09 - PART 2 Cardinal Manifestations and Presentation of Diseases

• 01 - SECTION 1 Pain
• 02 - 14 Pain- Pathophysiology and Management
• 03 - 15 Chest Discomfort
• 04 - 16 Abdominal Pain
• 05 - 17 Headache
• 06 - 18 Low Back Pain
• 07 - 19 Neck Pain
• 08 - SECTION 2 Alterations in Body Temperature
• 09 - 20 Fever
• 10 - 21 Fever and Rash
• 11 - 22 Fever of Unknown Origin
• 12 - SECTION 3 Nervous System Dysfunction
• 13 - 23 Syncope
• 14 - 24 Dizziness and Vertigo
• 15 - 25 Fatigue
• 17 - 27 Numbness, Tingling, and Sensory Loss
• 18 - 28 Gait Disorders, Imbalance, and Falls
• 19 - 29 Confusion and Delirium
• 20 - 30 Coma
• 21 - 31 Dementia
• 23 - 33 Sleep Disorders
• 25 - 34 Disorders of the Eye
• 26 - 35 Disorders of Smell and Taste
• 27 - 36 Disorders of Hearing
• 29 - 38 Oral Manifestations of Disease
• 31 - 39 Dyspnea
• 32 - 40 Cough
• 33 - 41 Hemoptysis
• 34 - 42 Hypoxia and Cyanosis
• 35 - 43 Edema
• 37 - 45 Palpitations
• 38 - 46 Exercise Intolerance
• 40 - 47 Dysphagia
• 41 - 48 Nausea, Vomiting, and Indigestion
• 42 - 49 Diarrhea and Constipation
• 43 - 50 Unintentional Weight Loss
• 44 - 51 Gastrointestinal Bleeding
• 45 - 52 Jaundice
• 46 - 53 Abdominal Swelling and Ascites
• 49 - 55 Azotemia and Urinary Abnormalities
• 50 - 56 Fluid and Electrolyte Disturbances
• 51 - 57 Hypercalcemia and Hypocalcemia
• 52 - 58 Acidosis and Alkalosis
• 53 - SECTION 8 Alterations in the Skin
• 56 - 61 Skin Manifestations of Internal Disease
• 57 - 62 Immunologically Mediated Skin Diseases
• 58 - 63 Cutaneous Drug Reactions
• 60 - SECTION 9 Hematologic Alterations
• 61 - 65 Interpreting Peripheral Blood Smears
• 62 - 66 Anemia and Polycythemia
• 63 - 67 Disorders of Granulocytes and Monocytes
• 65 - 69 Bleeding and Thrombosis
• 66 - 70 Enlargement of Lymph Nodes and Spleen

01 - SECTION 1 Pain

SECTION 1 Pain

Cardinal Manifestations and Presentation of Diseases PART 2 Section 1 Pain James P. Rathmell, Howard L. Fields

Pain: Pathophysiology

and Management The province of medicine is to preserve and restore health and to relieve suffering. Understanding pain is essential to both goals. Because pain is universally understood as a signal of disease, it is the most common symptom that brings a patient to a physician’s attention. The function of the pain sensory system is to protect the body and maintain homeostasis. It does this by detecting, localizing, and identi­ fying potential or actual tissue-damaging processes. Because different diseases produce characteristic patterns of tissue damage, the quality, time course, and location of a patient’s pain lend important diagnostic clues. It is the physician’s responsibility to assess each patient promptly for any remediable cause underlying the pain and to provide rapid and effective pain relief whenever possible. THE PAIN SENSORY SYSTEM Pain is an unpleasant sensation localized to a part of the body. It is often described in terms of a penetrating or tissue-destructive pro­ cess (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Furthermore, any pain of moderate or higher intensity is accompanied by anxiety and the urge to escape or terminate the feeling. These prop­ erties illustrate the duality of pain: it is both sensation and emotion. When it is acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction (e.g., limb flexion, abdominal wall rigidity) is often present. ■ ■PERIPHERAL MECHANISMS The Primary Afferent Nociceptor  A peripheral nerve consists of the axons of three different types of neurons: primary sensory afferents, motor neurons, and sympathetic postganglionic neurons (Fig. 14-1). The cell bodies of primary sensory afferents are in the dorsal root gan­ glia within the vertebral foramina. The primary afferent axon has two branches: one projects centrally into the spinal cord and the other projects peripherally to innervate tissues. Primary afferents are classified by their diameter, degree of myelination, and conduction veloc­ ity. The largest diameter afferent fibers, A-beta (Aβ), respond maximally to light touch and/or moving stimuli; they are present primarily in nerves that inner­ vate the skin. In normal individuals, the activity of these fibers does not produce pain. There are two other classes of primary afferent nerve fibers: the small diameter myelinated A-delta (Aδ) and the unmyelinated (C) axons (Fig. 14-1). These fibers are present in nerves to the skin and to deep somatic and visceral structures. Some tissues, such as the cornea, are innervated only by Aδ and C fiber afferents. Most Aδ and C fiber Aβ Aδ C Sympathetic preganglionic FIGURE 14-1  Components of a typical cutaneous nerve. There are two distinct functional categories of axons: primary afferents with cell bodies in the dorsal root ganglion and sympathetic postganglionic fibers with cell bodies in the sympathetic ganglion. Primary afferents include those with large-diameter myelinated (Aβ), small-diameter myelinated (Aδ), and unmyelinated (C) axons. All sympathetic postganglionic fibers are unmyelinated.

afferents respond maximally to intense (painful) stimuli and produce the subjective experience of pain when they are activated; this defines them as primary afferent nociceptors (pain receptors). The ability to detect painful stimuli is completely abolished when conduction in Aδ and C fiber axons is blocked. Individual primary afferent nociceptors can respond to several dif­ ferent types of noxious stimuli. For example, most nociceptors respond to heat; intense cold; intense mechanical distortion, such as a pinch; changes in pH, particularly an acidic environment; and application of chemical irritants including adenosine triphosphate (ATP), serotonin, bradykinin (BK), and histamine. The transient receptor potential cat­ ion channel subfamily V member 1 (TRPV1), also known as the vanil­ loid receptor, mediates perception of some noxious stimuli, especially heat sensations, by nociceptive neurons; it is activated by heat, acidic pH, endogenous mediators, and capsaicin, a component of hot chili peppers. Sensitization  When intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissues, the threshold for activating primary afferent nociceptors is lowered, and the frequency of firing is higher for all stimulus intensities. Inflammatory mediators such as BK, nerve-growth factor, some prostaglandins (PGs), and leukotrienes contribute to this process, which is called sensitization. Sensitization occurs at the level of the peripheral nerve terminal (peripheral sensi­ tization) as well as at the level of the dorsal horn of the spinal cord (central sensitization). Peripheral sensitization occurs in damaged or inflamed tissues, when inflammatory mediators activate intracellu­ lar signal transduction in nociceptors, prompting an increase in the production, transport, and membrane insertion of chemically gated and voltage-gated ion channels. These changes increase the excit­ ability of nociceptor terminals and lower their threshold for activation by mechanical, thermal, and chemical stimuli. Central sensitization occurs when activity, generated by nociceptors during inflammation, enhances the excitability of nerve cells in the dorsal horn of the spinal cord. Following injury and resultant sensitization, normally innocuous stimuli can produce pain (termed allodynia). Sensitization is a clini­ cally important process that contributes to tenderness, soreness, and hyperalgesia (increased pain intensity in response to the same noxious stimulus; e.g., pinprick causes severe pain). A striking example of sen­ sitization is sunburned skin, in which severe pain can be produced by a gentle slap or a warm shower. Sensitization is of particular importance for pain and tenderness in deep tissues. Viscera are normally relatively insensitive to noxious mechanical and thermal stimuli, although hollow viscera do generate Dorsal root ganglion Peripheral nerve Spinal cord Sympathetic postganglionic

02 - 14 Pain- Pathophysiology and Management

14 Pain: Pathophysiology and Management

Cardinal Manifestations and Presentation of Diseases PART 2 Section 1 Pain James P. Rathmell, Howard L. Fields

Pain: Pathophysiology

and Management The province of medicine is to preserve and restore health and to relieve suffering. Understanding pain is essential to both goals. Because pain is universally understood as a signal of disease, it is the most common symptom that brings a patient to a physician’s attention. The function of the pain sensory system is to protect the body and maintain homeostasis. It does this by detecting, localizing, and identi­ fying potential or actual tissue-damaging processes. Because different diseases produce characteristic patterns of tissue damage, the quality, time course, and location of a patient’s pain lend important diagnostic clues. It is the physician’s responsibility to assess each patient promptly for any remediable cause underlying the pain and to provide rapid and effective pain relief whenever possible. THE PAIN SENSORY SYSTEM Pain is an unpleasant sensation localized to a part of the body. It is often described in terms of a penetrating or tissue-destructive pro­ cess (e.g., stabbing, burning, twisting, tearing, squeezing) and/or of a bodily or emotional reaction (e.g., terrifying, nauseating, sickening). Furthermore, any pain of moderate or higher intensity is accompanied by anxiety and the urge to escape or terminate the feeling. These prop­ erties illustrate the duality of pain: it is both sensation and emotion. When it is acute, pain is characteristically associated with behavioral arousal and a stress response consisting of increased blood pressure, heart rate, pupil diameter, and plasma cortisol levels. In addition, local muscle contraction (e.g., limb flexion, abdominal wall rigidity) is often present. ■ ■PERIPHERAL MECHANISMS The Primary Afferent Nociceptor  A peripheral nerve consists of the axons of three different types of neurons: primary sensory afferents, motor neurons, and sympathetic postganglionic neurons (Fig. 14-1). The cell bodies of primary sensory afferents are in the dorsal root gan­ glia within the vertebral foramina. The primary afferent axon has two branches: one projects centrally into the spinal cord and the other projects peripherally to innervate tissues. Primary afferents are classified by their diameter, degree of myelination, and conduction veloc­ ity. The largest diameter afferent fibers, A-beta (Aβ), respond maximally to light touch and/or moving stimuli; they are present primarily in nerves that inner­ vate the skin. In normal individuals, the activity of these fibers does not produce pain. There are two other classes of primary afferent nerve fibers: the small diameter myelinated A-delta (Aδ) and the unmyelinated (C) axons (Fig. 14-1). These fibers are present in nerves to the skin and to deep somatic and visceral structures. Some tissues, such as the cornea, are innervated only by Aδ and C fiber afferents. Most Aδ and C fiber Aβ Aδ C Sympathetic preganglionic FIGURE 14-1  Components of a typical cutaneous nerve. There are two distinct functional categories of axons: primary afferents with cell bodies in the dorsal root ganglion and sympathetic postganglionic fibers with cell bodies in the sympathetic ganglion. Primary afferents include those with large-diameter myelinated (Aβ), small-diameter myelinated (Aδ), and unmyelinated (C) axons. All sympathetic postganglionic fibers are unmyelinated.

