerve biopsies reveal axonal degeneration and amyloid deposition in either a globular or diffuse pattern infiltrating the perineurial, epineurial, and endoneurial connected tissue and in blood vessel walls. The median survival of patients with primary amyloidosis is <2 years, with death usually from progressive congestive heart failure or renal failure. Chemotherapy with melphalan, prednisone, and colchicine, to reduce the concentration of monoclonal proteins, and autologous stem cell transplantation may prolong survival, but whether the neuropathy improves is controversial. ■ ■DIABETIC NEUROPATHY DM is the most common cause of peripheral neuropathy in developed countries. DM is associated with several types of polyneuropathy: distal symmetric sensory or sensorimotor polyneuropathy, autonomic neuropathy, diabetic neuropathic cachexia, polyradiculoneuropathies, cranial neuropathies, and other mononeuropathies. Risk factors for the development of neuropathy include long-standing, poorly controlled DM and the presence of retinopathy and nephropathy. Diabetic Distal Symmetric Sensory and Sensorimotor Polyneuropathy (DSPN)  DSPN is the most common form of diabetic neuropathy and manifests as sensory loss beginning in the toes that gradually progresses over time up the legs and into the fingers and arms (Pattern 2, Table 457-2). When severe, a patient may develop sensory loss in the trunk (chest and abdomen), initially in the midline anteriorly and later extending laterally. Tingling, burning, deep aching pains may also be apparent. NCS usually show reduced amplitudes and mild to moderate slowing of conduction velocities. Nerve biopsy reveals axonal degeneration, endothelial hyperplasia, and, occasionally, perivascular inflammation. Tight control of glucose may reduce the risk of developing neuropathy or improve the underlying neuropathy. A variety of medications have been used with variable success to treat painful symptoms associated with DSPN, including anticonvulsants, antidepressants, sodium channel blockers, and other analgesics (Table 457-6). PART 13 Neurologic Disorders Diabetic Autonomic Neuropathy  Autonomic neuropathy is typically seen in combination with DSPN. The autonomic neuropathy can manifest as abnormal sweating, dysfunctional thermoregulation, dry eyes and mouth, pupillary abnormalities, cardiac arrhythmias, postural hypotension, GI abnormalities (e.g., gastroparesis, postpran­ dial bloating, chronic diarrhea, or constipation), and genitourinary dysfunction (e.g., impotence, retrograde ejaculation, incontinence) (Pattern 10, Table 457-2). Tests of autonomic function are generally abnormal, including sympathetic skin responses and quantitative sudomotor axon reflex testing. Sensory and motor NCS generally dem­ onstrate features described above with DSPN. TABLE 457-6  Treatment of Painful Sensory Neuropathies THERAPY ROUTE DOSE SIDE EFFECTS First-Line Lidoderm 5% patch Apply to painful area Up to 3 patches qd Skin irritation Tricyclic antidepressants (e.g., amitriptyline, nortriptyline) PO 10–100 mg qhs Cognitive changes, sedation, dry eyes and mouth, urinary retention, constipation Gabapentin PO 300–1200 mg tid Cognitive changes, sedation, peripheral edema Pregabalin PO 50–100 mg tid Cognitive changes, sedation, peripheral edema Duloxetine PO 30–60 mg qd Cognitive changes, sedation, dry eyes, diaphoresis, nausea, diarrhea, constipation Second-Line Carbamazepine PO 200–400 mg q 6–8 h Cognitive changes, dizziness, leukopenia, liver dysfunction Phenytoin PO 200–400 mg qhs Cognitive changes, dizziness, liver dysfunction Venlafaxine PO 37.5–150 mg/d Asthenia, sweating, nausea, constipation, anorexia, vomiting, somnolence, dry mouth, dizziness, nervousness, anxiety, tremor, and blurred vision as well as abnormal ejaculation/orgasm and impotence Tramadol PO 50 mg qid Cognitive changes, gastrointestinal upset Third-Line Mexiletine PO 200–300 mg tid Arrhythmias Other Agents EMLA cream Apply cutaneously qid Local erythema 2.5% lidocaine 2.5% prilocaine Capsaicin 0.025–0.075% cream Apply cutaneously qid Painful burning skin Source: Modified from AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill, 2016, Table 22-3, p. 485. Diabetic Radiculoplexus Neuropathy (Diabetic Amyotrophy or Bruns-Garland Syndrome)  Diabetic radiculoplexus neuropa­ thy is the presenting manifestation of DM in approximately one-third of patients. Typically, patients present with severe pain in the low back, hip, and thigh in one leg. Rarely, the diabetic polyradiculoneuropathy begins in both legs at the same time (Pattern 4, Table 457-2). Atrophy and weakness of proximal and distal muscles in the affected leg become apparent within a few days or weeks. The neuropathy is often accom­ panied or heralded by severe weight loss. Weakness usually progresses over several weeks or months but can continue to progress for 18 months or more. Subsequently, there is slow recovery, but many are left with residual weakness, sensory loss, and pain. In contrast to the more typical lumbosacral radiculoplexus neuropathy, some patients develop thoracic radiculopathy or, even less commonly, a cervical polyradicu­ loneuropathy. CSF protein is usually elevated, while the cell count is normal. ESR is often increased. EDx reveals evidence of active denerva­ tion in affected proximal and distal muscles in the limbs and in para­ spinal muscles. Nerve biopsies may demonstrate axonal degeneration along with perivascular inflammation. Patients with severe pain are sometimes treated in the acute period with glucocorticoids, although a randomized controlled trial has yet to be performed, and the natural history of this neuropathy is gradual improvement. Diabetic Mononeuropathies or Multiple Mononeuropa­ thies  The most common mononeuropathies are median neuropathy at the wrist and ulnar neuropathy at the elbow, but peroneal neuropa­ thy at the fibular head and sciatic, lateral femoral, cutaneous, or cranial neuropathies also occur (Pattern 3, Table 457-2). In regard to cranial mononeuropathies, seventh nerve palsies are relatively common but may have other, nondiabetic etiologies. In diabetics, a third nerve palsy is most common, followed by sixth nerve and, less frequently, fourth nerve palsies. Diabetic third nerve palsies are characteristically pupilsparing (Chap. 34). ■ ■HYPOTHYROIDISM Hypothyroidism is more commonly associated with a proximal myopa­ thy, but some patients develop a neuropathy, most typically CTS. Rarely, a generalized sensory polyneuropathy characterized by painful paresthesias and numbness in both the legs and hands can occur. Treat­ ment is correction of the hypothyroidism. ■ ■SJÖGREN’S SYNDROME Sjögren’s syndrome, characterized by the sicca complex of xerophthal­ mia, xerostomia, and dryness of other mucous membranes, can be complicated by neuropathy (Chap. 373). Most common is a lengthdependent axonal sensorimotor neuropathy characterized mainly by sensory loss in the distal extremities (Pattern 2, Table 457-2). A pure small-fiber neuropathy or a cranial neuropathy, particularly involv­ ing the trigeminal nerve, can also be seen. Sjögren’s syndrome is also associated with sensory neuronopathy/ganglionopathy. Patients with sensory ganglionopathies develop progressive numbness and tingling of the limbs, trunk, and face in a non-length-dependent manner such that symptoms can involve the face or arms more than the legs. The onset can be acute or insidious. Sensory examination demonstrates severe vibratory and proprioceptive loss leading to sensory ataxia. Patients with neuropathy due to Sjögren’s syndrome may have ANAs, SS-A/Ro, and SS-B/La antibodies in the serum, but most do not. NCS demonstrate reduced amplitudes of sensory studies in the affected limbs. Nerve biopsy demonstrates axonal degeneration. Nonspecific perivascular inflammation may be present, but only rarely is there necrotizing vasculitis. There is no specific treatment for neuropathies related to Sjögren’s syndrome. When vasculitis is suspected, immu­ nosuppressive agents may be beneficial. Occasionally, the sensory neuronopathy/ganglionopathy stabilizes or improves with immuno­ therapy, such as intravenous immunoglobulin. ■ ■RHEUMATOID ARTHRITIS Peripheral neuropathy occurs in at least 50% of patients with rheu­ matoid arthritis (RA) and may be vasculitic in nature (Chap. 370). Vasculitic neuropathy can present with a mononeuropathy multiplex (Pattern 3, Table 457-2), a generalized symmetric pattern of involve­ ment (Pattern 2, Table 457-2), or a combination of these patterns (Chap. 375). Neuropathies may also result from drugs used to treat RA (e.g., tumor necrosis blockers, leflunomide). Nerve biopsy often reveals thickening of the epineurial and endoneurial blood vessels as well as perivascular inflammation or vasculitis, with transmural inflammatory cell infiltration and fibrinoid necrosis of vessel walls. The neuropathy is usually responsive to immunomodulating therapies. ■ ■SYSTEMIC LUPUS ERYTHEMATOSUS Between 2 and 27% of individuals with SLE develop a peripheral neu­ ropathy (Chap. 368). Affected patients typically present with a slowly progressive sensory loss beginning in the feet. Some patients develop burning pain and paresthesias with normal reflexes, and NCS suggest a pure small-fiber neuropathy (Pattern 2, Table 457-2). Less common are multiple mononeuropathies presumably secondary to necrotizing vasculitis (Pattern 3, Table 457-2). Rarely, a generalized sensorimotor polyneuropathy meeting clinical, laboratory, electrophysiologic, and histologic criteria for either GBS or CIDP may occur. Immunosuppres­ sive therapy may be beneficial in SLE patients with neuropathy due to vasculitis. Immunosuppressive agents are less likely to be effective in patients with a generalized sensory or sensorimotor polyneuropathy without evidence of vasculitis. Patients with a GBS or CIDP-like neu­ ropathy should be treated accordingly (Chap. 458). ■ ■SYSTEMIC SCLEROSIS (SCLERODERMA) A distal symmetric, mainly sensory polyneuropathy complicates 5–67% of scleroderma cases (Pattern 2, Table 457-2) (Chap. 372). Cranial mononeuropathies can also develop, most commonly of the trigeminal nerve, producing numbness and dysesthesias in the face. Multiple mononeuropathies also occur (Pattern 3, Table 457-2). The EDx and histologic features of nerve biopsy are those of an axonal sensory greater than motor polyneuropathy. ■ ■MIXED CONNECTIVE TISSUE DISEASE A mild distal axonal sensorimotor polyneuropathy occurs in ~10% of patients with mixed connective tissue disease. ■ ■SARCOIDOSIS The peripheral nervous system or CNS is involved in ~5% of patients with sarcoidosis (Chap. 379). The most common cranial nerve involved is the seventh nerve, which can be affected bilaterally. Some patients develop radiculopathy or polyradiculopathy (Pattern 4, Table 457-2). With a generalized root involvement, the clinical presenta­ tion can mimic GBS or CIDP. Patients can also present with multiple mononeuropathies (Pattern 3, Table 457-2) or a generalized, slowly progressive, sensory greater than motor polyneuropathy (Pattern 2, Table 457-2). Some have features of a pure small-fiber neuropathy. EDx reveals an axonal neuropathy. Nerve biopsy can reveal noncaseating granulomas infiltrating the endoneurium, perineurium, or epineurium along with lymphocytic necrotizing angiitis. Neurosarcoidosis may respond to treatment with glucocorticoids or other immunosuppres­ sive agents. ■ ■HYPEREOSINOPHILIC SYNDROME Hypereosinophilic syndrome is characterized by eosinophilia associ­ ated with various skin, cardiac, hematologic, and neurologic abnor­ malities. A generalized peripheral neuropathy or a mononeuropathy multiplex occurs in 6–14% of patients (Pattern 2, Table 457-2). CHAPTER 457 ■ ■CELIAC DISEASE (GLUTEN-INDUCED ENTEROPATHY OR NONTROPICAL SPRUE) Neurologic complications, particularly ataxia and peripheral neu­ ropathy, are estimated to occur in 10% of patients with celiac dis­ ease (Chap. 336). A generalized sensorimotor polyneuropathy, pure motor neuropathy, multiple mononeuropathies, autonomic neuropa­ thy, small-fiber neuropathy, and neuromyotonia have all been reported in association with celiac disease or antigliadin/antiendomysial anti­ bodies (Patterns 2, 3, and 9; Table 457-2). Nerve biopsy may reveal a loss of large myelinated fibers. The neuropathy may be secondary to malabsorption of vitamins B12 and E. However, some patients have no appreciable vitamin deficiencies. The pathogenic basis for the neuropa­ thy in these patients is unclear but may be autoimmune in etiology. The neuropathy does not appear to respond to a gluten-free diet. In patients with vitamin B12 or vitamin E deficiency, replacement therapy may improve or stabilize the neuropathy. Peripheral Neuropathy ■ ■INFLAMMATORY BOWEL DISEASE Ulcerative colitis and Crohn’s disease may be complicated by GBS, CIDP, generalized axonal sensory or sensorimotor polyneuropathy, small-fiber neuropathy, or mononeuropathy (Patterns 2 and 3, Table 457-2) (Chap. 337). These neuropathies may be autoimmune, nutri­ tional (e.g., vitamin B12 deficiency), treatment related (e.g., metronida­ zole), or idiopathic in nature. An acute neuropathy with demyelination resembling GBS, CIDP, or multifocal motor neuropathy may occur in patients treated with tumor necrosis factor α blockers. ■ ■UREMIC NEUROPATHY Approximately 60% of patients with renal failure develop a poly­ neuropathy characterized by length-dependent numbness, tingling, allodynia, and mild distal weakness (Pattern 2, Table 457-2). Rarely, a rapidly progressive weakness and sensory loss very similar to GBS can occur that improves with an increase in the intensity of renal dialysis or with transplantation (Pattern 1, Table 457-2). Mononeuropathies can also occur, the most common of which is CTS. Ischemic monomelic neuropathy (see below) can complicate arteriovenous shunts created in the arm for dialysis (Pattern 3, Table 457-2). EDx in uremic patients reveals features of a length-dependent, primarily axonal, sensorimotor polyneuropathy. Sural nerve biopsies demonstrate a loss of nerve fibers (particularly large myelinated nerve fibers), active axonal degenera­ tion, and segmental and paranodal demyelination. The sensorimotor polyneuropathy can be stabilized by hemodialysis and improved with successful renal transplantation. ■ ■CHRONIC LIVER DISEASE A generalized sensorimotor neuropathy characterized by numbness, tingling, and minor weakness in the distal aspects of primarily the lower limbs commonly occurs in patients with chronic liver failure. EDx studies are consistent with a sensory greater than motor axonopa­ thy. Occasionally patients with severe liver disease develop a combined neuropathy and myopathy. Sural nerve biopsy reveals both segmental demyelination and axonal loss. It is not known if hepatic failure in iso­ lation can cause peripheral neuropathy, as the majority of patients have liver disease secondary to other disorders, such as alcoholism or viral hepatitis, which can also cause neuropathy. ■ ■CRITICAL ILLNESS POLYNEUROPATHY The most common causes of acute generalized weakness leading to admission to a medical intensive care unit (ICU) are GBS and myas­ thenia gravis (Pattern 1, Table 457-2) (Chaps. 458 and 459). However, weakness developing in critically ill patients while in the ICU is usu­ ally caused by critical illness polyneuropathy (CIP) or critical illness myopathy (CIM) or, much less commonly, by prolonged neuromuscu­ lar blockade. From a clinical and EDx standpoint, it can be quite diffi­ cult to distinguish these disorders. Most specialists believe that CIM is more common. Both CIM and CIP develop as a complication of sepsis and multiple organ failure. They usually present as an inability to wean a patient from a ventilator. A coexisting encephalopathy may limit the neurologic examination, in particular the sensory examination. Muscle stretch reflexes are absent or reduced. PART 13 Neurologic Disorders Serum creatine kinase (CK) is usually normal; an elevated serum CK would point to CIM as opposed to CIP. NCS reveal absent or markedly reduced amplitudes of motor and sensory studies in CIP, whereas sensory studies are relatively preserved in CIM. Needle EMG usually reveals profuse positive sharp waves and fibrillation potentials, and it is not unusual in patients with severe weakness to be unable to recruit motor unit action potentials. The pathogenic basis of CIP is not known. Perhaps circulating toxins and metabolic abnormalities associated with sepsis and multiorgan failure impair axonal transport or mitochondrial function, leading to axonal degeneration. ■ ■LEPROSY (HANSEN’S DISEASE) Leprosy, caused by the acid-fast bacteria Mycobacterium leprae, is the most common cause of peripheral neuropathy in Southeast Asia, Africa, and South America (Chap. 184). Clinical manifestations range from tuberculoid leprosy at one end of the spectrum to lepro­ matous leprosy at the other end, with borderline leprosy in between. Neuropathies are most common in patients with borderline leprosy. Superficial cutaneous nerves of the ears and distal limbs are com­ monly affected. Mononeuropathies, multiple mononeuropathies, or a slowly progressive symmetric sensorimotor polyneuropathy may develop (Patterns 2 and 3, Table 457-2). Sensory NCS are usually absent in the lower limb and are reduced in amplitude in the arms. Motor NCS may demonstrate reduced amplitudes in affected nerves but occasionally can reveal demyelinating features. Leprosy is usually diagnosed by skin lesion biopsy. Nerve biopsy can also be diagnostic, particularly when there are no apparent skin lesions. The tuberculoid form is characterized by granulomas, and bacilli are not seen. In con­ trast, with lepromatous leprosy, large numbers of infiltrating bacilli, TH2 lymphocytes, and organism-laden, foamy macrophages with minimal granulomatous infiltration are evident. The bacilli are best appreciated using the Fite stain, where they can be seen as red-staining rods often in clusters free in the endoneurium, within macrophages, or within Schwann cells. Patients are generally treated with multiple drugs: dapsone, rifampin, and clofazimine. Other medications that are used include thalidomide, pefloxacin, ofloxacin, sparfloxacin, minocycline, and clarithromycin. Patients are generally treated for 2 years. Treatment is sometimes complicated by the so-called reversal reaction, particularly in borderline leprosy. The reversal reaction can occur at any time dur­ ing treatment and develops because of a shift to the tuberculoid end of the spectrum, with an increase in cellular immunity during treatment. The cellular response is upregulated as evidenced by an increased release of tumor necrosis factor α, interferon γ, and interleukin 2, with new granuloma formation. This can result in an exacerbation of the rash and the neuropathy as well as in appearance of new lesions. High-dose glucocorticoids blunt this adverse reaction and may be used prophylactically at treatment onset in high-risk patients. Ery­ thema nodosum leprosum (ENL) is also treated with glucocorticoids or thalidomide. ■ ■LYME DISEASE Lyme disease is caused by infection with Borrelia burgdorferi, a spiro­ chete usually transmitted by the deer tick Ixodes dammini (Chap. 191). Neurologic complications may develop during the second and third stages of infection. Facial neuropathy is most common and is bilateral in about half of cases, which is rare for idiopathic Bell’s palsy. Involve­ ment of nerves is frequently asymmetric. Some patients present with a polyradiculoneuropathy or multiple mononeuropathies (Pattern 3 or 4, Table 457-2). EDx is suggestive of a primary axonopathy. Nerve biop­ sies can reveal axonal degeneration with perivascular inflammation. Treatment is with antibiotics. ■ ■DIPHTHERITIC NEUROPATHY Diphtheria is caused by the bacteria Corynebacterium diphtheriae (Chap. 155). Infected individuals present with flu-like symptoms of generalized myalgias, headache, fatigue, low-grade fever, and irritabil­ ity within a week to 10 days of the exposure. Between 20 and 70% of patients develop a peripheral neuropathy caused by a toxin released by the bacteria. Three to 4 weeks after infection, patients may note decreased sensation in their throat and begin to develop dysphagia, dysarthria, hoarseness, and blurred vision due to impaired accommo­ dation. A generalized polyneuropathy may manifest 2 or 3 months fol­ lowing the initial infection, characterized by numbness, paresthesias, and weakness of the arms and legs and occasionally ventilatory failure (Pattern 1, Table 457-2). CSF protein can be elevated with or without lymphocytic pleocytosis. EDx suggests a diffuse axonal sensorimotor polyneuropathy. Antitoxin and antibiotics should be given within 48 h of symptom onset. Although early treatment reduces the incidence and severity of some complications (i.e., cardiomyopathy), it does not appear to alter the natural history of the associated peripheral neuropa­ thy. The neuropathy usually resolves after several months. ■ ■COVID-19 GBS (Chap. 458) has been reported in the setting of acute COVID-19 infection though a causal relationship has not been clearly established. There does appear to be an increased risk of GBS with adenovirusvector vaccines but not the messenger RNA vaccines. ■ ■HUMAN IMMUNODEFICIENCY VIRUS HIV infection can result in a variety of neurologic complications, including peripheral neuropathies (Chap. 208). Approximately 20% of HIV-infected individuals develop a neuropathy as a direct result of the virus itself or as a result of other associated viral infections (e.g., CMV) or neurotoxicity secondary to antiviral medications (see below). The major presentations of peripheral neuropathy associated with HIV infection include (1) distal symmetric polyneuropathy (DSP), (2) inflammatory demyelinating polyneuropathy (including both GBS and CIDP), (3) multiple mononeuropathies (e.g., vasculitis, CMV-related), (4) polyradiculopathy (usually CMV-related), (5) autonomic neuropa­ thy, and (6) sensory ganglionitis. HIV-Related Distal Symmetric Polyneuropathy  DSP is the most common form of peripheral neuropathy associated with HIV infection and usually is seen in patients with AIDS. It is characterized by numbness and painful paresthesias involving the distal extremities (Pattern 2, Table 457-2). The pathogenic basis for DSP is unknown but is not due to actual infection of the peripheral nerves. The neuropathy may be immune mediated, perhaps caused by the release of cytokines from surrounding inflammatory cells. Vitamin B12 deficiency may contribute in some instances but is not a major cause of most cases of DSP. Older antiretroviral agents (e.g., dideoxycytidine, dideoxyino­ sine, stavudine) are also neurotoxic and can cause a painful sensory neuropathy. HIV-Related Inflammatory Demyelinating Polyradiculoneu­ ropathy  Both acute inflammatory demyelinating polyneuropathy (AIDP) and CIDP can occur as a complication of HIV infection (Pat­ tern 1, Table 457-2). AIDP usually develops at the time of seroconver­ sion, whereas CIDP can occur any time in the course of the infection. Clinical and EDx features are indistinguishable from idiopathic AIDP or CIDP (Chap. 458). In addition to elevated protein levels, lympho­ cytic pleocytosis is evident in the CSF, a finding that helps distinguish this HIV-associated polyradiculoneuropathy from idiopathic AIDP/ CIDP. HIV-Related Progressive Polyradiculopathy  An acute, pro­ gressive lumbosacral polyradiculoneuropathy usually secondary to CMV infection can develop in patients with AIDS (Pattern 4, Table 457-2). Patients present with severe radicular pain, numbness, and weakness in the legs, which is usually asymmetric. CSF is abnormal, demonstrating a high protein level, along with a reduced glucose con­ centration and notably a neutrophilic pleocytosis. EDx studies reveal features of active axonal degeneration. The polyradiculoneuropathy may improve with antiviral therapy. HIV-Related Multiple Mononeuropathies  Multiple mono­ neuropathies can also develop in patients with HIV infection, usually in the context of AIDS. Weakness, numbness, paresthesias, and pain occur in the distribution of affected nerves (Pattern 3, Table 457-2). Nerve biopsies can reveal axonal degeneration with necrotizing vasculitis or perivascular inflammation. Glucocorticoid treatment is indicated for vasculitis directly due to HIV infection. HIV-Related Sensory Neuronopathy/Ganglionopathy  Dor­ sal root ganglionitis is a very rare complication of HIV infection, and neuronopathy can be the presenting manifestation. Patients develop sensory ataxia similar to idiopathic sensory neuronopathy/ ganglionopathy (Pattern 9, Table 457-2). NCS reveal reduced amplitudes or absence of sensory nerve action potentials (SNAPs). ■ ■HERPES VARICELLA-ZOSTER VIRUS Peripheral neuropathy from herpes varicella-zoster (HVZ) infection results from reactivation of latent virus or from a primary infection (Chap. 198). Two-thirds of infections in adults are characterized by dermal zoster in which severe pain and paresthesias develop in a der­ matomal region followed within a week or two by a vesicular rash in the same distribution (Pattern 3, Table 457-2). Weakness in muscles innervated by roots corresponding to the dermatomal distribution of skin lesions occurs in 5–30% of patients. Approximately 25% of affected patients have continued pain (postherpetic neuralgia [PHN]). A large clinical trial demonstrated that vaccination against zoster reduces the incidence of HVZ among vaccine recipients by 51% and reduces the incidence of PHN by 67%. Treatment of PHN is symptom­ atic (Table 457-6). ■ ■CYTOMEGALOVIRUS CMV can cause an acute lumbosacral polyradiculopathy and mul­ tiple mononeuropathies in patients with HIV infection and in other immune deficiency conditions (Pattern 4, Table 457-2) (Chap. 200). ■ ■EPSTEIN-BARR VIRUS EBV infection has been associated with GBS, cranial neuropathies, mononeuropathy multiplex, brachial plexopathy, lumbosacral radicu­ loplexopathy, and sensory neuronopathies (Patterns 1, 3, 4, and 9, Table 457-2) (Chap. 199). ■ ■HEPATITIS VIRUSES Hepatitis B and C can cause multiple mononeuropathies related to vasculitis, AIDP, or CIDP (Patterns 1 and 3, Table 457-2) (Chap. 352). NEUROPATHIES ASSOCIATED WITH MALIGNANCY Patients with malignancy can develop neuropathies due to (1) a direct effect of the cancer by invasion or compression of the nerves, (2) remote or paraneoplastic effect, (3) a toxic effect of treatment, or (4) as a consequence of immune compromise caused by immunosuppressive medications. The most common associated malignancy is lung cancer, but neuropathies also complicate carcinoma of the breast, ovaries, stomach, colon, rectum, and other organs, including the lymphopro­ liferative system. ■ ■PARANEOPLASTIC SENSORY NEURONOPATHY/ GANGLIONOPATHY Paraneoplastic encephalomyelitis/sensory neuronopathy (PEM/SN) usually complicates small-cell lung carcinoma (Chap. 99). Patients usually present with numbness and paresthesias in the distal extremi­ ties that are often asymmetric. The onset can be acute or insidiously progressive. Prominent loss of proprioception leads to sensory ataxia (Pattern 9; Table 457-2). Weakness can be present, usually secondary to an associated myelitis, motor neuronopathy, or concurrent LEMS. Many patients also develop confusion, memory loss, depression, hal­ lucinations or seizures, or cerebellar ataxia. Polyclonal antineuronal antibodies (IgG) directed against a 35- to 40-kDa protein or complex of proteins, the so-called Hu antigen, are found in the sera or CSF in the majority of patients with paraneoplastic PEM/SN. CSF may be normal or may demonstrate mild lymphocytic pleocytosis and elevated protein. PEM/SN is probably the result of antigenic similarity between proteins expressed in the tumor cells and neuronal cells, leading to an immune response directed against both cell types. Treatment of the underlying cancer generally does not affect the course of PEM/SN. However, occasional patients may improve following treatment of the tumor. Unfortunately, plasmapheresis, intravenous immunoglobulin, and immunosuppressive agents have not shown benefit. CHAPTER 457 Peripheral Neuropathy ■ ■NEUROPATHY SECONDARY TO TUMOR INFILTRATION Malignant cells, in particular leukemia and lymphoma, can infiltrate cranial and peripheral nerves, leading to mononeuropathy, mononeu­ ropathy multiplex, polyradiculopathy, plexopathy, or even a generalized symmetric distal or proximal and distal polyneuropathy (Patterns 1, 2, 3, and 4; Table 457-2). Neuropathy related to tumor infiltration is often painful; it can be the presenting manifestation of the cancer or the heralding symptom of a relapse. The neuropathy may improve with treatment of the underlying leukemia or lymphoma or with glucocorticoids. ■ ■NEUROPATHY AS A COMPLICATION OF BONE MARROW TRANSPLANTATION Neuropathies may develop in patients who undergo bone marrow transplantation (BMT) because of the toxic effects of chemotherapy, radiation, infection, or an autoimmune response directed against the peripheral nerves. Peripheral neuropathy in BMT is often associated with graft-versus-host disease (GVHD). Chronic GVHD shares many features with a variety of autoimmune disorders, and it is possible that an immune-mediated response directed against peripheral nerves is responsible. Patients with chronic GVHD may develop cranial neurop­ athies, sensorimotor polyneuropathies, multiple mononeuropathies, and severe generalized peripheral neuropathies resembling AIDP or CIDP (Patterns 1, 2, and 3; Table 457-2). The neuropathy may improve by increasing the intensity of immunosuppressive or immunomodulat­ ing therapy and resolution of the GVHD. ■ ■LYMPHOMA Lymphomas may cause neuropathy by infiltration or direct compres­ sion of nerves or by a paraneoplastic process. The neuropathy can be purely sensory or motor but most commonly is sensorimotor. The pattern of involvement may be symmetric, asymmetric, or multifocal, and the course may be acute, gradually progressive, or relapsing and remitting (Patterns 1, 2, and 3; Table 457-2). EDx can be compatible with either an axonal or demyelinating process. CSF may reveal lym­ phocytic pleocytosis and an elevated protein. Nerve biopsy may dem­ onstrate endoneurial inflammatory cells in both the infiltrative and the paraneoplastic etiologies. A monoclonal population of cells favors lymphomatous invasion. The neuropathy may respond to treatment of the underlying lymphoma or immunomodulating therapies. ■ ■MULTIPLE MYELOMA MM usually presents in the fifth to seventh decade of life with fatigue, bone pain, anemia, and hypercalcemia (Chap. 116). Clinical and EDx features of neuropathy occur in as many as 40% of patients. The most common pattern is that of a distal, axonal, sensory, or sensorimotor polyneuropathy (Pattern 2; Table 457-2). Less frequently, a chronic demyelinating polyradiculoneuropathy may develop (Pattern 1; Table 457-2) (see POEMS, Chap. 458). MM can be complicated by amyloid polyneuropathy and should be considered in patients with painful paresthesias, loss of pinprick and temperature discrimination, and autonomic dysfunction (suggestive of a small-fiber neuropathy) and CTS. Expanding plasmacytomas can compress cranial nerves and spinal roots as well. A monoclonal protein, usually composed of γ or μ heavy chains or κ light chains, may be identified in the serum or urine. EDx usually shows reduced amplitudes with normal or only mildly abnor­ mal distal latencies and conduction velocities. A superimposed median neuropathy at the wrist is common. Abdominal fat pad, rectal, or sural nerve biopsy can be performed to look for amyloid deposition. Unfor­ tunately, the treatment of the underlying MM does not usually affect the course of the neuropathy. ■ ■NEUROPATHIES ASSOCIATED WITH MONOCLONAL GAMMOPATHY OF UNCERTAIN SIGNIFICANCE (SEE CHAP. 458) PART 13 Neurologic Disorders Toxic Neuropathies Secondary to Chemotherapy  Many of the commonly used chemotherapy agents can cause a toxic neuropa­ thy (Table 457-7). The mechanisms by which these agents cause toxic neuropathies vary, as does the specific type of neuropathy produced. The risk of developing a toxic neuropathy or more severe neuropa­ thy appears to be greater in patients with a preexisting neuropathy (e.g., CMT disease, diabetic neuropathy) and those who also take other potentially neurotoxic drugs (e.g., nitrofurantoin, isoniazid, TABLE 457-7  Toxic Neuropathies Secondary to Chemotherapy MECHANISM OF NEUROTOXICITY CLINICAL FEATURES NERVE HISTOPATHOLOGY EMG/NCS DRUG Vinca alkaloids (vincristine, vinblastine, vindesine, vinorelbine) Interfere with axonal microtubule assembly; impairs axonal transport Symmetric, S-M, large-/smallfiber PN; autonomic symptoms common; infrequent cranial neuropathies Cisplatin Preferential damage to dorsal root ganglia: ? binds to and cross-links DNA ? inhibits protein synthesis ? impairs axonal transport Predominant large-fiber sensory neuronopathy; sensory ataxia Taxanes (paclitaxel, docetaxel) Promotes axonal microtubule assembly; interferes with axonal transport Symmetric, predominantly sensory PN; large-fiber modalities affected more than small-fiber Suramin   Axonal PN Unknown;? inhibition of neurotrophic growth factor binding;? neuronal lysosomal storage Symmetric, length-dependent, sensory-predominant PN   Demyelinating PN Unknown;? immunomodulating effects Subacute, S-M PN with diffuse proximal and distal weakness; areflexia; increased CSF protein Cytarabine (ARA-C) Unknown;? selective Schwann cell toxicity;? immunomodulating effects GBS-like syndrome; pure sensory neuropathy; brachial plexopathy Etoposide (VP-16) Unknown;? selective dorsal root ganglia toxicity Length-dependent, sensorypredominant PN; autonomic neuropathy Bortezomib (Velcade) Unknown Length-dependent, sensory, predominantly small-fiber PN Abbreviations: CMAP, compound motor action potential; CSF, cerebrospinal fluid; CVs, conduction velocities; EMG, electromyography; GBS, Guillain-Barré syndrome; NCS, nerve conduction studies; PN, polyneuropathy; QST, quantitative sensory testing; S-M, sensorimotor; SNAP, sensory nerve action potential. Source: Reproduced with permission from AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. New York: McGraw-Hill; 2016. disulfiram, pyridoxine). Chemotherapeutic agents usually cause a sensory greater than motor length-dependent axonal neuropathy or neuronopathy/ganglionopathy (Patterns 2 and 9; Table 457-2). OTHER TOXIC NEUROPATHIES Neuropathies can develop as complications of toxic effects of various drugs and other environmental exposures (Table 457-8). The more common neuropathies associated with these agents are discussed here. ■ ■CHLOROQUINE AND HYDROXYCHLOROQUINE Chloroquine and hydroxychloroquine can cause a toxic myopathy characterized by slowly progressive, painless, proximal weakness and atrophy, which is worse in the legs than the arms. In addition, neuropathy can also develop with or without the myopathy leading to sensory loss and distal weakness. The “neuromyopathy” usually appears in patients taking 500 mg daily for a year or more but has been reported with doses as low as 200 mg/d. Serum CK levels are usually elevated due to the superimposed myopathy. NCS reveal mild slowing of motor and sensory NCVs with a mild to moderate reduc­ tion in the amplitudes, although NCS may be normal in patients with only the myopathy. EMG demonstrates myopathic muscle action potentials (MUAPs), increased insertional activity in the form of positive sharp waves, fibrillation potentials, and occasionally myo­ tonic potentials, particularly in the proximal muscles. Neurogenic MUAPs and reduced recruitment are found in more distal muscles. Nerve biopsy demonstrates autophagic vacuoles within Schwann cells. Vacuoles may also be evident in muscle biopsies. The pathogenic basis Axonal degeneration of myelinated and unmyelinated fibers; regenerating clusters, minimal segmental demyelination Axonal sensorimotor PN; distal denervation on EMG; abnormal QST, particularly vibratory perception Loss of large > small myelinated and unmyelinated fibers; axonal degeneration with small clusters of regenerating fibers; secondary segmental demyelination Low-amplitude or unobtainable SNAPs with normal CMAPs and EMG; abnormal QST, particularly vibratory perception Loss of large > small myelinated and unmyelinated fibers; axonal degeneration with small clusters of regenerating fibers; secondary segmental demyelination Axonal sensorimotor PN; distal denervation on EMG; abnormal QST, particularly vibratory perception None described Abnormalities consistent with an axonal S-M PN Loss of large and small myelinated fibers with primary demyelination and secondary axonal degeneration; occasional epi- and endoneurial inflammatory cell infiltrates Features suggestive of an acquired demyelinating sensorimotor PN (e.g., slow CVs, prolonged distal latencies and F-wave latencies, conduction block, temporal dispersion) Loss of myelinated nerve fibers; axonal degeneration; segmental demyelination; no inflammation Axonal, demyelinating, or mixed S-M PN; denervation on EMG None described Abnormalities consistent with an axonal S-M PN Not reported Abnormalities consistent with an axonal sensory neuropathy with early small-fiber involvement (abnormal autonomic studies) TABLE 457-8  Toxic Neuropathies MECHANISM OF NEUROTOXICITY CLINICAL FEATURES NERVE HISTOPATHOLOGY EMG/NCS DRUG Misonidazole Unknown Painful paresthesias and loss of large- and small-fiber sensory modalities and sometimes distal weakness in length-dependent pattern Metronidazole Unknown Painful paresthesias and loss of large- and small-fiber sensory modalities and sometimes distal weakness in length-dependent pattern Chloroquine and hydroxychloroquine Amphiphilic properties may lead to drug-lipid complexes that are indigestible and result in accumulation of autophagic vacuoles Loss of large- and small-fiber sensory modalities and distal weakness in length-dependent pattern; superimposed myopathy may lead to proximal weakness Amiodarone Amphiphilic properties may lead to drug-lipid complexes that are indigestible and result in accumulation of autophagic vacuoles Paresthesias and pain with loss of large- and small-fiber sensory modalities and distal weakness in length-dependent pattern; superimposed myopathy may lead to proximal weakness Colchicine Inhibits polymerization of tubulin in microtubules and impairs axoplasmic flow Numbness and paresthesias with loss of large-fiber modalities in a lengthdependent fashion; superimposed myopathy may lead to proximal in addition to distal weakness Podophyllin Binds to microtubules and impairs axoplasmic flow Sensory loss, tingling, muscle weakness, and diminished muscle stretch reflexes in length-dependent pattern; autonomic neuropathy Thalidomide Unknown Numbness, tingling, and burning pain and weakness in a length-dependent pattern Disulfiram Accumulation of neurofilaments and impaired axoplasmic flow Numbness, tingling, and burning pain in a length-dependent pattern Dapsone Unknown Distal weakness that may progress to proximal muscles; sensory loss Leflunomide Unknown Paresthesias and numbness in a length-dependent pattern Nitrofurantoin Unknown Numbness, painful paresthesias, and severe weakness that may resemble GBS Pyridoxine (vitamin B6) Unknown Dysesthesias and sensory ataxia; impaired large-fiber sensory modalities on examination Isoniazid Inhibits pyridoxal phosphokinase leading to pyridoxine deficiency Dysesthesias and sensory ataxia; impaired large-fiber sensory modalities on examination Ethambutol Unknown Numbness with loss of large-fiber modalities on examination Antinucleosides Unknown Dysesthesia and sensory ataxia; impaired large-fiber sensory modalities on examination Phenytoin Unknown Numbness with loss of large-fiber modalities on examination Lithium Unknown Numbness with loss of large-fiber modalities on examination Axonal degeneration of large, myelinated fibers; axonal swellings; segmental demyelination Low-amplitude or unobtainable SNAPs with normal or only slightly reduced CMAP amplitudes Axonal degeneration Low-amplitude or unobtainable SNAPs with normal CMAPs Axonal degeneration with autophagic vacuoles in nerves as well as muscle fibers Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; distal denervation on EMG; irritability and myopathic-appearing MUAPs proximally in patients with superimposed toxic myopathy CHAPTER 457 Axonal degeneration and segmental demyelination with myeloid inclusions in nerves and muscle fibers Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; can also have prominent slowing of CVs; distal denervation on EMG; irritability and myopathic-appearing MUAPs proximally in patients with superimposed toxic myopathy Peripheral Neuropathy Nerve biopsy demonstrates axonal degeneration; muscle biopsy reveals fibers with vacuoles Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; irritability and myopathic-appearing MUAPs proximally in patients with superimposed toxic myopathy Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration; autopsy studies reveal degeneration of dorsal root ganglia Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration with accumulation of neurofilaments in the axons Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration and segmental demyelination Low-amplitude or unobtainable CMAPs with normal or reduced SNAP amplitudes Unknown Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration; autopsy studies reveal degeneration of dorsal root ganglia and anterior horn cells Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Marked loss of sensory axons and cell bodies in dorsal root ganglia Reduced amplitudes or absent SNAPs Marked loss of sensory axons and cell bodies in dorsal root ganglia and degeneration of the dorsal columns Reduced amplitudes or absent SNAPs and, to a lesser extent, CMAPs Axonal degeneration Reduced amplitudes or absent SNAPs Axonal degeneration Reduced amplitudes or absent SNAPs Axonal degeneration and segmental demyelination Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes (Continued) (Continued) TABLE 457-8  Toxic Neuropathies MECHANISM OF NEUROTOXICITY CLINICAL FEATURES NERVE HISTOPATHOLOGY EMG/NCS DRUG Acrylamide Unknown; may be caused by impaired axonal transport Numbness with loss of large-fiber modalities on examination; sensory ataxia; mild distal weakness Carbon disulfide Unknown Length-dependent numbness and tingling with mild distal weakness Ethylene oxide Unknown; may act as alkylating agent and bind DNA Length-dependent numbness and tingling; may have mild distal weakness Organophosphates Bind and inhibit neuropathy target esterase Early features are those of neuromuscular blockade with generalized weakness; later axonal sensorimotor PN ensues PART 13 Neurologic Disorders Hexacarbons Unknown; may lead to covalent cross-linking between neurofilaments Acute, severe sensorimotor PN that may resemble GBS Lead Unknown; may interfere with mitochondria Encephalopathy; motor neuropathy (often resembles radial neuropathy with wrist and finger drop); autonomic neuropathy; bluish-black discoloration of gums Mercury Unknown; may combine with sulfhydryl groups Abdominal pain and nephrotic syndrome; encephalopathy; ataxia; paresthesias Thallium Unknown Encephalopathy; painful sensory symptoms; mild loss of vibration; distal or generalized weakness may also develop; autonomic neuropathy; alopecia Arsenic Unknown; may combine with sulfhydryl groups Abdominal discomfort, burning pain, and paresthesias; generalized weakness; autonomic insufficiency; can resemble GBS Gold Unknown Distal paresthesias and reduction of all sensory modalities Abbreviations: CMAP, compound motor action potential; CVs, conduction velocities; EMG, electromyography; GBS, Guillain-Barré syndrome; MUAP, muscle action potential; NCS, nerve conduction studies; PN, polyneuropathy; S-M, sensorimotor; SNAP, sensory nerve action potential. Source: Reproduced with permission from AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. New York: McGraw-Hill; 2016. of the neuropathy is not known but may be related to the amphiphilic properties of the drug. These agents contain both hydrophobic and hydrophilic regions that allow them to interact with the anionic phos­ pholipids of cell membranes and organelles. The drug-lipid complexes may be resistant to digestion by lysosomal enzymes, leading to the formation of autophagic vacuoles filled with myeloid debris that may in turn cause degeneration of nerves and muscle fibers. The signs and symptoms of the neuropathy and myopathy are usually reversible fol­ lowing discontinuation of medication. ■ ■AMIODARONE Amiodarone can cause a neuromyopathy similar to chloroquine and hydroxychloroquine. The neuromyopathy typically appears after patients have taken the medication for 2–3 years. Nerve biopsy dem­ onstrates a combination of segmental demyelination and axonal loss. Electron microscopy reveals lamellar or dense inclusions in Schwann cells, pericytes, and endothelial cells. The inclusions in muscle and nerve biopsies have persisted as long as 2 years following discontinua­ tion of the medication. Degeneration of sensory axons in peripheral nerves and posterior columns, spinocerebellar tracts, mammillary bodies, optic tracts, and corticospinal tracts in the CNS Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal swellings with accumulation of neurofilaments Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration along with degeneration of gracile fasciculus and corticospinal tracts Early: repetitive firing of CMAPs and decrement with repetitive nerve stimulation; late: axonal sensorimotor PN Axonal degeneration and giant axons swollen with neurofilaments Features of a mixed axonal and/ or demyelinating sensorimotor axonal PN—reduced amplitudes, prolonged distal latencies, conduction block, and slowing of CVs Axonal degeneration of motor axons Reduction of CMAP amplitudes with active denervation on EMG Axonal degeneration; degeneration of dorsal root ganglia, calcarine, and cerebellar cortex Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes Axonal degeneration Low-amplitude or unobtainable SNAPs with normal or reduced CMAP amplitudes; may have demyelinating features: prolonged distal latencies and slowing of CVs Axonal degeneration Low-amplitude or unobtainable SNAPs ■ ■COLCHICINE Colchicine can also cause a neuromyopathy. Patients usually pres­ ent with proximal weakness and numbness and tingling in the distal extremities. EDx reveals features of an axonal polyneuropathy. Muscle biopsy reveals a vacuolar myopathy, whereas sensory nerves demon­ strate axonal degeneration. Colchicine inhibits the polymerization of tubulin into microtubules. The disruption of the microtubules prob­ ably leads to defective intracellular movement of important proteins, nutrients, and waste products in muscle and nerves. ■ ■THALIDOMIDE Thalidomide is an immunomodulating agent used to treat MM, GVHD, leprosy, and other autoimmune disorders. Thalidomide is associated with severe teratogenic effects as well as peripheral neu­ ropathy that can be dose-limiting. Patients develop numbness, painful tingling, and burning discomfort in the feet and hands and less com­ monly muscle weakness and atrophy. Even after stopping the drug for 4–6 years, as many as 50% patients continue to have significant symp­ toms. NCS demonstrate reduced amplitudes or complete absence of SNAPs, with preserved conduction velocities when obtainable. Motor NCS are usually normal. Nerve biopsy reveals a loss of large-diameter myelinated fibers and axonal degeneration. Degeneration of dorsal root ganglion cells has been reported at autopsy. PYRIDOXINE (VITAMIN B6) TOXICITY Pyridoxine is an essential vitamin that serves as a coenzyme for trans­ amination and decarboxylation. However, at high doses (116 mg/d), patients can develop a severe sensory neuropathy with dysesthesias and sensory ataxia. NCS reveal absent or markedly reduced SNAP ampli­ tudes with relatively preserved CMAPs. Nerve biopsy reveals axonal loss of fiber at all diameters. Loss of dorsal root ganglion cells with subsequent degeneration of both the peripheral and central sensory tracts have been reported in animal models. ■ ■ISONIAZID One of the most common side effects of isoniazid (INH) is peripheral neuropathy. Standard doses of INH (3–5 mg/kg per day) are associated with a 2% incidence of neuropathy, whereas neuropathy develops in at least 17% of patients taking in excess of 6 mg/kg per d. The elderly, malnourished, and “slow acetylators” are at increased risk for develop­ ing the neuropathy. INH inhibits pyridoxal phosphokinase, resulting in pyridoxine deficiency and the neuropathy. Prophylactic administration of pyridoxine 100 mg/d can prevent the neuropathy from developing. ■ ■ANTIRETROVIRAL AGENTS The nucleoside analogues zalcitabine (dideoxycytidine or ddC), didano­ sine (dideoxyinosine or ddI), stavudine (d4T), lamivudine (3TC), and antiretroviral nucleoside reverse transcriptase inhibitor (NRTI) are used to treat HIV infection. One of the major dose-limiting side effects of these medications is a predominantly sensory, length-dependent, symmetrically painful neuropathy (Pattern 2; Table 457-2). Zalcitabine (ddC) is the most extensively studied of the nucleoside analogues, and at doses >0.18 mg/kg per d, it is associated with a subacute onset of severe burning and lancinating pains in the feet and hands. NCS reveal decreased amplitudes of the SNAPs with normal motor studies. The nucleoside analogues inhibit mitochondrial DNA polymerase, which is the suspected pathogenic basis for the neuropathy. Because of a “coasting effect,” patients can continue to worsen even 2–3 weeks after stopping the medication. Following dose reduction, improvement in the neuropa­ thy is seen in most patients after several months (mean time ~10 weeks). ■ ■HEXACARBONS (n-HEXANE, METHYL n-BUTYL KETONE)/GLUE SNIFFER’S NEUROPATHY n-Hexane and methyl n-butyl ketone are water-insoluble industrial organic solvents that are also present in some glues. Exposure through inhalation, accidentally or intentionally (glue sniffing), or through skin absorption can lead to a profound subacute sensory and motor polyneuropathy (Pattern 2; Table 457-2). NCS demonstrate decreased amplitudes of the SNAPs and CMAPs with slightly slow conduction velocities. Nerve biopsy reveals a loss of myelinated fibers and giant axons that are filled with 10-nm neurofilaments. Hexacarbon exposure leads to covalent cross-linking between axonal neurofilaments that results in their aggregation, impaired axonal transport, swelling of the axons, and eventual axonal degeneration. ■ ■LEAD Lead neuropathy is uncommon, but it can be seen in children who accidentally ingest lead-based paints in older buildings and in indus­ trial workers exposed to lead-containing products. The most common presentation of lead poisoning is an encephalopathy; however, symp­ toms and signs of a primarily motor neuropathy can also occur. The neuropathy is characterized by an insidious and progressive onset of weakness usually beginning in the arms, in particular involving the wrist and finger extensors, resembling a radial neuropathy. Sensation is generally preserved; however, the autonomic nervous system can be affected (Patterns 2, 3, and 10; Table 457-2). Laboratory investigation can reveal a microcytic hypochromic anemia with basophilic stip­ pling of erythrocytes, an elevated serum lead level, and an elevated serum coproporphyrin level. A 24-h urine collection demonstrates elevated levels of lead excretion. The NCS may reveal reduced CMAP amplitudes, while the SNAPs are typically normal. The pathogenic basis may be related to abnormal porphyrin metabolism. The most impor­ tant principle of management is to remove the source of the exposure. Chelation therapy with calcium disodium ethylene-diaminetetraacetic acid (EDTA), British anti-Lewisite (BAL), and penicillamine also dem­ onstrates variable efficacy. ■ ■MERCURY Mercury toxicity may occur as a result of exposure to either organic or inorganic mercurials. Mercury poisoning presents with paresthesias in hands and feet that progress proximally and may involve the face and tongue. Motor weakness can also develop. CNS symptoms often overshadow the neuropathy. EDx shows features of a primarily axonal sensorimotor polyneuropathy. The primary site of neuromuscular pathology appears to be the dorsal root ganglia. The mainstay of treat­ ment is removing the source of exposure. CHAPTER 457 ■ ■THALLIUM Thallium can exist in a monovalent or trivalent form and is primarily used as a rodenticide. The toxic neuropathy usually manifests as burn­ ing paresthesias of the feet, abdominal pain, and vomiting. Increased thirst, sleep disturbances, and psychotic behavior may be noted. Within the first week, patients develop pigmentation of the hair, an acne-like rash in the malar area of the face, and hyperreflexia. By the second and third weeks, autonomic instability with labile heart rate and blood pres­ sure may be seen. Hyporeflexia and alopecia also occur but may not be evident until the third or fourth week following exposure. With severe intoxication, proximal weakness and involvement of the cranial nerves can occur. Some patients require mechanical ventilation due to respira­ tory muscle involvement. The lethal dose of thallium is variable, ranging from 8 to 15 mg/kg body weight. Death can result in <48 h following a particularly large dose. NCS demonstrate features of a primarily axonal sensorimotor polyneuropathy. With acute intoxication, potassium fer­ ric ferrocyanide II may be effective in preventing absorption of thal­ lium from the gut. However, there may be no benefit once thallium has been absorbed. Unfortunately, chelating agents are not very efficacious. Adequate diuresis is essential to help eliminate thallium from the body without increasing tissue availability from the serum. Peripheral Neuropathy ■ ■ARSENIC Arsenic is another heavy metal that can cause a toxic sensorimotor polyneuropathy. The neuropathy manifests 5–10 days after ingestion of arsenic and progresses for several weeks, sometimes mimicking GBS. The presenting symptoms are typically an abrupt onset of abdominal discomfort, nausea, vomiting, pain, and diarrhea followed within sev­ eral days by burning pain in the feet and hands. Examination of the skin can be helpful in the diagnosis as the loss of the superficial epidermal layer results in patchy regions of increased or decreased pigmentation on the skin several weeks after an acute exposure or with chronic low levels of ingestion. Mee’s lines, which are transverse lines at the base of the fingernails and toenails, do not become evident until 1 or 2 months after the exposure. Multiple Mee’s lines may be seen in patients with long fingernails who have had chronic exposure to arsenic. Mee’s lines are not specific for arsenic toxicity as they can also be seen following thallium poisoning. Because arsenic is cleared from blood rapidly, the serum concentration of arsenic is not diagnostically helpful. However, arsenic levels are increased in the urine, hair, and fingernails of patients exposed to arsenic. Anemia with stippling of erythrocytes is com­ mon, and occasionally, pancytopenia and aplastic anemia can develop. Increased CSF protein levels without pleocytosis can be seen; this can lead to misdiagnosis as GBS. NCS are usually suggestive of an axonal sensorimotor polyneuropathy; however, demyelinating features can be present. Chelation therapy with BAL has yielded inconsistent results; therefore, it is not generally recommended. NUTRITIONAL NEUROPATHIES ■ ■COBALAMIN (VITAMIN B12) Pernicious anemia is the most common cause of cobalamin defi­ ciency. Other causes include dietary avoidance (vegetarians), gastrec­ tomy, gastric bypass surgery, inflammatory bowel disease, pancreatic insufficiency, bacterial overgrowth, and possibly histamine-2 blockers and proton pump inhibitors. An underappreciated cause of cobalamin deficiency is food-cobalamin malabsorption. This typically occurs in older individuals and results from an inability to adequately absorb cobalamin in food protein. No apparent cause of deficiency is identi­ fied in a significant number of patients with cobalamin deficiency. The use of nitrous oxide as an anesthetic agent or as a recreational drug can produce acute cobalamin deficiency neuropathy and subacute combined degeneration. Complaints of numb hands typically appear before lower extremity paresthesias are noted. A preferential large-fiber sensory loss affecting proprioception and vibration with sparing of small-fiber modalities is present; an unsteady gait reflects sensory ataxia. These features, coupled with diffuse hyperreflexia and absent Achilles reflexes, should always focus attention on the possibility of cobalamin deficiency (Pat­ terns 2 and 6; Table 457-2). Optic atrophy and, in severe cases, behav­ ioral changes ranging from mild irritability and forgetfulness to severe dementia and frank psychosis may appear. The full clinical picture of subacute combined degeneration is uncommon. CNS manifestations, especially pyramidal tract signs, may be missing, and in fact, some patients may only exhibit symptoms of peripheral neuropathy. PART 13 Neurologic Disorders EDx shows an axonal sensorimotor neuropathy. CNS involvement produces abnormal somatosensory and visual evoked potential laten­ cies. The diagnosis is confirmed by finding reduced serum cobalamin levels. In up to 40% of patients, anemia and macrocytosis are lacking. Serum methylmalonic acid and homocysteine, the metabolites that accumulate when cobalamin-dependent reactions are blocked, are elevated. Antibodies to intrinsic factor are present in ~60% and anti­ parietal cell antibodies in ~90% of individuals with pernicious anemia. Cobalamin deficiency can be treated with various regimens of cobalamin. One typical regimen consists of 1000 μg cyanocobalamin IM weekly for 1 month and monthly thereafter. Patients with food cobalamin malabsorption can absorb free cobalamin and therefore can be treated with oral cobalamin supplementation. An oral cobalamin dose of 1000 μg/d should be sufficient. Treatment for cobalamin defi­ ciency usually does not completely reverse the clinical manifestations, and at least 50% of patients exhibit some permanent neurologic deficit. ■ ■THIAMINE DEFICIENCY Thiamine (vitamin B1) deficiency is an uncommon cause of peripheral neuropathy in developed countries. It is now most often seen as a con­ sequence of chronic alcohol abuse, recurrent vomiting, total parenteral nutrition, and bariatric surgery. Thiamine deficiency polyneuropathy can occur in normal, healthy young adults who do not abuse alcohol but who engage in inappropriately restrictive diets. Thiamine is watersoluble. It is present in most animal and plant tissues, but the greatest sources are unrefined cereal grains, wheat germ, yeast, soybean flour, and pork. Beriberi means “I can’t, I can’t” in Singhalese, the language of natives of what was once part of the Dutch East Indies (now Sri Lanka). Dry beriberi refers to neuropathic symptoms. The term wet beriberi is used when cardiac manifestations predominate (in reference to edema). Beriberi was relatively uncommon until the late 1800s when it became widespread among people for whom rice was a dietary main­ stay. This epidemic was due to a new technique of processing rice that removed the germ from the rice shaft, rendering the so-called polished rice deficient in thiamine and other essential nutrients. Symptoms of neuropathy follow prolonged deficiency. These begin with mild sensory loss and/or burning dysesthesias in the toes and feet and aching and cramping in the lower legs. Pain may be the pre­ dominant symptom. With progression, patients develop features of a nonspecific generalized polyneuropathy, with distal sensory loss in the feet and hands. Blood and urine assays for thiamine are not reliable for diagnosis of deficiency. Erythrocyte transketolase activity and the percent­ age increase in activity (in vitro) following the addition of thiamine pyrophosphate (TPP) may be more accurate and reliable. EDx shows nonspecific findings of an axonal sensorimotor polyneuropathy. When a diagnosis of thiamine deficiency is made or suspected, thiamine replacement should be provided until proper nutrition is restored. Thiamine is usually given intravenously or intramuscularly at a dose of 100 mg/d. Although cardiac manifestations show a striking response to thiamine replacement, neurologic improvement is usually more vari­ able and less dramatic. ■ ■VITAMIN E DEFICIENCY The term vitamin E is usually used for α-tocopherol, the most active of the four main types of vitamin E. Because vitamin E is present in animal fat, vegetable oils, and various grains, deficiency is usually due to factors other than insufficient intake. Vitamin E deficiency usually occurs secondary to lipid malabsorption or in uncommon disorders of vitamin E transport. One hereditary disorder is abetalipoproteinemia, a rare autosomal dominant disorder characterized by steatorrhea, pig­ mentary retinopathy, acanthocytosis, and progressive ataxia. Patients with cystic fibrosis may also have vitamin E deficiency secondary to steatorrhea. There are genetic forms of isolated vitamin E deficiency not associated with lipid malabsorption. Vitamin E deficiency may also occur as a consequence of various cholestatic and hepatobiliary disorders as well as short-bowel syndromes resulting from the surgical treatment of intestinal disorders. Clinical features may not appear until many years after the onset of deficiency. The onset of symptoms tends to be insidious, and progres­ sion is slow. The main clinical features are spinocerebellar ataxia and polyneuropathy, thus resembling Friedreich’s ataxia or other spinocer­ ebellar ataxias. Patients manifest progressive ataxia and signs of poste­ rior column dysfunction, such as impaired joint position and vibratory sensation. Because of the polyneuropathy, there is hyporeflexia, but plantar responses may be extensor as a result of the spinal cord involve­ ment (Patterns 2 and 6; Table 457-2). Other neurologic manifestations may include ophthalmoplegia, pigmented retinopathy, night blindness, dysarthria, pseudoathetosis, dystonia, and tremor. Vitamin E defi­ ciency may present as an isolated polyneuropathy, but this is very rare. The yield of checking serum vitamin E levels in patients with isolated polyneuropathy is extremely low, and this test should not be part of routine practice. Diagnosis is made by measuring α-tocopherol levels in the serum. EDx shows features of an axonal neuropathy. Treatment is replacement with oral vitamin E, but high doses are not needed. For patients with isolated vitamin E deficiency, treatment consists of 1500–6000 IU/d in divided doses. ■ ■VITAMIN B6 DEFICIENCY Vitamin B6, or pyridoxine, can produce neuropathic manifestations from both deficiency and toxicity. Vitamin B6 toxicity was discussed above. Vitamin B6 deficiency is most commonly seen in patients treated with isoniazid or hydralazine. The polyneuropathy of vitamin B6 is nonspe­ cific, manifesting as a generalized axonal sensorimotor polyneuropathy. Vitamin B6 deficiency can be detected by direct assay. Vitamin B6 supple­ mentation with 50–100 mg/d is suggested for patients being treated with isoniazid or hydralazine. This same dose is appropriate for replacement in cases of nutritional deficiency. ■ ■PELLAGRA (NIACIN DEFICIENCY) Pellagra is produced by deficiency of niacin. Although pellagra may be seen in alcoholics, this disorder has essentially been eradicated in most Western countries by means of enriching bread with niacin. Neverthe­ less, pellagra continues to be a problem in a number of underdeveloped regions, particularly in Asia and Africa, where corn is the main source of carbohydrate. Neurologic manifestations are variable; abnormalities can develop in the brain and spinal cord as well as peripheral nerves. When peripheral nerves are involved, the neuropathy is usually mild and resembles beriberi. Treatment is with niacin 40–250 mg/d. ■ ■COPPER DEFICIENCY A syndrome that has only recently been described is myeloneuropathy secondary to copper deficiency (see also Chap. 453). Most patients present with lower limb paresthesias, weakness, spasticity, and gait difficulties (Pattern 6; Table 457-2). Large-fiber sensory function is impaired, reflexes are brisk, and plantar responses are extensor. In some cases, light touch and pinprick sensation are affected, and NCS indicate sensorimotor axonal polyneuropathy in addition to myelopathy. Hematologic abnormalities are a known complication of copper deficiency; these can include microcytic anemia, neutropenia, and occasionally pancytopenia. Because copper is absorbed in the stomach and proximal jejunum, many cases of copper deficiency occur in the setting of prior gastric surgery. Excess zinc is an established cause of copper deficiency. Zinc upregulates enterocyte production of metallo­ thionine, which results in decreased absorption of copper. Excessive dietary zinc supplements or denture cream containing zinc can pro­ duce this clinical picture. Other potential causes of copper deficiency include malnutrition, prematurity, total parenteral nutrition, and ingestion of copper-chelating agents. Following oral or IV copper replacement, some patients show neu­ rologic improvement, but this may take many months or not occur at all. Replacement consists of oral copper sulfate or gluconate 2 mg one to three times a day. If oral copper replacement is not effective, elemen­ tal copper in the copper sulfate or copper chloride forms can be given as 2 mg IV daily for 3–5 days, then weekly for 1–2 months until copper levels normalize. Thereafter, oral daily copper therapy can be resumed. In contrast to the neurologic manifestations, most of the hematologic indices normalize in response to copper replacement therapy. ■ ■NEUROPATHY ASSOCIATED WITH GASTRIC SURGERY Polyneuropathy may occur following gastric surgery for ulcer, cancer, or weight reduction. This usually occurs in the context of rapid, sig­ nificant weight loss and recurrent, protracted vomiting. The clinical picture is one of acute or subacute sensory loss and weakness. Neu­ ropathy following weight loss surgery usually occurs in the first several months after surgery. Weight reduction surgical procedures include gastrojejunostomy, gastric stapling, vertical banded gastroplasty, and gastrectomy with Roux-en-Y anastomosis. The initial manifestations are usually numbness and paresthesias in the feet (Pattern 2; Table 457-2). In many cases, no specific nutritional deficiency factor is identified. Management consists of parenteral vitamin supplementation, espe­ cially including thiamine. Improvement has been observed following supplementation, parenteral nutritional support, and reversal of the surgical bypass. The duration and severity of deficits before identifi­ cation and treatment of neuropathy are important predictors of final outcome. CRYPTOGENIC (IDIOPATHIC) SENSORY AND SENSORIMOTOR POLYNEUROPATHY Cryptogenic (idiopathic) sensory and sensorimotor polyneuropathy (CSPN) is a diagnosis of exclusion, established after a careful medical, family, and social history; neurologic examination; and directed labora­ tory testing. Despite extensive evaluation, the cause of polyneuropathy in as many as 50% of all patients is idiopathic. CSPN should be consid­ ered a distinct diagnostic subset of peripheral neuropathy. The onset of CSPN is predominantly in the sixth and seventh decades. Patients complain of distal numbness, tingling, and often burning pain that invariably begins in the feet and may eventually involve the fingers and hands (“burning feet syndrome”). Patients exhibit a distal sensory loss to pinprick, touch, and vibration in the toes and feet, and occasionally in the fingers (Pattern 2; Table 457-2). It is uncommon to see signifi­ cant proprioception deficits, even though patients may complain of gait unsteadiness. However, tandem gait may be abnormal in a minority of cases. Neither subjective nor objective evidence of weakness is a promi­ nent feature. Most patients have evidence of both large- and smallfiber loss on neurologic examination and EDx. Approximately 10% of patients have only evidence of small-fiber involvement. The ankle muscle stretch reflex is frequently absent, but in cases with predomi­ nantly small-fiber loss, this may be preserved. The EDx findings range from isolated SNAP abnormalities (usually with loss of amplitude), to evidence for an axonal sensorimotor neuropathy, to a completely normal study (if primarily small fibers are involved). Therapy primar­ ily involves the control of neuropathic pain (Table 457-6) if present. A large comparative effectiveness study in CSPN showed that the drugs nortriptyline and duloxetine outperformed pregabalin and mexiletine. These drugs should not be used if the patient has only numbness and tingling but no pain. Although no treatment is available that can reverse an idiopathic distal peripheral neuropathy, the prognosis is good. Progression often does not occur or is minimal, with sensory symptoms and signs pro­ gressing proximally up to the knees and elbows. The disorder does not lead to significant motor disability over time. The relatively benign course of this disorder should be explained to patients. MONONEUROPATHIES/PLEXOPATHIES/ RADICULOPATHIES (PATTERN 3; TABLE 457-2) ■ ■MEDIAN NEUROPATHY CTS is a compression of the median nerve in the carpal tunnel at the wrist. The median nerve enters the hand through the carpal tunnel by coursing under the transverse carpal ligament. The symptoms of CTS consist of numbness and paresthesias variably in the thumb, index, middle, and half of the ring finger. At times, the paresthesias can include the entire hand and extend into the forearm or upper arm or can be isolated to one or two fingers. Pain is another common symp­ tom and can be located in the hand and forearm and, at times, in the proximal arm. CTS is common and often misdiagnosed as thoracic outlet syndrome. The signs of CTS are decreased sensation in the median nerve distribution; reproduction of the sensation of tingling when a percussion hammer is tapped over the wrist (Tinel sign) or the wrist is flexed for 30–60 s (Phalen sign); and weakness of thumb oppo­ sition and abduction. EDx is extremely sensitive and shows slowing of sensory and, to a lesser extent, motor median potentials across the wrist. Ultrasound can show focal swelling of the median nerve at the wrist. Treatment options consist of avoidance of precipitating activi­ ties; control of underlying systemic-associated conditions if present; nonsteroidal anti-inflammatory medications; neutral (volar) position wrist splints, especially for night use; glucocorticoid/anesthetic injec­ tion into the carpal tunnel; and surgical decompression by dividing the transverse carpal ligament. The surgical option should be considered if there is a poor response to nonsurgical treatments; if there is thenar muscle atrophy and/or weakness; and if there are significant denerva­ tion potentials on EMG. CHAPTER 457 Peripheral Neuropathy Other proximal median neuropathies are very uncommon and include the pronator teres syndrome and anterior interosseous neu­ ropathy. These often occur as a partial form of brachial plexitis. ■ ■ULNAR NEUROPATHY AT THE ELBOW—“CUBITAL TUNNEL SYNDROME” The ulnar nerve passes through the condylar groove between the medial epicondyle and the olecranon. Symptoms consist of paresthe­ sias, tingling, and numbness in the medial hand and half of the fourth and the entire fifth fingers, pain at the elbow or forearm, and weakness. Signs consist of decreased sensation in an ulnar distribution, Tinel’s sign at the elbow, and weakness and atrophy of ulnar-innervated hand muscles. The Froment sign indicates thumb adductor weakness and consists of flexion of the thumb at the interphalangeal joint when attempting to oppose the thumb against the lateral border of the second digit. EDx may show slowing of ulnar motor NCV across the elbow with prolonged ulnar sensory latencies. Ultrasound can show swell­ ing of the ulnar nerve around the elbow as well. Treatment consists of avoiding aggravating factors, using elbow pads, and surgery to decom­ press the nerve in the cubital tunnel. Ulnar neuropathies can also rarely occur at the wrist in the ulnar (Guyon) canal or in the hand, usually after trauma. ■ ■RADIAL NEUROPATHY The radial nerve winds around the proximal humerus in the spiral groove and proceeds down the lateral arm and enters the forearm, dividing into the posterior interosseous nerve and superficial nerve. The symptoms and signs consist of wrist drop; finger extension weak­ ness; thumb abduction weakness; and sensory loss in the dorsal web between the thumb and index finger. Triceps and brachioradialis strength is often normal, and triceps reflex is often intact. Most cases of radial neuropathy are transient compressive (neuropraxic) injuries that recover spontaneously in 6–8 weeks. If there has been prolonged compression and severe axonal damage, it may take several months to recover. Treatment consists of cock-up wrist and finger splints, avoiding further compression, and physical therapy to avoid flexion contracture. If there is no improvement in 2–3 weeks, an EDx study is recommended to confirm the clinical diagnosis and determine the degree of severity. ■ ■LATERAL FEMORAL CUTANEOUS NEUROPATHY (MERALGIA PARESTHETICA) The lateral femoral cutaneous nerve arises from the upper lumbar plexus (spinal levels L2/3), crosses through the inguinal ligament near its attachment to the iliac bone, and supplies sensation to the anterior lateral thigh. The neuropathy affecting this nerve is also known as meralgia paresthetica. Symptoms and signs consist of paresthesias, numbness, and occasionally pain in the lateral thigh. Symptoms are increased by standing or walking and are relieved by sitting. There is normal strength, and knee reflexes are intact. The diagnosis is clinical, and further tests usually are not performed. EDx is only needed to rule out lumbar plexopathy, radiculopathy, or femoral neuropathy. If the symptoms and signs are classic, EMG is not necessary. Symptoms often resolve spontaneously over weeks or months, but the patient may be left with permanent numbness. Treatment consists of weight loss and avoiding tight belts. Analgesics in the form of a lidocaine patch, nonsteroidal agents, and occasionally medications for neuropathic pain can be used (Table 457-6). Rarely, locally injecting the nerve with an anesthetic can be tried. There is no role for surgery. PART 13 Neurologic Disorders ■ ■FEMORAL NEUROPATHY Femoral neuropathies can arise as complications of retroperitoneal hematoma, lithotomy positioning, hip arthroplasty or dislocation, iliac artery occlusion, femoral arterial procedures, infiltration by hematog­ enous malignancy, penetrating groin trauma, pelvic surgery including hysterectomy and renal transplantation, and diabetes (a partial form of lumbosacral diabetic plexopathy); some cases are idiopathic. Patients with femoral neuropathy have difficulty extending their knee and flexing the hip. Sensory symptoms occurring either on the anterior thigh and/or medial leg occur in only half of reported cases. A promi­ nent painful component is the exception rather than the rule, may be delayed, and is often self-limited in nature. The quadriceps (patellar) reflex is diminished. ■ ■SCIATIC NEUROPATHY Sciatic neuropathies commonly complicate hip arthroplasty, pelvic procedures in which patients are placed in a prolonged lithotomy posi­ tion, trauma, hematomas, tumor infiltration, and vasculitis. In addi­ tion, many sciatic neuropathies are idiopathic. Weakness may involve all motions of the ankles and toes as well as flexion of the leg at the knee; abduction and extension of the thigh at the hip are spared. Sen­ sory loss occurs in the entire foot and the distal lateral leg. The ankle jerk and, on occasion, the internal hamstring reflex are diminished or more typically absent on the affected side. The peroneal subdivi­ sion of the sciatic nerve is typically involved disproportionately to the tibial counterpart. Thus, patients may have only ankle dorsiflexion and eversion weakness with sparing of knee flexion, ankle inversion, and plantar flexion; these features can lead to misdiagnosis of a common peroneal neuropathy. PERONEAL NEUROPATHY The sciatic nerve divides at the distal femur into the tibial and pero­ neal nerve. The common peroneal nerve passes posterior and laterally around the fibular head, under the fibular tunnel. It then divides into the superficial peroneal nerve, which supplies the ankle evertor mus­ cles and sensation over the anterolateral distal leg and dorsum of the foot, and the deep peroneal nerve, which supplies ankle dorsiflexors and toe extensor muscles and a small area of sensation dorsally in the area of the first and second toes. Symptoms and signs consist of foot drop (ankle dorsiflexion, toe extension, and ankle eversion weakness) and variable sensory loss, which may involve the superficial and deep peroneal pattern. There is usually no pain. Onset may be on awakening in the morning. Peroneal neuropathy needs to be distinguished from L5 radiculopathy. In L5 radiculopathy, ankle invertors and evertors are weak and needle EMG reveals denervation. EDx can help localize the lesion. Peroneal motor conduction velocity shows slowing and amplitude drop across the fibular head. Management consists of rapid weight loss and avoiding leg crossing. Foot drop is treated with an ankle brace. A knee pad can be worn over the lateral knee to avoid further compression. Most cases spontaneously resolve over weeks or months. RADICULOPATHIES Radiculopathies are most often due to compression from degenerative joint disease and herniated disks, but there are a number of unusual etiologies (Table 457-9). Degenerative spine disease affects a num­ ber of different structures, which narrow the diameter of the neural foramen or canal of the spinal column and compromise nerve root integrity; these are discussed in detail in Chaps. 