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:
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):
Absolute serum creatinine increase ≥0.3 mg/dL (>26.4 µmol/L)
A percentage increase in serum creatinine ≥50% (≥1.5-fold above
baseline)
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:
A history of renal disease (including solitary kidney, renal trans­
plant, renal tumor)
Age >60 years
History of hypertension
History of diabetes
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
Focal Onset
(Can be further described as having intact or impaired awareness, motor or
nonmotor onset, or evolve from focal to bilateral tonic clonic)
Generalized Onset
a.	 Motor
Tonic-clonic
Other motor (e.g., atonic, myoclonic)
b.	 Nonmotor (absence)
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.
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-B1502 are at particularly high risk of developing serious
skin reactions from carbamazepine, phenytoin, oxcarbazepine, and
lamotrigine. HLA-A31:01 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
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
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.
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.
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.
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)
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
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
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
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
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
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
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)
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
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
Small fiber neuropathy, including cryptogenic sensory polyneuropathy (CSPN)
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)
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
MRI of spinal cord with and without contrast (exclude compressive causes).
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.
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.
Vascular causes: MRI, CT myelogram; spinal angiogram.
Multiple sclerosis: Brain MRI scan; evoked potentials.
Neuromyelitis optica and related disorders: Serum anti-aquaporin-4
antibody, anti-MOG antibody, anti-GFAP antibody.
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.
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.
Paraneoplastic disorders: Antibody for amphiphysin, CRMP5, Hu, others.
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.
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.
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
DRB11501 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-DRB11501 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
At least one core clinical characteristic
Positive test for AQP4-IgG using best available detection method (cell-based
assay strongly recommended)
Exclusion of alternative diagnoses
Diagnostic Criteria for NMOSD without AQP4-IgG or NMOSD with
Unknown AQP4-IgG Status
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
Negative test for AQP4-IgG using best available detection method or testing
unavailable
Exclusion of alternative diagnoses
Core Clinical Characteristics
Optic neuritis
Acute myelitis
Area postrema syndrome: episode of otherwise unexplained hiccups or
nausea or vomiting
Acute brainstem syndrome
Symptomatic narcolepsy or acute diencephalic clinical syndrome
(hypothalamic dysfunction) with NMOSD-typical diencephalic MRI lesions
Symptomatic cerebral syndrome with NMOSD-typical brain lesions
Additional MRI Requirements for NMOSD without AQP4-IgG and
NMOSD with Unknown AQP4-IgG Status
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
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
Area postrema syndrome requires associated dorsal medulla/area postrema
lesions
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
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
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
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)
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
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
What systems are involved?
• Motor, sensory, autonomic, or combinations
What is the distribution of weakness?
• Only distal versus proximal and distal
• Focal/asymmetric versus symmetric
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)
Is there evidence of upper motor neuron involvement?
• Without sensory loss
• With sensory loss
What is the temporal evolution?
• Acute (days to 4 weeks)
• Subacute (4–8 weeks)
• Chronic (>8 weeks)
• Monophasic, progressive, or relapsing-remitting
Is there evidence for a hereditary neuropathy?
PART 13
Neurologic Disorders
• Family history of neuropathy
• Lack of sensory symptoms despite sensory signs
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).
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:
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.
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:
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.
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.
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.
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:
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:
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).
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:
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).
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:
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:
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.
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.
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
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:
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:
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,
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/
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