afferents respond maximally to intense (painful) stimuli and produce the subjective experience of pain when they are activated; this defines them as primary afferent nociceptors (pain receptors). The ability to detect painful stimuli is completely abolished when conduction in Aδ and C fiber axons is blocked. Individual primary afferent nociceptors can respond to several dif­ ferent types of noxious stimuli. For example, most nociceptors respond to heat; intense cold; intense mechanical distortion, such as a pinch; changes in pH, particularly an acidic environment; and application of chemical irritants including adenosine triphosphate (ATP), serotonin, bradykinin (BK), and histamine. The transient receptor potential cat­ ion channel subfamily V member 1 (TRPV1), also known as the vanil­ loid receptor, mediates perception of some noxious stimuli, especially heat sensations, by nociceptive neurons; it is activated by heat, acidic pH, endogenous mediators, and capsaicin, a component of hot chili peppers. Sensitization  When intense, repeated, or prolonged stimuli are applied to damaged or inflamed tissues, the threshold for activating primary afferent nociceptors is lowered, and the frequency of firing is higher for all stimulus intensities. Inflammatory mediators such as BK, nerve-growth factor, some prostaglandins (PGs), and leukotrienes contribute to this process, which is called sensitization. Sensitization occurs at the level of the peripheral nerve terminal (peripheral sensi­ tization) as well as at the level of the dorsal horn of the spinal cord (central sensitization). Peripheral sensitization occurs in damaged or inflamed tissues, when inflammatory mediators activate intracellu­ lar signal transduction in nociceptors, prompting an increase in the production, transport, and membrane insertion of chemically gated and voltage-gated ion channels. These changes increase the excit­ ability of nociceptor terminals and lower their threshold for activation by mechanical, thermal, and chemical stimuli. Central sensitization occurs when activity, generated by nociceptors during inflammation, enhances the excitability of nerve cells in the dorsal horn of the spinal cord. Following injury and resultant sensitization, normally innocuous stimuli can produce pain (termed allodynia). Sensitization is a clini­ cally important process that contributes to tenderness, soreness, and hyperalgesia (increased pain intensity in response to the same noxious stimulus; e.g., pinprick causes severe pain). A striking example of sen­ sitization is sunburned skin, in which severe pain can be produced by a gentle slap or a warm shower. Sensitization is of particular importance for pain and tenderness in deep tissues. Viscera are normally relatively insensitive to noxious mechanical and thermal stimuli, although hollow viscera do generate Dorsal root ganglion Peripheral nerve Spinal cord Sympathetic postganglionic

significant discomfort when distended. In contrast, when affected by a disease process with an inflammatory component, deep structures such as joints or hollow viscera characteristically become exquisitely sensitive to mechanical stimulation.

A large proportion of Aδ and C fiber afferents innervating viscera are completely insensitive in normal noninjured, noninflamed tissue. That is, they cannot be activated by known mechanical or thermal stimuli and are not spontaneously active. However, in the presence of inflammatory mediators, these afferents become sensitive to mechani­ cal stimuli. Such afferents have been termed silent nociceptors, and their characteristic properties may explain how, under pathologic condi­ tions, the relatively insensitive deep structures can become the source of severe and debilitating pain and tenderness. Low pH, PGs, leukotri­ enes, and other inflammatory mediators such as BK play a significant role in sensitization. PART 2 Cardinal Manifestations and Presentation of Diseases Nociceptor-Induced Inflammation  Primary afferent nocicep­ tors are not simply passive messengers of threats to tissue injury but also play an active role in tissue protection through a neuroeffector function. Most nociceptors contain polypeptide mediators, including substance P, calcitonin gene related peptide (CGRP), and cholecysto­ kinin, that are released from their peripheral terminals when they are activated (Fig. 14-2). Substance P is an 11-amino-acid peptide that is released in peripheral tissues from primary afferent nociceptors and has multiple biologic activities. It is a potent vasodilator, causes mast cell degranulation, is a chemoattractant for leukocytes, and increases the production and release of inflammatory mediators. Interestingly, depletion of substance P from joints reduces the severity of experi­ mental arthritis. ■ ■CENTRAL MECHANISMS The Spinal Cord and Referred Pain  The axons of primary afferent nociceptors enter the spinal cord via the dorsal root. They terminate in the dorsal horn of the spinal gray matter (Fig. 14-3). The terminals of primary afferent axons contact spinal neurons that transmit the pain signal to brain sites involved in pain perception. When primary afferents are activated by noxious stimuli, they release neurotransmitters from their terminals that excite the spinal cord neu­ rons. The major neurotransmitter released is glutamate, which rapidly excites the second-order dorsal horn neurons. Primary afferent noci­ ceptor terminals also release substance P and CGRP, which produce a slower and longer-lasting excitation of the dorsal horn neurons. The axon of each primary afferent contacts many spinal neurons, and each spinal neuron receives convergent inputs from many primary afferents. The convergence of sensory inputs to a single spinal pain-transmission neuron is of great importance because it underlies the phenomenon of referred pain. All spinal neurons that receive input from the viscera and deep musculoskeletal structures also receive input from the skin. The convergence patterns are determined by the spinal segment of the dorsal root ganglion that supplies the afferent innervation of a struc­ ture. For example, the afferents that supply the central diaphragm are derived from the third and fourth cervical dorsal root ganglia. Primary afferents with cell bodies in these same ganglia supply the skin of the shoulder and lower neck. Thus, sensory inputs from both the shoulder skin and the central diaphragm converge on pain-transmission neu­ rons in the third and fourth cervical spinal segments. Because of this convergence and the fact that the spinal neurons are most often activated by inputs from the skin, activity evoked in spinal neurons by input from deep structures is often mislocalized by the patient to a bodily location that roughly corresponds with the region of skin innervated by the same spinal segment. Thus, inflammation near the central diaphragm is often reported as shoulder discomfort. This spatial displacement of pain sensation from the site of the injury that produces it is known as referred pain. Ascending Pathways for Pain  Most spinal dorsal horn neurons activated by primary afferent nociceptors send their axons to the con­ tralateral thalamus. These axons form the contralateral spinothalamic tract, which lies in the anterolateral white matter of the spinal cord,

Primary activation K+ PG BK H+ A
Secondary activation Mast cell SP SP H BK 5HT Platelet B FIGURE 14-2  Events leading to activation, sensitization, and spread of sensitization of primary afferent nociceptor terminals. A. Direct activation by intense pressure and consequent cell damage. Cell damage induces lower pH (H+) and leads to release of potassium (K+) and to synthesis of prostaglandins (PGs) and bradykinin (BK). PGs increase the sensitivity of the terminal to BK and other pain-producing substances. B. Secondary activation. Impulses generated in the stimulated terminal propagate not only to the spinal cord but also into other terminal branches where they induce the release of peptides, including substance P (SP). Substance P causes vasodilation and neurogenic edema with further accumulation of BK. Substance P also causes the release of histamine (H) from mast cells and serotonin (5HT) from platelets. the lateral edge of the medulla, and the lateral pons and midbrain. The spinothalamic pathway is crucial for pain sensation in humans. Interruption of this pathway produces permanent deficits in pain and temperature discrimination. Spinothalamic tract axons ascend to several regions of the thala­ mus. There is significant divergence of the pain signal from these thalamic sites to several distinct areas of the cerebral cortex that sub­ serve different aspects of the pain experience (Fig. 14-4). One of the thalamic projections is to the somatosensory cortex. This projection mediates the sensory discriminative aspects of pain, i.e., its location, intensity, and quality. Other thalamic neurons project to cortical regions that are linked to emotional responses, such as the anterior cingulate and insular cortex. These pathways to the cortex subserve the affective or unpleasant emotional dimension of pain. This affec­ tive dimension of pain produces suffering and exerts potent control of behavior. Because of this dimension, fear is a constant companion of pain. Consequently, injury or surgical lesions to areas of the fron­ tal cortex activated by painful stimuli can diminish the emotional

Skin Viscus Anterolateral tract axon FIGURE 14-3  The convergence-projection hypothesis of referred pain. According to this hypothesis, visceral afferent nociceptors converge on the same painprojection neurons as the afferents from the somatic structures in which the pain is perceived. The brain has no way of knowing the actual source of input and mistakenly “projects” the sensation to the somatic structure. impact of pain while largely preserving the individual’s ability to localize and recognize stimuli as painful. ■ ■PAIN MODULATION The pain produced by injuries of similar magnitude is remarkably vari­ able in different situations and in different individuals. For example, athletes have been known to sustain serious fractures with only minor pain, and Beecher’s classic World War II survey revealed that many sol­ diers in battle were unbothered by injuries that would have produced F C SS Thalamus Hypothalamus Midbrain Spinothalamic tract Medulla Injury Spinal cord A
B
FIGURE 14-4  Pain-transmission and modulatory pathways. A. Transmission system for nociceptive messages. Noxious stimuli activate the sensitive peripheral ending of the primary afferent nociceptor by the process of transduction. The message is then transmitted over the peripheral nerve to the spinal cord, where it synapses with cells of origin of the major ascending pain pathway, the spinothalamic tract. The message is relayed in the thalamus to the anterior cingulate (C), frontal insular (F), and somatosensory cortex (SS). B. Pain-modulation network. Inputs from frontal cortex and hypothalamus activate cells in the midbrain that control spinal paintransmission cells via cells in the medulla.

agonizing pain in civilian patients. Furthermore, even the suggestion that a treatment will relieve pain can have a significant analgesic effect (the placebo effect). On the other hand, many patients find even minor injuries such as venipuncture frightening and unbearable, and the expectation of pain can induce pain even without a noxious stimulus. The suggestion that pain will worsen following administration of an inert substance can increase its perceived intensity (the nocebo effect).

The powerful effect of expectation and other psychological variables on the perceived intensity of pain is explained by brain circuits that modulate the activity of the pain-transmission pathways. One of these circuits has links to the hypothalamus, midbrain, and medulla, and it selectively controls spinal dorsal horn pain-transmission neurons through a descending pathway (Fig. 14-4). Pain: Pathophysiology and Management CHAPTER 14 Human brain-imaging studies have implicated this pain-modulating circuit in the pain-relieving effect of attention, suggestion, and opioid analgesic medications (Fig. 14-5). Furthermore, each of the compo­ nent structures of the pathway contains opioid receptors and is sensi­ tive to the direct application of opioid drugs. In animals, lesions of this FIGURE 14-5  Functional magnetic resonance imaging (fMRI) demonstrates placebo-enhanced brain activity in anatomic regions correlating with the opioidergic descending pain control system. Top panel: Frontal fMRI image shows placebo-enhanced brain activity in the dorsal lateral prefrontal cortex (DLPFC). Bottom panel: Sagittal fMRI images show placebo-enhanced responses in the rostral anterior cingulate cortex (rACC), the rostral ventral medullae (RVM), the periaqueductal gray (PAG) area, and the hypothalamus. The placebo-enhanced activity in all areas was reduced by naloxone, demonstrating the link between the descending opioidergic system and the placebo analgesic response. (Reproduced with permission from F Eippert et al: Activation of the opioidergic descending pain control system underlies placebo analgesia. Neuron 63:533, 2009.)

descending modulatory system reduce the analgesic effect of systemi­ cally administered opioids such as morphine. Along with the opioid receptor, the component nuclei of this pain-modulating circuit contain endogenous opioid peptides such as the enkephalins and β-endorphin.