18 and 19. PLEXOPATHIES (PATTERN 4; TABLE 457-2) ■ ■BRACHIAL PLEXUS The brachial plexus is composed of three trunks (upper, middle, and lower), with two divisions (anterior and posterior) per trunk (Fig. 457-2). Subsequently, the trunks divide into three cords (medial, lateral, and posterior), and from these, arise the multiple terminal nerves innervating the arm. The anterior primary rami of C5 and C6 fuse to form the upper trunk; the anterior primary ramus of C7 continues as the middle trunk, while the anterior rami of C8 and T1 join to form the lower trunk. There are several disorders commonly associated with brachial plexopathy. Immune-Mediated Brachial Plexus Neuropathy  Immunemediated brachial plexus neuropathy (IBPN) goes by various terms, including acute brachial plexitis, neuralgic amyotrophy, and ParsonageTurner syndrome. IBPN usually presents with an acute onset of severe pain in the shoulder region. The intense pain usually lasts several days to a few weeks, but a dull ache can persist. Individuals who are affected may not appreciate weakness of the arm early in the course because the pain limits movement. However, as the pain dissipates, weakness and often sensory loss are appreciated. Attacks can occasionally recur. Clinical findings are dependent on the distribution of involvement (e.g., specific trunk, divisions, cords, or terminal nerves). The most TABLE 457-9  Causes of Radiculopathy • Herniated nucleus pulposus • Degenerative joint disease • Rheumatoid arthritis • Trauma • Vertebral body compression fracture • Pott’s disease (tuberculosis) • Compression by extradural mass (e.g., meningioma, metastatic tumor, hematoma, abscess) • Primary nerve tumor (e.g., neurofibroma, schwannoma, neurinoma) • Carcinomatous meningitis • Perineurial spread of tumor (e.g., prostate cancer) • Acute inflammatory demyelinating polyradiculopathy • Chronic inflammatory demyelinating polyradiculopathy • Sarcoidosis • Amyloidoma • Diabetic radiculopathy • Infection (Lyme disease, herpes zoster, HIV, cytomegalovirus, syphilis, schistosomiasis, Strongyloides) • Arachnoiditis (e.g., postsurgical) • Radiation Upper subscapular L Axillary Musculocutaneous Radial P Median Ulnar Medial antibrachial cutaneous Thoracodorsal Lower subscapular Medial brachial cutaneous CORDS PERIPHERAL NERVES DIVISIONS TRUNKS ROOTS Anterior Posterior FIGURE 457-2  Brachial plexus anatomy. L, lateral; M, medial; P, posterior. (Reproduced with permission J Goodgold: Anatomical Correlates of Clinical Electromyography. Baltimore, Williams and Wilkins, 1974.) common pattern of IBPN involves the upper trunk or a single or multiple mononeuropathies primarily involving the suprascapular, long thoracic, or axillary nerves. Additionally, the phrenic and ante­ rior interosseous nerves may be concomitantly affected. Any of these nerves may also be affected in isolation. EDx is useful to confirm and localize the site(s) of involvement. Empirical treatment of severe pain with glucocorticoids is often used in the acute period. Brachial Plexopathies Associated with Neoplasms  Neo­ plasms involving the brachial plexus may be primary nerve tumors, local cancers expanding into the plexus (e.g., Pancoast lung tumor or lymphoma), and metastatic tumors. Primary brachial plexus tumors are less common than the secondary tumors and include schwanno­ mas, neurinomas, and neurofibromas. Secondary tumors affecting the brachial plexus are more common and are always malignant. These may arise from local tumors, expanding into the plexus. For example, a Pancoast tumor of the upper lobe of the lung may invade or compress the lower trunk, whereas a primary lymphoma arising from the cervi­ cal or axillary lymph nodes may also infiltrate the plexus. Pancoast tumors typically present as an insidious onset of pain in the upper arm, sensory disturbance in the medial aspect of the forearm and hand, and weakness and atrophy of the intrinsic hand muscles along with an ipsilateral Horner’s syndrome. Chest computed tomography (CT) scans or MRI can demonstrate extension of the tumor into the plexus. Metastatic involvement of the brachial plexus may occur with spread of breast cancer into the axillary lymph nodes and local spread into the nearby nerves. Perioperative Plexopathies (Median Sternotomy)  The most common surgical procedures associated with brachial plexopathy as a complication are those that involve median sternotomies (e.g., openheart surgeries and thoracotomies). Brachial plexopathies occur in as many as 5% of patients following a median sternotomy and typically affect the lower trunk. Thus, individuals manifest with sensory dis­ turbance affecting the medial aspect of forearm and hand along with weakness of the intrinsic hand muscles. The mechanism is related to the stretch of the lower trunk, so most individuals who are affected recover within a few months. Lumbosacral Plexus  The lumbar plexus arises from the ventral primary rami of the first to the fourth lumbar spinal nerves (Fig. 457-3). These nerves pass downward and laterally from the vertebral column within the psoas major muscle. The femoral nerve derives from the dorsal branches of the second to the fourth lumbar ventral rami. The obturator nerve arises from the ventral branches of the same lumbar Dorsal scapular Lateral anterior thoracic Suprascapular C5 C6 Subclavius C7 C8 M Medial anterior thoracic T1 Long thoracic CHAPTER 457 Peripheral Neuropathy rami. The lumbar plexus communicates with the sacral plexus by the lumbosacral trunk, which contains some fibers from the fourth and all of the fibers from the fifth lumbar ventral rami (Fig. 457-4). The sacral plexus is the part of the lumbosacral plexus that is formed by the union of the lumbosacral trunk with the ventral rami of the first to fourth sacral nerves. The plexus lies on the posterior and postero­ lateral wall of the pelvis with its components converging toward the sciatic notch. The lateral trunk of the sciatic nerve (which forms the common peroneal nerve) arises from the union of the dorsal branches of the lumbosacral trunk (L4, L5) and the dorsal branches of the S1 and S2 spinal nerve ventral rami. The medial trunk of the sciatic nerve (which forms the tibial nerve) derives from the ventral branches of the same ventral rami (L4-S2). ■ ■LUMBOSACRAL PLEXOPATHIES Plexopathies are typically recognized when motor, sensory, and if applicable, reflex deficits occur in multiple nerve and segmental distributions confined to one extremity. If localization within the lumbosacral plexus can be accomplished, designation as a lumbar plexopathy, a sacral plexopathy, a lumbosacral trunk lesion, or a panplexopathy is the best localization that can be expected. Although lumbar plexopathies may be bilateral, usually occurring in a stepwise and chronologically dissociated manner, sacral plexopathies are more likely to behave in this manner due to their closer anatomic proxim­ ity. The differential diagnosis of plexopathy includes disorders of the conus medullaris and cauda equina (polyradiculopathy). If there is a paucity of pain and sensory involvement, motor neuron disease should be considered as well. The causes of lumbosacral plexopathies are listed in Table 457-10. Diabetic radiculopathy (discussed above) is a fairly common cause of painful leg weakness. Lumbosacral plexopathies are a well-recognized complication of retroperitoneal hemorrhage. Various primary and metastatic malignancies can affect the lumbosacral plexus as well; these include carcinoma of the cervix, endometrium, and ovary; osteosar­ coma; testicular cancer; MM; lymphoma; acute myelogenous leukemia; colon cancer; squamous cell carcinoma of the rectum; adenocarcinoma of unknown origin; and intraneural spread of prostate cancer. ■ ■RECURRENT NEOPLASTIC DISEASE OR RADIATION-INDUCED PLEXOPATHY The treatment for various malignancies is often radiation therapy, the field of which may include parts of the brachial plexus. It can be difficult in such situations to determine if a new brachial or lum­ bosacral plexopathy is related to tumor within the plexus or from L1 L2 Genitofemoral nerve IIiohypogastric nerve L3 IIioinguinal nerve Lateral cutaneous nerve of thigh To lliacus and psoas muscles L4 Obturator nerve L5 Femoral nerve Lumbo-sacral trunk S1 S2 S3 Gluteal nerves PART 13 Neurologic Disorders S4 Pudendal nerve Sciatic nerve Post. cutaneous nerve of thigh FIGURE 457-3  Lumbosacral plexus. (Reproduced with permission from AA Amato, JA Russell (eds): Neuromuscular Disorders, 2nd ed. New York: McGraw-Hill Education; 2016.) PLEXUS ROOTS DIVISIONS (From anterior primary divisions) (Posterior [black] and anterior) TERMINAL AND COLLATERAL BRANCHES BRANCHES FROM POSTERIOR DIVISIONS (To lumbar plexus) (Lumbosacral trunk) Superior gluteal nerve (L4, 5, S1) Nerves to piriformis (S1, 2) Inferior gluteal nerve (L5, S1, 2) BRANCH FROM BOTH ANTERIOR AND POSTERIOR DIVISIONS Posterior femoral cutaneous nerve (S1, 2, 3) Sciatic nerve (To pudendal plexus) Inferior medial clunial nerve (S2, 3) Common peroneal nerve BRANCHES FROM ANTERIOR DIVISIONS Tibial nerve To quadratus femons and gemellus inferior muscles L4, 5, S1 (To hamstring muscles) L5, S1, 2 To obturator internus and gemellus superior muscles FIGURE 457-4  Lumbosacral trunk sacral plexus and sciatic nerve. (Reproduced with permission from AA Amato, JA Russell (eds): Neuromuscular Disorders, 2nd ed. New York: McGraw-Hill Education; 2016.) TABLE 457-10  Lumbosacral Plexopathies: Etiologies • Retroperitoneal hematoma • Psoas abscess • Malignant neoplasm • Benign neoplasm • Radiation • Amyloid • Diabetic radiculoplexus neuropathy • Idiopathic radiculoplexus neuropathy • Sarcoidosis • Aortic occlusion/surgery • Lithotomy positioning • Hip arthroplasty • Pelvic fracture • Obstetric injury radiation-induced nerve damage. Radiation can be associated with microvascular abnormalities and fibrosis of surrounding tissues, which can damage the axons and the Schwann cells. Radiation-induced plexopathy can develop months or years following therapy and is dose dependent. Tumor invasion is usually painful and more commonly affects the lower trunk, whereas radiation injury is often painless and affects the upper trunk. Imaging studies such as MRI and CT scans are useful but can be misleading, especially when there is small microscopic inva­ sion of the plexus. EMG can be informative if myokymic discharges are appreciated, as this finding strongly suggests radiation-induced damage. ■ ■EVALUATION AND TREATMENT OF PLEXOPATHIES Most patients with plexopathies will undergo both imaging with MRI and EDx evaluations. Severe pain from acute idiopathic lumbosacral plexopathy may respond to a short course of glucocorticoids. ■ ■FURTHER READING Amato AA, Ropper AH: Sensory ganglionopathy. N Engl J Med L4 383:1657, 2020. Amato AA, Russell J: Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill, 2016. Barohn RJ, Amato AA: Pattern-recognition approach to neuropathy L5 and neuronopathy. Neurol Clin 31:343, 2013. Barohn RJ et al: Patient Assisted Intervention for Neuropathy: Com­ S1 parison of Treatment in Real Life Situations (PAIN-CONTRoLS) Bayesian adaptive comparative effectiveness randomized trial. JAMA Neurol 78:68, 2021. Cortese A et al: Biallelic mutations in SORD cause a common and S2 potentially treatable hereditary neuropathy with implications for diabetes. Nat Genet 52:473, 2020. [Published correction appears in Nat Genet 52:640, 2020.] Cortese A et al: Cerebellar ataxia, neuropathy and vestibular areflexia S3 syndrome (CANVAS): Genetic and clinical aspects. Pract Neurol 22:14, 2022. Elafros MA et al: Towards prevention of diabetic peripheral neuropa­ thy: Clinical presentation, pathogenesis, and new treatments. Lancet Neurol 21:922, 2022. Hobson-Webb LD, Juel VC: Common entrapment neuropathies. Continuum (Minneap Minn) 23:487, 2017. Ioannou A et al: RNA Targeting and gene editing strategies for trans­ thyretin amyloidosis. BioDrugs 37:127, 2023. Jin PH, Shin SC: Neuropathy of connective tissue diseases and other systemic diseases. Semin Neurol 39:651, 2019. Klein CJ: Charcot-Marie-Tooth disease and other hereditary neuropa­ thies. Continuum (Minneap Minn) 26:1224, 2020. # 29 - 458 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies ### 458 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies Stephen L. Hauser, Anthony A. Amato GUILLAIN-BARRÉ SYNDROME Guillain-Barré syndrome (GBS) is an acute, frequently severe, and fulminant polyradiculoneuropathy that is autoimmune in nature. It occurs year-round at a rate of between 10 and 20 cases per million annually; in the United States, ~5000–6000 cases occur per year. Males are at slightly higher risk for GBS than females, and in Western coun­ tries, adults are more frequently affected than children. Clinical Manifestations  GBS manifests as a rapidly evolving areflexic motor paralysis with or without sensory disturbance. The usual pattern is an ascending paralysis that may be first noticed as rubbery legs. Weakness typically evolves over hours to a few days and is frequently accompanied by tingling dysesthesias in the extremities. The legs are usually more affected than the arms, and facial diparesis is present in 50% of affected individuals. The lower cranial nerves are also frequently involved, causing bulbar weakness with difficulty handling secretions and maintaining an airway; the diagnosis in these patients may initially be mistaken for brainstem ischemia. Pain in the neck, shoulder, back, or diffusely over the spine is also common in the early stages of GBS, occurring in ~50% of patients. Most patients require hospitalization, and in different series, up to 30% require ventilatory assistance at some time during the illness. The need for mechanical ventilation is associated with more severe weakness on admission, a rapid tempo of progression, and the presence of facial and/or bulbar weakness during the first week of symptoms. Fever and constitutional symptoms are absent at the onset and, if present, cast doubt on the diagnosis. Deep tendon reflexes attenuate or disappear within the first few days of onset. Cutaneous sensory deficits (e.g., loss of pain and temperature sensation) are usually relatively mild, but functions subserved by large sensory fibers, such as deep tendon reflexes and proprioception, are more severely affected. Bladder dysfunction may occur in severe cases but is usually transient. If bladder dysfunction is a prominent feature and comes early in the course or there is a sensory level on examination, diagnostic possibilities other than GBS should be considered, particularly spinal cord disease (Chap. 453). Once clini­ cal worsening stops and the patient reaches a plateau (almost always within 4 weeks of onset), further progression is unlikely. Autonomic involvement is common and may occur even in patients whose GBS is otherwise mild. The usual manifestations are loss of vasomotor control with wide fluctuations in blood pressure, postural hypotension, and cardiac dysrhythmias. These features require close monitoring and management and can be fatal. Pain is another common TABLE 458-1  Subtypes of Guillain-Barré Syndrome (GBS) SUBTYPE FEATURES ELECTRODIAGNOSIS PATHOLOGY Acute inflammatory demyelinating polyneuropathy (AIDP) Adults affected more than children; 90% of cases in Western world; recovery rapid; anti-GM1 antibodies (<50%) Acute motor axonal neuropathy (AMAN) Children and young adults; prevalent in China and Mexico; may be seasonal; recovery rapid; anti-GD1a antibodies Acute motor sensory axonal neuropathy (AMSAN) Mostly adults; uncommon; recovery slow, often incomplete; closely related to AMAN Miller Fisher syndrome (MFS) Adults and children; ophthalmoplegia, ataxia, and areflexia; anti-GQ1b antibodies (90%) feature of GBS; in addition to the acute pain described above, a deep aching pain may be present in weakened muscles that patients liken to having overexercised the previous day. Other pains in GBS include dysesthetic pain in the extremities as a manifestation of sensory nerve fiber involvement. These pains are self-limited and often respond to standard analgesics (Chap. 14). Several subtypes of GBS are recognized, as determined primarily by electrodiagnostic (EDx) and pathologic distinctions (Table 458-1). The most common variant is acute inflammatory demyelinating poly­ neuropathy (AIDP). Additionally, there are two “axonal” or “nodal/ paranodal” variants, which are often clinically severe: the acute motor axonal neuropathy (AMAN) and acute motor sensory axonal neuropa­ thy (AMSAN) subtypes. In addition, a range of limited or regional GBS syndromes are also encountered. Notable among these is the Miller Fisher syndrome (MFS), which presents as rapidly evolving ataxia and areflexia of limbs without weakness, and ophthalmoplegia, often with pupillary paralysis. The MFS variant accounts for ~5% of all cases and is strongly associated with antibodies to the ganglioside GQ1b (see “Immunopathogenesis,” below). Other regional variants of GBS include (1) pure sensory forms; (2) ophthalmoplegia with anti-GQ1b antibodies as part of severe motor-sensory GBS; (3) GBS with severe bulbar and facial paralysis, sometimes associated with antecedent cyto­ megalovirus (CMV) infection and anti-GM2 antibodies; and (4) acute pandysautonomia (Chap. 451). Antecedent Events  Approximately 70% of cases of GBS occur 1–3 weeks after an acute infectious process, usually respiratory or gastroin­ testinal. Culture and seroepidemiologic techniques show that 20–30% of all cases occurring in North America, Europe, and Australia are pre­ ceded by infection or reinfection with Campylobacter jejuni. A similar proportion is preceded by a human herpes virus infection, often CMV or Epstein-Barr virus. Other viruses (e.g., HIV, hepatitis E, Zika) and also Mycoplasma pneumoniae have been identified as agents involved in antecedent infections. Cases of GBS have been reported in associa­ tion with SARS-CoV-2 infection during the COVID-19 pandemic, but a causal relationship has not been established. CHAPTER 458 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies C. jejuni has also been implicated in summer outbreaks of AMAN among children and young adults exposed to chickens in rural China, as has infection by Zika virus in the increased incidence of GBS in Brazil and other endemic regions. Recent immunizations have also been implicated in GBS. The swine influenza vaccine, administered widely in the United States in 1976, is the most notable example. Influenza vaccines in use from 1992 to 1994, however, resulted in only one additional case of GBS per million persons vaccinated, and the more recent seasonal influenza vaccines appear to confer a GBS risk of <1 per million. Epidemiologic stud­ ies looking at H1N1 vaccination demonstrated at most only a slight increased risk of GBS. There appears to be an increased risk of GBS with SARS-CoV-2 vaccines using adenovirus vectors, but not the mes­ senger RNA vaccines. Meningococcal vaccinations (Menactra) do not appear to carry an increased risk. Older-type rabies vaccine, prepared in nervous system tissue, is implicated as a trigger of GBS in developing countries where it is still used; the mechanism is presumably immuni­ zation against neural antigens. Demyelinating First attack on Schwann cell surface; widespread myelin damage, macrophage activation, and lymphocytic infiltration; variable secondary axonal damage Axonal First attack at motor nodes of Ranvier; macrophage activation, few lymphocytes, frequent periaxonal macrophages; extent of axonal damage highly variable Axonal Same as AMAN, but also affects sensory nerves and roots; axonal damage usually severe Axonal or demyelinating Few cases examined; resembles AIDP GBS also occurs more frequently than can be attributed to chance alone in patients with lymphoma (including Hodgkin’s disease), in HIV-seropositive individuals, and in patients with systemic lupus ery­ thematosus (SLE) and possibly Sjogren’s syndrome. GBS, other inflam­ matory neuropathies, and myositis can also occur as a complication of immune checkpoint inhibitors used to treat various cancers. Immunopathogenesis  Several lines of evidence support an auto­ immune basis for AIDP, the most common and best-studied type of GBS; the concept extends to all of the subtypes of GBS (Table 458-1). It is likely that both cellular and humoral immune mechanisms contribute to tissue damage in AIDP. AIDP is also closely analogous to an experimental T cell–mediated immunopathy designated experi­ mental allergic neuritis (EAN). EAN is induced in laboratory animals by immune sensitization against protein fragments derived from peripheral nerve proteins and, in particular, against the P2 protein. Based on analogy to EAN, it was initially thought that AIDP was also likely to have a T cell–mediated pathogenesis, and consistent with this concept, autoreactive T cells against several peripheral myelin proteins have recently been identified in peripheral blood, cerebrospinal fluid (CSF), and infiltrating nerves from AIDP patients. However, abundant data also indicate that autoantibodies directed against T cell–independent nonprotein determinants may be the central mediators in many cases. Involvement of the humoral arm of the immune system in AIDP is supported by the demonstration of terminal complement complex on Schwann cells in autopsy series and induction of complementdependent demyelination and conduction block following injection of serum from patients with GBS into nerves of animals. In AMAN, there is deposition of IgG and complement activation products on the nodal and internodal axolemma of motor fibers. PART 13 Neurologic Disorders Circumstantial evidence suggests that all GBS results from immune responses to nonself antigens (infectious agents, vaccines) that misdirect o t s e i d o b it n a o t u a G g I s t n a ir a v d n a s e p y t b u S Guillain-Barré syndrome Acute inflammatory demyelinating polyneuropathy Facial variant: Facial diplegia and paresthesia Acute motor axonal neuropathy More and less extensive forms Acute motor-sensory axonal neuropathy Acute motor-conduction-block neuropathy Pharyngeal-cervical-brachial weakness Miller Fisher syndrome Incomplete forms Acute ophthalmoparesis (without ataxia) Acute ataxic neuropathy (without ophthalmoplegia) CNS variant: Bickerstaff’s brainstem encephalitis Cer GM1 KEY Galactose Glucose N-Acetylgalactosamine N-Acetylneuraminic acid Ceramide Cer Cer GD1a FIGURE 458-1  Spectrum of disorders in Guillain-Barré syndrome and associated antiganglioside antibodies. IgG autoantibodies against GM1 or GD1a are strongly associated with acute motor axonal neuropathy (AMAN), as well as the more extensive acute motor-sensory axonal neuropathy (AMSAN), and the less extensive acute motor-conduction-block neuropathy. IgG anti-GQ1b antibodies, which cross-react with GT1a, are strongly associated with Miller Fisher syndrome, its incomplete forms (acute ophthalmoparesis [without ataxia] and acute ataxic neuropathy [without ophthalmoplegia]), and its more extensive form, Bickerstaff’s brainstem encephalitis. Pharyngeal-cervical-brachial weakness is categorized as a localized form of acute motor axonal neuropathy or an extensive form of Miller Fisher syndrome. Half of patients with pharyngeal-cervical-brachial weakness have IgG anti-GT1a antibodies, which often cross-react with GQ1b. IgG anti-GD1a antibodies have also been detected in a small percentage of patients. The anti-GQ1b antibody syndrome includes Miller Fisher syndrome, acute ophthalmoparesis, acute ataxic neuropathy, Bickerstaff’s brainstem encephalitis, and pharyngeal-cervical-brachial weakness. The presence of clinical overlap also indicates that Miller Fisher syndrome is part of a continuous spectrum with these conditions. Patients who have had Guillain-Barré syndrome overlapped with Miller Fisher syndrome or with its related conditions have IgG antibodies against GM1 or GD1a as well as against GQ1b or GT1a, supporting a link between AMAN and anti-GQ1b syndrome. (From N Yuki, H-P Hartung: Guillain-Barré syndrome. N Engl J Med 366:2294, 2012. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.) to host nerve tissue through a resemblance-of-epitope (molecular mimicry) mechanism (Fig. 458-1). The neural targets are likely to be glycoconjugates, specifically gangliosides (Table 458-2; Fig. 458-2). Gangliosides are complex glycosphingolipids that contain one or more sialic acid residues; various gangliosides participate in cell-cell interactions (including those between axons and glia), modulation of receptors, and regulation of growth. They are typically exposed on the plasma membrane of cells, rendering them susceptible to an antibodymediated attack. Gangliosides and other glycoconjugates are present in large quantity in human nervous tissues and in key sites, such as nodes of Ranvier. Antiganglioside antibodies, most frequently to GM1, are common in GBS (20–50% of cases), particularly in AMAN and AMSAN, and in those cases, they are preceded by C. jejuni infection. Some AIDP autoantibodies may recognize glycolipid heterocomplexes, rather than single species, present on cell membranes. Furthermore, isolates of C. jejuni from stool cultures of patients with GBS have surface glycolipid structures that antigenically cross react with gan­ gliosides, including GM1, concentrated in human nerves. Sialic acid residues from pathogenic C. jejuni strains can also trigger activation of dendritic cells via signaling through Toll-like receptor 4 (TLR4), pro­ moting B-cell differentiation and further amplifying humoral autoim­ munity. Another line of evidence implicating humoral autoimmunity is derived from cases of GBS that followed intravenous administration of bovine brain gangliosides for treatment of various neuropathies; 5–15 days after injection, some recipients developed AMAN with high titers of anti-GM1 antibodies that recognized epitopes at nodes of Ranvier and motor endplates. Experimentally, anti-GM1 antibodies can trig­ ger complement-mediated injury at paranodal axon-glial junctions, disrupting the clustering of sodium channels and likely contributing to conduction block (see “Pathophysiology,” below). Anti-GQ1b IgG antibodies are found in >90% of patients with MFS (Table 458-2; Fig. 458-2), and titers of IgG are highest early in None None GM1, GD1a GM1, GD1a GM1, GD1a GT1a>GQ1b>>GD1a GQ1b, GT1a GQ1b, GT1a GQ1b, GT1a GQ1b, GT1a GT1a Cer GQ1b Cer TABLE 458-2  Principal Antiglycolipid Antibodies Implicated in Immune Neuropathies CLINICAL PRESENTATION ANTIBODY TARGET USUAL ISOTYPE Acute Immune Neuropathies (Guillain-Barré Syndrome) Acute inflammatory demyelinating polyneuropathy (AIDP) No clear patterns IgG (polyclonal) GM1 most common Acute motor axonal neuropathy (AMAN) GD1a, GM1, GM1b, GalNAc–GD1a (<50% for any) IgG (polyclonal) Miller Fisher syndrome (MFS) GQ1b (>90%) IgG (polyclonal) Acute pharyngeal cervicobrachial neuropathy (APCBN) GT1a (? most) IgG (polyclonal) Chronic Immune Neuropathies Chronic inflammatory demyelinating polyneuropathy (CIDP) (75%) Rarely to P0, myelin P2 protein, or PMP22 IgG, IgA CIDP-M (MGUS associated) (25%) Neural binding sites IgG, IgA (monoclonal) Anti-MAG neuropathy SGPG, SGLPG (on MAG) (50%) IgM (monoclonal) Uncertain (50%) IgM (monoclonal) Nodal/paranodal neuropathies Approximately 10% to CNTN1 or NF155, less often to NF140/186 and Caspr1 IgG4 with CNTN1, NF155, NF140/186, Caspr1 Rare IgM with NF155 Multifocal motor neuropathy (MMN) GM1, GalNAc–GD1a, others (25–50%) IgM (polyclonal, monoclonal) Chronic sensory ataxic neuropathy GD1b, GQ1b, and other b-series gangliosides IgM (monoclonal) Abbreviations: CIDP-M, CIDP with a monoclonal gammopathy; Caspr1, contactin associated protein-1; CNTN1, contactin-1; MAG, myelin-associated glycoprotein; MGUS, monoclonal gammopathy of undetermined significance; NF140/186, neurofascin 140/186; NF155, neurofascin 155; SGPG, sulfoglucuronyl paragloboside; SGLPG, sulfoglucuronyl lactosaminyl paragloboside. Source: Modified with permission from HJ Willison, N Yuki: Peripheral neuropathies and anti-glycolipid antibodies. Brain 125:2591, 2002. the course. Anti-GQ1b antibodies are not found in other forms of GBS unless there is extraocular motor nerve involvement. A pos­ sible explanation for this association is that extraocular motor nerves are enriched in GQ1b gangliosides in comparison to limb nerves. In addition, a monoclonal anti-GQ1b antibody raised against C. jejuni isolated from a patient with MFS blocked neuromuscular transmission experimentally. Taken together, these observations provide strong but still incon­ clusive evidence that autoantibodies play an important pathogenic role in GBS. Although antiganglioside antibodies have been studied most intensively, other antigenic targets may also be important. Proof that these antibodies are pathogenic requires that they be capable of mediating disease following direct passive transfer to naïve hosts; this has not yet been demonstrated, although one case of possible maternalfetal transplacental transfer of GBS has been described. In AIDP, an early step in the induction of tissue damage appears to be complement deposition along the outer surface of the Schwann cell. Activation of complement initiates a characteristic vesicular disinte­ gration of the myelin sheath and also leads to recruitment of activated macrophages, which participate in damage to myelin and axons. In AMAN, the pattern is different in that complement is deposited along with IgG at the nodes of Ranvier along large motor axons. Interest­ ingly, in cases of AMAN, antibodies against GD1a appear to have a fine specificity that favors binding to motor rather than sensory nerve roots, even though this ganglioside is expressed on both fiber types. Pathophysiology  In the demyelinating forms of GBS (AIDP), the basis for flaccid paralysis and sensory disturbance is conduction block. This finding, demonstrable electrophysiologically, implies that the axonal connections remain intact. Hence, recovery can take place rapidly as remyelination occurs. In severe cases of demyelinating GBS, secondary axonal degeneration usually occurs; its extent can be estimated electrophysiologically. More secondary axonal degeneration correlates with a slower rate of recovery and a greater degree of residual disability. With AMAN and AMSAN, a primary axonal pattern is encountered electrophysiologically (low-amplitude compound muscle action potentials). The implication has been that axons have degener­ ated and become disconnected from their targets, specifically the neu­ romuscular junctions, and must therefore regenerate for recovery to take place. However, the rapid recovery in many cases suggests the low amplitudes are often from reversible conduction block due to binding of antibodies to ion channel proteins in the nodes and paranodes. In severe cases, axonal degeneration can occur, and it is in these cases that recovery is much slower. Laboratory Features  CSF findings are distinctive, consisting of an elevated CSF protein level (1–10 g/L [100–1000 mg/dL]) without accompanying pleocytosis. The CSF is often normal when symptoms have been present for ≤48 h; by the end of the first week, the level of protein is usually elevated. A transient increase in the CSF white cell count (10–100/μL) occurs on occasion in otherwise typical GBS; however, a sustained CSF pleocytosis suggests an alternative diagnosis (viral myelitis) or a concurrent diagnosis such as unrecognized HIV infection, leukemia or lymphoma with infiltration of nerves, or neuro­ sarcoidosis. EDx features are mild or absent in the early stages of GBS and lag behind the clinical evolution. In AIDP, the earliest features are prolonged F-wave latencies, prolonged distal latencies, and reduced amplitudes of compound muscle action potentials (CMAPs), probably owing to the predilection for involvement of nerve roots and distal motor nerve terminals early in the course. Later, slowing of conduction velocity, conduction block, and temporal dispersion may be appre­ ciated (Table 458-1). Occasionally, sensory nerve action potentials (SNAPs) may be normal in the feet (e.g., sural nerve) when abnormal in the arms. This is also a sign that the patient does not have one of the more typical “length-dependent” polyneuropathies. As mentioned, in AMAN and AMSAN, the principal EDx finding is reduced amplitude of CMAPs (and also SNAPs with AMSAN) without conduction slow­ ing or prolongation of distal latencies, which early on is caused by conduction block but later can be due to axonal degeneration. Diagnosis  GBS is a descriptive entity. The diagnosis of AIDP is made by recognizing the pattern of rapidly evolving paralysis with are­ flexia, absence of fever or other systemic symptoms, and characteristic antecedent events. In 2011, the Brighton Collaboration developed a new set of case definitions for GBS in response to needs of epidemio­ logic studies of vaccination and assessing risks of GBS (Table 458-3). These criteria have subsequently been validated. Other disorders that may enter into the differential diagnosis include acute myelopathies (especially with prolonged back pain and sphincter disturbances); diphtheria (early oropharyngeal disturbances); Lyme polyradiculitis and other tick-borne paralyses; porphyria (abdominal pain, seizures, psychosis); vasculitic neuropathy (check erythrocyte sedimentation rate, described below); poliomyelitis and acute flaccid myelitis (wildtype poliovirus, West Nile virus, enterovirus D68, enterovirus A71, Japanese encephalitis virus, and the wild-type poliovirus); CMV polyradiculitis (in immunocompromised patients); critical illness neuropathy or myopathy; neuromuscular junction disorders such as myasthenia gravis and botulism (pupillary reactivity lost early); poi­ sonings with organophosphates, thallium, or arsenic; paralytic shellfish poisoning; or severe hypophosphatemia (rare). Cases of acute flaccid myelitis may pose particular challenges in distinguishing these from GBS because sphincter disturbances may be absent. CHAPTER 458 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies Laboratory tests are helpful primarily to exclude mimics of GBS. CSF pleocytosis is seen with poliomyelitis, acute flaccid myelitis, and Lyme and CMV polyradiculitis. EDx features may be minimal early in GBS, and the CSF protein level may not rise until the end of the first A Motor neuron Unidentified antigen Axon Myelin Antibody binding Complement activation PART 13 Neurologic Disorders B Axon Myelin Macrophage GM1, GD1a Schwann-cell microvilli Myelin Axon Axon Paranode Node Juxtaparanode KEY KEY IgG anti-GM1 or anti-GD1a antibodies C3 MAC Nav Cytoskeleton Kv Caspr FIGURE 458-2  Possible immune mechanisms in Guillain-Barré syndrome (GBS). Panel A shows the immunopathogenesis of AIDP. Although autoantigens have yet to be unequivocally identified, autoantibodies may bind to myelin antigens and activate complement. This is followed by the formation of membrane-attack complex (MAC) on the outer surface of Schwann cells and the initiation of vesicular degeneration. Macrophages subsequently invade myelin and act as scavengers to remove myelin debris. Panel B shows the immunopathogenesis of acute axonal forms of GBS (acute motor axonal neuropathy [AMAN] and acute motor-sensory axonal neuropathy [AMSAN]). Myelinated axons are divided into four functional regions: the nodes of Ranvier, paranodes, juxtaparanodes, and internodes. Gangliosides GM1 and GD1a are strongly expressed at the nodes of Ranvier, where the voltage-gated sodium (Nav) channels are localized. Contactin-associated protein (Caspr) and voltage-gated potassium (Kv) channels are respectively present at the paranodes and juxtaparanodes. IgG anti-GM1 or anti-GD1a autoantibodies bind to the nodal axolemma, leading to MAC formation. This results in the disappearance of Nav clusters and the detachment of paranodal myelin, which can lead to nerve-conduction failure and muscle weakness. Axonal degeneration may follow at a later stage. Macrophages subsequently invade from the nodes into the periaxonal space, scavenging the injured axons. (From N Yuki, H-P Hartung: Guillain-Barré syndrome. N Engl J Med 366:2294, 2012. Copyright © 2012 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.) week. If the diagnosis is strongly suspected, treatment should be initi­ ated without waiting for evolution of the characteristic EDx and CSF findings to occur. GBS patients with risk factors for HIV or with CSF pleocytosis should have a serologic test for HIV. TREATMENT Guillain-Barré Syndrome In the vast majority of patients with GBS, treatment should be initiated as soon after diagnosis as possible. Each day counts; ~2 weeks after the first motor symptoms, it is not known whether Macrophage MAC Myelin Axon Macrophage Nerve injury Macrophage scavenging Macrophage MAC Axon immunotherapy is still effective. If the patient has already reached the plateau stage, then treatment probably is no longer indicated, unless the patient has severe motor weakness and one cannot exclude the possibility that an immunologic attack is still ongoing. Either high-dose intravenous immune globulin (IVIg) or plasma­ pheresis (PLEX) can be initiated, as they are equally effective for typical GBS. A combination of the two therapies is not significantly better than either alone. IVIg is often the initial therapy chosen because of its ease of administration and good safety record. IVIg is usually administered as five daily infusions for a total dose of 2 g/kg body weight. There is some evidence that GBS autoantibod­ ies are neutralized by anti-idiotypic antibodies present in IVIg TABLE 458-3  Brighton Criteria for Diagnosis of Guillain-Barré Syndrome (GBS) and Miller Fisher Syndrome Clinical case definitions for diagnosis of GBS Level 1 of diagnostic certainty   Bilateral AND flaccid weakness of the limbs       AND   Decreased or absent deep tendon reflexes in weak limbs       AND   Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau       AND   Electrophysiologic findings consistent with GBS       AND   Cytoalbuminologic dissociation (i.e., elevation of CSF protein level above laboratory normal value AND CSF total white cell count <50 cells/μL)       AND   Absence of an identified alternative diagnosis for weakness Level 2 of diagnostic certainty   Bilateral AND flaccid weakness of the limbs       AND   Decreased or absent deep tendon reflexes in weak limbs       AND   Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau       AND   CSF total white cell count <50 cells/μL (with or without CSF protein elevation above laboratory normal value)       OR   If CSF not collected or results not available, electrophysiologic studies consistent with GBS       AND   Absence of identified alternative diagnosis for weakness Level 3 of diagnostic certainty   Bilateral and flaccid weakness of the limbs       AND   Decreased or absent deep tendon reflexes in weak limbs       AND   Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau       AND   Absence of identified alternative diagnosis for weakness Clinical case definitions for diagnosis of Miller Fisher syndrome Level 1 of diagnostic certainty   Bilateral ophthalmoparesis and bilateral reduced or absent tendon reflexes, and ataxia       AND Abbreviation: CSF, cerebrospinal fluid. Source: Reproduced with permission from JJ Sejvar et al: Guillain-Barré syndrome and Fisher syndrome: Case definitions and guidelines for collection, analysis, and presentation of immunization safety data. Vaccine 29:599, 2011. preparations, perhaps accounting for the therapeutic effect. A course of PLEX usually consists of ~40–50 mL/kg plasma exchange (PE) 4–6 times over 7–12 days. Meta-analysis of randomized clini­ cal trials indicates that treatment reduces the need for mechanical ventilation by nearly half (from 27 to 14% with PLEX) and increases the likelihood of full recovery at 1 year (from 55 to 68%). Function­ ally significant improvement may occur toward the end of the first week of treatment or may be delayed for several weeks. The lack of noticeable improvement following a course of IVIg or PLEX is not an indication to treat with the alternate treatment. However, there are occasional patients who are treated early in the course of GBS and improve, who then relapse within a month. Brief retreatment with the original therapy is usually effective in such cases. Gluco­ corticoids have not been found to be effective in GBS. Occasional patients with very mild forms of GBS, especially those who appear to have already reached a plateau when initially seen, may be man­ aged conservatively without IVIg or PLEX.   Absence of limb weakness       AND   Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau       AND   Cytoalbuminologic dissociation (i.e., elevation of cerebrospinal protein above the laboratory normal and total CSF white cell count <50 cells/μL)       AND   Nerve conduction studies are normal, OR indicate involvement of sensory nerves only       AND   No alterations in consciousness or corticospinal tract signs       AND   Absence of identified alternative diagnosis Level 2 of diagnostic certainty   Bilateral ophthalmoparesis and bilateral reduced or absent tendon CHAPTER 458 reflexes and ataxia       AND   Absence of limb weakness       AND   Monophasic illness pattern and interval between onset and nadir of Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies weakness between 12 h and 28 days and subsequent clinical plateau       AND   CSF with a total white cell count <50 cells/μL) (with or without CSF protein elevation above laboratory normal value)       OR   Nerve conduction studies are normal, OR indicate involvement of sensory nerves only       AND   No alterations in consciousness or corticospinal tract signs       AND   Absence of identified alternative diagnosis Level 3 of diagnostic certainty   Bilateral ophthalmoparesis and bilateral reduced or absent tendon reflexes and ataxia       AND   Absence of limb weakness       AND   Monophasic illness pattern and interval between onset and nadir of weakness between 12 h and 28 days and subsequent clinical plateau       AND   No alterations in consciousness or corticospinal tract signs       AND   Absence of identified alternative diagnosis In the worsening phase of GBS, most patients require monitoring in a critical care setting, with particular attention to vital capac­ ity, heart rhythm, blood pressure, nutrition, deep-vein thrombo­ sis prophylaxis, cardiovascular status, early consideration (after 2 weeks of intubation) of tracheotomy, and chest physiotherapy. As noted, ~30% of patients with GBS require ventilatory assistance, sometimes for prolonged periods of time (several weeks or longer). Frequent turning and assiduous skin care are important, as are daily range-of-motion exercises to avoid joint contractures and daily reassurance as to the generally good outlook for recovery. Prognosis and Recovery  Approximately 85% of patients with GBS achieve a full functional recovery within several months to a year, although minor findings on examination (such as areflexia) may persist and patients often complain of continued symptoms, including fatigue. The mortality rate is <5% in optimal settings; death usually results from secondary pulmonary complications. The outlook is worst in patients with severe proximal motor and sensory axonal damage. Such axonal damage may be either primary or secondary in nature (see “Pathophysiology,” above), but in either case, successful regeneration cannot occur. Other factors that worsen the outlook for recovery are advanced age, a fulminant or severe attack, and a delay in the onset of treatment. Elevated serum levels of neurofilament light (Nfl) chains and high titers of serum anti-GM1 antibodies are both associated with more axonal involvement in GBS and poor recovery. Between 5 and 10% of patients with typical GBS have one or more late relapses; many of these cases are then classified as chronic inflammatory demyelinat­ ing polyneuropathy (CIDP). CHRONIC INFLAMMATORY DEMYELINATING POLYNEUROPATHY CIDP is distinguished from GBS by its chronic course. In other respects, this neuropathy shares many features with the common demyelinating form of GBS, including elevated CSF protein levels and the EDx findings of acquired demyelination. Most cases occur in adults, and males are affected slightly more often than females. The incidence of CIDP is lower than that of GBS, but due to the protracted course, the prevalence is greater. As with GBS, CIDP and its variants can be triggered by use of immune checkpoint inhibitors used to treat various cancers. Clinical Manifestations  Onset is usually gradual over a few months or longer, but in a few cases, the initial attack is indistinguish­ able from that of GBS. An acute-onset form of CIDP may mimic GBS but should be considered if it deteriorates >9 weeks after onset or relapses at least three times. Symptoms are both motor and sen­ sory in most cases. Weakness of the limbs is usually symmetric but can be strikingly asymmetric in multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy variant (Lewis-Sumner syndrome) in which discrete peripheral nerves are involved. There is considerable variability from case to case. Some patients experience a chronic progressive course, whereas others, usually younger patients, have a relapsing and remitting course. A small proportion have cra­ nial nerve findings, including external ophthalmoplegia. Some have only motor findings, and a small proportion present with a relatively pure syndrome of sensory ataxia. The latter can be seen in the chronic inflammatory sensory polyradiculopathy (CISP) variant of CIDP in which demyelination predominantly occurs at the sensory roots or with the distal acquired demyelinating symmetric (DADS) variant. Some patients with CISP have mild motor involvement, and these cases are termed CISP-plus. New European Academy of Neurology/Periph­ eral Nerve Society (EAN/PNS) criteria for CIDP considers CISP as a separate entity, but we and others still feel it belongs as a subcategory of CIDP as the histopathology and response to treatment are similar. CIDP tends to ameliorate over time with treatment; the result is that many years after onset, nearly 75% of patients have reasonable func­ tional status. Death from CIDP is uncommon. Diagnosis  The diagnosis rests on characteristic clinical, CSF, and electrophysiologic findings. The CSF is usually acellular with an elevated protein level, sometimes several times normal. As with GBS, a CSF pleocytosis should lead to the consideration of HIV infection, leukemia or lymphoma, and neurosarcoidosis. EDx findings reveal variable degrees of conduction slowing, prolonged distal latencies, distal and temporal dispersion of CMAPs, and conduction block as the principal features. In particular, the presence of conduction block is a certain sign of an acquired demyelinating process. Evidence of axonal loss, presumably secondary to demyelination, is present in >50% of patients. Serum protein electrophoresis with immunofixation is indi­ cated to search for monoclonal gammopathy and associated condi­ tions (see “Monoclonal Gammopathy of Undetermined Significance,” below). Magnetic resonance imaging (MRI) can demonstrate enlarged nerves, clumping of cauda equina, and enhancement. Ultrasound is cheaper and often more readily available and can likewise show enlargement of nerves at the roots or more distally. Studies have shown that imaging complements EDx findings and increases sensitivity. In all patients with presumptive CIDP, it is also reasonable to exclude PART 13 Neurologic Disorders vasculitis, collagen vascular disease (especially SLE), chronic hepatitis, HIV infection, amyloidosis, and diabetes mellitus. Other associated conditions include inflammatory bowel disease and lymphoma. Pathogenesis  Biopsy in typical CIDP reveals little inflammation and onion-bulb changes (imbricated layers of attenuated Schwann cell processes surrounding an axon) that result from recurrent demy­ elination and remyelination (Fig. 458-1). The response to therapy suggests that CIDP is immune-mediated; CIDP responds to gluco­ corticoids, whereas GBS does not. Passive transfer of demyelination into experimental animals has been accomplished using IgG purified from the serum of some patients with CIDP, lending support for a humoral autoimmune pathogenesis. A minority of patients have serum antibodies against P0, myelin P2 protein, or PMP22 (proteins whose genes are mutated in certain forms of hereditary Charcot-Marie-Tooth neuropathy). As many as 25% of patients with clinical features of CIDP also have a monoclonal gammopathy of undetermined significance (MGUS), discussed below. Cases associated with monoclonal IgA or IgG kappa usually respond to treatment as favorably as cases without a mono­ clonal gammopathy. Patients with IgM-kappa monoclonal gammopa­ thy and antibodies directed against myelin-associated glycoprotein (MAG) have a distinct demyelinating polyneuropathy with more sen­ sory findings, usually only distal weakness, and a poor response to immunotherapy. TREATMENT Chronic Inflammatory Demyelinating Polyneuropathy Most authorities initiate treatment for CIDP when progression is rapid or walking is compromised. If the disorder is mild, manage­ ment can be expectant, awaiting spontaneous remission. Controlled studies have shown that high-dose IVIg, subcutaneous Ig (scIg), PLEX, and glucocorticoids are all more effective than placebo. Initial therapy is usually with IVIg, administered as 2.0 g/kg body weight given in divided doses over 2–5 days; three monthly courses are generally recommended before concluding a patient has failed treatment. If the patient responds, the infusion intervals can be gradually increased or the dosage decreased (e.g., starting at 1 g/kg every 3–4 weeks). Patients who require more frequent IVIg, experi­ ence side effects with IVIg (headaches), have poor venous access, or find it more convenient are treated with scIg (2–3 times a week such that the total dosage per month is the same or slightly higher than the monthly dosage of IVIg). PLEX, which appears to be as effective as IVIg, is initiated at 2–3 treatments per week for 6 weeks; periodic retreatment may also be required. Treatment with glucocorticoids is another option (60–80 mg prednisone PO daily for 1–2 months, followed by a gradual dose reduction of 10 mg per month as tolerated), but long-term adverse effects including bone demin­ eralization, gastrointestinal bleeding, and cushingoid changes are problematic. As many as one-third of patients with CIDP fail to respond adequately to the initial therapy chosen; a different treat­ ment should then be tried. Patients who fail therapy with IVIg, scIg, PLEX, and glucocorticoids may benefit from treatment with immunosuppressive agents such as azathioprine, methotrexate, cyclosporine, and cyclophosphamide, either alone or as adjunctive therapy. Use of these therapies requires periodic reassessment of their risks and benefits. A trial of efgartigimod alfa, a human neonatal Fc antibody fragment approved for myasthenia gravis (Chap. 457), demonstrated effectiveness in preventing relapses in CIDP; however, the medication will need to be compared with other more established options to determine its place in the CIDP treatment algorithm. In patients with a CIDP-like neuropathy who fail to respond to treatment, it is important to evaluate for a nodopathy, paranodopathy, or POEMS syndrome (polyneuropa­ thy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes; see below). NODOPATHIES AND PARANODOPATHIES Approximately 10% of patients previously considered to have CIDP have autoantibodies targeting antigens residing in nodal and paranodal regions that are responsible for the positioning and anchoring of ion channels and myelin folds in strategic locations along the axolemma. The EAN/PNS criteria now consider these separate from CIDP, and they are called nodopathies and paranodopathies. These neuropathies are associated with IgG4 isotype antibodies directed against nodal or paranodal antibodies including contactin-1 (CNTN1) or neurofas­ cin 155 (NF155) and, less commonly, IgM anti-NF140/186. Patients typically manifest with progressive symmetric, distally predominant weakness, sensory ataxia, and postural and intention tremor. Renal failure and nephrotic syndrome from membranous glomerulone­ phritis are associated with CNTN1 neuropathy. Of note, the CNTN1 protein is also present on podocytes on kidneys, and antibodies that deposit along the glomerular basement membrane are visible on renal biopsy. Other antibodies have less clinical specificity. Anti-contactin associated protein-1 (Caspr1) antibodies are associated with severe neuropathic pain. Passive transfer of IgG4 CNTN1 antibodies produces paranodal damage and ataxia in rodents. Electrophysiology is indistin­ guishable from typical CIDP. Importantly, as these nodopathies and paranodopathies are usually associated with IgG4 antibodies, they are less responsive to IVIg. How­ ever, they can respond to rituximab. MULTIFOCAL MOTOR NEUROPATHY Multifocal motor neuropathy (MMN) is a distinctive but uncommon neuropathy that presents with slowly progressive motor weakness and atrophy evolving over years in the distribution of selected nerve trunks, associated with sites of persistent focal motor conduction block in the same nerve trunks. Sensory fibers are relatively spared. The arms are affected more frequently than the legs, and >75% of all patients are male. Some cases have been confused with lower motor neuron forms of amyotrophic lateral sclerosis (Chap. 448). Less than 50% of patients present with high titers of polyclonal IgM antibody to the ganglioside GM1. It is uncertain how this finding relates to the discrete foci of persistent motor conduction block, but high concentrations of GM1 gangliosides are normal constituents of nodes of Ranvier in peripheral nerve fibers. Pathology reveals demyelination and mild inflammatory changes at the sites of conduction block. Most patients with MMN respond to high-dose IVIg or scIg (dos­ ages as for CIDP, above); periodic retreatment is required (usually at least monthly) to maintain the benefit. Some refractory patients have responded to rituximab or cyclophosphamide. Glucocorticoids and PE are not effective. NEUROPATHIES WITH MONOCLONAL GAMMOPATHY ■ ■MULTIPLE MYELOMA Clinically overt polyneuropathy occurs in ~5% of patients with the commonly encountered type of multiple myeloma, which exhibits either lytic or diffuse osteoporotic bone lesions. These neuropathies are sensorimotor, are usually mild and slowly progressive but may be severe, and generally do not reverse with successful suppression of the myeloma. In most cases, EDx and pathologic features are consistent with a process of axonal degeneration. In contrast, myeloma with osteosclerotic features, although repre­ senting only 3% of all myelomas, is associated with polyneuropathy in one-half of cases. These neuropathies, which may also occur with solitary plasmacytoma, are distinct because they (1) are demyelinat­ ing or mixed axonal and demyelinating by EDx, have elevated CSF protein, and clinically resemble CIDP; (2) often respond to radiation therapy or removal of the primary lesion; (3) are associated with dif­ ferent monoclonal proteins and light chains (almost always lambda as opposed to primarily kappa in the lytic type of multiple myeloma); (4) are typically refractory to standard treatments of CIDP; and (5) may occur in association with other systemic findings including thicken­ ing of the skin, hyperpigmentation, hypertrichosis, organomegaly, endocrinopathy, anasarca, and clubbing of fingers. These are features of POEMS syndrome. Levels of vascular endothelial growth factor (VEGF) are increased in the serum, and this factor is thought to some­ how play a pathogenic role in this syndrome. Treatment of the neu­ ropathy is best directed at the osteosclerotic myeloma using surgery, radiotherapy, chemotherapy, or autologous peripheral blood stem cell transplantation. Neuropathies are also encountered in other systemic conditions with gammopathy, including Waldenström macroglobulinemia, pri­ mary systemic amyloidosis, and cryoglobulinemic states (mixed essen­ tial cryoglobulinemia, some cases of hepatitis C). ■ ■MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE Chronic polyneuropathies occurring in association with MGUS are usually associated with the immunoglobulin isotypes IgG, IgA, and IgM. Most patients present with isolated sensory symptoms in their distal extremities and have EDx features of an axonal sensory or senso­ rimotor polyneuropathy. These patients otherwise resemble idiopathic sensory polyneuropathy, and the MGUS might just be coincidental. They usually do not respond to immunotherapies designed to reduce the concentration of the monoclonal protein. Some patients, however, present with generalized weakness and sensory loss and EDx stud­ ies indistinguishable from CIDP without monoclonal gammopathy (see “Chronic Inflammatory Demyelinating Polyneuropathy,” above), and their response to immunosuppressive agents is also similar. An exception is the syndrome of IgM-kappa monoclonal gammopathy associated with an indolent, long-standing, sometimes static sensory neuropathy, frequently with tremor and sensory ataxia. Most patients are men and aged >50 years. In the majority, the monoclonal IgM immunoglobulin binds to a normal peripheral nerve constituent, MAG, found in the paranodal regions of Schwann cells. Binding appears to be specific for a polysaccharide epitope that is also found in other normal peripheral nerve myelin glycoproteins, P0 and PMP22, and also in other normal nerve-related glycosphingolipids (Fig. 4581). In the MAG-positive cases, IgM paraprotein is incorporated into the myelin sheaths of affected patients and widens the spacing of the myelin lamellae, thus producing a distinctive ultrastructural pattern. Demyelination and remyelination are the hallmarks of the lesions, but axonal loss develops over time. These anti-MAG polyneuropathies are typical refractory to immunotherapy. In a small proportion of patients (30% at 10 years), MGUS will in time evolve into frankly malignant conditions such as multiple myeloma or lymphoma. CHAPTER 458 Guillain-Barré Syndrome and Other Immune-Mediated Neuropathies VASCULITIC NEUROPATHY Peripheral nerve involvement is common in polyarteritis nodosa (PAN), appearing in half of all cases clinically and in 100% of cases at postmortem studies (Chap. 375). The most common pattern is multifocal (asymmetric) motor-sensory neuropathy (mononeuropathy multiplex) due to ischemic lesions of nerve trunks and roots; however, some cases of vasculitic neuropathy present as a distal, symmetric sensorimotor polyneuropathy. Symptoms of neuropathy are a common presenting complaint in patients with PAN. The EDx findings are those of an axonal process. Small- to medium-sized arteries of the vasa ner­ vorum, particularly the epineural vessels, are affected in PAN, resulting in a widespread ischemic neuropathy. A high frequency of neuropathy occurs in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome [CSS]). Systemic vasculitis should always be considered when a subacute or chronically evolving mononeuropathy multiplex occurs in conjunc­ tion with constitutional symptoms (fever, anorexia, weight loss, loss of energy, malaise, and nonspecific pains). Diagnosis of suspected vascu­ litic neuropathy is made by a combined nerve and muscle biopsy, with serial section or skip-serial techniques. Approximately one-third of biopsy-proven cases of vasculitic neu­ ropathy are “nonsystemic” in that the vasculitis appears to affect only peripheral nerves. Constitutional symptoms are absent, and the course is more indolent than that of PAN. The erythrocyte sedimentation rate may be elevated, but other tests for systemic disease are negative. # 30 - 459 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction ### 459 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction Nevertheless, clinically silent involvement of other organs is likely, and vasculitis is frequently found in muscle biopsied at the same time as nerve. Vasculitic neuropathy may also be seen as part of the vasculitis syndrome occurring in the course of other connective tissue disorders. The most frequent is rheumatoid arthritis, but ischemic neuropathy due to involvement of vasa nervorum may also occur in mixed cryo­ globulinemia, Sjögren’s syndrome, granulomatosis with polyangiitis (formerly known as Wegener’s), hypersensitivity angiitis, SLE, and progressive systemic sclerosis. Some vasculitides are associated with antineutrophil cytoplasmic antibodies (ANCAs), which in turn are subclassified as cytoplasmic (cANCA) or perinuclear (pANCA). cANCAs are directed against proteinase 3 (PR3), whereas pANCAs target myeloperoxidase (MPO). PR3/cANCAs are associated with eosinophilic granulomatosis with polyangiitis, whereas MPO/pANCAs are typically associated with microscopic polyangiitis, CSS, and less commonly PAN. Of note, MPO/pANCA has also been seen in minocycline-induced vasculitis. PART 13 Neurologic Disorders Management of these neuropathies, including the “nonsystemic” vasculitic neuropathy, consists of treatment of the underlying condi­ tion as well as the aggressive use of glucocorticoids and cyclophospha­ mide. Use of these immunosuppressive agents has resulted in dramatic improvements in outcome, with 5-year survival rates now >80%. Clini­ cal trials found that the combination of rituximab and glucocorticoids is not inferior to cyclophosphamide and glucocorticoids. Thus, com­ bination therapy with glucocorticoids and rituximab is recommended as the standard initial treatment, particularly for ANCA-associated vasculitis. Mepolizumab, an anti–interleukin 5 monoclonal antibody, when added to standard care, is also effective for treatment of eosino­ philic granulomatosis with polyangiitis. ANTI-Hu PARANEOPLASTIC NEUROPATHY (Chap. 99) This uncommon immune-mediated disorder manifests as a sensory neuronopathy (i.e., selective damage to sensory nerve bodies in dorsal root ganglia). The onset is often asymmetric with dysesthesias and sensory loss in the limbs that soon progress to affect all limbs, the torso, and the face. Marked sensory ataxia, pseudoatheto­ sis, and inability to walk, stand, or even sit unsupported are frequent features and are secondary to the extensive deafferentation. Subacute sensory neuronopathy may be idiopathic, but more than half of cases are paraneoplastic, primarily related to lung cancer, and most of those are small-cell lung cancer (SCLC). Diagnosis of the underlying SCLC requires awareness of the association, testing for the paraneoplastic antibody, and often positron emission tomography (PET) scanning for the tumor. The target antigens are a family of RNA-binding proteins (HuD, HuC, and Hel-N1) that in normal tissues are only expressed by neurons. The same proteins are usually expressed by SCLC, triggering in some patients an immune response characterized by antibodies and cytotoxic T cells that cross-react with the Hu proteins of the dor­ sal root ganglion neurons, resulting in immune-mediated neuronal destruction. An encephalomyelitis may accompany the sensory neu­ ronopathy and presumably has the same pathogenesis. Neurologic symptoms usually precede, by ≤6 months, the identification of SCLC. The sensory neuronopathy runs its course in a few weeks or months and stabilizes, leaving the patient disabled. Most cases are unrespon­ sive to treatment with glucocorticoids, IVIg, PE, or immunosuppres­ sant drugs. ■ ■FURTHER READING Amato AA, Ropper AH: Sensory ganglionopathy. N Engl J Med 383:1657, 2020. Cortese A et al: Antibodies to neurofascin, contactin-1, and contactinassociated protein 1 in CIDP: Clinical relevance of IgG isotype. Neurol Neuroimmunol Neuroinflamm 7:E639, 2020. Gwathmey KG et al: Peripheral nerve vasculitis: Classification and disease associations. Neurol Clin 37:303, 2019. Keh RYS et al: COVID-19 vaccination and Guillain-Barré syn­ drome: Analyses using the National Immunoglobulin Database. Brain 146:739, 2023. Koike H et al: ANCA-associated vasculitic neuropathies: A review. Neurol Ther 11:21, 2022. Puwanant A et al: Clinical spectrum of neuromuscular complications after immune checkpoint inhibition. Neuromuscul Disord 29:127, 2019. Súkeníková L et al: Autoreactive T cells target peripheral nerves in Guillain-Barré syndrome. Nature 626:160, 2024. Van den Bergh PYK et al: European Academy of Neurology/Peripheral Nerve Society guideline on diagnosis and treatment of chronic inflammatory demyelinating polyradiculoneuropathy: Report of a joint Task Force—Second revision. Eur J Neurol 28:3556, 2021. van Doorn PA et al: European Academy of Neurology/Peripheral Nerve Society Guideline on diagnosis and treatment of Guillain-Barré syndrome. Eur J Neurol 30:3646, 2023. Willison AG et al: SARS-CoV-2 vaccination and neuroimmunologi­ cal disease: A review. JAMA Neurol 81:179, 2024. Anthony A. Amato, Amanda C. Guidon Myasthenia Gravis and Other Diseases of the Neuromuscular Junction Myasthenia gravis (MG) is a neuromuscular junction (NMJ) disorder characterized by weakness and fatigability of skeletal muscles. The under­ lying defect is a decrease in the number of available acetylcholine recep­ tors (AChRs) at NMJs due to an antibody-mediated autoimmune attack. Available treatments for MG are highly effective, although side effects can limit their use and a cure has remained elusive. ■ ■PATHOPHYSIOLOGY At the NMJ (Fig. 459-1, Video 459-1), acetylcholine (ACh) is syn­ thesized in the motor nerve terminal and stored in vesicles (quanta). When an action potential travels down a motor nerve and reaches the nerve terminal, ACh from 150 to 200 vesicles is released and com­ bines with AChRs that are densely packed at the crests of postsynaptic folds on skeletal muscle. The AChR consists of five subunits (2α, 1β, 1δ, 1γ, or ε) arranged around a central pore. When ACh combines with the binding sites on α subunits of the AChR, the channel in the AChR opens, permitting the rapid entry of cations, chiefly sodium, which produces depolarization at the end-plate region of the muscle fiber. If the depolarization is sufficiently large, it initiates an action potential that is propagated along the muscle fiber, triggering muscle contraction. This process is rapidly terminated by hydrolysis of ACh by acetylcholinesterase, which is present within the synaptic cleft, and by diffusion of ACh away from the receptor. Muscle-specific tyrosine kinase (MuSK) is a postsynaptic trans­ membrane protein that helps stabilize postsynaptic clustering of AChRs. Agrin is released from the presynaptic motor nerve terminal and binds low-density lipoprotein receptor-related protein 4 (LRP4). This agrin-LRP4 complex activates MuSK. This facilitates recruitment of cytoplasmic proteins, including downstream of tyrosine kinase 7 (DOK7) and rapsyn, to assist in clustering AChR. These various pro­ teins are important in the pathogenesis of not only MG but also some of the hereditary congenital myasthenic syndromes. In MG, the fundamental defect is a decrease in the number of available AChRs at the postsynaptic muscle membrane. In addition, the postsynaptic folds are flattened, or “simplified.” These changes result in decreased efficiency of neuromuscular transmission. There­ fore, although ACh is released normally, it produces small end-plate potentials that may fail to trigger muscle action potentials. Failure of transmission results in muscle weakness. The amount of ACh released per impulse normally declines on repeated activity (termed presynaptic rundown). In myasthenic patients, reduced efficiency of neuromuscular transmission, combined with this normal rundown, results in activation of fewer and fewer muscle fibers by successive nerve impulses, and hence increasing weakness, or myasthenic fatigue. This mechanism also accounts for the decremental response to repetitive nerve stimulation seen on electro­ diagnostic testing. MG is an autoimmune disorder most commonly caused by antiAChR antibodies. The anti-AChR antibodies reduce the number of available AChRs at NMJs by three distinct mechanisms: (1) accelerated turnover of AChRs by a mechanism involving cross-linking and rapid endocytosis of the receptors; (2) damage to the postsynaptic muscle membrane through antibody-mediated complement activation; and (3) blockade of the active site of the AChR (i.e., the site that normally binds ACh). An immune response to MuSK, a protein involved in AChR clustering at the NMJ (as noted above), also results in MG, with reduction of AChRs demonstrated experimentally. Anti-MuSK anti­ body occurs in ~10% of patients (~40% of AChR antibody–negative patients with generalized MG), whereas 1–3% have antibodies to Myelin sheath Acetate Choline Ca+ ions AChE Voltage-gated Na+ channels A FIGURE 459-1  Illustrations of (A) a normal presynaptic neuromuscular junction, (B) a normal postsynaptic terminal, and (C) a myasthenic neuromuscular junction. AChE, acetylcholinesterase. See text for description of normal neuromuscular transmission. The myasthenia gravis (MG) junction demonstrates a reduced number of acetylcholine receptors (AChRs); flattened, simplified postsynaptic folds; and a widened synaptic space. See Video 459-1 also. (Reproduced with permission from AA Amato, J Russell: Neuromuscular Disorders, 2nd ed. New York, McGraw-Hill; 2016.) another protein at the NMJ—LRP4—that, as mentioned, is also important for clustering of AChRs. These pathogenic antibodies are IgG and are T-cell dependent. Thus, immunotherapeutic strategies directed against either the antibody-producing B cells or helper T cells, directly reducing the pathogenic antibodies, or blocking complementmediated destruction of the AChRs are all effective in anti-AChRpositive MG. MuSK antibodies exert their pathogenic effect by directly inhibiting binding between MuSK and LRP4, leading to loss of AChRs and other functions of MuSK. Of note, MuSK antibodies are of the IgG4 subtype and, as such, do not activate complement. As a result, anti-MuSK-positive MG does not respond to complement inhibition. LRP4 antibodies are of the IgG1 subclass and also cause complementmediated destruction, similar to AChR antibodies, and possibly inter­ rupt agrin-induced MuSK activation. Although MG is caused by autoantibodies, a significant contribution exists from T cells, including T regulatory (Treg) cells. These Tregs are critical in suppressing activation of other immune cells that have escaped negative selection in the thymus. Because these other cells have not been deleted by negative selection or suppressed in the periphery, they attack “self” antigens. Deficiency or dysfunction of Tregs contrib­ utes to the pathogenesis not only of MG but of many other autoim­ mune diseases. The primary source of Treg cells is the thymus, which CHAPTER 459 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction SNARE proteins Syntaxin-1 SNAP 25 Synaptotagmin Synaptobrevin ChAT Choline acetyltransferase Acetylcholine receptor Axon Voltage-gated K+ channel ChAT Agrin Active zone Voltage-gated Ca+ channel Myofibril ACh (acetylcholine) Vesicle SNARE proteins Syntaxin-1 SNAP 25 Synaptotagmin Synaptobrevin Vesicle fusion Agrin ACh receptor AChE Dystroglycan β δ α α γ Rapsyn PART 13 Neurologic Disorders Dok-7 MuSK Lrp4 Na+ channels Myofibril B FIGURE 459-1  (Continued) is abnormal in ~75% of patients with AChR antibody–positive MG. In ~65%, the thymus is “hyperplastic,” with the presence of active germi­ nal centers detected histologically. The hyperplastic thymus may be but is not necessarily enlarged. An additional 10% of patients have thymic tumors (thymomas). Muscle-like cells within the thymus (myoid cells), which express AChRs on their surface, may serve as a source of auto­ antigen and trigger the autoimmune reaction within the thymus gland. ■ ■CLINICAL FEATURES MG has an incidence ranging from 6.3 to 29 per million and a preva­ lence ranging from 100 to 361 per million. It affects individuals in all age groups, but peak incidence occurs in women in their twenties and thirties and in men in their fifties and sixties. Overall, women are affected more frequently than men, in a ratio of ~3:2. Cardinal features are weakness and fatigability of muscles. Myasthenic weakness often worsens during repeated use (fatigue) and/or late in the day and may improve following rest or sleep. The course of MG is variable. Exacerbations and remissions may occur, particularly during the first 1–3 years after disease onset. In ~85% of patients, myasthenic weakness becomes generalized, affecting facial, bulbar, axial, or limb muscles in addition to ocular muscles. If weakness remains restricted to ocular muscles for 3 years, future generalization is unlikely, and these patients are said to have ocular MG. However, we have seen rare patients generalize >5 years after onset of ocular MG. Unrelated infections, systemic disorders, or tapering of MG therapies can lead to increased myasthenic weakness and may precipitate myasthenic exacerbation or “crisis” (see below). Some exacerbations occur without any identifiable precipitating factors. The distribution of muscle weakness often has a characteristic pat­ tern. Cranial muscles, particularly extraocular and eyelid muscles, are frequently involved early in the course of MG; diplopia and ptosis are common initial symptoms. Facial weakness produces a “snarling” Vesicle SNARE proteins ACh Syntaxin-1 SNAP 25 Synaptotagmin Synaptobrevin Vesicle fusion Agrin AChR autoantibody Dystroglycan Complement AChE α α α α Lysis of ACh receptors Na+ channel Myofibril C expression when the patient attempts to smile. Weakness in chewing is most noticeable after prolonged effort or chewing hard or tough foods like meat. Speech may have a nasal timbre caused by weakness of the palate or a dysarthric “mushy” quality due to tongue weakness. Hoarseness can occur from laryngeal weakness. Difficulty in swallow­ ing (dysphagia) may occur as a result of weakness of the palate, tongue, or pharynx, giving rise to nasal regurgitation or aspiration of liquids or food. Bulbar, neck, and ventilatory weakness can be especially promi­ nent in MuSK antibody–positive MG. Weakness in neck extensor muscles can lead to head drop. Limb weakness in MG is often proximal and may be asymmetric. Nonetheless, some patients manifest with mainly distal weakness (finger and wrist drop or foot drop). Deep ten­ don reflexes are typically preserved. Sensory symptoms, sensory loss, and pain are absent. If ventilatory weakness necessitates intubation or noninvasive ventilation to avoid intubation, the patient is said to be in MG crisis. All other worsening is termed exacerbation. ■ ■DIAGNOSIS AND EVALUATION (TABLE 459-1) The diagnosis is suspected based on weakness and fatigability in the typical distribution described above, without loss of deep tendon reflexes or sensory signs or symptoms or abnormality of other neuro­ logic functions. The suspected diagnosis should be confirmed defini­ tively before treatment is undertaken; this is essential because (1) other treatable conditions may closely resemble MG and (2) the treatment of MG may involve surgery and the prolonged use of drugs with potential side effects. Ice-Pack Test  If a patient has ptosis, application of a pack of ice over a ptotic eye for 2 min often results in improvement if the ptosis is due to an NMJ defect. A lid rise of 2 mm following this cooling is considered a positive result. This is hypothesized to be due to less depletion of quanta of AChR in the cold and reduced activity of TABLE 459-1  Diagnosis of Myasthenia Gravis (MG) History   Diplopia, ptosis, dysarthria, dysphagia, dyspnea   Weakness in characteristic distribution: proximal limbs, neck extensors, generalized   Fluctuation and fatigue: worse with repeated activity, improved by rest   Effects of previous treatments Physical examination   Evaluation for ptosis at rest and following 1 min of exercise, extraocular muscles and subjective diplopia, orbicularis oculi and oris strength, jaw opening and closure   Assessment of muscle strength in neck and extremities   Weakness following repeated shoulder abduction   Vital capacity measurement   Absence of other neurologic signs Laboratory testing   Anti-AChR radioimmunoassay: ~85% positive in generalized MG; 50% in ocular MG; definite diagnosis if positive; negative result does not exclude MG; ~40% of AChR antibody–negative patients with generalized MG have anti-MuSK antibodies and ~2% have LRP4 antibodies   Repetitive nerve stimulation: decrement of >10% at 3 Hz: highly probable   Single-fiber electromyography: blocking and jitter, with normal fiber density; confirmatory, but not specific   Edrophonium chloride (Enlon) 2 mg + 8 mg IV; highly probable diagnosis if unequivocally positive Ice-pack test looking for improvement in ptosis is very sensitive For ocular or cranial MG: exclude intracranial lesions by CT or MRI Abbreviations: AChR, acetylcholine receptor; CT, computed tomography; LRP4, lipoprotein receptor-related protein 4; MRI, magnetic resonance imaging; MuSK, muscle-specific tyrosine kinase. acetylcholinesterase at the NMJ. It is a quick and easy test to do in the clinic or at the bedside of a hospitalized patient. Autoantibodies Associated with MG  As previously mentioned, anti-AChR antibodies are detectable in the serum of ~85% of all myas­ thenic patients but in only ~50% of patients with weakness confined to the ocular muscles. The presence of anti-AChR antibodies is virtually diagnostic of MG, but a negative test does not exclude the disease. The measured level of anti-AChR antibody does not correspond well with the severity of MG in different patients. Antibodies to MuSK are pres­ ent in up to 40% of AChR antibody–negative patients with generalized MG depending on the population. MuSK antibodies are rarely present in AChR antibody–positive patients or in patients with MG limited to ocular muscles. A small proportion of MG patients without antibodies to AChR or MuSK have antibodies to LRP4. Sending LRP4 antibodies has a low specificity. As such, we only check them in patients with clear MG by phenotype and electrodiagnostic testing but absent AChR and MuSK antibodies. Additionally, antibodies against agrin also have been found in rare patients with MG, but it is unclear if they are pathogenic, and they are not currently tested in clinical practice. Additionally, anti-striated muscle antibodies directed against titin and other skeletal muscle components have been identified in some patients. However, they are not pathogenic, and their presence does not confirm the diagnosis of MG or the presence of a thymoma. Given their limited utility and potential for misinterpretation, we do not order them. Furthermore, antibodies directed against Caspr2 (contactin-associated protein-like 2) may coexist primarily in patients with thymoma who have MG and neuromyotonia or Morvan’s syndrome. The presence of these antibodies can help confirm the diagnosis of a second paraneo­ plastic syndrome in these clinical situations. Electrodiagnostic Testing  Repetitive nerve stimulation may provide helpful diagnostic evidence of MG. Medications that inhibit acetylcholinesterase should be stopped 12–24 h or for as long as pos­ sible before testing. It is best to test weak muscles or proximal muscle groups. Electrical stimulation is delivered at a rate of two or three per second to the appropriate nerves, and action potentials are recorded from the muscles. In normal individuals, the amplitude of the evoked muscle action potentials does not change by >10% at these rates of stimulation. However, in myasthenic patients, there is a rapid reduc­ tion of >10% in the amplitude of the evoked responses. If repetitive nerve stimulation is normal and/or symptoms are exclusively ocular, single-fiber electromyography (EMG), a specialized more sensitive test typically done at MG referral centers, is performed. Anticholinesterase Test  Drugs that inhibit the enzyme ace­ tylcholinesterase allow ACh to interact repeatedly with the limited number of AChRs in MG, producing improvement in muscle strength. Edrophonium was most commonly used historically for diagnostic testing because of the rapid onset (30 s) and short duration (~5 min) of its effect, with an objective endpoint such as ptosis typically measured. Edrophonium is no longer used due to potential for side effects and lack of availability. CHAPTER 459 Pulmonary Function Tests (Chap. 295)  Measurements of ven­ tilatory function are valuable because of the frequency and seriousness of respiratory impairment in myasthenic patients. Differential Diagnosis  Other conditions that cause weakness of the cranial and/or somatic musculature include nonautoimmune congenital myasthenia, drug-induced myasthenia, Lambert-Eaton myasthenic syndrome (LEMS), hyperthyroidism (Graves’ disease), botulism, intracranial mass lesions, oculopharyngeal dystrophy, and mitochondrial myopathy (Kearns-Sayre syndrome, progressive exter­ nal ophthalmoplegia). Treatment with immune checkpoint inhibitors (ICIs) for cancer may also result in autoimmune MG. Myositis and myocarditis are also often found in combination with MG as a compli­ cation of ICIs (Chap. 377). Symptoms typically begin after the first or second cycle of treatment, with ptosis, diplopia, bulbar, neck, extrem­ ity weakness, and respiratory weakness. ICI-related myositis without disordered neuromuscular transmission can mimic MG, itself causing a similar pattern of weakness including ocular and bulbar weakness, which is uncommon in other autoimmune myopathies. Patients usu­ ally improve when the ICI is discontinued and a short course of gluco­ corticoids is given, with intravenous immunoglobulin (IVIg) or plasma exchange depending on severity; however, with fulminant disease, the fatality rate remains high, mainly due to the concurrent myocarditis. Treatment with penicillamine (used for scleroderma or rheumatoid arthritis) has also been associated with MG. Aminoglycoside, quino­ lone and macrolide antibiotics, intravenous magnesium, or procain­ amide can also cause exacerbation of weakness in myasthenic patients; very large doses can cause neuromuscular weakness in normal indi­ viduals. Botulinum toxin injections should be avoided in MG patients. Myasthenia Gravis and Other Diseases of the Neuromuscular Junction The congenital myasthenic syndromes (CMS) comprise a rare het­ erogeneous group of disorders of the NMJ that are not autoimmune but rather are due to mutations in >30 identified genes. Virtually any component of the NMJ may be affected. Alterations in function of the presynaptic nerve terminal, in the various subunits of the AChR, acetylcholinesterase, or the other molecules involved in end-plate development or maintenance, have been identified in the different forms of CMS. These disorders share many of the clinical features of autoimmune MG, including weakness and fatigability of proximal or distal extremity muscles and often involving extraocular and eyelid muscles similar to the distribution in autoimmune MG. CMS is most often suspected when symptoms of myasthenia began in infancy or childhood; however, some patients initially present in adulthood. As in autoimmune MG, repetitive nerve stimulation is often associated with a decremental response. Some forms of CMS (e.g., acetylcholinesterase deficiency, prolonged open channel syndrome) have a feature of afterdischarges that are not seen in MG. An additional clue is the absence of AChR and MuSK antibodies, although these are absent in ~10% of generalized MG patients (so-called double seronegative MG). The prevalence of CMS is estimated at ~3.8 per 100,000. The most common genetic defects occur in the ε subunit of the AChR, account­ ing for ~50% of CMS cases, with mutations in the genes encoding for rapsin, COLQ, DOK7, agrin, and GFPT together accounting for ~40%. In most of the recessively inherited forms of CMS, the mutations are heteroallelic; that is, different mutations affecting each of the two alleles are present. Features of the most common forms of CMS are summarized in Table 459-2. Molecular analysis is required for precise elucidation of the defect; this may lead to helpful treatment as well as genetic counseling. Some forms of CMS improve with acetylcholines­ terase inhibitors, while others (e.g., slow channel syndrome, acetylcho­ linesterase deficiency, DOK7-related CMS) actually worsen. Fluoxetine and quinidine can be useful for slow channel syndrome, and albuterol for mutations affecting acetylcholinesterase, DOK7, rapsyn, and agrin. Additionally, ephedrine and 3,4-diaminopyridine (3,4-DAP) may be of benefit in some forms of CMS. LEMS is a presynaptic disorder of the NMJ that causes skeletal muscle weakness; however, the pattern of involvement differs from that in MG. The proximal muscles of the lower limbs are most commonly affected, although other muscles may be involved as well. Cranial and bulbar weakness, including ptosis of the eyelids, diplopia, dysarthria, and dysphagia may occur but are not typically the presenting or prominent symptoms. However, LEMS can be further distinguished from MG because patients with LEMS often have depressed or absent reflexes and experience autonomic symptoms such as dry mouth, orthostasis, and impotence (Chap. 451). Nerve stimulation produces an initial low-amplitude compound muscle action potential and, at low rates of repetitive stimulation (2–3 Hz), a decremental response as seen in MG; however, at high rates (20–50 Hz) or following brief exer­ cise, incremental responses occur. LEMS is caused by autoantibodies directed against P/Q-type calcium channels at the presynaptic motor nerve terminals detected in ~85% of LEMS patients. These autoan­ tibodies impair the release of ACh from nerve terminals. In young adults, particularly women, LEMS is less commonly associated with an underlying cancer. However, in older adults, LEMS is associated with malignancy, most commonly small-cell lung cancer (SCLC), and virtually all of these patients have P/Q-type calcium channel autoanti­ bodies. The tumor cells may express calcium channels that stimulate the autoimmune response. Initial management requires comprehensive evaluation for malignancy and reassessment if the initial malignancy evaluation is negative. Treatment of LEMS symptoms involves therapy first with 3,4-DAP and pyridostigmine. 