The most reliable way to activate this endogenous opioid-mediated modulating system is by suggestion of pain relief or by intense emotion directed away from the pain-causing injury (e.g., during severe threat or an athletic competition). In fact, pain-relieving endogenous opioids are released following surgical procedures and in patients given a pla­ cebo for pain relief. Pain-modulating circuits can enhance as well as suppress pain. Both pain-inhibiting and pain-facilitating neurons in the medulla project to and control spinal pain-transmission neurons. Because pain-transmission neurons can be activated by modulatory neurons, it is theoretically possible to generate a pain signal with no peripheral noxious stimulus. In fact, human functional imaging studies have dem­ onstrated increased activity in this circuit during migraine headaches. A central circuit that facilitates pain could account for the finding that pain can be induced by suggestion or enhanced by expectation and provides a framework for understanding how psychological factors can contribute to chronic pain. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■NEUROPATHIC PAIN Lesions of the peripheral or central nociceptive pathways typically result in a loss or impairment of pain sensation. Paradoxically, damage to or dysfunction of these pathways can also produce pain. For exam­ ple, damage to peripheral nerves, as occurs in diabetic neuropathy, or to primary afferents, as in herpes zoster infection, can result in pain that is referred to the body region innervated by the damaged nerves. Pain may also be produced by damage to the central nervous system (CNS), for example, in some patients following trauma or vascular injury to the spinal cord, brainstem, or thalamic areas that contain central nociceptive pathways. Such pains are termed neuropathic and are often severe and resistant to standard treatments for pain. Neuropathic pain typically has an unusual burning, tingling, or elec­ tric shock-like quality and may occur spontaneously, without any stimu­ lus, or be triggered by very light touch. These features are rare in other types of pain. On examination, a sensory deficit is characteristically co-extensive with the area of the patient’s pain. Hyperpathia, a greatly exaggerated pain response to innocuous or mild nociceptive stimuli, especially when applied repeatedly, is also characteristic of neuropathic pain; patients often complain that the very lightest moving stimulus evokes exquisite pain (allodynia). In this regard, it is of clinical interest that a topical preparation of 5% lidocaine in patch form is effective for patients with postherpetic neuralgia who have prominent allodynia. A variety of mechanisms contribute to neuropathic pain. As with sensitized primary afferent nociceptors, damaged primary affer­ ents, including nociceptors, become highly sensitive to mechanical stimulation and may generate impulses in the absence of stimulation. Increased sensitivity and spontaneous activity are due, in part, to an increased density of sodium channels in the damaged nerve fiber. Damaged primary afferents may also develop sensitivity to norepi­ nephrine. Interestingly, spinal cord pain-transmission neurons cut off from their normal input may also become spontaneously active. Thus, both central and peripheral nervous system hyperactivity contribute to neuropathic pain. Sympathetically Maintained Pain  Patients with peripheral nerve injury occasionally develop spontaneous pain in or beyond the region innervated by the nerve. This pain is often described as having a burning quality. The pain typically begins after a delay of hours to days or even weeks and is accompanied by swelling of the extremity, periarticular bone loss, and arthritic changes in the distal joints. Early in the course of the condition, the pain may be relieved by a local anes­ thetic block of the sympathetic innervation to the affected extremity. Damaged primary afferent nociceptors acquire adrenergic sensitivity and can be activated by stimulation of the sympathetic outflow. This constellation of spontaneous pain and signs of sympathetic dysfunc­ tion following injury has been termed complex regional pain syndrome

(CRPS) (Chap. 19). When this occurs after an identifiable nerve injury, it is termed CRPS type II (also known as posttraumatic neuralgia or, if severe, causalgia). When a similar clinical picture appears without obvious nerve injury, it is termed CRPS type I (also known as reflex sympathetic dystrophy). CRPS can be produced by a variety of injuries, including fractures of bone, soft tissue trauma, myocardial infarction, and stroke. CRPS type I typically resolves with symptomatic treatment; however, when it persists, detailed examination often reveals evidence of peripheral nerve injury. Although the pathophysiology of CRPS is poorly understood, the pain and the signs of inflammation, when acute, can be rapidly relieved by blocking the sympathetic nervous system. This implies that sympathetic activity can activate undam­ aged nociceptors when inflammation is present. Signs of sympathetic hyperactivity should be sought in patients with posttraumatic pain and inflammation and no other obvious explanation. TREATMENT Acute Pain The ideal treatment for any pain is to remove the cause; thus, while treatment can be initiated immediately, efforts to establish the underlying etiology should always proceed as treatment begins. Sometimes, treating the underlying condition does not immediately relieve pain. Furthermore, some conditions are so painful that rapid and effective analgesia is essential (e.g., the postoperative state, burns, trauma, cancer, or sickle cell crisis). Analgesic medications are a first line of treatment in these cases, and all practitioners should be familiar with their use. ASPIRIN, ACETAMINOPHEN, AND NONSTEROIDAL

ANTI-INFLAMMATORY AGENTS (NSAIDS) These drugs are considered together because they are used for similar problems and may have a similar mechanism of action (Table 14-1). All these compounds inhibit cyclooxygenase (COX), and except for acetaminophen, all have anti-inflammatory actions, especially at higher dosages. They are particularly effective for mild to moderate headache and for pain of musculoskeletal origin. Because they are effective for these common types of pain and are available without prescription, COX inhibitors are by far the most used analgesics. They are absorbed well from the gastro­ intestinal tract and, with occasional use, have only minimal side effects. With chronic use, gastric irritation is a common side effect of aspirin and NSAIDs and is the problem that most frequently limits the dose that can be given. Gastric irritation is most severe with aspirin, which may cause erosion and ulceration of the gastric mucosa leading to bleeding or perforation. Because aspirin irrevers­ ibly acetylates platelet COX and thereby interferes with coagulation of the blood, gastrointestinal bleeding is a particular risk. Older age and history of gastrointestinal disease increase the risks of aspirin and NSAIDs. In addition to the well-known gastrointestinal toxic­ ity of NSAIDs, nephrotoxicity is a significant problem for patients using these drugs on a chronic basis. Patients at risk for renal insuf­ ficiency, particularly those with significant contraction of their intravascular volume as occurs with chronic diuretic use or acute hypovolemia, should avoid NSAIDs. NSAIDs can also increase blood pressure in some individuals. Long-term treatment with NSAIDs requires regular blood pressure monitoring and treatment if necessary. Although toxic to the liver when taken in high doses, acetaminophen rarely produces gastric irritation and does not interfere with platelet function. The introduction of parenteral forms of NSAIDs, ketorolac and diclofenac, extends the usefulness of this class of compounds in the management of acute severe pain. Both agents are sufficiently potent and rapid in onset to supplant opioids as first-line treatment for many patients with acute severe headache and musculoskeletal pain. There are two major classes of COX: COX-1 is constitutively expressed, and COX-2 is induced in the inflammatory state.

TABLE 14-1  Drugs for Relief of Pain GENERIC NAME DOSE, mg INTERVAL COMMENTS Nonnarcotic Analgesics: Usual Doses and Intervals Acetylsalicylic acid 650 PO q4h Enteric-coated preparations available Acetaminophen 650 PO q4h Side effects uncommon Ibuprofen 400 PO q4–6h Available without prescription Naproxen 250–500 PO q12h Naproxen is the common NSAID that poses the least cardiovascular risk, but it has a somewhat higher incidence of gastrointestinal bleeding Fenoprofen 200 PO q4–6h Contraindicated in renal disease Indomethacin 25–50 PO q8h Gastrointestinal side effects common Ketorolac 15–60 IM/IV q4–6h Available for parenteral use Celecoxib 100–200 PO q12–24h Useful for arthritis Valdecoxib 10–20 PO q12–24h Removed from U.S. market in 2005 GENERIC NAME PARENTERAL DOSE, mg PO DOSE, mg COMMENTS Narcotic Analgesics: Usual Doses and Intervals Codeine 30–60 q4h 30–60 q4h Nausea common Oxycodone — 5–10 q4–6h Usually available with acetaminophen or aspirin Oxycodone extended-release — 10-40 q12h Oral extended-release tablet; high potential for misuse Morphine 5 q4h 30 q4h   Morphine sustained release — 15–60 bid to tid Oral slow-release preparation Hydromorphone 1–2 q4h 2–4 q4h Shorter acting than morphine sulfate Levorphanol 2 q6–8h 4 q6–8h Longer acting than morphine sulfate; absorbed well PO Methadone 5–10 q6–8h 5–20 q6–8h Due to long half-life, respiratory depression and sedation may persist after analgesic effect subsides; therapy should not be initiated with >40 mg/d, and dose escalation should be made no more frequently than every 3 days Meperidine 50–100 q3–4h 300 q4h Poorly absorbed PO; normeperidine is a toxic metabolite; routine use of this agent is not recommended Butorphanol — 1–2 q4h Intranasal spray Fentanyl 25–100 μg/h — 72-h transdermal patch Buprenorphine 5–20 μg/h   7-day transdermal patch Buprenorphine 0.3 q6–8h   Parenteral administration Tramadol — 50–100 q4–6h Mixed opioid/adrenergic action UPTAKE BLOCKADE SEDATIVE POTENCY ANTICHOLINERGIC POTENCY RANGE,

mg/d 5-HT NE GENERIC NAME Antidepressantsa Doxepin ++ + High Moderate Moderate Less

75–400 Amitriptyline ++++ ++ High Highest Moderate Yes

25–300 Imipramine ++++ ++ Moderate Moderate High Yes

75–400 Nortriptyline +++ ++ Moderate Moderate Low Yes

40–150 Desipramine +++ ++++ Low Low Low Yes

50–300 Venlafaxine +++ ++ Low None None No

75–400 Duloxetine +++ +++ Low None None No

30–60 GENERIC NAME PO DOSE, mg INTERVAL COMMENTS Anticonvulsants and Antiarrythmicsa Carbamazepine 200–300 q6h Rare aplastic anemia, GI irritation, hepatoitoxicity Oxcarbamazepine

bid Similar to carbamazepine Gabapentinb 600–1200 q8h Dizziness, GI irritation; useful in trigeminal neuralgia Pregabalin 150–600 bid Similar to gabapentin; dry mouth, edema aAntidepressants, anticonvulsants, and antiarrhythmics have not been approved by the U.S. Food and Drug Administration (FDA) for the treatment of pain. bGabapentin in doses up to 1800 mg/d is FDA approved for postherpetic neuralgia. Abbreviations: GI, gastrointestinal; 5-HT, serotonin; NE, norepinephrine; NSAID, nonsteroidal anti-inflammatory agent. COX-2-selective drugs have similar analgesic potency and pro­ duce less gastric irritation than the nonselective COX inhibitors. The use of COX-2-selective drugs does not appear to lower the risk of nephrotoxicity compared to nonselective NSAIDs. On the other hand, COX-2-selective drugs offer a significant benefit in the management of acute postoperative pain because they do not affect blood coagulation. Nonselective COX inhibitors (especially

Pain: Pathophysiology and Management CHAPTER 14 ORTHOSTATIC HYPOTENSION CARDIAC ARRHYTHMIA AVERAGE DOSE, mg/d aspirin) are usually contraindicated postoperatively because they impair platelet-mediated blood clotting and are thus associated with increased bleeding at the operative site. COX-2 inhibitors, including celecoxib (Celebrex), are associated with increased car­ diovascular risk, including cardiovascular death, myocardial infarc­ tion, stroke, heart failure, or a thromboembolic event. It appears that this is a class effect of NSAIDs, excluding aspirin. These drugs are

contraindicated in patients in the immediate period after coronary artery bypass surgery and should be used with caution in elderly patients and those with a history of or significant risk factors for cardiovascular disease.

OPIOID ANALGESICS Opioids are the most potent pain-relieving drugs currently avail­ able. Of all analgesics, they have the broadest range of efficacy and provide the most reliable and effective treatment for rapid pain relief. Although side effects are common, most are revers­ ible: nausea, vomiting, pruritus, sedation, and constipation are the most frequent and bothersome side effects. Respiratory depression is uncommon at standard analgesic doses but can be life-threatening. Opioid-related side effects can be reversed rapidly with the narcotic antagonist naloxone. Many physicians, nurses, and patients have a certain trepidation about using opioids that is based on a fear of initiating addiction in their patients. There is a small chance of patients becoming addicted to narcotics as a result of their appropriate medical use. For chronic pain, particularly chronic noncancer pain, the risk of addiction in patients taking opioids on a chronic basis remains small, and the risk appears to increase with dose escalation and duration of treatment. The physician should not hesitate to use opioid anal­ gesics in patients with acute severe pain. Table 14-1 lists the most commonly used opioid analgesics. PART 2 Cardinal Manifestations and Presentation of Diseases Opioids produce analgesia by actions in the CNS. They acti­ vate pain-inhibitory neurons and directly inhibit pain-transmission neurons. Most of the commercially available opioid analgesics act at the same opioid receptor (μ-receptor), differing mainly in potency, speed of onset, duration of action, and optimal route of administration. Some side effects are due to accumulation of nono­ pioid metabolites that are unique to individual drugs. One striking example of this is normeperidine, a metabolite of meperidine. At higher doses of meperidine, typically >1 g/d, accumulation of normeperidine can produce hyperexcitability and seizures that are not reversible with naloxone. Normeperidine accumulation is increased in patients with renal failure. The most rapid pain relief is obtained by intravenous admin­ istration of opioids; relief with oral administration is significantly slower. Because of the potential for respiratory depression, patients with any form of respiratory compromise must be kept under close observation following opioid administration; an oxygen-saturation monitor may be useful, but only in a setting where the monitor is under constant surveillance. Opioid-induced respiratory depres­ sion is primarily manifest as a reduction in respiratory rate and is typically accompanied by sedation. A fall in oxygen saturation represents a critical level of respiratory depression and the need for immediate intervention to prevent life-threatening hypoxemia. Newer monitoring devices that incorporate capnography or pha­ ryngeal air flow can detect apnea at the point of onset and are now commonly used in hospitalized patients. Ventilatory assistance should be maintained until the opioid-induced respiratory depres­ sion has resolved. The opioid antagonist naloxone should be readily available whenever opioids are used at high doses or in patients with compromised pulmonary function. Opioid effects are dose-related, and there is great variability among patients in the doses that relieve pain and produce side effects. Synergistic respiratory depression is common when opioids are administered with other CNS depres­ sants. Co-administration of benzodiazepines is particularly likely to produce respiratory depression and should be avoided, especially in outpatient pain management. Because of this variability in patient response, initiation of therapy requires titration to optimal dose and interval. The most important principle is to provide adequate pain relief. This requires determining whether the drug has adequately relieved the pain and timely reassessment to determine the optimal interval for dosing. The most common error made by physicians in managing severe pain with opioids is to prescribe an inadequate dose. Because many patients are reluctant to complain, this practice leads to needless suffering. In the absence of sedation at the expected time of

peak effect, a physician should not hesitate to repeat the initial dose to achieve satisfactory pain relief. A now standard approach to the problem of achieving adequate pain relief is the use of patient-controlled analgesia (PCA). PCA uses a microprocessor-controlled infusion device that can deliver a baseline continuous dose of an opioid drug as well as prepro­ grammed additional doses whenever the patient pushes a button. The patient can then titrate the dose to the optimal level. This approach is used most extensively for the management of postop­ erative pain, but there is no reason it should not be used for any hospitalized patient with persistent severe pain. PCA is also used for short-term home care of patients with intractable pain, such as that caused by metastatic cancer. It is important to understand that the PCA device delivers small, repeated doses to maintain pain relief; in patients with severe pain, the pain must first be brought under control with a loading dose before transitioning to the PCA device. The bolus dose of the drug (typically 1 mg of morphine, 0.2 mg of hydromorphone, or 10 μg of fentanyl) can then be delivered repeatedly as needed. To prevent overdosing, PCA devices are programmed with a lockout period after each demand dose is delivered (typically starting at 10 min) and a limit on the total dose delivered per hour. Although some have advocated the use of a simultaneous continuous or basal infusion of the PCA drug, this may increase the risk of respiratory depression and has not been shown to increase the overall efficacy of the technique. The availability of new routes of administration has extended the usefulness of opioid analgesics. Most important is the avail­ ability of spinal administration. Opioids can be infused through a spinal catheter placed either intrathecally or epidurally. By apply­ ing opioids directly to the spinal or epidural space adjacent to the spinal cord, regional analgesia can be obtained using relatively low total doses. Indeed, the dose required to produce effective analgesia when using morphine intrathecally (0.1–0.3 mg) is a fraction of that required to produce similar analgesia when administered intrave­ nously (5–10 mg). In this way, side effects such as sedation, nausea, and respiratory depression can be minimized. This approach has been used extensively during labor and delivery and for postopera­ tive pain relief following surgical procedures. Continuous intrathe­ cal delivery via implanted spinal drug-delivery systems is now commonly used, particularly for the treatment of cancer-related pain that would require sedating doses for adequate pain control if given systemically. Opioids can also be given intranasally (butor­ phanol), rectally, and transdermally (fentanyl and buprenorphine), or through the oral mucosa (fentanyl), thus avoiding the discomfort of frequent injections in patients who cannot be given oral medica­ tion. The fentanyl and buprenorphine transdermal patches have the advantage of providing steady plasma levels, which may improve patient comfort. Recent additions to the armamentarium for treating opioidinduced side effects are the peripherally acting opioid antagonists alvimopan (Entereg) and methylnaltrexone (Rellistor). Alvimopan is available as an orally administered agent that is restricted to the intestinal lumen by limited absorption; methylnaltrexone is avail­ able in a subcutaneously administered form that has virtually no penetration into the CNS. Both agents act by binding to peripheral μ-receptors, thereby inhibiting or reversing the effects of opioids at these peripheral sites. The action of both agents is restricted to receptor sites outside of the CNS; thus, these drugs can reverse the adverse effects of opioid analgesics that are mediated through their peripheral receptors without reversing their CNS-mediated analge­ sic effects. Alvimopan has proven effective in lowering the duration of persistent ileus following abdominal surgery in patients receiving opioid analgesics for postoperative pain control. Methylnaltrexone has proven effective for relief of opioid-induced constipation in patients taking opioid analgesics on a chronic basis. Opioid and COX Inhibitor Combinations  When used in combi­ nation, opioids and COX inhibitors have additive or synergistic

effects. Because a lower dose of each can be used to achieve the same degree of pain relief and their side effects are typically dose related, such combinations are used to lower the severity of dose-

related side effects. However, fixed-ratio combinations of an opi­ oid with acetaminophen carry an important risk. Dose escalation because of increased severity of pain or decreased opioid effect as a result of tolerance may lead to ingestion of levels of acetamino­ phen that are toxic to the liver. Although acetaminophen-related hepatotoxicity is uncommon, it remains a significant cause for liver failure. Thus, many practitioners have moved away from the use of opioid-acetaminophen combination analgesics to avoid the risk of excessive acetaminophen exposure as the dose of the analgesic is escalated. CHRONIC PAIN Managing patients with chronic pain is intellectually and emotionally challenging. Sensitization of the nervous system can occur without an obvious precipitating cause, e.g., fibromyalgia, or chronic headache. In many patients, chronic pain becomes a distinct disease unto itself. The pain-generating mechanism is often difficult or impossible to deter­ mine with certainty; such patients are demanding of the physician’s time and often appear emotionally distraught. The traditional medical approach of seeking an obscure organic pathology is often unhelpful. On the other hand, psychological evaluation and behaviorally based treatment paradigms are frequently helpful, particularly in the set­ ting of a multidisciplinary pain-management center. Unfortunately, this approach, while effective, remains largely underused in current medical practice. There are several factors that can cause, perpetuate, or exacerbate chronic pain. First, of course, the patient may simply have a disease that is characteristically painful for which there is presently no cure. Arthritis, cancer, chronic daily headaches, fibromyalgia, and diabetic neuropathy are examples of this. Second, there may be secondary perpetuating factors that are initiated by disease and persist after that disease has resolved. Examples include damaged sensory nerves, sympathetic efferent activity, and painful reflex muscle contraction (spasm). Finally, a variety of psychological conditions can exacerbate or even cause pain. There are certain areas to which special attention should be paid in a patient’s medical history. Because depression (Chap. 463) is the most common emotional disturbance in patients with chronic pain, patients should be questioned about their mood, appetite, sleep patterns, and daily activity. A simple standardized questionnaire, such as the Beck Depression Inventory, can be a useful screening device. It is important to remember that major depression is a common, treatable, and poten­ tially fatal illness. Other clues that a significant emotional disturbance is contributing to a patient’s chronic pain complaint include pain that occurs in mul­ tiple, unrelated sites; a pattern of recurrent, but separate, pain problems beginning in childhood or adolescence; pain beginning at a time of emotional trauma, such as the loss of a parent or spouse; a history of physical or sexual abuse; and past or present substance abuse. On examination, special attention should be paid to whether the patient guards the painful area and whether certain movements or postures are avoided because of pain. Discovering a mechanical component to the pain can be useful both diagnostically and thera­ peutically. Painful areas should be examined for deep tenderness, noting whether this is localized to muscle, ligamentous structures, or joints. Chronic myofascial pain is very common, and in these patients, deep palpation may reveal highly localized trigger points that are firm bands or knots in muscle. Relief of the pain follow­ ing injection of local anesthetic into these trigger points supports the diagnosis. A neuropathic component to the pain is indicated by evidence of nerve damage, such as sensory impairment, exquisitely sensitive skin (allodynia), weakness, and muscle atrophy, or loss of deep tendon reflexes. Evidence suggesting sympathetic nervous sys­ tem involvement includes the presence of diffuse swelling, changes in skin color and temperature, and hypersensitive skin and joint

tenderness compared with the normal side. Relief of the pain with a sympathetic block supports the diagnosis, but once the condition becomes chronic, the response to sympathetic blockade is of variable magnitude and duration; the role for repeated sympathetic blocks in the overall management of CRPS is unclear.

A guiding principle in evaluating patients with chronic pain is to assess both emotional and somatic causal and perpetuating factors before initiating therapy. Addressing these issues together, rather than waiting to address emotional issues after somatic causes of pain have been ruled out, improves compliance in part because it assures patients that a psychological evaluation does not mean that the phy­ sician is questioning the validity of their complaint. Even when a somatic cause for a patient’s pain can be found, it is still wise to look for other factors. For example, a cancer patient with painful bony metastases may have additional pain due to nerve damage and may also be depressed. Optimal therapy requires that each of these factors be assessed and treated. Pain: Pathophysiology and Management CHAPTER 14 TREATMENT Chronic Pain Once the evaluation process has been completed and the likely causative and exacerbating factors identified, an explicit treatment plan should be developed. An important part of this process is to identify specific and realistic functional goals for therapy, such as getting a good night’s sleep, being able to go shopping, or return­ ing to work. A multidisciplinary approach that uses medications, counseling, physical therapy, nerve blocks, and even surgery may be required to improve the patient’s quality of life. There are also some newer, minimally invasive procedures that can be helpful for some patients with intractable pain. These include image-guided interventions such as epidural injection of glucocorticoids for acute radicular pain and radiofrequency treatment of the facet joints for chronic facet-related back and neck pain. For patients with severe and persistent pain that is unresponsive to more con­ servative treatment, placement of electrodes on peripheral nerves or within the spinal canal on nerve roots or in the space overlying the dorsal columns of the spinal cord (spinal cord stimulation) has shown significant benefit. The criteria for predicting which patients will respond to these procedures continue to evolve. They are generally reserved for patients who have not responded to conventional pharmacologic approaches. Referral to a multidisci­ plinary pain clinic for a full evaluation should precede any invasive procedure. Such referrals are clearly not necessary for all chronic pain patients. For some, pharmacologic management alone can provide adequate relief. ANTIDEPRESSANT MEDICATIONS The tricyclic antidepressants (TCAs), particularly nortriptyline and desipramine (Table 14-1), are useful for the management of chronic pain. Although developed for the treatment of depression, the TCAs have a spectrum of dose-related biologic activities that include analgesia in a variety of chronic clinical conditions. Although the mechanism is unknown, the analgesic effect of TCAs has a more rapid onset and occurs at a lower dose than is typically required for the treatment of depression. Furthermore, patients with chronic pain who are not depressed obtain pain relief with antidepressants. There is evidence that TCAs potentiate opioid analgesia, so they may be useful adjuncts for the treatment of severe persistent pain such as occurs with malignant tumors. Table 14-2 lists some of the painful conditions that respond to TCAs. TCAs are of particular value in the management of neuropathic pain such as occurs in diabetic neuropathy and postherpetic neuralgia, for which there are few other therapeutic options. The TCAs that have been shown to relieve pain have significant side effects (Table 14-1; Chap. 463). Some of these side effects, such as orthostatic hypotension, drowsiness, cardiac conduction delay, memory impairment, constipation, and urinary retention,