3,4-DAP acts by blocking potassium channels, which results in prolonged depolarization of the motor nerve terminals, thus enhancing ACh release. Pyridostigmine prolongs the action of ACh, allowing repeated interactions with AChRs. If symptoms are severe or life-threatening or if symptomatic therapy is insufficient, immunomodulatory therapy including IVIg or plasma exchange can be used. PART 13 Neurologic Disorders Botulism (Chap. 158) is due to potent bacterial toxins produced by any of eight different strains of Clostridium botulinum. The toxins enzymatically cleave specific proteins essential for the release of ACh from the motor nerve terminal, thereby interfering with neuromuscu­ lar transmission. Most commonly, botulism is caused by ingestion of improperly prepared food containing toxin. Rarely, the nearly ubiq­ uitous spores of C. botulinum may germinate in wounds. In infants, the spores may germinate in the gastrointestinal (GI) tract and release toxin, causing muscle weakness. Patients present with myasthenia-like bulbar weakness (e.g., diplopia, dysarthria, dysphagia) and lack sensory symptoms and signs. Weakness may generalize to the limbs and may result in respiratory failure. Reflexes are present early, but they may be diminished as the disease progresses. Mentation is normal. Auto­ nomic findings include paralytic ileus, constipation, urinary retention, dilated or poorly reactive pupils, and dry mouth. The demonstration of toxin in serum by bioassay is definitive, but the results usually take a relatively long time to be completed and may be negative. Nerve stimulation studies reveal reduced compound muscle action potential (CMAP) amplitudes that increase following high-frequency repetitive stimulation. Treatment includes ventilatory support and aggressive inpatient supportive care (e.g., nutrition, deep-vein thrombosis pro­ phylaxis) as needed. Antitoxin should be given as early as possible to be effective and can be obtained through the Centers for Disease Control and Prevention. A preventive vaccine is available for laboratory work­ ers or other highly exposed individuals. Hyperthyroidism is readily diagnosed or excluded by tests of thyroid function, which should be carried out routinely in patients with suspected MG. Abnormalities of thyroid function (hyper- or hypothyroidism) may increase myasthenic weakness. Diplopia resem­ bling that in MG may occasionally be due to an intracranial mass lesion that compresses nerves to the extraocular muscles (e.g., sphenoid ridge meningioma), but magnetic resonance imaging (MRI) of the head and orbits usually reveals the lesion. Progressive external ophthalmoplegia is a rare condition resulting in weakness of the extraocular muscles and often symmetric ptosis, which may be accompanied by weakness of the proximal muscles of the limbs and other systemic features. Most patients with this condition have mitochondrial disorders that can be detected by genetic testing or with muscle biopsy (Chap. 460). Search for Associated Conditions (Table 459-3)  Myasthenic patients have an increased incidence of several associated disorders. Thymic abnormalities occur in ~75% of AChR antibody–positive patients, as noted above. Neoplastic change (thymoma) may produce enlargement of the thymus, which is detected by chest computed tomography (CT) or MRI. A thymic shadow on CT scan may normally be present through young adulthood, but enlargement of the thymus in a patient age >40 years is highly suspicious for thymoma. Approxi­ mately 10–15% of patients with MG have thymoma, and therefore, chest imaging to evaluate this possibility is performed at diagnosis. Hyperthyroidism occurs in 3–8% of patients and may aggravate the myasthenic weakness. Thyroid function tests should be obtained in all patients with suspected MG. Other autoimmune disorders, most com­ monly systemic lupus erythematosus and rheumatoid arthritis, can coexist with MG; associations also occur with neuromyelitis optica, multiple sclerosis, neuromyotonia, Morvan’s syndrome (encephalitis, insomnia, confusion, hallucinations, autonomic dysfunction, and neuromyotonia), rippling muscle disease, granulomatous myositis/ myocarditis, and chronic inflammatory demyelinating polyneuropathy. An infection of any kind can exacerbate typical MG and should be sought carefully in patients with relapses. Because of the side effects of glucocorticoids and other immunotherapies used in the treatment of MG, a thorough medical investigation should be undertaken, searching specifically for evidence of chronic or latent infection (such as tubercu­ losis or hepatitis), hypertension, diabetes, renal disease, and glaucoma. TREATMENT Myasthenia Gravis The prognosis of MG has improved strikingly as a result of advances in treatment. Nearly all myasthenic patients can be returned to full productive lives with proper therapy. Common treatments for MG include anticholinesterase medications, glucocorticoids and other immunosuppressive agents, thymectomy, plasmapheresis, IVIg, rituximab, and the recently approved complement inhibitors and neonatal Fc receptor (FcRn) antagonists (Fig. 459-2). ANTICHOLINESTERASE MEDICATIONS Anticholinesterase medication produces at least partial improve­ ment in most myasthenic patients, although improvement is com­ plete in only a few. Patients with anti-MuSK MG generally obtain less benefit from anticholinesterase agents than those with AChR antibodies and may actually worsen. Pyridostigmine is the most widely used anticholinesterase drug and is initiated at a dosage of 30–60 mg three to four times daily. The beneficial action of oral pyridostigmine begins within 15–30 min and lasts for 3–4 h, but individual responses vary. The frequency and amount of the dose should be tailored to the patient’s individual requirements through­ out the day. For example, patients with weakness in chewing and swallowing may benefit by taking the medication before meals so that peak strength coincides with mealtimes. Long-acting pyr­ idostigmine may occasionally be useful to get the patient through the night but should not be used for daytime medication because of variable absorption. The maximum useful dose of pyridostigmine TABLE 459-2  Congenital Myasthenic Syndromes (CMS) CMS SUBTYPE GENE CLINICAL FEATURES Presynaptic Disorders CMS with paucity of ACh release CHAT; CHT AR; early onset, respiratory failure at birth, episodic apnea, improvement with age Synaptic Disorders AChE deficiency COLQ AR; early onset; variable severity; axial weakness with scoliosis; apnea; +/– EOM involvement, slow or absent pupillary responses Postsynaptic Disorders Involving AChR Deficiency or Kinetics Primary AChR deficiency AChR subunit genes AR; early onset; variable severity; fatigue; typical MG features AChR kinetic disorder: slow channel syndrome AChR subunit genes AD; onset childhood to early adult; weak forearm extensors and neck; respiratory weakness; variable severity AChR kinetic disorder: fast channel syndrome AChR subunit genes AR; early onset; mild to severe; ptosis, EOM involvement; weakness and fatigue Postsynaptic Disorders Involving Abnormal Clustering/Function of AChR   DOK 7 AR; limb girdle weakness with ptosis but no EOM involvement   Rapsyn AR; early onset with hypotonia, respiratory failure, and arthrogryposis at birth to early adult onset resembling MG   Agrin AR; limb girdle or distal weakness, apnea Decremental response to RNS   MuSK AR; congenital or childhood onset of ptosis, EOM and progressive limb girdle weakness   LRP4 AR; congenital onset with hypotonia; ventilatory failure, mild ptosis, and EOM weakness Other Postsynaptic Disorders Limb-girdle CMS with tubular aggregates GFPT1; DPAGT1; ALG2; ALG14; DPAGT1 AR; limb-girdle weakness usually without ptosis or EOM weakness; onset in infancy or early adult Congenital muscular dystrophy with myasthenia Plectin AR; infantile or childhood onset of generalized weakness including ptosis and EOM; epidermolysis bullosa simplex; elevated CK Abbreviations: ACh, acetylcholine; AChE, acetylcholinesterase; AChR, acetylcholine receptor; AD, autosomal dominant; AR, autosomal recessive; CHAT, choline acetyl transferase; CHT, sodium-dependent high-affinity choline transport 1; CK, creatine kinase; CMA, congenital myasthenic syndrome; COLQ, collaganic tail of endplate acetylcholinesterase; 3,4-DAP, 3,4-diaminopyridine; Dok7, downstream of tyrosine kinase 7; DPAGT1, UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosamine phosphotransferase; EOM, extraocular muscle; GFPT1, glutamine-fructose-6-phosphate aminotransferase 1; LRP4, lipoprotein receptor-related protein 4; MG, myasthenia gravis; MuSK, muscle specific kinase; RNS, repetitive nerve stimulation. Source: Reproduced with permission from AA Amato, et al (eds): Amato and Russell’s Neuromuscular Disorders, 3rd ed. New York: McGraw Hill; 2025. rarely exceeds 360–480 mg daily. Overdosage with anticholines­ terase medication may cause increased weakness and other side effects. In some patients, muscarinic side effects of the anticholin­ esterase medication (diarrhea, abdominal cramps, excess salivation, nausea) may limit the dose tolerated. Atropine/diphenoxylate or loperamide is useful for the treatment of gastrointestinal symptoms. THYMECTOMY Two separate issues should be distinguished: (1) surgical removal of thymoma, and (2) thymectomy as a treatment for MG. Surgical removal of a thymoma is necessary because of the possibility of local tumor spread, although most thymomas are histologically benign. A large international study (the MGTX trial) of extended transsternal thymectomy in nonthymomatous, AChR antibody–positive, gener­ alized MG demonstrated that participants who underwent thymec­ tomy had improved strength and function, required less prednisone and fewer additions of second-line agents (e.g., azathioprine), and ELECTROPHYSIOLOGIC FEATURES RESPONSE TO ACHE INHIBITORS TREATMENT Decremental response to RNS Improve AChE inhibitors; 3,4-DAP After discharges on nerve stimulation and decrement on RNS Worsen Albuterol; ephedrine; 3,4-DAP; avoid AChE inhibitors Decremental response to RNS Improve AChE inhibitors; 3,4-DAP After discharges on nerve stimulation and decrement on RNS Worsen Fluoxetine and quinidine; avoid AChE inhibitors CHAPTER 459 Decremental response to RNS Improve AChE inhibitors; caution with 3,4-DAP Myasthenia Gravis and Other Diseases of the Neuromuscular Junction Decremental response to RNS Variable Albuterol; ephedrine; may worsen with AChE inhibitors Decremental response to RNS Variable Albuterol Variable Albuterol; may worsen with AChE inhibitors Decremental response to RNS Variable Variable response to AChE inhibitors and 3,4-DAP Positive response to albuterol Decremental response to RNS Worsen Worsen with AChE inhibitors Decremental response to RNS Variable Albuterol; ephedrine; variable response to AChE inhibitors and 3,4DAP; albuterol Decremental response to RNS Variable No response to AChE and 3,4-DAP had fewer hospitalizations for exacerbations lasting at least 5 years. Whether or not less invasive thymectomy provides identical ben­ efit is unknown; however, less invasive techniques are now used in most thymectomies at many institutions. Importantly, patients with ocular myasthenia, MuSK-positive, and seronegative MG were all excluded from the MGTX study; retrospective and anecdotal evidence suggests that these patients may not benefit from thymec­ tomy. Thymectomy should never be carried out as an emergency procedure, but only when the patient is adequately prepared. If nec­ essary, treatment with IVIg or plasmapheresis may be used before surgery to maximize strength in weak patients. IMMUNOTHERAPY The choice of immunotherapy should be guided by the relative benefits and risks for the individual patient and the urgency of treatment. It is helpful to develop a treatment plan based on shortterm, intermediate-term, and long-term objectives. For example, TABLE 459-3  Disorders Associated with Myasthenia Gravis and Recommended Laboratory Tests Associated disorders   Disorders of the thymus: thymoma, hyperplasia   Other autoimmune neurologic disorders: chronic inflammatory demyelinating polyneuropathy, neuromyelitis optica   Other autoimmune disorders: Hashimoto’s thyroiditis, Graves’ disease, rheumatoid arthritis, systemic lupus erythematosus, skin disorders, family history of autoimmune disorder   Disorders or circumstances that may exacerbate myasthenia gravis: hyperthyroidism or hypothyroidism, occult infection, medical treatment for other conditions (see Table 459-5)   Disorders that may interfere with therapy: tuberculosis, diabetes, peptic ulcer, gastrointestinal bleeding, renal disease, hypertension, asthma, osteoporosis, obesity Recommended laboratory tests or procedures   CT or MRI of chest PART 13 Neurologic Disorders   Tests for antinuclear antibodies, rheumatoid factor   Thyroid function tests   Testing for tuberculosis   Fasting blood glucose, hemoglobin A1c   Pulmonary function tests   Bone densitometry Abbreviations: CT, computed tomography; MRI, magnetic resonance imaging. Establish diagnosis unequivocally (see Table 459-1) Search for associated conditions (see Table 459-3) Ocular only Crisis Generalized MRI of brain (if positive, reassess) Anticholinesterase (pyridostigmine) Anticholinesterase (pyridostigmine) Intensive care (tx respiratory infection; fluids) Evaluate for thymectomy (indications: thymoma or generalized MG with anti-AChR antibodies); evaluate surgical risk, FVC Good risk (good FVC) Poor risk (low FVC) Plasmapheresis or intravenous Ig then If unsatisfactory Thymectomy Improved If not improved Evaluate clinical status; if indicated, go to immunosuppression Immunosuppression See text for short-term, intermediate, and long-term treatments FIGURE 459-2  Algorithm for the management of myasthenia gravis. FVC, forced vital capacity; MRI, magnetic resonance imaging. if immediate improvement is essential typically because of the severity of weakness, IVIg should be administered or plasmapher­ esis should be undertaken as “rescue” therapy. For the intermediate term, glucocorticoids, cyclosporine or tacrolimus, rituximab, and the newer complement inhibitors and FcRn antagonists generally produce clinical improvement within a period of 1–3 months. They can be used for bridging until other immunotherapies become effective or in refractory patients. The beneficial effects of other nonsteroidal immunosuppressive therapies, azathioprine and myco­ phenolate mofetil, usually begin after many months (and as long as 1–1.5 years), However, these drugs have advantages over glucocor­ ticoids for the long-term treatment of patients with MG. Rituximab is highly effective in patients with MuSK antibody–positive MG. Glucocorticoid Therapy  Glucocorticoids, when used properly, produce improvement in myasthenic weakness in the great major­ ity of patients. To minimize adverse side effects, prednisone should be given in a single morning dose rather than in divided doses throughout the day. In patients with only ocular or mild general­ ized weakness, the initial dose can be relatively low (15–25 mg/d). The dose is increased stepwise, as tolerated by the patient (usually by 5 mg/d at 7- to 14-day intervals), until there is marked clinical improvement or a dose of 50–60 mg/d is reached. The full effect of a particular dose of prednisone often takes 2–3 weeks to observe. In patients with more severe weakness and those already in the hospital and/or intubated, starting at a high dose is reasonable, typically after pretreatment with IVIg or plasma exchange to protect against early steroid-associated worsening. Patients are maintained for about a month on the dose that controls their symptoms, and then the dosage is slowly tapered (no faster than 10 mg a month until on 20 mg daily and then by 2.5–5 mg every 1–3 months until on 10 mg daily, and more slowly thereafter) to determine the minimum effective dose. Close monitoring both for side effects and for efficacy is essential. Some patients can be managed with­ out the addition of other immunotherapies. Patients on long-term glucocorticoid therapy must be followed carefully to prevent or treat adverse side effects. The most common errors include (1) an insufficient duration or dose of prednisone—improvement may be delayed and gradual; (2) tapering the dosage too early, too rapidly, or excessively; and (3) lack of attention to prevention and treatment of side effects. Other Immunotherapies  Mycophenolate mofetil, azathioprine, cyclosporine, tacrolimus, rituximab, and rarely, cyclophospha­ mide are effective in many patients, either alone or in various combinations. Mycophenolate mofetil is widely used because of its presumed effectiveness and relative lack of side effects. A dose of 1–1.5 g bid is recommended. Its mechanism of action involves inhibition of purine synthesis by the de novo pathway. Since lymphocytes have only the de novo pathway, but lack the alternative salvage pathway that is present in all other cells, mycophenolate inhibits proliferation of lymphocytes but not proliferation of other cells. It does not kill or eliminate preexisting autoreactive lymphocytes, and therefore, clinical improvement may be delayed for many months to a year, until the preexisting autoreactive lymphocytes die spontaneously. The advantage of mycophenolate lies in its relative paucity of adverse side effects. The primary side effect is diarrhea or other GI symptoms. Rare side effects are development of leukopenia and very small risks of malignancy or progressive multifocal leukoencephalopathy inherent in nearly all immu­ nosuppressive treatments. Although two published studies did not show positive outcomes, most experts attribute the negative results to flaws in the trial designs, and mycophenolate is widely used and supported in many guidelines for long-term treatment of myasthenic patients. Azathioprine has long been used for MG, and a randomized, clinical trial demonstrated that it was effective in reducing the dos­ age of prednisone necessary to control MG symptoms. However, the beneficial effect can take a year or more to become evident. Approximately 10–15% of patients are unable to tolerate aza­ thioprine because of idiosyncratic reactions consisting of flulike symptoms (e.g., fever and malaise, abdominal pain), bone marrow suppression, or abnormalities of liver function. An initial dose of 50 mg/d is given for about a week to test for these side effects. If this dose is tolerated, it is increased by 50 mg weekly to 150 mg daily. Some patients require additional increases to reach a dose of ~2–3 mg/kg of total body weight or until the white blood count falls to 3000–4000/μL. Allopurinol should never be used in combination with azathioprine because the two drugs share a common degrada­ tion pathway; the result may be severe bone marrow suppression due to increased effects of the azathioprine. The calcineurin inhibitors cyclosporine and tacrolimus are effec­ tive in MG and work more rapidly than azathioprine and mycophe­ nolate. However, both, and cyclosporin in particular, are associated with more frequent severe side effects including hypertension, nephrotoxicity, and drug interactions. The usual dose of cyclo­ sporine is 4–5 mg/kg per d, and the average dose of tacrolimus is 0.07–0.1 mg/kg per d, given in two equally divided doses. “Trough” blood levels are measured 12 h after the evening dose. The thera­ peutic range for the trough level of cyclosporine is 150–200 ng/L, and for tacrolimus, it is 5–15 ng/L. Rituximab is a monoclonal antibody that binds to the CD20 mol­ ecule on B lymphocytes. It is widely used for the treatment of B-cell lymphomas and has also proven successful in the treatment of several autoimmune diseases including rheumatoid arthritis, pem­ phigus, and some IgM-related neuropathies. Rituximab can induce prolonged remissions in MuSK antibody–positive MG, which was previously more difficult to treat than anti-AChR–positive MG. We treat MuSK antibody–positive MG patients with 1 g IV on two occasions 2 weeks apart. Periodically, a repeat course needs to be administered; some MuSK patients can go up to 2–3 years between infusions. A large National Institutes of Health–sponsored randomized trial of rituximab in AChR antibody–positive generalized MG failed to demonstrate efficacy, but many of the participants had longstanding MG that failed other therapies. However, a more recent randomized, placebo-controlled trial from Sweden of new-onset MG (<1 year) reported that a single infusion of 500 mg IV ritux­ imab resulted in greater likelihood of participants achieving mini­ mal MG manifestations and reduced need for rescue medications compared with placebo at 48 weeks. Further studies are needed, however, to determine how long this improvement may last and the need for retreatment. For the rare refractory MG patient, a course of high-dose cyclophosphamide may induce long-lasting benefit. At high doses, cyclophosphamide eliminates mature lymphocytes but spares hematopoietic precursors (stem cells), because they express the enzyme aldehyde dehydrogenase, which hydrolyzes cyclophospha­ mide. This procedure is reserved for refractory patients and should be administered only in a facility fully familiar with this approach. Maintenance immunotherapy after treatment is usually required to sustain the beneficial effect. NEWLY APPROVED TREATMENTS Special attention needs to be given to the newly approved therapies for MG. Complement inhibitors and FcRn inhibitors have revolu­ tionized treatment of patients with MG (Table 459-4). Because they work quickly in most patients, they may be used as bridge therapies until other immunotherapies can “kick in” or in those who are refractory to standard treatments. Complement Inhibitors  Currently, three complement inhibitors are U.S. Food and Drug Administration (FDA) approved for AChR antibody–positive generalized MG based on positive clinical trial results. Most patients who will improve on these agents will do so within the first 12 weeks, and improvement is appreciated in many within the first 1–4 weeks. These drugs each work by inhibiting the cleavage of C5 in the terminal complement cascade. Eculizumab was shown to be effective in a positive phase 3 study, which led to FDA approval in 2017. Subsequently, ravulizumab was approved in 2021. Both eculizumab and ravulizumab are monoclonal antibod­ ies given intravenously; ravulizumab has a longer effect. Zilucoplan is the latest complement inhibitor and was approved in 2023. Unlike eculizumab and ravulizumab, zilucoplan is a subcutaneously administered macrocyclic peptide inhibitor of C5. Because it is not a monoclonal antibody like eculizumab and ravulizumab, it can be coadministered with plasma exchange, IVIg, or FcRn antagonists. An additional benefit is that patients can self-administer zilucoplan with a prefilled syringe. In practice, we typically reassess efficacy at 12 weeks in patients treated with C5 inhibitors and decide whether or not to continue treatment. Complement inhibition increases the risk of meningococcal infection. Therefore, a first series of vaccinations with both quadri­ valent and MenB vaccines is given at least 14 days prior to initiation of treatment and then again 1–2 months later. Those patients in whom treatment needs to be started sooner than this initial vac­ cination series is complete should receive antibiotic prophylaxis (penicillin). Vaccination reduces, but does not eliminate, the risk of meningitis. Physicians must enroll in drug-specific risk evaluation and mitigation strategy programs for all complement inhibitors and counsel patients regarding the risk and signs and symptoms of men­ ingitis. Patients are recommended to carry a safety/alert wallet card. CHAPTER 459 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction Neonatal Fc Receptor (FcRn) Antagonists   FcRns on endothelial cells salvage IgG and albumin from degradation by lysosomes, lead­ ing to longer IgG half-lives. Blocking the FcRn results in increased catabolism of IgG, thereby reducing IgG (and pathogenic antibody) levels. The potential benefits over plasma exchange include the ease of administration, increased availability, and reduced risk in patients with coagulopathies or limited peripheral venous access. Efgartigimod and rozanolixizumab are now approved for clinical use based on their efficacy in clinical trials (Table 459-4). Efgar­ tigimod can be given intravenously or subcutaneously, whereas rozanolixizumab is given via a subcutaneous infusion. Importantly, only rozanolixizumab is approved for both anti-AChR and antiMuSK generalized myasthenia. As with complement inhibitors, the FcRn inhibitors usually are effective within the first 3 months of treatment, again often within the first month. Side effects are some­ what variable and include increased risk of respiratory and urinary infections, headaches (including aseptic meningitis with rozano­ lixizumab), and hypoalbuminemia (FcRn also prevents lysosomes from degrading albumin). Comparative efficacy with one another or with complement inhibitors cannot be readily ascertained with existing clinical trial data. One potential benefit of FcRn antagonists over complement inhibitors is that guidance from clinical trials exists on how to ramp up or ramp down administration frequency based on clinical response. PLASMAPHERESIS AND INTRAVENOUS IMMUNOGLOBULIN Plasmapheresis has long been used therapeutically in MG. Plasma, which contains the pathogenic antibodies, is mechanically sepa­ rated from the blood cells, which are then returned to the patient. A course of five or six exchanges (3–4 L per exchange) is generally administered over a 10- to 14-day period. Plasmapheresis produces a short-term reduction in anti-AChR antibodies, with clinical improvement in many patients. It is most useful as a temporary treatment in severely affected patients or to improve the patient’s condition prior to surgery (e.g., thymectomy). The indications for the use of IVIg are the same as those for plasma exchange: to produce rapid improvement to help the patient through a difficult period of myasthenic weakness or prior to sur­ gery. This treatment has the advantages of not requiring special equipment or large-bore venous access. The usual dose is 2 g/kg, which is typically administered over 2–5 days. Improvement occurs in ~70% of patients, beginning during treatment or within a week and continuing for weeks to months. The exact mechanism of TABLE 459-4  Comparison of New Complement Inhibitors and FcRn Inhibitors for Generalized Myasthenia DRUG/MECHANISM TRIAL(S) FDA APPROVED DOSING CLINICAL TRIAL POPULATION NOTES Approved Complement Inhibitors Eculizumab (humanized monoclonal Ab anti-C5, inhibits terminal complement/MAC activation) Phase 2 REGAIN : 26 weeks REGAIN open-label extension: 22.7 months (median), up to 3 years Loading: 900 mg IV weekly × 4 Maintenance: 1200 mg IV on week 5 then q2 weeks Ravulizumab (humanized monoclonal Ab anti-C5, inhibits terminal complement/MAC activation) Phase 2 CHAMPION MG: 26 weeks CHAMPION MG open-label extension Actual body weight–based dosing Loading: 40 to <60 kg: 2400 mg IV; 60 to <100 kg: 2700 mg IV; ≥100 kg: 3000 mg IV Maintenance (14 days after loading and then q8 weeks): 40 to <60 kg: 3000 mg IV; 60 to <100 kg: 3300 mg IV; ≥100 kg: 3600 mg IV PART 13 Neurologic Disorders Zilucoplan (synthetic macrocyclic peptide targeting C5/C5b, inhibits terminal complement/MAC activation) Phase 2 RAISE: 12 weeks RAISE-XT open-label extension   Phase 3 dosing 0.3 mg/kg SC daily Label dosing (prefilled syringes): Actual body weight–based daily SC injections <56 kg: 16.6 mg daily; 56 kg to <77 kg: 23 mg; ≥77 kg: 32.4 mg Approved FcRn Inhibitors Efgartigimod IV/SC (human anti-FcRn IgG1 Fc fragment; reduces autoantibody levels and IgG recycling) Phase 2 ADAPT: 26 weeks ADAPT open-label extension: up to 3 years ADAPT-SC noninferiority study, open-label parallel-group: 12 weeks with open-label extension Weight-based IV: 10 mg/kg IV (up to 1200 mg) weekly × 4 = 1 cycle Fixed dose SC: 1,008 mg SC weekly × 4 = 1 cycle Rozanolixizumab (human anti-FcRn IgG4 monoclonal antibody; reduces autoantibody levels and IgG recycling) Phase 2 MycarinG: 18 weeks Open-label extension: completed Phase 3 included 7 and 10 mg/ kg given as SC infusion weekly for 6 weeks followed by 8 weeks off. Patients averaged 4 treatment cycles per year (range 1–7) Clinical dosing: <50 kg: 420 mg; 50 to <100 kg: 560 mg; ≥100 kg: 840 mg given as a weekly health care provider–administered SC infusion for 6 weeks (1 cycle) Abbreviations: AChR, acetylcholine receptor; Ab, antibody; FcRn, neonatal Fc receptor; FDA, Food and Drug Administration; gMG, generalized myasthenia gravis; IVIg, intravenous immunoglobulin; MAC, membrane attack complex; MGADL, Myasthenia Gravis Activities of Daily Living; MuSK, muscle-specific tyrosine kinase; NSIST, nonsteroidal immunosuppressant therapy; PLEX, plasma exchange; QMG, quantitative myasthenia gravis. Source: Reproduced with permission from AA Amato et al (eds): Amato and Russell’s Neuromuscular Disorders, 3rd ed. New York: McGraw Hill; 2025. action of IVIg in MG is unknown; the treatment has no consistent long-term effect on the measurable amount of circulating AChR antibody. Adverse reactions are generally not serious but may include headache, fluid overload, and rarely aseptic meningitis, renal failure, hemolytic anemia, and embolic or thrombotic events. IVIg or plasma exchange is occasionally used in combination with other immunosuppressive therapy for maintenance treatment of difficult MG, though this is less common in the contemporary era since the advent of C5 inhibitors and FcRn antagonists. INVESTIGATIONAL TREATMENTS Several trials of different complement and FcRn inhibitors are underway. Inhibitors of interleukin 6 and CD19 targets on B cells are also being studied. Notably, CD19-targeting chimeric antigen AChR ab + gMG (class II–IV) Refractory (at least 2 NSISTs or at least 1 NSIST and PLEX/IVIg) MGADL score ≥6 Did not reach statistical significance for primary MGADL endpoint Reached significance for multiple secondary endpoints Requires meningococcal vaccination Adults with AChR ab + gMG (class II–IV) MGADL score ≥6 Requires meningococcal vaccination   Adults with AChR ab + gMG (class II–IV) MGADL score ≥6 QMG ≥12 Requires meningococcal vaccination Self-administered SC Adults with gMG regardless of Ab status, MGADL at least 5 with 50% nonocular ADAPT was designed to observe wearing off – cycles repeated at return of symptoms and no sooner than every 8 weeks Number of infusions per cycle and time between cycles can be individualized (as was done in the open-label extension) Efgartigimod SC is not currently approved for selfinjection; health care provider administered; refrigeration required Adults with AChR or MuSK Ab + gMG (11% of participants) MGADL score ≥3 QMG score ≥11 Headache occurred in 38–45% of treatment group and 19% of placebo, including rare aseptic meningitis Infection rate higher in 10 mg/kg dosing group; efficacy equivalent Shorter mean disease duration than other phase 3 trials (5–6 years) Hypoalbuminemia and peripheral edema receptor (CAR) therapy and chimeric autoantibody receptor T (CAART) therapy targeting the antibody ligand on T cells are also in clinical trials for MG. MANAGEMENT OF MYASTHENIC CRISIS Myasthenic crisis is defined as an exacerbation of weakness suf­ ficient to endanger life; it usually includes ventilatory failure caused by diaphragmatic and intercostal muscle weakness. Treatment should be carried out in intensive care units staffed with teams experienced in the management of MG. The possibility that dete­ rioration could be due to excessive anticholinesterase medica­ tion (“cholinergic crisis”) is unlikely given that very high doses of cholinesterase inhibitors are rarely used but is considered in the differential. The most common cause of crisis is intercurrent infection. This should be treated immediately because the mechani­ cal and immunologic defenses of the patient can be assumed to be compromised. The myasthenic patient with fever and early infec­ tion should be treated like other immunocompromised patients. Early and effective antibiotic therapy, ventilatory assistance, and pulmonary physiotherapy are essentials of the treatment program. As discussed above, plasmapheresis or IVIg is frequently helpful in hastening recovery. MANAGEMENT OF MYASTHENIA ASSOCIATED WITH IMMUNE CHECKPOINT INHIBITOR THERAPY MG is a rare complication of ICI therapy for cancer. It can develop de novo or as an exacerbation of preexisting diagnosed or undiag­ nosed disease. Patients usually manifest with ocular, bulbar, neck, and respiratory weakness within the first one to four cycles of ICI therapy. Compared to idiopathic MG, ICI-associated MG is more likely to be seronegative and overlap with myositis and myocarditis. The mortality rate is 20–50%, most often because of severe myocar­ ditis. Importantly, ICI-associated myositis is more common than immune-related MG. It can resemble MG clinically, with prominent or exclusively ocular weakness but without evidence for a decre­ menting response on repetitive nerve stimulation. The mainstay of treatment for ICI-associated MG is glucocorticoids, including IV solumedrol (which differs from idiopathic MG), and with plasma exchange or IVIg added for severe weakness. Complement inhibi­ tors have recently been reported as effective in AChR antibody– positive ICI-associated MG with myositis and myocarditis. DRUGS TO AVOID IN MYASTHENIC PATIENTS Many drugs can potentially exacerbate weakness in patients with MG (Table 459-5). As a rule, the listed drugs should be avoided whenever possible. TABLE 459-5  Drugs with Interactions in Myasthenia Gravis (MG) Drugs That May Exacerbate Weakness in Patients with MG Antibiotics Aminoglycosides: e.g., streptomycin, tobramycin, kanamycin Quinolones: e.g., ciprofloxacin, levofloxacin, ofloxacin, gatifloxacin Macrolides: e.g., erythromycin, azithromycin Nondepolarizing muscle relaxants for surgery d-Tubocurarine (curare), pancuronium, vecuronium, atracurium Beta-blocking agents Propranolol, atenolol, metoprolol Local anesthetics and related agents Procaine, Xylocaine in large amounts Procainamide (for arrhythmias) Botulinum toxin Botox exacerbates weakness Quinine derivatives Quinine, quinidine, chloroquine, mefloquine (Lariam) Magnesium Decreases acetylcholine release Penicillamine May cause MG Checkpoint inhibitors May cause MG and other autoimmune neuromuscular disorders (e.g., myositis, inflammatory neuropathy) Drugs with Important Interactions in MG Cyclosporine and tacrolimus Broad range of drug interactions, which may raise or lower levels Azathioprine Avoid allopurinol—combination may result in myelosuppression ■ ■PATIENT ASSESSMENT To evaluate the effectiveness of treatment as well as drug-induced side effects, it is important to assess the patient’s clinical status systemati­ cally at baseline and on repeated interval examinations. Following the patient with spirometry with determination of forced vital capacity and mean inspiratory and expiratory pressures is important. PROGNOSIS Approximately 20% of patients with MG achieve a sustained remission and can be tapered off all immunotherapies. There does not appear to be a correlation between disease severity and likelihood of remis­ sion. Thymectomy may increase the chance of achieving remission in anti-AChR MG, but the large, randomized MGTX trial was too short in duration to examine this endpoint; rather, the results revealed only that thymectomy was efficacious and led to less use of glucocorticoids and second-line agents. Mortality from MG diminished greatly during the twentieth century, changing from a “grave” illness with mortality of nearly 70% a century ago, to 2–30% by the 1950s, with contemporary estimates in the 1–5% range. Anti-MuSK patients generally were more difficult to treat than anti-AChR MG in the past. However, recent series suggest that rituximab is effective in this subgroup, thereby reducing these risks and improving the prognosis. Nonparaneoplastic LEMS is usually responsive to immunotherapy and symptomatic treatment with pyridostigmine and 3,4-DAP. In older adults, LEMS is most often paraneoplastic, and screening for an underlying tumor is indicated (Chap. 99). Recent studies suggest that survival in patients with LEMS has improved, for uncertain reasons and likely not due to earlier diag­ nosis and treatment of the tumor. There is wide variability in age of onset, severity, and prognosis of the many types of CMS. CHAPTER 459 Myasthenia Gravis and Other Diseases of the Neuromuscular Junction GLOBAL ISSUES The incidence of MG and its subtypes varies in different populations, for example, occurring in ~2–10/106 individuals in the United States and the Netherlands and up to 20/106 individuals in Spain. Estimates of prevalence in different parts of the world range widely from 2–360/106. The age of onset may also be influenced by geographic and/or ethnic differences. Juvenile-onset MG is uncommon in Western popula­ tions but may represent more than half of cases in Asians. MuSK MG appears to be more common in the Mediterranean area of Europe than in northern Europe and is also more common in the northern regions of East Asia than in the southern regions. A concern during the COVID-19 pandemic is whether MG patients on immunosuppressive therapies might be at increased risk of infection or developing a more severe course. Furthermore, flares of MG can be triggered by infection, and contracting COVID-19 may lead to an exacerbation, including MG crisis. We have not reduced the dosage of immunosuppressive medications in MG patients who are doing well but have been more likely to manage worsening disease by treating with IVIg rather than increasing the dosage of, or adding new, immunosuppressive agents. Patients are strongly advised to receive the COVID-19 vaccine, wear masks, and maintain social distancing, particularly when infection levels are high in their communities. An international panel published guidelines for management of MG patients during the pandemic. ■ ■FURTHER READING Amato AA et al: Amato and Russell’s Neuromuscular Disorders, 3rd ed. New York, McGraw Hill, 2025. Guidon AC: Lambert-Eaton myasthenic syndrome, botulism, and immune checkpoint inhibitor-related myasthenia gravis. Continuum (Minneap Minn) 25:1785, 2019. Gwathmey KG et al: How should newer therapeutic agents be incor­ porated into the treatment of patients with myasthenia gravis? Muscle Nerve 69:389, 2024. Hehir MK 2nd, Li Y: Diagnosis and management of myasthenia gra­ vis. Continuum (Minneap Minn) 28:1615, 2022. International mg/covid-19 working group et al: Guidance for the management of myasthenia gravis (MG) and Lambert-Eaton myas­ thenic syndrome (LEMS) during the COVID-19 pandemic. J Neurol Sci 412:116803, 2020. # 31 - 460 Muscular Dystrophies and Other Muscle Diseases ### 460 Muscular Dystrophies and Other Muscle Diseases Narayanaswami P et al: International consensus guidance for man­ agement of myasthenia gravis: 2020 update. Neurology 96:114, 2021. Ohno K et al: Clinical and pathologic features of congenital myas­ thenic syndromes caused by 35 genes: A comprehensive review. Int J Mol Sci 24:3730, 2023. Piehl F et al: Efficacy and safety of rituximab for new-onset general­ ized myasthenia gravis: The RINOMAX randomized clinical trial. JAMA Neurol 79:1105, 2022. Sacca F et al: Efficacy of innovative therapies in myasthenia gravis: A systematic review, meta-analysis and network meta-analysis. Eur J Neurol 30:3854, 2023. Salari N et al: Global prevalence of myasthenia gravis and the effec­ tiveness of common drugs in its treatment: A systematic review and meta-analysis. J Transl Med 19:516, 2021. Wolfe GI et al: Long-term effect of thymectomy plus prednisone ver­ sus prednisone alone in patients with non-thymomatous myasthenia gravis: 2-year extension of the MGTX randomised trial. Lancet Neu­ rol 18:259, 2019. PART 13 Neurologic Disorders VIDEO 459-1  Myasthenia gravis and other diseases of the neuromuscular junction. Anthony A. Amato, Robert H. Brown, Jr. Muscular Dystrophies and Other Muscle Diseases Myopathies are disorders with structural changes or functional impair­ ment of muscle and can be differentiated from other diseases of the motor unit (e.g., lower motor neuron or neuromuscular junction pathologies) by characteristic clinical and laboratory findings. Myas­ thenia gravis and related disorders are discussed in Chap. 459; inflammatory myopathies are discussed in Chap. 377. ■ ■CLINICAL FEATURES The most important aspect of assessing individuals with neuromus­ cular disorders is taking a thorough history of the patient’s symp­ toms, disease progression, and past medical and family history, as well as performing a detailed neurologic examination. Based on this and additional laboratory workup (e.g., serum creatine kinase [CK], electromyography [EMG]), one can usually localize the site of the lesion to muscle (as opposed to motor neurons, peripheral nerves, or neuromuscular junction) and the pattern of muscle involvement. It is this pattern of muscle involvement that is most useful in narrow­ ing the differential diagnosis (Table 460-1). Most myopathies present with proximal, symmetric limb weakness with preserved reflexes and sensation. However, asymmetric and predominantly distal weakness can be seen in some myopathies. An associated sensory loss suggests a peripheral neuropathy or a central nervous system (CNS) abnormal­ ity (e.g., myelopathy) rather than a myopathy. On occasion, disorders affecting the motor nerve cell bodies in the spinal cord (anterior horn cell disease), the neuromuscular junction, or peripheral nerves can mimic findings of myopathy. Muscle Weakness  Symptoms of muscle weakness can be either intermittent or persistent. Disorders causing intermittent weakness (Table 460-1 and Fig. 460-1) include myasthenia gravis, periodic paralyses (hypokalemic or hyperkalemic), and metabolic energy defi­ ciencies of glycolysis (especially myophosphorylase deficiency), fatty acid utilization (carnitine palmitoyltransferase [CPT] deficiency), and some mitochondrial myopathies. The states of energy deficiency cause activity-related muscle breakdown accompanied by myoglobinuria. Most muscle disorders cause persistent weakness (Table 460-1 and Fig. 460-2). In the majority of these, including most types of muscular dystrophy and inflammatory myopathies, the proximal muscles are weaker than the distal and are symmetrically affected, and the facial muscles are spared, a pattern referred to as limb-girdle weakness. The differential diagnosis is more restricted for other patterns of weak­ ness. Facial weakness (difficulty with eye closure and impaired smile) and scapular winging (Fig. 460-3) are characteristic of facioscapulo­ humeral dystrophy (FSHD). Facial and distal limb weakness associated with hand grip myotonia is virtually diagnostic of myotonic dystrophy type 1. When other cranial nerve muscles are weak, causing ptosis or extraocular muscle weakness, the most important disorders to consider include neuromuscular junction disorders, oculopharyngeal muscu­ lar dystrophy, mitochondrial myopathies, or some of the congenital myopathies (Table 460-1). A pathognomonic pattern characteristic of inclusion body myositis is atrophy and weakness of the flexor forearm (e.g., wrist and finger flexors) and quadriceps muscles that is often asymmetric. Less frequently seen, but important diagnostically, are the axial myopathies that predominantly affect the paraspinal muscles and include dropped head syndrome indicative of selective neck exten­ sor muscle weakness. The most important neuromuscular diseases associated with this axial muscle weakness include myasthenia gravis, amyotrophic lateral sclerosis, sporadic late-onset nemaline rod myopa­ thy (SLONM), late-onset ryanodine receptor 1 (RyR1) myopathies, hyperparathyroidism, focal myositis, and some forms of inclusion body myopathy. A final pattern, recognized because of preferential distal extremity weakness, is seen in the distal myopathies. It is important to examine functional capabilities to help disclose certain patterns of weakness (Table 460-1 and Table 460-2). The Gower sign (Fig. 460-4) is particularly useful. Observing the gait of an individual may disclose a hyperlordotic posture caused by combined trunk and hip weakness, frequently exaggerated by toe walking (Fig. 460-5). A waddling gait is caused by the inability of weak hip muscles to prevent hip drop or hip dip. Hyperextension of the knee (genu recurvatum or back-kneeing) is characteristic of quadriceps muscle weakness, and a steppage gait, due to foot drop, accompanies distal weakness. Any disorder causing muscle weakness may be accompanied by fatigue, referring to an inability to maintain or sustain a force (patho­ logic fatigability). This condition must be differentiated from asthenia, a type of fatigue caused by excess tiredness or lack of energy. Associated symptoms may help differentiate asthenia and pathologic fatigability. Asthenia is often accompanied by a tendency to avoid physical activi­ ties, complaints of daytime sleepiness, necessity for frequent naps, and difficulty concentrating on activities such as reading. There may be feelings of overwhelming stress and depression. In contrast, pathologic fatigability occurs in disorders of neuromuscular transmission and in disorders altering energy production, including defects in glycolysis, lipid metabolism, or mitochondrial energy production. Pathologic fati­ gability also occurs in chronic myopathies because of difficulty accom­ plishing a task with less muscle. Pathologic fatigability is accompanied by abnormal clinical or laboratory findings. Fatigue without those supportive features almost never indicates a primary muscle disease. Muscle Pain (Myalgias), Cramps, and Stiffness  Some myopa­ thies can be associated with muscle pain, cramps, contractures, stiff or rigid muscles, or inability to relax the muscles (e.g., myotonia) (Table 460-1). Muscle cramps are abrupt in onset, short in duration, triggered by voluntary muscle contraction, and may cause abnormal postur­ ing of the joint. Muscle cramps often occur in neurogenic disorders, especially motor neuron disease (Chap. 448), radiculopathies, and polyneuropathies (Chap. 457), but are not a feature of most primary muscle diseases. A muscle contracture is different from a muscle cramp. In both con­ ditions, the muscle becomes hard, but a contracture is associated with energy failure in glycolytic disorders. The muscle is unable to relax after an active muscle contraction. The EMG shows electrical silence. Confusion is created because contracture also refers to a muscle that cannot be passively stretched to its proper length (fixed contracture) TABLE 460-1  Myopathies by Pattern of Weakness/Muscle Involvement Proximal (Limb-Girdle) Weakness Late-onset central core (RYR1 mutations) SLONM Metabolic (late-onset Pompe, McArdle disease, lipid storage, mitochondrial) Hyperparathyroidism/osteomalacia/vitamin D deficiency Myasthenia gravis Most dystrophies (e.g., dystrophinophies, limb-girdle, myofibrillar myopathy, myotonic dystrophy type 2, rare FSHD) Congenital myopathies (e.g., central core, multiminicore, centronuclear, nemaline rod) Metabolic myopathies (e.g., glycogen and lipid storage diseases) Mitochondrial myopathies Inflammatory myopathies (DM, PM, IMNM, anti-synthetase syndrome) Toxic myopathies (see Table 460-6) Endocrine myopathies Neuromuscular junction disorders (myasthenia gravis, LEMS, congenital myasthenia, botulism, see Chap. 459) SLONM Distal Weakness Distal muscular dystrophies/myofibrillar myopathy (see Table 460-5) Congenital myopathies (e.g., late-onset centronuclear and nemaline rod myopathies) Oculopharyngeal distal myopathy Metabolic   Glycogen storage disease (e.g., brancher and debrancher deficiency, rarely McArdle disease)   Lipid storage disease (e.g., neutral lipid storage myopathy, multiacyldehydrogenase deficiency) NMJ disorders (e.g., rare myasthenia gravis and congenital myasthenia) Proximal Arm/Distal Leg Weakness (Scapuloperoneal or Humeroperonal) Weakness Facioscapulohumeral muscular dystrophy (FSHD) Scapuloperoneal myopathy and neuropathy Myofibrillar myopathies Emery-Dreifuss muscular dystrophy (EDMD) Bethlem myopathy Distal Arm/Proximal Leg Weakness Inclusion body myositis (usually wrist and finger flexors in arms, hip flexors and knee extensors in legs, and asymmetric) Myotonic dystrophy (uncommon presentation) Axial Muscle Weakness Inflammatory (cervicobrachial myositis) sIBM and hIBM Myotonic dystrophy 2 Isolated neck extensor myopathy/bent spine syndrome FSHD Abbreviations: DM, dermatomyositis; hIBM, hereditary inclusion body myopathy; IMNM, immune-mediated necrotizing myopathy; LEMS, Lambert-Eaton myasthenic syndrome; NMJ, neuromuscular junction; PM, polymyositis; sIBM, sporadic inclusion body myositis; SLONM, sporadic late-onset nemaline myopathy. because of fibrosis. In some muscle disorders, especially in Emery-Dreifuss muscular dystrophy (EDMD) and Bethlem myopathy, fixed contrac­ tures occur early and represent distinctive features of the disease. Myotonia is a condition of prolonged muscle contraction followed by slow muscle relaxation. It always follows muscle activation (action myotonia), usually voluntary, but may be elicited by mechanical stimu­ lation (percussion myotonia) of the muscle. Myotonia typically causes difficulty in releasing objects after a firm grasp. In myotonic muscular dystrophy type 1 (DM1), distal weakness usually accompanies myoto­ nia, whereas in DM2, proximal muscles are more affected. Myotonia also occurs with myotonia congenita (a chloride channel disorder), but in this condition, muscle weakness is usually not prominent. Myotonia may also be seen in individuals with sodium channel mutations (hyper­ kalemic periodic paralysis or potassium-sensitive myotonia). Another sodium channelopathy, paramyotonia congenita (PC), also is associated with muscle stiffness. In contrast to other disorders associated with myotonia in which the myotonia is eased by repetitive activity, PC is named for a paradoxical phenomenon whereby the myotonia worsens Eye Muscle Weakness (Ptosis/Ophthalmoparesis) Ptosis without ophthalmoparesis   Myotonic dystrophy   Congenital myopathies   Neuromuscular junction disorders Ptosis with ophthalmoparesis   Oculopharyngeal dystrophy   Oculopharygeal distal myopathy   Mitochondrial myopathy   hIBM type 3   Neuromuscular junction disorders CHAPTER 460 Episodic Weakness or Myoglobinuria Related to exercise   Glycogenoses (e.g., McArdle disease, etc.)   Lipid disorders (e.g., CPT2 deficiency)   Mitochondrial myopathies (e.g., cytochrome B deficiency) Not related to exercise   RYR1 mutations can cause malignant hyperthermia, episodic rhabdomyolysis/ Muscular Dystrophies and Other Muscle Diseases myoglobinuria, and atypical periodic paralysis   Other causes of malignant hyperthermia Drugs/toxins (e.g., statins)   Prolonged/intensive eccentric exercise   Inflammatory (e.g., PM/DM—rare, viral/bacterial infections) Delayed or unrelated to exercise   Periodic paralysis (e.g., hereditary hyper- or hypokalemic, thyrotoxic, associated renal tubular acidosis, acquired electrolyte imbalance)   NMJ disorders Muscle Stiffness/Decreased Ability to Relax Myotonic dystrophy 1 and 2 Myotonia congenita Paramyotonia congenita Hyperkalemic periodic paralysis with myotonia Potassium aggravated myotonia Schwartz-Jampel syndrome Other: rippling muscle disease (acquired and hereditary), acquired neuromyotonia (Isaacs’ syndrome), stiff-person syndrome, Brody’s disease with repetitive activity. Potassium-aggravated myotonia is an allelic disorder in which myotonia is brought on by consumption of too much potassium-containing foods. Muscle stiffness can refer to different phenomena. Some patients with inflammation of joints and periarticular surfaces feel stiff. This condition is different from the disorders of hyperexcitable motor nerves causing stiff or rigid muscles. In stiff-person syndrome, spon­ taneous discharges of the motor neurons of the spinal cord cause involuntary muscle contractions mainly involving the axial (trunk) and proximal lower extremity muscles. The gait becomes stiff and labored, with hyperlordosis of the lumbar spine. Superimposed episodic muscle spasms are precipitated by sudden movements, unexpected noises, and emotional upset. The muscles relax during sleep. Serum antibodies against glutamic acid decarboxylase are present in approximately twothirds of cases. In acquired neuromyotonia (Isaacs’ syndrome), there is hyperexcitability of the peripheral nerves manifesting as continuous muscle fiber activity in the form of widespread fasciculations and myokymia with impaired muscle relaxation. Muscles of the leg are stiff, Yes No Exam normal between attacks Proximal > distal weakness during attacks Variable weakness includes EOMs, ptosis, bulbar and limb muscles AChR or Musk AB positive Abnormal Yes No Check for dysmorphic features Genetic testing for Anderson-Tawil syndrome Decrement on 2–3 Hz repetitive nerve stimulation (RNS) or increased jitter on single fiber EMG (SFEMG) Acquired seropositive MG Check chest CT for thymoma Yes No PART 13 Neurologic Disorders Consider: Seronegative MG Congenital myasthenia* Psychosomatic weakness** Lambert-Eaton myasthenic syndrome Check: Voltage gated Ca channel Abs Chest CT for lung Ca *Genetic testing (Chap. 459) **If Abs, RNS, SFEMG are all normal or negative FIGURE 460-1  Diagnostic evaluation of intermittent weakness. AChR AB, acetylcholine receptor antibody; CPT, carnitine palmitoyltransferase; EKG, electrocardiogram; EMG, electromyogram; EOMs, extraocular muscles; MG, myasthenia gravis; PP, periodic paralysis. and the constant contractions of the muscle cause increased sweating of the extremities. This peripheral nerve hyperexcitability is mediated by antibodies that target voltage-gated potassium channels. There are two painful muscle conditions of particular importance, neither of which is associated with muscle weakness. Fibromyalgia is a common, yet poorly understood myofascial pain syndrome in which patients complain of severe muscle pain and tenderness, severe fatigue, and often poor sleep. Serum CK, erythrocyte sedimentation rate (ESR), EMG, and muscle biopsy are normal (Chap. 385). Polymyalgia rheu­ matica occurs mainly in patients aged >50 years and is characterized by stiffness and pain in the shoulders, lower back, hips, and thighs Persistent Weakness Patterns of Weakness on Neurologic Exam Proximal > distal IMNM; PM; DM; anti-synthetase syndrome; muscular dystrophies; mitochondrial and metabolic myopathies; toxic, endocrine myopathies Facial, distal, quadriceps; handgrip myotonia Myotonic muscular dystrophy Ptosis, EOMs OPMD; mitochondrial myopathy; myotubular myopathy Facial weakness and scapular winging (FSHD) Myopathic EMG confirms muscle disease and excludes ALS Repetitive nerve stimulation abnormalities suggest a neuromuscular junction disorder (e.g., MG, LEMS, botulism) CK elevation supports myopathy May need DNA testing for further distinction of inherited myopathies Muscle biopsy will help distinguish many disorders FIGURE 460-2  Diagnostic evaluation of persistent weakness. Examination reveals one of seven patterns of weakness. The pattern of weakness in combination with the laboratory evaluation leads to a diagnosis. ALS, amyotrophic lateral sclerosis; CK, creatine kinase; DM, dermatomyositis; EMG, electromyography; EOMs, extraocular muscles; FSHD, facioscapulohumeral dystrophy; IBM, inclusion body myositis; IMNM, immune-mediated necrotizing myopathy; MG, myasthenia gravis; OPMD, oculopharyngeal muscular dystrophy; PM, polymyositis. Intermittent weakness Myoglobinuria Exam usually normal between attacks Proximal > distal weakness during attacks EKG Forearm exercise Normal Normal lactic acid rise Consider CPT deficiency or other fatty acid metabolism disorders No Yes Myotonia on exam Reduced lactic acid rise Consider glycolytic defect Low potassium level Normal or elevated potassium level Genetic testing Hypokalemic PP Hyperkalemic PP Paramyotonia congenita No diagnosis Muscle biopsy DNA test confirms diagnosis (Chap. 375). The ESR and CRP are elevated, while serum CK, EMG, and muscle biopsy are normal. Muscle Enlargement and Atrophy  In most myopathies, muscle tissue is replaced by fat and connective tissue, but the size of the muscle is usually not affected. However, in many limb-girdle mus­ cular dystrophies, enlarged calf muscles are typical. The enlargement represents true muscle hypertrophy; thus, the term pseudohypertrophy should be avoided when referring to these patients. The calf muscles remain very strong even late in the course of these disorders. Muscle enlargement can also result from infiltration by sarcoid granulomas, amyloid deposits, bacterial and parasitic infections, and focal myositis. Dropped head/ Axial MG; PM; ALS; hyperpara- thyroid; Axial myopathy Proximal & distal (hand grip), and quadriceps IBM Distal Distal myopathy (see Table 460-1) FIGURE 460-3  Facioscapulohumeral dystrophy with prominent scapular winging. In contrast, muscle atrophy is characteristic of other myopathies. In Miyoshi myopathy, which can be caused by mutations in the genes that encode for dysferlin and anoctamin 5, there is a predilection for early atrophy of the gastrocnemius muscles, particularly the medial aspect. Atrophy of the humeral muscles is characteristic of FSHD and EDMD. ■ ■LABORATORY EVALUATION Various tests can be used to evaluate a suspected myopathy, including CK levels, endocrine studies (e.g., thyroid function tests, parathyroid hormone and vitamin D levels), autoantibodies (associated with myo­ sitis and systemic disorders), forearm exercise test, muscle biopsy, and genetic testing. Electrodiagnostic studies can be useful to differenti­ ate myopathies from other neuromuscular disorders (motor neuron disease, peripheral neuropathies, neuromuscular junction disorders) but, in most instances, do not help distinguish the specific type of myopathy. Serum Enzymes  CK is the most sensitive measure of muscle dam­ age. The MM isoenzyme predominates in skeletal muscle, whereas CK-myocardial bound (CK-MB) is the marker for cardiac muscle. Serum CK can be elevated in normal individuals without provocation, presumably on a genetic basis or after strenuous activity, trauma, a pro­ longed muscle cramp, or a generalized seizure. Aspartate aminotrans­ ferase (AST), alanine aminotransferase (ALT), aldolase, and lactate dehydrogenase (LDH) are enzymes sharing an origin in both muscle and liver. Problems arise when the levels of these enzymes are found to be elevated in a routine screening battery, leading to the erroneous TABLE 460-2  Observations on Examination That Disclose Muscle Weakness FUNCTIONAL IMPAIRMENT MUSCLE WEAKNESS Inability to forcibly close eyes Upper facial muscles Impaired pucker Lower facial muscles Inability to raise head from prone position Neck extensor muscles Inability to raise head from supine position Neck flexor muscles Inability to raise arms above head Proximal arm muscles (may be only scapular stabilizing muscles) Inability to walk without hyperextending knee (back-kneeing or genu recurvatum) Knee extensor muscles Inability to walk with heels touching the floor (toe walking) Shortening of the Achilles tendon Inability to lift foot while walking (steppage gait or foot drop) Anterior compartment of leg Inability to walk without a waddling gait Hip muscles Inability to get up from the floor without climbing up the extremities (Gowers’ sign) Hip, thigh, and trunk muscles Inability to get up from a chair without using arms Hip muscles CHAPTER 460 Muscular Dystrophies and Other Muscle Diseases FIGURE 460-4  Gower sign showing a patient using his arms to climb up the legs in attempting to get up from the floor. assumption that liver disease is present when in fact muscle could be the cause. An elevated γ-glutamyl transferase (GGT) helps to establish a liver origin because this enzyme is not found in muscle. Rarely, aldose can be elevated in an inflammatory myopathy when CK, AST, and ALT are normal, signifying that the inflammation predominantly affects the perimysium (dermatomyositis, graft-versus-host disease) or the sur­ rounding fascia (fasciitis). Electrodiagnostic Studies  EMG, repetitive nerve stimulation, and nerve conduction studies (NCS) (Chap. 457) are helpful in dif­ ferentiating myopathies from motor neuron disease, neuropathies, and neuromuscular junction diseases. Routine NCS are typically normal in myopathies, but reduced amplitudes of compound muscle action potentials may be seen in atrophied muscles. The needle EMG may reveal irritability on needle insertion and spontaneously that is suggestive of a myopathy with active necrosis or muscle membrane instability (inflammatory myopathies, dystrophies, toxic myopathies, myotonic myopathies), whereas a lack of irritability is characteristic of long-standing myopathic disorders (muscular dystrophies with severe fibrofatty replacement, endocrine myopathies, disuse atrophy, and many of the metabolic myopathies between bouts of rhabdomyolysis). In addition, the EMG may demonstrate myotonic discharges that will narrow the differential diagnosis (Table 460-1). Another important PART 13 Neurologic Disorders FIGURE 460-5  Hyperlordotic posture, exaggerated by standing on toes, associated with trunk and hip weakness. EMG finding is the presence of short-duration, small-amplitude, polyphasic motor unit action potentials (MUAPs). In myopathies, the MUAPs fire early but at a normal rate to compensate for the loss of individual muscle fibers, whereas in neurogenic disorders, the MUAPs fire faster. An EMG is usually normal in steroid or disuse myopathy, both of which are associated with type 2 fiber atrophy; this is because the EMG preferentially assesses the physiologic function of type 1 fibers. The EMG can supplement the clinical examination in choosing an appropriately affected muscle to biopsy. Imaging Studies  Skeletal magnetic resonance imaging (MRI) and ultrasound are increasingly utilized to assess the pattern of muscle involvement, which can help in narrowing the diagnosis, and are often more sensitive than the clinical examination and EMG, particularly early in a disease course. For example, there is early predilection of the vastus lateralis and medialis muscles with relative sparing of the rectus femoris muscles on imaging of thigh muscles in patients with inclusion body myositis, and this can be appreciated on imaging prior to weakness being detected on manual muscle testing. MRI can also demonstrate fasciitis when the clinical examination and EMG are normal. Imaging can also be used to help guide what muscle to biopsy in patients with weakness on manual muscle testing and EMG abnormalities only in muscles that are not typically biopsied (e.g., paraspinal or hip girdle). We have found imaging helpful in patients with presumed muscular dystrophy when the muscle biopsy is not diagnostic and genetic test­ ing shows only a variation of unclear significance. In this situation, the pattern of muscle involvement on imaging can support the known pattern of muscle involvement of a specific hereditary myopathy. The cost and availability of MRI preclude routine use in some settings, but ultrasound is more readily available and less expensive. Genetic Testing  This is increasingly available and is the gold stan­ dard for diagnosing patients with hereditary myopathies. Next-generation sequencing panels are increasing utilized, but clinicians need to know their limitations; large deletions and duplications can be missed, as can mutations in noncoding (intronic) regions. Furthermore, testing often reveals sequence alterations of unclear significance. Forearm Exercise Test  With exercise-induced muscle pain and myoglobinuria, there may be a defect in glycolysis. For safety, the test should not be performed under ischemic conditions to avoid an unnec­ essary insult to the muscle, causing rhabdomyolysis. The test is per­ formed by placing a small indwelling catheter into an antecubital vein. A baseline blood sample is obtained for lactic acid and ammonia. The forearm muscles are exercised by asking the patient to vigorously open and close the hand for 1 min. Blood is then obtained at intervals of 1, 2, 4, 6, and 10 min for comparison with the baseline sample. A three- to fourfold rise of lactic acid is typical. The simultaneous measurement of ammonia serves as a control because it should also rise with exercise. In patients with myophosphorylase deficiency and certain other glyco­ lytic defects, the lactic acid rise will be absent or below normal, while the rise in ammonia will reach control values. If there is lack of effort, neither lactic acid nor ammonia will rise. Patients with selective failure to increase ammonia may have myoadenylate deaminase deficiency. This condition has been reported to be a cause of myoglobinuria, but deficiency of this enzyme in asymptomatic individuals makes interpre­ tation controversial. Muscle Biopsy  Muscle biopsy is extremely helpful in evaluation of acquired myopathies but is performed less frequently in suspected hereditary myopathies as genetic testing has become more widely available. However, muscle biopsy can be helpful in cases of suspected hereditary myopathy in which genetic testing was nondiagnostic. Almost any superficial muscle can be biopsied, but it is important to biopsy one that is affected clinically but not too severely (for example, grade 4 out of 5 strength or movement against moderate resistance by manual muscle testing) (Chap. 433). A specific diagnosis can be estab­ lished in many disorders. HEREDITARY MYOPATHIES Muscular dystrophy refers to a group of hereditary progressive dis­ eases, each with unique phenotypic and genetic features (Tables 460-3 through 460-6 and Fig. 460-6). The prognosis of dystrophies is slow progressive weakness, though the severity and course are variable between and even within subtypes. Some are associated with cardiac and ventilatory muscle involvement, which are the leading causes of mor­ tality. Unfortunately, there are no specific medical therapies for most of the muscular dystrophies, and treatment is aimed at maintaining function with physical and occupational therapy. Noninvasive ventila­ tion and tracheostomy may be warranted. Those with cardiomyopathy may require afterload reduction, antiarrhythmic agents, pacemakers or intracardiac defibrillators, and occasionally cardiac transplantation. We will focus primarily on those that manifest in adulthood. ■ ■DUCHENNE AND BECKER MUSCULAR DYSTROPHY (DMD AND BMD) DMD and BMD are X-linked recessive muscular dystrophies caused by mutations in the dystrophin gene. Affecting 1 in 3000 male births, DMD is the most common mutational disease affecting boys. The inci­ dence of BMD is ~5 per 100,000. Clinical Features  Proximal muscles, especially of the lower extremities, are prominently involved in both disorders. This becomes evident in DMD very early; boys with DMD have difficulty climbing stairs and never run well. As the disease progresses, weakness becomes more generalized. Hypertrophy of muscles, particularly in the calves, is an early and prominent finding. Most patients with BMD first experience difficulties between ages 5 and 15 years, although onset in the third or fourth decade or even later can occur. Life expectancy for DMD and BMD is reduced, but most BMD cases survive into the fourth or fifth decade. Intellectual disability may occur in both dis­ orders but is less common in BMD. Cardiac involvement is common in both DMD and BMD and may result in heart failure; some BMD TABLE 460-3  Autosomal Dominant (AD) Limb-Girdle Muscular Dystrophies (LGMDs) OLD / NEW NOMENCLATURE INHERITANCE GENE AFFECTED PROTEIN LGMD1A / MFM3 AD MYOT Myotilin LGMD1B / EDMD AD LMNA Lamin A and C LGMD1C / Rippling muscle disease AD CAV3 Caveolin-3 LGMD1D / LMGDD1  AD DNAJB6 DNAJ heat shock protein family (Hsp40) member B6 LGMD1E / MFM1 AD DES Desmin LGMD1F / LGMDD2 AD TNPO3 Transportin 3 LGMD1G / LGMDD3 AD HNRNPDL Heterogeneous nuclear ribonucleoprotein D like protein LGMD1H / Discarded due to false linkage LGMD1I / LGMDD4 AD CAPN3 Calpain 3 Bethlem myopathy / LGMDD5 AD  COL6A1/2/3  Collagen type VI alpha  patients manifest with only heart failure. Other less common presenta­ tions of dystrophinopathy are asymptomatic hyper-CK-emia, myalgias without weakness, and myoglobinuria. Laboratory Features  Serum CK levels are usually elevated. Mus­ cle biopsies demonstrate dystrophic features. Western blot analysis of muscle biopsy samples demonstrates absent dystrophin in DMD or reduction in levels or size of dystrophin in BMD. In both disor­ ders, mutations can be established using DNA from peripheral blood TABLE 460-4  Autosomal Recessive (AR) Limb-Girdle Muscular Dystrophies (LGMDs) OLD / NEW NOMENCLATURE INHERITANCE GENE AFFECTED PROTEIN LGMD2A / LGMDR1 AR CAPN3 Calpain 3 LGMD2B / LGMDR2 AR DYSF Dysferlin LGMD2C / LGMDR5 AR SGCG γ-Sarcoglycan LGMD2D / LGMDR3 AR SGCA α-Sarcoglycan LGMD2E / LGMDR4 AR SCGB β-Sarcoglycan LGMD2F / LGMDR6 AR SCGD δ-Sarcoglycan LGMD2G / LGMDR7 AR TCAP Telethonin LGMD2H / LGMDR8 AR TRIM32 Tripartite motif-containing 32 LGMD2I / LGMDR9 AR FKRP Fukutin-related protein LGMD2J / LGMDR10 AR TTN Titin LGMD2K / LGMDR11 AR POMT1 Protein O-mannosyltransferase 1 LGMD2L / LGMDR12 AR ANO5 Anoctamin 5 LGMD2M / LGMDR13 AR FKTN Fukutin LGMD2N / LGMDR14 AR POMT2 Protein O-mannosyltransferase 2 LGMD2O / LGMDR15 AR POMGnT1 Protein O-linked mannose Beta-1,2-N-acetyl glucosaminyltranferase-1 LGMD2P / LGMDR16 AR DAG1 α-Dystroglycan LGMD2Q / LGMDR17 AR PLEC1 Plectin 1 LGMD2R / MFM1 AR DES Desmin LGMD2S / LGMDR18 AR TRAPPC11 Trafficking protein particle complex 11 LMGD2T / LGMDDR19 AR GMPPB DP-mannose pyrophosphorylase B LGMD2U / LGMDR20 AR CRPPA CDP-L-ribitol pyrophosphorylase A (also known as ISPD) LGMD2V / Pompe disease AR GAA A Alpha-glucosidase LGMD2W / PINCH-2-related myopathy AR LIMS2 PINCH-2 LGMD2X / LGMDR25 AR BVES Blood vessel endothelial substance LGMD2Y / TOR1AIP1-related myopathy AR TOR1AIP1 Torsin A interacting protein 1 LGMD2Z / LGMDR21 AR POGLUT1 Protein O-glucosyltransferase 1 Bethlem myopathy /LGMDR22 AR COL6A1/2/3 Collagen VI subunits A1, A2, or A3 Laminin α2-related dystrophy / LGMDR23 AR LAMA2 Laminin subunit alpha 2 POMGNT2-related dystrophy/ LGMDR24  AR  POMGNT2  Protein O-linked mannose beta 1,4-N-acetylglucosaminyltransferase 2 NA / LGMDR26 AR POPDC3 Popeye domain-containing protein 3 NA / LGMDR27 AR JAG2 Jagged2 Abbreviation: NA, not applicable. CHAPTER 460 leukocytes. In most cases, muscle biopsies are no longer performed when DMD or BMD is suspected, as genetic testing is less invasive, less costly, and routinely available. Deletions within or duplications of the dystrophin gene are common in both DMD and BMD; in ~95% of cases, the mutation does not alter the translational reading frame of messenger RNA. These “in-frame” mutations allow for production of some dys­ trophin, which accounts for the presence of altered rather than absent dystrophin on Western blot analysis and a milder clinical phenotype. Muscular Dystrophies and Other Muscle Diseases TABLE 460-5  Hereditary Distal Myopathies/Dystrophies DISORDER INHERITANCE GENE AFFECTED PROTEIN Welander AD TIA1 T-cell restricted intracellular antigen Udd AD TTN Titin Markesbery-Griggs AD LDB3 ZASP GNE myopathy (Nonaka; hIBM2) AR GNE UDP-N-acetylglucosamine 2-epimerase/ n-acetylmannosamine kinase Miyoshi 1 AR DYSF Dysferlin Miyoshi 3 AR ANO5 Anoctamin 5 Laing AD MYH7 Myosin heavy chain 7 Williams AD FLNC Filamin C Distal myopathy with vocal cord and pharyngeal weakness (VCPDM) AD MTR3 Matrin 3 KLHL9 myopathy AD KLH9 KELCH-like homologue 9 ADSSL myopathy AR ADSSL Adenylosuccinate synthase PART 13 Neurologic Disorders PLIN4 myopathy AD PLIN4 Perilipin-4 Abbreviations: AD, autosomal dominant; AR, autosomal recessive. TREATMENT Duchenne and Becker Muscular Dystrophy Glucocorticoids slow progression in DMD, but their use has not been adequately studied in BMD. Physical and occupational ther­ apy are important in helping maintain function. As death is often from the associated cardiomyopathy, it is important to follow patients with a cardiologist and treat appropriately. Small studies suggest that there may be a clinical benefit in selected cases of DMD from short oligonucleotides that permit skipping of mutant exons, leading to expression of a short but nonetheless functional dystro­ phin protein. In parallel, other studies suggest that small molecules may permit read-through of protein-truncating mutations in some DMD cases. Gene therapy studies have not as yet been conducted in BMD. ■ ■LIMB-GIRDLE MUSCULAR DYSTROPHY The limb-girdle muscular dystrophies (LGMDs) are a genetically heterogenous group of dystrophies in which males and females are affected equally, with typical onset ranging from late in the first decade to the fourth decade. The LGMDs usually manifest with progressive weakness of pelvic and shoulder girdle musculature and are often clini­ cally indistinguishable from DMD and BMD. Respiratory insufficiency from weakness of the diaphragm may occur, as may cardiomyopathy. Serum CKs are elevated, and the EMG is myopathic. Muscle biopsies reveal dystrophic features, but the findings are not specific to differ­ entiate subtypes from one another unless immunohistochemistry is employed (e.g., immunostaining for various sarcoglycans, dysferlin, TABLE 460-6  Myofibrillary Myopathies (MFM) MYOFIBRILLAR MYOPATHY INHERITANCE GENE AFFECTED PROTEIN MFM1 AD/AR DES Desmin MFM2 AD CRYAB Alpha-B crystallin MFM3 AD MYOT Myotolin MFM4 AD LDP3 ZASP MFM5 AD FLNC Filamin C MFM6 AD BAG3 Bcl-2-binding protein MFM7 AD KY Kyphoscoliosis peptidase MFM8 AD PYROXD1 Pyridine nucleotide-disulfide oxidoreductase domain-containing protein 1 MFM9 AD TTN Titin MFM10 AD SVIL Supervillin MFM11 AD UNC45B UNC45 myosin chaperone B MFM12 AD MYL2 Myosin light chain 2 Abbreviations: AD, autosomal dominant; AR, autosomal recessive. alpha-dystroglycan) or there are features to suggest one of the myofi­ brillar myopathies. Nonetheless, definitive diagnosis requires genetic testing. The traditional classification of LGMD is based on autosomal domi­ nant (LGMD1) and autosomal recessive (LGMD2) inheritance. Super­ imposed on the backbone of LGMD1 and LGMD2, the classification uses a sequential alphabetical lettering system (LGMD1A, LGMD2A, etc.) based on genotype. However, ever-expanding discoveries of new genes have outgrown the alphabet. The European Neuromuscular Centre (ENMC) proposed a new nomenclature in which autosomal dominant cases are termed LGMD “D” and autosomal recessive as LGMD “R,” followed by a numerical number based on genotype. Fur­ thermore, this new classification only includes cases in which at least two unrelated families have been reported, the predominant weakness at onset was proximal, independent ambulation was achieved at some time, CK is elevated, and muscle biopsies or imaging revealed dystro­ phic features. Thus, mutations in the CPN3 gene leading to a deficiency in calpain-3, which traditionally were classified as LGMD2A, are classified as LGMDR1 by this new system. In contrast, mutations in myotilin (LGMD1A) and desmin (LGMD1E and LGMD2R) and that often have more distal weakness and have biopsy features of a myofi­ brillar myopathy are not classified as a LGMD in this new scheme but rather as subtypes of myofibrillar myopathy. Likewise, laminopathies (LGMD1B) are considered a subtype of EDMD rather than an LGMD. The myofibrillar myopathies are now considered as being separate from LGMD. This new classification of LGMD and distal muscular dystrophies is summarized in Tables 460-3 and 460-4. A recent metanalysis reported the prevalence of LGMD to be 1.63 per 100,000 (range, 0.56–5.75 per 100,000), while estimated prevalences MDC1A, LGMDR23 (α 2 lamin or merosin) ISPD, LARGE, TMEM5, GMPPB, B3GNT1, GTDC2, B3GALNT2, POMK, cause MDDGA, MDDGB, MDDC and LGMD (FKRP) LGMDR9 LGMDD5, LGMDR22 Bethlem and Ullrich myopathy (Collagen VI) LGMDR6 Sarcospan LGMDR4 LGMDR3 α-SG β-SG LGMDR5 α-SG γ-SG Rippling muscle disease LGMD1C (Caveolin-3) LGMDR2 (Dysferlin) (Duchenne and Becker dystrophy) LGMDR12 (Anoctamin 5) MFM3/LGMD1A (myotilin) LGMDR7 (Telethonin) Other Z-disk proteins; ZASP, BAG3, α B-crystallin, Nebulin, α Actinin, FHL1, Filamin C, Kyphoscoliosis peptidase, Supervillin, PYROXD1, UNC45B Titin Myosin Actin LGMDR10 Udd distal myopathy HMERR MFM10 Myofibrillar myopathy Nemaline myopathy FIGURE 460-6  Proteins involved in the muscular dystrophies. This schematic shows the location of various sarcolemmal, sarcomeric, nuclear, and enzymatic proteins associated with muscular dystrophies. The diseases associated with mutations in the genes responsible for encoding these proteins are shown in boxes. Dystrophin, via its interaction with the dystroglycan complex, connects the actin cytoskeleton to the extracellular matrix. Extracellularly, the sarcoglycan complex interacts with biglycan, which connects this complex to the dystroglycan complex and the extracellular matrix collagen. Various enzymes are important in the glycosylation of the α-dystroglycan and mediate its binding to the extracellular matrix and usually cause a congenital muscular dystrophy with severe brain and eye abnormalities but may cause milder limbgirdle muscular dystrophy (LGMD) phenotype. Mutations in genes that encode for sarcomeric and Z-disk proteins cause forms of LGMD and distal myopathies (including myofibrillar myopathy, forms of hereditary inclusion body myopathy) as well as nemaline rod myopathy and other “congenital” myopathies. Mutations affecting nuclear membrane proteins are responsible for most forms of Emery-Dreifuss muscular dystrophy (EDMD). Mutations in other nuclear genes cause other forms of dystrophy. (Reproduced with permission from AA Amato et al (eds): Amato and Russell’s Neuromuscular disorders, 3rd ed. New York: McGraw Hill; 2025.) of individual specific subtypes of LGMDs vary. The most common types of adult-onset LGMD are calpainopathy (LGMD2A/LGMDR1), fukutin-related protein (FKRP) deficiency (LGMD2I/LGMDR9), and anoctaminopathy (LGMD2L/LGMDR12). Calpainopathy (LGMD2A/ LGMDR1), the most common cause of LGMD in those with ancestry from Spain, France, Italy, and Great Britain, is associated with marked scapular winging, lack of calf muscle hypertrophy, and lack of cardiac and lung involvement. Of note, autosomal dominant mutations in an intron of the calpain-3 gene is responsible for LGMD1I/LGMDD4. LGMD2I/LGMDR9 is more common in individuals with northern European ancestry, is associated with calf muscle hypertrophy, and can have cardiac and lung involvement out of proportion to extremity weakness. LGMD2L/LGMDR12 accounts for ~7% of LGMD in the United States, and the prevalence is higher in northern Europe; as seen in dysferlinopathies (LGMD2B/LGMDR2 and Miyoshi myopathy type 1), anoctaminopathy has an early predilection for medial calf atrophy and weakness. Importantly, immune-mediated necrotizing myopathies can mimic LGMD clinically and histopathologically (Chap. 377). Any­ one suspected of having an LGMD but without definite pathogenic mutation(s) identified on genetic testing should be screened for the Extra cellular matrix (POMT1) LGMDR11 also cause forms of MDDG (Fukutin) LGMDR13 (POMT2) LGMDR14 (POMGnT1) LGMDR15 LGMDR16 α-DG (POMGnT2) LGMDR24 also cause forms of MDDG β-DG LGMDR8 LGMDR18 TRIM32 TRAPPC11 Myofibrillar myopathy MFM1 (Desmin) CHAPTER 460 EDMD7 (TMEM43) Dystrophin EDMD4, EDMD5 (Nesprin 1, Nesprin 2) LGMDR1 (Calpain-3) EDMD1 (Emerin) Muscular Dystrophies and Other Muscle Diseases LGMD1B EDMD2, 3 (Lamin A/C) Nucleus PABN2 Transportin3 LGMDD3 OPMD LRP12 GIPC1 NOTCH2NLC RILPL1 VCP HNRPA2BI HNRNPAI Sequestome Matrin3 OPDM1 OPDM2 OPDM3 OPDM4 MSP1 MSP2 MSP3 MSP4 MSP5 Laing myopathy Hyaline myopathy H-IBM3 MFM12 Torsin A-Interacting Protein 1 presence of serum antibodies against HMGCR and SRP to assess for a treatable autoimmune cause. ■ ■EMERY-DREIFUSS MUSCULAR DYSTROPHY There are at least seven subtypes of EDMD that have been associated with mutations in EMD (EDMD1), LMNA (EDMD2 and EDMD3), SYNE1 (EDMD4), SYNE2 (EDMD5), FHL1 (EDMD6), and TMEM43 (EDMD7), encoding emerin, lamin A/C, nesprin-1, nesprin-2, FHL1, and LUMA, respectively. Mutations in EMD and FHL produce X-linked inheritance, whereas the others can be autosomal dominant (LMNA, SYNE1, SYNE2, LUMA) or autosomal recessive (LMNA1). The clinical phenotypes are quite similar. Clinical Features  Prominent contractures can be recognized in early childhood and teenage years, often preceding muscle weak­ ness. The contractures persist throughout the course of the disease and are present at the elbows, ankles, and neck. Muscle weakness affects humeral and peroneal muscles at first and later spreads to a limb-girdle distribution (Table 460-1). The cardiomyopathy is poten­ tially life threatening and may result in sudden death. A spectrum of atrial rhythm and conduction defects includes atrial fibrillation, atrial standstill, and atrioventricular heart block. Some patients have a dilated cardiomyopathy. Female carriers of the X-linked variant may manifest with a cardiomyopathy. Laboratory Features  Serum CK is usually slightly elevated, and the EMG is myopathic. Muscle biopsy usually shows nonspecific dystrophic features, although cases associated with FHL1 mutations have features of myofibrillar myopathy. Immunohistochemistry reveals absent emerin staining of myonuclei in X-linked EDMD due to emerin mutations. Electrocardiograms (ECGs) demonstrate atrial and atrio­ ventricular rhythm disturbances. X-linked EDMD usually arises from defects in the emerin gene encoding a nuclear envelope protein. FHL1 mutations are also a cause of X-linked scapuloperoneal dystrophy but can also present with an X-linked form of EDMD. The autosomal dominant disease can be caused by mutations in the LMNA gene encoding Lamin A/C; in the synaptic nuclear envelope protein 1 (SYNE1) or 2 (SYNE2) encod­ ing nesprin-1 and nesprin-2, respectively; and in TMEM43 encoding LUMA. These proteins are essential components of the filamentous network underlying the inner nuclear membrane. Loss of structural integrity of the nuclear envelope from defects in emerin, Lamin A/C, nesprin-1, nesprin-2, and LUMA accounts for overlapping phenotypes. PART 13 Neurologic Disorders TREATMENT Emery-Dreifuss Muscular Dystrophy Supportive care should be offered for neuromuscular disability, including ambulatory aids, if necessary. Stretching of contractures is difficult. Management of cardiomyopathy and arrhythmias (e.g., early use of a defibrillator or cardiac pacemaker) may be lifesaving. ■ ■MYOTONIC DYSTROPHY There are two distinct forms of myotonic dystrophy (dystrophia myo­ tonica [DM]), namely myotonic dystrophy type 1 (DM1) and myotonic dystrophy type 2 (DM2), also called proximal myotonic myopathy (PROMM). Clinical Features  The clinical expression of DM1 varies widely and involves many systems other than muscle. Affected patients may have a “hatchet-faced” appearance due to temporalis, masseter, and facial muscle atrophy and weakness. Frontal baldness is frequent. Weakness of wrist and fingers occurs early, as does foot drop. Proximal muscles are less affected. Palatal, pharyngeal, and tongue involvement can lead to dysarthria and dysphagia. Some patients have diaphragm and intercostal muscle weakness, resulting in ventilatory insufficiency. Myotonia is usually apparent by the age of 5 years and is best demon­ strable by percussion of the thenar eminence or asking patients to close their fingers very tightly and then relax. ECG abnormalities include first-degree heart block and more exten­ sive conduction system involvement. Complete heart block and sudden death can occur. Congestive heart failure occurs infrequently but may result from cor pulmonale secondary to respiratory failure. Other associated features include intellectual impairment, hypersomnia, pos­ terior subcapsular cataracts, gonadal atrophy, insulin resistance, and decreased esophageal and colonic motility. Congenital myotonic dystrophy is a more severe form of DM1 and occurs in ~25% of infants of affected mothers. It is characterized by severe facial and bulbar weakness, transient neonatal respiratory insuf­ ficiency, and intellectual disability. DM2 or PROMM involves mainly proximal muscles. Other features of the disease overlap with DM1, including cataracts, testicular atrophy, insulin resistance, constipation, hypersomnia, and cognitive defects. Cardiac conduction defects occur but are less common. The hatchet face and frontal baldness are also less consistent features. A very strik­ ing difference is the failure to clearly identify a congenital form of DM2. Laboratory Features  The diagnosis of myotonic dystrophy can usually be made on the basis of clinical findings. Serum CK levels may be normal or mildly elevated. EMG evidence of myotonia is present in most cases of DM1 but is more patchy in DM2. Muscle biopsy is not typically performed for diagnosis but is sometimes done when the clinical features and electrophysiologic features are not recognized. The major histopathologic features in both DM1 and DM2 are numerous internalized nuclei in individual muscle fibers combined with many atrophic fibers with pyknotic nuclear clumps. DM1 and DM2 are autosomal dominant disorders. DM1 is transmit­ ted by an intronic mutation consisting of an unstable expansion of a CTG trinucleotide repeat in a serine-threonine protein kinase gene (named DMPK). An increase in the severity of the disease phenotype in succes­ sive generations (genetic anticipation) is accompanied by an increase in the number of trinucleotide repeats. The unstable triplet repeat in myo­ tonic dystrophy can be used for prenatal diagnosis. Congenital disease occurs almost exclusively in infants born to affected mothers. DM2 is caused by a DNA expansion mutation consisting of a CCTG repeat in intron 1 of the CNBP gene encoding the CCHC-type zinc finger nucleic acid binding protein. The DNA expansions in DM1 and DM2 impair muscle function by a toxic gain of function of the mutant mRNA. In both DM1 and DM2, the mutant RNA appears to form intranuclear inclusions composed of aberrant RNA. These RNA inclusions sequester RNA-binding proteins essential for proper splicing of a variety of other mRNAs. This leads to abnormal transcription of multiple proteins in a variety of tissues/organ systems, in turn causing the systemic manifestations of DM1 and DM2. TREATMENT Myotonic Dystrophy The myotonia in DM1 and DM2 is usually not so bothersome to warrant treatment, but when it is, mexiletine may be helpful. A cardiac pacemaker or implantable cardioverter defibrillator should be considered for patients with significant arrhythmia. Molded ankle-foot orthoses help stabilize gait in patients with foot drop. Excessive daytime somnolence with or without sleep apnea is not uncommon. Sleep studies, noninvasive respiratory support (bipha­ sic positive airway pressure [BiPAP]), and treatment with modafinil may be beneficial. ■ ■FACIOSCAPULOHUMERAL (FSHD) MUSCULAR DYSTROPHY There are two forms of FSHD that have similar pathogenesis. Most patients have FSHD type 1 (95%), whereas ~5% have FSHD2. Both forms are clinically and histopathologically identical. The prevalence FSHD is ~5 per 100,000 individuals. Clinical Features  FSHD typically presents in childhood or young adulthood. In most cases, facial weakness is the initial manifestation, appearing as an inability to smile, whistle, or fully close the eyes. Loss of scapular stabilizer muscles makes arm elevation difficult. Scapular winging (Fig. 460-3) becomes apparent with attempts at abduction and forward movement of the arms. Biceps and triceps muscles may be severely affected, with relative sparing of the deltoid muscles. Weak­ ness is invariably worse for wrist extension than for wrist flexion, and weakness of the anterior compartment muscles of the legs may lead to foot drop. In 20% of patients, weakness progresses to involve the pelvic muscles, and severe functional impairment and possible wheel­ chair dependency result. The heart is not involved, but there can be ventilatory muscle weakness in 5% of affected individuals. There is an increased incidence of nerve deafness. Coats’ disease, a disorder consist­ ing of telangiectasia, exudation, and retinal detachment, also occurs. Laboratory Features  The serum CK level may be normal or mildly elevated. EMG and muscle biopsy show nonspecific abnormali­ ties but on occasion can reveal a prominent inflammatory infiltrate leading to an incorrect diagnosis of myositis (Chap. 377). FSHD1 is associated with deletions of tandem 3.3-kb repeats at 4q35. The deletion reduces the number of repeats to a fragment of <35 kb in most patients. Within these repeats lies the DUX4 gene, which usually is not expressed after early muscle development. In patients with FSHD1, these deletions in the setting of a specific poly­ morphism lead to hypomethylation of the region and toxic expression of the DUX4 gene. In cases of FSHD2, there is no deletion, but rather mutations in three different genes have been identified, each of which interestingly leads to hypomethylation of the DUX4 region and the permissive expression of the DUX4 gene. Dominant mutations in the structural maintenance of chromosomes hinge domain 1 (SMCHD1) gene are the most common cause of FSHD2, but heterozygous muta­ tions in the DNA methyltransferase 3B (DNMT3B) gene and homozy­ gous mutations in the ligand-dependent nuclear receptor-interacting factor 1 (LRIF1) gene also cause autosomal recessive FSHD2. These proteins normally interact with SMCHD1, and mutations lead to hypo­ methylation of DUX4. As in FSHD1, this leads to an overexpression of the DUX4 transcript that encodes for double homeobox 4, which itself is a transcription factor controlling the expression of other genes. In turn, this likely results in the altered expression of additional genes. TREATMENT Facioscapulohumeral Muscular Dystrophy No specific treatment is available, though clinical trials assessing the safety and efficacy of reducing DUX4 expression are ongoing. Physical and occupational therapy are the current mainstays of treatment. Ankle-foot orthoses are helpful for foot drop. Scapular stabilization procedures improve scapular winging and function. ■ ■OCULOPHARYNGEAL DYSTROPHY (OPMD) OPMD represents one of several disorders characterized by progressive external ophthalmoplegia, which consists of slowly progressive ptosis and limitation of eye movements with sparing of pupillary reactions for light and accommodation. Patients usually do not complain of diplo­ pia, in contrast to patients having conditions with a more acute onset of ocular muscle weakness (e.g., myasthenia gravis). Clinical Features  OPMD has a late onset; it usually presents in the fourth to sixth decade with ptosis or dysphagia. The extraocular muscle impairment is less prominent in the early phase but may become severe over time. The swallowing problem may lead to aspiration. Weakness of the neck and proximal extremities can develop but is usually mild in degree. Laboratory Features  The serum CK level may be two to three times normal. EMG can identify myopathic changes in weak muscles. Muscle biopsies are no longer necessary for diagnosis in most cases but, when performed, demonstrate muscle fibers with rimmed vacuoles. On electron microscopy, a distinctive feature of OPMD is the presence of 8.5-nm tubular filaments in some muscle cell nuclei. OPMD is an autosomal dominant disorder that has a high inci­ dence in certain populations (e.g., French-Canadians, individuals of Spanish ancestry, and Ashkenazi Jews). The molecular defect in OPMD is an expansion of a polyalanine repeat tract in a poly-RNAbinding protein (PABP2) gene. PABP2 is involved in polyadenylation of mRNAs and their transport through the nuclei pores into the cyto­ plasm. The expansion of the GCG repeats results in abnormal folding of the polyalanine domains of PABP2 and its resistance to nuclear proteasomal degradation. This in turn may result in (1) direct toxicity of the intranuclear aggregates; (2) intranuclear sequestration of essential transcription factors, molecular chaperones, RNA binding proteins, and RNAs by these