TABLE 14-2  Painful Conditions That Respond to Tricyclic Antidepressants Postherpetic neuralgiaa Diabetic neuropathya Fibromyalgiaa Tension headachea Migraine headachea Rheumatoid arthritisa,b Chronic low back painb Cancer Central poststroke pain PART 2 Cardinal Manifestations and Presentation of Diseases aControlled trials demonstrate analgesia. bControlled studies indicate benefit but not analgesia. are particularly problematic in elderly patients, and several are additive to the side effects of opioid analgesics. The selective sero­ tonin reuptake inhibitors such as fluoxetine (Prozac) have fewer and less serious side effects than TCAs, but they are much less effective for relieving pain. In contrast, venlafaxine (Effexor) and duloxetine (Cymbalta), which are nontricyclic antidepressants that block both serotonin and norepinephrine reuptake, appear to retain most of the pain-relieving effects of TCAs with a side effect profile more like that of the selective serotonin reuptake inhibitors. Because of their favorable adverse effect profiles, these drugs have largely supplanted the use of TCAs in treatment of chronic pain. ANTICONVULSANTS AND ANTIARRHYTHMICS These drugs are useful primarily for patients with neuropathic pain. Phenytoin (Dilantin) and carbamazepine (Tegretol) were first shown to relieve the pain of trigeminal neuralgia (Chap. 452). This pain has a characteristic brief, shooting, electric shock-like quality. In fact, anticonvulsants seem to be particularly helpful for pains that have such a lancinating quality. Newer anticonvulsants, the calcium channel alpha-2-delta subunit ligands gabapentin (Neurontin) and pregabalin (Lyrica), are effective for a broad range of neuropathic pains. Furthermore, because of their favorable side effect profiles, these newer anticonvulsants are often used as firstline agents. CANNABINOIDS These agents are widely used for their analgesic properties, although published evidence suggests that any analgesic effects are modest, with small increases in pain threshold reported and variable reduc­ tions in clinical pain intensity. Cannabis more consistently reduces the unpleasantness of the pain experience and, in cancer-related pain, can lessen the nausea and vomiting associated with chemo­ therapy use. Marijuana and related compounds are discussed in Chap. 466. CHRONIC OPIOID MEDICATION The long-term use of opioids is accepted for patients with pain due to malignant disease. Although opioid use for chronic pain of nonmalignant origin is controversial, for many patients, opioids are the only option that produces meaningful pain relief. This is understandable because opioids are the most potent and have the broadest range of efficacy of any analgesic medications. Although addiction is rare in patients who first use opioids for pain relief, some degree of tolerance and physical dependence is likely with long-term use. Furthermore, studies suggest that long-term opioid therapy may worsen pain in some individuals, termed opioid-

induced hyperalgesia. Therefore, before embarking on opioid ther­ apy, other options should be explored, and the limitations and risks of opioids should be explained to the patient. It is also important to recognize that some opioid analgesic medications have mixed ago­ nist-antagonist properties (e.g., butorphanol and buprenorphine). From a practical standpoint, this means that they may worsen pain

by inducing an abstinence syndrome in patients who are actively being treated with other opioids and are physically dependent. With long-term outpatient use of orally administered opioids, it may be desirable to use long-acting compounds such as levor­ phanol, methadone, extended-release morphine or oxycodone, or transdermal fentanyl (Table 14-1). The pharmacokinetic profiles of these drug preparations enable the maintenance of sustained analgesic blood levels, potentially minimizing side effects such as sedation that are associated with high peak plasma levels and reducing the likelihood of rebound pain associated with a rapid fall in plasma opioid concentration. Extended-release opioid formula­ tions are approved primarily for patients who are already taking other opioids and should not be used as first-line opioids for pain. Although long-acting opioid preparations may provide superior pain relief in patients with a continuous pattern of ongoing pain, others suffer from intermittent severe episodic pain and experience superior pain control and fewer side effects with the periodic use of short-acting opioid analgesics. Constipation is a virtually universal side effect of opioid use and should be treated expectantly. As noted earlier in the discussion of acute pain treatment, an advance for patients is the development of peripherally acting opioid antago­ nists that can reverse the constipation associated with opioid use without interfering with analgesia. Soon after the introduction of an extended-release oxycodone formulation (OxyContin) in the late 1990s, a dramatic rise in emergency department visits and deaths associated with oxycodone ingestion appeared. This appears to be due primarily to individu­ als using a prescription opioid nonmedically. Drug-induced deaths have rapidly risen and are now the second leading cause of death in Americans, just behind motor vehicle fatalities. In 2011, the Office of National Drug Control Policy established a multifaceted approach to address prescription drug abuse, including prescrip­ tion drug monitoring programs (PDMPs) that allow practitioners to determine if patients are receiving prescriptions from multiple providers and use of law enforcement to eliminate improper pre­ scribing practices. In 2016, the Centers for Disease Control and Prevention (CDC) released the CDC Guideline for Prescribing Opioids for Chronic Pain, with recommendations for primary care clini­ cians who are prescribing opioids for chronic noncancer pain. A modified approach to opioid prescribing was published in 2019 by the Health and Human Services Task Force on chronic pain best medical practices and updated in 2022. These guidelines address (1) when to initiate or continue opioids for chronic pain; (2) opioid selection, dosage, duration, follow-up, and discontinuation; and (3) assessing risk and addressing harms of opioid use. The recent increase in scrutiny leaves many practitioners hesitant to prescribe opioid analgesics, other than for brief periods to control pain asso­ ciated with illness or injury. For now, the choice to begin chronic opioid therapy for a given patient is left to the individual practi­ tioner. The new CDC guidelines aim to help practitioners reduce the risk of opioid misuse and overdose deaths while providing effective pain management for their patients. Pragmatic guidelines for properly selecting and monitoring patients receiving chronic opioid therapy are shown in Table 14-3; a checklist for primary care clinicians prescribing opioids for noncancer pain is shown in Table 14-4. Practitioners should refer to the 2022 Clinical Practice Guideline for prescribing opioids for pain (referenced in Further Reading, below). Opioid use disorders are comprehensively dis­ cussed in Chap. 467. TREATMENT OF NEUROPATHIC PAIN It is important to individualize treatment for patients with neu­ ropathic pain. Several general principles should guide therapy: the first is to move quickly to provide relief, and the second is to minimize drug side effects. For example, in patients with posther­ petic neuralgia and significant cutaneous hypersensitivity, topical lidocaine (e.g. Lidoderm patches) can provide immediate relief without side effects. The anticonvulsants gabapentin or pregabalin

TABLE 14-3  Guidelines for Selecting and Monitoring Patients Receiving Chronic Opioid Therapy (COT) for the Treatment of Chronic, Noncancer Pain Patient Selection • Conduct a history, physical examination, and appropriate testing, including an assessment of risk of substance abuse, misuse, or addiction. • Consider a trial of COT if pain is moderate or severe, pain is having an adverse impact on function or quality of life, and potential therapeutic benefits outweigh potential harms. • A benefit-to-harm evaluation, including a history, physical examination, and appropriate diagnostic testing, should be performed and documented before and on an ongoing basis during COT. Informed Consent and Use of Management Plans • Informed consent should be obtained. A continuing discussion with the patient regarding COT should include goals, expectations, potential risks, and alternatives to COT. • Consider using a written COT management plan to document patient and clinician responsibilities and expectations and assist in patient education. Initiation and Titration • Initial treatment with opioids should be considered as a therapeutic trial to determine whether COT is appropriate. • Opioid selection, initial dosing, and titration should be individualized according to the patient’s health status, previous exposure to opioids, attainment of therapeutic goals, and predicted or observed harms. Monitoring • Reassess patients on COT periodically and as warranted by changing circumstances. Monitoring should include documentation of pain intensity and level of functioning, assessments of progress toward achieving therapeutic goals, presence of adverse events, and adherence to prescribed therapies. • In patients on COT who are at high risk or who have engaged in aberrant drugrelated behaviors, clinicians should periodically obtain urine drug screens or other information to confirm adherence to the COT plan of care. • In patients on COT not at high risk and not known to have engaged in aberrant drug-related behaviors, clinicians should consider periodically obtaining urine drug screens or other information to confirm adherence to the COT plan

of care. Source: Reproduced with permission from R Chou et al: Clinical guidelines for the use of chronic opioid therapy in chronic noncancer pain. J Pain 10:113-130, 2009. Source: Centers for Disease Control and Prevention, available at https://stacks.cdc. gov/view/cdc/38025. Accessed February 18, 2024 (Public Domain). (see above) or antidepressants (nortriptyline, desipramine, dulox­ etine, or venlafaxine) can be used as first-line drugs for patients with neuropathic pain. Systemically administered antiarrhythmic drugs such as lidocaine and mexiletine are less likely to be effective. Although intravenous infusion of lidocaine can provide analgesia for patients with different types of neuropathic pain, the relief is usually transient, typically lasting just hours after the cessation of the infusion. The oral lidocaine congener mexiletine is poorly tol­ erated, producing frequent gastrointestinal adverse effects. There is no consensus on which class of drug should be used as a first-line treatment for any chronically painful condition. However, because relatively high doses of anticonvulsants are required for pain relief, sedation is not uncommon. Sedation is also a problem with TCAs but is much less of a problem with serotonin/norepinephrine reup­ take inhibitors (SNRIs; e.g., venlafaxine and duloxetine). Thus, in the elderly or in patients whose daily activities require high-level mental activity, these drugs should be considered the first line. In contrast, opioid medications should be used as a second- or third-line drug class. Although highly effective for many painful conditions, opioids are sedating, and their effect tends to lessen over time, leading to dose escalation and, occasionally, a worsen­ ing of pain. A couple of interesting alternatives to pure opioids are two drugs with mixed opioid and norepinephrine reuptake action: tramadol and tapentadol. Tramadol is a relatively weak opioid but is sometimes effective for pain unresponsive to nonopioid anal­ gesics. Tapentadol is a stronger opioid, but its analgesic action is apparently enhanced by the norepinephrine reuptake blockade.

TABLE 14-4  Centers for Disease Control and Prevention Checklist for Prescribing Opioids for Chronic Pain For Primary Care Providers Treating Adults (18+) with Chronic Pain

≥3 Months, Excluding Cancer, Palliative, and End-of-Life Care CHECKLIST WHEN CONSIDERING LONG-TERM OPIOID THERAPY • Set realistic goals for pain and function based on diagnosis (e.g., walk around the block). • Check that nonopioid therapies tried and optimized. • Discuss benefits and risks (e.g., addiction, overdose) with patient. • Evaluate risk of harm or misuse. Pain: Pathophysiology and Management CHAPTER 14 • Discuss risk factors with patient. • Check prescription drug monitoring program (PDMP) data. • Check urine drug screen. • Set criteria for stopping or continuing opioids. • Assess baseline pain and function (e.g., Pain, Enjoyment, General Activity [PEG] scale). • Schedule initial reassessment within 1–4 weeks. • Prescribe short-acting opioids using lowest dosage on product labeling; match duration to scheduled reassessment. IF RENEWING WITHOUT A PATIENT VISIT • Check that return visit is scheduled ≤3 months from last visit. WHEN REASSESSING AT A PATIENT VISIT • Continue opioids only after confirming clinically meaningful improvements in pain and function without significant risks or harm. • Assess pain and function (e.g., PEG); compare results to baseline. • Evaluate risk of harm or misuse: • Observe patient for signs of oversedation or overdose risk. If yes: Taper dose. • Check PDMP. • Check for opioid use disorder if indicated (e.g., difficulty controlling use).