intranuclear aggregates; or (3) suppression of the normal function of the wild-type protein. TREATMENT Oculopharyngeal Dystrophy Dysphagia can lead to significant undernourishment and aspira­ tion. Cricopharyngeal myotomy may improve swallowing. Eyelid crutches can improve vision when obstructed by ptosis; candidates for ptosis surgery must be carefully selected—those with severe facial weakness are not suitable. ■ ■OCULOPHARYNGEAL DISTAL MYOPATHY (OPDM) Clinical Features  OPDM is characterized by adult-onset ptosis, external ophthalmoplegia, facial muscle weakness, distal limb muscle weakness and atrophy, and pharyngeal involvement, resulting in dys­ phagia and dysarthria. Some patients manifest with only ptosis without pharyngeal or distal weakness. Laboratory Features  Serum CK levels are normal or only mildly elevated. EMG is myopathic. Muscle biopsies reveal dystrophic fea­ tures including muscle fibers with rimmed vacuoles. Intramyonuclear inclusions immunostaining with anti-phospho-p62/SQSTM1 anti­ bodies are evident. Similar intranuclear inclusions are found on skin biopsies. OPDM is a genetically heterogeneous autosomal disorder caused by trinucleotide repeat expansions (CTG) in the 5′ untranslated region (UTR) regions of LRP12 (OPDM1), G1PC1 (OPDM2), NOTCH2NLC (OPDM3), and RILPL1 (OPMD4). Notably, the CGG repeat expan­ sion in NOTCH2NLC is also the cause of neuronal intranuclear hya­ line inclusion disease and other neurodegenerative diseases affecting the brain. These repeat expansion disorders lead to RNA-mediated sequestration of RNA-binding proteins and altered translation of proteins. CHAPTER 460 Muscular Dystrophies and Other Muscle Diseases TREATMENT Oculopharyngeal Distal Myopathy Treatment of dysphagia and ptosis is similar to that noted with OPMD. ■ ■DISTAL MYOPATHIES/DYSTROPHIES The distal myopathies are notable for their preferential distal distri­ bution of muscle weakness in contrast to most muscle conditions associated with proximal weakness. The major distal myopathies are summarized in Tables 460-1, 460-5, and 460-6. Clinical Features  Welander, Udd, and Markesbery-Griggs type distal myopathies are all late-onset, dominantly inherited disorders of distal limb muscles, usually beginning after age 40 years. Welander distal myopathy preferentially involves the wrist and finger exten­ sors, whereas the others are associated with anterior tibial weakness leading to progressive foot drop. Laing distal myopathy is also a dominantly inherited disorder heralded by tibial weakness; however, it is distinguished by onset in childhood or early adult life. GNE myopathy (previously known as Nonaka distal myopathy and auto­ somal recessive hereditary inclusion body myopathy) and Miyoshi myopathy are distinguished by autosomal recessive inheritance and onset in the late teens or twenties. GNE and Williams myopathy pro­ duce prominent anterior tibial weakness, whereas Miyoshi myopathy is unique in that gastrocnemius muscles are preferentially affected at onset. Finally, the myofibrillar myopathies (MFMs) are a clini­ cally and genetically heterogeneous group of muscular dystrophies that can be associated with prominent distal or proximal weakness; they can be inherited in an autosomal dominant or recessive pattern (Table 460-6). Laboratory Features  Serum CK levels are markedly elevated in Miyoshi myopathy, but in the other conditions, serum CK is only slightly increased. EMGs are myopathic and can be irritable with myotonic discharges in MFM. Muscle biopsy shows nonspecific dystrophic features and, with the exception of Laing and Miyoshi myopathies, often shows rimmed vacuoles. MFM is associated with the accumulation of dense inclusions and amorphous material best seen on Gomori trichrome staining along with myofibrillar disruption on electron microscopy. Immune staining sometimes demonstrates accumulation of desmin and other proteins in MFM, large depos­ its of myosin heavy chain in the subsarcolemmal region of type 1 muscle fibers in Laing myopathy, and reduced or absent dysferlin in Miyoshi myopathy type 1. TREATMENT Distal Myopathies Occupational therapy is offered for loss of hand function; anklefoot orthoses can support distal lower limb muscles. The MFMs can be associated with cardiomyopathy (congestive heart failure or arrhythmias) and respiratory failure that may require medical management. Laing-type distal myopathy can also be associated with a cardiomyopathy. ■ ■MULTISYSTEM PROTEINOPATHIES (MSP) The multisystem proteinopathies (MSPs) are genetically heterogenous disorders featured by hereditary inclusion body myopathy (IBM), amyotrophic lateral sclerosis, parkinsonism, frontotemporal dementia, and Paget disease of bone. Some forms have also been referred to as IBMPFD for some of the above major clinical features. Patients present in adulthood with progressive proximal or distal weakness. Serum CK is usually mildly elevated. EMG shows features of an irritable myopathy but also neurogenic features as well. Muscle biopsies in patients with myopathy show rimmed vacuoles, inclusions that immunostain with ubiquitin, and TDP-43 extrusion from myonuclei. Most are caused by mutations in genes that encode for RNA-binding proteins or proteins involved in the elimination of other aged proteins. There are at least five types of MSP (Table 460-7). PART 13 Neurologic Disorders ■ ■SPORADIC LATE-ONSET NEMALINE MYOPATHY Clinical Features  Sporadic late onset nemaline myopathy (SLONM) should not be confused with congenital forms of nemaline myopathy, which usually are congenital and/or hereditary in nature. SLONM is not a genetic disorder and usually presents after the age of 40 years with proximal extremity weakness. Some patients may present with an axial myopathy, isolated head drop, or bent spine syndrome from paraspinal muscle weakness. Ventilatory muscle involvement and cardiomyopathy may develop. Additionally, SLONM can complicate HIV infection. Laboratory Features  Serum CK is usually normal or mildly ele­ vated and can be lower than normal. EMG reveals signs of an irritable myopathy. About 50% of cases are associated with a monoclonal gam­ mopathy of undetermined significance (IgG or IgA). Muscle biopsies can reveal inflammatory cell infiltrates, trabeculated or lobulated fibers, many atrophic muscle fibers, and fibers with nemaline rods. The rods are often smaller than ones seen in the hereditary nemaline myopathies and may be missed on routine light microscopy if thick­ ness of the sections is >3 μm. However, the rods are almost always appreciated on electron microscopy, and on immunohistochemistry, the rods are usually immunoreactive to anti-α-actinin antibody. TREATMENT SLONM Some patients with SLONM respond to intravenous immunoglobu­ lin or other immunosuppressive therapies. Autologous stem cell transplantation has been beneficial in some patients with SLONM and a monoclonal gammopathy. TABLE 460-7  Multisystem Proteinopathies MULTISYSTEM PROTEINOPATHY INHERITANCE GENE AFFECTED PROTEIN MSP1 / IBMPFD1 AD VCP Valosin-containing protein MSP2 / IBMPFD2 AD HNRPA2B1 HNRPA2B1 MSP3 / IBMPFD3 AD HNRNPA1 HNRNPA1 MSP4 AD SQTM1 Sequestome MSP5 AD MTR3 Matrin 3 Abbreviations: AD, autosomal dominant; HNRNPA1, heterogeneous nuclear ribonucleoprotein A1; HNRPA2B1, heterogeneous nuclear ribonucleoprotein A2/B1; IBMPFD, inclusion body myopathy, Paget disease, frontotemporal dementia; MSP, multisystem proteinopathy. DISORDERS OF MUSCLE ENERGY METABOLISM There are two principal sources of energy for skeletal muscle—fatty acids and glucose. Abnormalities in either glucose or lipid utilization can be associated with distinct clinical presentations that can range from an acute, painful syndrome with rhabdomyolysis and myoglo­ binuria to a chronic, progressive muscle weakness simulating muscular dystrophy (Table 460-1). As with the muscular dystrophies, there are no specific medical treatments available. ■ ■GLYCOGEN STORAGE AND GLYCOLYTIC DEFECTS Disorders of Glycolysis Causing Exercise Intolerance  Sev­ eral glycolytic defects are associated with recurrent myoglobinuria. The most common is McArdle disease caused by mutations in the PYGM gene leading to myophosphorylase deficiency. Symptoms of muscle pain and stiffness usually begin in adolescence. With severe episodes, myoglobinuria can occur. Certain features help distinguish some enzyme defects. In McArdle disease, exercise tolerance can be enhanced by a slow induction phase (warm-up) or brief periods of rest, allowing for the start of the “second-wind” phenomenon (switching to utilization of fatty acids). Varying degrees of hemolytic anemia accompany deficiencies of both phosphofructokinase (mild) and phosphoglycerate kinase (severe). In phosphoglycerate kinase deficiency, the usual clinical presentation is a seizure disorder associated with intellectual disability; exercise intoler­ ance is an infrequent manifestation. In all of these conditions, the serum CK levels fluctuate widely and may be elevated even during symptom-free periods. CK levels >100 times normal are expected accompanying myoglobinuria. A forearm exercise test reveals a blunted rise in venous lactate with a normal rise in ammonia. A definitive diagnosis of glycolytic disease can be made by muscle biopsy with appropriate staining and enzyme assays, but genetic testing is now done in lieu of biopsy in most cases. Training may enhance exercise tolerance, perhaps by increasing perfusion to muscle. Dietary intake of free glucose or fructose prior to activity may improve function, but care must be taken to avoid obesity from ingesting too many calories. Disorders of Glycogen Storage Causing Progressive Weakness  •  `-GLUCOSIDASE, OR ACID MALTASE, DEFICIENCY (POMPE DISEASE)  Three clinical forms of α-glucosidase, or acid maltase, deficiency (type II glycogenosis) can be distinguished. The infantile form is the most common, with onset of symptoms in the first 3 months of life. Infants develop severe muscle weakness, car­ diomegaly, hepatomegaly, and respiratory insufficiency. Glycogen accumulation in motor neurons of the spinal cord and brainstem con­ tributes to muscle weakness. Death usually occurs by 1.5 years of age. In the childhood form, the picture resembles DMD with delayed motor milestones resulting from proximal limb muscle weakness and involve­ ment of respiratory muscles. The heart may be involved, but the liver and brain are unaffected. The adult form usually begins in the third or fourth decade but can present as late as the seventh decade. Ventila­ tory weakness can be the initial and only manifestation in 20–30% of late-onset cases. The serum CK level is 2–10 times normal in infantile or childhoodonset Pompe disease but can be normal in adult-onset cases. EMG can demonstrate muscle membrane irritability, particularly in the paraspinal muscles. The muscle biopsy in infants typically reveals vacuoles containing glycogen and the lysosomal enzyme acid phos­ phatase. Electron microscopy reveals membrane-bound and free tissue glycogen. However, muscle biopsies in late-onset Pompe disease may demonstrate only nonspecific abnormalities. Enzyme analysis of dried blood spots is a sensitive technique to screen for Pompe disease. A definitive diagnosis is established by genetic testing. Pompe disease is inherited as an autosomal recessive disorder caused by mutations of the α-glucosidase gene. Enzyme replacement therapy (ERT) with IV recombinant human α-glucosidase is beneficial in infantile-onset Pompe disease. In late-onset cases, ERT has a more modest benefit. OTHER GLYCOGEN STORAGE DISEASES WITH PROGRESSIVE WEAK­ NESS  In debranching enzyme deficiency (type III glycogenosis), a slowly progressive form of muscle weakness can develop after puberty. Rarely, myoglobinuria may be seen. Patients are usually diagnosed in infancy, however, because of hypotonia and delayed motor milestones; hepa­ tomegaly, growth retardation, and hypoglycemia are other manifesta­ tions. Branching enzyme deficiency (type IV glycogenosis) is a rare and fatal glycogen storage disease characterized by failure to thrive and hepatomegaly. Hypotonia and muscle wasting may be present, but the skeletal muscle manifestations are minor compared to liver failure. An autosomal dominant glycogen storage disease was reported in a single family that was due to a mutation in the PYGM gene that typically causes autosomal recessive McArdle disease. Affected individuals pre­ sented with progressive proximal weakness, no exercise intolerance, normal CK, and a normal lactic acid increase with exercise. ■ ■LIPID AS AN ENERGY SOURCE AND ASSOCIATED DEFECTS Lipid is an important muscle energy source during rest and during prolonged, submaximal exercise. Oxidation of fatty acids occurs in the mitochondria. To enter the mitochondria, a fatty acid must first be converted to an “activated fatty acid,” acyl-CoA. The acyl-CoA must be linked with carnitine by the enzyme CPT for transport into the mitochondria. Carnitine Palmitoyltransferase 2 (CPT2) Deficiency  CPT2 deficiency is the most common recognizable cause of recurrent myoglobinuria. Onset is usually in the teenage years or early twen­ ties. Muscle pain and myoglobinuria typically occur after prolonged exercise but can also be precipitated by fasting or infections; up to 20% of patients do not exhibit myoglobinuria, however. Strength is normal between attacks. In contrast to disorders caused by defects in glycolysis, in which muscle cramps follow short, intense bursts of exercise, the muscle pain in CPT2 deficiency does not occur until the limits of utilization have been exceeded and muscle breakdown has already begun. Serum CK levels and EMG findings are both usually normal between episodes. A normal rise of venous lactate during forearm exercise dis­ tinguishes this condition from glycolytic defects. Muscle biopsy does not show lipid accumulation and is usually normal between attacks. The diagnosis requires direct measurement of muscle CPT or genetic testing. Attempts to improve exercise tolerance with frequent meals and a low-fat, high-carbohydrate diet, or by substituting medium-chain triglycerides in the diet, have not proven to be beneficial. MITOCHONDRIAL MYOPATHIES Mitochondria play a key role in energy production. Oxidation of the major nutrients derived from carbohydrate, fat, and protein leads to the generation of reducing equivalents. The latter are transported through the respiratory chain in the process known as oxidative phosphoryla­ tion. The energy generated by the oxidation-reduction reactions of the respiratory chain is stored in an electrochemical gradient coupled to ATP synthesis. A novel feature of mitochondria is their genetic composition. Each mitochondrion possesses a DNA genome that is distinct from that of the nuclear DNA. Human mitochondrial DNA (mtDNA) consists of a double-strand, circular molecule comprising 16,569 base pairs (bp). It codes for 22 transfer RNAs, 2 ribosomal RNAs, and 13 polypeptides of the respiratory chain enzymes. The genetics of mitochondrial dis­ eases differ from the genetics of chromosomal disorders. The DNA of mitochondria is directly inherited from the cytoplasm of the gametes, mainly from the oocyte. The sperm contributes very little of its mito­ chondria to the offspring at the time of fertilization. Thus, mitochon­ drial genes are derived almost exclusively from the mother, accounting for maternal inheritance of some mitochondrial disorders. Patients with mitochondrial myopathies have clinical manifesta­ tions that usually fall into three groups: chronic progressive external ophthalmoplegia (CPEO), skeletal muscle–CNS syndromes, and pure myopathy simulating muscular dystrophy or metabolic myopathy. Unfortunately, no specific medical therapies are clearly beneficial, although coenzyme Q10 supplements are often prescribed. Kearns-Sayre Syndrome (KSS)  This is a widespread multiorgan system disorder with a defined triad of clinical findings: onset before age 20, CPEO, and pigmentary retinopathy, plus one or more of the following features: complete heart block, cerebrospinal fluid (CSF) protein >1 g/L (100 mg/dL), or cerebellar ataxia. The cardiac disease includes syncopal attacks and cardiac arrest related to the abnor­ malities in the cardiac conduction system: prolonged intraventricular conduction time, bundle branch block, and complete atrioventricular block. Death attributed to heart block occurs in ~20% of the patients. Varying degrees of progressive limb muscle weakness and easy fatiga­ bility affect activities of daily living. Many affected individuals have intellectual disabilities. Endocrine abnormalities are also common, including gonadal dysfunction in both sexes with delayed puberty, short stature, and infertility. Diabetes mellitus occurs in ~13% of KSS patients. Other less common endocrine disorders include thyroid dis­ ease, hyperaldosteronism, Addison’s disease, and hypoparathyroidism. CHAPTER 460 Serum CK and lactate levels are normal or slightly elevated. Serum levels of fibroblast growth factor 21 (FGF-21) and growth and dif­ ferentiation factor 15 (GDF-15) are often elevated in mitochondrial disorders with muscle weakness. EMG is often myopathic. NCS may be abnormal related to an associated neuropathy. Muscle biopsies reveal ragged red fibers and cytochrome oxidase (COX)–negative fibers. By electron microscopy, there are increased numbers of mitochondria that often appear enlarged and contain paracrystalline inclusions. Muscular Dystrophies and Other Muscle Diseases KSS is a sporadic disorder caused by single mtDNA deletions that are presumed to arise spontaneously in the ovum or zygote. The most common deletion, occurring in about one-third of patients, removes 4977 bp of contiguous mtDNA. Monitoring for cardiac conduction defects is critical. Prophylactic pacemaker implantation is indicated when ECGs demonstrate a bifascicular block. Progressive External Ophthalmoplegia (PEO)  PEO can be caused by nuclear DNA mutations affecting mtDNA and thus inherited in a Mendelian fashion or by mutations in mtDNA. Onset is usually after puberty. Fatigue, exercise intolerance, dysphagia, and complaints of muscle weakness are typical. The neurologic examination confirms the ptosis and ophthalmoplegia, usually asymmetric in distribution. Patients do not complain of diplopia. Mild facial, neck flexor, and proximal weakness is typical. Rarely, respiratory muscles may be pro­ gressively affected and may be the direct cause of death. Serum CK and lactate can be normal or mildly elevated. The EMG can be myopathic. Ragged red and COX-negative fibers are promi­ nently displayed in the muscle biopsy. This autosomal dominant form of CPEO is most commonly caused by mutations in the genes encoding adenine nucleotide translocator 1 (ANT1), twinkle gene (C10orf2), and mtDNA polymerase 1 (POLG1). Autosomal recessive PEO can also be caused by mutations in POLG1. Point mutations have been identified within various mitochondrial tRNA (Leu, Ile, Asn, Trp) genes in families with maternal inheritance of PEO. There is no specific medical treatment available; exercise may improve function, but this will depend on the patient’s ability to participate. Myoclonic Epilepsy with Ragged Red Fibers (MERRF)  The onset of MERRF is variable, ranging from late childhood to middle adult life. Characteristic features include myoclonic epilepsy, cerebellar ataxia, and progressive proximal muscle weakness. The seizure disor­ der is an integral part of the disease and may be the initial symptom. Cerebellar ataxia precedes or accompanies epilepsy. Other more vari­ able features include dementia, peripheral neuropathy, optic atrophy, hearing loss, and diabetes mellitus. Serum CK levels and lactate may be normal or elevated. EMG is myopathic, and in some patients, NCS show a neuropathy. The electroencephalogram is abnormal, corroborating clinical findings of epilepsy. Typical ragged red fibers are seen on muscle biopsy. MERRF is caused by maternally inherited point mutations of mitochondrial tRNA genes. The most common mutation found in 80% of MERRF patients is an A to G substitution at nucleotide 8344 of tRNA lysine (A8344G tRNAlys). Only supportive treatment is possible, with special attention to epilepsy. Mitochondrial Myopathy, Encephalopathy, Lactic Acido­ sis, and Stroke-like Episodes (MELAS)  MELAS is the most common mitochondrial encephalomyopathy. The term stroke-like is appropriate because the cerebral lesions do not conform to a strictly vascular distribution. The onset in the majority of patients is before age 20. Seizures, usually partial motor or generalized, are common and may represent the first clearly recognizable sign of disease. The cerebral insults that resemble strokes cause hemiparesis, hemianopia, and cortical blindness. A presumptive stroke occurring before age 40 should place this mitochondrial encephalomyopathy high in the differential diagnosis. Associated conditions include hearing loss, diabetes mellitus, hypothalamic pituitary dysfunction causing growth hormone deficiency, hypothyroidism, and absence of secondary sexual characteristics. In its full expression, MELAS leads to dementia, a bedridden state, and a fatal outcome. Serum lactic acid is typically elevated. PART 13 Neurologic Disorders The CSF protein is also increased but is usually ≤1 g/L (100 mg/dL). Muscle biopsies show ragged red fibers. Neuroimaging demonstrates basal ganglia calcification in a high percentage of cases. Focal lesions that mimic infarction are present predominantly in the occipital and parietal lobes. Strict vascular territories are not respected, and cerebral angiography fails to demonstrate lesions of the major cerebral blood vessels. MELAS is usually caused by maternally inherited point muta­ tions of mitochondrial tRNA genes. The A3243G point mutation in tRNALeu(UUR) is the most common, occurring in ~80% of MELAS cases. No specific treatment is available. Supportive treatment is essential for the stroke-like episodes, seizures, and endocrinopathies. Mitochondrial DNA Depletion Syndromes  Mitochondrial DNA depletion syndrome (MDS) is a heterogeneous group of disorders that are inherited in an autosomal recessive fashion and can present in infancy or in adults. MDS can be caused by mutations in several genes (TK2, DGUOK, RRM2B, TYMP, SUCLA1, and SUCLA2) that lead to depletion of mitochondrial deoxyribonucleotides (dNTP) necessary for mtDNA replication. The other major cause of MDS is a set of mutations in genes essential for mtDNA replication (e.g., POLG1 and C10orf2). The clinical phenotypes associated with MDS vary. Patients may develop a severe encephalopathy (e.g., Leigh’s syndrome), PEO, an isolated myopathy, myo-neuro-gastrointestinal encephalopathy (MNGIE), and a sensory neuropathy with ataxia. DISORDERS OF MUSCLE MEMBRANE EXCITABILITY Muscle membrane excitability is affected in a group of disorders referred to as channelopathies. These disorders usually present with episodic muscle weakness (periodic paralysis) and sometimes myoto­ nia or paramyotonia (Table 460-1). ■ ■CALCIUM CHANNEL DISORDERS OF MUSCLE Hypokalemic Periodic Paralysis (HypoKPP)  This is an auto­ somal dominant disorder with onset in adolescence. Males are more often affected because of decreased penetrance in females. Episodic weakness with onset after age 25 is almost never due to periodic paralyses, with the exception of thyrotoxic periodic paralysis. Attacks are often provoked by meals high in carbohydrates or sodium and may accompany rest following prolonged exercise. Weakness usually affects proximal limb muscles more than distal. Ocular and bulbar muscles are less likely to be affected. Respiratory muscles are usually spared, but when they are involved, the condition may prove fatal. Weakness may take as long as 24 h to resolve. Life-threatening cardiac arrhythmias related to hypokalemia may occur during attacks. As a late complication, patients commonly develop severe, disabling proximal lower extremity weakness. Attacks of thyrotoxic periodic paralysis resemble those of primary HypoKPP. Despite a higher incidence of thyrotoxicosis in women, men, particularly those of Asian descent, are more likely to manifest this complication. Attacks abate with treatment of the underlying thy­ roid condition. A low serum potassium level during an attack, excluding secondary causes, establishes the diagnosis. In the midst of an attack of weak­ ness, motor conduction studies may demonstrate reduced amplitudes, whereas EMG may show electrical silence in severely weak muscles. In between attacks, the EMG and routine NCS are normal. However, a long exercise NCS test may demonstrate decrementing amplitudes. HypoKPP type 1 is the most common form and is caused by muta­ tions in the voltage-sensitive, skeletal muscle calcium channel gene, CALCL1A3. Approximately 10% of cases are HypoKPP type 2, arising from mutations in the voltage-sensitive sodium channel gene (SCN4A). In both forms, the mutations lead to an abnormal gating pore current that predisposes the muscle cell to depolarize when potassium levels are low. TREATMENT Hypokalemic Periodic Paralysis Mild attacks usually do not require medical treatment. However, severe attacks of weakness can be improved by the administration of potassium. Oral KCl (0.2–0.4 mmol/kg) can be given every 30 min. Only rarely is IV therapy necessary (e.g., when swallowing prob­ lems or vomiting is present). The long-term goal of therapy is to avoid attacks. Patients should be made aware of the importance of a low-carbohydrate, low-sodium diet and consequences of intense exercise. Prophylactic administration of acetazolamide or dichlor­ phenamide can reduce attacks of periodic weakness. However, in patients with HypoKPP type 2, attacks of weakness can be exacer­ bated with these medications. ■ ■SODIUM CHANNEL DISORDERS OF MUSCLE Hyperkalemic Periodic Paralysis (HyperKPP)  The term hyperkalemic is misleading because patients are often normokalemic during attacks. That attacks are precipitated by potassium administra­ tion best defines the disease. The onset is usually in the first decade; males and females are affected equally. Attacks are brief and mild, usually lasting 30 min to several hours. Weakness affects proximal muscles, sparing bulbar muscles. Attacks are precipitated by rest fol­ lowing exercise and fasting. Potassium may be slightly elevated or normal during an attack. As in HypoKPP, NCS in HyperKPP muscle may demonstrate reduced motor amplitudes and the EMG may be silent in very weak muscles. A long exercise NCS test can reveal diminished amplitudes as well. The EMG may demonstrate myotonic discharges. HyperKPP is caused by mutations of the voltage-gated sodium channel SCN4A gene. Acetazol­ amide or dichlorphenamide can reduce the frequency and severity of attacks. Mexiletine may be helpful in patients with significant clinical myotonia. Paramyotonia Congenita  In PC, the attacks of weakness are coldinduced or occur spontaneously and are mild. Myotonia is a prominent feature but worsens with muscle activity (paradoxical myotonia). This is in contrast to classic myotonia in which exercise alleviates the condition. Attacks of weakness are seldom severe enough to require emergency room treatment. Over time, patients develop inter-attack weakness as they do in other forms of periodic paralysis. Serum CK is usually mildly elevated. Routine NCS are normal. Short exercise NCS tests may be abnormal, however, and cooling of the muscle often dramatically reduces the amplitude of the compound muscle action potentials. EMG reveals diffuse myotonic potentials in PC. Upon local cooling of the muscle, the myotonic discharges disap­ pear as the patient becomes unable to activate MUAPs. PC is inherited as an autosomal dominant condition; voltage-gated sodium channel mutations are responsible, and thus, this disorder is allelic with HyperKPP. Mexiletine is reported to be helpful in reducing the myotonia. ■ ■POTASSIUM CHANNEL DISORDERS Andersen-Tawil Syndrome  This rare disease is characterized by episodic weakness, cardiac arrhythmias, and dysmorphic features (short stature, scoliosis, clinodactyly, hypertelorism, small or promi­ nent low-set ears, micrognathia, and broad forehead). The cardiac arrhythmias are potentially serious and life threatening. They include long QT, ventricular ectopy, bidirectional ventricular arrhythmias, and tachycardia. The disease is most commonly caused by mutations of the inwardly rectifying potassium channel (Kir 2.1) gene that heighten muscle cell excitability. The episodes of weakness may differ between patients because of potassium variability. Acetazolamide may decrease the attack frequency and severity. ■ ■CHLORIDE CHANNEL DISORDERS Two forms of this disorder, autosomal dominant (Thomsen disease) and autosomal recessive (Becker disease), are both caused by muta­ tions in the chloride channel 1 gene (CLCN1). Symptoms are noted in infancy and early childhood. The severity lessens in the third to fourth decade. Myotonia is worsened by cold and improved by activity. The gait may appear slow and labored at first but improves with walking. In Thomsen disease, muscle strength is normal, but in Becker disease, which is usually more severe, there may be muscle weakness. Muscle hypertrophy is usually present. Myotonic dis­ charges are prominently displayed by EMG recordings. Serum CK is normal or mildly elevated. Mexiletine is helpful in relieving the myotonia. ENDOCRINE AND METABOLIC MYOPATHIES Endocrinopathies can cause weakness, but fatigue is more common than true weakness. The serum CK level is often normal (except in hypothyroidism), and the muscle histology is characterized by atrophy rather than destruction of muscle fibers. Nearly all endocrine myopa­ thies respond to treatment. ■ ■THYROID DISORDERS Hypothyroidism (Chap. 395)  Patients with hypothyroidism have frequent muscle complaints, and about one-third have proximal muscle weakness. Muscle cramps, pain, and stiffness are common. Some patients have enlarged muscles. Features of slow muscle con­ traction and relaxation occur in 25% of patients; the relaxation phase of muscle stretch reflexes is characteristically prolonged and best observed at the ankle or biceps brachii reflexes. The serum CK level is often elevated (up to 10 times normal). EMG is typically normal. Muscle biopsy shows no distinctive morphologic abnormalities. Hyperthyroidism (Chap. 396)  Patients who are thyrotoxic commonly have proximal muscle weakness, but they rarely complain of myopathic symptoms. Activity of deep tendon reflexes may be enhanced. Fasciculations may be apparent and, when coupled with increased muscle stretch reflexes, may lead to an erroneous diagnosis of amyotrophic lateral sclerosis. A form of hypokalemic periodic paral­ ysis can occur in patients who are thyrotoxic. Mutations in the KCNJ18 gene that encodes for the inwardly rectifying potassium channel, Kir 2.6, have been discovered in up to a third of cases. ■ ■PARATHYROID DISORDERS (SEE ALSO CHAP. 422) Hyperparathyroidism  Proximal muscle weakness, muscle wast­ ing, and brisk muscle stretch reflexes are the main features of this endocrinopathy. Some patients develop neck extensor weakness (part of the dropped head syndrome). Serum CK levels are usually normal or slightly elevated. Serum parathyroid hormone levels are elevated, while vitamin D and calcium levels are usually reduced. Muscle biopsies show only mild type 2 fiber atrophy. Hypoparathyroidism  An overt myopathy due to hypocalce­ mia rarely occurs. Neuromuscular symptoms are usually related to localized or generalized tetany. Serum CK levels may be increased secondary to muscle damage from sustained tetany. Hyporeflexia or areflexia is usually present and contrasts with the hyperreflexia in hyperparathyroidism. ■ ■ADRENAL DISORDERS (SEE ALSO CHAP. 398) Conditions associated with glucocorticoid excess cause a myopathy; steroid myopathy is the most commonly diagnosed endocrine muscle disease. Proximal muscle weakness combined with a cushingoid appearance are the key clinical features. Serum CK and EMG are normal. Muscle biopsy, not typically done for diagnostic purposes, reveals type 2b muscle fiber atrophy. In primary hyperaldosteron­ ism (Conn’s syndrome), neuromuscular complications are due to potassium depletion. The clinical picture is one of persistent muscle weakness. Long-standing hyperaldosteronism may lead to proximal limb weakness and wasting. Serum CK levels may be elevated, and a muscle biopsy may demonstrate necrotic fibers. These changes relate to hypokalemia and are not a direct effect of aldosterone on skeletal muscle. CHAPTER 460 Muscular Dystrophies and Other Muscle Diseases ■ ■PITUITARY DISORDERS (SEE ALSO CHAP. 392) Patients with acromegaly usually have mild proximal weakness. Mus­ cles often appear enlarged but exhibit decreased force generation. The duration of acromegaly, rather than the serum growth hormone levels, correlates with the degree of myopathy. ■ ■DIABETES MELLITUS (SEE ALSO CHAP. 417) Neuromuscular complications of diabetes mellitus are most often related to neuropathy. The only notable myopathy is ischemic infarc­ tion of leg muscles, usually involving one of the thigh muscles but on occasion affecting the distal leg. This condition occurs in patients with poorly controlled diabetes and presents with the abrupt onset of pain, tenderness, and edema of a thigh or calf. The area of muscle infarction is hard and indurated. The muscles most often affected include the vastus lateralis, thigh adductors, and biceps femoris. Computed tomography (CT) or MRI can demonstrate focal abnor­ malities in the affected muscle. Diagnosis by imaging is preferable to muscle biopsy, if possible, as hemorrhage into the biopsy site can occur. MYOPATHIES OF SYSTEMIC ILLNESS Systemic illnesses such as chronic respiratory, cardiac, or hepatic failure are frequently associated with severe muscle wasting and com­ plaints of weakness. Fatigue is usually a more significant problem than weakness, which is typically mild. DRUG-INDUCED OR TOXIC MYOPATHIES The most common toxic myopathies are caused by the cholesterollowering agents and glucocorticoids. Others impact practice to a lesser degree but are important to consider in specific situations. Table 460-8 provides a comprehensive list of drug-induced myopathies with their distinguishing features. ■ ■MYOPATHY FROM LIPID-LOWERING AGENTS All classes of lipid-lowering agents have been implicated in muscle toxicity, including HMG-CoA reductase inhibitors (statins) and, to a much lesser extent, fibrates, niacin, and ezetimibe. Myalgia and elevated CKs are the most common manifestations. Rarely, patients exhibit proximal weakness or myoglobinuria. Concomitant use of statins with fibrates and cyclosporine increases the risk of severe TABLE 460-8  Drug-Induced Myopathies DRUGS MAJOR TOXIC REACTION Drugs belonging to all three of the major classes of lipid-lowering agents can produce a spectrum of toxicity: asymptomatic serum creatine kinase elevation, myalgias, exercise-induced pain, rhabdomyolysis, and myoglobinuria. Lipid-lowering agents   HMG-CoA reductase inhibitors   Fibric acid derivatives   Niacin (nicotinic acid) Glucocorticoids Acute, high-dose glucocorticoid treatment can cause acute quadriplegic myopathy. These high doses of steroids are often combined with nondepolarizing neuromuscular blocking agents, but the weakness can occur without their use. Chronic steroid administration produces predominantly proximal weakness. Nondepolarizing neuromuscular blocking agents Acute quadriplegic myopathy can occur with or without concomitant glucocorticoids. PART 13 Neurologic Disorders Zidovudine Mitochondrial myopathy with ragged red fibers. All drugs in this group can lead to widespread muscle breakdown, rhabdomyolysis, and myoglobinuria. Local injections cause muscle necrosis, skin induration, and limb contractures. Drugs of abuse   Alcohol   Amphetamines   Cocaine   Heroin   Phencyclidine   Meperidine Use of statins may cause an immune-mediated necrotizing myopathy associated with HMG-CoA reductase antibodies. Checkpoint inhibitors can be complicated by myositis, myocarditis, myasthenia gravis, and immune-mediated neuropathies. Myasthenia gravis has also been reported with penicillamine. Autoimmune myopathy   Statins   Checkpoint inhibitors   D-Penicillamine All amphophilic drugs have the potential to produce painless, proximal weakness associated with necrosis and autophagic vacuoles in the muscle biopsy. Amphophilic cationic drugs   Amiodarone   Chloroquine   Hydroxychloroquine This drug produces painless, proximal weakness especially in the setting of renal failure. Muscle biopsy shows necrosis and fibers with autophagic vacuoles. Antimicrotubular drugs   Colchicine myotoxicity. EMG demonstrates irritability, and myopathic units and muscle biopsies reveal necrotic muscle fibers in weak muscles. Severe myalgia, weakness, marked elevations in serum CK (>3–5 times baseline), and myoglobinuria are indications for stopping the drug. Patients usually improve with drug cessation, although this may take several weeks. Rare cases continue to progress after the offending agent is discontinued. It is possible that in such cases the statin may have triggered an immune-mediated necrotizing myopathy, as these individuals require immunotherapy (e.g., intravenous immunoglobulin or immunosuppressive agents) to improve and often relapse when these therapies are discontinued (Chap. 377). Autoantibodies directed against HMG-CoA reductase have been identified in many of these cases. ■ ■GLUCOCORTICOID-RELATED MYOPATHIES Glucocorticoid myopathy occurs with chronic treatment or as “acute quadriplegic” myopathy secondary to high-dose IV glucocorticoid use. Chronic administration produces proximal weakness accompanied by cushingoid manifestations, which can be quite debilitating; the chronic use of prednisone at a daily dose of ≥30 mg/d is most often associated with toxicity. Patients taking fluorinated glucocorticoids (triamcinolone, betamethasone, dexamethasone) appear to be at especially high risk for myopathy. In chronic steroid myopathy, the serum CK is usually normal. Serum potassium may be low. The muscle biopsy in chronic cases shows preferential type 2 muscle fiber atrophy; this is not reflected in the EMG, which is usually normal. Patients receiving high-dose IV glucocorticoids for status asthmaticus, chronic obstructive pulmonary disease, organ transplantation, or other indications may develop severe generalized weakness (critical illness myopathy). This myopathy, also known as acute quadriplegic myopathy, can also occur in the setting of sepsis. Involvement of the diaphragm and intercostal muscles causes ventilatory muscle weakness and is usually appreciated when patients are unable to be weaned off a ventilatory in the intensive care unit. NCS demonstrate reduced compound muscle action potentials in the setting of relatively preserved sensory potentials. EMG can demonstrate abnormal insertional and spontaneous activity and early recruitment of myopathic appearing units in those muscles that can be activated. Muscle biopsy can show a distinctive loss of thick filaments (myosin) by electron microscopy. Treatment is withdrawal of glucocorticoids and physical therapy, but the recovery is slow. Patients require supportive care and rehabilitation. ■ ■OTHER DRUG-INDUCED MYOPATHIES Certain drugs produce painless, largely proximal muscle weakness. These drugs include the amphophilic cationic drugs (amiodarone, chloroquine, hydroxychloroquine) and antimicrotubular drugs (colchicine) (Table 460-6). Muscle biopsy can be useful in the identification of toxicity because autophagic vacuoles are prominent pathologic features of these toxins. ■ ■GLOBAL ISSUES As previously discussed, certain dystrophies have an increased prevalence in different parts of the world. LGMD2A/LGMDR1 is the most common LGMD in individuals from Spain, France, Italy, and Great Britain; LGMD2I/LGMDR9 is more common in those with northern European ancestry. GNE myopathy is the most common form of distal myopathy in Japan but is also prevalent in the Ashkenazi population. OPMD is most common in those with ancestry from Spain and French-Canada as well as among Ashkenazi. Epidemiologic studies are lacking regarding other forms of myopathy and their prevalence in different areas of the world. ■ ■FURTHER READING Amato AA et al: Amato and Russell’s Neuromuscular Disorders, 3rd ed. McGraw Hill, 2025. Chin HL et al: A clinical approach to diagnosis and management of mitochondrial myopathies. Neurotherapeutics 21:e00304, 2024. Doughty CT, Amato AA: Toxic myopathies. Continuum (Minneap Minn) 25:1712, 2019. Heller SA et al: Emery-Dreifuss muscular dystrophy. Muscle Nerve 61:436, 2020. Johnson NE: Myotonic muscular dystrophies. Continuum (Minneap Minn) 25:1682, 2019. Johnson NE, Statland JM: The limb-girdle muscular dystrophies. Continuum (Minneap Minn) 28:1698, 2022. Mah JK et al: A systematic review and meta-analysis on the epidemiology of the muscular dystrophies. Can J Neurol Sci 43:163, 2016. Mul K: Facioscapulohumeral Muscular Dystrophy. Continuum (Minneap Minn) 28:1735, 2022. Rodolico C et al: Endocrine myopathies: Clinical and histopathological features of the major forms. Acta Myol 39:130, 2020. Rosow LK, Amato AA: The role of electrodiagnostic testing, imaging, and muscle biopsy in the investigation of muscle disease. Continuum (Minneap Minn) 22:1787, 2016. Straub V et al: LGMD Workshop Study Group. 229th ENMC international workshop: Limb girdle muscular dystrophies—Nomenclature and reformed classification Naarden, the Netherlands, 17-19 March 2017. Neuromuscul Disord 28:702, 2018. # 32 - SECTION 4 Syndromes Associated with Chronic Fatigue ## SECTION 4 Syndromes Associated with Chronic Fatigue Section 4 Syndromes Associated with Chronic Fatigue Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Elizabeth R. Unger, Jin-Mann S. Lin, Jeanne Bertolli Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic complex illness with multisystem manifestations and longterm impact on functional impairment comparable to multiple sclero­ sis, rheumatoid arthritis, and congestive heart failure. The hallmark of ME/CFS is persistent and unexplained fatigue resulting in significant impairment in daily functioning, along with worsening symptoms following physical or mental exertion that would have been tolerated before illness (postexertional malaise). Besides intense fatigue, many patients report concomitant symptoms such as pain, cognitive dys­ function, and unrefreshing sleep. Additional symptoms can include headache, sore throat, tender lymph nodes, muscle aches, joint aches, feverishness, difficulty sleeping, psychiatric problems, allergies, and abdominal cramps. The recognition that ME/CFS is one diagnosable condition in Long COVID has raised clinical awareness about this poorly understood illness, although patients still face stigma and mis­ understanding among health care providers. The condition has been known by many names, and debate about the name and case definition continues. The composite name ME/CFS was adopted by the U.S. Department of Health and Human Services in rec­ ognition of the limitations of either ME (absence of definitive inflam­ mation in brain and spinal cord) or CFS (trivializes an often devastating illness through confusion with fatigue that everyone experiences). EPIDEMIOLOGY Determining how frequently ME/CFS occurs and characteristics of those affected has been complicated by variability in study design and application of case definitions. In the absence of a simple diagnostic test, evaluation by an experienced clinician is required for case iden­ tification. Clinic-based studies most accurately identify patients with ME/CFS but overrepresent higher socioeconomic groups with access to ME/CFS clinics. Population-based studies with or without a clinical evaluation estimated that between 836,000 and 3.3 million Americans have ME/CFS. However, studies indicate that ≥80% of those meeting criteria for ME/CFS had not been diagnosed by a health care provider. The illness costs the U.S. economy between $18 and $51 billion annu­ ally in medical costs and lost income. ME/CFS is three to four times more common in women than men. The highest prevalence is among those 40–50 years of age, but the age range is broad and includes chil­ dren and adolescents. Persons of all races and ethnicities are affected, and there is some evidence that socioeconomically disadvantaged groups are at increased risk. RISK FACTORS AND PATHOPHYSIOLOGY A wide variety of infectious agents have been reported to be associ­ ated with a postinfectious fatiguing illness resembling ME/CFS. These include both viral and nonviral pathogens, such as Epstein-Barr virus, Ross River virus, Coxiella burnetti (Q fever), Ebola virus, SARS-CoV-1, and Giardia. While recovery from these infections is the rule, ~10% of those infected remain ill for ≥6 months. Most recently, published reports suggest that SARS-CoV-2 infection is also associated with prolonged fatiguing illness. Host and pathogen factors associated with recovery versus persistent disease remain elusive. In addition to infectious insults, Fatigue Post-Exertional Malaise Diet/Nutrition Lifestyle Genetics HypothalamicPituitaryAdrenal Axis Cognitive Impairment Sleep Problems Central Nervous System Immune System Metabolism Pain Autonomic Nervous System Infection Stress CHAPTER 461 Orthostatic Intolerance FIGURE 461-1  A multisystem model for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). An example of a unifying model for ME/CFS demonstrating the interactions of multiple organ systems and environmental, genetic, and behavioral factors contributing to symptoms. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome a variety of stressors, including toxins, physical trauma, adverse events, and allostatic load (or “wear and tear” on the body), have been found to be associated with ME/CFS. Twin studies and family histories suggest a role for shared environment as well as genetic factors. Evidence for immunologic dysfunction is inconsistent. Modest ele­ vations in titers of antinuclear antibodies, reductions in immunoglobu­ lin subclasses, deficiencies in mitogen-driven lymphocyte proliferation, reductions in natural killer cell activity, disturbances in cytokine pro­ duction, and altered T-cell metabolism have been described. None of these immune findings has been firmly established and none of these changes appear in most patients. In theory, symptoms of ME/CFS could result from excessive production of a cytokine, such as interleukin 1 or interferon α, which induces fatigue and other flulike symptoms; how­ ever, compelling data in support of this hypothesis are lacking. Other studies have reported various nonspecific changes in regional brain structures estimated by magnetic resonance imaging; dysfunction of the autonomic nervous system; abnormalities in the hypothalamicpituitary-adrenal (HPA) axis; altered metabolism; and dysbiosis of the intestinal microbiome. Confirmatory studies are needed, and none of the findings are consistent enough to be used for diagnosis. It is clear that ME/CFS represents a complex disorder with alterations in multiple interrelated homeostatic systems. A variety of unifying models for the illness have been proposed, and discoveries about the pathophysiology of ME/CFS hold promise for elucidating novel mechanisms and inter­ actions important in other illnesses (Fig. 461-1). APPROACH TO THE PATIENT Myalgic Encephalomyelitis/Chronic Fatigue Syndrome DIAGNOSIS A diagnosis of ME/CFS is made based on patient-reported symp­ toms that fit a characteristic profile. After a careful review of the literature and symptom-based case definitions for ME, CFS, or ME/ CFS, the Institute of Medicine (IOM) committee recommended in 2015 straightforward diagnostic criteria (Table 461-1). This includes the symptoms consistently noted in prior consensus case definitions: fatigue limiting the patient’s ability to participate in their usual pre-illness activities, sleep problems, and postexertional malaise (PEM). PEM is a relapse in symptoms triggered by physi­ cal, emotional, or mental exertion that would not have been prob­ lematic for the patient before onset of ME/CFS. The relapse lasts more than a day and sometimes weeks. In addition, either difficulty # 33 - 461 Myalgic Encephalomyelitis- Chronic Fatigue Syndrome ### 461 Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Section 4 Syndromes Associated with Chronic Fatigue Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome Elizabeth R. Unger, Jin-Mann S. Lin, Jeanne Bertolli Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic complex illness with multisystem manifestations and longterm impact on functional impairment comparable to multiple sclero­ sis, rheumatoid arthritis, and congestive heart failure. The hallmark of ME/CFS is persistent and unexplained fatigue resulting in significant impairment in daily functioning, along with worsening symptoms following physical or mental exertion that would have been tolerated before illness (postexertional malaise). Besides intense fatigue, many patients report concomitant symptoms such as pain, cognitive dys­ function, and unrefreshing sleep. Additional symptoms can include headache, sore throat, tender lymph nodes, muscle aches, joint aches, feverishness, difficulty sleeping, psychiatric problems, allergies, and abdominal cramps. The recognition that ME/CFS is one diagnosable condition in Long COVID has raised clinical awareness about this poorly understood illness, although patients still face stigma and mis­ understanding among health care providers. The condition has been known by many names, and debate about the name and case definition continues. The composite name ME/CFS was adopted by the U.S. Department of Health and Human Services in rec­ ognition of the limitations of either ME (absence of definitive inflam­ mation in brain and spinal cord) or CFS (trivializes an often devastating illness through confusion with fatigue that everyone experiences). EPIDEMIOLOGY Determining how frequently ME/CFS occurs and characteristics of those affected has been complicated by variability in study design and application of case definitions. In the absence of a simple diagnostic test, evaluation by an experienced clinician is required for case iden­ tification. Clinic-based studies most accurately identify patients with ME/CFS but overrepresent higher socioeconomic groups with access to ME/CFS clinics. Population-based studies with or without a clinical evaluation estimated that between 836,000 and 3.3 million Americans have ME/CFS. However, studies indicate that ≥80% of those meeting criteria for ME/CFS had not been diagnosed by a health care provider. The illness costs the U.S. economy between $18 and $51 billion annu­ ally in medical costs and lost income. ME/CFS is three to four times more common in women than men. The highest prevalence is among those 40–50 years of age, but the age range is broad and includes chil­ dren and adolescents. Persons of all races and ethnicities are affected, and there is some evidence that socioeconomically disadvantaged groups are at increased risk. RISK FACTORS AND PATHOPHYSIOLOGY A wide variety of infectious agents have been reported to be associ­ ated with a postinfectious fatiguing illness resembling ME/CFS. These include both viral and nonviral pathogens, such as Epstein-Barr virus, Ross River virus, Coxiella burnetti (Q fever), Ebola virus, SARS-CoV-1, and Giardia. While recovery from these infections is the rule, ~10% of those infected remain ill for ≥6 months. Most recently, published reports suggest that SARS-CoV-2 infection is also associated with prolonged fatiguing illness. Host and pathogen factors associated with recovery versus persistent disease remain elusive. In addition to infectious insults, Fatigue Post-Exertional Malaise Diet/Nutrition Lifestyle Genetics HypothalamicPituitaryAdrenal Axis Cognitive Impairment Sleep Problems Central Nervous System Immune System Metabolism Pain Autonomic Nervous System Infection Stress CHAPTER 461 Orthostatic Intolerance FIGURE 461-1  A multisystem model for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). An example of a unifying model for ME/CFS demonstrating the interactions of multiple organ systems and environmental, genetic, and behavioral factors contributing to symptoms. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome a variety of stressors, including toxins, physical trauma, adverse events, and allostatic load (or “wear and tear” on the body), have been found to be associated with ME/CFS. Twin studies and family histories suggest a role for shared environment as well as genetic factors. Evidence for immunologic dysfunction is inconsistent. Modest ele­ vations in titers of antinuclear antibodies, reductions in immunoglobu­ lin subclasses, deficiencies in mitogen-driven lymphocyte proliferation, reductions in natural killer cell activity, disturbances in cytokine pro­ duction, and altered T-cell metabolism have been described. None of these immune findings has been firmly established and none of these changes appear in most patients. In theory, symptoms of ME/CFS could result from excessive production of a cytokine, such as interleukin 1 or interferon α, which induces fatigue and other flulike symptoms; how­ ever, compelling data in support of this hypothesis are lacking. Other studies have reported various nonspecific changes in regional brain structures estimated by magnetic resonance imaging; dysfunction of the autonomic nervous system; abnormalities in the hypothalamicpituitary-adrenal (HPA) axis; altered metabolism; and dysbiosis of the intestinal microbiome. Confirmatory studies are needed, and none of the findings are consistent enough to be used for diagnosis. It is clear that ME/CFS represents a complex disorder with alterations in multiple interrelated homeostatic systems. A variety of unifying models for the illness have been proposed, and discoveries about the pathophysiology of ME/CFS hold promise for elucidating novel mechanisms and inter­ actions important in other illnesses (Fig. 461-1). APPROACH TO THE PATIENT Myalgic Encephalomyelitis/Chronic Fatigue Syndrome DIAGNOSIS A diagnosis of ME/CFS is made based on patient-reported symp­ toms that fit a characteristic profile. After a careful review of the literature and symptom-based case definitions for ME, CFS, or ME/ CFS, the Institute of Medicine (IOM) committee recommended in 2015 straightforward diagnostic criteria (Table 461-1). This includes the symptoms consistently noted in prior consensus case definitions: fatigue limiting the patient’s ability to participate in their usual pre-illness activities, sleep problems, and postexertional malaise (PEM). PEM is a relapse in symptoms triggered by physi­ cal, emotional, or mental exertion that would not have been prob­ lematic for the patient before onset of ME/CFS. The relapse lasts more than a day and sometimes weeks. In addition, either difficulty TABLE 461-1  2015 Institute of Medicine Diagnostic Criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Substantial reduction or impairment in the ability to engage in pre-illness levels of activity (occupational, educational, social, or personal life) that: • lasts for >6 months • is accompanied by fatigue that is often profound, of new or definite onset (not lifelong), not the result of ongoing excessive exertion, and is not substantially alleviated by rest Postexertional malaise (PEM)a—worsening of symptoms after physical, mental, or emotional exertion that would not have caused a problem before the illness Unrefreshing sleepa Cognitive impairment or orthostatic intolerancea aFrequency and severity of symptoms should be assessed; should be present at least half of the time and with at least moderate intensity. thinking and concentrating (often referred to by patients as “brain fog”) or orthostatic intolerance should be present. PART 13 Neurologic Disorders Patients with ME/CFS may experience a wide range of other symptoms not specified in the IOM diagnostic criteria (Table 461-2). As a result, patients meeting ME/CFS criteria could have very dif­ ferent clinical features based on the type, frequency, and severity of their symptoms. Patients may describe a precipitating cause for their illness, such as a known or presumed infection, but frequently no initiating factor is recognized. The symptoms may occur sud­ denly within a day or week or may occur gradually. While the diagnostic criteria specifies that illness must be pres­ ent at least 6 months, the possibility of ME/CFS should be consid­ ered for patients with consistent symptoms persisting >1 month, and evaluation and supportive care can begin as early as 4–6 weeks after onset. Listening to patients’ descriptions of what they are expe­ riencing is important. Asking questions can help patients accurately describe their experience with fatigue and PEM. These include ask­ ing about current activity levels compared with before they became ill, what happens when they are as active as they were pre-illness, and how long it takes to recover after exertion. Whereas patients recognize relapses, the relation of relapse to activity level may not be apparent, and as a result, PEM may not be recognized. Patients may also appear well during an office visit, only to relapse afterward from exertion surrounding the consultation. Although the 2015 IOM ME/CFS criteria do not list medical or psychological conditions that exclude the diagnosis of ME/ CFS, a careful clinical evaluation is required to identify and treat other illnesses that could explain or contribute to the patient’s symptoms. The initial evaluation also requires reviewing family his­ tory, medical history (including infections, traumas/surgeries, and occupational exposure to environmental toxins), and medications and supplements; performing a physical examination, including lean test for postural orthostatic tachycardia syndrome (POTS; Chap. 451); a mental health assessment (screen for depression and anxiety); and routine screening laboratory tests (if recent results are not on record). As routine laboratory tests are usually within nor­ mal limits, their role is in identifying other illnesses, and the specific TABLE 461-2  Additional Symptoms Experienced by Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Joint pain without swelling or redness Muscle aches New headaches Tender lymph nodes Sensitivity to sensory stimuli (e.g., light, noise, smells) Sore throat Shortness of breath Irregular heartbeat Alcohol intolerance Difficulties with temperature regulation (feeling feverish or chilled) panel of tests should be adjusted based on the patient’s presenta­ tion. Typically the tests include complete blood count, erythrocyte sedimentation rate, electrolytes, fasting glucose, renal function tests (blood urea nitrogen, glomerular filtration rate), calcium, phosphate, liver function (bilirubin, alanine aminotransferase, alkaline phospha­ tase, aspartate aminotransferase, gamma-glutamyl transferase, total protein, albumin/globulin ratio), C-reactive protein, thyroid func­ tion (thyroid-stimulating hormone, free thyroxine), iron studies to assess both iron overload and iron deficiency (serum iron, transfer­ rin saturation, ferritin), celiac disease screening tests, and urinalysis. DIFFERENTIAL DIAGNOSIS AND COMORBID CONDITIONS While the differential diagnosis for fatigue is quite broad (Chap. 25), further workups and referrals should be chosen carefully based on the patient’s history, symptoms (particularly those that are new, worsening, or unusual), and results of initial laboratory tests. Con­ ditions reported to occur in association with ME/CFS (Table 461-3) should be kept in mind during the evaluation and follow-up, as management and treatment modalities for these comorbidities could contribute to an improved quality of life. MANAGEMENT While there are no approved drugs to treat or cure ME/CFS, patients benefit from receiving a diagnosis and an individualized plan that addresses the symptoms that are most problematic for the patient. Some symptoms, in particular, disturbed sleep (Chap. 33) and pain (Chap. 14), may improve with nonpharmacologic thera­ pies (e.g., sleep hygiene, massage, acupuncture, hot or cold packs) or medications. Any medications should be started at lower doses than usual and only slowly increased. Patients with ME/CFS have been reported to be more sensitive to medications than the general population, and benefits with fewer toxicities may be achieved at lower doses. Narcotics should be avoided, and referral to sleep cen­ ters or other specialists may be required. Controlled therapeutic trials have not established significant benefit for patients with ME/CFS from acyclovir, fludrocortisone, galantamine, modafinil, and IV immunoglobulin, among other agents. These studies have been limited by small numbers and lack power to investigate benefit in patient subgroups. Preliminary small studies reported the possible effectiveness of the B-celltargeting anti-CD20 monoclonal antibody rituximab in ME/CFS, but a subsequent large, well-designed, prospective, double-blind study found no benefit. Numerous anecdotes circulate regarding other traditional and nontraditional therapies. It is important to guide patients away from therapeutic modalities that are toxic, expensive, or unreasonable. Educating the patient and family about PEM can be helpful in avoiding the harmful cycle of overexertion during “good days” followed by relapse that can negate any functional gains. This is often referred to as “push and crash.” Recognizing limits and using activity management (pacing) can help limit PEM. It is important to maintain tolerated activity levels to minimize deconditioning. Activity may be advanced very gradually as tolerated. TABLE 461-3  Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Comorbid Conditions Chronic overlapping pain conditions: fibromyalgia (FM), chronic migraine, temporomandibular joint disease (TMJ), irritable bowel syndrome (IBS), endometriosis, vulvodynia, urologic chronic pelvic pain syndromes (UCPPS) Postural orthostatic tachycardia syndrome (POTS) Allergies Sjögren’s syndrome Ehlers-Danlos syndrome Mast cell activation syndrome (MCAS) Dysautonomia Multiple chemical sensitivities # 34 - SECTION 5 Psychiatric and Addiction Disorders ## SECTION 5 Psychiatric and Addiction Disorders Counseling may help patients and their families cope with the long-term consequences of living with a chronic illness. Consulta­ tion with a physical or occupational therapist may identify energysaving strategies for activities of daily living as well as needed accommodations, such as a wheelchair for activities that require walking longer distances or prolonged standing. COURSE AND PROGNOSIS The illness severity varies from mild or moderate, with patients retaining varying degrees of pre-illness function, to severe, with patients essentially homebound. Most patients experience some improvement and stabilize, although return to their prior level of function is unusual. A continued decline in function should prompt evaluation for other illnesses. Patients should be re-evaluated at scheduled intervals to adjust treatments and detect any intercur­ rent disease. New or changing symptoms should be worked up to identify any new illnesses. Given the social isolation and loss of hope associated with a debilitating chronic illness, serious depres­ sion and an increased risk of suicide are reported for patients with ME/CFS. Clinicians should be prepared to screen for this and refer patients as needed. ■ ■FURTHER READING Centers for Disease Control and Prevention: Myalgic enceph­ alomyelitis/chronic fatigue syndrome (ME/CFS). Available from https://www.cdc.gov/me-cfs/about/index.html. Accessed June 4, 2024. Choutka J et al: Unexplained post-acute infection syndromes. Nat Med 28:911, 2022. Grach SL et al: Diagnosis and management of myalgic encephalomy­ elitis/chronic fatigue syndrome. Mayo Clin Proc 98:1544, 2023. Institute of Medicine: Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press, 2015. Komaroff AL et al: ME/CFS and Long COVID share similar symp­ toms and biological abnormalities: Road map to the literature. Front Med (Lausanne) 10:1187163, 2023. Lapp CW: Initiating care of a patient with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). Front Pediatr 6:415, 2019. Rowe PC et al: Myalgic encephalomyelitis/chronic fatigue syndrome diagnosis and management in young people: A primer. Front Pediatr 5:121, 2017. Vahratian A et al: Myalgic encephalomyelitis/chronic fatigue syndrome in adults: United States, 2021-2022. NCHS Data Brief 488:1, 2023. Walitt B et al: Deep phenotyping of post-infectious myalgic encepha­ lomyelitis/chronic fatigue syndrome. Nat Commun 15:907, 2024. Section 5 Psychiatric and Addiction Disorders Robert O. Messing, Eric J. Nestler, Matthew W. State Biology of Psychiatric Disorders Psychiatric disorders are central nervous system diseases characterized by disturbances in emotion, cognition, motivation, and socialization. They are highly heritable, with genetic risk comprising 20–90% of disease vulnerability depending on the syndrome. As a result of their prevalence, early onset, and persistence, they contribute substantially to the burden of illness worldwide. All psychiatric disorders are broad heterogeneous syndromes that currently lack well-defined neuropa­ thology and bona fide biologic markers. Therefore, diagnoses continue to be made solely from clinical observations using criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), of the American Psychiatric Association (see Chap. 463). There is increasing agreement that the classification of psychiatric illnesses in the DSM does not accurately reflect their underlying biol­ ogy. Uncertainties in diagnosis complicate efforts to study the genetic basis and attendant neurobiological mechanisms underlying mental illness, though recent technologic advances along with the consoli­ dation of very large patient cohorts have, for multiple disorders, led to significant progress in these realms. In addition, there have been efforts to address the limitations of a categorical nosology directly through the development of an alternative diagnostic scheme, termed Research Domain Criteria (RDoC). This system classifies mental ill­ ness on the basis of core behavioral abnormalities shared across several syndromes—such as psychosis (loss of reality) or anhedonia (decreased ability to experience pleasure)—and the associated brain circuitry that controls these behavioral domains. Such classifications may assist in defining the biologic basis of key symptoms. Other factors that have impeded progress in understanding mental illness include the lack of access to pathologic brain tissue except upon death and inherent limitations of animal models for disorders defined largely by behavioral abnormalities (e.g., hallucinations, delusions, guilt, suicidality) that are inaccessible in animals. CHAPTER 462 Biology of Psychiatric Disorders Despite these limitations, the past decade has been marked by real progress. Neuroimaging methods are beginning to provide evidence of brain pathology; genome-wide association studies and high-throughput sequencing are reliably identifying genes and genomic loci that confer risk for severe forms of mental illness; and investigations of bettervalidated animal models, leveraging a host of new methods to study molecular, cellular, and circuit-level processes, are offering new insight into disease pathogenesis. There is also excitement in the utility of neurons, glia, and brain organoids induced in vitro from patientderived pluripotent stem cells, providing novel ways to study disease pathophysiology and screen for new treatments. There is consequently justified optimism that the field of psychiatry will better integrate behaviorally defined syndromes with an understanding of biological substrates in a way that will drive the development of improved treat­ ments and eventually cures and preventive measures. This chapter describes several examples of recent discoveries in basic neuroscience and genetics that have informed our current understanding of disease mechanisms in psychiatry. ■ ■NEUROGENETICS Because the human brain can only be examined indirectly during life, genome analyses have been extremely important for obtaining molecu­ lar clues about the pathogenesis of psychiatric disorders. Moreover, the identification of germline risk alleles and mutations provides potential traction on the question of cause versus effect. In other types of crosssectional studies, it may be impossible to determine whether a phe­ notype or biomarker observed in affected humans or model systems reflects an etiologic factor or a compensatory response. In contrast, germline genetic risk is present before the brain develops—at least theoretically allowing for experiments to address temporal sequencing. A wealth of new information has been made possible by two decades of advances subsequent to the sequencing of the human genome. These have enabled affordable, very large-scale genome-wide association and high-throughput sequencing studies. A striking example of the impact of these developments has been progress in the genetics of autism spectrum disorders (ASDs), a phenotypically heterogeneous neurodevelopmental syndrome characterized by impaired social com­ munication and restricted, repetitive patterns of behavior. ASDs are highly heritable. Concordance rates in monozygotic twins range from 60–90%, a four- to sixfold increase compared to dizygotic twins and siblings. ASDs are also highly genetically heterogeneous and, like many psychiatric conditions, are mainly inherited in a polygenic fashion, # 35 - 462 Biology of Psychiatric Disorders ### 462 Biology of Psychiatric Disorders Counseling may help patients and their families cope with the long-term consequences of living with a chronic illness. Consulta­ tion with a physical or occupational therapist may identify energysaving strategies for activities of daily living as well as needed accommodations, such as a wheelchair for activities that require walking longer distances or prolonged standing. COURSE AND PROGNOSIS The illness severity varies from mild or moderate, with patients retaining varying degrees of pre-illness function, to severe, with patients essentially homebound. Most patients experience some improvement and stabilize, although return to their prior level of function is unusual. A continued decline in function should prompt evaluation for other illnesses. Patients should be re-evaluated at scheduled intervals to adjust treatments and detect any intercur­ rent disease. New or changing symptoms should be worked up to identify any new illnesses. Given the social isolation and loss of hope associated with a debilitating chronic illness, serious depres­ sion and an increased risk of suicide are reported for patients with ME/CFS. Clinicians should be prepared to screen for this and refer patients as needed. ■ ■FURTHER READING Centers for Disease Control and Prevention: Myalgic enceph­ alomyelitis/chronic fatigue syndrome (ME/CFS). Available from https://www.cdc.gov/me-cfs/about/index.html. Accessed June 4, 2024. Choutka J et al: Unexplained post-acute infection syndromes. Nat Med 28:911, 2022. Grach SL et al: Diagnosis and management of myalgic encephalomy­ elitis/chronic fatigue syndrome. Mayo Clin Proc 98:1544, 2023. Institute of Medicine: Beyond Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Redefining an Illness. Washington, DC: The National Academies Press, 2015. Komaroff AL et al: ME/CFS and Long COVID share similar symp­ toms and biological abnormalities: Road map to the literature. Front Med (Lausanne) 10:1187163, 2023. Lapp CW: Initiating care of a patient with myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). Front Pediatr 6:415, 2019. Rowe PC et al: Myalgic encephalomyelitis/chronic fatigue syndrome diagnosis and management in young people: A primer. Front Pediatr 5:121, 2017. Vahratian A et al: Myalgic encephalomyelitis/chronic fatigue syndrome in adults: United States, 2021-2022. NCHS Data Brief 488:1, 2023. Walitt B et al: Deep phenotyping of post-infectious myalgic encepha­ lomyelitis/chronic fatigue syndrome. Nat Commun 15:907, 2024. Section 5 Psychiatric and Addiction Disorders Robert O. Messing, Eric J. Nestler, Matthew W. State Biology of Psychiatric Disorders Psychiatric disorders are central nervous system diseases characterized by disturbances in emotion, cognition, motivation, and socialization. They are highly heritable, with genetic risk comprising 20–90% of disease vulnerability depending on the syndrome. As a result of their prevalence, early onset, and persistence, they contribute substantially to the burden of illness worldwide. All psychiatric disorders are broad heterogeneous syndromes that currently lack well-defined neuropa­ thology and bona fide biologic markers. Therefore, diagnoses continue to be made solely from clinical observations using criteria in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), of the American Psychiatric Association (see Chap. 463). There is increasing agreement that the classification of psychiatric illnesses in the DSM does not accurately reflect their underlying biol­ ogy. Uncertainties in diagnosis complicate efforts to study the genetic basis and attendant neurobiological mechanisms underlying mental illness, though recent technologic advances along with the consoli­ dation of very large patient cohorts have, for multiple disorders, led to significant progress in these realms. In addition, there have been efforts to address the limitations of a categorical nosology directly through the development of an alternative diagnostic scheme, termed Research Domain Criteria (RDoC). This system classifies mental ill­ ness on the basis of core behavioral abnormalities shared across several syndromes—such as psychosis (loss of reality) or anhedonia (decreased ability to experience pleasure)—and the associated brain circuitry that controls these behavioral domains. Such classifications may assist in defining the biologic basis of key symptoms. Other factors that have impeded progress in understanding mental illness include the lack of access to pathologic brain tissue except upon death and inherent limitations of animal models for disorders defined largely by behavioral abnormalities (e.g., hallucinations, delusions, guilt, suicidality) that are inaccessible in animals. CHAPTER 462 Biology of Psychiatric Disorders Despite these limitations, the past decade has been marked by real progress. Neuroimaging methods are beginning to provide evidence of brain pathology; genome-wide association studies and high-throughput sequencing are reliably identifying genes and genomic loci that confer risk for severe forms of mental illness; and investigations of bettervalidated animal models, leveraging a host of new methods to study molecular, cellular, and circuit-level processes, are offering new insight into disease pathogenesis. There is also excitement in the utility of neurons, glia, and brain organoids induced in vitro from patientderived pluripotent stem cells, providing novel ways to study disease pathophysiology and screen for new treatments. There is consequently justified optimism that the field of psychiatry will better integrate behaviorally defined syndromes with an understanding of biological substrates in a way that will drive the development of improved treat­ ments and eventually cures and preventive measures. This chapter describes several examples of recent discoveries in basic neuroscience and genetics that have informed our current understanding of disease mechanisms in psychiatry. ■ ■NEUROGENETICS Because the human brain can only be examined indirectly during life, genome analyses have been extremely important for obtaining molecu­ lar clues about the pathogenesis of psychiatric disorders. Moreover, the identification of germline risk alleles and mutations provides potential traction on the question of cause versus effect. In other types of crosssectional studies, it may be impossible to determine whether a phe­ notype or biomarker observed in affected humans or model systems reflects an etiologic factor or a compensatory response. In contrast, germline genetic risk is present before the brain develops—at least theoretically allowing for experiments to address temporal sequencing. A wealth of new information has been made possible by two decades of advances subsequent to the sequencing of the human genome. These have enabled affordable, very large-scale genome-wide association and high-throughput sequencing studies. A striking example of the impact of these developments has been progress in the genetics of autism spectrum disorders (ASDs), a phenotypically heterogeneous neurodevelopmental syndrome characterized by impaired social com­ munication and restricted, repetitive patterns of behavior. ASDs are highly heritable. Concordance rates in monozygotic twins range from 60–90%, a four- to sixfold increase compared to dizygotic twins and siblings. ASDs are also highly genetically heterogeneous and, like many psychiatric conditions, are mainly inherited in a polygenic fashion, conferred by a conspiracy of alleles that are common in the population and carry small individual effects. Indeed, the increments of increased risk for any common ASD risk allele are so modest that studies of tens of thousands of individuals have identified only a handful of asso­ ciations meeting gold-standard genome-wide statistical thresholds. However, with increasingly large cohorts and an associated increase in statistical power, the number of identified risk loci is destined to continue to grow. At the same time, the development of next-generation DNA sequencing has identified a substantial minority of ASD patients who carry rare, often spontaneous (de novo), heterozygous, proteindamaging mutations. This latter group has served as a powerful resource for the identification of specific ASD risk genes of very large effect (Fig. 462-1). To date, about 70–250 ASD genes have been identi­ fied by high-throughput sequencing analyses based on false discovery rates ranging from <0.001 to <0.1, respectively. In addition, approxi­ mately 10% of ASD-affected individuals carry rare, typically de novo, submicroscopic gains or losses of chromosomal material, known as copy number variations (CNVs), that also confer very large risks. All told, these mutations in individual genes or gene-rich genomic regions account for ~20–30% of cases of ASD seen in clinic, although none individually account for >1%. Importantly, as gene discovery in ASD has progressed, considerable overlap, both phenotypically and geneti­ cally, has been found among ASD, epilepsy, and well-established intel­ lectual disability syndromes. For example, individuals with fragile X syndrome or tuberous sclerosis (Chap. 95) show elevated rates of ASD, and mutations in the causal genes may be found in patients who pres­ ent with otherwise idiopathic ASD. PART 13 Neurologic Disorders The discovery of very large-effect ASD risk genes that are vul­ nerable to protein-damaging mutations has provided important opportunities to delve into pathologic mechanisms. From the earli­ est successes in gene discovery, several common biological themes have emerged. For instance, many of the identified pathogenic rare mutations are in genes that encode proteins involved in synaptic structure or function or in transcriptional and chromatin regula­ tion (Fig. 462-1). More recently, studies of high-confidence ASD risk mutations in model systems have confirmed these predictions and pointed to neurogenesis and neuronal migration as additional shared pathological mechanisms. Moreover, the availability of increasingly comprehensive maps of human brain gene expression has enabled studies of when and where ASD risk genes converge. These transcrip­ tomic studies have repeatedly pointed to glutamatergic neurons in the mid-fetal human cortex (Fig. 462-1) as one of several regions and cell types enriched for ASD genetic vulnerability. Given that many autism risk genes are biologically pleiotropic—that is, they serve multiple different functions—the identification of anatomic and temporal dimensions of risk should help narrow in on pathophysiologic mecha­ nisms and potential therapeutic targets. Moreover, as the number of large-effect ASD risk genes grows and the scale of transcriptomic, epigenomic, and proteomic mapping of human brain development expands, points of pathogenic convergence promise to be identifiable at single-cell resolution. A deeper understanding of disease pathogenesis and the identifica­ tion of genetic subtypes is ultimately aimed at developing more effec­ tive, rational, and personalized therapies, particularly for those who are most severely affected. In this regard, in humans, increasing attention has turned to nucleic acid targeting to treat severe phenotypes in cases in which a highly penetrant coding mutation is present, for example, with CRISPR-based therapies or the use of antisense oligonucleotides (ASOs). Remarkable success with very early intervention in spinal muscular atrophy using these strategies has piqued interest in their utility in a range of brain-based conditions. Currently, among neuro­ developmental disorders, these approaches are being actively pursued for well-known intellectual disability syndromes that may also manifest core features of or elevated risk for ASD, such as Angelman syndrome and SHANK3 deletion/Phelan-McDermid syndrome. If successful, such efforts would be transformational, and potentially not only for the individuals carrying mutations that may be amenable to nucleic acid–targeting approaches. The ability to catalog common genetic variants and assay them on array-based platforms and carry out whole exome sequencing has also allowed investigators to leverage large patient cohorts to reliably detect risk loci for schizophrenia and bipolar disorder. In contrast to ASD, where the lion’s share of early success resulted from the study of rare, large-effect, de novo mutations, much of gene discovery for these syn­ dromes has resulted from genome-wide association studies of common inherited polymorphisms. To date, several hundred distinct genomic regions, marked by associated single nucleotide polymorphisms, have been identified in schizophrenia, some of which show risk as well for bipolar disorder. Several identified genes are parts of molecular complexes, such as voltage-gated calcium channels (in particular, CACNA1C and CACNB2) and the postsynaptic density of excitatory synapses. Notably, as the scale of high-throughput sequencing studies has expanded, rare large-effect mutations have also been identified in schizophrenia. To date, 10 high-confidence genes have been identified. Genes that promote risk for addiction and depression have also begun to emerge from large studies. One susceptibility locus for addic­ tion is the CHRNA5-A3-B4 nicotinic acetylcholine receptor gene clus­ ter on chromosome 15 associated with nicotine and alcohol addiction. Genome-wide association studies of depression and addiction have required hundreds of thousands of cases and controls to identify the first statistically significant loci using state-of-the-art approaches. For example, a meta-analysis of >1 million individuals was able to identify 110 unique genetic variants associated with problematic alcohol use. Such findings collectively point to the tremendous heterogeneity of these disorders as well as the very small biological effects conferred by any individual common allele. A recurrent theme in genetic studies of psychiatric disorders is phenotypic pleiotropy, namely, that individual risk genes may be asso­ ciated with multiple psychiatric and neurodevelopmental syndromes. For example, functionally identical heterozygous deletions of the gene NRXN1 are associated with ASD, schizophrenia, intellection disability, epilepsy, and other neurodevelopmental phenotypes. Common poly­ morphisms in CACNA1C are associated with both schizophrenia and bipolar disorder. Rare mutations in this same gene may lead to severe neurodevelopmental syndromes and congenital heart disease, includ­ ing Timothy syndrome, which may include autistic features. Likewise, there is striking overlap among the phenotypes associated with largeeffect CNVs, including ASD, schizophrenia, and bipolar disorder, as well as epilepsy and intellectual disability. For example, duplication of chromosome 16p is associated with both schizophrenia and autism, whereas deletions in the DiGeorge’s (velocardiofacial) syndrome region are associated with schizophrenia, autism, and bipolar disorder. These findings attest to the complexity of psychiatric disorders, the very large gap between molecular mechanisms and the current categorical diag­ nostic schemes, and the influence of additional factors that combine to specify the ultimate phenotype. The latter might include polygenic “background,” stochastic events, epigenetic effects, and environmental factors. This pleiotropy of consequences for a given genetic mutation in psychiatry is akin to the pleiotropy seen for neurodegenerative dis­ orders as well as for many cancer-causing mutations, where the same mutation can lead to very different disorders across the population. ■ ■SIGNAL TRANSDUCTION Studies of signal transduction disturbances in psychiatric disorders have provided insight into development of new therapeutic agents. For example, lithium is a highly effective drug for bipolar disorder and competes with magnesium to inhibit numerous magnesium-dependent enzymes, including GSK3β and several enzymes involved in phos­ phoinositide signaling that lead to activation of protein kinase C. These findings have led to discovery programs focused on developing GSK3β or protein kinase C inhibitors as potential novel treatments for mood disorders, although none have demonstrated clinical efficacy to date. The observations that tricyclic antidepressants (e.g., imipramine) inhibit serotonin and/or norepinephrine reuptake and that mono­ amine oxidase inhibitors (e.g., tranylcypromine) are effective anti­ depressants initially led to the view that depression is caused by a deficiency of these monoamines. However, this hypothesis has not DPYSL2 cAMP Ca2 + Ch. ANK2 Spectrin Network L1 DYNC1H1 AP2S1 Ca2 + Ch. MINT CASK NRNX1 ?+ SCN2A GRIN2B MGluR KCNQ3 NMDARs NLGNs CAMKII CK2 PSD95 CNTNAP2 Homer SHANK3 CAMKII PI3K PSD95 GKAP1 SYNGAP1 GKAP1 PTEN Ras-GTP SHANK2/3 Ras-GDP Endoplasmic Reticulum CTNNB1 AGO1-4 SRPR TNRC6B** DSCAM Membrane/ Vessicle Targeting GIGYF1 2EHP A ASH1L KMT2C SETD5 KDM6B KDM5B ARTKQTARKSTGGKAPRKQLATKAARKSAPATGGVK CHD8 SGRGKGGKGLGKGGAKRHRKVLRDNIQGITKPAIR SUV420H1 Methyl group Ubiquitine ligase Lysine demethylase Lysine methyltransferase Other chromatin remodeler B Convergence of Autism Associated Genes & Co-expression Network Analysis Mid-fetal Development Prefrontal and Primary Motor-Somatosensory Cortex C Co-expression of Autism Associated Genes FIGURE 462-1  Functional characteristics and developmental convergence of autism spectrum disorder (ASD) associated genes. A representative selection of genes associated with ASD based on recurrent rare coding mutations is shown in A and B. Those genes encoding proteins with a false discovery rate (FDR) <0.01 in Sanders et al, Neuron 2015, and Satterstrom et al, Cell 2020, are highlighted with respect to their putative functions. Genes meeting the highest confidence criteria in Sanders et al 2015 and showing either an FDR >0.01 or an FDR >0.3 in Satterstrom are noted (* and **, respectively). Additional interacting and functionally related molecules that do not meet the above criteria are shown in green. FMR1, TSC1, and TSC2 are syndromic ASD genes included in the figure (A). Multiple gene ontology analyses of ASD genes have highlighted both pre- and postsynaptic molecules (A) and chromatin modifiers (B) as points of enrichment. In C, an alternative strategy for grouping ASD risk genes is highlighted (Willsey et al, Cell 2013), based on their spatiotemporal expression patterns as opposed to putative functions. One analytic strategy, illustrated in C, leveraged only high-confidence ASD genes and examined their developmental expression patterns using the BrainSpan data set. Convergence for ASD risk was identified in deep layer (V and VI) excitatory neurons in mid-fetal human cortex. Multiple analyses have similarly found glutamatergic neurons in mid-fetal prefrontal cortex as one point of convergence, with somewhat less agreement on layer specificity and potential additional spatiotemporal points of convergence. Microtubule SCN2A KATNAL2** DYRK1A MAP1A Presynaptic Phos. localizes RBX1 CUL3** CK2 Channels KCT13 Ubiquitin Ligases Ub Cell Adhesion Proteins Scaffolding Proteins RhoA GABRB3 Phosphatase SLC6A1 Kinases GABRB3 Other Transcription Factors Adaptor Proteins Actin Cytoskeleton FDR>0.01 CAMKII CHAPTER 462 PIKE-L RAC1 Postsynaptic ∆ NCKAP1** FMR1 WRC Nucleus MBD5 AKT CYFIP1 PAX5 MKX MED13L CYFIP1 TBR1* MYT1L BCL11A FMR1 Biology of Psychiatric Disorders TCF7L2* POGZ RORB WAC MEK TSC1 TSC2 TTT-Pontin/ Reptin complex FOXP1 DEAF1 CTNNB1 MAPK mTORC1 Transcription ∆ ∆ Translation RNF20 RNF40 WAC Ub TRIP12* H3 H2B RNF168 Ub H4 H2A ARID1B ADNP DNMT3A SIN3A RAI1 ANKRD11 Reader TLK2 CHD2 FDR > 0.01 TBL1XR1 Map of Gene Expression in the Developing Human Brain been substantiated. A cardinal feature of these drugs is that long-term (weeks to months) administration is needed for their antidepressant effects. This means that their short-term actions, namely promotion of serotonin or norepinephrine function, are not per se antidepressant but rather induce a cascade of adaptations in the brain that underlie their slowly developing clinical effects. The nature of these therapeutic druginduced adaptations has not been identified with certainty. A subset of depressed patients display upregulation of the hypothalamic-pituitaryadrenal (HPA) axis characterized by increased secretion of cortico­ tropin-releasing factor (CRF) and glucocorticoids. One hypothesis posits that in these patients excessive glucocorticoids cause atrophy of hippocampal neurons, which is associated with reduced hippocampal volumes seen clinically. Chronic antidepressant administration might reverse this atrophy by increasing brain-derived neurotrophic factor (BDNF) or a host of other neurotrophic factors in the hippocampus. A role for stress-induced decreases in the generation of newly born hippocampal granule cell neurons, and its reversal by antidepressants through BDNF or other growth factors, has also been suggested. PART 13 Neurologic Disorders A major advance in recent years has been the identification of several rapidly acting antidepressants with non–monoamine-based mechanisms of action. The best established is ketamine, a noncompeti­ tive antagonist of N-methyl-d-aspartate (NMDA) glutamate receptors among other actions, which exerts rapid (hours) and robust antidepres­ sant effects in severely depressed patients who have not responded to other treatments. Ketamine, which at higher doses is psychotomimetic and anesthetic, exerts these antidepressant effects at lower doses with minimal side effects. However, the response to ketamine is transient, which has led to several approaches to maintain treatment response, such as repeated ketamine delivery. The mechanism underlying ket­ amine’s antidepressant action is not known, and its action as an NMDA receptor antagonist has recently been called into question. Neverthe­ less, ketamine’s striking clinical efficacy has stimulated animal research on the role of glutamate neurotransmission and synaptic plasticity in key limbic regions. Recent evidence supports a role for TORC1 or BDNF activation, as blockade of either blocks the antidepressant-like effects of ketamine in animal models. Mechanisms by which ketamine activates these signaling cascades are currently an active area of investigation. Another area of great interest is the potential clinical utility of psy­ chedelic drugs and 3,4-methylenedioxy-methamphetamine (MDMA or ecstasy). Psychedelic drugs are thought to act as partial agonists of serotonin 5-HT2A receptors, whereas MDMA promotes serotonin release from nerve terminals. Both are being studied for treatment of depression and posttraumatic stress disorder, although much addi­ tional clinical research is needed to establish their efficacy, safety, and mechanism of action. A major goal in the field of substance use disorders has been to identify neuroadaptive mechanisms that lead from recreational use to addiction. Such research has determined that repeated intake of abused drugs induces specific changes in cellular signal transduction, leading to changes in synaptic strength (long-term potentiation or depression) and neuronal structure (altered dendritic branching or cell soma size) within the brain’s reward circuitry. These drug-induced modifications are mediated in part by changes in gene expression, achieved by regu­ lation of transcription factors (e.g., CREB [cAMP response elementbinding protein] and ΔFOSB [a FOS family protein]) and their target genes. Such alterations in gene expression are associated with lasting alterations in epigenetic modifications, including histone acetylation and methylation and DNA methylation. These adaptations provide opportunities for developing treatments targeted to drug-addicted individuals. The fact that the spectrum of these adaptations differs in part depending on the particular addictive substance used raises hope that treatments could be developed that are specific for different classes of addictive drugs and less likely to disturb basic mechanisms that gov­ ern normal motivation and reward. Increasingly, causal relationships are being established between individual molecular and cellular adaptations and specific behavioral abnormalities that characterize the addicted state. For example, acute activation of μ-opioid receptors by morphine or other opioids activates µ-opioid receptor K+ Ca2+ AC Gi/o + – – Increased excitability cAMP + R R Regulation of proteins by PKA phosphorylation C C C C PKA Nucleus + P CREB Altered gene expression FIGURE 462-2  Opioid action in the locus coeruleus (LC). Binding of opioid agonists to μ-opioid receptors on LC neurons catalyzes nucleotide exchange on Gi and Go proteins, leading to inhibition of adenylyl cyclase (AC), neuronal hyperpolarization via activation of K+ channels, and perhaps inhibition of Ca2+ channels. Inhibition of AC reduces protein kinase A (PKA) activity and phosphorylation of several PKA substrate proteins, thereby altering their function. For example, opioids reduce phosphorylation of the cAMP response element-binding protein (CREB), which initiates longer term changes in neuronal function. Chronic administration of opioids increases levels of AC isoforms, PKA catalytic (C) and regulatory (R) subunits, and the phosphorylation of several proteins, including CREB (indicated by red arrows). These changes contribute to the altered phenotype of the drug-addicted state. For example, the excitability of LC neurons is increased by enhanced cAMP signaling. Activation of CREB causes upregulation of AC isoforms and tyrosine hydroxylase, the rate-limiting enzyme in catecholamine biosynthesis. Gi/o proteins, leading to inhibition of adenylyl cyclase (AC), resulting in reduced cyclic AMP (cAMP) production, protein kinase A (PKA) activation, and activation of the transcription factor CREB. Repeated administration of these drugs (Fig. 462-2) evokes a homeostatic response involving upregulation of ACs and PKA and increased acti­ vation of CREB. Such upregulation of cAMP-CREB signaling has been identified in the locus coeruleus (LC), periaqueductal gray, ventral tegmental area (VTA), nucleus accumbens (NAc), and several other central nervous system (CNS) regions and contributes to opioid crav­ ing and signs of opioid withdrawal. The fact that endogenous opioid peptides do not produce tolerance and dependence, while morphine and related drugs do, may relate to the observation that, unlike endog­ enous opioids, morphine and like drugs are weak inducers of μ-opioid receptor desensitization and endocytosis. Therefore, these drugs cause prolonged receptor activation and inhibition of ACs, which provides a powerful stimulus for the upregulation of cAMP-CREB signaling that characterizes the opioid-dependent state. ■ ■SYSTEMS NEUROSCIENCE The study of interconnected brain circuits that drive behavior has been greatly advanced through newer methods in brain imaging that have documented abnormalities in neural function and connectivity in psy­ chiatric disorders. Electroceutical devices, which use electrical or mag­ netic stimulation to control neuronal activity, have had some success in depression, obsessive-compulsive disorder, pain, and addiction. The past decade has also witnessed the development of revolutionary new FC VTA Hyp NAc HP LC Amy Glutamatergic GABAergic Dopaminergic Peptidergic FIGURE 462-3  Neural circuitry of depression and addiction. The figure shows a simplified summary of a series of limbic circuits in the brain that regulate mood and motivation and are implicated in depression and addiction. Shown in the figure are the hippocampus (HP) and amygdala (Amy) in the temporal lobe, regions of prefrontal cortex, nucleus accumbens (NAc), and hypothalamus (Hyp). Only a subset of the known interconnections among these brain regions is shown. Also shown is the innervation of several of these brain regions by monoaminergic neurons. The ventral tegmental area (VTA) provides dopaminergic input to each of the limbic structures. Norepinephrine (from the locus coeruleus [LC]) and serotonin (from the dorsal raphe [DR] and other raphe nuclei) innervate all of the regions shown. In addition, there are strong connections between the hypothalamus and the VTA-NAc pathway. Important peptidergic projections from the hypothalamus include those from the arcuate nucleus that release β-endorphin and melanocortin and from the lateral hypothalamus that release orexin. techniques—optogenetics, designer receptors, and ligands—that pro­ vide unprecedented temporal and spatial control of neural circuits. The development of genetically encoded calcium detectors and of high-density electrode arrays has allowed in vivo monitoring of thou­ sands of neurons in multiple brain regions simultaneously. Advances in histology and microscopy now permit three-dimensional imaging of specific proteins in the intact brain, while advances in endoscopic microscopy allow imaging of hundreds of neurons within deep brain structures in awake, freely moving animals. Together with recent advances in machine learning and artificial intelligence for analysis of large complex datasets, these new methods are revolutionizing our ability to understand the circuit basis of brain function. Positron emission tomography (PET), diffusion tensor imaging (DTI), and functional magnetic resonance imaging (fMRI) have identified neural circuits that contribute to psychiatric disorders, for example, defining the neural circuitry of mood within the brain’s lim­ bic system (Fig. 462-3). Integral to this system are the NAc (impor­ tant also for brain reward—see below), amygdala, hippocampus, and regions of prefrontal cortex. Recent optogenetic research in animals, where the activity of specific types of neurons in defined circuits can be controlled with light, has confirmed the importance of this limbic circuitry in controlling depression-related behavioral abnormalities. Given that many symptoms of depression (so-called neurovegetative symptoms) involve physiologic functions, a key role for the hypothal­ amus is presumed as well. A subset of depressed individuals shows a small reduction in hippocampal size, as noted above. In addition, brain imaging investigations have revealed increased activation of the amygdala by negative stimuli and reduced activation of the NAc by rewarding stimuli. There is also evidence for altered activity in prefrontal cortex, such as hyperactivity of subgenual area 25 in anterior cingu­ late cortex. Such findings have led to trials of deep brain stimulation (DBS) of either the NAc or subgenual area 25 (see Fig. 32-1), which appears to be therapeutic in some severely depressed individuals. In schizophrenia, structural and func­ tional imaging studies have confirmed earlier pathologic studies that show enlargement of the ventricular system and reduction of cortical and subcortical gray matter in frontal and temporal lobes and in the limbic system. Functional imaging studies show reduced metabolic (presumably neural) activity in the dorso­ lateral prefrontal cortex at rest and when performing tests of executive function, including working memory. There is also evidence for impaired structural and taskrelated functional connectivity, mainly in frontal and temporal lobes. The reduc­ tion in cortical thickness seen in schizo­ phrenia is associated with increased cell packing density and reduced neuropil (defined as axons, dendrites, and glial cell processes) without an apparent change in neuronal cell number. Specific classes of interneurons in prefrontal cortex con­ sistently show reduced expression of the gene encoding the enzyme glutamic acid decarboxylase 1 (GAD1), which syn­ thesizes γ-aminobutyric acid (GABA), the principal inhibitory neurotransmit­ ter in the brain. Recently, results from well-powered genome-wide association studies point to synaptic pruning, includ­ ing the involvement of microglia, as a potential contributing mechanism. In the region of the genome most strongly associated with schizophrenia risk, variations in the relative expression of two isotypes of comple­ ment component 4, C4A and C4B, have been found to account for a significant proportion of this genetic signal. Studies of loss of C4 in mice show deficient synaptic pruning, leading to the hypothesis that increased expression of C4A in humans may result in excessive syn­ aptic pruning. Such results point to the potential for a gene-driven understanding of pathophysiology; however, the findings also leave some important questions unanswered. The strongest effect haplo­ type in humans still only accounts for a very small increase in risk, with an odds ratio of <1.3. In contrast, having a sibling with schizo­ phrenia increases risk approximately tenfold. In short, whether this allele reflects a driving pathophysiologic mechanism remains to be determined. Moreover, humans have diverged at the C4 locus com­ pared with rodents such that only a single C4 isotype is present in the mouse, preventing any analysis of the putative effects of changing the ratio of C4A to C4B—the phenomenon associated with disease risk in humans. Nonetheless, all the aforementioned findings support the notion that schizophrenia is a developmental neurodegenerative disorder with some evidence pointing to loss of cortical interneurons in frontal and temporal lobes. CHAPTER 462 DR Biology of Psychiatric Disorders Work in rodent and nonhuman primate models of addiction has established the brain’s reward regions as key neural substrates for the acute actions of drugs of abuse and for addiction induced in vulner­ able individuals by repeated drug administration (Fig. 462-3). Mid­ brain dopamine neurons in the VTA function normally as rheostats of reward: they are activated by natural rewards (food, sex, social interaction) or even by the expectation of such rewards, and many are suppressed by the absence of an expected reward or by aversive TABLE 462-1  Initial Actions of Drugs of Abuse NEUROTRANSMITTER AFFECTED DRUG TARGET (ACTION) DRUG Opioids Endorphins, enkephalins μ- and δ-opioid receptors (agonist) Psychostimulants (cocaine, amphetamine, methamphetamine) Dopamine Dopamine transporter (antagonist—cocaine; reverse transport—amphetamine, methamphetamine) Nicotine Acetylcholine Nicotinic cholinergic receptors (agonist) Ethanol GABA GABAA receptors (positive allosteric modulator)   Glutamate NMDA glutamate receptors (antagonist)   Acetylcholine Nicotinic cholinergic receptors (allosteric modulator) PART 13 Neurologic Disorders   Serotonin 5-HT3 receptor (positive allosteric modulator)   Others Calcium-activated K+ channel (activator) Marijuana Endocannabinoids (anandamide, 2-arachidonoylglycerol) CB1 receptor (agonist) Phencyclidine Glutamate NMDA glutamate receptor (antagonist) Abbreviations: GABA, γ-aminobutyric acid; NMDA, N-methyl-d-aspartate. stimuli. These neurons thereby transmit crucial survival signals to the rest of the limbic brain to promote reward-related behavior, includ­ ing motor responses to seek and obtain the rewards (NAc), memories of reward-related cues and contexts (amygdala, hippocampus), and executive control of obtaining rewards (prefrontal cortex). Drugs of abuse alter neurotransmission through initial actions at different classes of ion channels, neurotransmitter receptors, or neu­ rotransmitter transporters (Table 462-1). Studies in animal models have demonstrated that although the initial targets differ, the actions of these drugs converge on the brain’s reward circuitry by promoting dopamine neurotransmission in the NAc and other limbic targets of the VTA. In addition, some drugs promote activation of opioid and cannabinoid receptors, which modulate this reward circuitry. By these mechanisms, drugs of abuse produce powerful rewarding signals, which, after repeated drug administration, corrupt a vulnerable brain’s reward circuitry in ways that promote addiction. Three major patho­ logic adaptations have been described. First, drugs produce tolerance in reward circuits and increased activity in limbic stress circuits, which promote escalating drug intake and a negative emotional state during drug withdrawal that promotes relapse. Second, sensitization to the rewarding effects of the drugs and associated cues is seen during pro­ longed abstinence and also triggers relapse. Third, executive function is impaired in such a way as to increase impulsivity and compulsivity, both of which promote relapse. Imaging studies in humans confirm that addictive drugs, as well as craving for them, activate the brain’s reward circuitry. In addition, patients who abuse alcohol or psychostimulants show reduced gray matter in the prefrontal cortex as well as reduced activity in ante­ rior cingulate and orbitofrontal cortex during tasks of attention and inhibitory control. It is thought that damage to these cortical areas contributes to addiction by impairing decision-making and increasing impulsivity. ■ ■NEUROINFLAMMATION There is increasing evidence for the involvement of nonneuronal cell types and inflammatory mechanisms in a wide range of psychiatric syndromes. For example, a subset of depressed patients displays elevated blood levels of interleukin 6 (IL-6), tumor necrosis factor α (TNF-α), and other proinflammatory cytokines. Moreover, rodents exposed to chronic stress exhibit similar increases in peripheral levels of these cytokines, and peripheral or central delivery of those cyto­ kines to normal rodents increases their susceptibility to chronic stress. These findings have led to the novel idea of using peripheral cytokines as biomarkers of a subtype of depression and the potential utility of developing new antidepressants that oppose the actions of specific cytokines. Recent evidence has also linked proinflammatory signaling in the brain to addiction, particularly to alcohol. Alcohol use disorder is associated with impaired innate immunity, increases in circulat­ ing proinflammatory cytokines, and increases in brain expression of several immune-related genes. Many of these genes are expressed by astrocytes and microglia and by neurons under certain pathologic conditions, where they play important roles in modifying neuronal function and plasticity. For example, cytokine monocyte chemotactic protein-1 (MCP-1) modulates the release of certain neurotransmit­ ters and, when administered into the VTA, increases neuronal excit­ ability, promotes dopamine release, and increases locomotor activity. Gene expression studies of alcohol drinking in mice have identified a network of regulated neuroimmune proteins in brain, and a role in regulation of alcohol consumption has been validated for several, including chemokines MCP-1 and chemokine (C-C motif) ligand 3 (CCL3), beta-2 microglobulin, CD14, IL-1 receptor antagonist, tolllike receptors 3 (TLR3) and 7 (TLR7), and cathepsins S and F. This work has led to discovery of anti-inflammatory medications that reduce alcohol intake in animals, such as antagonists of phosphodies­ terase 4, which regulates cAMP availability, or agonists of peroxisome proliferator-activated receptors (PPARs), which are transcription fac­ tors that repress key inflammatory signaling molecules such as nuclear factor-κB (NF-κB) and nuclear factor of activated T cells (NFAT). A major focus of current research is to define the sites and mechanisms by which proinflammatory cytokines impair brain function to elicit a depressive episode or promote drug abuse, including a role for astro­ cytes and microglia. ■ ■CONCLUSIONS This brief narrative illustrates the substantial progress that is being made in understanding the genetic and neurobiological basis of mental illness. It is anticipated that biologic measures will be used increas­ ingly to more accurately diagnose and subtype psychiatric disorders and that targeted therapeutics will become available for these complex conditions. ■ ■FURTHER READING Fu MJ et al: Rare coding variation provides insight into the genetic architecture and phenotypic context of autism. Nat Genet 54:1320, 2022. Gandal MJ et al: The road to precision psychiatry: Translating genet­ ics into disease mechanisms. Nat Neurosci 19:1397, 2016. Howes OD et al: Schizophrenia: from neurochemistry to circuits, symptoms and treatments. Nat Rev Neurol 20:22, 2024. Koob GF, Volkow ND: Neurobiology of addiction: A neurocircuitry analysis. Lancet Psychiatry 3:760, 2016. McClellan JM et al: An evolutionary perspective on complex neuro­ psychiatric disease. Neuron 112:7, 2024. Rajasethupathy P et al: Targeting neural circuits. Cell 165:524, 2016. Ron D, Barak S: Molecular mechanisms underlying alcohol-drinking behaviours. Nat Rev Neurosci 17:576, 2016. Satterstrom FK et al: Large-scale exome sequencing study implicates both developmental and functional changes in the neurobiology of autism. Cell 180:568, 2020. Tian R et al: Whole-exome sequencing in UK Biobank reveals rare genetic architecture for depression. Nat Commun 15:1755, 2024. Wohleb ES et al: Integrating neuroimmune systems in the neurobiol­ ogy of depression. Nat Rev Neurosci 17:497, 2016. Zhou H et al: Multi-ancestry study of the genetics of problematic alco­ hol use in over 1 million individuals. Nat Med 29:231, 2023. # 36 - 463 Psychiatric Disorders ### 463 Psychiatric Disorders Victor I. Reus Psychiatric Disorders Psychiatric disorders are common in medical practice and may present either as a primary disorder or as a comorbid condition. The prevalence of mental or substance use disorders in the United States is ~30%, but only one-third of affected individuals are currently receiv­ ing treatment. Global burden of disease statistics indicates that 4 of the 10 most important causes of morbidity and attendant health care costs worldwide are psychiatric in origin. Changes in health care delivery underscore the need for primary care physicians to assume responsibility for the initial diagnosis and treatment of the most common mental disorders. Prompt diagnosis is essential to ensure that patients have access to appropriate medical services and to maximize the clinical outcome. Validated patient-based questionnaires have been developed that systematically probe for signs and symptoms associated with the most prevalent psychiatric diagno­ ses and guide the clinician into targeted assessment. The Primary Care Evaluation of Mental Disorders (PRIME-MD; and a self-report form, the Patient Health Questionnaire) and the Symptom-Driven Diagnos­ tic System for Primary Care (SDDS-PC) are inventories that require only 10 min to complete and link patient responses to the formal diagnostic criteria of anxiety, mood, somatoform, and eating disorders and to alcohol abuse or dependence. A variety of smart phone apps for assessment and monitoring of psychiatric conditions and for psycho­ logical and pharmacologic treatment interventions are also available. A physician who refers patients to a psychiatrist should know not only when doing so is appropriate but also how to refer because societal misconceptions and the stigma of mental illness impede the process. Primary care physicians should base referrals to a psychiatrist on the presence of signs and symptoms of a mental disorder and not simply on the absence of a physical explanation for a patient’s complaint. The physician should discuss with the patient the reasons for requesting the referral or consultation and provide reassurance that they will continue to provide medical care and work collaboratively with the mental health professional. Consultation with a psychiatrist or transfer of care is appropriate when physicians encounter evidence of psychotic symptoms, mania, severe depression, or anxiety; symptoms of post­ traumatic stress disorder (PTSD); suicidal or homicidal preoccupation; or a failure to respond to first-order treatment. This chapter reviews the clinical assessment and treatment of some of the most common mental disorders presenting in primary care and is based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revi­ sion (DSM-5-TR), the framework for categorizing psychiatric illness used in the United States. Eating disorders are discussed later in this chapter, and the biology of psychiatric and addictive disorders is discussed in Chap. 462. ■ ■GLOBAL CONSIDERATIONS The DSM-5-TR and the tenth revision of the International Classifica­ tion of Diseases (ICD-10-CM), which is used more commonly world­ wide, have taken somewhat differing approaches to the diagnosis of mental illness, but considerable effort has been expended to provide an operational translation between the two nosologies. Both systems are in essence purely descriptive and emphasize clinical pragmatism, in distinction to the Research Domain Criteria (RDOC) proposed by the National Institute of Mental Health, which aspires to provide a causal framework for classification of behavioral disturbance. More recently, an alternative approach, based on a hierarchy of dimensions gener­ ated by factor analytic techniques, HiTOP (Hierarchical Taxonomy of Psychopathology) has been put forward as a possible improvement over DSM-5-TR for clinical usage, although it too lacks validity and is prone to diagnostic error. None of these diagnostic systems has as yet achieved adequate validation, and large-scale genetic investiga­ tions have revealed that differing psychiatric disorders overlap in their genetic risk variants and phenotypic symptoms. The Global Burden of Disease Study (2019), using available epidemiologic data, nevertheless has reinforced the conclusion that, regardless of nosologic differences, mental and substance abuse disorders are the major cause of life-years lost to disability among all medical illnesses, affecting >300 million individuals worldwide. There is general agreement that high-income countries will need to build capacity in professional training in low- and middle-income countries in order to provide an adequate balanced care model for the delivery of evidence-based therapies for mental disorders. Recent surveys that indicate a dramatic increase in mental disorder prevalence in rapidly developing countries, such as China, may reflect both an increased recognition of the issue and also the consequence of social turmoil, stigma, and historically inadequate resources. A salient example of the ways in which societal disruption and isolation may contribute to exacerbating already unmet mental health needs can be seen in the COVID-19 pandemic, which resulted in an increased incidence of diagnosed psychiatric disorders in both affected and unaffected individuals, as well as caregivers. The need for improved prevention strategies and for more definitive and effective interventional treatments remains a global concern. CHAPTER 463 ANXIETY DISORDERS Anxiety disorders, the most prevalent psychiatric illnesses in the general community, are present in 15–20% of medical clinic patients. Anxiety, defined as a subjective sense of unease, dread, or foreboding, can indicate a primary psychiatric condition or can be a component of, or reaction to, a primary medical disease. The primary anxiety disorders are classified according to their duration and course and the existence and nature of precipitants. Psychiatric Disorders When evaluating the anxious patient, the clinician must first deter­ mine whether the anxiety antedates or postdates a medical illness or is due to a medication side effect. Approximately one-third of patients presenting with anxiety have a medical etiology for their psychiatric symptoms, but an anxiety disorder can also present with somatic symp­ toms in the absence of a diagnosable medical condition. ■ ■PANIC DISORDER Clinical Manifestations  Panic disorder is defined by the pres­ ence of recurrent and unpredictable panic attacks, which are distinct episodes of intense fear and discomfort associated with a variety of physical symptoms, including palpitations, sweating, trembling, short­ ness of breath, chest pain, dizziness, and a fear of impending doom or death. Paresthesias, gastrointestinal distress, and feelings of unreal­ ity are also common. Diagnostic criteria require at least 1 month of concern or worry about the attacks or a change in behavior related to them. The lifetime prevalence of panic disorder is 2–3%. Panic attacks have a sudden onset, developing within 10 min and usually resolving over the course of an hour, and can occur in an unexpected fashion, such as when waking from sleep. The frequency and severity of panic attacks vary, ranging from once a week to clusters of attacks separated by months of well-being. The first attack is usually outside the home, and onset is typically in late adolescence to early adulthood. In some individuals, anticipatory anxiety develops over time and results in a generalized fear and a progressive avoidance of places or situations in which a panic attack might recur. Agoraphobia, which occurs com­ monly in patients with panic disorder, is an acquired irrational fear of being in places where one might feel trapped or unable to escape. It may, however, be diagnosed even if panic disorder is not present. Typi­ cally, it leads the patient into a progressive restriction in lifestyle and, in a literal sense, in geography. Frequently, patients are embarrassed that they are housebound and dependent on the company of others to go out into the world and do not volunteer this information; thus, physicians will fail to recognize the syndrome if direct questioning is not pursued. Differential Diagnosis  A diagnosis of panic disorder is made after a medical etiology for the panic attacks has been ruled out. A variety of cardiovascular, respiratory, endocrine, and neurologic condi­ tions can present with anxiety as the chief complaint. Patients with true panic disorder will often focus on one specific feature to the exclusion of others. For example, 20% of patients who present with syncope as a primary medical complaint have a primary diagnosis of a mood, anxiety, or substance abuse disorder, the most common being panic disorder. The differential diagnosis of panic disorder is complicated by a high rate of comorbidity with other psychiatric conditions, especially alcohol and benzodiazepine abuse, which patients initially use in an attempt at self-medication. Some 75% of panic disorder patients will also satisfy criteria for major depression at some point in their illness. When the history is nonspecific, physical examination and focused laboratory testing must be used to rule out anxiety states resulting from medical disorders such as pheochromocytoma, thyrotoxicosis, or hypoglycemia. Electrocardiogram (ECG) and echocardiogram may detect some cardiovascular conditions associated with panic, such as paroxysmal atrial tachycardia and mitral valve prolapse. In two studies, panic disorder was the primary diagnosis in 43% of patients with chest pain who had normal coronary angiograms and was present in 9% of all outpatients referred for cardiac evaluation. Panic disorder has also been diagnosed in many patients referred for pulmonary function test­ ing or with symptoms of irritable bowel syndrome. PART 13 Neurologic Disorders Etiology and Pathophysiology  The etiology of panic disorder is unknown but appears to involve a genetic predisposition, altered auto­ nomic responsivity, and social learning. Panic disorder shows familial aggregation; the disorder is concordant in 30–45% of monozygotic twins, and genome-wide screens have identified suggestive risk loci. Acute panic attacks appear to be associated with increased noradrener­ gic discharges in the locus coeruleus. Intravenous infusion of sodium lactate evokes an attack in two-thirds of panic disorder patients, as do the α2-adrenergic antagonist yohimbine, cholecystokinin tetrapeptide (CCK-4), and carbon dioxide inhalation. It is hypothesized that each of these stimuli activates a pathway involving noradrenergic neurons in the locus coeruleus and serotonergic neurons in the dorsal raphe. Resting-state functional magnetic resonance imaging (fMRI) has iden­ tified abnormalities in the default mode network involving the medial temporal lobe, with greater activation in the sensorimotor cortex in panic disorder and in amygdala-frontal connectivity in social anxiety disorder. TREATMENT Panic Disorder Patients with panic disorder have a heightened sensitivity to somatic symptoms, which triggers increasing arousal, setting off the panic attack; accordingly, therapeutic intervention involves altering the patient’s cognitive interpretation of anxiety-producing experiences, as well as preventing the attack itself. Achievable goals of treatment are to decrease the frequency of panic attacks and to reduce their intensity. The cornerstone of drug therapy is antidepressant medication (Tables 463-1 through 463-3). Selective serotonin reuptake inhibitors (SSRIs) benefit the majority of panic disorder patients and do not have the adverse effects of tricyclic antidepressants (TCAs). Fluoxetine, paroxetine, sertraline, and the selective serotonin-norepinephrine reuptake inhibitor (SNRI) venlafaxine have received approval from the U.S. Food and Drug Administration (FDA) for this indication. These drugs should be started at one-third to one-half of their usual antidepressant dose (e.g., 5–10 mg fluoxetine, 25–50 mg sertra­ line, 10 mg paroxetine, venlafaxine 37.5 mg). Monoamine oxidase inhibitors (MAOIs) are also effective and may specifically benefit patients who have comorbid features of atypical depression (i.e., hypersomnia and weight gain). Insomnia, orthostatic hypotension, and the need to maintain a low-tyramine diet (avoidance of cheese and wine) have limited their use, however. Antidepressants typi­ cally take 2–6 weeks to become effective, and doses may need to be adjusted based on the clinical response. Because of anticipatory anxiety and the need for immediate relief of panic symptoms, benzodiazepines are useful early in the course of treatment and sporadically thereafter (Table 463-4). FDAapproved agents include alprazolam and clonazepam. A recent Cochrane review found no difference between antidepressants and benzodiazepines in response rate, with desipramine and alpra­ zolam ranked highest in achieving remission and clonazepam and alprazolam in reducing frequency of panic attacks. In treatmentresistant cases, short-term augmentation with aripiprazole, dival­ proex sodium, or pindolol has some evidence for efficacy. There also is no clear difference in short-term efficacy between psycho­ logical therapies and antidepressant or benzodiazepine treatment, alone or in combination. Early psychotherapeutic intervention and education aimed at symptom control enhance the effectiveness of drug treatment. Patients can be taught breathing techniques, be educated about physiologic changes that occur with panic, and learn to expose them­ selves voluntarily to precipitating events in a treatment program spanning 12–15 sessions. Homework assignments and monitored compliance are important components of successful treatment. Once patients have achieved a satisfactory response, drug treatment should be maintained for 1–2 years to prevent relapse. Controlled trials indicate a success rate of 75–85%, although the likelihood of complete remission is somewhat lower. ■ ■GENERALIZED ANXIETY DISORDER Clinical Manifestations  Patients with generalized anxiety disor­ der (GAD) have persistent, excessive, and/or unrealistic worry associ­ ated with muscle tension, impaired concentration, autonomic arousal, feeling “on edge” or restless, and insomnia (Table 463-5). Onset is usually before age 20 years, and a history of childhood fears and social inhibition may be present. The lifetime prevalence of GAD is 5–6%; the risk is higher in first-degree relatives of patients with the diagnosis. Interestingly, family studies indicate that GAD and panic disorder segregate independently. More than 80% of patients with GAD also suffer from major depression, dysthymia, or social phobia. Comorbid substance abuse is common in these patients, particularly alcohol and/or sedative/hypnotic abuse. Patients with GAD worry excessively over minor matters, with life-disrupting effects; unlike panic disorder, complaints of shortness of breath, palpitations, and tachycardia are relatively rare. Etiology and Pathophysiology  Most anxiogenic and anxiolytic agents act on the γ-aminobutyric acid (GABA)A receptor/chloride ion channel complex, implicating this neurotransmitter system in patho­ genesis. Benzodiazepines are thought to bind two separate GABAA receptor sites: type I, which has a broad neuroanatomic distribution, and type II, which is concentrated in the hippocampus, striatum, and neocortex. The antianxiety effects of the various benzodiazepines are influenced by their relative binding to alpha 2 and 3 subunits of the GABAA receptor, and sedation and memory impairment to the alpha 1 subunit. Serotonin (5-hydroxytryptamine [5-HT]) and 3α-reduced neuroactive steroids (allosteric modulators of GABAA) also appear to have a role in anxiety, and buspirone, a partial 5-HT1A receptor agonist, and certain 5-HT2A and 5-HT2C receptor antagonists (e.g., mirtazapine and nefazodone) may have beneficial effects. TREATMENT Generalized Anxiety Disorder A combination of pharmacologic and psychotherapeutic interven­ tions is most effective in GAD, but complete symptomatic relief is rare. A short course of a benzodiazepine is usually indicated, pref­ erably lorazepam, oxazepam, clonazepam, or alprazolam, although only the last two are FDA approved. (The first two of these agents are metabolized via conjugation rather than oxidation and thus do not accumulate if hepatic function is impaired; the latter also has limited active metabolites.) Treatment should be initiated at the lowest dose possible and prescribed on an as-needed basis as symptoms warrant. Benzodiazepines differ in their milligram per kilogram potency, half-life, lipid solubility, metabolic pathways, and presence of active metabolites. Agents that are absorbed rapidly and TABLE 463-1  Antidepressants USUAL DAILY DOSE (mg) SIDE EFFECTS COMMENTS NAME SSRIs Fluoxetine (Prozac) Sertraline (Zoloft) Paroxetine (Paxil) Fluvoxamine (Luvox) Citalopram (Celexa) Escitalopram (Lexapro) 10–80 50–200 20–60 100–300 20–60 10–30 Headache; nausea and other GI effects; jitteriness; insomnia; sexual dysfunction; can affect plasma levels of other medicines (except sertraline); akathisia rare TCAs and Tetracyclics Amitriptyline (Elavil) Nortriptyline (Pamelor) Imipramine (Tofranil) Desipramine (Norpramin) Doxepin (Sinequan) Clomipramine (Anafranil) Maprotiline (Ludiomil) Protriptyline (Vivactil) Trimipramine (Surmontil) Amoxapine (Asendin) 150–300 50–200 150–300 150–300 150–300 150–300 25–150 15–40 75–200 100–300 Anticholinergic (dry mouth, tachycardia, constipation, urinary retention, blurred vision); sweating; tremor; postural hypotension; cardiac conduction delay; sedation; weight gain Nausea, anxiety, dry mouth     Drowsiness, constipation, dry mouth Mixed Serotonin-Norepinephrine Reuptake Inhibitors (SNRI) and Receptor Blockers Venlafaxine (Effexor), XR 75–375 Nausea; dizziness; dry mouth; headaches; increased blood pressure; anxiety and insomnia Desvenlafaxine (Pristiq) 50–400 Nausea, dizziness, insomnia Primary metabolite of venlafaxine; no increased efficacy with higher dosing Duloxetine (Cymbalta) 40–60 Nausea, dizziness, headache, insomnia, constipation Mirtazapine (Remeron) 15–45 Somnolence, weight gain; neutropenia rare Once-a-day dosing; 5-HT3 antagonist Vilazodone (Viibryd) Nausea, diarrhea, headache; dosage adjustment if given with CYP3A4 inhibitor/stimulator Vortioxetine (Trintellix) 5–20 Nausea, diarrhea, sweating, headache; low incidence of sedation or weight gain Levomilnacipran (Fetzima) 40–120 Nausea, constipation, sweating; rare increase in blood pressure/pulse Mixed-Action Drugs Bupropion (Wellbutrin), CR, XR 250–450 Jitteriness; flushing; seizures in at-risk patients; anorexia; tachycardia; psychosis Trazodone (Desyrel) 200–600 Sedation; dry mouth; ventricular irritability; postural hypotension; priapism rare Trazodone extended-release (Oleptro) 150–375 Daytime somnolence, dizziness, nausea   Nefazodone Gepirone extended-release (Exxua)   Esketamine (Spravato)    Zuranolone (Zurzuvae)   Dextromethorphan-bupropion (Auvelity) 300–600 18.2–72.6    56–84 1–2 times a week  50 qhs for 14 days   45/105 bid Headache, nausea, dizziness Dizziness, nausea, insomnia    Sedation, dissociation, respiratory depression   Somnolence, confusion, dizziness   Dizziness, headache, diarrhea MAOIs Phenelzine (Nardil) Tranylcypromine (Parnate) 45–90 20–50 Insomnia; hypotension; edema; anorgasmia; weight gain; neuropathy; hypertensive crisis; toxic reactions with SSRIs; narcotics Isocarboxazid (Marplan) 20–60   Less weight gain and hypotension than phenelzine Transdermal selegiline (Emsam) 6–12 Local skin reaction, hypertension No dietary restrictions with 6-mg dose Abbreviations: ADD, attention-deficit disorder; EPS, extrapyramidal symptoms; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; MAOIs, monoamine oxidase inhibitors; OCD, obsessive-compulsive disorder; OD, overdose; SSRIs, selective serotonin reuptake inhibitors; TCAs, tricyclic antidepressants. Once-daily dosing, usually in the morning; fluoxetine has very long half-life; must not be combined with MAOIs Once-daily dosing, usually qhs; blood levels of most TCAs available; can be lethal in overdose (lethal dose = 2 g); nortriptyline best tolerated, especially by elderly CHAPTER 463 FDA-approved for OCD     tid or qid dosing required Lethality in OD, EPS possible Psychiatric Disorders bid–tid dosing (extended-release available); lower potential for drug interactions than SSRIs; contraindicated with MAOIs May have utility in treatment of neuropathic pain and stress incontinence Also 5-HT1A receptor partial agonist No specific p450 effects; 5-HT3A and 5-HT7 receptor antagonist, 5-HT1B partial agonist, and 5-HT1A agonist Most noradrenergic of SNRIs tid dosing, but sustained-release also available; fewer sexual side effects than SSRIs or TCAs; may be useful for adult ADD Useful in low doses for sleep because of sedating effects with no anticholinergic side effects Rare risk of liver failure, priapism Partial agonist/5-HT1A; 5-HT2A antagonist    Ketamine isomer for treatment-resistant depression and/or suicidal risk  Oral neuroactive steroid for postpartum depression Possible increased speed of response May be more effective in patients with atypical features or treatment-refractory depression TABLE 463-2  Management of Antidepressant Side Effects SYMPTOMS COMMENTS AND MANAGEMENT STRATEGIES Gastrointestinal     Nausea, loss of Usually short-lived and dose-related; consider temporary dose reduction or administration with food and antacids appetite   Diarrhea Famotidine, 20–40 mg/d   Constipation Wait for tolerance; try diet change, stool softener, exercise; avoid laxatives Sexual dysfunction Consider dose reduction; drug holiday   Anorgasmia/ Bethanechol, 10–20 mg, 2 h before activity, or cyproheptadine, 4–8 mg, 2 h before activity, or bupropion, 100 mg bid, or amantadine, 100 mg bid/tid impotence; impaired ejaculation Orthostasis Tolerance unlikely; increase fluid intake, use calf exercises/support hose; fludrocortisone, 0.025 mg/d Anticholinergic Wait for tolerance PART 13 Neurologic Disorders Dry mouth, eyes Maintain good oral hygiene; use artificial tears, sugar-free gum Tremor/jitteriness Antiparkinsonian drugs not effective; use dose reduction/ slow increase; lorazepam, 0.5 mg bid, or propranolol, 10–20 mg bid Insomnia Schedule all doses for the morning; trazodone, 50–100 mg qhs Sedation Caffeine; schedule all dosing for bedtime; bupropion, 75–100 mg in afternoon Headache Evaluate diet, stress, other drugs; try dose reduction; amitriptyline, 50 mg/d Weight gain Decrease carbohydrates; exercise; consider fluoxetine Loss of therapeutic benefit over time Related to tolerance? Increase dose or drug holiday; add amantadine, 100 mg bid, buspirone, 10 mg tid, or pindolol, 2.5 mg bid are lipid soluble, such as diazepam, have a rapid onset of action and a higher abuse potential. Benzodiazepines should generally not be prescribed for >4–6 weeks because of the development of toler­ ance and the serious risk of abuse and dependence. Withdrawal must be closely monitored as relapses can occur. It is important to warn patients that concomitant use of alcohol or other sedating drugs may exacerbate side effects and impair their ability to func­ tion. An optimistic approach that encourages the patient to clarify TABLE 463-4  Anxiolytics EQUIVALENT PO DOSE (mg) ONSET OF ACTION HALF-LIFE (h) COMMENTS NAME Benzodiazepines Diazepam (Valium) Fast 20–70 Active metabolites; quite sedating Flurazepam (Dalmane) Fast 30–100 Flurazepam is a prodrug; metabolites are active; quite sedating Triazolam (Halcion) 0.25 Intermediate 1.5–5 No active metabolites; can induce confusion and delirium, especially in elderly Lorazepam (Ativan) Intermediate 10–20 No active metabolites; direct hepatic glucuronide conjugation; quite sedating; FDA-approved for anxiety with depression Alprazolam (Xanax) 0.5 Intermediate 12–15 Active metabolites; not too sedating; FDA-approved for panic disorder and anxiety with depression; tolerance and dependence develop easily; difficult to withdraw Chlordiazepoxide (Librium) Intermediate 5–30 Active metabolites; moderately sedating Oxazepam (Serax) Slow 5–15 No active metabolites; direct glucuronide conjugation; not too sedating Temazepam (Restoril) Slow 9–12 No active metabolites; moderately sedating Clonazepam (Klonopin) 0.5 Slow 18–50 No active metabolites; moderately sedating; FDA-approved for panic disorder Clorazepate (Tranxene) Fast 40–200 Low sedation; unreliable absorption Prazepam (Centrax) 10–60 Fast 29–224 Less sedating than diazepam Nonbenzodiazepines Buspirone (BuSpar) 7.5 2 weeks 2–3 Active metabolites; tid dosing—usual daily dose 10–20 mg tid; nonsedating; no additive effects with alcohol; useful for controlling agitation in demented or brain-injured patients Abbreviation: FDA, U.S. Food and Drug Administration. TABLE 463-3  Possible Drug Interactions with Selective Serotonin Reuptake Inhibitors AGENT EFFECT Monoamine oxidase inhibitors Serotonin syndrome— absolute contraindication Serotonergic agonists, e.g., tryptophan, fenfluramine, triptans Potential serotonin syndrome Drugs that are metabolized by P450 isoenzymes: tricyclics, other SSRIs, antipsychotics, beta blockers, codeine, triazolobenzodiazepines, calcium channel blockers Delayed metabolism resulting in increased blood levels and potential toxicity Drugs that are bound tightly to plasma proteins, e.g., warfarin Increased bleeding secondary to displacement Drugs that inhibit the metabolism of SSRIs by P450 isoenzymes, e.g., quinidine Increased SSRI side effects Abbreviation: SSRIs, selective serotonin reuptake inhibitors. environmental precipitants, anticipate their reactions, and plan effective response strategies is an essential element of therapy. Adverse effects of benzodiazepines generally parallel their rela­ tive half-lives. Longer-acting agents, such as diazepam, chlordiaz­ epoxide, flurazepam, and clonazepam, tend to accumulate active metabolites, with resultant sedation, impairment of cognition, and poor psychomotor performance. Shorter-acting compounds, such as alprazolam, lorazepam, and oxazepam, can produce daytime anx­ iety, early-morning insomnia, and, with discontinuation, rebound anxiety and insomnia. Although patients develop tolerance to the sedative effects of benzodiazepines, they are less likely to habituate to the adverse psychomotor effects. Withdrawal from the longer half-life benzodiazepines can be accomplished through gradual, stepwise dose reduction (by 10% every 1–2 weeks) over 6–12 weeks. It is usually more difficult to taper patients off shorter-acting benzodiazepines. Physicians may need to switch the patient to a benzodiazepine with a longer half-life or use an adjunctive medica­ tion such as a beta blocker or carbamazepine, before attempting to discontinue the benzodiazepine. Withdrawal reactions vary in severity and duration; they can include depression, anxiety, leth­ argy, diaphoresis, autonomic arousal, and, rarely, seizures. Buspirone is a nonbenzodiazepine anxiolytic agent. It is nonse­ dating, does not produce tolerance or dependence, does not interact TABLE 463-5  Diagnostic Criteria for Generalized Anxiety Disorder A.  Excessive anxiety and worry (apprehensive expectation), occurring more days than not for at least 6 months, about a number of events or activities (such as work or school performance). B.  The individual finds it difficult to control the worry. C.  The anxiety and worry are associated with three (or more) of the following six symptoms (with at least some symptoms having been present for more days than not for the past 6 months): Note: Only one item is required in children. 1.  Restlessness or feeling keyed up or on edge. 2.  Being easily fatigued. 3.  Difficulty concentrating or mind going blank. 4.  Irritability. 5.  Muscle tension. 6.  Sleep disturbance (difficulty falling or staying asleep, or restless, unsatisfying sleep). D.  The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. E.  The disturbance is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication) or another medical condition (e.g., hyperthyroidism). F.  The disturbance is not better explained by another mental disorder (e.g., anxiety or worry about having panic attacks in panic disorder, negative evaluation in social anxiety disorder, contamination or other obsessions in obsessive-compulsive disorder, separation from attachment figures in separation anxiety disorder, reminders of traumatic events in posttraumatic stress disorder, gaining weight in anorexia nervosa, physical complaints in somatic symptom disorder, perceived appearance flaws in body dysmorphic disorder, having a serious illness in illness anxiety disorder, or the content of delusional beliefs in schizophrenia or delusional disorder). Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders-Text Revision, 5th ed. (Copyright © 2022). American Psychiatric Association. All Rights Reserved. with benzodiazepine receptors or alcohol, and has no abuse or disinhibition potential. However, it requires several weeks to take effect and requires thrice-daily dosing. Patients who were previ­ ously responsive to a benzodiazepine are unlikely to rate buspirone as equally effective, but patients with head injury or dementia who have symptoms of anxiety and/or agitation may do well with this agent. Escitalopram, paroxetine, duloxetine, and venlafaxine are FDA approved for the treatment of GAD, usually at doses that are comparable to their efficacy in major depression, and may be preferable to usage of benzodiazepines in the treatment of chronic anxiety. Benzodiazepines are contraindicated during pregnancy and breast-feeding. Anticonvulsants with GABAergic properties may also be effec­ tive against anxiety. Gabapentin, oxcarbazepine, tiagabine, prega­ balin, and divalproex have all shown some degree of benefit in a variety of anxiety-related syndromes in off-label usage. ■ ■PHOBIC DISORDERS Clinical Manifestations  The cardinal feature of phobic disorders is a marked and persistent fear of objects or situations, exposure to which results in an immediate anxiety reaction. The patient avoids the phobic stimulus, and this avoidance usually impairs occupational or social functioning. Panic attacks may be triggered by the phobic stimulus or may occur spontaneously. Unlike patients with other anxi­ ety disorders, individuals with phobias usually experience anxiety only in specific situations. Common phobias include fear of closed spaces (claustrophobia), fear of blood, and fear of flying. Social phobia is distinguished by a specific fear of social or performance situations in which the individual is exposed to unfamiliar individuals or to possible examination and evaluation by others. Examples include having to con­ verse at a party, using public restrooms, or meeting strangers. In each case, the affected individual is aware that the experienced fear is exces­ sive and unreasonable given the circumstance. The specific content of a phobia may vary across gender, ethnic, and cultural boundaries. Phobic disorders are common, affecting ~7–9% of the popula­ tion. Twice as many females are affected than males. Full criteria for diagnosis are usually satisfied first in early adulthood, but behavioral avoidance of unfamiliar people, situations, or objects dating from early childhood is common. In one study of female twins, concordance rates for agoraphobia, social phobia, and animal phobia were found to be 23% for monozy­ gotic twins and 15% for dizygotic twins. A twin study of fear condition­ ing, a model for the acquisition of phobias, demonstrated a heritability of 35–45%. Animal studies of fear conditioning have indicated that processing of the fear stimulus occurs through the lateral nucleus of the amygdala, extending through the central nucleus and projecting to the periaqueductal gray region, lateral hypothalamus, and paraventricular hypothalamus. TREATMENT Phobic Disorders CHAPTER 463 Beta blockers (e.g., propranolol, 20–40 mg orally 2 h before the event) are particularly effective in the treatment of “performance anxiety” (but not general social phobia) and appear to work by blocking the peripheral manifestations of anxiety such as perspira­ tion, tachycardia, palpitations, and tremor. MAOIs alleviate social phobia independently of their antidepressant activity, and parox­ etine, sertraline, fluvoxamine CR, and venlafaxine XR have received FDA approval for treatment of social anxiety. Benzodiazepines can be helpful in reducing fearful avoidance, but the chronic nature of phobic disorders limits their usefulness. Psychiatric Disorders Behaviorally focused psychotherapy is an important compo­ nent of treatment because relapse rates are high when medication is used as the sole treatment. Cognitive-behavioral strategies are based on the finding that distorted perceptions and interpreta­ tions of fear-producing stimuli play a major role in perpetuation of phobias. Individual and group therapy sessions teach the patient to identify specific negative thoughts associated with the anxietyproducing situation and help to reduce the patient’s fear of loss of control. In desensitization therapy, hierarchies of feared situations are constructed, and the patient is encouraged to pursue and master gradual exposure to the anxiety-producing stimuli. Patients with social phobia, in particular, have a high rate of comorbid alcohol abuse, as well as of other psychiatric conditions (e.g., eating disorders), necessitating the need for parallel manage­ ment of each disorder if anxiety reduction is to be achieved. ■ ■STRESS DISORDERS Clinical Manifestations  Patients may develop anxiety after expo­ sure to extreme traumatic events such as the threat of personal death or injury or the death of a loved one. The reaction may occur shortly after the trauma (acute stress disorder) or be delayed and subject to recurrence (PTSD) (Table 463-6). In both syndromes, individuals experience associated symptoms of detachment and loss of emotional responsivity. The patient may feel depersonalized and unable to recall specific aspects of the trauma, although typically, it is reexperienced through intrusions in thought, dreams, or flashbacks, particularly when cues of the original event are present. Patients often actively avoid stimuli that precipitate recollections of the trauma and demonstrate a resulting increase in vigilance, arousal, and startle response. Patients with stress disorders are at risk for the development of other disorders related to anxiety, mood, and substance abuse (especially alcohol). Between 5 and 10% of Americans will at some time in their life satisfy criteria for PTSD, with women more likely to be affected than men. A validated four-item screen for PTSD (PC-PTSD) is available. Risk factors for the development of PTSD include a past psychi­ atric history and personality characteristics of high neuroticism and extroversion. Twin studies show a substantial genetic influence on all symptoms associated with PTSD, with less evidence for an environ­ mental effect. PART 13 Neurologic Disorders TABLE 463-6  Diagnostic Criteria for Posttraumatic Stress Disorder Posttraumatic Stress Disorder in Individuals Older Than 6 Years Note: The following criteria apply to adults, adolescents, and children older than 6 years. For children 6 years and younger, see corresponding criteria below. A.  Exposure to actual or threatened death, serious injury, or sexual violence in one (or more) of the following ways: 1. Directly experiencing the traumatic event(s). 2. Witnessing, in person, the event(s) as it occurred to others. 3. Learning that the traumatic event(s) occurred to a close family member or close friend. In cases of actual or threatened death of a family member or friend, the event(s) must have been violent or accidental. 4. Experiencing repeated or extreme exposure to aversive details of the traumatic event(s) (e.g., first responders collecting human remains; police officers repeatedly exposed to details of child abuse). Note: Criterion A4 does not apply to exposure through electronic media, television, movies, or pictures, unless this exposure is work related. B.  Presence of one (or more) of the following intrusion symptoms associated with the traumatic event(s), beginning after the traumatic event(s) occurred: 1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s). Note: In children older than 6 years, repetitive play may occur in which themes or aspects of the traumatic event(s) are expressed. 2. Recurrent distressing dreams in which the content and/or affect of the dream are related to the traumatic event(s). Note: In children, there may be frightening dreams without recognizable content. 3. Dissociative reactions (e.g., flashbacks) in which the individual feels or acts as if the traumatic event(s) were recurring. (Such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings.) Note: In children, trauma-specific reenactment may occur in play. 4. Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event(s). 5. Marked physiological reactions to internal or external cues that symbolize or resemble an aspect of the traumatic event(s). C.  Persistent avoidance of stimuli associated with the traumatic event(s), beginning after the traumatic event(s) occurred, as evidenced by one or both of the following: 1. Avoidance of or efforts to avoid distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s). 2. Avoidance of or efforts to avoid external reminders (people, places, conversations, activities, objects, situations) that arouse distressing memories, thoughts, or feelings about or closely associated with the traumatic event(s). D.  Negative alterations in cognitions and mood associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of the following: 1. Inability to remember an important aspect of the traumatic event(s) (typically due to dissociative amnesia and not to other factors such as head injury, alcohol, or drugs). 2. Persistent and exaggerated negative beliefs or expectations about oneself, others, or the world (e.g., “I am bad,” “No one can be trusted,” “The world is completely dangerous,” “My whole nervous system is permanently ruined”). 3. Persistent, distorted cognitions about the cause or consequences of the traumatic event(s) that lead the individual to blame himself/herself or others. 4. Persistent negative emotional state (e.g., fear, horror, anger, guilt, or shame). 5. Markedly diminished interest or participation in significant activities. 6. Feelings of detachment or estrangement from others. 7. Persistent inability to experience positive emotions (e.g., inability to experience happiness, satisfaction, or loving feelings). E.  Marked alterations in arousal and reactivity associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of the following: 1. Irritable behavior and angry outbursts (with little or no provocation) typically expressed as verbal or physical aggression toward people or objects. 2. Reckless or self-destructive behavior. 3. Hypervigilance. 4. Exaggerated startle response. 5. Problems with concentration. 6. Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep). F.  Duration of the disturbance (Criteria B, C, D, and E) is more than 1 month. G.  The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. H.  The disturbance is not attributable to the physiological effects of a substance (e.g., medication, alcohol) or another medical condition. Specify whether: With dissociative symptoms: The individual’s symptoms meet the criteria for posttraumatic stress disorder, and in addition, in response to the stressor, the individual experiences persistent or recurrent symptoms of either of the following: 1.  1. Depersonalization: Persistent or recurrent experiences of feeling detached from, and as if one were an outside observer of, one’s mental processes or body (e.g., feeling as though one were in a dream; feeling a sense of unreality of self or body or of time moving slowly). 2. Derealization: Persistent or recurrent experiences of unreality of surroundings (e.g., the world around the individual is experienced as unreal, dreamlike, distant, or distorted). 2.  Note: To use this subtype, the dissociative symptoms must not be attributable to the physiological effects of a substance (e.g., blackouts, behavior during alcohol intoxication) or another medical condition (e.g., complex partial seizures). Specify if: With delayed expression: If the full diagnostic criteria are not met until at least 6 months after the event (although the onset and expression of some symptoms may be immediate). Posttraumatic Stress Disorder in Children 6 Years and Younger A.  In children 6 years and younger, exposure to actual or threatened death, serious injury, or sexual violence in one (or more) of the following ways: 1. Directly experiencing the traumatic event(s). 2. Witnessing, in person, the event(s) as it occurred to others, especially primary caregivers. 3. Learning that the traumatic event(s) occurred to a parent or caregiving figure. B.  Presence of one (or more) of the following intrusion symptoms associated with the traumatic event(s), beginning after the traumatic event(s) occurred: 1. Recurrent, involuntary, and intrusive distressing memories of the traumatic event(s). Note: Spontaneous and intrusive memories may not necessarily appear distressing and may be expressed as play reenactment. 2. Recurrent distressing dreams in which the content and/or affect of the dream are related to the traumatic event(s). Note: It may not be possible to ascertain that the frightening content is related to the traumatic event. 3. Dissociative reactions (e.g., flashbacks) in which the child feels or acts as if the traumatic event(s) were recurring. (Such reactions may occur on a continuum, with the most extreme expression being a complete loss of awareness of present surroundings.) Such trauma-specific reenactment may occur in play. 4. Intense or prolonged psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event(s). 5. Marked physiological reactions to reminders of the traumatic event(s). C.  One (or more) of the following symptoms, representing either persistent avoidance of stimuli associated with the traumatic event(s) or negative alterations in cognitions and mood associated with the traumatic event(s), must be present, beginning after the event(s) or worsening after the event(s): Persistent Avoidance of Stimuli 1. Avoidance of or efforts to avoid activities, places, or physical reminders that arouse recollections of the traumatic event(s). 2. Avoidance of or efforts to avoid people, conversations, or interpersonal situations that arouse recollections of the traumatic event(s). (Continued) TABLE 463-6  Diagnostic Criteria for Posttraumatic Stress Disorder Negative Alterations in Cognitions 3. Substantially increased frequency of negative emotional states (e.g., fear, guilt, sadness, shame, confusion). 4. Markedly diminished interest or participation in significant activities, including constriction of play. 5. Socially withdrawn behavior. 6. Persistent reduction in expression of positive emotions. D.  Alterations in arousal and reactivity associated with the traumatic event(s), beginning or worsening after the traumatic event(s) occurred, as evidenced by two (or more) of the following: 1. Irritable behavior and angry outbursts (with little or no provocation) typically expressed as verbal or physical aggression toward people or objects (including extreme temper tantrums). 2. Hypervigilance. 3. Exaggerated startle response. 4. Problems with concentration. 5. Sleep disturbance (e.g., difficulty falling or staying asleep or restless sleep). E.  The duration of the disturbance is more than 1 month. F.  The disturbance causes clinically significant distress or impairment in relationships with parents, siblings, peers, or other caregivers or with school behavior. G.  The disturbance is not attributable to the physiological effects of a substance (e.g., medication or alcohol) or another medical condition. Specify whether: With dissociative symptoms: The individual’s symptoms meet the criteria for posttraumatic stress disorder, and the individual experiences persistent or recurrent symptoms of either of the following: 1. Depersonalization: Persistent or recurrent experiences of feeling detached from, and as if one were an outside observer of, one’s mental processes or body (e.g., feeling as though one were in a dream; feeling a sense of unreality of self or body or of time moving slowly). 2. Derealization: Persistent or recurrent experiences of unreality of surroundings (e.g., the world around the individual is experienced as unreal, dreamlike, distant, or distorted). Note: To use this subtype, the dissociative symptoms must not be attributable to the physiological effects of a substance (e.g., blackouts) or another medical condition (e.g., complex partial seizures). Specify if: With delayed expression: If the full diagnostic criteria are not met until at least 6 months after the event (although the onset and expression of some symptoms may be immediate). Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders-Text Revision, 5th ed. (Copyright © 2022). American Psychiatric Association. All Rights Reserved. Etiology and Pathophysiology  It is hypothesized that in PTSD there is excessive release of norepinephrine from the locus coeruleus in response to stress and increased noradrenergic activity at projection sites in the hippocampus and amygdala. These changes theoretically facilitate the encoding of fear-based memories. Greater sympathetic responses to cues associated with the traumatic event occur in PTSD, although pitu­ itary adrenal responses are blunted. In addition to fear learning, changes in threat detection (insula overactivity), executive function, emotional regulation, and contextual learning have been documented. Predictive bio­ markers include increased heart rate and serum lactate, decreased coagula­ tion, insulin resistance, and alterations in glycolysis and fatty acid uptake. TREATMENT Stress Disorders Acute stress reactions are usually self-limited, and treatment typi­ cally involves the short-term use of benzodiazepines and support­ ive/expressive psychotherapy. The chronic and recurrent nature of PTSD, however, requires a more complex approach using drug and behavioral treatments. PTSD is highly correlated with peritraumatic dissociative symptoms and the development of an acute stress dis­ order at the time of the trauma. Attempts to prevent or ameliorate PTSD through usage of agents such as escitalopram, hydrocorti­ sone, and intranasal oxytocin in the acute stress period have proven equivocal. The SSRIs (paroxetine and sertraline are FDA approved for PTSD), venlafaxine, fluoxetine, and topiramate can all reduce anxi­ ety, symptoms of intrusion, and avoidance behaviors. Recently, the psychedelic agent MDMA (3,4-methylenedioxymethamphetamine) demonstrated efficacy as an adjunct to intensive psychotherapeutic intervention, as did stellate ganglion block. Low-dose trazodone and mirtazapine, sedating antidepressants, are frequently used at night to help with insomnia. Benzodiazepines and SSRIs, however, should not be given in the early aftermath of trauma. Psychotherapeutic strate­ gies for PTSD help the patient overcome avoidance behaviors and demoralization and master fear of recurrence of the trauma; therapies that encourage the patient to dismantle avoidance behaviors through stepwise focusing on the experience of the traumatic event, such as trauma-focused cognitive-behavioral and eye movement desensitiza­ tion and reprocessing (EMDR) therapies and prolonged exposure therapy utilizing augmented or virtual reality are the most effective. Debriefing after the traumatic event does not prevent PTSD and may exacerbate symptoms. (Continued) CHAPTER 463 Psychiatric Disorders ■ ■OBSESSIVE-COMPULSIVE DISORDER Clinical Manifestations  Obsessive-compulsive disorder (OCD) is characterized by obsessive thoughts and compulsive behaviors that impair everyday functioning. Fears of contamination and germs are common, as are handwashing, counting behaviors, and having to check and recheck such actions as whether a door is locked. The degree to which the disorder is disruptive for the individual varies, but in all cases, obsessive-compulsive activities take up >1 h per day and are undertaken to relieve the anxiety triggered by the core fear. Patients often conceal their symptoms, usually because they are embarrassed by the content of their thoughts or the nature of their actions. Physicians must ask specific questions regarding recurrent thoughts and behav­ iors, particularly if physical clues such as chafed and reddened hands or patchy hair loss (from repetitive hair pulling, or trichotillomania) are present. Comorbid conditions are common, the most frequent being depression, other anxiety disorders, eating disorders, and tics. OCD has a lifetime prevalence of 2–3% worldwide. Onset is usually gradual, beginning in early adulthood, but childhood onset is not rare. The disorder usually has a waxing and waning course, but some cases may show a steady deterioration in psychosocial functioning. Etiology and Pathophysiology  A genetic contribution to OCD is suggested by twin studies, but no susceptibility gene for OCD has been identified to date. Insulin signaling has been implicated in some recent reports. Family studies show an aggregation of OCD with Tourette’s dis­ order, and both are more common in males and in first-born children. The anatomy of obsessive-compulsive behavior is thought to include the orbital frontal cortex, caudate nucleus, and globus pallidus. The caudate nucleus appears to be involved in the acquisition and mainte­ nance of habit and skill learning, and interventions that are successful in reducing obsessive-compulsive behaviors also decrease metabolic activity in the caudate. TREATMENT Obsessive-Compulsive Disorder Clomipramine, fluoxetine, fluvoxamine, paroxetine, and sertraline are approved for the treatment of OCD in adults (and all but par­ oxetine are also approved for children). Clomipramine is a TCA that is often tolerated poorly owing to anticholinergic and sedative side effects at the doses required to treat the illness (25–250 mg/d); its efficacy in OCD is unrelated to its antidepressant activity. Fluoxetine (5–60 mg/d), fluvoxamine (25–300 mg/d), paroxetine (40–60 mg/d), and sertraline (50–150 mg/d) are as effective as clo­ mipramine and have a more benign side effect profile. Venlafaxine and duloxetine also have shown efficacy but are not FDA approved. Only 50–60% of patients with OCD show adequate improvement with pharmacotherapy alone. In treatment-resistant cases, augmen­ tation with other serotonergic agents such as buspirone, or with a neuroleptic or benzodiazepine, may be beneficial, or alternatively, high-dose theta burst repetitive transcranial magnetic stimula­ tion (rTMS). In severe cases, closed loop deep-brain stimulation has been found to be effective. When a therapeutic response is achieved, long-duration maintenance therapy is usually indicated. For many individuals, particularly those with time-consuming com­ pulsions, behavior therapy and exposure response prevention will result in as much improvement as that afforded by medication. Effec­ tive techniques include the gradual increase in exposure to stressful situations, maintenance of a diary to clarify stressors, and homework assignments that substitute new activities for compulsive behaviors. PART 13 Neurologic Disorders MOOD DISORDERS Mood disorders are characterized by a disturbance in the regulation of mood, behavior, and affect. Mood disorders are subdivided into (1) depressive disorders, (2) bipolar disorders, and (3) depression in asso­ ciation with medical illness or alcohol and substance abuse (Chaps. 464 through 468). Major depressive disorder (MDD) is differentiated from bipolar disorder by the absence of a manic or hypomanic episode. The relationship between pure depressive syndromes and bipolar disorders is not well understood; MDD is more frequent in families of bipolar individuals, but the reverse is not true. In the most recent Global Burden of Disease Study conducted by the World Health Organization (2019), depression was the single largest factor contributing to disability, which had increased 61% as measured by disability-adjusted life-years (DALYs) since 1990. In the United States, lost productivity directly related to mood disorders has been estimated at $55.1 billion per year. ■ ■DEPRESSION IN ASSOCIATION WITH MEDICAL ILLNESS Depression occurring in the context of medical illness is difficult to evaluate. Depressive symptomatology may reflect the psychological stress of coping with the disease, may be caused by the disease process itself or by the medications used to treat it, or may simply coexist in time with the medical diagnosis. Virtually every class of medication includes some agent that can induce depression. Antihypertensive drugs, anticholesterolemic agents, and antiarrhythmic agents are common triggers of depressive symp­ toms. Iatrogenic depression should also be considered in patients receiving glucocorticoids, antimicrobials, systemic analgesics, anti­ parkinsonian medications, and anticonvulsants. To decide whether a causal relationship exists between pharmacologic therapy and a patient’s change in mood, it may sometimes be necessary to undertake an empirical trial of an alternative medication. Between 20 and 30% of cardiac patients manifest a depressive disor­ der; an even higher percentage experience depressive symptomatology when self-reporting scales are used. Depressive symptoms following unstable angina, myocardial infarction, cardiac bypass surgery, or heart transplant impair rehabilitation and are associated with higher rates of mortality and medical morbidity. Depressed patients often show decreased variability in heart rate (an index of reduced parasym­ pathetic nervous system activity), which may predispose individuals to ventricular arrhythmia and increased morbidity. Depression also appears to increase the risk of coronary heart disease, possibly through increased platelet aggregation. TCAs are contraindicated in patients with bundle branch block, and TCA-induced tachycardia is an addi­ tional concern in patients with congestive heart failure. SSRIs appear not to induce ECG changes or adverse cardiac events and thus are reasonable first-line drugs for patients at risk for TCA-related compli­ cations. SSRIs may interfere with hepatic metabolism of anticoagulants, however, causing increased anticoagulation. In patients with cancer, the mean prevalence of depression is 25%, but depression occurs in 40–50% of patients with cancers of the pancreas or oropharynx. This association is not due to the effect of cachexia alone, as the higher prevalence of depression in patients with pancreatic cancer persists when compared to those with advanced gas­ tric cancer. Initiation of antidepressant medication in cancer patients has been shown to improve quality of life as well as mood. Psychothera­ peutic approaches, particularly group therapy, may have some effect on short-term depression, anxiety, and pain symptoms. Depression occurs frequently in patients with neurologic disorders, particularly cerebrovascular disorders, Parkinson’s disease, dementia, multiple sclerosis, and traumatic brain injury. One in five patients with left-hemisphere stroke involving the dorsolateral frontal cortex experi­ ences major depression. Late-onset depression in otherwise cognitively normal individuals increases the risk of a subsequent diagnosis of Alzheimer’s disease. All classes of antidepressant agents are effective against these depressions, as are, in some cases, stimulant compounds. SNRIs such as duloxetine or levomilnacipran may be more effective in depression associated with chronic pain. The reported prevalence of depression in patients with diabetes mellitus varies from 8 to 27%, with the severity of the mood state cor­ relating with the level of hyperglycemia and the presence of diabetic complications. Treatment of depression may be complicated by effects of antidepressive agents on glycemic control. MAOIs can induce hypo­ glycemia and weight gain, whereas TCAs can produce hyperglycemia and carbohydrate craving. SSRIs and SNRIs, like MAOIs, may reduce fasting plasma glucose but are easier to use and may also improve dietary and medication compliance. Hypothyroidism is frequently associated with features of depres­ sion, most commonly depressed mood and memory impairment. Hyperthyroid states may also present in a similar fashion, usually in geriatric populations. Improvement in mood usually follows normal­ ization of thyroid function, but adjunctive antidepressant medication is sometimes required. Patients with subclinical hypothyroidism can also experience symptoms of depression and cognitive difficulty that respond to thyroid replacement. The lifetime prevalence of depression in HIV-positive individuals has been estimated at 22–45%. The relationship between depression and disease progression is multifactorial and likely to involve psy­ chological and social factors, alterations in immune function, and central nervous system (CNS) disease. Chronic hepatitis C infection is also associated with depression, which may worsen with interferon-α treatment. Some chronic disorders of uncertain etiology, such as chronic fatigue syndrome (Chap. 461) and fibromyalgia (Chap. 385), are strongly associated with depression and anxiety; patients may ben­ efit from antidepressant treatment or anticonvulsant agents such as pregabalin. ■ ■DEPRESSIVE DISORDERS Clinical Manifestations  Major depression is defined as depressed mood on a daily basis for a minimum duration of 2 weeks (Table 463-7). An episode may be characterized by sadness, indifference, apathy, or irri­ tability and is usually associated with changes in sleep patterns, appetite, and weight; motor agitation or retardation; fatigue; impaired concentra­ tion and decision-making; feelings of shame or guilt; and thoughts of death or dying. Patients with depression have a profound loss of pleasure in all enjoyable activities, exhibit early-morning awakening, feel that the dysphoric mood state is qualitatively different from sadness, and often notice a diurnal variation in mood (worse in morning hours). Patients experiencing bereavement or grief may exhibit many of the same signs and symptoms of major depression, although the emphasis is usually on feelings of emptiness and loss, rather than anhedonia and loss of selfesteem, and the duration is usually limited. In certain cases, however, the diagnosis of major depression may be warranted even in the context of a significant loss. Approximately 15% of the population experiences a major depres­ sive episode at some point in life, and 6–8% of all outpatients in TABLE 463-7  Criteria for a Major Depressive Episode A.  Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly attributable to another medical condition. 1.  Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.) 2.  Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3.  Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.) 4.  Insomnia or hypersomnia nearly every day. 5.  Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6.  Fatigue or loss of energy nearly every day. 7.  Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). 8.  Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). 9.  Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. B.  The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C.  The episode is not attributable to the physiological effects of a substance or another medical condition. Note: Criteria A–C represent a major depressive episode. Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) may include the feelings of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which may resemble a depressive episode. Although such symptoms may be understandable or considered appropriate to the loss, the presence of a major depressive episode in addition to the normal response to a significant loss should also be carefully considered. This decision inevitably requires the exercise of clinical judgment based on the individual’s history and the cultural norms for the expression of distress in the context of loss.1 D.  At least one major depressive episode is not better explained by schizoaffective disorder and is not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or other specified and unspecified schizophrenia spectrum and other psychotic disorders. E.  