If yes: Refer for treatment. • Check that nonopioid therapies optimized. Determine whether to continue, adjust, taper, or stop opioids. • Calculate opioid dosage morphine milligram equivalent (MME). • If ≥50 MME/day total (≥50 mg hydrocodone; ≥33 mg oxycodone), increase frequency of follow-up; consider offering naloxone. • Avoid ≥90 MME/day total (≥90 mg hydrocodone; ≥60 mg oxycodone), or carefully justify; consider specialist referral. • Schedule reassessment at regular intervals (≤3 months). Similarly, drugs of different classes can be used in combination to optimize pain control. It is worth emphasizing that many patients, especially those with chronic pain, seek medical attention primarily because they are suffering and because only physicians can provide the medications required for pain relief. A primary responsibility of all physicians is to minimize the physical and emotional discomfort of their patients. Familiarity with pain mechanisms and analgesic medica­ tions is an important step toward accomplishing this aim. ■ ■FURTHER READING De Vita MJ et al: Association of cannabinoid administration with experimental pain in healthy adults a systematic review and metaanalysis. JAMA Psychiatry 75:1118, 2018. Dowell D et al: CDC Clinical Practice Guideline for prescribing opioids for pain—United States, 2022. MMWR Recomm Rep 71:1,

Finnerup NB et al: Neuropathic pain: From mechanisms to treatment. Physiol Rev 101:259, 2021. Sun EC et al: Incidence of and risk factors for chronic opioid use among opioid-naive patients in the postoperative period. JAMA Intern Med 176:1286, 2016.

03 - 15 Chest Discomfort

15 Chest Discomfort

David A. Morrow

Chest Discomfort Chest discomfort is among the most common reasons for which patients present for medical attention at either an emergency depart­ ment (ED) or an outpatient clinic. The evaluation of nontraumatic chest discomfort is inherently challenging owing to the broad variety of possible causes, a minority of which are life-threatening conditions that should not be missed. It is helpful to frame the initial diagnostic assessment and triage of patients with acute chest discomfort around three categories: (1) myocardial ischemia; (2) other cardiopulmonary causes (myopericardial disease, aortic emergencies, and pulmonary conditions); and (3) noncardiopulmonary causes. Although rapid identification of high-risk conditions is a priority of the initial assess­ ment, strategies that incorporate routine liberal use of testing carry the potential for adverse effects of unnecessary investigations. PART 2 Cardinal Manifestations and Presentation of Diseases EPIDEMIOLOGY AND NATURAL HISTORY Chest discomfort is one of the three most common reason for visits to the ED in the United States, resulting in 6–7 million emergency visits each year. More than 60% of patients with this presentation are hospi­ talized for further testing, and most of the remainder undergo addi­ tional investigation in the ED. Fewer than 15% of evaluated patients are eventually diagnosed with acute coronary syndrome (ACS), with rates of 10–20% in most series of unselected populations, and a rate as low as 5% in some studies. The most common diagnoses are gastrointestinal causes (Fig. 15-1), and as few as 5% are other life-threatening cardio­ pulmonary conditions. In a large proportion of patients with transient acute chest discomfort, ACS or another acute cardiopulmonary cause is excluded but the cause is not determined. Therefore, the resources and time devoted to the evaluation of chest discomfort in the absence of a severe cause are substantial. Nevertheless, historically, a disconcerting 2–6% of patients with chest discomfort of presumed nonischemic etiol­ ogy who are discharged from the ED were later deemed to have had a missed myocardial infarction (MI). The natural histories of ACS, myocarditis, acute pericardial diseases, pulmonary embolism, and aortic emergencies are discussed in Chaps. 281, 284, 285, 286, 290, and 291, respectively. The estimated rate of major cardiovascular events through 30 days in patients with acute chest pain who had been stratified as low risk was 2.5% in a large population-based study that excluded patients with ST-segment eleva­ tion or definite noncardiac chest pain. CAUSES OF CHEST DISCOMFORT The major etiologies of chest discomfort are discussed in this sec­ tion and summarized in Table 15-1. Additional elements of the history, physical examination, and diagnostic testing that aid in FIGURE 15-1  Distribution of final discharge diagnoses in patients with nontraumatic acute chest pain. (Figure prepared from data in P Fruergaard et al: Eur Heart J 17:1028, 1996.)

distinguishing these causes are discussed in a later section (see “Approach to the Patient”). ■ ■MYOCARDIAL ISCHEMIA/INJURY Myocardial ischemia causing chest discomfort, termed angina pec­ toris, is a primary clinical concern in patients presenting with chest symptoms. Myocardial ischemia is precipitated by an imbalance between myocardial oxygen requirements and myocardial oxygen supply, resulting in insufficient delivery of oxygen to meet the heart’s metabolic demands. Myocardial oxygen consumption may be elevated by increases in heart rate, ventricular wall stress, and myocardial con­ tractility, whereas myocardial oxygen supply is determined by coronary blood flow and coronary arterial oxygen content. When myocardial ischemia is sufficiently severe and prolonged in duration (as little as 20 min), irreversible cellular injury occurs, resulting in MI. The pathobiology of ischemic heart disease is described in Chap. 284. Stable angina is characterized by ischemic episodes that are typically precipitated by a superimposed increase in oxygen demand during physical exertion and relieved upon resting. Unstable ischemic heart disease (Chaps. 285 and 286) is classified clinically by the presence or absence of detectable acute myocardial injury and the presence or absence of ST-segment elevation on the patient’s electrocardiogram (ECG). Unstable ischemic heart disease is classified as unstable angina when there is no detectable acute myocardial injury and either as non– ST elevation MI (NSTEMI; see Chap. 285) or ST-elevation MI (STEMI; see Chap. 286) when there is evidence of acute myocardial injury. Clinicians should be aware that unstable ischemic symptoms may also occur predominantly because of increased myocardial oxygen demand (e.g., during intense psychological stress) or because of decreased oxygen delivery due to anemia, hypoxia, or hypotension. However, the term acute coronary syndrome, which encompasses unstable angina, NSTEMI, and STEMI, is in general reserved for ischemia precipitated by acute coronary atherothrombosis. To guide therapeutic strategies, a standardized system for classification of MI has been expanded to discriminate MI resulting from acute coronary thrombosis (type 1 MI) from MI occurring secondary to other imbal­ ances of myocardial oxygen supply and demand (type 2 MI; see Chap. 285). Conditions associated with extreme myocardial oxygen demand and impaired endocardial blood flow, such as aortic valve disease (Chap. 291), hypertrophic cardiomyopathy, or idiopathic dilated cardiomyopathy (Chaps. 266–270), can precipitate myocardial ischemia in patients with or without underlying obstructive atheroscle­ rosis. Ischemic causes of chest pain and myocardial injury are addition­ ally distinguished from nonischemic causes of acute myocardial injury, such as myocarditis. Characteristics of Ischemic Chest Discomfort  The clinical characteristics of angina pectoris, often referred to simply as “angina,” are highly similar in quality and location whether the ischemic discom­ fort is a manifestation of stable ischemic heart disease, unstable angina, or MI (Table 15-1). Heberden initially described angina as a sense of Gastrointestinal 42% Ischemic heart disease 31% Chest wall syndrome 28% Pericarditis 4% Pleuritis 2% Pulmonary embolism 2% Lung cancer 1.5% Aortic aneurysm 1% Aortic stenosis 1% Herpes zoster 1%

TABLE 15-1  Typical Clinical Features of Major Causes of Acute Chest Discomfort SYSTEM CONDITION ONSET/DURATION QUALITY LOCATION ASSOCIATED FEATURES Cardiopulmonary Cardiac Myocardial ischemia Stable angina: Precipitated by exertion, cold, or stress; 2–10 min Unstable angina: Increasing pattern or at rest Myocardial infarction: Usually >30 min   Pericarditis Variable; hours to days; may be episodic Vascular Acute aortic syndrome Sudden onset of unrelenting pain   Pulmonary embolism Sudden onset Pleuritic; may manifest as heaviness with massive pulmonary embolism   Pulmonary hypertension Variable; often exertional Pressure Substernal Dyspnea, signs of increased venous pressure Pulmonary Pneumonia or pleuritis Variable Pleuritic Unilateral, often localized Dyspnea, cough, fever, rales, occasional rub   Spontaneous pneumothorax Sudden onset Pleuritic Lateral to side of pneumothorax Noncardiopulmonary Gastrointestinal Esophageal reflux 10–60 min Burning Substernal, epigastric Worsened by postprandial recumbency; relieved by antacids   Esophageal spasm 2–30 min Pressure, tightness, burning, intense squeezing   Esophageal injury Prolonged Intense squeezing Retrosternal Includes Mallory-Weiss tear or esophageal rupture (Boerhaave’s syndrome) from vomiting   Peptic ulcer Prolonged; 60–90 min after meals   Gallbladder disease, including cholecystitis and biliary colic Prolonged; steady, usually hours   Pancreatitis Prolonged Typically aching Epigastric, radiates to the back Neuromuscular Costochondritis Variable Aching Sternal Sometimes swollen, tender, warm over joint; may be reproduced by localized pressure on examination   Cervical disk disease Variable; may be sudden Aching; may include numbness   Trauma or strain Usually constant Aching Localized to area of strain Reproduced by movement or palpation   Herpes zoster Usually prolonged Sharp or burning Dermatomal distribution Vesicular rash in area of discomfort Psychological Emotional and psychiatric conditions Variable; may be fleeting or prolonged “strangling and anxiety.” Chest discomfort characteristic of myocardial ischemia is typically described as aching, heavy, squeezing, crushing, or constricting. However, in a substantial minority of patients, the qual­ ity of discomfort is extremely vague and may be described as a mild tightness, or merely an uncomfortable feeling, that sometimes is expe­ rienced as numbness or a burning sensation. The site of the discomfort is usually retrosternal, but radiation is common and generally occurs down the ulnar surface of the left arm; the right arm, both arms, neck,

Pressure, tightness, squeezing, heaviness, burning Retrosternal; often radiation to neck, jaw, shoulders, or arms; sometimes epigastric S4 gallop or mitral regurgitation murmur (rare) during pain; S3 or rales if severe ischemia or complication of myocardial infarction Chest Discomfort CHAPTER 15 Pleuritic, sharp Retrosternal or toward cardiac apex; may radiate to left shoulder May be relieved by sitting up and leaning forward; pericardial friction rub Tearing or ripping; knifelike Anterior chest, often radiating to back, between shoulder blades Associated with hypertension and/or underlying connective tissue disorder; murmur of aortic insufficiency; loss of peripheral pulses Often lateral, on the side of the embolism Dyspnea, tachypnea, tachycardia, and hypotension Dyspnea, decreased breath sounds on side of pneumothorax Retrosternal Can closely mimic angina. May be relieved by nitroglycerin or dihydropyridine calcium channel antagonists Burning Epigastric (most common), substernal Relieved with food or antacids Aching or colicky Epigastric, right upper quadrant; sometimes to the back, scapula, and lower chest May follow meal and may subside spontaneously   Arms and shoulders May be exacerbated by movement of neck Variable; often manifests as tightness and dyspnea with feeling of panic or doom Variable; may be retrosternal Situational factors may precipitate symptoms; history of panic attacks, depression jaw, or shoulders may also be involved. These and other characteristics of ischemic chest discomfort pertinent to discrimination from other causes of chest pain are discussed later in this chapter (see “Approach to the Patient”). Stable angina usually begins gradually and reaches its maximal intensity over a period of minutes before dissipating within several minutes with rest or with nitroglycerin. The discomfort typically occurs predictably at a characteristic level of exertion or psychological

stress. By definition, unstable angina is manifest by anginal chest discomfort that occurs with progressively lower intensity of physical activity or even at rest. Chest discomfort associated with MI is com­ monly more severe, is prolonged (usually lasting ≥30 min), and is not relieved by rest.