There has never been a manic episode or a hypomanic episode. Note: This exclusion does not apply if all of the manic-like or hypomanic-like episodes are substance-induced or are attributable to the physiological effects of another medical condition. 1In distinguishing grief from a major depressive episode (MDE), it is useful to consider that in grief the predominant affect is feelings of emptiness and loss, while in an MDE it is persistent depressed mood and the inability to anticipate happiness or pleasure. The dysphoria in grief is likely to decrease in intensity over days to weeks and occurs in waves, the so-called pangs of grief. These waves tend to be associated with thoughts or reminders of the deceased. The depressed mood of an MDE is more persistent and not tied to specific thoughts or preoccupations. The pain of grief may be accompanied by positive emotions and humor that are uncharacteristic of the pervasive unhappiness and misery characteristic of an MDE. The thought content associated with grief generally features a preoccupation with thoughts and memories of the deceased, rather than the self-critical or pessimistic ruminations seen in an MDE. In grief, self-esteem is generally preserved, whereas in an MDE feelings of worthlessness and self-loathing are common. If selfderogatory ideation is present in grief, it typically involves perceived failings vis-àvis the deceased (e.g., not visiting frequently enough, not telling the deceased how much he or she was loved). If a bereaved individual thinks about death and dying, such thoughts are generally focused on the deceased and possibly about “joining” the deceased, whereas in an MDE such thoughts are focused on ending one’s own life because of feeling worthless, undeserving of life, or unable to cope with the pain of depression. Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders-Text Revision, 5th ed. (Copyright © 2022). American Psychiatric Association. All Rights Reserved. primary care settings satisfy diagnostic criteria for the disorder. Depression is often undiagnosed and, even more frequently, is treated inadequately. If a physician suspects the presence of a major depres­ sive episode, the initial task is to determine whether it represents unipolar or bipolar depression or is one of the 10–15% of cases that are secondary to general medical illness or substance abuse. Physicians should also assess the risk of suicide by direct questioning, as patients are often reluctant to verbalize such thoughts without prompting. If specific plans are uncovered or if significant risk factors exist (e.g., a past history of suicide attempts, profound hopelessness, concurrent medical illness, substance abuse, or social isolation), the patient must be referred to a mental health specialist for immediate care. The physi­ cian should specifically probe each of these areas in an empathic and hopeful manner, being sensitive to denial and possible minimization of distress. The presence of anxiety, panic, or agitation significantly increases near-term suicidal risk. Approximately 4–5% of all depressed patients will commit suicide; most will have sought help from physi­ cians within 1 month of their deaths. CHAPTER 463 In some depressed patients, the mood disorder does not appear to be episodic and is not clearly associated with either psychosocial dys­ function or change from the individual’s usual experience in life. Per­ sistent depressive disorder (dysthymic disorder) consists of a pattern of chronic (at least 2 years), ongoing depressive symptoms that are usually less severe and/or less numerous than those found in major depression, but the functional consequences may be equivalent to or even greater; the two conditions are sometimes difficult to separate and can occur together (“double depression”). Many patients who exhibit a profile of pessimism, disinterest, and low self-esteem respond to antidepressant treatment. Persistent and chronic depressive disorders occur in ~2% of the general population. Psychiatric Disorders Depression is approximately twice as common in women as in men, and the incidence increases with age in both sexes. Twin studies indi­ cate that the liability to major depression of early onset (before age 25 years) is largely genetic in origin. Negative life events can precipitate and contribute to depression, but genetic factors influence the sensitiv­ ity of individuals to these stressful events. In most cases, both biologic and psychosocial factors are involved in the precipitation and unfold­ ing of depressive episodes. The most potent stressors appear to involve death of a relative, assault, or severe marital or relationship problems. Unipolar depressive disorders usually begin in early adulthood and recur episodically over the course of a lifetime. The best predictor of future risk is the number of past episodes; 50–60% of patients who have a first episode have at least one or two recurrences. Some patients experience multiple episodes that become more severe and frequent over time. The duration of an untreated episode varies greatly, ranging from a few months to ≥1 year. The pattern of recurrence and clinical progression in a developing episode are also variable. Within an indi­ vidual, the nature of episodes (e.g., specific presenting symptoms, frequency, and duration) may be similar over time. In a minority of patients, a severe depressive episode can progress to a psychotic state, and in elderly patients, depressive symptoms can be associated with cognitive deficits mimicking dementia (“pseudodementia”). A seasonal pattern of depression, called seasonal affective disorder, may manifest with onset and remission of episodes at predictable times of the year. This disorder is more common in women, with symptoms of anergy, fatigue, weight gain, hypersomnia, and episodic carbohydrate craving. The prevalence increases with distance from the equator, and improve­ ment may occur by altering light exposure. Etiology and Pathophysiology  Although evidence for genetic transmission of unipolar depression is not as strong as in bipolar dis­ order, monozygotic twins have a higher concordance rate (46%) than dizygotic siblings (20%), with little support for any effect of a shared family environment. Large-scale genome-wide association studies (GWAS) involving hundreds of thousands of cases and controls have identified several hundred loci across the genome, some of which are unique to major depression, but others of which overlap with findings from disparate psychiatric disorders, indicating possible pleiotropy. Epigenetic changes are also likely to contribute to risk. Neuroendocrine abnormalities that reflect the neurovegetative signs and symptoms of depression include increased cortisol and corticotropin-releasing hormone (CRH) secretion, a decreased inhibi­ tory response of glucocorticoids to dexamethasone, and a blunted response of thyroid-stimulating hormone (TSH) level to infusion of thyroid-releasing hormone (TRH). Antidepressant treatment leads to normalization of these abnormalities. Major depression is also associated with changes in levels of proinflammatory cytokines and neurotrophins, an increase in measures of oxidative stress and cellular aging, telomere shortening, epigenetic changes, and mitochondrial dysfunction. Alterations in the gut microbiome may also be involved. Diurnal variations in symptom severity and alterations in circadian rhythmicity of a number of neurochemical and neurohumoral factors suggest that a primary defect may be present in regulation of biologic rhythms. Patients with major depression show consistent findings of a decrease in rapid eye movement (REM)–sleep onset (REM latency), an increase in REM density, and, in some subjects, a decrease in stage IV delta slow-wave sleep. PART 13 Neurologic Disorders Although antidepressant drugs inhibit neurotransmitter uptake within hours, their therapeutic effects typically emerge over several weeks, implicating adaptive changes in second messenger systems and neurotrophic and transcription factors as possible mechanisms of action. TREATMENT Depressive Disorders Treatment planning requires coordination of short-term strate­ gies to induce remission combined with longer-term maintenance designed to prevent recurrence. The most effective intervention for achieving remission and preventing relapse is medication, but com­ bined treatments, incorporating psychotherapy to help the patient cope with decreased self-esteem and demoralization, improve out­ comes, as do self-help strategies such as exercise (Fig. 463-1). Approximately 40% of primary care patients with depression drop out of treatment and discontinue medication if symptomatic Determine whether there is a history of good response to a medication in the patient or a first-degree relative; if yes, consider treatment with this agent if compatible with considerations in step 2. Evaluate patient characteristics and match to drug; consider health status, side effect profile, convenience, cost, patient preference, drug interaction risk, suicide potential, and medication compliance history. Begin new medication at 1/3 to 1/2 target dose if drug is a TCA, bupropion, venlafaxine, or mirtazapine, or full dose as tolerated if drug is an SSRI. If problem side effects occur, evaluate possibility of tolerance; consider temporary decrease in dose or adjunctive treatment. If unacceptable side effects continue, taper drug over 1 week and initiate new trial; consider potential drug interactions in choice. Evaluate response after 6 weeks at target dose; if response is inadequate, increase dose in stepwise fashion as tolerated. If inadequate response after maximal dose, consider tapering and switching to a new drug vs adjunctive treatment; if drug is a TCA, obtain plasma level to guide further treatment. FIGURE 463-1  A guideline for the medical management of major depressive disorder. SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant. improvement is not noted within a month, unless additional sup­ port is provided. Outcome improves with (1) increased intensity and frequency of visits during the first 4–6 weeks of treatment, (2) supplemental educational materials, and (3) psychiatric consul­ tation as indicated. Despite the widespread use of SSRIs and other second-generation antidepressant drugs, there is no convincing evidence that these classes of antidepressants are more efficacious than TCAs. Between 60 and 70% of all depressed patients respond to any drug chosen, if it is given in a sufficient dose for 6–8 weeks. A rational approach to selecting which antidepressant to use (Table 463-1) involves matching the patient’s preference and medi­ cal history with the metabolic and side effect profile of the drug (Tables 463-2 and 463-3). A previous response, or a family history of a positive response, to a specific antidepressant often suggests that drug should be tried first. Before initiating antidepressant therapy, the physician should evaluate the possible contribution of comorbid illnesses and consider their specific treatment. In indi­ viduals with suicidal ideation, particular attention should be paid to choosing a drug with low toxicity if taken in overdose. Newer antidepressant drugs are distinctly safer in this regard; nevertheless, the advantages of TCAs have not been completely superseded. The existence of generic equivalents makes TCAs relatively cheap, and for secondary tricyclics, particularly nortriptyline and desipramine, well-defined relationships among dose, plasma level, and therapeu­ tic response exist. The steady-state plasma level achieved for a given drug dose can vary more than tenfold between individuals, and plasma levels may help in interpreting apparent resistance to treat­ ment and/or unexpected drug toxicity. The principal side effects of TCAs are antihistaminergic (sedation) and anticholinergic (con­ stipation, dry mouth, urinary hesitancy, blurred vision). TCAs are contraindicated in patients with serious cardiovascular risk factors, and overdoses of tricyclic agents can be lethal, with desipramine carrying the greatest risk. It is judicious to prescribe only a 10-day supply when suicide is a risk. Most patients require a daily dose of 150–200 mg of imipramine or amitriptyline or its equivalent to achieve a therapeutic blood level of 150–300 ng/mL and a satisfac­ tory remission; some patients show a partial effect at lower doses. Geriatric patients may require a low starting dose and slow escala­ tion. Ethnic differences in drug metabolism are significant, with Hispanic, Asian, and black patients generally requiring lower doses to achieve a comparable blood level. Second-generation antidepressants are similar to tricyclics in their effect on neurotransmitter reuptake, although some also have specific actions on catecholamine and indolamine receptors as well. Amoxapine is a dibenzoxazepine derivative that blocks norepinephrine and serotonin reuptake and has a metabolite that shows a degree of dopamine blockade. Long-term use of this drug carries a risk of tardive dyskinesia. Maprotiline is a potent norad­ renergic reuptake blocker that has little anticholinergic effect but may produce seizures. Bupropion is a novel antidepressant whose mechanism of action is thought to involve enhancement of norad­ renergic function. It has no anticholinergic, sedating, or orthostatic side effects and has a low incidence of sexual side effects. It may, however, be associated with stimulant-like side effects, may lower seizure threshold, and has an exceptionally short half-life, requiring frequent dosing. An extended-release preparation is available, as is a version combining it with dextromethorphan, an N-methyld-aspartate (NMDA) receptor agonist, that is proposed to result in a more rapid therapeutic response. SSRIs such as fluoxetine, sertraline, paroxetine, citalopram, and escitalopram cause a lower frequency of anticholinergic, sedating, and cardiovascular side effects but a possibly greater incidence of gastrointestinal complaints, sleep impairment, and sexual dysfunc­ tion than do TCAs. Akathisia, involving an inner sense of restless­ ness and anxiety in addition to increased motor activity, may also be more common, particularly during the first week of treatment. One concern is the risk of “serotonin syndrome,” which is thought to result from hyperstimulation of brainstem 5-HT1A receptors and is charac­ terized by myoclonus, agitation, abdominal cramping, hyperpyrexia, hypertension, and potentially death. Serotonergic agonists taken in combination should be monitored closely for this reason. Consider­ ations such as half-life, compliance, toxicity, and drug-drug interac­ tions may guide the choice of a particular SSRI. Fluoxetine and its principal active metabolite, norfluoxetine, for example, have a com­ bined half-life of almost 7 days, resulting in a delay of 5 weeks before steady-state levels are achieved and a similar delay for complete drug excretion once their use is discontinued; paroxetine appears to incur a greater risk of withdrawal symptoms with abrupt discontinuation. All the SSRIs may impair sexual function, resulting in diminished libido, impotence, or difficulty in achieving orgasm. Sexual dysfunc­ tion frequently results in noncompliance and should be asked about specifically. Sexual dysfunction can sometimes be ameliorated by lowering the dose, by instituting weekend drug holidays (two or three times a month), or by treatment with amantadine (100 mg tid), bethanechol (25 mg tid), buspirone (10 mg tid), or bupropion (100–150 mg/d). Paroxetine appears to be more anticholinergic than either fluoxetine or sertraline, and sertraline carries a lower risk of producing an adverse drug interaction than the other two. Rare side effects of SSRIs include angina due to vasospasm and prolongation of the prothrombin time. Escitalopram is the most specific of currently available SSRIs and appears to have no significant inhibitory effects on the P450 system. Venlafaxine, desvenlafaxine, duloxetine, and levomilnacipran block the reuptake of both norepinephrine and serotonin but pro­ duce relatively little in the way of traditional tricyclic side effects. Vortioxetine, also a 5-HT1A agonist, and vilazodone block reuptake of serotonin but have negligible effects on norepinephrine reuptake, although vortioxetine may increase norepinephrine levels through wide effects on serotonergic receptors, as a 5-HT1A agonist, 5-HT1B partial agonist, and a 5-HT1D, 5-HT3, and 5-HT7 antagonist. Unlike the SSRIs, venlafaxine and vortioxetine have relatively linear doseresponse curves. Patients on immediate-release venlafaxine should be monitored for a possible increase in diastolic blood pressure, and multiple daily dosing is required because of the drug’s short half-life. An extended-release form is available and has a somewhat lower incidence of gastrointestinal side effects. Mirtazapine is a tetracyclic that has a unique spectrum of activity, as it increases nor­ adrenergic and serotonergic neurotransmission through a blockade of central α2-adrenergic receptors and postsynaptic 5-HT2 and 5-HT3 receptors. It is also strongly antihistaminic and, as such, may produce sedation. Levomilnacipran is the most noradrenergic of the SNRIs and theoretically may be appropriate for patients with more severe fatigue and anergia. Gepirone, an older drug recently approved, is a partial 5-HT1A agonist and 5-HT2A antagonist. With the exception of citalopram and escitalopram, each of the SSRIs may inhibit one or more cytochrome P450 enzymes. Depend­ ing on the specific isoenzyme involved, the metabolism of a number of concomitantly administered medications can be dramatically affected. Fluoxetine and paroxetine, for example, by inhibiting 2D6, can cause dramatic increases in the blood level of type 1C antiar­ rhythmics, whereas sertraline, by acting on 3A4, may alter blood levels of carbamazepine or digoxin. Depending on drug specificity for a particular CYP enzyme for its own metabolism, concomitant medications or dietary factors, such as grapefruit juice, may in turn affect the efficacy or toxicity of the SSRI. The MAOIs are highly effective, particularly in atypical depression, but the risk of hypertensive crisis following intake of tyramine-con­ taining food or sympathomimetic drugs makes them inappropriate as first-line agents. Transdermal selegiline may avert this risk at low dose. Common side effects include orthostatic hypotension, weight gain, insomnia, and sexual dysfunction. MAOIs should not be used concomitantly with SSRIs, because of the risk of serotonin syndrome, or with TCAs, because of possible hyperadrenergic effects. Electroconvulsive therapy is at least as effective as medication, but its use is reserved for treatment-resistant cases and delusional depressions. rTMS is approved for treatment-resistant depression and has been shown to have efficacy in several controlled trials. Vagus nerve stimulation (VNS) has also recently been approved for treatment-resistant depression, but its degree of efficacy is controversial. Some meta-analyses of low-intensity transcranial current stimulation (tCS) have shown a positive benefit over sham treatment, but whether this is comparable to or synergistic with antidepressant treatment is unclear. In off-label usage, intravenous ketamine, a dissociative anesthetic, and intranasal esketamine (an isomer that has FDA approval in treatment-resistant cases) have been shown to have short-term antidepressant efficacy, often after a single administration, and may decrease suicidality. Questions remain, however, about the risk/benefit ratio over the longer term. Psilocybin, a hallucinogen, has also shown some potential benefit in controlled administration. Lastly, deep brain stimulation of the ventral anterior limb of the internal capsule and of the subcallosal cingulate region has demonstrable efficacy in randomized experi­ mental trials of treatment-resistant depression. Postpartum depression may respond to any of the above inter­ ventions, but a neuroactive steroid, brexanolone (Zulresso), admin­ istered in a continuous intravenous infusion over 60 h, can provide symptomatic relief for at least 30 days. Sedation and loss of con­ sciousness are possible adverse effects. An oral version, zuranolone (Zurzuvae), can be given on an outpatient basis. CHAPTER 463 Regardless of the treatment undertaken, the response should be evaluated after ~2 months. Three-quarters of patients show improvement by this time, but if remission is inadequate, the patient should be questioned about compliance, and an increase in medica­ tion dose should be considered if side effects are not troublesome. If this approach is unsuccessful, referral to a mental health special­ ist is advised. Strategies for treatment resistance include selection of an alternative drug, combinations of antidepressants, and/or adjunctive treatment with other classes of drugs, including lithium, thyroid hormone, l-methylfolate, S-adenosylmethionine, N-acetyl cysteine, atypical antipsychotic agents, and dopamine agonists. In switching to a different monotherapy, other drugs from the same class appear to be as likely to be efficacious as choosing a drug from a different class. A large randomized trial (STAR-D) was unable to show preferential efficacy, but the addition of certain atypical anti­ psychotic drugs (quetiapine extended-release; aripiprazole; brex­ piprazole) has received FDA approval, as has usage of a combined medication, olanzapine and fluoxetine (Symbyax). Patients whose response to an SSRI wanes over time may benefit from the addition of buspirone (10 mg tid) or pindolol (2–5 mg tid) or small amounts of a TCA such as nortriptyline (25 mg bid or tid). Most patients will show some degree of response, but aggressive treatment should be pursued until remission is achieved, and drug treatment should be continued for at least 6–9 months to prevent relapse. In patients who have had two or more episodes of depression, indefinite main­ tenance treatment should be considered. Pharmacogenomic testing focusing on cytochrome p450 allelic variation may sometimes be helpful in identifying individuals who are poor or rapid metaboliz­ ers, but assessing pharmacodynamic gene variants has not been shown to be cost-effective or affect clinical outcomes. Psychiatric Disorders It is essential to educate patients both about depression and the benefits and side effects of medications they are receiving. Advice about stress reduction and cautions that alcohol may exacerbate depressive symptoms and impair drug response are helpful. Patients should be given time to describe their experience, their outlook, and the impact of the depression on them and their families. Occasional empathic silence may be as helpful for the treatment alliance as verbal reassurance. Controlled trials have shown that cognitivebehavioral and interpersonal therapies are effective in improving psychological and social adjustment and that a combined treat­ ment approach is more successful than medication alone for many patients. ■ ■BIPOLAR DISORDER Clinical Manifestations  Bipolar disorder is characterized by unpredictable swings in mood from mania (or hypomania) to depression. Some patients suffer only from recurrent attacks of mania, which in its pure form is associated with increased psychomotor activ­ ity; excessive social extroversion; decreased need for sleep; impulsivity and impaired judgment; and expansive, elated, grandiose, and some­ times irritable mood (Table 463-8). In severe mania, patients may experience delusions and paranoid thinking indistinguishable from schizophrenia. One-half of patients with bipolar disorder present not with euphoria but with a mixture of psychomotor agitation and acti­ vation, accompanied by dysphoria, anxiety, and irritability. It may be difficult to distinguish such a mixed state from agitated depression. In some bipolar patients (bipolar II disorder), the full criteria for mania are lacking, and the requisite recurrent depressions are separated by periods of mild activation and increased energy (hypomania). In cyclothymic disorder, there are numerous hypomanic periods, usually of relatively short duration, alternating with clusters of depressive symptoms that fail, either in severity or duration, to meet the criteria of major depression. The mood fluctuations are chronic and should be present for at least 2 years before the diagnosis is made. PART 13 Neurologic Disorders Manic episodes typically emerge over a period of days to weeks, but onset within hours is possible, usually in the early-morning hours. An untreated episode of either depression or mania can be as short as several weeks or last as long as 8–12 months, and rare patients have an unremitting chronic course. The term rapid cycling is used for patients who have four or more episodes of either depression or mania in a given year. This pattern occurs in 15% of all patients, most of whom are women. In some cases, rapid cycling is linked to an underlying thyroid dysfunction, and in others, it is iatrogenically triggered by prolonged antidepressant treatment. Approximately one-half of patients have sus­ tained difficulties in work performance and psychosocial functioning, with depressive phases being more responsible for impairment than mania. Bipolar disorder is common, affecting ~1.5% of the population in the United States. Onset is typically between 20–30 years of age, but many individuals report premorbid symptoms in late childhood or early adolescence. The prevalence is similar for men and women; women are likely to have more depressive and men more manic episodes over a lifetime. Recognizing a bipolar diathesis in an individual who presents with a depressive episode but no history of mania is difficult but essen­ tial in optimizing treatment planning, because antidepressants may be contraindicated and result in symptom worsening and cycle accel­ eration. Suggestive features of bipolarity include a childhood onset, a history of antidepressant treatment failure, atypical features of hyper­ somnolence and weight gain, and marked irritability or impulsivity. Differential Diagnosis  The differential diagnosis of mania includes secondary mania induced by stimulant or sympathomimetic drugs, hyperthyroidism, AIDS, neurologic disorders such as Hunting­ ton’s or Wilson’s disease, frontotemporal dementia, and cerebrovascular accidents. Comorbidity with alcohol and substance abuse is common, either because of shared genetic risk, poor judgment, and increased impulsivity or because of an attempt to self-treat the underlying mood symptoms and sleep disturbances. Etiology and Pathophysiology  Genetic predisposition to bipolar disorder is evident from family studies; the concordance rate for mono­ zygotic twins approaches 80%. A number of risk genes that have been identified to date overlap with those conveying risk for other psychiat­ ric disorders, such as schizophrenia and autism, implying some degree of shared pathophysiology. Replicated loci include the alpha subunit of the L-type calcium channel (CACNA1C), teneurin transmembrane protein 4 (ODZ4), ankyrin 3 (ANK3), neurocan (NCAN), and tetratri­ copeptide repeat and ankyrin repeat containing 1 (TRANK1). Com­ mon variants convey little individual risk but collectively account for 25% of heritability. A few rarer, more penetrant variants have also been reported, but no causative mutations have as yet been confirmed. Simi­ larly, no clear biomarkers have been identified, but there is evidence for circadian rhythm and calcium dysregulation and oxidative stress, and mitochondrial, microRNA, and endoplasmic reticulum abnormalities. Reported MRI findings include gray matter thinning in frontal, tem­ poral, and parietal cortex. TREATMENT Bipolar Disorder (Table 463-9) Lithium carbonate is the mainstay of treatment in bipolar disorder, although paradoxically underutilized. Sodium valproate and carbamazepine, as well as a number of secondgeneration antipsychotic agents (e.g., aripiprazole, asenapine, carip­ razine, olanzapine, quetiapine, risperidone, ziprasidone), also have FDA approval for the treatment of acute mania. Oxcarbazepine is not FDA approved but appears to enjoy carbamazepine’s spectrum of efficacy. The response rate to lithium carbonate is 70–80% in acute mania, with beneficial effects appearing in 1–2 weeks. Lithium also has a prophylactic effect in prevention of recurrent mania and, to a lesser extent, in the prevention of recurrent depression, which is more difficult to treat than unipolar depression. A simple cation, lithium is rapidly absorbed from the gastrointestinal tract and remains unbound to plasma or tissue proteins. Some 95% of a given dose is excreted unchanged through the kidneys within 24 h. Serious side effects from lithium are rare, but minor complaints such as gastrointestinal discomfort, nausea, diarrhea, polyuria, weight gain, skin eruptions, alopecia, and edema are common. Over time, urine-concentrating ability may be decreased, but significant nephrotoxicity is relatively rare. Lithium exerts an antithyroid effect by interfering with the synthesis and release of thyroid hormones. More serious side effects include tremor, poor concentration and memory, ataxia, dysarthria, and incoordination. In the treatment of acute mania, lithium is initiated at 300 mg bid or tid, and the dose is then increased by 300 mg every 2–3 days to achieve blood levels of 0.8–1.2 meq/L. Because the therapeutic effect of lithium may not appear until after 7–10 days of treatment, adjunctive usage of lorazepam (1–2 mg every 4 h) or clonazepam (0.5–1 mg every 4 h) may be beneficial to control agitation. Antipsy­ chotics are indicated in patients with severe agitation who respond only partially to benzodiazepines. Patients using lithium should be monitored closely, because the blood levels required to achieve a therapeutic benefit are close to those associated with toxicity. Valproic acid may be more effective than lithium for patients who experience rapid cycling (i.e., more than four episodes a year) or who present with a mixed or dysphoric mania. Tremor and weight gain are the most common side effects; hepatotoxicity and pancreatitis are rare toxicities. The recurrent nature of bipolar mood disorder necessitates maintenance treatment. A sustained blood lithium level of at least 0.8 meq/L is important for optimal prophylaxis and has been shown to reduce the risk of suicide, a finding not yet apparent for other mood stabilizers. Decrease in acute suicidal risk may also result from treatment with parenteral ketamine or intranasal esket­ amine. Combinations of mood stabilizers together or with atypical antipsychotic drugs are sometimes required to maintain mood stability. Quetiapine extended release, olanzapine, risperidone, and lamotrigine have been approved for maintenance treatment as sole agents, in combination with lithium and with aripiprazole and ziprasidone as adjunctive drugs. Lurasidone, olanzapine/fluoxetine, and quetiapine are also approved to treat acute depressive episodes in bipolar disorder. Compliance is frequently an issue and often requires enlistment and education of concerned family members. Efforts to identify and modify psychosocial factors that may trig­ ger episodes are important, as is an emphasis on lifestyle regularity (social rhythm therapy). Mobile apps for smartphones that alert the individual and clinician to changes in activity and speech are prov­ ing useful in early detection of behavioral change and in delivering clinical interventions and education. Antidepressant medications are sometimes required for the treatment of severe breakthrough depressions, but their use should generally be avoided during maintenance treatment because of the risk of precipitating mania or accelerating the cycle frequency. Alternative off-label agents for bipolar depression include pramipexole, modafinil, omega-3 fatty acids, and N-acetyl cysteine; interventions such as electroconvulsive TABLE 463-8  Criteria for Bipolar I Disorder For a diagnosis of bipolar I disorder, it is necessary to meet the following criteria for a manic episode. The manic episode may have been preceded by and may be followed by hypomanic or major depressive episodes. Manic Episode A.  A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 1 week and present most of the day, nearly every day (or any duration if hospitalization is necessary). B.  During the period of mood disturbance and increased energy or activity, three (or more) of the following symptoms (four if the mood is only irritable) are present to a significant degree and represent a noticeable change from usual behavior: 1.  Inflated self-esteem or grandiosity. 2.  Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 3.  More talkative than usual or pressure to keep talking. 4.  Flight of ideas or subjective experience that thoughts are racing. 5.  Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed. 6.  Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation (i.e., purposeless non-goal-directed activity). 7.  Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments). C.  The mood disturbance is sufficiently severe to cause marked impairment in social or occupational functioning or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. D.  The episode is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication, other treatment) or another medical condition. Note: A full manic episode that emerges during antidepressant treatment (e.g., medication, electroconvulsive therapy) but persists at a fully syndromal level beyond the physiological effect of that treatment is sufficient evidence for a manic episode and, therefore, a bipolar I diagnosis. Note: Criteria A–D constitute a manic episode. At least one lifetime manic episode is required for the diagnosis of bipolar I disorder. Hypomanic Episode A.  A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 4 consecutive days and present most of the day, nearly every day. B.  During the period of mood disturbance and increased energy and activity, three (or more) of the following symptoms (four if the mood is only irritable) have persisted, represent a noticeable change from usual behavior, and have been present to a significant degree: 1.  Inflated self-esteem or grandiosity. 2.  Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). 3.  More talkative than usual or pressure to keep talking. 4.  Flight of ideas or subjective experience that thoughts are racing. 5.  Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed. 6.  Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation. 7.  Excessive involvement in activities that have a high potential for painful consequences (e.g., engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments). C.  The episode is associated with an unequivocal change in functioning that is uncharacteristic of the individual when not symptomatic. D.  The disturbance in mood and the change in functioning are observable by others. E.  The episode is not severe enough to cause marked impairment in social or occupational functioning or to necessitate hospitalization. If there are psychotic features, the episode is, by definition, manic. F.  The episode is not attributable to the physiological effects of a substance (e.g., a drug of abuse, a medication, other treatment) or another medical condition. Note: A full hypomanic episode that emerges during antidepressant treatment (e.g., medication, electroconvulsive therapy) but persists at a fully syndromal level beyond the physiological effect of that treatment is sufficient evidence for a hypomanic episode diagnosis. However, caution is indicated so that one or two symptoms (particularly increased irritability, edginess, or agitation following antidepressant use) are not taken as sufficient for diagnosis of a hypomanic episode, nor necessarily indicative of a bipolar diathesis. Note: Criteria A–F constitute a hypomanic episode. Hypomanic episodes are common in bipolar I disorder but are not required for the diagnosis of bipolar I disorder. Major Depressive Episode A.  Five (or more) of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either (1) depressed mood or (2) loss of interest or pleasure. Note: Do not include symptoms that are clearly attributable to another medical condition. 1.  Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad, empty, or hopeless) or observation made by others (e.g., appears tearful). (Note: In children and adolescents, can be irritable mood.) 2.  Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day (as indicated by either subjective account or observation). 3.  Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month), or decrease or increase in appetite nearly every day. (Note: In children, consider failure to make expected weight gain.) 4.  Insomnia or hypersomnia nearly every day. 5.  Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). 6.  Fatigue or loss of energy nearly every day. 7.  Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). 8.  Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). 9.  Recurrent thoughts of death (not just fear of dying); recurrent suicidal ideation without a specific plan; a specific suicide plan; or a suicide attempt. B.  The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. C.  The episode is not attributable to the physiological effects of a substance or another medical condition. Note: Criteria A–C constitute a major depressive episode. Major depressive episodes are common in bipolar I disorder but are not required for the diagnosis of bipolar I disorder. Note: Responses to a significant loss (e.g., bereavement, financial ruin, losses from a natural disaster, a serious medical illness or disability) may include the feelings of intense sadness, rumination about the loss, insomnia, poor appetite, and weight loss noted in Criterion A, which may resemble a depressive episode. Although such symptoms may be understandable or considered appropriate to the loss, the presence of a major depressive episode in addition to the normal response to a significant loss should also be carefully considered. This decision inevitably requires the exercise of clinical judgment based on the individual’s history and the cultural norms for the expression of distress in the context of loss. Bipolar I Disorder A.  Criteria have been met for at least one manic episode (Criteria A–D under “Manic Episode” above). B.  At least one manic episode is not better explained by schizoaffective disorder and is not superimposed on schizophrenia, schizophreniform disorder, delusional disorder, or other specified or unspecified schizophrenia spectrum and other psychotic disorder. Source: Reprinted with permission from the Diagnostic and Statistical Manual of Mental Disorders-Text Revision, 5th ed. (Copyright © 2022). American Psychiatric Association. All Rights Reserved. CHAPTER 463 Psychiatric Disorders TABLE 463-9  Clinical Pharmacology of Mood Stabilizers AGENT AND DOSING SIDE EFFECTS AND OTHER EFFECTS Lithium Common Side Effects Starting dose: 300 mg bid or tid Therapeutic blood level: 0.8–1.2 meq/L Nausea/anorexia/diarrhea, fine tremor, thirst, polyuria, fatigue, weight gain, acne, folliculitis, neutrophilia, hypothyroidism Blood level is increased by thiazides, tetracyclines, and NSAIDs Blood level is decreased by bronchodilators, verapamil, and carbonic anhydrase inhibitors Rare side effects: Neurotoxicity, renal toxicity, hypercalcemia, ECG changes Valproic Acid Common Side Effects Starting dose: 250 mg tid Therapeutic blood level: 50–125 μg/mL Nausea/anorexia, weight gain, sedation, tremor, rash, alopecia Inhibits hepatic metabolism of other medications PART 13 Neurologic Disorders Rare side effects: Pancreatitis, hepatotoxicity, Stevens-Johnson syndrome Carbamazepine/ Oxcarbazepine Common Side Effects Starting dose: 200 mg bid for carbamazepine, 150 mg bid for oxcarbazepine Therapeutic blood level: 4–12 μg/mL for carbamazepine Nausea/anorexia, sedation, rash, dizziness/ ataxia Carbamazepine, but not oxcarbazepine, induces hepatic metabolism of other medications Rare side effects: Hyponatremia, agranulocytosis, Stevens-Johnson syndrome Lamotrigine Common Side Effects Starting dose: 25 mg/d Rash, dizziness, headache, tremor, sedation, nausea Rare side effect: Stevens-Johnson syndrome Abbreviations: ECG, electrocardiogram; NSAIDs, nonsteroidal anti-inflammatory drugs. therapy, light therapy, and rTMS may also be effective. Loss of effi­ cacy over time may be observed with any of the mood-stabilizing agents. In such situations, an alternative agent or combination therapy is usually helpful. SOMATIC SYMPTOM DISORDER Many patients presenting in general medical practice, perhaps as many as 5–7%, will experience a somatic symptom(s) as particularly distressing and preoccupying, to the point that it comes to dominate their thoughts, feelings, and beliefs and interferes to a varying degree with everyday functioning. Although the absence of a medical explana­ tion for these complaints was historically emphasized as a diagnostic element, it has been recognized that the patient’s interpretation and elaboration of the experience is the critical defining factor and that patients with well-established medical causation may qualify for the diagnosis. Multiple complaints are typical, but severe single symptoms can occur as well. Comorbidity with depressive and anxiety disor­ ders is common and may affect the severity of the experience and its functional consequences. Personality factors may be a significant risk factor, as may a low level of educational or socioeconomic status or a history of recent stressful life events. Cultural factors are relevant as well and should be incorporated into the evaluation. Individuals who have persistent preoccupations about having or acquiring a serious illness, but who do not have a specific somatic complaint, may qualify for a related diagnosis—illness anxiety disorder. The diagnosis of con­ version disorder (functional neurologic symptom disorder) is used to specifically identify individuals whose somatic complaints involve one or more symptoms of altered voluntary motor or sensory function that cannot be medically explained and that cause significant distress or impairment or require medical evaluation. In factitious illnesses, the patient consciously and voluntarily pro­ duces physical symptoms of illness. The term Munchausen’s syndrome is reserved for individuals with particularly dramatic, chronic, or severe factitious illness. In true factitious illness, the sick role itself is gratifying. A variety of signs, symptoms, and diseases have been either simulated or caused by factitious behavior, the most common includ­ ing chronic diarrhea, fever of unknown origin, intestinal bleeding or hematuria, seizures, and hypoglycemia. Factitious disorder is usually not diagnosed until 5–10 years after its onset, and it can produce signif­ icant social and medical costs. In malingering, the fabrication derives from a desire for some external reward such as a narcotic medication or disability reimbursement. TREATMENT Somatic Symptom Disorder and Related Disorders Patients with somatic symptom disorder are frequently subjected to many diagnostic tests and exploratory surgeries in an attempt to find their “real” illness. Such an approach is doomed to failure and does not address the core issue. Successful treatment is best achieved through behavior modification, in which access to the physician is tightly regulated and adjusted to provide a sustained and predictable level of support that is less clearly contingent on the patient’s level of presenting distress. Visits can be brief and should not be associated with a need for a diagnostic or treatment action. Although the literature is limited, some patients may benefit from antidepressant treatment. Any attempt to confront the patient usually creates a sense of humiliation and causes the patient to abandon treatment from that caregiver. A better strategy is to introduce psychological causa­ tion as one of a number of possible explanations in the differential diagnoses that are discussed. Without directly linking psychothera­ peutic intervention to the diagnosis, the patient can be offered a face-saving means by which the pathologic relationship with the health care system can be examined and alternative approaches to life stressors developed. Specific medical treatments also may be indicated and effective in treating some of the functional conse­ quences of conversion disorder. FEEDING AND EATING DISORDERS ■ ■CLINICAL MANIFESTATIONS Feeding and eating disorders constitute a group of conditions in which there is a persistent disturbance of eating or associated behaviors that significantly impair an individual’s physical health or psychosocial functioning. In DSM-5-TR, the described categories (with the excep­ tion of pica) are defined to be mutually exclusive in a given episode, based on the understanding that although they are phenotypically similar in some ways, they differ in course, prognosis, and effective treatment interventions. ■ ■PICA Pica is diagnosed when the individual, aged >2 years, eats one or more nonnutritive, nonfood substances for a month or more and requires medical attention as a result. There is usually no specific aversion to food in general but a preferential choice to ingest substances such as clay, starch, soap, paper, or ash. The diagnosis requires the exclusion of specific culturally approved practices and has not been commonly found to be caused by a specific nutritional deficiency. Onset is most common in childhood, but the disorder can occur in association with other major psychiatric conditions in adults. An association with preg­ nancy has been observed, but the condition is only diagnosed when medical risks are increased by the behavior. ■ ■RUMINATION DISORDER In this condition, individuals who have no demonstrable associated gastrointestinal or other medical condition repeatedly regurgitate their food after eating and then either rechew or swallow it or spit it out. The behavior typically occurs on a daily basis and must persist for at least 1 month. Weight loss and malnutrition are common sequelae, and individuals may attempt to conceal their behavior, either by covering their mouth or through social avoidance while eating. In infancy, the onset is typically between 3 and 12 months of age, and the behavior may remit spontaneously, although in some, it appears to be recurrent. ■ ■AVOIDANT/RESTRICTIVE FOOD INTAKE DISORDER The cardinal feature of this disorder is avoidance or restriction of food intake, usually stemming from a lack of interest in or distaste of food and associated with weight loss, nutritional deficiency, dependency on nutritional supplementation, or marked impairment in psychosocial functioning, either alone or in combination. Culturally approved prac­ tices, such as fasting or a lack of available food, must be excluded as pos­ sible causes. The disorder is distinguished from anorexia nervosa by the presence of emotional factors, such as a fear of gaining weight and dis­ tortion of body image in the latter condition. Onset is usually in infancy or early childhood, but avoidant behaviors may persist into adulthood. The disorder is equally prevalent in males and females and is frequently comorbid with anxiety and cognitive and attention-deficit disorders and situations of familial stress. Developmental delay and functional deficits may be significant if the disorder is long-standing and unrecognized. ■ ■ANOREXIA NERVOSA Individuals are diagnosed with anorexia nervosa if they restrict their caloric intake to a degree that their body weight deviates significantly from age, gender, health, and developmental norms and if they also exhibit a fear of gaining weight and an associated disturbance in body image. The condition is further characterized by differentiating those who achieve their weight loss predominantly through restricting intake or by excessive exercise (restricting type) from those who engage in recurrent binge eating and/or subsequent purging, self-induced vomit­ ing, and usage of enemas, laxatives, or diuretics (binge-eating/purging type). Such subtyping is more state- than trait-specific, as individuals may transition from one profile to the other over time. Determination of whether an individual satisfies the primary criterion of significant low weight is complex and must be individualized, using all available historical information and comparison of body habitus to international body-mass norms and guidelines. Individuals with anorexia nervosa frequently lack insight into their condition and are in denial about possible medical consequences; they often are not comforted by their achieved weight loss and persist in their behaviors despite having met previously self-designated weight goals. Alterations in the circuitry of reward sensitivity and executive function have been reported in anorexia, implicating disturbances in frontal cortex and anterior insula regulation of interoceptive awareness of satiety and hunger. Neurochemical findings, including the role of ghrelin, remain controversial. Onset is most common in adolescence, although onset in later life can occur. Many more females than males are affected, with a lifetime prevalence in women of up to 4%. The disorder appears most prevalent in postindustrialized and urbanized countries and is frequently comorbid with preexisting anxiety disorders. The medical consequences of pro­ longed anorexia nervosa are multisystemic and can be life-threatening in severe presentations. Changes in laboratory values may be present, includ­ ing leukopenia with lymphocytosis, elevations in blood urea nitrogen, and metabolic alkalosis and hypokalemia when purging is present. History and physical examination may reveal amenorrhea in females, skin abnormali­ ties (petechiae, lanugo hair, dryness), and signs of hypometabolic function, including hypotension, hypothermia, and sinus bradycardia. Endocrine effects include hypogonadism, growth hormone resistance, and hypercor­ tisolemia. Osteoporosis is a longer-term concern. The course of the disorder is variable, with some individuals recov­ ering after a single episode, while others exhibit recurrent episodes or a chronic course. Untreated anorexia has a mortality of 5.1/1000, the highest among psychiatric conditions. Maudsley Anorexia Ner­ vosa Treatment for Adults (MANTRA) and eating disorder–focused cognitive-behavior therapy have proven to be effective therapies, with strict behavioral contingencies used when weight loss becomes critical. No pharmacologic intervention has proven to be specifically beneficial, but comorbid depression and anxiety should be treated. Weight gain should be undertaken gradually with a goal of 0.5–1 pound per week to prevent refeeding syndrome. Most individuals are able to achieve remission within 5 years of the original diagnosis. ■ ■BULIMIA NERVOSA Bulimia nervosa describes individuals who engage in recurrent and frequent (at least once a week for 3 months) periods of binge eating and who then resort to compensatory behaviors, such as self-induced purg­ ing, enemas, use of laxatives, or excessive exercise, to avoid weight gain. Binge eating itself is defined as excessive food intake in a prescribed period of time, usually <2 h. As in anorexia nervosa, disturbances in body image occur and promote the behavior, but unlike in anorexia, individuals are of normal weight or even somewhat overweight. Sub­ jects typically describe a loss of control and express shame about their actions, and often relate that their episodes are triggered by feelings of negative self-esteem or social stresses. The lifetime prevalence in women is ~2%, with a 10:1 female-to-male ratio. The disorder typically begins in adolescence and may be persistent over a number of years. Transition to anorexia occurs in only 10–15% of cases. Many of the medical risks associated with bulimia nervosa parallel those of anorexia nervosa and are a direct consequence of purging, including fluid and electrolyte dis­ turbances and cardiac conduction abnormalities. Physical examination often results in no specific findings, but dental erosion and parotid gland enlargement may be present. Effective treatment approaches include SSRI antidepressants, usually in combination with cognitive-behavioral, emotion regulation, or interpersonal-based psychotherapies. CHAPTER 463 Psychiatric Disorders ■ ■BINGE-EATING DISORDER Binge-eating disorder is distinguished from bulimia nervosa by the absence of compensatory behaviors to prevent weight gain after an episode and by a lack of effort to restrict weight gain between epi­ sodes. Other features are similar, including distress over the behavior and the experience of loss of control, resulting in eating more rapidly or in greater amounts than intended or eating when not hungry. The 12-month prevalence in females is 1.6%, with a much lower female-tomale ratio than bulimia nervosa. Little is known about the course of the disorder, given its recent categorization, but its prognosis is mark­ edly better than for other eating disorders, both in terms of its natural course and response to treatment. Transition to other eating disorder conditions is thought to be rare. PERSONALITY DISORDERS ■ ■CLINICAL MANIFESTATIONS Personality disorders are characteristic patterns of thinking, feeling, and interpersonal behavior that are relatively inflexible and cause sig­ nificant functional impairment or subjective distress for the individual. The observed behaviors are not secondary to another mental disorder, nor are they precipitated by substance abuse or a general medical con­ dition. This distinction is often difficult to make in clinical practice, because personality change may be the first sign of serious neurologic, endocrine, or other medical illness. Patients with frontal-lobe tumors, for example, can present with changes in motivation and personality while the results of the neurologic examination remain within normal limits. Individuals with personality disorders are often regarded as “difficult patients” in clinical medical practice because they are seen as excessively demanding and/or unwilling to follow recommended treatment plans. Although DSM-5-TR portrays personality disorders as qualitatively distinct categories, there is an alternative and emerg­ ing perspective that personality characteristics vary as a continuum between normal functioning and formal mental disorder, the essential features being moderate or greater impairment in self/interpersonal functioning and one or more pathological personality traits. Personality disorders have been grouped into three overlapping clusters. Cluster A includes paranoid, schizoid, and schizotypal per­ sonality disorders. It includes individuals who are odd and eccentric and who maintain an emotional distance from others. Individuals have a restricted emotional range and remain socially isolated. Patients with schizotypal personality disorder frequently have unusual perceptual experiences and express magical beliefs about the external world. The essential feature of paranoid personality disorder is a pervasive mis­ trust and suspiciousness of others to an extent that is unjustified by available evidence. Cluster B disorders include antisocial, borderline, histrionic, and narcissistic types and describe individuals whose behav­ ior is impulsive, excessively emotional, and erratic. Cluster C incorpo­ rates avoidant, dependent, and obsessive-compulsive personality types; enduring traits are anxiety and fear. The boundaries between cluster types are to some extent artificial, and many patients who meet criteria for one personality disorder also meet criteria for aspects of another. The risk of a comorbid major mental disorder is increased in patients who qualify for a diagnosis of personality disorder. ■ ■ETIOLOGY AND PATHOPHYSIOLOGY Genetic studies have increasingly suggested a genetic contribution to the development of personality disorders. One study of 106,000 sub­ jects identified nine loci significantly linked to aspects of neuroticism. PART 13 Neurologic Disorders TREATMENT Personality Disorders Dialectical behavior therapy (DBT) is a cognitive-behavioral approach that focuses on behavioral change while providing acceptance, com­ passion, and validation of the patient. Several randomized trials have demonstrated the efficacy of DBT in the treatment of personality disorders. Antidepressant medications and low-dose antipsychotic drugs have some efficacy in cluster A personality disorders, whereas anticonvulsant mood-stabilizing agents and MAOIs may be consid­ ered for patients with cluster B diagnoses who show marked mood reactivity, behavioral dyscontrol, and/or rejection hypersensitivity. Anxious or fearful cluster C patients often respond to medications used for axis I anxiety disorders (see above). It is important that the physician and the patient have reasonable expectations vis-à-vis the possible benefit of any medication used and its side effects. Improve­ ment may be subtle and observable only over time. SCHIZOPHRENIA ■ ■CLINICAL MANIFESTATIONS Schizophrenia is a heterogeneous syndrome characterized by perturba­ tions of language, perception, thinking, social activity, affect, and voli­ tion. There are no pathognomonic features. The syndrome commonly begins in late adolescence, has an insidious (and less commonly, acute) onset, and, often, a poor outcome, progressing from social withdrawal and perceptual distortions to recurrent delusions and hallucinations. Patients may present with positive symptoms (such as conceptual disorganization, delusions, or hallucinations) or negative symptoms (loss of function, anhedonia, decreased emotional expression, impaired concentration, and diminished social engagement) and must have at least two of these for a 1-month period and continuous signs for at least 6 months to meet formal diagnostic criteria. Disorganized thinking or speech and grossly disorganized motor behavior, including catatonia, may also be present. As individuals age, positive psychotic symptoms tend to attenuate, and some measure of social and occupational func­ tion may be regained. “Negative” symptoms predominate in one-third of the schizophrenic population and are associated with a poor longterm outcome and a poor response to drug treatment. However, marked variability in the course and individual character of symptoms is typical. The term schizophreniform disorder describes patients who meet the symptom requirements but not the duration requirements for schizophrenia, and schizoaffective disorder is used for those who manifest symptoms of schizophrenia and independent periods of mood disturbance. The terms schizotypal and schizoid refer to specific personality disorders and are discussed in that section. The diagnosis of delusional disorder is used for individuals who have delusions of various content for at least 1 month but who otherwise do not meet criteria for schizophrenia. Patients who experience a sudden onset of a brief (<1 month) alteration in thought processing, characterized by delusions, hallucinations, disorganized speech, or gross motor behavior, are most appropriately designated as having a brief psychotic disorder. Catatonia is recognized as a nonspecific syndrome that can occur as a consequence of other severe psychiatric/medical disorders and is diagnosed by the documentation of three or more of a cluster of motor and behavioral symptoms, including stupor, cataplexy, mutism, waxy flexibility, and stereotypy, among others. Prognosis depends not on symptom severity but on the response to antipsychotic medication. A permanent remission without recurrence does occasionally occur. About 10% of schizophrenic patients commit suicide. Schizophrenia is present in 0.85% of individuals worldwide, with a lifetime prevalence of ~1–1.5%. An estimated 300,000 episodes of acute schizophrenia occur annually in the United States, resulting in direct and indirect costs of $155.7 billion. ■ ■DIFFERENTIAL DIAGNOSIS The diagnosis is principally one of exclusion, requiring the absence of significant associated mood symptoms, any relevant medical condition, and substance abuse. Drug reactions that cause hallucinations, para­ noia, confusion, or bizarre behavior may be dose-related or idiosyn­ cratic; parkinsonian medications, clonidine, quinacrine, and procaine derivatives are the most common prescription medications associated with these symptoms. Drug causes should be ruled out in any case of newly emergent psychosis. The general neurologic examination in patients with schizophrenia is usually normal, but motor rigidity, tremor, and dyskinesias are noted in one-quarter of untreated patients. ■ ■EPIDEMIOLOGY AND PATHOPHYSIOLOGY Epidemiologic surveys identify several risk factors for schizophrenia, including genetic susceptibility, early developmental insults, winter birth, and increasing parental age. Genetic factors are involved in at least a subset of individuals who develop schizophrenia. Schizophre­ nia is observed in ~6.6% of all first-degree relatives of an affected proband. If both parents are affected, the risk for offspring is 40%. The concordance rate for monozygotic twins is 50%, compared to 10% for dizygotic twins. Schizophrenia-prone families are also at risk for other psychiatric disorders, including schizoaffective disorder and schizotypal and schizoid personality disorders, the latter terms designat­ ing individuals who show a lifetime pattern of social and interpersonal deficits characterized by an inability to form close interpersonal rela­ tionships, eccentric behavior, and mild perceptual distortions. Largescale GWASs have identified several hundred small effect risk loci and a few larger effect copy number variants, along with epigenetic effects, and have led to initial exploration in the clinical use of polygenic risk scores in diagnosis and prognosis. Pathways identified include ones involved in immunity, inflammation, and cell signaling. There is also recent evidence that brain gene expression in schizophrenia is similar to that seen in older aging adults without the disorder, implicating parallel mechanisms for cognitive deterioration. TREATMENT Schizophrenia Antipsychotic agents (Table 463-10) are the cornerstone of acute and maintenance treatment of schizophrenia and are effective in the treatment of hallucinations, delusions, and thought disorders, regardless of etiology. The mechanism of action involves, at least in part, binding to dopamine D2/D3 receptors in the ventral striatum; the clinical potencies of traditional antipsychotic drugs parallel their affinities for the D2 receptor, and even the newer “atypical” agents exert some degree of D2 receptor blockade. All current neu­ roleptics induce expression of the immediate-early gene c-fos in the nucleus accumbens, a dopaminergic site connecting prefrontal and limbic cortices. The development of newer atypical neuroleptics, however, is increasingly focusing on different targets: D3, 5-HT1A, 5-HT7, mGlu2/3, and muscarinic acetylcholine (M1, M4) recep­ tors; α1- and α2-noradrenergic activity; and altering the relationship between 5-HT2 and D2 receptor activity, resulting in faster dissocia­ tion of D2 binding and effects on neuroplasticity. TABLE 463-10  Antipsychotic Agents USUAL PO DAILY DOSE (mg) SIDE EFFECTS SEDATION COMMENTS NAME First-Generation Antipsychotics Low potency           Chlorpromazine (Thorazine)   Thioridazine (Mellaril) 100–1000 100–600 Anticholinergic effects; orthostasis; photosensitivity; cholestasis; QT prolongation Midpotency           Trifluoperazine (Stelazine) 2–50 Fewer anticholinergic side effects ++ Well tolerated by most patients   Perphenazine (Trilafon) 4–64 Fewer EPSEs than with higher-potency agents ++     Loxapine (Loxitane) 30–100 Frequent EPSEs ++     Molindone (Moban) 30–100 Frequent EPSEs Little weight gain High potency           Haloperidol (Haldol) 5–20 No anticholinergic side effects; EPSEs often prominent   Fluphenazine (Prolixin) 1–20 Frequent EPSEs 0/+     Thiothixene (Navane) 2–50 Frequent EPSEs 0/+   Second-Generation Antipsychotics Clozapine (Clozaril) 150–600 Agranulocytosis (1%); weight gain; seizures; drooling; hyperthermia Risperidone (Risperdal) 2–8 Orthostasis + Requires slow titration; EPSEs observed with doses >6 mg qd Olanzapine (Zyprexa) 10–30 Weight gain ++ Mild prolactin elevation Quetiapine (Seroquel) 350–800 Sedation; weight gain; anxiety +++ bid dosing Ziprasidone (Geodon) 120–200 Orthostatic hypotension +/++ Minimal weight gain; increases QT interval Aripiprazole (Abilify) 10–30 Nausea, anxiety, insomnia 0/+ Mixed agonist/antagonist; extended-release available Paliperidone (Invega) 3–12 Restlessness, EPSEs, increased prolactin, headache + Active metabolite of risperidone Iloperidone (Fanapt) 12–24 Dizziness, hypotension 0/+ Requires dose titration; long-acting injectable available Asenapine (Saphris) 10–20 Dizziness, anxiety, EPSEs, minimal weight gain ++ Sublingual tablets; bid dosing Lurasidone (Latuda) 40–80 Nausea, EPSEs ++ Uses CYP3A4 Brexpiprazole (Rexulti) 1–4 Anxiety, dizziness, fatigue ++ CYP3A4 and 2D6 interactions Pimavanserin (Nuplazid) Edema, confusion, sedation ++ Approved for Parkinson’s disease psychosis Cariprazine (Vraylar)   Lumateperone (Caplyta) 1.5–6   EPSEs, vomiting   Fatigue, dry mouth; no apparent metabolic/motor effects Abbreviations: EPSEs, extrapyramidal side effects; WBC, white blood cell. Conventional neuroleptics differ in their potency and side effect profile. Older agents, such as chlorpromazine and thioridazine, are more sedating and anticholinergic and more likely to cause ortho­ static hypotension, whereas higher-potency antipsychotics, such as haloperidol, perphenazine, and thiothixene, are more likely to induce extrapyramidal side effects. The model “atypical” antipsy­ chotic agent is clozapine, a dibenzodiazepine that has a greater potency in blocking the 5-HT2 than the D2 receptor and a much higher affinity for the D4 than the D2 receptor. Its principal disad­ vantage is a risk of blood dyscrasias. Paliperidone is a metabolite of risperidone and shares many of its properties. Unlike other antipsy­ chotics, clozapine does not cause a rise in prolactin levels. Approxi­ mately 30% of patients who do not benefit from conventional antipsychotic agents will have a better response to this drug, which also has a demonstrated superiority to other antipsychotic agents in preventing suicide; however, its side effect profile makes it most appropriate for treatment-resistant cases. Risperidone, a benzisoxa­ zole derivative, is more potent at 5-HT2 than D2 receptor sites, like clozapine, but it also exerts significant α2 antagonism, a property that may contribute to its perceived ability to improve mood and increase motor activity. Risperidone is not as effective as clozapine in treat­ ment-resistant cases but does not carry a risk of blood dyscrasias. Olanzapine is similar neurochemically to clozapine but has a signifi­ cant risk of inducing weight gain. Quetiapine is distinct in having a +++ EPSEs usually not prominent; can cause anticholinergic delirium in elderly patients 0/+ Often prescribed in doses that are too high; long-acting injectable forms of haloperidol and fluphenazine available CHAPTER 463 Psychiatric Disorders + + Requires weekly WBC count for first 6 months, then biweekly if stable ++   ++ Preferential D3 receptor affinity 5-HTA > D2 receptor affinity weak D2 effect but potent α1 and histamine blockade. Ziprasidone causes minimal weight gain and is unlikely to increase prolactin but may increase QT prolongation. Aripiprazole also has little risk of weight gain or prolactin increase but may increase anxiety, nausea, and insomnia as a result of its partial agonist properties. Asenapine is associated with minimal weight gain and anticholinergic effect but may have a higher than expected risk of extrapyramidal symptoms (EPSs). Cariprazine, a D2/D3 partial agonist, has no QT or prolactin elevation risk but can result in EPS as well. Antipsychotic agents are effective in 70% of patients present­ ing with a first episode. Improvement may be observed within hours or days, but full remission usually requires 6–8 weeks. The choice of agent depends principally on the side effect profile and cost of treatment or on a past personal or family history of a favor­ able response to the drug in question. Atypical agents appear to be more effective in treating negative symptoms and improving cognitive function. An equivalent treatment response can usually be achieved with relatively low doses of any drug selected (i.e., 4–6 mg/d of haloperidol, 10–15 mg of olanzapine, or 4–6 mg/d of risperidone). Doses in this range result in >80% D2 receptor blockade, and there is little evidence that higher doses increase either the rapidity or degree of response. Maintenance treatment requires careful attention to the possibility of relapse and moni­ toring for the development of a movement disorder. Intermittent drug treatment is less effective than regular dosing, but gradual dose reduction is likely to improve social functioning in many schizophrenic patients who have been maintained at high doses. If medications are completely discontinued, however, the relapse rate is 60% within 6 months. Long-acting injectable (LAI) prepara­ tions (risperidone, paliperidone, olanzapine, aripiprazole) are con­ sidered when noncompliance with oral therapy leads to relapses but should not be considered interchangeable because the agents differ in their indications, injection intervals and sites/volumes, and pos­ sible adverse reactions, among other factors. Extended treatment studies indicate a significant decrease in relapse with LAI usage. In treatment-resistant patients, a transition to clozapine usually results in rapid improvement, but a prolonged delay in response in some cases necessitates a 6- to 9-month trial for maximal benefit to occur. Antipsychotic medications can cause a broad range of side effects, including lethargy, weight gain, postural hypotension, constipation, and dry mouth. Extrapyramidal symptoms such as dystonia, akathi­ sia, and akinesia are also frequent with first-generation agents and may contribute to poor adherence if not specifically addressed. Anticholinergic and parkinsonian symptoms respond well to trihexy­ phenidyl, 2 mg bid, or benztropine mesylate, 1–2 mg bid. Akathisia may respond to beta blockers. In rare cases, more serious and occa­ sionally life-threatening side effects may emerge, including hyperp­ rolactinemia, ventricular arrhythmias, gastrointestinal obstruction, retinal pigmentation, obstructive jaundice, and neuroleptic malig­ nant syndrome (characterized by hyperthermia, autonomic dysfunc­ tion, muscular rigidity, and elevated creatine phosphokinase levels). The most serious adverse effects of clozapine are agranulocytosis, which has an incidence of 1%, and induction of seizures, which has an incidence of 10%. Weekly white blood cell counts are required, particularly during the first 3 months of treatment. PART 13 Neurologic Disorders The risk of type 2 diabetes mellitus appears to be increased in schizophrenia, and second-generation agents as a group, with the exception of lumateperone, produce greater adverse effects on glu­ cose regulation, independent of effects on obesity, than traditional agents. Clozapine, olanzapine, and quetiapine seem more likely to cause hyperglycemia, weight gain, and hypertriglyceridemia than other atypical antipsychotic drugs. Close monitoring of plasma glucose and lipid levels is indicated with the use of these agents. A serious side effect of long-term use of first-generation and, to a lesser extent, second-generation antipsychotic agents is tar­ dive dyskinesia, characterized by repetitive, involuntary, and potentially irreversible movements of the tongue and lips (buccolinguo-masticatory triad) and, in approximately half of cases, choreoathetosis. Tardive dyskinesia has an incidence of 2–4% per year of exposure and a prevalence of 20% in chronically treated patients. The prevalence increases with age, total dose, and duration of drug administration and may involve formation of free radicals and perhaps mitochondrial energy failure. Valbenazine (Ingrezza), a vesicular monoamine transporter 2 inhibitor that depletes pre­ synaptic dopamine, is approved for treatment of tardive dyskinesia. The CATIE study, a large-scale investigation of the effectiveness of antipsychotic agents in “real-world” patients, revealed a high rate of discontinuation of treatment after >18 months. Olanzapine showed greater effectiveness than quetiapine, risperidone, perphenazine, or ziprasidone but also a higher discontinuation rate due to weight gain and metabolic effects. Surprisingly, perphenazine, a first-generation agent, showed little evidence of inferiority to newer drugs. Drug treatment of schizophrenia is by itself insufficient. Edu­ cational efforts directed toward families and relevant community resources have proved to be necessary to maintain stability and optimize outcome. A collaborative treatment model using social cognition interventions and involving a multidisciplinary casemanagement team that seeks out and closely follows the patient in the community has proved particularly effective. Attempts to pre­ vent schizophrenia through early identification and treatment (both psychosocial and psychopharmacologic) of high-risk children and adolescents are currently being evaluated. ASSESSMENT AND EVALUATION OF VIOLENCE Primary care physicians may encounter situations in which fam­ ily, domestic, or societal violence is discovered or suspected. Such an awareness can carry legal and moral obligations; many state laws mandate reporting of child, spousal, and elder abuse. Physicians are frequently the first point of contact for both victim and abuser. Approximately 2 million older Americans and 1.5 million U.S. children are thought to experience some form of physical maltreatment each year. Spousal abuse is believed to be even more prevalent. An interview study of 24,000 women in 10 countries found a lifetime prevalence of physical or sexual violence that ranged from 15–71%; these individu­ als are more likely to suffer from depression, anxiety, and substance abuse and to have attempted suicide. In addition, abused individuals frequently express low self-esteem, vague somatic symptomatology, social isolation, and a passive feeling of loss of control. Although it is essential to treat these elements in the victim, the first obligation is to ensure that the perpetrator has taken responsibility for preventing any further violence. Substance abuse and/or dependence and serious men­ tal illness in the abuser may contribute to the risk of harm and require direct intervention. Depending on the situation, law enforcement agencies, community resources such as support groups and shelters, and individual and family counseling can be appropriate components of a treatment plan. A safety plan should be formulated with the vic­ tim, in addition to providing information about abuse, its likelihood of recurrence, and its tendency to increase in severity and frequency. Antianxiety and antidepressant medications may sometimes be useful in treating the acute symptoms, but only if independent evidence for an appropriate psychiatric diagnosis exists. ■ ■FURTHER READING Alon N et al: Social determinants of mental health in major depressive disorder: Umbrella review of 26 meta-analyses and systemic reviews. Psychiatry Res 335:115854, 2024. Anderson E et al: Depression treatment options and managing depression in primary care. N Eng J Med 390:e44, 2024. Barry R et al: Prevalence of mental health disorders among individuals experiencing homelessness: A systematic review and meta-analysis. JAMA Psychiatry 81:691, 2024. Bertolini F et al: Early pharmacological interventions for prevention of post-traumatic stress disorder (PTSD) in individuals experienc­ ing acute traumatic stress symptoms. Cochrane Database Sys Rev 5:CD013613, 2024. Birnbaum R, Weinberger DR: The genesis of schizophrenia: An ori­ gin story. Am J Psychiatry 181:482, 2024. Borque VR et al: Genetic and phenotypic similarities across major psychiatric disorders: A systematic review and quantitative assess­ ment. Trans Psychiatry 14:171, 2024. Cristancho M et al: Depression-advanced treatments for treatment resistant depression. N Eng J Med 390:e44, 2024. Gargano SP et al: A closer look to neural pathways and psychophar­ macology of obsessive compulsive disorder. Front Behav Neurosci 17:1282246, 2023. Guaiana G et al: Pharmacological treatment in panic disorder in adults: A network meta-analysis. Cochrane Database Sys Rev 11:1465, 2023. Nestler EJ, Russo SJ: Neurobiological basis of stress resilience. Neu­ ron 112:1911, 2024. Park JH et al: Global perspectives on bipolar disorder treatments: In depth comparative analysis of international guidelines for medication selection. BJPsych Open 10:e75, 2024. Reilly S et al: Collaborative care approaches for people with severe mental illness. Cochrane Database Sys Rev 5:CD009531, 2024. Solmi M et al: An umbrella review of predictors of response, remis­ sion, recovery and relapse across mental disorders. Mol Psychiatry 28:3671, 2023. Szuhany KL, Simon NM: Anxiety disorders: A review. JAMA 328:2431, 2022. # 37 - 464 Alcohol and Alcohol Use Disorders ### 464 Alcohol and Alcohol Use Disorders Marc A. Schuckit Alcohol and Alcohol Use Disorders Most patients drink alcohol, including many who take this drug at levels that can adversely affect their medical conditions or interfere with the effects of prescribed medications. Therefore, it is important to note that this chapter presents information relevant to all patients, not just those with alcohol problems. Alcohol (beverage ethanol) has diverse and widespread effects on the body and impacts directly or indirectly on almost every neurochemical system in the brain. At even relatively low doses, this drug can exacerbate most medical problems and affect medications metabolized in the liver, and at higher doses, it can tempo­ rarily mimic many medical (e.g., diabetes) and psychiatric (e.g., depres­ sion) conditions. Frequent and heavier drinking is also associated with the treatable but life-threatening condition of alcohol use disorder (the modern term for alcoholism). Physicians from all specialties play an important role in screening, using brief interventions, and treating or referring for treatment individuals with repetitive alcohol problems, a process abbreviated as SBIRT. The lifetime risk for repetitive serious alcohol problems (e.g., alcohol use disorder) in patients is at least 20% for men and 10% for women, regardless of a person’s education or income, and U.S. yearly costs for these disorders exceed $249 billion. Although low doses of alcohol might have healthful benefits, drinking more than three stan­ dard drinks per day enhances the risk for cancer and vascular disease, and alcohol use disorders decrease the life span by ~10 years. Unfortu­ nately, most clinicians have had only limited training in identifying and treating alcohol-related disorders. ■ ■PHARMACOLOGY AND NUTRITIONAL IMPACT OF ETHANOL Ethanol blood levels are expressed as milligrams or grams of ethanol per deciliter (e.g., 100 mg/dL = 0.10 g/dL), with values of ~0.02 g/dL resulting from the ingestion of one typical drink. In round figures, a standard drink is 10–12 g of ethanol, as seen in 340 mL (12 oz) of beer, 115 mL (4 oz) of nonfortified wine, and 43 mL (1.5 oz) (a shot) of 80-proof (40% ethanol by volume) beverage (e.g., whisky); 0.5 L (1 pint) of 80-proof beverage contains ~160 g of ethanol (~16 standard drinks), and 750 mL of wine contains ~60 g of ethanol. These beverages also have additional components (congeners) that affect the drink’s taste and might contribute to adverse effects on the body. Congeners include methanol, butanol, acetaldehyde, histamine, tannins, iron, and lead. As a depressant drug, alcohol acutely decreases neuronal activity and has similar behavioral effects and cross-tolerance with other depressants, including benzodiazepines, barbiturates, and some anticonvulsants. Alcohol is absorbed from mucous membranes of the mouth and esophagus (in small amounts), from the stomach and large bowel (in modest amounts), and from the proximal portion of the small intestine (the major site). The rate of absorption is increased by rapid gastric emp­ tying (as seen with carbonated beverages); by the absence of proteins, fats, or carbohydrates (which interfere with absorption); and by dilution to a modest percentage of ethanol (maximum at ~20% by volume). Between 2% (at low blood alcohol concentrations) and 10% (at high blood alcohol concentrations) of ethanol is excreted directly through the lungs, urine, or sweat, but most is metabolized to acetaldehyde, primarily in the liver. The most important pathway occurs in the cell cytosol where alcohol dehydrogenase (ADH) produces acetaldehyde, which is then rapidly destroyed by aldehyde dehydrogenase (ALDH) in the cytosol and mitochondria (Fig. 464-1). A second pathway occurs in the microsomes of the smooth endoplasmic reticulum (the microsomal ethanol-oxidizing system [MEOS]) that is responsible for ≥10% of ethanol oxidation at high blood alcohol concentrations. Although a standard drink contains ~300 kJ, or 70–100 kcal, these are devoid of minerals, proteins, and vitamins. In addition, alcohol MEOS 20% Acetaldehyde Ethanol Alcohol 80% Acetaldehyde dehydrogenase Aldehyde dehydrogenase Acetyl CoA Acetate Citric acid cycle Fatty acids CHAPTER 464 CO2 + Water FIGURE 464-1  The metabolism of alcohol. CoA, coenzyme A; MEOS, microsomal ethanol oxidizing system. interferes with absorption of vitamins in the small intestine and decreases their storage in the liver with modest effects on folate (folacin or folic acid), pyridoxine (B6), thiamine (B1), nicotinic acid (niacin, B3), and vitamin A. Alcohol and Alcohol Use Disorders Heavy drinking in a fasting, healthy individual can produce tran­ sient hypoglycemia within 6–36 h, secondary to the acute actions of ethanol that decrease gluconeogenesis. This can result in temporary abnormal glucose tolerance tests (with a resulting erroneous diagnosis of diabetes mellitus) until the heavy drinker has abstained for 2–4 weeks. Alcohol ketoacidosis, probably reflecting a decrease in fatty acid oxidation coupled with poor diet or persistent vomiting, can be misdiagnosed as diabetic ketosis. With alcohol-related ketoacidosis, patients show an increase in serum ketones along with a mild increase in glucose but a large anion gap, a mild to moderate increase in serum lactate, and a β-hydroxybutyrate/lactate ratio of between 2:1 and 9:1 (with normal being 1:1). In the brain, alcohol affects almost all neurotransmitter systems, with acute effects that are often the opposite of those seen follow­ ing desistance after a period of heavy drinking. The most prominent acute actions relate to boosting γ-aminobutyric acid (GABA) activity, especially at GABAA receptors. Enhancement of this complex chloride channel system contributes to anticonvulsant, sleep-inducing, anti­ anxiety, and muscle relaxation effects of all GABA-boosting drugs. Acutely administered alcohol produces a release of GABA, and con­ tinued use increases density of GABAA receptors, whereas alcohol withdrawal states are characterized by decreases in GABA-related activity. Equally important is the ability of acute alcohol to inhibit postsynaptic N-methyl-d-aspartate (NMDA) excitatory glutamate receptors, whereas chronic drinking and desistance are associated with an upregulation of these excitatory receptor subunits. The relationships between greater GABA and diminished NMDA receptor activity dur­ ing acute intoxication and diminished GABA with enhanced NMDA actions during alcohol withdrawal explain much of intoxication and withdrawal phenomena. As with all pleasurable activities, alcohol acutely increases dopamine levels in the ventral tegmentum and related brain regions, and this effect plays an important role in continued alcohol use, craving, and relapse. The changes in dopamine pathways are also linked to increases in “stress hormones,” including cortisol and adrenocorticotropic hor­ mone (ACTH), during intoxication and in the context of the stresses of withdrawal. Such alterations are likely to contribute to both feelings of reward during intoxication and depression during falling blood alcohol concentrations. Also closely linked to alterations in dopamine (especially in the nucleus accumbens) are alcohol-induced changes in opioid receptors, with acute alcohol causing release of β-endorphins. Additional neurochemical changes include increases in synaptic levels of serotonin during acute intoxication and subsequent upregula­ tion of serotonin receptors. Acute increases in nicotinic acetylcholine TABLE 464-1  Effects of Blood Alcohol Levels in the Absence of Tolerance BLOOD LEVEL, g/dL USUAL EFFECT 0.02 Decreased inhibitions, a slight feeling of intoxication 0.08 Decrease in complex cognitive functions and motor performance 0.20 Obvious slurred speech, motor incoordination, irritability, and poor judgment 0.30 Light coma and depressed vital signs 0.40 Death systems contribute to the impact of alcohol in the ventral tegmental region, which occurs in concert with enhanced dopamine activity. In the same regions, alcohol impacts on cannabinol receptors, with result­ ing release of dopamine, GABA, and glutamate as well as subsequent effects on brain reward circuits. PART 13 Neurologic Disorders ■ ■BEHAVIORAL EFFECTS, TOLERANCE, AND WITHDRAWAL The acute effects of a drug depend on the dose, the rate of increase in plasma, the concomitant presence of other drugs, and past experience with the agent. “Legal intoxication” with alcohol in most states is based on a blood alcohol concentration of 0.08 g/dL, some states are con­ sidering lowering acceptable levels to <0.05 g/dL, and levels of 0.04 g/dL are cited for pilots in the United States and automobile drivers in some other countries. However, behavioral, psychomotor, and cognitive changes are seen at 0.02–0.04 g/dL (i.e., after one to two drinks) (Table 464-1). Deep but disturbed sleep can be seen at 0.15 g/dL in individuals who have not developed tolerance, and death can occur with levels between 0.30 and 0.40 g/dL. Beverage alcohol is probably responsible for more overdose deaths than any other drug. Repeated use of alcohol contributes to the need for a greater number of standard drinks to produce effects originally observed with fewer drinks (acquired tolerance), a phenomenon involving at least three compensatory mechanisms. (1) After 1–2 weeks of daily drinking, metabolic or pharmacokinetic tolerance can be seen, with up to 30% increases in the rate of hepatic ethanol metabolism. This alteration disappears almost as rapidly as it develops. (2) Cellular or pharmacody­ namic tolerance develops through neurochemical changes that main­ tain relatively normal physiologic functioning despite the presence of alcohol. Subsequent decreases in blood levels contribute to symptoms of withdrawal. (3) Individuals learn to adapt their behavior so that they can function better than expected under the influence of the drug (learned or behavioral tolerance). The cellular changes caused by chronic ethanol exposure may not resolve for several weeks or longer following cessation of drinking. Rapid decreases in blood alcohol levels before that time can produce a withdrawal syndrome, which is most intense during the first 5 days, but with some symptoms (e.g., disturbed sleep and anxiety) lasting up to 4–6 months as part of a “protracted withdrawal” syndrome. THE EFFECTS OF ETHANOL ON ORGAN SYSTEMS Relatively low doses of alcohol (one or two drinks per day) may have mild potential beneficial effects by, for example, decreasing aggregation of platelets and potentially decreasing the risk for vascular dementia and Alzheimer’s disease. However, any potential healthful effects dis­ appear with the regular consumption of three or more drinks per day, and knowledge about the deleterious effects of alcohol can both help the physician to identify patients with alcohol use disorders and supply them with information that might help motivate changes in behavior. ■ ■NERVOUS SYSTEM Approximately 35% of drinkers overall, including as many as 50% of drinking college students and a much higher proportion of individu­ als with alcohol use disorders, ever experience a blackout. This is an episode of temporary anterograde amnesia, in which the person was awake but forgot all (en bloc blackouts at blood alcohol levels >0.20 mg/dL) or part (fragmentary blackouts at >0.12 mg/dL) of what occurred during a drinking period. Another common problem, one seen after as few as one or two drinks shortly before bedtime, is disturbed sleep. Although alcohol might initially help a person fall asleep, it disrupts sleep throughout the rest of the night. The stages of sleep are altered, and times spent in rapid eye movement (REM) and deep sleep early in the night are reduced. Alcohol relaxes muscles in the pharynx, which can cause snoring and exacerbate sleep apnea; symptoms of the latter occur in 75% of men with alcohol use disorders aged ≥60 years. Patients may also experience prominent and sometimes disturbing dreams later in the night. All these sleep impairments can contribute to relapses to drinking in persons with alcohol use disorders. Other common consequences of alcohol use even at relatively low alcohol levels are impaired judgment and coordination, which increase the risk of injuries. In the United States, ~40% of drinkers have at some time driven while intoxicated. Heavy drinking can also be associated with headache, thirst, nausea, vomiting, and fatigue the following day, a hangover syndrome that is responsible for much missed work and school time and temporary cognitive deficits. Chronic high alcohol doses cause peripheral neuropathy in ~10% of individuals with alcohol use disorders. Similar to diabetes, patients experience bilateral limb numbness, tingling, and paresthesias, all of which are more pronounced distally. Approximately 1% of those with alcohol use disorders develop cerebellar degeneration or atrophy, producing a syndrome of progressive unsteady stance and gait often accompanied by mild nystagmus. Perhaps 1 in 500 individuals with alcohol use disorders develop full Wernicke’s (ophthalmoparesis, ataxia, and encephalopathy) and Korsakoff’s (severe retrograde and antero­ grade amnesia) syndromes. These result from low levels of thiamine, especially in predisposed individuals with transketolase deficiencies. Repeated heavy drinking can contribute to cognitive problems and temporary memory impairment lasting for weeks to months after abstinence. Brain ventricular enlargement and widened cortical sulci on magnetic resonance imaging (MRI) and computed tomography (CT) scans occurs in ~50% of individuals with long-term alcohol use disorders; these changes are usually reversible if abstinence is main­ tained. Adolescents may be especially vulnerable to alcohol-related brain changes, as indicated by preclinical studies and prospective investigations in humans suggesting that alcohol exposure in the devel­ oping brain may adversely impact future cognitive processes related to cognition, reward recognition, and cue processing. There is no single “alcoholic dementia” syndrome; rather, this label describes patients who have irreversible cognitive changes (possibly from diverse causes) in the context of chronic alcohol use disorders. Psychiatric Comorbidity  Alcohol temporarily alters brain neu­ rochemistry in a manner similar to ways observed in some psychi­ atric conditions, resulting in mood, anxiety, and psychotic disorders. However, those alcohol-induced psychiatric symptoms that are only observed during intense intoxication or withdrawal syndromes are likely to disappear within days to weeks of abstinence. For example, while about 40% of individuals with alcohol use disorder will at some point meet criteria for a major depressive episode, about half of those conditions are temporary substance-induced mood disorders that are likely to disappear within a month of abstinence without the use of antidepressant medications. In addition, several preexisting psychiat­ ric disorders increase the risk for future alcohol use disorder includ­ ing schizophrenia, manic-depressive disease, posttraumatic stress disorder, and anxiety syndromes such as panic disorder (Chap. 463). The comorbidities of alcohol use disorders with independent psychi­ atric disorders might represent an overlap in genetic vulnerabilities, impaired judgment regarding the use of alcohol as a consequence of the independent psychiatric condition, or an attempt to use alcohol to alleviate symptoms of the disorder or side effects of medications. Treatment of all forms of alcohol-induced psychopathology includes helping patients achieve abstinence and offering supportive care, as well as reassurance and “talk therapy” such as cognitive-behavioral approaches. However, with the exception of short-term antipsychotic medications for substance-induced psychoses, substance-induced psy­ chiatric conditions only rarely require medications. Recovery is likely within several days to 4 weeks of abstinence. Conversely, because alcohol-induced conditions are temporary and do not indicate a need for long-term pharmacotherapy, a history of heavy alcohol intake is an important part of the workup for any patient who presents with any of these psychiatric syndromes. ■ ■THE GASTROINTESTINAL SYSTEM Esophagus and Stomach  Alcohol can cause inflammation of the esophagus and stomach causing epigastric distress and gastrointestinal bleeding, making alcohol one of the most common causes of hemor­ rhagic gastritis. Violent vomiting can produce severe bleeding through a Mallory-Weiss lesion, a longitudinal tear in the mucosa at the gastro­ esophageal junction. Pancreas and Liver  The incidence of acute pancreatitis (~25 per 1000 per year) is almost threefold higher in individuals with alcohol use disorders than in the general population, accounting for an esti­ mated 10% or more of the total cases. Alcohol impairs gluconeogenesis in the liver, resulting in a fall in the amount of glucose produced from glycogen, increased lactate production, and decreased oxidation of fatty acids. These contribute to an increase in fat accumulation in liver cells. In healthy individuals, these changes are reversible, but with repeated exposure to ethanol, especially daily heavy drinking, more severe changes in the liver occur, including alcohol-induced hepatitis, perivenular sclerosis, and cirrhosis, with the latter observed in an estimated 15% of individuals with alcohol use disorders (Chap. 353). Perhaps through an enhanced vulnerability to infections, individuals with alcohol use disorders have an elevated rate of hepatitis C, and drinking in the context of that disease is associated with more severe liver deterioration. ■ ■CANCER As few as 1.5 drinks per day increases a woman’s risk of breast cancer 1.4-fold. For both sexes, four drinks per day increases the risk for oral and esophageal cancers approximately threefold and rectal cancers by a factor of 1.5; seven to eight or more drinks per day produces an approximately fivefold increased risk for many other cancers. These consequences may result directly from cancer-promoting effects of alcohol and acetaldehyde or indirectly by interfering with immune homeostasis. ■ ■HEMATOPOIETIC SYSTEM Ethanol causes an increase in red blood cell size (mean corpuscular volume [MCV]), which reflects its effects on stem cells. If heavy drinking is accompanied by folic acid deficiency, there can also be hypersegmented neutrophils, reticulocytopenia, and a hyperplastic bone marrow; if malnutrition is present, sideroblastic changes can be observed. Chronic heavy drinking can decrease production of white blood cells, decrease granulocyte mobility and adherence, and impair delayed-hypersensitivity responses to novel antigens (with a possible false-negative tuberculin skin test). Associated immune deficiencies can contribute to vulnerability toward infections, including hepatitis and HIV, and interfere with their treatment. Finally, many individuals with alcohol use disorders have mild thrombocytopenia, which usually resolves within a week of abstinence unless there is hepatic cirrhosis or congestive splenomegaly. ■ ■CARDIOVASCULAR SYSTEM Acutely, ethanol decreases myocardial contractility and causes periph­ eral vasodilation, with a resulting mild decrease in blood pressure and a compensatory increase in cardiac output. Exercise-induced increases in cardiac oxygen consumption are higher after alcohol intake. These acute effects have little clinical significance for the average healthy drinker but can be problematic when persisting cardiac disease is present. The consumption of three or more drinks per day results in a dosedependent increase in blood pressure, which returns to normal within weeks of abstinence. Thus, heavy drinking is an important factor in mild to moderate hypertension. Chronic heavy drinkers also have a sixfold increased risk for coronary artery disease, related, in part, to increased low-density lipoprotein cholesterol, and carry an increased risk for cardiomyopathy through direct effects of alcohol on heart muscle. Symptoms of the latter include unexplained arrhythmias in the presence of left ventricular impairment, heart failure, hypocontractility of heart muscle, and dilation of all four heart chambers with associated potential mural thrombi and mitral valve regurgitation. Atrial or ven­ tricular arrhythmias, especially paroxysmal tachycardia, can also occur temporarily after heavy drinking in individuals showing no other evidence of heart disease—a syndrome known as the “holiday heart.” ■ ■GENITOURINARY SYSTEM CHANGES, SEXUAL FUNCTIONING, AND FETAL DEVELOPMENT Heavy drinking in adolescence can affect normal sexual development and reproductive onset. At any age, modest ethanol doses (e.g., blood alcohol concentrations of 0.06 g/dL) can increase sexual drive but also decrease erectile capacity in men. Even in the absence of liver impair­ ment, a significant minority of chronic heavy-drinking men show irre­ versible testicular atrophy with shrinkage of the seminiferous tubules, decreases in ejaculate volume, and a lower sperm count (Chap. 403). CHAPTER 464 Alcohol and Alcohol Use Disorders The repeated ingestion of high doses of ethanol by women can result in amenorrhea, a decrease in ovarian size, absence of corpora lutea with associated infertility, and an increased risk of spontaneous abor­ tion. Drinking during pregnancy results in the rapid placental transfer of both ethanol and acetaldehyde, which may contribute to a range of consequences known as fetal alcohol spectrum disorder (FASD). One severe result is the fetal alcohol syndrome (FAS), seen in ~5% of children born to heavy-drinking mothers, which can include any of the following: facial changes with epicanthal eye folds; poorly formed ear concha; small teeth with faulty enamel; cardiac atrial or ventricular septal defects; an aberrant palmar crease and limitation in joint move­ ment; and microcephaly with intellectual impairment. Less pervasive FASD conditions include combinations of low birth weight, a lower intelligence quotient (IQ), hyperactive behavior, and some modest cognitive deficits. The amount of ethanol required and the time of vul­ nerability during pregnancy have not been defined, making it advisable for pregnant women to abstain from alcohol completely. ■ ■OTHER EFFECTS Between one-half and two-thirds of individuals with alcohol use disor­ ders have skeletal muscle weakness caused by acute alcoholic myopathy, a condition that improves but that might not fully remit with absti­ nence. Effects of repeated heavy drinking on the skeletal system include changes in calcium metabolism, lower bone density, and decreased growth in the epiphyses, leading to an increased risk for fractures and osteonecrosis of the femoral head. Hormonal changes include an increase in cortisol levels, which can remain elevated during heavy drinking; inhibition of vasopressin secretion at rising blood alcohol concentrations and enhanced secretion at falling blood alcohol con­ centrations (with the final result that most individuals with alcohol use disorders are likely to be slightly overhydrated); a modest and revers­ ible decrease in serum thyroxine (T4); and a more marked decrease in serum triiodothyronine (T3). Hormone irregularities may disappear after a month or more of abstinence. ■ ■ALCOHOL USE DISORDERS Because many drinkers occasionally imbibe to excess, temporary alcohol-related problems are common, especially in the late teens to the late twenties. However, repeated problems in multiple life areas can indicate an alcohol use disorder as defined in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). ■ ■DEFINITIONS AND EPIDEMIOLOGY An alcohol use disorder (also called alcoholism or alcohol dependence in prior diagnostic manuals) is defined in DSM-5 of the American Psy­ chiatric Association as repeated alcohol-related difficulties in at least 2 of 11 life areas that cluster together in the same 12-month period (Table 464-2). Ten of the 11 items in DSM-5 (published in 2013) were TABLE 464-2  Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Classification of Alcohol Use Disorder (AUD) Criteria Two or more of the following items occurring in the same 12-month period must be endorsed for the diagnosis of an alcohol use disordera:   Drinking resulting in recurrent failure to fulfill role obligations   Recurrent drinking in hazardous situations   Continued drinking despite alcohol-related social or interpersonal problems   Tolerance   Withdrawal, or substance use for relief/avoidance of withdrawal   Drinking in larger amounts or for longer than intended   Persistent desire/unsuccessful attempts to stop or reduce drinking   Great deal of time spent obtaining, using, or recovering from alcohol   Important activities given up/reduced because of drinking   Continued drinking despite knowledge of physical or psychological problems caused by alcohol   Alcohol craving PART 13 Neurologic Disorders aMild AUD: 2–3 criteria required; moderate AUD: 4–5 items endorsed; severe AUD: 6 or more items endorsed. taken directly from the dependence and abuse criteria in DSM-IV, after deleting legal problems and adding craving. Thus, diagnoses estab­ lished across the two systems agree at >.84. Severity of DSM-5 alcohol use disorder is based on the number of items endorsed: mild is two or three items; moderate is four or five; and severe is six or more of the 11 criterion items. The lifetime risk for an alcohol use disorder in most Western coun­ tries is ~10–20% for men and 5–10% for women; higher rates are seen in individuals who seek help from health care deliverers. Between 2001 and 2013, the proportion of the U.S. population with a current (i.e., past 12 months) alcohol use disorder increased by 49% with increases of almost 100% in women, African Americans, and individuals aged ≥45. Rates are similar in the United States, Canada, Germany, Australia, and the United Kingdom; tend to be lower in most Mediterranean countries, such as Italy, Greece, and Israel; and may be higher in Ireland, France, Eastern Europe (e.g., Russia), and Scandinavia. An even higher lifetime prevalence has been reported for most native cultures, including Native Americans, Eskimos, Maori groups, and aboriginal tribes of Australia. These differences in prevalence reflect both cultural and genetic influences, as described below. In Western countries, the typical individual with alcohol use disorder has a family and a career, and the lifetime risk among physicians is similar to that of the general population. ■ ■GENETICS Some of the most exciting recent research developments into alcohol-related disorders have clarified the contribution of genetic influences to these conditions. These investigations include how variations in genes relate to environmental and attitudinal mediators of genetic effects. Understanding how specific gene variations contribute to the risk for a condition has the potential to help with early identifica­ tion of individuals at high risk, development of effective prevention efforts, and, perhaps, identifying individuals most likely to respond to specific medications. Approximately 60% of the risk for alcohol use disorder is attributed to genes, as indicated by the fourfold higher risk in children with an alcohol use disorder parent (even if adopted early in life and raised by nonalcoholics) and a higher risk in identical twins compared to fraternal twins of affected individuals. Like most medical and psychi­ atric conditions that are referred to as complex genetically influenced disorders, the risk for alcohol use disorders is related to hundreds of gene variations, many of which explain <1% of the risk. As a result, vul­ nerabilities toward the condition are often approached by considering multiple gene variations at the same time using polygenic risk scores. These genetic variations operate primarily through intermediate characteristics that subsequently combine with environmental influ­ ences to alter the risk for heavy drinking and alcohol problems. These include genes relating to a high risk for all substance use disorders that operate through impulsivity, schizophrenia, and bipolar disorder. Another characteristic, an intense skin flushing response when drink­ ing, decreases risk for only alcohol use disorders, and not substance use conditions related to other drugs, through gene variations for several alcohol-metabolizing enzymes, especially ALDH (a mutation only seen in Japanese, Chinese, and Korean individuals), and to a lesser extent, variations in ADH. An additional genetically influenced characteristic that increases the risk for heavy drinking, a low level of response or low sensitivity to alcohol, can be seen very early in the drinking career and before acquired tolerance or alcohol used disorders develop. The low response per drink operates, in part, through variations in genes relating to calcium and potassium channels, GABA, nicotinic, dopamine, and serotonin systems. Prospective studies have demonstrated that this need for higher doses of alcohol to achieve effects predicts future heavy drinking, alcohol problems, and alcohol use disorders, but not prob­ lems with drugs other than alcohol. The impact of a low response to alcohol on adverse drinking outcomes is partially mediated by a range of environmental and attitudinal influences, including the selection of heavier-drinking friends, more positive expectations of the effects of high doses of alcohol, and using alcohol to cope with stress. Several studies of college freshmen demonstrated that helping students who have a low sensitivity to alcohol modify these influences was associated with lower drinking quantities and fewer alcohol-related problems over the subsequent year. ■ ■NATURAL HISTORY Although the average age of the first drink (~15 years) is similar in individuals who do and do not go on to develop alcohol use disorders, an earlier onset of regular drinking and drunkenness, especially in the context of conduct problems, is associated with a higher risk for later alcohol-related diagnoses. By the mid-twenties, most nonalcoholic men and women begin to moderate their drinking (perhaps learning from negative consequences), whereas those with alcohol use disorders are likely to escalate their drinking despite difficulties. The first major life problem from alcohol often appears in the late teens to early twen­ ties, and a pattern of multiple alcohol difficulties by the mid-twenties. Once established, the course is likely to include exacerbations and remissions, with little difficulty in temporarily stopping or controlling alcohol use when problems develop, but without help desistance usu­ ally gives way to escalations in alcohol intake and subsequent problems. Following treatment, for at least a year, more than half of those with alcohol use disorder maintain a marked decrease in alcohol use and related problems or achieve full abstinence, including many who stop drinking permanently. Even without formal treatment or self-help groups, there is at least a 20% chance of spontaneous remission with long-term abstinence. However, should the individual continue to drink heavily, the life span is shortened by ~10 years on average, with the leading causes of early death being enhanced rates of heart disease, cancer, accidents, and suicide. ■ ■IDENTIFICATION AND TREATMENT The approach to treating alcohol-related conditions is relatively straightforward: (1) recognize that at least 20% of patients have an alcohol use disorder; (2) learn how to identify and treat acute alcoholrelated conditions (e.g., severe intoxication); (3) know how to help patients begin to address their alcohol problems; (4) know how to treat alcohol withdrawal symptoms; and (5) learn how to appropriately treat or refer patients for additional help. ■ ■IDENTIFICATION OF PATIENTS WITH ALCOHOL USE DISORDERS Even in affluent locales, the ~20% of patients who have an alcohol use disorder can be identified by asking questions about alcohol problems and noting laboratory test results that can reflect regular consump­ tion of six to eight or more drinks per day. The two blood tests with ≥60% sensitivity and specificity for heavy alcohol consumption are γ-glutamyl transferase (GGT) (>35 U) and carbohydrate-deficient TABLE 464-3  The Alcohol Use Disorders Identification Test (AUDIT)a 5-POINT SCALE (LEAST TO MOST) ITEM   1.  How often do you have a drink containing Never (0) to 4+ per week (4) alcohol?   2.  How many drinks containing alcohol do you 1 or 2 (0) to 10+ (4) have on a typical day?   3.  How often do you have six or more drinks on Never (0) to daily or almost daily (4) one occasion?   4.  How often during the last year have you found Never (0) to daily or almost daily (4) that you were not able to stop drinking once you had started?   5.  How often during the last year have you failed Never (0) to daily or almost daily (4) to do what was normally expected from you because of drinking?   6.  How often during the last year have you Never (0) to daily or almost daily (4) needed a first drink in the morning to get yourself going after a heavy drinking session?   7.  How often during the last year have you had a Never (0) to daily or almost daily (4) feeling of guilt or remorse after drinking?   8.  How often during the last year have you been Never (0) to daily or almost daily (4) unable to remember what happened the night before because you had been drinking?   9.  Have you or someone else been injured as a No (0) to yes, during the last year (4) result of your drinking? 10.  Has a relative, friend, doctor, or other health No (0) to yes, during the last year (4) worker been concerned about your drinking or suggested that you should cut down? aThe AUDIT is scored by simply summing the values associated with the endorsed response. A score ≥8 may indicate harmful alcohol use. transferrin (CDT) (>20 U/L or >2.6%); the combination of the two tests is likely to be more accurate than either alone. The values for these serologic markers are likely to return toward normal within several weeks of abstinence. Other useful blood tests include high-normal MCVs (≥91 μm3) and serum uric acid (>416 mol/L, or 7 mg/dL). The diagnosis of alcohol use disorder ultimately rests on the docu­ mentation of a pattern of repeated difficulties associated with alcohol (Table 464-2). The criteria can be paraphrased as reaching a point where alcohol means more to the person than the significant repetitive problems that it causes. Thus, in screening, it is important to probe for marital or job problems, legal difficulties, histories of accidents, medi­ cal problems, evidence of tolerance, and so on, and then attempt to relate these issues to use of alcohol. Some standardized questionnaires can be helpful, including the 10-item Alcohol Use Disorders Identifica­ tion Test (AUDIT) (Table 464-3), but these are only screening tools, and a face-to-face interview is still required for a meaningful diagnosis. The diagnostic criteria in the fourth and fifth versions of the American Psychiatric Association DSM (DSM-IV and DSM-5) are very similar, both are reliable across different clinicians, and both labels are very good at predicting future problems, especially for individuals with moderate or severe disorders. TREATMENT Alcohol-Related Conditions ACUTE INTOXICATION The first priority in treating severe intoxication is to assess vital signs and manage respiratory depression, cardiac arrhythmias, and blood pressure instability, if present. The possibility of intoxication with other drugs should be considered by obtaining, if needed, toxicology screens for other central nervous system (CNS) depres­ sants such as benzodiazepines and for opioids. Aggressive behavior should be handled by offering reassurance but also by calling for help from an intervention team. If the aggressive behavior contin­ ues, relatively low doses of a short-acting benzodiazepine such as lorazepam (e.g., 1–2 mg PO or IV) may be used and can be repeated as needed, but care must be taken not to destabilize vital signs or worsen confusion. An alternative approach is to use an antipsy­ chotic medication (e.g., olanzapine 2.5–10 mg IM repeated at 2 and 6 h, if needed). INTERVENTION The steps presented here follow the acronym of SBIRT, indicating screening, brief interventions, and treatment or referral to treat­ ment. There are two main elements to highlighting the need for compliance with treatment in a person with an alcohol use disorder: motivational interviewing and brief interventions. During motiva­ tional interviewing, the clinician helps the patient to think through the assets (e.g., comfort in social situations) and liabilities (e.g., health- and interpersonal-related problems) of the current pat­ tern of drinking. The clinician should listen empathetically to the responses, help the patient weigh options, and encourage the taking of responsibility for needed changes. Patients should be reminded that only they can decide to avoid the consequences that will occur if heavy drinking continues. The process of brief intervention, a similar approach, has been summarized by the acronym FRAMES: Feedback to the patient; Responsibility to be taken by the patient; Advice, rather than orders, on what needs to be done; Menus of options that might be considered; Empathy for understanding the patient’s thoughts and feelings; and Self-efficacy, i.e., offering sup­ port for the capacity of the patient to make changes. CHAPTER 464 Alcohol and Alcohol Use Disorders Once the patient begins to consider change, the discussions can focus more on the consequences of high alcohol consumption, suggested approaches to stopping drinking, and help in recogniz­ ing and avoiding situations likely to lead to heavy drinking such as going to bars or associating with heavy-drinking friends. Both motivational interviewing and brief interventions can be carried out in 15-min sessions, but because patients often do not change behavior immediately, multiple meetings are often required to explore the problem and possible options, discuss optimal treat­ ments, and explain the benefits of abstinence. ALCOHOL WITHDRAWAL If the patient agrees to stop drinking, sudden decreases in alcohol intake can produce withdrawal symptoms, most of which are the opposite of those produced by intoxication. Features include tremor of the hands (shakes); agitation and anxiety; autonomic nervous system overactivity including an increase in pulse, respiratory rate, sweating, and body temperature; and insomnia. These symptoms usu­ ally begin within 5–10 h of decreasing ethanol intake, peak on day 2 or 3, and improve by day 4 or 5, although mild levels of these problems may persist for 4–6 months as a protracted abstinence syndrome. About 2% of individuals with alcohol use disorder experience a withdrawal seizure, with the risk increasing in the context of older age, concomitant medical problems, misuse of additional drugs, and higher alcohol quantities. The same risk factors also contribute to the ~1% rate of withdrawal delirium, also known as delirium tremens (DTs), where the withdrawal includes a severe agitated delirium (mental confusion, agitation, and fluctuating levels of con­ sciousness) associated with a tremor and autonomic overactivity (e.g., marked increases in pulse, blood pressure, and respirations). The risks for seizures and DTs can be diminished by identifying and treating underlying medical conditions early in the course of with­ drawal and by instituting adequate doses of depressant medications such as benzodiazepines. Thus, the first step in dealing with possible withdrawal phenom­ ena is a thorough physical examination in all heavy drinkers who are considering abstinence. This includes evaluation of possible liver impairment, gastrointestinal bleeding, cardiac arrhythmias, infection, and glucose or electrolyte imbalances. It is also important to offer adequate nutrition and oral multiple B vitamins, includ­ ing 50–100 mg of oral thiamine daily for a week or more. Because most patients with alcohol use disorders who enter withdrawal are either normally hydrated or mildly overhydrated, IV fluids should be avoided unless there is a relevant medical problem or significant recent bleeding, vomiting, or diarrhea. The next step is to recognize that because withdrawal symptoms reflect the acute decrease in the usual blood levels of a CNS depres­ sant (i.e., alcohol), the symptoms can be controlled by administer­ ing any other depressant in doses that decrease symptoms (e.g., a rapid pulse and tremor) and then tapering the dose over 3–5 days. Although most depressants are effective, benzodiazepines (Chap. 463) have the most supportive data for use in this situa­ tion, combining a high level of safety and low cost. Short-half-life benzodiazepines can be considered for patients with serious liver impairment or evidence of significant brain damage, but they must be given every 4 h to avoid abrupt blood-level fluctuations that may increase the risk for seizures. Therefore, most clinicians use drugs with longer half-lives (e.g., chlordiazepoxide), adjusting the dose if signs of withdrawal escalate and withholding the drug if the patient is sleeping or has orthostatic hypotension. The average patient requires 25–50 mg of chlordiazepoxide or 10 mg of diazepam given PO every 4–6 h on the first day, with doses then decreased to zero over the next 5 days. Although alcohol withdrawal can be treated in a hospital, patients in good physical condition who demonstrate mild signs of withdrawal despite low blood alcohol concentrations and who have no prior history of DTs or withdrawal seizures can be considered for outpatient detoxification. For the next 4 or 5 days, these patients should receive only 1 or 2 days of medications at a time and return daily for evaluation of vital signs. They can be hos­ pitalized if signs and symptoms of withdrawal markedly escalate. PART 13 Neurologic Disorders Treatment of patients with DTs can be challenging, and the con­ dition is likely to run a course of 3–5 days regardless of the therapy used. However, conditions that meet the criteria for DTs outlined above represent medical emergencies that carry an estimated mor­ tality as high as 5%, and treatment is best carried out in an intensive care unit by well-trained clinicians who closely monitor vital signs. Medications can include high-dose benzodiazepines (e.g., as much as 800 mg/d of chlordiazepoxide has been reported) or, for those who do not respond to that regimen, closely monitored doses of propofol or dexmedetomidine. The focus of care is to identify and correct medical problems and to control behavior and prevent injuries. Antipsychotic medications are not recommended for treat­ ment of alcohol withdrawal symptoms; although antipsychotics are less likely than benzodiazepines to exacerbate confusion, they may increase the risk of seizures. Generalized withdrawal seizures rarely require more than the administration of an adequate dose of benzodiazepines. There is little evidence that anticonvulsants such as phenytoin or gabapentin are more effective than benzodiazepines for alcohol-withdrawal sei­ zures, and the risk of seizures has usually passed by the time effec­ tive drug levels are reached. The rare patient with status epilepticus must be treated aggressively (Chap. 436). HELPING INDIVIDUALS WITH ALCOHOL USE DISORDERS TO STOP OR SIGNIFICANTLY DECREASE DRINKING: THE REHABILITATION PHASE An Overview  After completing alcoholic rehabilitation, ≥50% of individuals with alcohol use disorders, especially highly function­ ing patients, maintain abstinence or significant diminution of alco­ hol intake for at least a year; many also achieve long-term sobriety. The ideal outcome is abstinence, but treatment trials are increasing recognizing that outcomes shy of total abstinence can still improve levels of functioning and quality of life. The core components of the rehabilitation phase of treatment include cognitive-behavioral approaches to help patients recognize the need to change, while working with them to alter their behaviors to enhance compliance. A key step is to optimize motivation toward abstinence through education of patients and their significant others about alcohol use disorders and their likely course over time. It is important to recognize that contrary to what some physicians might think, the typical person with an alcohol use disorder is likely to have a job and a family and not fit the inaccurate “down and out” stereotype. However, after years of heavy drinking, some patients require voca­ tional or avocational counseling to help to structure their days, and all patients should try self-help groups such as Alcoholics Anony­ mous (AA) to assist them in developing a sober peer group and to learn how to deal with life’s stresses while remaining sober. Relapse prevention education helps patients identify situations in which a return to drinking is likely (e.g., stopping in a bar to meet friends but planning to only have a nonalcoholic beverage), formulate ways to avoid the risky situation, and when that is not possible, to mitigate the risks to which they are exposed. It is also important to develop coping strategies that increase the chances of a quick return to abstinence after an episode of drinking. Although many individuals can be treated as outpatients, more intense interventions are more effective and some individuals with alcohol use disorders do not respond to just AA or outpatient groups. Whatever the setting, ongoing contact with outpatient treatment staff should be maintained for at least 6 months and pref­ erably for a year after abstinence. Counseling focuses on areas of improved functioning in the absence of alcohol (i.e., why it is a good idea to continue abstinence), helping patients to manage free time without alcohol, encouraging them to develop a nondrinking peer group, and discussions of ways to handle stress without drinking. The physician serves an important role in identifying the alcohol problem, diagnosing and treating associated medical and inde­ pendent or substance-induced psychiatric syndromes, oversee­ ing detoxification, referring the patient to outpatient or inpatient rehabilitation programs, providing counseling, and, if appropriate, selecting which (if any) medication might be needed. For insomnia, patients should be reassured that troubled sleep is likely to improve over subsequent weeks. They should be taught the elements of “sleep hygiene” including maintaining consistent schedules for bedtime and awakening, avoiding exercise or consumption of large meals before bedtime, and keeping the bedroom cool, dark, and quiet at night (Chap. 33). Depressant sleep medications are not the optimal approach for this type of insomnia that often continues for several weeks or months. Patients are likely to develop rebound insomnia when the depressant dose is decreased or stopped. The rebound increases the chance they will increase the dose and potentially develop problems controlling the prescribed depressant drug. Sedating antidepressants (e.g., trazodone) should not be used because they interfere with cognitive functioning the next morning and disturb the normal sleep architecture, but occasional use of over-the-counter sleeping medications (sedating antihistamines) can be considered. An additional problem, anxiety symptoms, can be addressed by increasing patients’ insights into the temporary nature of the symptoms and helping them develop strategies to achieve relaxation by using forms of cognitive therapy. Medications for the Alcohol Rehabilitation Treatment Phase  The core of the rehabilitation phase for any chronic relapsing condition, including alcohol use disorder, relates to cognitive and behavioral approaches that help people comply with treatment goals and improve health and quality of life. Any medication for this disorder is likely to operate optimally in the context of such cognitivebehavioral approaches. As a result, the efficacy of a medication is best measured as the gain in functioning over and above improvements associated with the motivational interviewing, brief interventions, and related behavioral approaches. Such additional treatments (e.g., medications) are likely to have modest effect sizes, which can be diffi­ cult to document. Adding to the challenge of establishing the efficacy of a medication for this condition are the fluctuations of the inten­ sity of alcohol-related symptoms over time and the 20% or higher spontaneous remission for alcohol use disorder. Recognizing that all treatments might cause harm through side effects and financial costs, it is important to demonstrate that a medication has a beneficial asset-to-liability ratio using double-blind controlled treatment trials. In that light, to date, well-structured controlled trials have revealed only a few medications that have even modest benefits when used in the first 6–12 months of recovery from an alcohol use disorder. The opioid antagonist naltrexone may shorten sub­ sequent relapses, whether used in the oral form (50–150 mg/d) or # 38 - 465 Nicotine Addiction ### 465 Nicotine Addiction as a once-per-month 380-mg injection. By blocking opioid recep­ tors, naltrexone decreases activity in the dopamine-rich ventral tegmental reward system and decreases the feeling of pleasure if alcohol is imbibed. A second medication, acamprosate (Campral) (~2 g/d divided into three oral doses), has similar modest effects. Acamprosate inhibits NMDA receptors, decreasing mild symptoms of protracted withdrawal. Several trials of combined naltrexone and acamprosate have reported that the combination is well tolerated, and the efficacy might be superior to either drug alone, although not all studies agree. It is more difficult to establish the asset-to-liability ratio of a third drug, disulfiram, an ALDH inhibitor, used clinically at doses of 250 mg/d, a dose selected to avoid the side effects of the more effective 500 mg/d regimen. This drug produces vomiting and autonomic nervous system instability after drinking as a result of rapidly rising blood levels of acetaldehyde. This reaction to alcohol can be dangerous, especially for patients with heart disease, stroke, diabetes mellitus, or hypertension. The drug itself carries potential risks of temporary depressive or psychotic symptoms, peripheral neuropathy, and liver damage. Disulfiram is best given under super­ vision by someone (such as a spouse), especially during high-risk drinking situations (such as the Christmas holidays). Regarding other medications, a 16-week, placebo-controlled trial in patients with histories of relatively severe acute withdrawal syn­ dromes reported good outcomes during the rehabilitation phase with another depressant medication (gabapentin 1200 mg/d), but side effects were considerable; those results have not yet been replicated, and gabapentin can itself be misused. Additional drugs under inves­ tigation include another opioid antagonist, nalmefene; the nicotinic receptor agonist varenicline; the serotonin antagonist ondansetron; the α-adrenergic agonist prazosin, especially in combination with naltrexone; the GABAB receptor agonist baclofen; the anticonvul­ sant topiramate; ibudilast in individuals with low-intensity alcohol responses; and possible enhanced outcomes when talk therapies are combined with ketamine or psilocybin sessions. However, it is important to emphasize that currently there are insufficient data to determine the asset-to-liability ratio for these medications in treating alcohol use disorders, and therefore, there is insufficient support for the routine use of these medications in clinical settings. ■ ■GLOBAL CONSIDERATIONS As described above, rates of alcohol use disorders differ across sex, age, ethnicity, and country. There are also differences across countries regarding the definition of a standard drink (e.g., 10–12 g of ethanol in the United States and 8 g in the United Kingdom) and the definition of being legally drunk. The preferred alcoholic beverage also varies across groups, even within countries. That said, regardless of sex, ethnicity, or country, the actual drug in the drink is still ethanol, and the risks for problems, course of alcohol use disorders, and approaches to treatment are similar across the world. ■ ■FURTHER READING Bogenschutz MP et al: Percentage of heavy drinking days following psilocybin-assisted psychotherapy vs placebo in the treatment of adult patients with alcohol use disorder: A randomized clinical trial. JAMA Psychiatry 79:953, 2022. Finn SW et al: Treatment of alcohol dependence in primary care com­ pared with outpatient specialist treatment: Twelve-month follow-up of a randomized controlled trial, with trajectories of change. J Stud Alcohol Drugs 81:300, 2020. Lai D et al: Evaluating risk for alcohol use disorder: Polygenic risk scores and family history. Alcohol Clin Exp Res 46:374, 2022. Livne O et al: Agreement between DSM-5 and DSM-IV measures of substance use disorders in a sample of adult substance users. Drug Alcohol Depend 227:108958, 2021. Mattle A et al: Gabapentin to treat acute alcohol withdrawal in hospitalized patients: A systematic review and meta-analysis. Drug Alcohol Depend 241:109671, 2022. McPheeters M et al: Pharmacotherapy for alcohol use disorder: A sys­ tematic review and meta-analysis. JAMA 330:1653, 2023. Meredith LR et al: The effect of neuroimmune modulation on subjec­ tive response to alcohol in the natural environment. Alcohol Clin Exp Res 46:879, 2022. Schuckit MA et al: The low level of response to alcohol-based heavy drinking prevention program: One-year follow-up. J Stud Alcohol Drugs 77:25, 2016. Witkiewitz K et al: Can alcohol use disorder recovery include some heavy drinking? A replication and extension up to 9 years following treatment. Alcohol Clin Exp Res 44:1862, 2020. Witt SH et al: Acute alcohol withdrawal and recovery in men lead to profound changes in DNA methylation profiles: A longitudinal clini­ cal study. Addiction 115:2034, 2020. Wood E et al: Canadian guideline for the clinical management of highrisk drinking and alcohol use disorder. CMAJ 195:E1364, 2023. CHAPTER 465 David M. Burns Nicotine Addiction Nicotine Addiction Ingestion of nicotine in any form (combusted or heated tobacco leaf, oral use, nicotine pouches, or inhaled by vaping nicotine or nicotine salt) can create and sustain addiction if used with sufficient intensity for a sufficient duration. Addicted users of nicotine regulate their nicotine intake by adjusting the frequency and intensity of their tobacco use, both to obtain the desired psychoactive effects and avoid withdrawal. While nicotine does cause some disease processes including complications of pregnancy, the vast majority of the diseases produced by nicotine addiction result from repetitive exposure to the carcinogens and other toxicants in various nicotine containing prod­ ucts. These exposures produce incremental changes that accumulate to progress toward disease, but it is the addiction to nicotine that causes the long-term, multiple times per day exposures to these agents needed to create sufficient damage to manifest as cancer, heart, and lung disease. Over the last decade, there have been major shifts in product use, with about 40% of the nicotine delivery products being noncombusted and non-tobacco-leaf formulations. This shift has made practitioner advice about nicotine addiction more complicated, in part because many of the noncombusted products offer the potential to deliver nicotine sufficient to satisfy addiction, but with dramatic reductions in most of the toxic constituents found in smoke. Substantial reduction in disease risk can be achieved with the use of nicotine “vaping” products to aid cessation success for combusted cigarette smokers, and their use is likely to provide meaningful disease reduction with long-term complete substitution for combusted cigarette smoking even without breaking nicotine addiction. Nicotine offers little or no benefit for the nonaddicted individual, but regular use of inhaled nicotine can produce a powerful addiction that is difficult to break and expensive to sustain. Any use of nicotine earlier in life predicts a greater use of some nicotine product later in life. For the practitioner, despite the likelihood of much lower disease risks compared to combusted cigarette use, it is hard to justify, or ignore, high-frequency use of noncombusted inhaled nicotine prod­ ucts in recommendations to patients who have never used combusted tobacco products. THE PROCESS OF NICOTINE ADDICTION When nicotine reaches the brain, it reversibly attaches to nicotinic acetylcholine receptors, which are particularly active in brain networks involved in depression, joy, excitement, and happiness. With prolonged high exposure to nicotine, nicotinic receptors are upregulated on brain cells. For most individuals, daily nicotine use is needed to produce changes in the brain that are the hallmark of addiction. The strength of addiction, and the speed with which it can develop, are influenced by the frequency of use and concentration of arterial levels of nico­ tine reaching the brain, which can vary widely with use of different products. As the time since last cigarette becomes longer, nicotine levels in the blood drop, and nicotine detaches from the receptors, leaving them increasingly uncovered. Without high levels of nicotine attaching to these receptors, addicted smokers no longer feel “normal,” creating a compulsive need for the next dose of nicotine. Addicted individuals perceive increasing withdrawal symptoms with increasing duration of abstinence, which can persist for 4–6 weeks. For the practicing clinician, the diagnosis of nicotine addiction is straightforward and is manifest by the patient’s loss of control over their next use of nicotine-containing products. The individual’s need for the next dose of nicotine can be satisfied by the use of multiple products at different times. The loss of control is demonstrated by a history of daily nicotine use coupled with behaviors such as high numbers of uses per day, use shortly after waking in the morning, craving after periods of abstinence, and/or failure of past cessation efforts, among others. PART 13 Neurologic Disorders Several genes have been associated with nicotine addiction. Some reduce the clearance of nicotine, and others have been associated with an increased likelihood of becoming dependent on tobacco and other drugs or a higher incidence of depression. It is likely that genetic sus­ ceptibility can influence the probability that adolescent experimenta­ tion with tobacco will lead to addiction as an adult. However, rates of smoking cessation have increased, and rates of nicotine addiction have decreased dramatically since the mid-1950s, suggesting that factors other than genetics are more important influences for tobacco use. In tobacco smoke or vaping aerosol, the fraction of nicotine pres­ ent in the unprotonated (freebase) form is greater at alkaline pH, and unprotonated nicotine is more easily absorbed into the bloodstream across the oral mucosa. However, high concentrations of unprotonated nicotine are irritating to the airway, reducing the tendency to inhale, limiting the amount of nicotine users will tolerate in the aerosol and slowing the rate of rise in nicotine blood levels. Products delivering nicotine that are highly addictive (cigarettes and aerosols of nicotine salts) are able to deliver high doses of nicotine and rapid rises in arterial blood concentration by producing aerosols that are mildly acidic in the mouth, reducing the irritation that inhibits inhalation. However, as the particles are inhaled into the lung, the pH of the smoke rapidly changes Per-capita consumption 18+ Male lung cancer death rate Female lung cancer death rate Per-capita consumption 18+ FIGURE 465-1  Changes in per-capita consumption and lung cancer death rates from 1900 to 2023. to the more alkaline pH of the blood (~7.4), increasing the fraction of readily absorbable unprotonated nicotine present in the alveoli. The high rate of blood flow through the alveoli rapidly removes the unpro­ tonated nicotine, increasing conversion of the protonated nicotine or the nicotine salt to release the unprotonated form and allowing most of the nicotine in the aerosol to be absorbed into the bloodstream. The resulting rapid rise in arterial blood nicotine levels reaching the brain makes cigarettes and nicotine salt vaping devices more addictive, and more able to satisfy addiction, compared with other forms of nicotine delivery. TRENDS IN NICOTINE PRODUCT USE Manufactured cigarettes have been the dominant form of nicotine exposure over the last 100 years. Figure 465-1 presents the rise and decline in U.S. per-capita consumption (total cigarettes sold divided by the U.S. population over age 18) since 1900, together with the rise and subsequent fall of the male and female lung cancer death rates resulting from that consumption. The figure demonstrates the enormous success of tobacco control efforts in changing a human risk behavior, with current adult cigarette smoking prevalence now approaching 10%. Among high school seniors, any cigarette use in the last 30 days has declined from 31% in 2000 to 2.9% in 2023, with only 0.7% smoking daily. As these post-2000 high school students aged into their 20s, their smoking initiation rates did not increase substantially, and only 5% of 18- to 24-year-old adults currently smoke. Unfortunately, smoking prevalence rates among those over age 40, the population more likely to develop disease, have declined more slowly. In addition, the population continuing to smoke has shifted heavily toward socially disadvantaged groups, indicating that the need for health care–based smoking inter­ ventions remains a priority. A vast array of devices to deliver nicotine without smoke have been introduced over the last decade. These include devices, many sold without U.S. Food and Drug Administration (FDA) approval, that aerosolize nicotine solution or nicotine salts, or deliver nicotine as strips or flavored nicotine pouches for oral use. With the exception of vaping, very limited data are available on patterns of use for most of these products in the United States. For vaping among adolescents, any use in the last 30 days peaked at about 25% in high school seniors in 2019 and declined to about 17% in 2023 with daily use at about 5.8% in 2023. The dramatic fall in combusted cigarette use over the past 2 decades among adolescents resulted from changes in the regulation of cigarette advertising and Lung cancer death rate per 100,000 Year the increasing social stigma associated with cigarette smoking. The introduction of vaping products as substitute sources of nicotine had little effect on the reduction in adolescent cigarette smoking, and the availability of vaping products has not increased adolescent smoking prevalence. For adults, about 5% report using e-cigarettes some days or every day, with 11% of the 18–24 group reporting at least some days. Rea­ sons for using e-cigarettes may include the following: for recreation, to sustain addiction, or to attempt to quit cigarette smoking. A substantial proportion of those using e-cigarettes for cessation report use of both e-cigarettes and combusted cigarettes interchangeably, called dual use. In contrast to the United States, tobacco consumption in many other countries remains high, particularly among lesser developed countries. Worldwide tobacco consumption recently declined slightly for the first time after a persistent rise over the recent decades. Changes in cost and relative rates of taxation for different tobacco products has resulted in an increase in smoking of cigars and “roll your own” cigarettes, but past recommendations about lower risk with use of cigars and pipe tobacco no longer apply. Most cigars are now manufac­ tured in much the same way as cigarettes with small changes in weight to qualify for lower tax rates, and most pipe tobacco is now used for “roll your own” cigarettes also because of lower tax rates. As a result, smok­ ing these products currently has risks similar to smoking manufactured cigarettes. Practitioners should ask about their use and should not rec­ ommend them as lower-risk forms of satisfying nicotine addiction. DISEASE MANIFESTATIONS OF CIGARETTE SMOKING Approximately 40% of cigarette smokers will die prematurely due to cigarette smoking unless they are able to quit. The major diseases caused by cigarette smoking are listed in Table 465-1. The ratio of smoking-related disease rates in smokers compared to never smokers (relative risk) increases with advancing age for most cancers and for chronic obstructive pulmonary disease (COPD). Relative risk declines with advancing age for cardiovascular diseases due to the increas­ ing contribution of other risk factors to cardiovascular disease as age advances. Nevertheless, even for cardiovascular disease, the absolute difference in mortality rate between smokers and never smokers, called excess death rate, continues to increase with advancing age, as one would expect from a process of cumulative injury. ■ ■CARDIOVASCULAR DISEASES Cigarette smokers are more likely than nonsmokers to develop both large-vessel atherosclerosis and small-vessel disease. Approximately 90% of peripheral vascular disease in the nondiabetic population can be attributed to cigarette smoking, as can ~50% of aortic aneurysms. In contrast, 24% of coronary artery disease and ~11% of ischemic and hemorrhagic strokes are attributed to cigarette smoking. There is a multiplicative interaction between cigarette smoking and other cardiac risk factors such that the increment in risk produced by smok­ ing among individuals with hypertension or elevated serum lipids is substantially greater than the increment in risk produced by smoking for individuals without these risk factors. In addition to its role in promoting atherosclerosis, cigarette smok­ ing also increases the likelihood of myocardial infarction and sudden cardiac death by promoting platelet aggregation and vascular occlu­ sion. Reversal of these effects on coagulation may explain the rapid benefit of smoking cessation for a new coronary event demonstrable among those who have survived a first myocardial infarction. This effect may also explain the substantially higher rates of graft occlusion among continuing smokers following vascular bypass surgery for cardiac or peripheral vascular disease. Cessation of cigarette smoking reduces the risk of a second coronary event within 6–12 months. Rates of first myocardial infarction and death from coronary heart disease decline within 2–4 years following cessation among those with no prior cardiovascular history. After 15 years of abstinence, the risk of stroke, a new myocardial infarction, and death from coronary heart disease in former smokers is similar to that for those who have never smoked. TABLE 465-1  Relative Risks for Current Smokers of Cigarettes AGE 35–44 45–64 65–74 ≥75 Males Lung cancer 14.33 19.03 28.29 22.51 Coronary heart disease 3.88 2.99 2.76 1.98 Cerebrovascular disease 2.17 1.48 1.23 1.12 Other vascular diseases     7.25 4.93 Chronic obstructive pulmonary disease (COPD)     29.69 23.01 All causes 2.55 2.97 3.02 2.40 Females Lung cancer 13.30 18.95 23.65 23.08 Other tobacco-related cancers 1.28 2.08 2.06 1.93 Coronary heart disease 4.98 3.25 3.29 2.25 CHAPTER 465 Cerebrovascular disease 2.27 1.70 1.24 1.10 Other vascular diseases     6.81 5.77 COPD     38.89 20.96 All causes 1.79 2.63 2.87 2.47 Relative Risks for Selected Other Cancers Nicotine Addiction Other cancers Male   Female   Larynx 14.6   Lip, oral cavity, pharynx 10.9   5.1   Esophagus 6.8   7.8   Bladder 3.3   2.2   Kidney 2.7   1.3   Pancreas 2.3   2.3   Stomach 1.4   Liver 1.7   1.7   Colorectal 1.2   1.2   Cervix     1.6   Acute myeloid leukemia 1.4   1.4   ■ ■CANCER Tobacco smoking causes cancer of the lung; lip; oral cavity; naso-, oro-, and hypopharynx; nasal cavity and paranasal sinuses; larynx; esophagus; stomach; pancreas; liver (hepatocellular); colon and rec­ tum; kidney (body and pelvis); ureter; urinary bladder; uterine cervix; and acute myeloid leukemia. There does not appear to be a causal link between cigarette smoking and cancer of the endometrium, and there is a lower risk of uterine cancer among postmenopausal women who smoke. The risks of cancer increase linearly with the increasing num­ ber of cigarettes smoked per day and logarithmically with increasing duration of smoking. Additionally, there are synergistic interactions between cigarette smoking and alcohol use for cancer of the oral cavity and esophagus. Several occupational exposures synergistically increase lung cancer risk among cigarette smokers, most notably occupational asbestos and radon exposure. Cessation of cigarette smoking reduces the risk of developing cancer relative to continuing smoking after about 4 years of abstinence, but even 20 years after cessation, there is a persistent three- to fourfold increased risk of developing lung cancer compared to those who have never smoked. ■ ■RESPIRATORY DISEASE Cigarette smoking is responsible for 80% of COPD. Within 1–2 years of beginning to smoke regularly, many young smokers will develop inflammatory changes in their small airways, although lung function measures of these changes do not predict subsequent development of chronic airflow obstruction. Chronic mucous hyperplasia of the larger airways results in a chronic productive cough in as many as 80% of smokers >60 years of age. Chronic inflammation and narrowing of the small airways, and/or enzymatic digestion of alveolar walls resulting in pulmonary emphysema, reduce expiratory airflow sufficiently to produce clinical symptoms of respiratory limitation in ~15–25% of smokers. Changes in the small airways of young smokers will reverse after 1–2 years of abstinence. There is also a small increase in measures of expiratory airflow following smoking cessation among many individu­ als who have already developed chronic airflow obstruction, but the major change following cessation is a slowing of the rate of decline in lung function with advancing age rather than a return of lung function toward normal. ■ ■PREGNANCY Cigarette smoking is associated with several maternal complications of pregnancy: premature rupture of membranes, abruptio placentae, and placenta previa. There is also a small increase in the risk of spontane­ ous abortion among smokers. Infants of smoking mothers are more likely to experience preterm delivery, have a higher perinatal mortality rate, be small for their gestational age, and have higher rates of infant respiratory distress syndrome. They are more likely to die of sudden infant death syndrome and appear to have a developmental lag for at least the first several years of life. Since it is likely that some of these pregnancy-related risks are caused or enhanced by nicotine, vaping and oral use of nicotine remain a concern in pregnancy except as a strategy to abstain from cigarette smoking. PART 13 Neurologic Disorders ■ ■OTHER CONDITIONS Smoking delays healing of peptic ulcers and increases the risk of devel­ oping periodontal disease, diabetes, active tuberculosis, rheumatoid arthritis, osteoporosis, senile cataracts, and neovascular and atrophic forms of macular degeneration. It results in premature menopause, wrinkling of the skin, gallstones, cholecystitis in women, and male impotence. Patients who continue to smoke during treatment for can­ cer with chemotherapy or radiation have poorer outcomes and reduced survival. ■ ■ENVIRONMENTAL TOBACCO SMOKE Long-term exposure to environmental tobacco smoke increases the risk of lung cancer and coronary artery disease among nonsmokers. It also increases the incidence of respiratory infections, chronic otitis media, and asthma in children, and it causes exacerbation of asthma in children. LOWER TAR AND NICOTINE CIGARETTES Filtered cigarettes with lower machine-measured yields of tar and nico­ tine commonly use ventilation holes in the filters and other engineer­ ing designs to artificially lower the machine measurements. Smokers compensate for the lowered nicotine delivery resulting from these design changes by changing the manner in which they puff on the ciga­ rette or the number of cigarettes smoked per day to restore their level of nicotine intake to that needed to satisfy their addiction. As a result, actual tar and nicotine deliveries to smokers are not reduced with use of these products, negating any reduction in disease risks from switch­ ing to these products. The amount of carcinogenic tobacco-specific nitrosamines in the tobacco used in cigarettes has increased over time, and cigarette design changes that reduce machine-measured tar and nicotine also lead to deeper inhalation of the smoke in the lung, presenting increased amounts of the more carcinogenic smoke to the alveolar portions of the lung. These changes increase the risk of adenocarcinoma of the lung above that produced by smoking older nonfiltered cigarettes. The changes in cigarette design and composition of cigarettes over the past six decades are the cause of the increase in rates of adenocarcinoma of the lung observed over the past half century, and the increased adeno­ carcinoma rate has increased total lung cancer rates, as there has not been a decline in the risk of other cell types with the changes in ciga­ rette design. An increased risk for COPD may also be present. There has been no increase in risk of all lung cancer or adenocarcinoma of the lung over the same period among never smokers. PHARMACOLOGIC INTERACTIONS Cigarette smoking may interact with a variety of other drugs. Cigarette smoking induces the cytochrome P450 system, which may alter the metabolic clearance of drugs such as warfarin. This may result in inad­ equate serum levels in smokers as outpatients when the dosage is estab­ lished in the hospital under nonsmoking conditions. Correspondingly, serum levels may rise when smokers are hospitalized and not allowed to smoke. Smokers may also have higher first-pass clearance for drugs such as lidocaine, and the stimulant effects of nicotine may reduce the effect of benzodiazepines or beta blockers. OTHER FORMS OF TOBACCO USE Other major forms of tobacco use are loose moist snuff or packets deposited between the cheek and gum and chewing tobacco. Oral tobacco use leads to gum disease and can result in oral and pancreatic cancer. There are dramatically higher risks evident for products used in Africa or Asia as, including for heart disease, compared to those used in the United States and Europe. NICOTINE AEROSOLS A continually expanding array of devices and oral formulations that deliver nicotine in quantities capable of creating and sustaining addic­ tion are available. Many of these devices deliver levels of nicotine comparable to a cigarette, and different concentrations of nicotine are often offered. Nicotine salt aerosols use mild acids to facilitate inhala­ tion of the aerosol and can deliver very high amounts of nicotine even with novice users, potentially enhancing their addictiveness compared to devices that deliver solutions of nicotine. Nicotine intake is higher for users of devices delivering nicotine salts, and they report a greater frequency of symptoms of dependence with abstinence. Biomarker evidence on exposure to smoke toxicants demonstrates markedly lower exposures among those using e-cigarettes exclusively compared to cigarette smokers, suggesting that they have less disease risk with use. However, both biomarker and behavioral evidence dem­ onstrate the capacity for these devices to create and sustain addiction. The long-term rates with which adults addicted to nicotine vaping quit nicotine completely or migrate to or relapse back to combusted prod­ uct use as they age remain to be determined. There is convincing randomized controlled cessation trial evi­ dence that the use of e-cigarettes that deliver sufficient nicotine are as effective as other nicotine-replacement or varenicline medications in achieving sustained abstinence from cigarettes, but a meaningful proportion of those who achieve abstinence still use e-cigarettes at 12-month follow-up, suggesting continued nicotine addiction. Rates of longer-term relapse back to smoking among individuals with persistent nicotine addiction remain to be examined. An additional concern is that evidence on e-cigarette use in the United States shows that approximately one-half of adult e-cigarette users continue to also smoke conventional cigarettes, negating the ben­ efits of reduced toxicant exposure and successful abstinence. Refillable or reloadable e-cigarette devices can be used to aerosolize a variety of liquids other than those provided by the manufacturer. Disposable “pods” and liquids for these devices can be purchased from the manufacturer but are also available from other sources that may use poor-quality manufacturing practices and control of contaminants. They may also contain marijuana oils, other drugs, and flavors not evaluated for potential lung injury with inhalation. CESSATION The process of stopping smoking is commonly a cyclical one, with the smoker sometimes making multiple attempts to quit, and failing, before finally being successful. Approximately 70–80% of smokers would like to quit smoking. More than one-half of current cigarette smokers attempted to quit in the last year, but only 6% quit for 6 months, and only 3% remain abstinent for 2 years. Clinician-based smoking interventions should repeatedly encourage smokers to try to quit and to use different forms of cessation assistance with each new cessation attempt. Advice from a clinician to quit smoking, particularly at the time of an acute illness, is a powerful trigger for cessation attempts, with up to half of patients who are advised to quit making a cessation effort. CLINICIAN INTERVENTIONS (TABLE 465-2) The shift in the nicotine market to products containing nicotine but not tobacco, and particularly to aerosolized nicotine salt products, has complicated provider diagnosis and treatment recommendations. Two considerations should guide this process. First, assessment of nicotine addiction should include the cumulative number of episodes of use for all nicotine products used regularly when considering the intensity of nicotine ingestion. This is important particularly when there is varia­ tion in the type of product used from day to day. Inquiries about cigar and roll your own use, as well as vaping and oral nicotine products, are necessary. It is the frequency of any nicotine dosing, not the product source, that creates and sustains addiction. Second, it is the other toxicants carried along with the nicotine that cause the majority of the disease risk, so eliminating the smoke intake can have benefits even in the presence of continued addiction to nicotine. All patients should be asked the total daily frequency with which they use any nicotine product, how long they have used at least one nicotine product regularly, their past experience with quitting, and whether they are currently interested in quitting. The goal is to identify whether the individual has a pattern of use that demonstrates a compulsive need for the next dose of nicotine. The number of episodes of smoking or vaping per day, how they are spaced during the day, as well as use of nicotine smoking within 30 min of waking are helpful measures of the intensity of nicotine addiction. Even those who are not interested in quitting should be encouraged and motivated to quit by providing a clear, strong, and personalized message by the clinician that smoking cigarettes is an important health concern and that vaping can be addicting. Those uninterested indi­ viduals should be told that assistance is available if they become inter­ ested in quitting in the future. Many of those not currently expressing an interest in quitting may nevertheless make an attempt to quit in the subsequent year. TABLE 465-2  Clinical Practice Guidelines Physician Actions Ask: Systematically identify all tobacco and nicotine use at every visit Advise: Strongly urge all smokers to quit Identify smokers willing to quit Assist the patient in quitting Arrange follow-up contact Effective Pharmacologic Interventionsa First-line therapies   Nicotine gum (1.5)   Nicotine patch (1.9)   Nicotine nasal inhaler (2.3)   Nicotine oral inhaler (2.1)   Nicotine lozenge (2 mg: 2.0, 4 mg: 2.8)   Bupropion (2.0)   Varenicline (3.1) Other Effective Interventionsa Physician or other medical personnel counseling (10 min) (1.84) Intensive group smoking cessation programs (at least 4–7 sessions of 20- to 30-min duration lasting at least 2 and preferably 8 weeks) (1.3) Intensive individual counseling (1.7) Systemwide cessation tracking and assistance (5) Telephone counseling (1.6) Exclusive E-cigarette use (3.0) aNumerical value following the intervention is the multiple for cessation success compared to no intervention. For those interested in quitting, a quit date should be negotiated, usually not the day of the visit but within the next few weeks. A followup contact by office staff around the time of the quit date should be provided. There is a relationship between the amount of assistance a patient is willing to accept and the success of the cessation attempt. Building smoking cessation as a priority into health care delivery systems by including systemwide tracking of smoking status, prompt­ ing of practitioners to ask about smoking and interest in cessation, system-based outreach to smokers to offer cessation assistance and programs between visits, and tracking of cessation outcomes can dramatically enhance sustained abstinence, with 12-month abstinence rates as high as 25%. There are a variety of cessation products listed in Table 465-2, including over-the-counter nicotine patches, gum, and lozenges, as well as nicotine nasal and oral inhalers available by prescription. These products can be used for up to 3–6 months, and some products are formulated to allow a gradual step-down in dosage with increasing duration of smoking abstinence. Antidepressants such as bupropion (300 mg in divided doses for up to 6 months) have also been shown to be effective, as has varenicline, a partial agonist for the nicotinic ace­ tylcholine receptor (initial dose 0.5 mg daily increasing to 1 mg twice daily at day 8; treatment duration up to 6 months). Combined use of nicotine-replacement therapy (NRT) and antidepressants, as well as the use of gum or lozenges for acute cravings in patients using patches, can increase cessation outcomes. CHAPTER 465 Nicotine Addiction Pretreatment with antidepressants or varenicline is recommended for 1–2 weeks prior to the quit date. Pretreatment with nicotine patches for 2 weeks prior to a cessation date is also useful. Longer duration of nicotine replacement as a maintenance therapy for those who are unsuccessful in quitting with a shorter duration of use is a useful strategy. NRT is provided in different dosages, with higher doses being recommended for more intense smokers. Antidepressants are more effective among smokers with a history of depression symptoms. Current recommendations are to offer pharmacologic treatment, usually with nicotine patches or varenicline, to all who will accept it, and to provide counseling and other support as a part of the cessation attempt. Cessation advice alone by clinicians or their staff is likely to increase success compared with no intervention, but a more compre­ hensive approach with advice, pharmacologic assistance, and counsel­ ing can increase cessation success nearly threefold. Data from multiple studies show that switching from cigarettes to exclusive use of e-cigarettes, particularly those with nicotine salts that deliver high doses of nicotine, is as or more effective in achieving smok­ ing abstinence compared to FDA-approved medications, and it may be more acceptable for some patients. It should be recommended only with a strong caution to avoid dual use. Dual use with combusted cigarettes is unlikely to lead to smoking cessation or long-term risk reduction. Current recommendations suggest that FDA-approved cessation methods be tried initially, with aerosolized nicotine salt products rec­ ommended to those who fail initial attempts to quit, are quitting on their own, or are reluctant to use FDA-approved medications. PREVENTION Prevention of smoking initiation must begin early, preferably in the elementary school years. Practitioners who treat adolescents should be sensitive to the prevalence of this problem even in the preteen popula­ tion. Practitioners should ask all adolescents whether they have experi­ mented with nicotine or currently use nicotine products, reinforce the fact that most adolescents and adults do not smoke or use nicotine, and explain that all forms of nicotine intake can be both addictive and potentially harmful. ■ ■FURTHER READING Christen SE et al: Pharmacokinetics and pharmacodynamics of inhaled nicotine salt and free-base using an e-cigarette: A random­ ized crossover study. Nicotine Tob Res 10:ntae074, 2024. Eisenberg MJ et al: Effect of e-cigarettes plus counseling vs counsel­ ing alone on smoking cessation: A randomized clinical trial. JAMA 324:1844, 2020. # 39 - 466 Cannabis and Cannabis Use Disorder ### 466 Cannabis and Cannabis Use Disorder Hajek P et al: A randomized trial of e-cigarettes versus nicotine- replacement therapy. N Engl J Med 380:629, 2019. Kaplan B et al: Effectiveness of ENDS, NRT and medication for smok­ ing cessation among cigarette-only users. Tob Control 32:302, 2023. Leone FT et al: Initiating pharmacologic treatment in tobacco-dependent adults. An official American Thoracic Society Clinical Practice Guideline. Am J Respir Crit Care Med 202:e5, 2020. Meza R et al: Trends in US adult smoking prevalence, 2011 to 2022. JAMA Health Forum 4:e234213, 2023. Royal College of Physicians: E-cigarettes and harm reduction: An evidence review. RCP, 2024. Available at https://www.rcplondon.ac.uk/ news/rcp-calls-regulations-protect-children-and-young-people-vaping. U.S. Department of Health and Human Services: The Health Consequences of Smoking: 50 Years of Progress. A Report of the Surgeon General. Atlanta, GA, 2014. Available at https://www.ncbi.nlm.nih. gov/books/NBK179276/pdf/Bookshelf_NBK179276.pdf. PART 13 Neurologic Disorders Nora D. Volkow, Aidan Hampson, Ruben Baler Cannabis and Cannabis Use Disorder Cannabis/marijuana is used by more than >150 million people world­ wide. The 2023 United States National Survey on Drug Use and Health, estimated that 42 million people used “marijuana” over the last month, while 62 million people used nicotine and 136 million drank alcohol (https://www.samhsa.gov/data/release/2023-national-survey-drug-useand-health-nsduh-releases). Notably in 2023, 10 million younger people (12-25 year olds) consumed marijuana each month, while 12 million used tobacco products. For reference, nearly 19 million 12-25 year olds used alcohol on a monthly basis. Since the Agriculture Improvement Act of 2018 (AIA; Public Law 115-334) amended the Controlled Substance Act, products made from Cannabis sativa species have been defined as marijuana when the plant or finished product contains >0.3% Δ-9-tetrahydrocannabinol (D9THC) by dry weight. Conversely, cannabis plant material, extracts, and derivatives that contain no more than 0.3% D9THC by dry weight are defined as “hemp.” We will be using the terms marijuana and can­ nabis interchangeably in this report since marijuana is the term used in multiple surveys, and in state and Federal laws. Marijuana is primarily grown for its euphoric and medicinal properties, which are principally mediated by D9THC acting on neuronal type 1 cannabinoid receptors (CB1R). The contribution of minor cannabinoids (including cannabi­ diol [CBD]) or terpenes is limited and largely unproven to be clinically relevant at concentrations found in marijuana. Marijuana remains federally illegal as of May 2024, but 24 states, 3 U.S. territories, and Washington, DC, have passed measures to legalize nonmedicinal (adult) use, whereas 38 states, 4 U.S. territories, and Washington, DC, have legalized medicinal cannabis use. Hemp varietals are federally legal to grow and manufacture into seed/oil products, fiber, or CBD extracts. Some varietals can contain >12% (w/w) of the nonintoxicat­ ing CBD, while the D9THC level remains within the definition of “hemp” (0.3%). High CBD hemp was first envisaged as a source for the treatment of childhood seizure disorders (Federal bill H.R. 5226, 2014). However, after hemp legalization, processors began to derivatize hemp into Δ-8-tetrahydrocannabinol (D8THC) and other intoxicat­ ing hemp products (IHPs). According to one recent survey, people who use D8THC report it to be milder than D9THC and perceive it to be legal. Pharmacologic studies support lower potency of D8THC than D9THC, but other IHPs such as tetrahydrocannabiphorol can be considerably more potent (20–30×). It is worth noting that the 2023 Monitoring the Future national survey found that 11% of 12th-grade U.S. students reported past-year D8THC use. Marijuana legalization has increased the demand for, and supply of, increasingly high D9THC-containing cannabis strains. Can­ nabis flower products now range from <0.3% in hemp to 20–30% in legal dispensary products. Further, extracts used as liquids in “vape pens” purportedly contain up to 75% D9THC, while adver­ tisements of solid extracts (e.g., “shatter”) containing up to 95% D9THC are not uncommon, although most of these claims appear to be exaggerated. Solid high-D9THC preparations are used for high-temperature vaporization (“dabbing”). Inhalation is a highly bioavailable (efficient) and rapid route of absorption for D9THC, so vaping products deliver high D9THC doses with rapid effect onset, conditions linked to increased risk of addiction. In contrast, edible D9THC-infused products (e.g., candies, cookies, and drinks) have slower rates of onset and are perceived to be associated with reduced harm. Edible products are less bioavailable than inhaled D9THC, but absorption can vary depending on the presence and nature of food in the stomach. Notably, “edibles” are favored by younger users and are associated with a higher probability of accidental dosing than inhaled products. PHARMACOLOGIC EFFECTS Cannabis is used recreationally because it enhances the subjective sense of well-being, provides rewarding sensations, and can dampen stress responses. However, consumption of high doses of D9THC can induce anxiety, paranoia, and panic. D9THC is primarily a par­ tial agonist (activator) of G protein–coupled cannabinoid receptors (CB1R and CB2R), with the euphorigenic effects mediated through CB1Rs primarily located on excitatory glutamatergic and inhibitory γ-aminobutyric acid (GABA)-ergic interneurons and glial cells in brain regions that process stress, mood, and reward. These receptors are the effectors of the endocannabinoid system (ECS), which is physi­ ologically activated by the endogenous ligands 2-arachidonoylglycerol (2-AG; a full agonist), and anandamide (a partial agonist). According to current understanding, 2-AG modulates synaptic signaling by inhib­ iting overstimulated synapses. Endocannabinoids are synthesized and eliminated on demand and thus provide a temporally and regionally specific modulatory signal. In contrast, the effect of intoxicating can­ nabinoids are defined by dose and their period of effect, not subtle “just in time” synaptic synthesis. Consequently exogenous cannabinoids disrupt important ECS neuroregulatory processes. The rewarding effects of D9THC are thought to be mediated by modulating glutamatergic and GABAergic activity in the midbrain ventral tegmental area (VTA), from where dopaminergic neurons project into the nucleus accumbens (NAc). In the NAc, rewarding experiences are reinforced (learned) by glutamatergic and dopaminer­ gic signal interactions. The anxiolytic effects of D9THC are mediated by its effects on the amygdala, a region critical for threat perception and emotional reactivity. CANNABIS PHARMACOKINETICS Smoking (e.g., joints and water pipes) remains the most common route of cannabis administration, but e-cigarette–type “vape pens” are increasingly being used. Vape pens use “e-liquid” concentrates, and the plasma concentrations achieved following their use depend on the e-liquid D9THC concentration and the “puffing profile.” The ability to take a single puff from a vape pen offers easier dose control than smoking. Vaping is perceived to be less harmful than smoking, but the long-term toxicology of e-liquids in humans is not yet clear. The subjective effects of cannabis are affected by dose, route of administration, (smoked, vaped, or ingested), and the subject’s prior experience (which also modulates expectation). Smoked D9THC exhib­ its a bioavailability of 10–35%, with interindividual differences stem­ ming from variations in the capacity to hold smoke in the lungs. The pharmacokinetics of heated (not burnt) cannabis flower and vaporized ethanolic extracts are similar to those of smoked flower, but no data are available to compare pharmacokinetics of smoked flower and commer­ cial e-liquids or solid concentrates. When cannabis is smoked, plasma D9THC concentrations become maximal within 5–10 min. After this time, plasma levels decrease with two phases governed by different elimination exponentials. There is an initial distribution phase with an (alpha) half-life (t1/2) of ~6 min, governed by absorption into lipophilic tissues (e.g., brain). During this alpha phase, brain concentrations continue to increase even as plasma levels fall, resulting in a hysteresis (lag) between changes in plasma concentration and pharmacodynamic effects. Subjective effects tend to be maximal at 20–30 min after smoking. The plasma beta t1/2 is approximately 1–2 h, and the total period of phar­ macodynamic effect ranges from 4 to 8 h. Elimination of D9THC occurs by