■ ■OTHER CARDIOPULMONARY CAUSES Pericardial and Other Myocardial Diseases (See also Chap. 281)  Inflammation of the pericardium due to infectious or noninfectious causes can be responsible for acute or chronic chest discomfort. The visceral surface and most of the parietal surface of the pericardium are insensitive to pain. Therefore, the pain of pericarditis is thought to arise principally from associated pleural inflammation. Because of this pleural association, the discomfort of pericarditis is usually pleuritic pain that is exacerbated by breathing, coughing, or changes in position. Moreover, owing to the overlapping sensory supply of the central diaphragm via the phrenic nerve with somatic sensory fibers originating in the third to fifth cervical segments, the pain of pleural and pericardial inflammation is often referred to the shoulder and neck. Involvement of the pleural surface of the lateral diaphragm can lead to pain in the upper abdomen. PART 2 Cardinal Manifestations and Presentation of Diseases Acute inflammatory and other nonischemic myocardial diseases can also produce chest discomfort. The symptoms of acute myocar­ ditis are highly varied. Chest discomfort may either originate with inflammatory injury of the myocardium or be due to severe increases in wall stress related to poor ventricular performance. The symptoms of Takotsubo (stress-related) cardiomyopathy often start abruptly with chest pain and shortness of breath. This form of cardiomyopathy, in its most recognizable form, is triggered by an emotionally or physi­ cally stressful event and may mimic acute MI because of its commonly associated ECG abnormalities, including ST-segment elevation, and elevated biomarkers of myocardial injury. Diseases of the Aorta (See also Chap. 291)  Acute aortic dis­ section (Fig. 15-1) is a less common cause of chest discomfort but is important because of the catastrophic natural history of certain subsets of cases when recognized late or left untreated. Acute aortic syndromes encompass a spectrum of acute aortic diseases related to disruption of the media of the aortic wall, including penetrating ulcer and intramural hematoma (see Chap. 291). Each of these subtypes of acute aortic syndrome typically presents with chest discomfort that is often severe, sudden in onset, and some­ times described as “tearing” in quality. Acute aortic syndromes involv­ ing the ascending aorta tend to cause pain in the midline of the anterior chest, whereas descending aortic syndromes most often present with pain in the back. Therefore, dissections that begin in the ascending aorta and extend to the descending aorta tend to cause pain in the front of the chest that extends toward the back, between the shoulder blades. Nontraumatic aortic dissections are very rare in the absence of hypertension or conditions associated with deterioration of the elastic or muscular components of the aortic media, including pregnancy, bicuspid aortic disease, or inherited connective tissue diseases, such as Marfan and Ehlers-Danlos syndromes. Aortitis, whether of noninfec­ tious or infectious etiology, in the absence of aortic dissection is a rare cause of chest or back discomfort. Pulmonary Conditions  Pulmonary and pulmonary-vascular conditions that cause chest discomfort usually do so in conjunction with dyspnea and often produce symptoms that have a pleuritic nature. PULMONARY EMBOLISM (SEE ALSO CHAP. 290)  Pulmonary emboli can produce dyspnea and chest discomfort that is sudden in onset. Typi­ cally pleuritic in pattern, the chest discomfort associated with pulmo­ nary embolism may result from (1) involvement of the pleural surface of the lung adjacent to a resultant pulmonary infarction; (2) distention of the pulmonary artery; or (3) possibly, right ventricular wall stress and/or subendocardial ischemia related to acute pulmonary hyperten­ sion. The pain associated with small pulmonary emboli is often lateral and pleuritic and is believed to be related to the first of these three pos­ sible mechanisms. In contrast, massive pulmonary emboli may cause

severe substernal pain that may mimic an MI and that is plausibly attributed to the second and third of these potential mechanisms. Mas­ sive or submassive pulmonary embolism may also be associated with syncope, hypotension, and signs of right heart failure. Other typical characteristics that aid in the recognition of pulmonary embolism are discussed later in this chapter (see “Approach to the Patient”). PNEUMOTHORAX (SEE ALSO CHAP. 305)  Primary spontaneous pneu­ mothorax is a rare cause of chest discomfort. Risk factors include male sex, smoking, family history, and Marfan syndrome. The symptoms are usually sudden in onset, and dyspnea may be mild; thus, presenta­ tion to medical attention is sometimes delayed. Secondary spontaneous pneumothorax may occur in patients with underlying lung disorders, such as chronic obstructive pulmonary disease, asthma, or cystic fibrosis, and usually produces symptoms that are more severe. Tension pneumothorax is a medical emergency caused by trapped intrathoracic air that precipitates hemodynamic collapse. Other Pulmonary Parenchymal, Pleural, or Vascular Disease (See also Chaps. 294, 295, and 305)  Most pulmonary diseases that produce chest pain, including pneumonia and malignancy, do so because of involvement of the pleura or surrounding structures. Pleurisy is typically described as a knifelike pain that is worsened by inspiration or coughing. In contrast, chronic pulmonary hypertension can manifest as chest pain that may be very similar to angina in its characteristics, suggesting right ventricular myocardial ischemia in some cases. Reactive airways diseases similarly can cause chest tight­ ness associated with breathlessness rather than pleurisy. ■ ■NONCARDIOPULMONARY CAUSES Gastrointestinal Conditions (See also Chap. 332)  Gastroin­ testinal disorders are the most common cause of nontraumatic chest discomfort and often produce symptoms that are difficult to discern from more serious causes of chest pain and are described in Table 15-1. Esophageal disorders, in particular, may simulate angina in the charac­ ter and location of the pain. Gastroesophageal reflux and disorders of esophageal motility are common (Fig. 15-1 and Table 15-1). Musculoskeletal and Other Causes (See also Chap. 372)  Chest discomfort can be produced by any musculoskeletal disorder involving the chest wall or the nerves of the chest wall, neck, or upper limbs. Cos­ tochondritis causing tenderness of the costochondral junctions (Tietze’s syndrome) is relatively common. Cervical radiculitis may manifest as a prolonged or constant aching discomfort in the upper chest and limbs. The pain may be exacerbated by motion of the neck. Occasionally, chest pain can be caused by compression of the brachial plexus by the cervical ribs, and tendinitis or bursitis involving the left shoulder may mimic the radiation of angina. Pain in a dermatomal distribution can also be caused by cramping of intercostal muscles or by herpes zoster (Chap. 198). Emotional and Psychiatric Conditions  As many as 10% of patients who present to EDs with acute chest discomfort have a panic disorder or related condition (Table 15-1). APPROACH TO THE PATIENT Chest Discomfort Given the broad set of potential causes and the heterogeneous risk of serious complications in patients who present with acute nontraumatic chest discomfort, the priorities of the initial clinical encounter include assessment of (1) the patient’s clinical stability and (2) the probability that the patient has an underlying cause of the discomfort that may be life-threatening. The high-risk condi­ tions of principal concern are acute cardiopulmonary processes, including ACS, acute aortic syndrome, pulmonary embolism, ten­ sion pneumothorax, and pericarditis with tamponade. Fulminant myocarditis also carries a poor prognosis but is usually also mani­ fest by heart failure symptoms. Among noncardiopulmonary causes

TABLE 15-2  Considerations in the Assessment of the Patient with Chest Discomfort

1. Could the chest discomfort be due to an acute, potentially life-threatening condition that warrants urgent evaluation and management? Unstable ischemic heart disease Aortic dissection Pneumothorax Pulmonary embolism
2. If not, could the discomfort be due to a chronic condition likely to lead to serious complications? Stable angina Aortic stenosis Pulmonary hypertension  
3. If not, could the discomfort be due to an acute condition that warrants specific treatment? Pericarditis Pneumonia/pleuritis Herpes zoster  
4. If not, could the discomfort be due to another treatable chronic condition? Esophageal reflux Cervical disk disease Esophageal spasm Arthritis of the shoulder or spine Peptic ulcer disease Costochondritis Gallbladder disease Other musculoskeletal disorders Other gastrointestinal conditions Anxiety state Source: Developed by Dr. Thomas H. Lee for the 18th edition of Harrison’s Principles of Internal Medicine. of chest pain, esophageal rupture likely holds the greatest urgency for diagnosis. The remaining population with noncardiopulmo­ nary conditions has a more favorable prognosis during comple­ tion of the diagnostic workup. A rapid targeted assessment for a serious cardiopulmonary cause is most relevant for patients with acute ongoing pain who have presented for emergency evaluation. Among patients presenting in the outpatient setting with chronic pain or pain that has resolved, a general diagnostic assessment is reasonably undertaken (see “Outpatient Evaluation of Chest Dis­ comfort,” below). A series of questions that can be used to structure the clinical evaluation of patients with chest discomfort is shown in Table 15-2. INCREASED LIKELIHOOD OF AMI Radiation to right arm or shoulder Radiation to both arms or shoulders Associated with exertion Radiation to left arm Associated with diaphoresis Associated with nausea or vomiting Worse than previous angina or similar to previous MI Described as pressure DECREASED LIKELIHOOD OF AMI Inframammary location Reproducible with palpation Described as sharp Described as positional Described as pleuritic

0.5

1.5

2.5

3.5

4.5

FIGURE 15-2  Association of chest pain characteristics with the probability of acute myocardial infarction (AMI). Note that a subsequent larger study showed a nonsignificant association with radiation to the right arm. (Figure prepared from data in CJ Swap, JT Nagurney: JAMA 294:2623, 2005.)