conversion to 11-hydroxy-THC (pharmacologically active) and subsequent conversion to a long-lasting, but pharmacologically inactive, 11-norcarboxy THC metabolite (11-COOH-THC). It is this analyte that is detected during marijuana urinalysis. Terminal elimina­ tion of 11-norcarboxy-THC exhibits a t1/2 ranging from 20 to 35+ h, so THC use remains detectable for days in those who use occasionally and for weeks in those who use frequently and with saturated fat stores. Regular D9THC use results in tolerance to its pharmacologic effects, so a given D9THC plasma concentration may not correlate to similar impairment levels in those using occasionally versus regularly. This chal­ lenge in correlating D9THC levels in biological matrices with behavioral effects has hampered efforts to regulate marijuana-impaired driving. Orally consumed cannabis products (edibles and drinks) typically exhibit slower effect onset than smoked/vaped D9THC. This is partly due to stomach residence time but mainly because lipophilic cannabinoids are poorly absorbed through the water/mucus-rich layer of the intestine. The comparatively slower rate of oral cannabinoid absorption means that no hysteresis is observed, unlike after inhalation. Orally administered D9THC is extensively metabolized by intestinal and hepatic cytochromes (first-pass metabolism), so bioavailability ranges from 5 to 6% (compared to 30+% when smoked). However, when consumed with fatty foods, can­ nabinoids can exhibit 200–400% increased bioavailability because fatty foods (or pharmaceutical triglyceride vehicles) stimulate bile release. This emulsifies fat-associated cannabinoids, thus increasing the surface area for absorption into portal blood and stimulating absorption by enterocytes, which secrete into lymphatic lacteals. This allows a portion of fat-dissolved cannabinoids to bypass hepatic elimination, increasing bio­ availability. However, lymphatic flow is slower than blood, so while lym­ phatically transported D9THC exhibits higher bioavailability, it also has a slower effect onset. In summary, depending on the edible product design or the consumer’s feeding status, D9THC bioavailability and onset time can vary greatly. This unpredictability can complicate efforts to determine a precise dose and presents a potential overdose risk for the unwary. HARMFUL EFFECTS The frequency and severity of cannabis adverse effects are influenced by dose, frequency of use, route of administration, and the individual’s health, age, and genetic background. Especially concerning are the potential negative effects of cannabis on the brain during early life stages. Perturbation of ECS signaling during early fetal development affects neuronal development, migration, and connectivity. A recent animal study found that deficiencies in vital fatty acids like docosa­ hexaenoic acid could help explain the association between intrauterine exposure to D9THC and lifelong health disturbances in the offspring, including cognitive and memory impairments. The relevant human studies, which are few and confounded by the frequent use of other drugs, provide substantial evidence of lower birth weight and suggest an association between maternal marijuana use and fetal growth and preterm delivery. In addition, early results from the Adolescent Brain and Child Development (ABCD) study, a longitudinal neuroim­ aging, behavioral, and genetic study of close to 12,000 children in the United States, provide some evidence that exposure to cannabis during pregnancy can increase intracranial volumes and blunt development of visuospatial processing. Another analysis of the same cohort also found small but significant effects on white matter integrity during childhood, especially in the fornix, which has been implicated in the processing of emotions and memory. Not surprisingly, the American College of Obstetricians and Gynecologists recommends discouraging use of marijuana by women who are pregnant or planning a pregnancy. Children and adolescents are also more vulnerable to the harmful effects of cannabis, the use of which increases markedly during adoles­ cence and has been associated with lower grades, lower IQ, and higher risk of dropping out of school, although a causal relationship cannot yet be established. Brain imaging studies have revealed that use of cannabis at this stage is associated with structural and functional brain changes (not always replicated) often in the form of reduced brain connectivity and cortical thickness. Though it is not clear whether these are caused by early exposure to cannabis, research in 799 adolescents in Europe found a negative, dose-dependent correlation between self-reported cannabis use at age 14 and prefrontal cortex thickness at age 19, sug­ gesting that cannabis use in middle to late adolescence may alter corti­ cal development. Moreover, recent results from the ABCD study are consistent with the notion that preadolescence exposure to cannabis may contribute to lower scores on an episodic memory task and that more cannabis use may lead to poorer performances on verbal, inhibi­ tory, working memory, and episodic memory tasks. CHAPTER 466 In 2019–2020, a syndrome known as e-cigarette or vaping product use-associated lung injury (EVALI) was observed. It became associated with vitamin E acetate, a thickening agent used to dilute black-market marijuana e-liquids. Once known, EVALI incidents diminished as this unapproved agent disappeared from use. Cannabis and Cannabis Use Disorder CANNABIS USE DISORDER Repeated cannabis use, especially during adolescence, can result in can­ nabis use disorder (CUD), which the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, defines as “a problematic pattern of cannabis use leading to clinically significant impairment or distress.” The diagnostic criteria for a use disorder include drug craving, toler­ ance to effects, a withdrawal syndrome, and failure to fulfill role obliga­ tions due to recurrent use and drug seeking. The risk of CUD increases with earlier age of initiation, frequency of use, and exposure to canna­ bis with high THC content. Several studies have found a broad reduc­ tion in cannabinoid receptors in the brains of people who use cannabis when compared to control participants who do not use cannabis, but receptor density recovers rapidly, returning to values similar to those of control participants within 28 days of abstinence. In people who use cannabis regularly, abstinence results in a withdrawal syndrome that peaks within 1–3 days of drug discontinuation and manifests as anxiety, restlessness, insomnia, depression, and reduced appetite. Many of these symptoms resolve within approximately 2 weeks of discontinu­ ation. Insomnia often persists longer and may contribute to relapse, although the degree to which this represents withdrawal rather than cannabis use to self-medicate disordered sleep is unclear. ■ ■PREVENTION Preventing cannabis use during adolescence reduces the risk for CUD and the risk of other substance use disorders. There are several evidencebased prevention strategies focused on children and adolescents that have shown benefits in decreasing cannabis use during adolescence or in delaying its age of initiation. Such prevention interventions can target the individual (e.g., Keepin’ It Real, Life Skills, InShape), the family (e.g., Brief Strategic Family Therapy, Coping Power Program [CPP], Familia Adelante), or the community (e.g., The Abecedarian Project, Midwest­ ern Prevention Project, Caring School Community). School-based prevention programs are the most widely implemented. Evidence from randomized controlled trials, prospective cohort trials, and longitudinal studies all demonstrate that comprehensive interventions that include antidrug information with refusal skills, self-management skills, and social skills training provide the most effective approaches for long-term reduction of cannabis (and alcohol) use in adolescents. ■ ■TREATMENT The treatment of CUD involves tapering cannabis use and providing psychosocial support to alleviate withdrawal symptoms. There are cur­ rently no U.S. Food and Drug Administration (FDA)-approved medi­ cations for CUD. There is evidence of effectiveness of several behavioral interventions as CUD treatments. Contingency management is an effective therapeutic and combined motivational enhancement, and # 40 - 467 Opioid-Related Disorders ### 467 Opioid-Related Disorders cognitive behavioral techniques have also shown clinically significant improvements in abstinence and reduced cannabis use. OTHER ADVERSE EFFECTS ■ ■MENTAL ILLNESS The association between marijuana use and increased risk of mental illnesses is an area of major concern. The risk of psychosis increases with the frequent consumption of high-THC-content cannabis (>10% THC). Even upon first exposure, high-potency cannabis can trigger acute psychotic episodes, which constitute one of the main causes for emergency department (ED) visits associated with cannabis use. Most of these psychotic episodes are transient but can become chronic with regular cannabis use. In those vulnerable, cannabis may trigger or exac­ erbate the presentation of schizophrenia. Many earlier studies (though not all) have linked adolescent cannabis use with higher risk and earlier onset of chronic psychosis, particularly for those using cannabis at higher frequency or with higher D9THC content. A large recent study showed a stronger association between cannabis use during adoles­ cence and risk of psychotic disorder than that documented in previous studies, consistent with the rise in cannabis potency. Concerns have also been raised regarding cannabis use during adolescence and a higher risk for depression and suicidality, though these associations have been much less studied. PART 13 Neurologic Disorders ■ ■ACCIDENTS Cannabis use increases the risk of injuries when driving under its influence. D9THC impairs judgment, motor coordination, and reac­ tion time, all necessary for safe driving. Studies have found a direct relationship between blood D9THC levels and impaired driving ability. ■ ■ACUTE AND CHRONIC TOXICITY The increased availability of high-D9THC-content products over the past decade has been paralleled by increased marijuana-related ED vis­ its and hospital admissions. Such emergencies can be caused by acute toxicity and chronic use syndromes. Cannabis edibles are involved in a significant portion of acute cannabis toxicity events. Patients include children accidentally consuming sweet edibles and infrequent users such as “cannabis tourists” with limited experience of the consumed products or the longer onset time of edible products. Actual D9THC dose is difficult to envisage, for both edible or inhaled products, so naïve or infrequent users are at increased risk of overdosing. Can­ nabis toxicity is frequently manifested by severe anxiety, tachycardia, and even acute psychoses. Chronic high-dose cannabis use can also induce a cannabis hyperemesis syndrome (presenting as severe cycles of nausea, vomiting, and abdominal pain), a growing cause for ED and hospital admissions. THERAPEUTIC POTENTIAL Currently, no FDA-approved medications contain cannabis-derived THC, although synthetic D9THC (or dronabinol) is approved for treatment of chemotherapy-induced nausea and appetite stimulation. Several countries have approved the cannabis-derived D9THC:CBD formulation Sativex for treating chronic pain and multiple sclerosis (MS)-induced spasticity. However, evidence of Sativex efficacy in MS is largely based on patient reports. Chronic pain is one of the most frequent indications for which medical marijuana is used. A recent analysis of data from the New York prescription drug monitoring data­ base, from the years 2017-2019, revealed that chronic pain patients on long-term stable doses of opioid therapy (n >8000) who used medical marijuana for >8 months (compared to those who used medical marijuana for <30 days to 8 months) had a 30–50% reduction in opioid use. ■ ■FURTHER READING Albaugh MD et al: Association of cannabis use during adolescence with neurodevelopment. JAMA Psychiat 78:1, 2021. Evanski JM et al: The first “hit” to the endocannabinoid system? Associations between prenatal cannabis exposure and frontolimbic white matter pathways in children. Biol Psychiatry Glob Open Sci 4:11, 2024. Hagler DJ Jr et al: Image processing and analysis methods for the Adolescent Brain Cognitive Development Study. Neuroimage 202:116091, 2019. Hiraoka D et al: Effects of prenatal cannabis exposure on devel­ opmental trajectory of cognitive ability and brain volumes in the Adolescent Brain Cognitive Development (ABCD) Study. Dev Cogn Neurosci 60:101209, 2023. McDonald AJ et al: Age-dependent association of cannabis use with risk of psychotic disorder. Psychol Med 22:1, 2024. National Survey on Drug Use and Health: Substance Use and Mental Health Services Administration, 2023. https://www.samhsa.gov/data/ release/2023-national-survey-drug-use-and-health-nsduh-releases. Sarikahya MH et al: Prenatal THC exposure induces long-term, sex-dependent cognitive dysfunction associated with lipidomic and neuronal pathology in the prefrontal cortex-hippocampal network. Mol Psychiat 28:4234, 2023. Schwabe AL et al: Uncomfortably high: Testing reveals inflated THC potency on retail cannabis labels. PLoS One 18:e0282396, 2023. Volkow ND et al: Don’t worry, be happy: Endocannabinoids and can­ nabis at the intersection of stress and reward. Annu Rev Pharmacol Toxicol 57:285, 2017. Wade NE et al: Cannabis use and neurocognitive performance at 13-14 years-old: Optimizing assessment with hair toxicology in the Adolescent Brain Cognitive Development (ABCD) Study. Addict Behav 150:107930, 2024. Thomas R. Kosten, Colin N. Haile Opioid-Related Disorders Opioid analgesics have been used since at least 300 b.c. Nepenthe (Greek for “free from sorrow”) helped the hero of the Odyssey, but widespread opium smoking in China and the Near East has caused harm for centuries. Since the first chemical isolation of opium and codeine 200 years ago, a wide range of synthetic opioids have been developed, and opioid receptors were cloned in the 1990s. Two of the most important adverse effects of all these agents are the development of opioid use disorder and overdose. Prescription opioids are primarily used for pain management, but due to ease of availability individuals procure and misuse these drugs with dire consequences. In 2022, for example, 8.9 million United States residents misused pain relievers and >76,000 overdose deaths involved opioids, nearly half combined with stimulants. These numbers continue to increase and have accelerated due to mixing of high-potency fentanyl derivatives with other opioids and stimulants. The accelerating death rates are partially because rever­ sal of fentanyl overdoses can require severalfold larger doses of nalox­ one than the doses in the intranasal devices used for nonmedical street resuscitations. Fentanyl-associated deaths also increased during the COVID-19 pandemic. The World Drug Report attributes the greatest global burden of morbidity and mortality to opioid misuse, including disease transmission, increased health care, crime, law enforcement, family distress, and lost productivity. The terms dependence and addiction have been replaced with opioid use disorder, opioid intoxication, and opioid withdrawal. Opioid use disorder is defined in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5; 2022) as the repeated use of the opiate during a 12-month period while producing problems in two or more areas including tolerance, withdrawal, use of greater amounts of opioids than intended, craving, and use despite adverse consequences. This new definition reduces the diagnostic criteria from three problem areas to two, but this reduction has not changed the rates of these disorders because most opioid-using individuals meet more than three criteria. A striking recent aspect of illicit opioid use has been its marked increase as the gateway to illicit drugs in the United States. Since 2007, prescription opiates have surpassed marijuana as the most common illicit drug that adolescents initially use, although overall rates of opi­ oid use are far lower than marijuana. The most used opioids had been diverted prescriptions for oxycodone and hydrocodone until about 2015, when fentanyl misuse and lethal overdose rose exponentially. Two opi­ oid maintenance treatment agents—methadone and buprenorphine— are also misused, but at substantially lower rates, and the partial opioid agonists such as butorphanol, tramadol, and pentazocine are misused even less frequently. Because the chemistry and general pharmacology of these agents are covered in major pharmacology texts, this chapter focuses on neurobiology and pharmacology relevant to opioid use disor­ der and its treatments. Although the neurobiology of misuse involves all four of the known opioid receptors—mu, kappa, delta, and nociceptin/ orphanin—the mu receptor is the most clinically related to opioids. ■ ■NEUROBIOLOGY After binding to mu opioid receptors, opioids downregulate intracel­ lular messenger systems and activate potassium ion channels, as sum­ marized in Table 467-1. All opioid receptors are G protein–linked and coupled to the cyclic adenosine monophosphate (cAMP) second mes­ senger system and to G protein–coupled inwardly rectifying potassium channels (GIRKs). The GIRKs increase permeability to potassium ions, causing hyperpolarization and inhibiting action potential production. Thus, opioids inhibit the activity of all neurons with opioid receptors and induce analgesia, sedation, and drug reinforcement through vari­ ous brain pathways. Relevant pathways for the reinforcing euphoric effects of opioids include the mesolimbic dopaminergic pathway from the ventral teg­ mental area (VTA) to the nucleus accumbens (NAc), where opioids indirectly increase synaptic levels of dopamine through inhibition of GABAergic neurons that inhibit both the VTA and the NAc. The positive subjective effects of opioid drugs also include mu receptor desensitization and internalization, potentially related to stimulation of β-arrestin signaling pathways. However, the “high” only occurs when the rate of change in dopamine is fast. Large, rapidly administered doses of opioids block γ-aminobutyric acid (GABA) inhibition and produce a burst of VTA dopamine neuron activity that is associated with a “high” in commonly misused substances. Therefore, routes of administration that slowly increase opioid blood and brain levels, such as oral and transdermal routes, are effective for analgesia and sedation but do not produce an opioid “high” that follows smoking and intra­ venous routes. Other acute effects such as analgesia and respiratory β-endorphin enkephalins K+ µ µ Na+ Na+ Gi/o Gi/o AC Nucleus Nucleus PKA PKA BDNF BDNF TH TH cAMP cAMP CREB CREB A B FIGURE 467-1  Normal mu-receptor activation by endogenous opioids inhibits the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA)-cAMP responseelement binding protein (CREB) cascade in noradrenergic neurons within the locus coeruleus (A) through inhibitory Gi/o protein influence on adenylyl cyclase (AC). Similarly, acute exposure to opioids (e.g., morphine) inhibits this system, whereas chronic exposure to opiates (B) leads to upregulation of the cAMP pathway in an attempt to oppose opioid-induced inhibitory influence. Upregulation of this system is involved in opioid tolerance, and when the opioid is removed, unopposed noradrenergic neurotransmission is involved in opioid withdrawal. Upregulated PKA phosphorylates CREB, initiating the expression of various genes such as tyrosine hydroxylase (TH) and brain-derived neurotrophic factor (BDNF). BDNF is implicated in long-term neuroplastic changes in response to chronic opioids. TABLE 467-1  Actions of Opioid Receptors RECEPTOR TYPE ACTIONS Mu (μ) (e.g., morphine, buprenorphine) Analgesia, reinforcement euphoria, cough and appetite suppression, decreased respirations, decreased GI motility, sedation, hormone changes, dopamine and acetylcholine release Dysphoria, decreased GI motility, decreased appetite, decreased respiration, psychotic symptoms, sedation, diuresis, analgesia Kappa (κ) (e.g., butorphanol) Analgesia, euphoria, physical dependence, hormone changes, appetite suppression, dopamine release Delta (δ) (e.g., etorphine) Nociceptin/orphanin (e.g., buprenorphine) Analgesia, appetite, anxiety, tolerance to opioids, hypotension, decreased GI motility, 5-HT and NE release Abbreviations: GI, gastrointestinal; 5-HT, serotonin; NE, norepinephrine. CHAPTER 467 depression involve opioid receptors located in other brain areas such as the periaqueductal grey for pain and medulla oblongata for respiration. Opioid tolerance and withdrawal are related to genetic polymor­ phisms that impact several proteins and that after chronic opioid dos­ ing affect the functioning of the cAMP–protein kinase A (PKA)–cAMP response-element binding protein (CREB) intracellular cascade within the locus coeruleus (LC) (Fig. 467-1). Up to 50% of the risk for with­ drawal is related to specific functional polymorphisms including one in the mu opioid receptor gene producing a threefold increase in this receptor’s affinity for opioids and the endogenous ligand β-endorphin. Epigenetic DNA methylation changes in the mu receptor gene also appear to act as compensation by inhibiting gene transcription and reducing the number of mu receptors. Opioid-Related Disorders After chronic opioid dosing and its sustained inhibition of the cAMP molecular cascade as shown in Fig. 467-1, a compensation occurs in this cascade within the LC neurons that mediate opioid toler­ ance and withdrawal. Noradrenergic (NE) neurons in the LC activate the cerebral cortex. When large opioid doses saturate and activate all of the LC’s mu receptors, action potentials cease. When this direct inhibi­ tory effect is sustained over weeks and months of opioid use, a second­ ary set of adaptive changes occur to upregulate cyclic AMP enzyme activity. When the inhibiting opioid is abruptly discontinued, overac­ tivity occurs in NE neurons of the LC that contribute to withdrawal symptoms (Fig. 467-1). This molecular model of NE neuronal activa­ tion during withdrawal has had important treatment implications, such as the use of the presynaptic α2-agonists clonidine and lofexidine to treat opioid withdrawal by again suppressing NE neuronal activation Morphine HO H H O N CH3 K+ HO Modified gene expression, neuroplasticity, genetic effects AC through feedback inhibition of this neuronal activity. Other contribu­ tors to withdrawal include deficits within the dopamine reward system and overactive neurotransmission within the glutamatergic system. ■ ■PHARMACOLOGY Tolerance and withdrawal commonly occur with chronic daily use, developing as quickly as 6–8 weeks depending on dose concentration and dosing frequency. Tolerance is primarily pharmacodynamic with relatively limited induction of cytochrome P450 2D6 and 3A4 or other liver enzymes. Metabolism then includes conjugation to glucuronic acid and excretion of small amounts in feces. The plasma half-lives generally range from 2.5 to 3 h for morphine and >22 h for methadone. The shortest half-lives of several minutes are for fentanyl-related opi­ oids, and the longest are for buprenorphine and its active metabolites, which can block opioid withdrawal for up to 3 days after a single dose. Tolerance to opioids leads to the need for increasing amounts of drugs to sustain the desired euphoric effects—as well as to avoid the discom­ fort of withdrawal. This combination has the expected consequence of strongly reinforcing misuse once it has started. Methadone taken chronically at maintenance doses is stored in the liver, which may reduce the occurrence of withdrawal between daily doses. The role of endogenous opioid peptides in tolerance and withdrawal is uncertain. PART 13 Neurologic Disorders The clinical features of opioid misuse are tied to the route of admin­ istration and rapidity of the drug reaching the brain. Intravenous and smoked administration rapidly produces high drug concentrations in the brain. This produces a “rush,” followed by euphoria, a feeling of tranquility, and sleepiness (“the nod”). Heroin produces effects that last 3–5 h, and several doses a day are required to forestall manifestations of withdrawal in chronic users. Symptoms of opioid withdrawal begin 8–10 h after the last dose; lacrimation, rhinorrhea, yawning, and sweat­ ing appear first. Restless sleep followed by weakness, chills, gooseflesh (“cold turkey”), nausea and vomiting, muscle aches, involuntary move­ ments (“kicking the habit”), hyperpnea, hyperthermia, and hyperten­ sion occur in later stages of the withdrawal syndrome. The acute course of withdrawal may last 7–10 days. A secondary phase of protracted abstinence lasts for 26–30 weeks and is characterized by hypotension, bradycardia, hypothermia, mydriasis, and decreased responsiveness of the respiratory center to carbon dioxide. Besides the brain effects of opioids on sedation and euphoria and the combined brain and peripheral nervous system effects on analgesia, a wide range of other organs can be affected. The release of several pitu­ itary hormones is inhibited, including corticotropin-releasing factor (CRF) and luteinizing hormone, which reduces levels of cortisol and sex hormones and can lead to impaired stress responses and reduced libido. An increase in prolactin also contributes to the reduced sex drive in males. Two other hormones affected are thyrotropin, which is reduced, and growth hormone, which is increased. Respiratory depres­ sion results from opioid-induced insensitivity of brainstem neurons to increases in carbon dioxide, and in patients with pulmonary disease, this can result in clinically significant complications. In overdoses, aspiration pneumonia is common due to loss of the gag reflex. Opioids reduce gut motility, which is helpful for treating diarrhea but can lead to nausea, constipation, and anorexia with weight loss. Deaths occurred in early methadone maintenance programs due to severe constipa­ tion and toxic megacolon. Opioids such as methadone may prolong QT intervals and lead to sudden death in some patients. Orthostatic hypotension may occur due to histamine release and peripheral blood vessel dilation, which is an opioid effect usefully applied to managing acute myocardial infarction. During opioid maintenance, interactions with other medications are of concern; these include inducers of the cytochrome P450 system (usually CYP3A4) such as rifampin and carbamazepine. Heroin users, in particular, tend to use opioids intravenously and are likely to be polydrug users, also using alcohol, sedatives, cannabinoids, and stimulants. None of these other drugs are substitutes for opioids, but they have desired additive effects. Therefore, one needs to be sure that the person undergoing a withdrawal reaction is not also withdraw­ ing from alcohol or sedatives, which might be more dangerous and more difficult to manage. Intravenous opioid use carries with it the risk of serious compli­ cations. The common sharing of hypodermic syringes can lead to infections with hepatitis B and HIV/AIDS, among others. Bacte­ rial infections can lead to septic complications such as meningitis, osteomyelitis, and abscesses in various organs. Off-target effects or additions of other agents to opioids synthesized in illicit drug labs can lead to serious toxicity. For example, attempts to illicitly manufacture meperidine in the 1980s produced a parkinsonism-inducing neuro­ toxin, MPTP (Chap. 446). More recently, adding xylazine to illicit fentanyl markedly increased fentanyl’s respiratory suppression, leading to overdose deaths. Individuals who inject fentanyl and xylazine also can develop necrosis and have an increased risk of limb amputation. TREATMENT Opioid Overdose The acute treatment of opioid overdose with naloxone or nalmefene is a medical emergency, and after reversal of that life-threatening complication, clinicians have two general treatment options: opioid maintenance or detoxification. Opioid agonist and partial agonist medications are commonly used for both maintenance and detoxi­ fication purposes. α2-Adrenergic agonists are primarily used for detoxification. Antagonists are used to accelerate detoxification and then continued after detoxification to prevent relapse. The residential medication-free programs have had some success but generally less than the medication-based programs. Success of the various treatment approaches is assessed as retention in treatment and reduced opioid and other drug use; secondary outcomes, such as reduced HIV risk behaviors, crime, psychiatric symptoms, medi­ cal comorbidity, and overdoses, also indicate successful treatment. Potentially lethal overdoses require rapid recognition and treat­ ment with naloxone or nalmefene, two highly specific reversal agents that are relatively free of complications. The diagnosis is based on recognition of characteristic signs and symptoms, includ­ ing shallow and slow respirations, pupillary miosis (mydriasis does not occur until significant brain anoxia supervenes), bradycardia, hypothermia, and stupor or coma. Blood or urine toxicology stud­ ies can confirm a suspected diagnosis, but immediate management must be based on clinical criteria. If naloxone is not administered, progression to respiratory and cardiovascular collapse leading to death occurs. With fentanyl overdoses, the naloxone dose may be twice that needed for other opioids, and recent rescue preparations contain twice the traditional dosing. Additionally, nalmefene has recently become available for treatment of overdose and has higher potency and lasts longer than naloxone. Opioids generally do not produce seizures except for unusual cases of polydrug use with the opioid meperidine, with high doses of tramadol, or in the newborn. In addition to naloxone, management of overdose requires sup­ port of vital functions, including intubation if needed (Table 467-2). If the overdose is due to buprenorphine or fentanyl, then naloxone might be required at total doses of 10 mg or greater, but primary buprenorphine overdose is nearly impossible because this agent is a partial opioid agonist, meaning that as the dose of buprenorphine is increased, it has greater opioid antagonist than agonist activity. Thus, a 0.2-mg buprenorphine dose leads to analgesia and seda­ tion, while a hundred times greater 20-mg dose produces profound TABLE 467-2  Management of Opioid Overdose Establish airway. Intubation and mechanical ventilation may be necessary. Naloxone 0.4–2.0 mg (IV, IM, or endotracheal tube). Onset of action with IV is ~1–2 min. Repeat doses of naloxone if needed to restore adequate respiration or a continuous infusion of naloxone can be used. One-half to two-thirds of the initial naloxone dose that reversed the respiratory depression is administered on an hourly basis (note: naloxone dosing is not necessary if the patient has been intubated). opioid antagonism, precipitating opioid withdrawal in a person who had opioid use disorder from morphine or methadone. It is important to recognize that the goal is to reverse respiratory depres­ sion and not to administer so much naloxone that it precipitates opiate withdrawal. Because naloxone only lasts a few hours and most opioids last considerably longer, an IV naloxone drip with close monitoring is frequently employed to provide a continuous level of antagonism for 24–72 h depending on the opioid used in the overdose (e.g., morphine vs methadone). Whenever nalox­ one has only a limited effect, other sedative drugs that produce significant overdoses must be considered. The most common are benzodiazepines, which have produced overdoses and deaths in combination with buprenorphine. A specific antagonist for benzo­ diazepines, flumazenil at 0.2 mg/min can rapidly reverse overdoses, but it may precipitate seizures and increase intracranial pressure. Like naloxone, administration for a prolonged period is usually required because most benzodiazepines remain active for consider­ ably longer than flumazenil. Support of vital functions may include oxygen and positive-pressure breathing, IV fluids, pressor agents for hypotension, and cardiac monitoring to detect QT prolongation, which might require specific treatment. Activated charcoal and gas­ tric lavage may be helpful for oral ingestions, but intubation will be needed if the patient is stuporous. OPIOID WITHDRAWAL The principles of detoxification are the same for all drugs: to sub­ stitute a longer-acting, orally active, pharmacologically equivalent medication for the substance being used, stabilize the patient on that medication, and then gradually withdraw the substituted medication. Methadone and buprenorphine are the two principal medications used to treat opioid use disorder. Clonidine, a centrally acting sympatholytic agent, has also been used for detoxification in the United States. By reducing central sympathetic outflow, clonidine mitigates many of the signs of sympathetic overactivity but typically requires augmentation with other agents. Clonidine has no narcotic action and is not addictive. Lofexidine, a clonidine analogue with fewer hypotensive effects, was approved for use in the United States in 2018 for management of opioid withdrawal symptomology. Methadone for Detoxification  Dose-tapering regimens for detox­ ification using methadone range from 2–3 weeks to as long as 180 days, but this approach is controversial given the relative effectiveness of methadone maintenance and the low success rates of detoxification. Unfortunately, most patients tend to relapse to heroin or other opioids during or after the detoxification period, indicative of the chronic and relapsing nature of opioid use disorder. Buprenorphine for Detoxification  Buprenorphine does not appear to lead to better outcomes than methadone but is superior to cloni­ dine in reducing symptoms of withdrawal, in retaining patients in a withdrawal protocol, and in completing treatment, although it can precipitate withdrawal in patients dependent on fentanyl or on maintenance doses of methadone (>80 mg daily). `2-Adrenergic Agonists for Detoxification  Several α2-adrenergic agonists have relieved opioid withdrawal by suppressing brain NE hyperactivity. Clonidine relieves some signs and symptoms of opi­ oid withdrawal such as lacrimation, rhinorrhea, muscle pain, joint pain, restlessness, and gastrointestinal symptoms. Related agents are lofexidine, guanfacine, and guanabenz acetate. Lofexidine can be dosed up to ~2 mg/d and appears to be associated with fewer adverse effects. Clonidine or lofexidine is typically administered orally, in three or four doses per day, with dizziness, sedation, leth­ argy, and dry mouth as the primary adverse side effects. Outpatientmanaged withdrawal regimens require close follow-up, often with naltrexone maintenance to prevent relapse. Rapid and Ultrarapid Opioid Detoxification  The opioid antago­ nist naltrexone, typically combined with an α2-adrenergic agonist, has been purported to shorten the duration of withdrawal without significantly increasing patient discomfort. Completion rates using naltrexone and clonidine range from 75 to 81% compared to 40 to 65% for methadone or clonidine alone. Ultrarapid opioid detoxi­ fication is an extension of this approach using anesthetics but is highly controversial due to the medical risks and mortality associ­ ated with it. Medications for Preventing Relapse to Illicit Opioids  Stopping opioid use is much easier than preventing relapse. Long-term relapse prevention for individuals with opioid use disorder requires combined pharmacologic and psychosocial approaches. Chronic users tend to prefer pharmacologic approaches; those with shorter histories of drug use are more amenable to detoxification and psychosocial interventions. Methadone maintenance substitutes a once-daily oral opioid dose for three to four times daily heroin. Methadone saturates the opioid receptors and, by inducing a high level of opioid tolerance, blocks the euphoria from additional opioids. Buprenorphine, a partial opioid agonist, also can be given once daily at sublingual doses of 4–32 mg daily, and in contrast to methadone, it can be given in an office-based primary care setting. CHAPTER 467 Opioid-Related Disorders METHADONE MAINTENANCE  Methadone’s slow onset of action when taken orally, long elimination half-life (24–36 h), and production of cross-tolerance at doses from 80 to 150 mg are the basis for its efficacy in treatment retention and reductions in IV drug use, criminal activ­ ity, and HIV risk behaviors and mortality. Methadone can prolong the QT interval at rates as high as 16% above rates in non-methadonemaintained, drug-injecting patients, but it has been used safely in the treatment of opioid use disorder for >40 years. BUPRENORPHINE MAINTENANCE  Sublingual buprenorphine main­ tenance was first approved by the U.S. Food and Drug Administration (FDA) in 2002 as a Schedule III drug for managing opioid use disorder. Unlike the full agonist methadone, buprenorphine is a partial agonist of mu-opioid receptors with a slow onset and long duration of action. Its partial agonism reduces the risk of unintentional overdose but lim­ its its efficacy to patients who need the equivalent of only 60–70 mg of methadone, and many patients in methadone maintenance require higher doses of up to 150 mg daily. Buprenorphine is combined with naloxone at a 4:1 ratio to reduce its abuse liability. Because of pediatric exposures and diversion of buprenorphine to illicit use, mucosal films are now used rather than sublingual pills that can be crushed and snorted. A long-acting buprenorphine injection that lasts a month is also available to prevent illicit diversion and to enhance compliance. Primary care physicians often prescribe buprenorphine for opioid use disorder, which has reduced opioid-related deaths and druginjection-related medical morbidity with treatment retention as high as 70% over a 6-month follow-up period. Opioid Antagonist Medications  Antagonist therapy blocks the action of self-administered opioids and should eventually extinguish the habit, but this therapy is poorly accepted by patients. Naltrexone, a long-acting pure opioid antagonist, can be given orally three times a week, or by monthly injection, which markedly improves adherence, retention, and drug use. Because it is an antagonist, the patient must first be detoxified from opioids before starting naltrexone. It is safe even when taken chronically for years, is associated with few side effects (headache, nausea, abdominal pain), and can be given to patients infected with hepatitis B or C without producing hepatotoxicity. How­ ever, most providers refrain from prescribing naltrexone if liver func­ tion tests are three times above normal levels. Naltrexone maintenance combined with psychosocial therapy is effective in reducing heroin use. Medication-Free Treatment  Most opioid users enter medicationfree treatments in inpatient, residential, or outpatient settings, but 1- to 5-year outcomes are very poor compared to pharmacotherapy except for residential settings lasting 6–18 months. The residential programs require full immersion in a regimented system with progressively increasing levels of independence and responsibility within a controlled # 41 - 468 Cocaine, Other Psychostimulants, and Hallucinogens ### 468 Cocaine, Other Psychostimulants, and Hallucinogens community of fellow drug users. These medication-free programs, as well as the pharmacotherapy programs, also include counseling and behavioral treatments designed to teach interpersonal and cognitive skills for coping with stress and for avoiding situations leading to easy access to drugs or to craving. Relapse is prevented by having the indi­ vidual very gradually reintroduced to greater responsibilities and to the working environment outside of the protected therapeutic community. ■ ■PREVENTION Preventing the development of opioid use disorder represents a criti­ cally important challenge for physicians. Opioid prescriptions are a common source of drugs accessed by adolescents who begin a pat­ tern of illicit drug use. The major sources of these drugs are family members, not drug dealers or the Internet. Pain management involves providing sufficient opioids to relieve the pain over as short a time as the pain warrants (Chap. 14). The patient then needs to dispose of any remaining opioids, not save them in the medicine cabinet, because this behavior leads to diversion by adolescents. Finally, physicians should never prescribe opioids for themselves. PART 13 Neurologic Disorders ■ ■FURTHER READING Blanco C, Volkow ND: Management of opioid use disorder in the USA: Present status and future directions. Lancet 393:1760, 2019. Bruneau J et al: Management of opioid use disorders: A national clini­ cal practice guideline. CMAJ 190:E247, 2018. Food and Drug Administration: Information about medica­ tions for opioid use disorder. Accessed May 24, 2024. Available at https://www.fda.gov/drugs/information-drug-class/information- about-medications-opioid-use-disorder-moud. White House Office of National Drug Control Policy (ONDCP): White House announces over $276 million for law enforcement to help address the overdose epidemic and crack down on illicit drug trafficking. Accessed May 23, 2024. Available at https:// www.whitehouse.gov/ondcp/briefing-room/2024/05/23/white-houseannounces-over-276-million-for-law-enforcement-to-help-address-theoverdose-epidemic-and-crack-down-on-illicit-drug-trafficking/. Karran A. Phillips, Wilson M. Compton Cocaine, Other Psychostimulants, and Hallucinogens The use of cocaine, methamphetamine, other psychostimulants, and hallucinogens reflects a complex interaction between the pharmacology of the drug, the personality and expectations of the individual using the drug, and the environmental context in which the drug is used. These substances cause significant harm, although they are less commonly used than other addictive substances such as alcohol (Chap. 464), nic­ otine (Chap. 465), cannabis (Chap. 466), and opioids (Chap. 467). It is also important to recognize that polydrug use, involving the concur­ rent use of several drugs with different pharmacologic effects, is com­ mon. Sometimes one drug is used to enhance the effects of another, as with the combined use of cocaine and nicotine, or cocaine and heroin in methadone-treated patients. Some forms of polydrug use, such as the combined use of intravenous (IV) heroin and cocaine, are espe­ cially dangerous and account for many hospital emergency department visits. Cocaine and psychostimulant use (especially chronic patterns of use) may cause adverse health consequences and exacerbate preexist­ ing disorders such as hypertension and cardiac disease. In addition, the combined use of two or more drugs may accentuate medical complications associated with use of one drug. Chronic use is often associated with immune system dysfunction and increased vulner­ ability to infections, including risk for HIV infection. The concurrent use of cocaine and opiates (“speedball”) is frequently associated with needle sharing by people using drugs intravenously (IV). People who use IV drugs represent the largest single group of individuals with HIV infection in several major metropolitan areas in the United States as well as in many parts of Europe and Asia. Furthermore, several out­ breaks of HIV in the United States since 2015 in rural and suburban areas have been attributed to clusters of injection drug use. Psychostimulants and hallucinogens have been used for centuries to induce euphoria and alter consciousness. Hallucinogens have become popular recently, and new drugs are continually being developed. This chapter describes the subjective and adverse medical effects of cocaine, other psychostimulants including methamphetamine, 3,4-methylene­ dioxymethamphetamine (MDMA), and cathinones; hallucinogens such as phencyclidine (PCP), d-lysergic acid diethylamide (LSD), and Salvia divinorum; and emerging drugs. PSYCHOSTIMULANTS Psychostimulants include cocaine and methamphetamine, as well as drugs with stimulant-like properties such as MDMA and cathinones. In addition, prescribed psychostimulants such as methylphenidate, dextroamphetamine, and amphetamine are considered here. ■ ■COCAINE Cocaine is a powerful psychostimulant drug made from the cocoa plant. It has local anesthetic, vasoconstrictor, and stimulant properties. Cocaine is a Drug Enforcement Agency (DEA) Schedule II drug, which means that it has “high potential for abuse and the potential to create psychological and/or physical dependence” but can be administered by a physician for legitimate medical uses, such as local anesthesia for some eye, ear, and throat surgeries. Pharmacology  Cocaine comes in a variety of forms, the most com­ monly used being the hydrochloride salt, sulfate, and a base. The salt is an acidic, water-soluble powder with a high melting point, used by snorting or sniffing intranasally or by dissolving it in water and inject­ ing it. When used intranasally, the bioavailability of cocaine is about 60%. Cocaine sulfate (“paste”) has a melting point of almost 200°C, so it has limited use, but it is sometimes smoked with tobacco. The base form can be freebase or crystallized as crack. Cocaine freebase is made by adding a strong base to an aqueous solution of cocaine and extract­ ing the alkaline freebase precipitate. It has a melting point of 98°C and can be vaporized and inhaled. Freebase cocaine can also be crystallized and sold as crack or rock, which is also smoked or inhaled. Street deal­ ers often dilute (or “cut”) cocaine with nonpsychoactive substances such as cornstarch, talcum powder, flour, or baking soda, or adulterate it with other substances with similar effects (like procaine or amphet­ amine) to increase their profits. A recent concern has been the adul­ teration of cocaine (and other psychostimulants) with fentanyl-related opioids, resulting in overdose deaths due to opioid effects or polydrug use. Xylazine, a nonopioid sedative, analgesic, and muscle relaxant only approved for veterinary use in the United States, has also been found cut into cocaine and other psychostimulants, as described below under “Psychostimulant Clinical Manifestations”. Given the extensive pulmonary vasculature, smoked or vaporized cocaine reaches the brain very quickly, similar in speed of onset to injected cocaine. The result is a rapid, intense, transient high, which enhances its addictive potential. Cocaine binds to the dopamine (DA) transporter and blocks DA reuptake, which increases synaptic levels of the monoamine neurotransmitters DA, norepinephrine (NE), and serotonin (5HT), in both the central nervous system (CNS) and the peripheral nervous system (PNS). Use of cocaine, like other harmful drugs abuse, induces long-term changes in the brain. Animal studies have shown adaptations in neurons that release the excitatory neu­ rotransmitter glutamate after cocaine exposure. Epidemiology  According to the National Survey on Drug Use and Health (NSDUH), in 2023 an estimated 5 million people aged 12 years or older (1.8% of the population) were past-year consumers of cocaine, including crack. Among those, 470,000 used cocaine for the first time (1287 cocaine initiates/day) including 23,000 adolescents aged 12–17 years. About 1.3 million people aged 12 years or older (0.4% of the pop­ ulation) in 2023 had a cocaine use disorder. According to the Centers for Disease Control and Prevention (CDC) National Center for Health Statistics, the age-adjusted rate of drug overdose deaths involving cocaine more than quintupled from 1.5 deaths per 100,000 standard population in 2011 to 8.2 in 2022. The rate of drug overdose deaths per 100,000 standard population involving both cocaine and opioids in 2021 (5.9) was 7.4 times the rate in 2011 (0.8) and was driven by the involvement of synthetic opioids including fentanyl and fentanyl ana­ logues. The rate involving cocaine without opioid co-involvement in 2021 (1.5) was 2.1 times the rate in 2011 (0.7). The data are concerning because they describe increases over time in cocaine-related overdose both with and without the co-ingestion of opioids. ■ ■METHAMPHETAMINE Methamphetamine is a psychostimulant drug usually used as a white, bitter-tasting powder or a pill. Crystal methamphetamine is a form of the drug that looks like glass fragments or shiny, bluish-white rocks. It can be inhaled/smoked, swallowed (pill), snorted, or injected (after being dissolved in water or alcohol). Pharmacology  When smoked, methamphetamine exhibits 90.3% bioavailability, compared to 67.2% for oral ingestion. Methamphet­ amine exists in two stereoisomers, the l- and d-forms. d-Metham­ phetamine, or the dextrorotatory enantiomer, is a more powerful psychostimulant, with 3–5 times the CNS activity as compared with l-methamphetamine. Methamphetamine is a cationic lipophilic mol­ ecule, which stimulates the release, and partially blocks the reuptake, of newly synthesized catecholamines in the CNS. Methamphetamine has a similar structure to the DA, NE, 5HT, and vesicular monoamine transporters and reverses their endogenous function, resulting in release of monoamines from storage vesicles into the synapse. Meth­ amphetamine also attenuates the metabolism of monoamines by inhib­ iting monoamine oxidase. Methamphetamine is more potent than amphetamine, resulting in much higher concentrations of synaptic DA and more toxic effects on nerve terminals. Outside the medical context, methamphetamine’s pharmacokinetics and low cost often result in a chronic and continu­ ous, high-dose self-administered use pattern. Epidemiology  According to the NSDUH, in 2023, 2.6 million people aged 12 years or older (0.9% of the population) used metham­ phetamine (not including use or misuse of prescription amphetamines or other stimulants) in the past year; of those, 78,000 used metham­ phetamine for the first time (213 people per day). In 2023, an estimated 1.8 million people aged 12 years or older (0.6% of the population and 69% of those with past-year use) had a methamphetamine use disorder. High rates of co-occurring substance use and mental illness exist in adults who use methamphetamine, and only about one-third of adults with past-year methamphetamine use disorder received addiction treatment. Methamphetamine availability and methamphetaminerelated harms (e.g., overdose deaths, treatment admissions, infectious disease transmission) continue to increase in the United States. According to CDC data, psychostimulants (primarily methamphetamine) caused 36,251 overdose deaths in 2023. Stimulant-involved overdose deaths have risen markedly in recent years; with rates of psychostimulant overdose deaths increasing from 0.7 in 2011 to 10.4 in 2022. Further, while preliminary reports show overdose deaths involving opioids decreasing from an estimated 84,181 in 2022 to 81,083 in 2023, over­ dose deaths due to cocaine and psychostimulants (like methamphet­ amine) increased. ■ ■MDMA AND CATHINONES MDMA also known as Molly, ecstasy, or X, is an illegal synthetic drug that has stimulant and psychedelic effects. Khât is a plant found in East Africa and the Middle East; it has been used for centuries for its mild stimulant-like effect. Synthetic cathinones or “bath salts” are manufactured psychostimulants that are chemically similar to the naturally occurring substance cathinone found in the khât plant and are discussed under “Emerging Drugs” below. MDMA  Molly, slang for “molecular,” refers to the crystalline pow­ der form of MDMA usually sold as powder or in capsules. The content of Molly varies and is often not MDMA at all but rather contains methylone or ethylone, which are synthetic substances commonly found in so-called bath salts and pose significant health risks. The cli­ nician should always consider the possibility that the drug reported by the individual may be unwittingly contaminated with other substances. With MDMA use, individuals experience increased physical and mental energy, distortions in time and perception, emotional warmth, empathy toward others, a general sense of well-being, decreased anxi­ ety, and an enhanced enjoyment of tactile experiences. MDMA is usu­ ally taken orally in a tablet, capsule, or liquid form with first effect at 45 min on average, peak effect at 1–2 h, and duration ~3–6 h. MDMA binds to serotonin transporters and increases the release of serotonin, NE, and DA. Research in animals has shown that MDMA in moder­ ate to high doses can cause loss of serotonin-containing nerve endings and permanent damage. MDMA is a Schedule I drug, along with other substances with no proven therapeutic value. MDMA has been given a breakthrough therapy designation by the U.S. Food and Drug Administration (FDA) as a possible treatment for posttraumatic stress disorder allowing for expedited clinical trials, but at present MDMA remains a Schedule I drug, along with other substances with no proven therapeutic value. CHAPTER 468 Cocaine, Other Psychostimulants, and Hallucinogens Adulteration of MDMA tablets with methamphetamine, ketamine, caffeine, the over-the-counter cough suppressant dextromethorphan (DXM), the diet drug ephedrine, and cocaine is common. MDMA is rarely used alone and is often mixed with other substances, such as alcohol and marijuana, making the specific impacts of its use difficult to ascertain. According to NSDUH 2023 data, among individuals aged 12 or older, 0.8% used MDMA in the past year and 507,000 people tried MDMA for the first time (>1300 per day). MDMA is predominantly used by men 18–25 years of age, with use typically beginning at age 21 years. There is evidence that gay or bisexual men and women are more likely than their heterosexual counterparts to have used MDMA in the last 30 days. Cathinone  This is an alkaloid psychostimulant structurally similar to amphetamine found in the khât (Catha edulis) plant, which grows at high altitudes in East Africa and the Middle East and whose leaves are chewed for their mild stimulant-like effect. The extraction of cathinone and other alkaloids from the leaves by chewing is very effective, leaving little as unabsorbed residue. The leaves and twigs can also be smoked, infused in tea, or sprinkled on food. Cathinone increases dopamine release and reduces dopamine reuptake. Originally limited to its area of cultivation, with advances in rapid transportation and postal delivery, khât is now available in several con­ tinents including Europe and North America. Worldwide it is estimated that 10 million people chew khât, including up to 80% of all adults in some areas where the evergreen shrub is indigenous. In regions where the plant is indigenous, there have also been reports of khât use as a study aid among university students. Cathinone is a Schedule I drug in the United States, making its possession and use illegal. ■ ■PRESCRIBED PSYCHOSTIMULANTS Methylphenidate, dextroamphetamine, and dextroamphetamine/ amphetamine combination products are psychostimulants approved in the United States for treatment of attention-deficit hyperactivity disorder (ADHD), weight control, and narcolepsy. Prescription psy­ chostimulants increase alertness, attention, and energy. Phenylpropa­ nolamine, a psychostimulant used primarily for weight control, was found to be related to hemorrhagic stroke in women and removed from the market in 2005. Nonprescribed amphetamines and methylpheni­ date are used quite frequently by college students and as energy and productivity boosters by others. According to the 2023 NSDUH, pastyear prescription stimulant misuse was reported by 3.9 million (1.4%) people aged 12 years or older. Of note, in 2023 among individuals aged 12 or older, 786,000 individuals misused prescription stimulants and cocaine; 190,000 misused prescription stimulants and methamphet­ amine; and 182,000 people misused or used all three. Past-year initiates of prescription stimulant misuse totaled 712,000, which averages to ~1950 people misusing prescription stimulants for the first time each day, including >1000 young adults aged 12–25 each day. Among people aged 12 years or older, 0.6% of the population in 2023 had a prescrip­ tion stimulant use disorder in the past year. ■ ■PSYCHOSTIMULANT CLINICAL MANIFESTATIONS Psychostimulants produce the same acute CNS effects: euphoria/ elevated mood, increased energy/decreased fatigue, reduced need for sleep, decreased appetite, heightened sense of alertness, decreased distractibility, dose-dependent effects on focus, attention, and curios­ ity, increased self-confidence, increased libido, and prolonged orgasm, independent of the specific psychostimulant or route of administra­ tion. Peripheral effects may include tremor, diaphoresis, hypertonia, tachypnea, hyperreflexia, and hyperthermia. Many of the effects are biphasic; for example, low doses improve psychomotor performance, while higher doses may cause tremors or convulsions. α-Adrenergically mediated cardiovascular effects are also biphasic, with low doses result­ ing in increased vagal tone and decreased heart rate and high doses causing increased heart rate and blood pressure. Psychostimulant use can result in restlessness, irritability, and insomnia and, at higher doses, suspiciousness, repetitive stereotyped behaviors, and bruxism. Endocrine effects resulting from chronic use may include impotence, gynecomastia, menstrual function disruptions, and persistent hyperp­ rolactinemia (Table 468-1). PART 13 Neurologic Disorders Overdose presents as sympathetic nervous system overactivity with psychomotor agitation, hypertension, tachycardia, headache, and mydriasis, and can lead to convulsions, cerebral hemorrhage or infarc­ tion, cardiac arrhythmias or ischemia, respiratory failure, or rhabdo­ myolysis. It is a medical emergency; treatment is largely symptomatic and should occur in an intensive care or telemetry unit. Inhalation of crack cocaine that is vaporized at high temperatures can cause airway burns, bronchospasm, and other symptoms of pulmonary disease. MDMA has also been shown to raise body temperature and can occa­ sionally result in liver, kidney, or heart failure, or even death. Psychostimulants are often used with other drugs, including opi­ oids and alcohol, whose CNS-depressant effects tend to attenuate psychostimulant-induced CNS stimulation. These combinations often have additive deleterious effects, increasing the risk of morbidity and mortality. An example of this risk is the use of cocaine with alcohol, which results in the metabolite cocaethylene. Cocaethylene’s effects on the cardiovascular system are additive to that of cocaine’s effects, result­ ing in intensified pathophysiologic consequences. Adulteration of psychostimulants, particularly cocaine, with other drugs is common and can have additional health consequences. In addition to contamination with fentanyl-related compounds, poten­ tially resulting in fatal overdose, multiple other substances have been noted as contaminants of psychostimulants. Levamisole, an anthelminthic and immunomodulator used primarily in veterinary medicine, has been found in cocaine and can cause agranulocytosis, leukoencephalopathy, and cutaneous vasculitis, which has resulted in skin necrosis. Clenbuterol, a sympathomimetic amine used clinically as a bronchodilator, has also been found in cocaine and can result in tachycardia, hyperglycemia, palpitations, and hypokalemia. Xylazine, a nonopioid veterinary sedative, analgesic, and muscle relaxant, is most often described in the context of an opioid adulterant; however, it is also seen as an adulterant of cocaine, methamphetamine, and other stimulants. Effects associated with xylazine include dry mouth, drowsi­ ness, hypertension, and tachycardia followed by hypotension and bradycardia, hyperglycemia, hypothermia, coma, respiratory depres­ sion, and dysrhythmia. Xylazine injection has been associated with necrotic soft tissue lesions both at the site of injection and elsewhere on the body. There is some evidence that xylazine itself can result in withdrawal symptoms such as sharp chest pains and seizures and cause physical dependence. Studies in Europe have found that, in addition to levamisole, some of the most common adulterants in cocaine include TABLE 468-1  Complications of Psychostimulant Use Cardiovascular Acute • Arterial vasoconstriction • Thrombosis • Tachycardia • Hypertension • Increased myocardial oxygen demand • Increased vascular shearing forces • Coronary vasoconstriction • Cardiac ischemia • Left ventricular dysfunction/heart failure (high blood concentrations) • Supraventricular and ventricular dysrhythmias • Aortic dissection/rupture Chronic • Accelerated atherogenesis • Left ventricular hypertrophy • Dilated cardiomyopathy Central and peripheral nervous systems • Hyperthermia • Psychomotor agitation • Tremor • Hyperreflexia • Hypertonia • Headache • Seizures • Coma • Intracranial hemorrhage • Focal neurologic symptoms Pulmonary • Angioedema (inhaled) • Pharyngeal burns (inhaled) • Pneumothorax • Pneumomediastinum • Pneumopericardium • Reversible airway disease exacerbations • Bronchospasm • Shortness of breath (“crack lung”) • Tachypnea • Pulmonary infarction Gastrointestinal • Perforated ulcers • Ischemic colitis • Bowel infarction • Impaction (body packing) • Hepatic enzyme elevation Renal • Metabolic acidosis • Renal infarction • Rhabdomyolysis Endocrine • Impotence • Gynecomastia • Menstrual function disruptions • Hyperprolactinemia Other • Diaphoresis • Irritability • Insomnia • Bruxism • Stereotypy • Splenic infarction • Acute angle-closure glaucoma • Vasospasm of the retinal vessels (unilateral or bilateral vision loss) • Mydriasis • Madarosis • Abruptio placentae phenacetin, lidocaine, caffeine, diltiazem, hydroxyzine, procaine, tetra­ caine, paracetamol, creatine, and benzocaine. Withdrawal from psychostimulants often includes hypersomnia, increased appetite, and depressed mood. Acute withdrawal typically lasts 7–10 days, but residual symptoms, possibly associated with neuro­ toxicity, may persist for several months. Debate remains whether psy­ chostimulant withdrawal symptoms decline monotonically or occur in discrete phases, becoming worse before they improve. Psychostimulant withdrawal is not thought to be a major driver of ongoing use. Most current theories of psychostimulant addiction emphasize the primary role of conditioned craving, which can persist long after physiological withdrawal has abated. Conditioned craving includes the urge to use drugs in response to cues in the environment associated with drug use, such as associates who use drugs, drug paraphernalia, or drug-using locations. Injection of psychostimulants places people at increased risk of con­ tracting infectious diseases from exposure to HIV and hepatitis B or C in blood or other bodily fluids, as well as skin abscesses and endocardi­ tis. Psychostimulant use can also increase risk for infection by causing altered judgment and decision-making, leading to risky behaviors such as unprotected sex. There is some evidence that psychostimulant use may worsen the progression of HIV/AIDS via increased injury to nerve cells exacerbating cognitive problems. The actions and effects of khât are like those of other psychostimu­ lants. Short-term effects include euphoria, increased alertness and arousal, loss of appetite, insomnia, headaches, and tremors. Long-term use may result in gastrointestinal disorders such as constipation, ulcers, and stomach inflammation, as well as increased risk for acute myocar­ dial infarction and stroke due to inotropic and chronotropic effects on the heart, vasospasm of coronary arteries, and catecholamine-induced platelet aggregation. There is evidence that, rarely, heavy khât use may cause mild to moderate psychological dependence. Compulsive use has been described, with resulting grandiose delusions, paranoia, and hallucinations. A mild withdrawal syndrome from khât can include depression, nightmares, low blood pressure, and lack of energy. ■ ■DIAGNOSIS The Diagnostic and Statistical Manual of Psychiatric Disorders, 5th edi­ tion (DSM-5) defines a stimulant use disorder (SUD) as a pattern of use of amphetamine-type substances, cocaine, or other stimulants lead­ ing to clinically significant impairment or distress, as manifested by at least 2 of the following 11 problems within a 12-month period: taking larger amounts, or over a longer period of time, than intended; persis­ tent desire or unsuccessful efforts to reduce or control use; a great deal of time spent in activities necessary to obtain, use, or recover; craving; use resulting in failure to fulfill major role obligations; continued use, despite recurrent social or interpersonal problems; giving up social, occupational, or recreational activities; recurrent use in physically haz­ ardous situations; continued use despite persistent or recurrent physi­ cal or psychological problems; tolerance; and withdrawal symptoms, or avoidance of withdrawal symptoms, by continued use. The International Classification of Diseases (ICD) 10th Revision (ICD-10) recognizes “stimulant dependence syndrome” and “stimulant withdrawal state,” and the ICD 11th Revision (ICD-11) further speci­ fies the definition to “stimulant dependence including amphetamines, methamphetamines, or methcathinone.” TREATMENT Acute Intoxication As with all emergency situations, the first task is to check a patient’s circulation, airway, and breathing. With cocaine use, succinyl­ choline is relatively contraindicated in rapid-sequence intubation; consider rocuronium (1 mg/kg IV) or another nondepolarizing agent as an alternative. If psychomotor agitation occurs, rule out hypoglycemia and hypoxemia first, and then administer benzodi­ azepines (e.g., diazepam 10 mg IV and then 5–10 mg IV every 3–5 hours until agitation controlled). Benzodiazepines are usually sufficient to address cardiovascular side effects. Severe or symptom­ atic hypertension can be treated with phentolamine, nitroglycerin, or nitroprusside. Hyperthermic patients should be cooled within ≤30 min with the goal to achieve a core body temperature of <39°C (102°F). Evaluation of chest pain in someone using cocaine should include an electrocardiogram, chest radiograph, and biomarkers to exclude myocardial infarction. The treatment approach is similar to nonstimulant-induced chest pain; however, it is recommended that whenever possible beta blockers not be used in people who use cocaine. The concern arises from the potential unopposed alphaadrenergic stimulation that results from beta blockade possibly causing coronary arterial vasoconstriction, ischemia, and infarction and limited data supporting the benefit of beta blockers in cocainerelated cardiovascular complications. If beta blockers are to be given, it is suggested that mixed alpha/beta blockers, e.g., labetalol and carvedilol, be used rather than nonselective beta blockers, and only in situations where the benefits outweigh the risks. Because many instances of psychostimulant-related mortality have been associated with concurrent use of other illicit drugs (particularly opioids), the physician must be prepared to institute effective emer­ gency treatment for multiple drug toxicities. CHAPTER 468 Cocaine, Other Psychostimulants, and Hallucinogens Psychostimulant Use Disorders Treatment of psychostimulant use disorders requires the combined efforts of primary care physicians, addiction medicine physicians, psychiatrists, and psychosocial care providers. Early abstinence from psychostimulant use is often complicated by symptoms of depression and guilt, insomnia, and anorexia, which may be as severe as those observed in major affective disorders and can last for months and even years after use has stopped. Behavioral therapies, including cognitive-behavioral therapy (CBT), the community reinforcement approach (CRA), con­ tingency management (CM; providing structured and specific incentives to patients who remain substance free), motivational enhancement therapy (MET), combinations of these, and others, remain the mainstay of treatment for SUDs and show modest benefit. These behavioral therapies are designed to help modify the patient’s thinking, expectancies, and behaviors, and to increase life-coping skills, with behavioral interventions to support longterm, drug-free recovery. There is robust evidence, including recent meta-analyses and systematic reviews, that contingency manage­ ment, when implemented with fidelity to the principles of operant conditioning, is a highly effective treatment for psychostimulant use disorder, the benefit of which continues for up to 2 years beyond treatment discontinuation. There are no FDA-approved medications for psychostimulant addiction. Current research includes several neurotransmitterbased strategies targeting DA, serotonin, γ-aminobutyric acid (GABA), and glutamate. Trials of agonist therapy with longeracting psychostimulant medications such as dexamphetamine and methylphenidate have not been conclusive. Studies with the anti­ depressants mirtazapine, bupropion, sertraline, imipramine, and atomoxetine have been equivocal, as have studies with the atypical antipsychotic aripiprazole and the anticonvulsant topiramate. Other therapies being studied for the treatment of psychostimulant use disorder include acamprosate (possibly via a role in modulating the NMDA receptor), galantamine (reversible acetylcholine esterase inhibitor, which may strengthen impulse control, as well as cogni­ tive and social abilities depleted by long-term psychostimulant use), naltrexone (opiate receptor antagonist), doxazosin (alpha-adrener­ gic antagonist), and varenicline (partial agonist of the α4β2 nico­ tinic acetylcholine receptor and DA neurotransmission enhancer). Overall, it is promising that some of the medications studied showed significant outcome improvements over placebo, but many were also underpowered due to issues of small sample size, sample bias, low participant retention, and low treatment adherence rates. Ongoing studies are investigating lisdexamfetamine (a dexamphet­ amine prodrug), a combination of extended-release naltrexone with bupropion, pomaglumetad (a glutamate agonist), and sev­ eral monoclonal antibodies. Special attention needs to be paid to the inclusion of underrepresented populations including women in future stimulant use disorder medication trials. Vaccines for cocaine and methamphetamine use disorders are also being devel­ oped. Finally, recent preliminary studies have brought attention to the potential use of brain stimulation techniques such as transcra­ nial magnetic stimulation (TMS), theta-burst stimulation (TBS), and transcranial direct current stimulation (tDCS) to treat psycho­ stimulant use disorders, although further studies will be required to determine their value, if any, in this situation. HALLUCINOGENS Hallucinogens are a diverse group of drugs causing alteration of thoughts, feelings, sensations, and perceptions. Some hallucinogens are found naturally in plants and mushrooms, while others are syn­ thetic. They include ayahuasca (a tea made from Amazonian plants containing dimethyltryptamine [DMT], the primary mind-altering ingredient), DMT (aka Dimitri; can also be synthesized in a lab), LSD (clear or white odorless material made from lysergic acid found in rye and other grain fungus); peyote (mescaline, derived from a small, spineless cactus or made synthetically); and 4-phosphoryloxy-N,Ndimethyltryptamine (psilocybin, comes from certain South and North American mushrooms). PART 13 Neurologic Disorders A subgroup of hallucinogens produces the added sensation of feel­ ing out of control or disconnected from one’s body or surroundings. These dissociative drugs include DXM (an over-the-counter cough suppressant, when used in high doses), ketamine (an FDA-approved human and veterinary anesthetic and a nasal spray [esketamine] for treatment-resistant depression); phencyclidine (PCP; a cyclohexyl­ amine derivative and dissociative anesthetic); and S. divinorum (salvia, a Mexican, Central American, and South American plant). Dissociative drugs distort the way the user perceives time, motion, color, sound, and self, and their use can lead to bizarre and dangerous behavior and cause respiratory depression, heart rate abnormalities, and a withdrawal syndrome including drug craving, confusion, headache, and sweating. Use of hallucinogens in religious and spiritual rituals goes back centuries, and they are ingested in a wide variety of ways, including orally, by smoking, intranasally, and transmucosally. Especially when taken orally, the onset of action of hallucinogens is within 20–90 min and the duration of action can be as long as 6–12 h, except for salvia, whose effects generally last about 30 min. Hallucinogens specifically disrupt the neurotransmitters serotonin and glutamate. Effects on the serotonin system can disturb mood, sensory perception, sleep, appetite, body temperature, sexual behavior, and muscle control. Glutamate sys­ tem effects include perturbations in pain perception, responses to the environment, emotion, and learning and memory. According to the NSDUH, in 2023, 2.6 million adults reported pastmonth use of hallucinogens and 8.8 million (3.1% of the population) reported past-year use of hallucinogens. Of these, 1.5 million used hallucinogens for the first time. Of note, these statistics include ecstasy (MDMA or “Molly”) in the overall hallucinogen use category as well as LSD, PCP, peyote, mescaline, psilocybin mushrooms, ketamine, N,N-dimethyltryptamine (DMT)/Alpha-Methyltryptamine (AMT)/ “Foxy,” and S. divinorum. Past-year initiation numbers among people aged 12 years and older include 364,000 for LSD, 24,000 for PCP, and 507,000 for ecstasy. In 2023, 0.2% of people aged 12 or older had a hal­ lucinogen use disorder. Clinical manifestations of hallucinogen use include false sensory experiences (i.e., hallucinations), intensified feelings, heightened sen­ sory experiences, and time perturbations. Additional physiologic responses include nausea; increases in heart rate, blood pressure, respiratory rate, or body temperature; loss of appetite; xerostomia; sleep problems; synesthesia; impaired coordination; and hyperhidrosis. Extremely negative experiences with hallucinogen use (the “bad trip”) can include panic, paranoia, and psychosis, which may persist for up to 24 h. Such experiences are best treated with supportive reassur­ ance, but benzodiazepines (e.g., diazepam 10 mg or lorazepam if liver damage is present) may be administered if agitation is severe. There is some evidence that chronic effects of hallucinogen use can occur, including persistent psychosis, memory loss, anxiety, depression, and flashbacks. Long-term effects of PCP and other dissociative drug use can include persistent speech difficulties, memory loss, depression, suicidal thoughts, anxiety, and social withdrawal that may persist for a year or more after chronic use stops. The FDA issued breakthrough therapy designation for MDMA to expedite research into treatment of posttraumatic stress disorder and additional breakthrough therapy designations for two formulations of psilocybin for treatment of depression. In addition, some hallucino­ gens are being studied as potential treatment for certain SUDs, includ­ ing psilocybin for alcohol and tobacco use disorders and ketamine for cocaine and methamphetamine use disorders. There is also some evi­ dence that psilocybin and LSD may relieve pain in certain chronic pain conditions such as cluster headache, lower back pain, cancer-related pain, and phantom limb pain; studies are ongoing. The DSM-5 defines hallucinogen use disorder as meeting 2 or more of the first 10 criteria (see above for SUD) in the past 12 months. The withdrawal criterion does not apply to hallucinogens, because hal­ lucinogen use disorder is atypical in that use patterns are generally not chronic. There are currently no FDA-approved medications for the treatment of hallucinogen addiction. Research on behavioral treat­ ments for hallucinogen addiction is underway. EMERGING DRUGS With the aid of the Internet and some basic over-the-counter (and other) ingredients, the rise of the “kitchen chemist” is upon us. The production of new psychoactive substances (NPS), such as recreation­ ally manufactured synthetic cathinones (bath salts) and synthetic cannabinoids (K2, spice), is on the rise and has resulted in the use of unregulated psychoactive substances that are intended to copy the effects of more expensive illegal drugs such as methamphetamine and cocaine. NPS also include recreationally manufactured synthetic opioids containing brorphine and U-47700 and recreationally manu­ factured synthetic benzodiazepines such as bromazepams, desalkylgid­ azepam, and flubromazepam. In addition to NPS, nitazines (a synthetic opioid that can be more powerful than fentanyl) and tianeptine (a non-U.S.-approved antidepressant with opioid-like effects at high doses) are emerging and reemerging in the drug supply both alone and mixed into other drugs. These emerging drugs can be found online or sold in drug markets or convenience stores. Depending on the type of substance, whether a new type of opioid, depressant, synthetic can­ nabinoid, psychedelic, or stimulant, the effects will differ and may be unpredictable and unwanted, especially if unwittingly ingested as an adulterant in another drug. In addition, emerging substances are often not included in emergency department drug tests and are not routinely tested for when determining the cause of death after a fatal overdose. Synthetic cathinones (bath salts) are human-made drugs chemi­ cally similar to cathinone found in khât and are often stronger and more dangerous than the natural product. They usually take the form of a white or brown crystal-like powder, packaged in small plastic or foil bundles labeled “not for human consumption,” or as “plant food,” “jewelry cleaner,” or “phone screen cleaner,” and sold online and in drug paraphernalia stores. The popular nickname Molly (slang for “molecular”) often refers to the purported “pure” crystalline powder form of MDMA, usually sold in capsules. However, people who pur­ chase powder or capsules sold as Molly often actually receive other drugs, such as synthetic cathinones. The uncertainty of what is actually in these synthetic products, whose components might change from batch to batch, makes them even more dangerous, as anyone using them is unaware of what the products actually contain and how they might respond. The three most common synthetic cathinones are mephedrone, methylone, and MDPV (3,4-methylenedioxypyrovalerone). With oral ingestion, these drugs have an onset of action from 15–45 min, and a duration that varies from 2–7 h. Studies have found that MDPV affects the brain in a manner similar to cocaine but is at least 10 times more potent. MDPV is the most common synthetic cathinone found in the blood and urine of patients admitted to emergency departments after taking “bath salts.” High doses, or chronic use, of synthetic cathinones can lead to dangerous medical consequences, including psychosis, vio­ lent behaviors, tachycardia, hyperthermia, and even death. The ability to synthesize addictive and dangerous drugs relatively simply and rapidly, changing just a few molecules, yet retaining the effects, has allowed many of these emerging drugs to outpace efforts to regulate them, resulting in a developing global public health concern. SUBSTANCE USE AND MENTAL HEALTH According to the NSDUH, in 2023, among adults aged 18 and older with no mental illness, 21% consumed illicit drugs, compared to 51.9% with severe mental illness and 42.4% with any mental illness. In 2023, among adults 18 years of age or older, 84.5 million people had either any mental illness or an SUD in the past year, 38.2 million had any mental illness in the absence of an SUD, 25.8 million had an SUD and no mental illness, and 20.4 million (7.2% of the population) had both. The percentage of adults aged 18 or older in 2023 who had both any mental illness and an SUD in the past year was highest among young adults aged 18 to 25 (14.1% or 4.8 million people). The percentage of adults aged 18 or older in 2023 who had both any mental illness and an SUD in the past year was higher among multiracial adults (13.3%) than among white (8.4%), black (7.8%), Hispanic (7.1%), or Asian adults (3.5%); the percentage could not be calculated with sufficient precision for Native Hawaiian or other Pacific Islander adults. Among the 20.4 million adults aged 18 or older in 2023 with cooccurring any mental illness and an SUD in the past year, 62.4% (or 12.8 million people) received either substance use treatment or mental health treatment in the past year, and 37.6% (or 7.7 million people) received neither type of treatment. This equates to about two in five adults aged 18 or older with co-occurring any mental illness and an SUD in the past year who did not receive treatment for either condi­ tion. Taken together, these data point to the significant overlap of substance-related and other mental health problems and highlight the prodigious treatment gap that exists for both. GLOBAL CONSIDERATIONS After nicotine, alcohol, and cannabis, stimulants are the next most used drugs globally, worldwide in 2021, an estimated 22 million people used cocaine and 36 million people used amphetamines. The global cocaine supply reached a record high in 2022 with >2700 tons of cocaine pro­ duced, 20% more than the previous year, with main trafficking from the Andean region to other countries in the Americas and to Western and Central Europe. The two largest emerging methamphetamine markets in recent years have been the Near and Middle East/Southwest Asia and Southeastern Europe. The trafficking and use of synthetic stimulants, mainly cathinones, has risen notably in Central Asia and Eastern Europe. Globally, psychostimulant use has been associated with elevated mortality, increased incidence of HIV and hepatitis C infection, poor mental health (suicidality, psychosis, depression, and violence), and increased risk of cardiovascular events. The World Health Organization estimates that in 2019 global deaths attributed to cocaine and amphetamine use were 26,082 and 46,661, respectively. Worldwide 7.4 million individuals have a stimulant use disorder, and the United Nations Office on Drugs and Crime (UNODC) esti­ mates that only one in seven people with SUDs receives treatment. The number receiving treatment is much lower in individuals with stimulant use disorder despite the fact that cocaine treatment demand alone has risen almost 60% from 2011 to 2022 in subregions in Europe. Globally, stigma and marginalization make treatment of drug use disorders difficult and hinder sustainable inclusive development incor­ porating gender and racial equity and the empowerment of women and underrepresented minorities. The existing treatment gap is further magnified when the intersectionality of gender, race, age, and ethnicity is considered, as is the treatment gap faced by populations with housing instability, low socioeconomic status, or low educational attainment, as well as LGBTQIA+, and veterans, among others. FUTURE DIRECTIONS Despite their prevalence and public health impact, psychostimulant and hallucinogen use disorders have no FDA-approved treatment medications. While behavioral therapies, such as contingency man­ agement and CBT, have been shown effective in psychostimulant use disorders, further research needs to be done regarding their utility for hallucinogen use disorders. Based on experience with opioid and alco­ hol use disorders, it is also likely that the most efficacious treatments will employ a combination of behavioral and pharmacologic therapy. Research on medications to treat psychostimulant use disorder is ongoing. Additionally, new approaches that utilize emerging technolo­ gies have considerable potential for future treatment of psychostimu­ lant use disorders. These include neurostimulation/neuromodulation (TMS, TBS, tDCS), wearable biosensors, and mobile technology, including ecologic and geographic momentary assessment (EMA/ GMA), as well as real-time interventions delivered via smartphone or other mobile devices. CHAPTER 468 Cocaine, Other Psychostimulants, and Hallucinogens ■ ■FURTHER READING Centers for Disease Control and Prevention: A stimulant guide: Answers to emerging questions about stimulants in the context of the overdose epidemic in the United States. National Center for Injury Prevention and Control, Centers for Disease Control and Prevention, U.S. Department of Health and Human Services, 2022. Compton WM: Polysubstance use in the U.S. opioid crisis. Mol Psychiatry 26:41, 2021. Farrell M et al: Responding to global stimulant use: Challenges and opportunities. Lancet 394:1652, 2019. Substance Abuse and Mental Health Services Administration: Treatment for Stimulant Use Disorders. Treatment Improvement Protocol (TIP) Series 33. SAMHSA Publication No. PEP21-02-01 004. Rockville, MD: Substance Abuse and Mental Health Services Administration, 2021. Trivedi MH et al: Bupropion and naltrexone in methamphetamine use disorder. N Engl J Med 384:140, 2021. ■ ■WEBSITES American Society of Addiction Medicine: https://www.asam.org/ public-resources National Institute on Drug Abuse: https://www.drugabuse.gov/ drugs-abuse Substance Abuse and Mental Health Services Administration: https://www.samhsa.gov World Health Organization: http://www.who.int/substance_abuse/en/ This page intentionally left blank