HISTORY The evaluation of nontraumatic chest discomfort relies heavily on the clinical history and physical examination to direct subsequent diagnostic testing. The evaluating clinician should assess the qual­ ity, location (including radiation), and pattern (including onset and duration) of the pain as well as any provoking or alleviating factors. The presence of associated symptoms may also be useful in estab­ lishing a diagnosis. Quality of Pain  The quality of chest discomfort alone is never sufficient to establish a diagnosis. However, the characteristics of the pain are pivotal in formulating an initial clinical impression and assessing the likelihood of a serious cardiopulmonary process (Table 15-1; Fig. 15-2). Pressure or tightness is consistent with a typical presentation of myocardial ischemic pain. Nevertheless, the clinician must remember that some patients with ischemic chest symptoms deny any “pain” but rather complain of dyspnea or a vague sense of anxiety. The severity of the discomfort has poor diagnostic accuracy. It is often helpful to ask about the similarity of the discomfort to previous definite ischemic symptoms. It is unusual for angina to be sharp, as in knifelike, stabbing, or pleuritic; however, patients sometimes use the word “sharp” to convey the intensity of discomfort rather than the quality. Pleuritic discomfort is suggestive of a process involving the pleura, including pericardi­ tis, pulmonary embolism, or pulmonary parenchymal processes. “Tearing” or “ripping” pain is often described by patients with acute aortic dissection. However, acute aortic emergencies also present commonly with knifelike pain. A burning quality can suggest acid reflux or peptic ulcer disease but may also occur with myocardial ischemia. Esophageal pain, particularly with spasm, can be a severe squeezing discomfort identical to angina. Chest Discomfort CHAPTER 15 Location of Discomfort  A substernal location with radiation to the neck, jaw, shoulder, or arms is typical of myocardial ischemic discomfort. Radiation to both arms has a particularly high associa­ tion with MI as the etiology. Some patients present with aching in sites of radiated pain as their only symptoms of ischemia. However, pain that is highly localized—e.g., that which can be demarcated by the tip of one finger—is highly unusual for angina. A retrosternal Likelihood ratio for AMI

location should prompt consideration of esophageal pain; however, other gastrointestinal conditions usually present with pain that is most intense in the abdomen or epigastrium, with possible radia­ tion into the chest. Angina may also occur in an epigastric location. Pain that occurs solely above the mandible or below the epigastrium is rarely angina. Severe pain radiating to the back, particularly between the shoulder blades, should prompt consideration of acute aortic syndrome. Radiation to the trapezius ridge is characteristic of pericardial pain and does not usually occur with angina. Pattern  Myocardial ischemic discomfort usually builds over min­ utes and is exacerbated by activity and mitigated by rest. In contrast, pain that reaches its peak intensity immediately is more suggestive of aortic dissection, pulmonary embolism, or spontaneous pneu­ mothorax. Pain that is fleeting (lasting only a few seconds) is rarely ischemic in origin. Similarly, pain that is constant in intensity for a prolonged period (many hours to days) is unlikely to represent myocardial ischemia if it occurs in the absence of other clinical con­ sequences, such as abnormalities of the ECG, elevation of cardiac biomarkers, or clinical sequelae (e.g., heart failure or hypotension). Both myocardial ischemia and acid reflux may have their onset in the morning. Provoking and Alleviating Factors  Patients with myocardial isch­ emic pain usually prefer to rest, sit, or stop walking. However, clini­ cians should be aware of the phenomenon of “warm-up angina” in which some patients experience relief of angina as they continue at the same or even a greater level of exertion (Chap. 284). Alterations in the intensity of pain with changes in position or movement of the upper extremities and neck are less likely with myocardial ischemia and suggest a musculoskeletal etiology. The pain of pericarditis, however, often is worse in the supine position and relieved by sit­ ting upright and leaning forward. Gastroesophageal reflux may be exacerbated by alcohol, some foods, or a reclined position. Relief can occur with sitting. PART 2 Cardinal Manifestations and Presentation of Diseases Exacerbation by eating suggests a gastrointestinal etiology such as peptic ulcer disease, cholecystitis, or pancreatitis. Peptic ulcer disease tends to become symptomatic 60–90 min after meals. How­ ever, in the setting of severe coronary atherosclerosis, redistribution of blood flow to the splanchnic vasculature after eating can trigger postprandial angina. The discomfort of acid reflux and peptic ulcer disease is usually diminished promptly by acid-reducing therapies. In contrast with its impact in some patients with angina, physical exertion is very unlikely to alter symptoms from gastrointestinal causes of chest pain. Relief of chest discomfort within minutes after administration of nitroglycerin is suggestive of but not suffi­ ciently sensitive or specific for a definitive diagnosis of myocardial ischemia. Esophageal spasm may also be relieved promptly with nitroglycerin. A delay of >10 min before relief is obtained after nitroglycerin suggests that the symptoms either are not caused by ischemia or are caused by severe ischemia, such as during acute MI. Associated Symptoms  Symptoms that accompany myocardial ischemia may include diaphoresis, dyspnea, nausea, fatigue, faint­ ness, and eructations. In addition, these symptoms may exist in isolation as anginal equivalents, particularly in women and the elderly. Dyspnea may occur with multiple conditions considered in the differential diagnosis of chest pain and thus is not discrimina­ tive, but the presence of dyspnea is important because it suggests a cardiopulmonary etiology. Sudden onset of significant respiratory distress should lead to consideration of pulmonary embolism and spontaneous pneumothorax. Hemoptysis may occur with pulmo­ nary embolism or as blood-tinged frothy sputum in severe heart failure but usually points toward a pulmonary parenchymal etiol­ ogy of chest symptoms. Presentation with syncope or presyncope should prompt consideration of hemodynamically significant pul­ monary embolism or aortic dissection as well as ischemic arrhyth­ mias. Although nausea and vomiting suggest a gastrointestinal disorder, these symptoms may occur in the setting of MI (more commonly inferior MI), presumably because of activation of the

vagal reflex or stimulation of left ventricular receptors as part of the Bezold-Jarisch reflex. Past Medical History  The past medical history is useful in assess­ ing the patient for risk factors for coronary atherosclerosis and venous thromboembolism (Chap. 290) as well as for conditions that may predispose the patient to specific disorders. For example, a history of connective tissue diseases such as Marfan syndrome should heighten the clinician’s suspicion of acute aortic syndrome or spontaneous pneumothorax. PHYSICAL EXAMINATION In addition to providing an initial assessment of the patient’s clinical stability, the physical examination of patients with chest discomfort can provide direct evidence of specific etiologies of chest pain (e.g., unilateral absence of lung sounds) and can identify potential precipitants of acute cardiopulmonary causes of chest pain (e.g., uncontrolled hypertension), relevant comorbid conditions (e.g., obstructive pulmonary disease), and complications of the present­ ing syndrome (e.g., heart failure). However, because the findings on physical examination may be normal in patients with unstable ischemic heart disease, an unremarkable physical exam is not definitively reassuring. General  The patient’s general appearance is helpful in establishing an initial impression of the severity of illness. Patients with acute MI or other acute cardiopulmonary disorders often appear anxious, uncom­ fortable, pale, cyanotic, or diaphoretic. Patients who are massaging or clutching their chests may describe their pain with a clenched fist held against the sternum (Levine’s sign). Occasionally, body habitus is helpful—e.g., in patients with Marfan syndrome or the prototypical young, tall, thin man with spontaneous pneumothorax. Vital Signs  Significant tachycardia and hypotension are indica­ tive of important hemodynamic consequences of the underlying cause of chest discomfort and should prompt a rapid survey for the most severe conditions, such as acute MI with cardiogenic shock, massive pulmonary embolism, pericarditis with tamponade, or ten­ sion pneumothorax. Acute aortic emergencies usually present with severe hypertension but may be associated with profound hypoten­ sion when there is coronary arterial compromise or dissection into the pericardium. Sinus tachycardia is an important manifestation of submassive pulmonary embolism. Tachypnea and hypoxemia point toward a pulmonary cause. The presence of low-grade fever is non­ specific because it may occur with MI and with thromboembolism in addition to infection. Pulmonary  Examination of the lungs may localize a primary pulmonary cause of chest discomfort, as in cases of pneumonia, asthma, or pneumothorax. Left ventricular dysfunction from severe ischemia/infarction as well as acute valvular complications of MI or aortic dissection can lead to pulmonary edema, which is an indica­ tor of high risk. Cardiac  The jugular venous pulse is often normal in patients with acute myocardial ischemia but may reveal characteristic patterns with pericardial tamponade or acute right ventricular dysfunction (Chaps. 246 and 281). Cardiac auscultation may reveal a third or, more commonly, a fourth heart sound, reflecting myocardial sys­ tolic or diastolic dysfunction. Murmurs of mitral regurgitation or a ventricular-septal defect may indicate mechanical complications of STEMI. A murmur of aortic insufficiency may be a complication of ascending aortic dissection. Other murmurs may reveal underly­ ing cardiac disorders contributory to ischemia (e.g., aortic stenosis or hypertrophic cardiomyopathy). Pericardial friction rubs reflect pericardial inflammation. Abdominal  Localizing tenderness on the abdominal exam is useful in identifying a gastrointestinal cause of the presenting syndrome. Abdominal findings are infrequent with purely acute cardiopulmonary problems, except in the case of right-sided heart failure leading to hepatic congestion.

Extremities  Vascular pulse deficits may reflect underlying chronic atherosclerosis, which increases the likelihood of coronary artery disease. However, evidence of acute limb ischemia with loss of the pulse and pallor, particularly in the upper extremities, can indicate catastrophic consequences of aortic dissection. Unilateral lower-extremity swelling should raise suspicion about venous thromboembolism. Musculoskeletal  Pain arising from the costochondral and chon­ drosternal articulations may be associated with localized swelling, redness, or marked localized tenderness. Pain on palpation of these joints is usually well localized and is a useful clinical sign, although deep palpation may elicit pain in the absence of costochondritis. Although palpation of the chest wall often elicits pain in patients with various musculoskeletal conditions, it should be appreciated that chest wall tenderness does not exclude myocardial ischemia. Sensory deficits in the upper extremities may be indicative of cervi­ cal disk disease. ELECTROCARDIOGRAPHY Electrocardiography is crucial in the evaluation of nontraumatic chest discomfort. The ECG is pivotal for identifying patients with ongoing ischemia as the principal reason for their presentation as well as secondary cardiac complications of other disorders. Profes­ sional society guidelines recommend that an ECG be obtained within 10 min of presentation, with the primary goal of identifying patients with ST-segment elevation diagnostic of MI who are can­ didates for immediate interventions to restore flow in the occluded coronary artery. ST-segment depression and symmetric T-wave inversions at least 0.2 mV in depth are useful for detecting myo­ cardial ischemia in the absence of STEMI and are also indicative of higher risk of death or recurrent ischemia. Serial performance of ECGs (every 30–60 min) is recommended early in the ED evaluation of suspected ACS. In addition, an ECG with right-sided lead placement should be considered in patients with clinically suspected ischemia and a nondiagnostic standard 12-lead ECG. Despite the value of the resting ECG, its sensitivity for ischemia is poor—as low as 20% in some studies. Abnormalities of the ST segment and T wave may occur in a variety of conditions, including pulmonary embolism, ventricular hypertrophy, acute and chronic pericarditis, myocarditis, electro­ lyte imbalance, and metabolic disorders. Notably, hyperventilation associated with panic disorder can also lead to nonspecific ST and T-wave abnormalities. Pulmonary embolism is most often associ­ ated with sinus tachycardia but can also lead to rightward shift of the ECG axis, manifesting as an S-wave in lead I, with a Q-wave and T-wave in lead III (Chaps. 247 and 290). In patients with STsegment elevation, the presence of diffuse lead involvement not corresponding to a specific coronary anatomic distribution and PR-segment depression can aid in distinguishing pericarditis from acute MI. CHEST RADIOGRAPHY (See Chap. A12) Plain radiography of the chest is performed routinely when patients present with acute chest discomfort and selectively when individuals who are being evaluated as outpatients have subacute or chronic pain. The chest radiograph is most use­ ful for identifying pulmonary processes, such as pneumonia or pneumothorax. Findings are often unremarkable in patients with ACS, but pulmonary edema may be evident. Other specific findings include widening of the mediastinum in some patients with aortic dissection, Hampton’s hump or Westermark’s sign in patients with pulmonary embolism (Chaps. 290 and A12), or pericardial calcifi­ cation in chronic pericarditis. CARDIAC BIOMARKERS Laboratory testing in patients with acute chest pain is focused on the detection of myocardial injury. Such injury can be detected by the presence of circulating proteins released from damaged

cardiomyocytes. Owing to the time necessary for this release, initial biomarkers of injury may be in the normal range, even in patients with STEMI. Cardiac troponin is the preferred biomarker for the diagnosis of MI and should be measured in all patients with sus­ pected ACS. It is not necessary or advisable to measure troponin in patients without suspicion of ACS unless this test is being used specifically for risk stratification (e.g., in pulmonary embolism or heart failure). The development of cardiac troponin assays with progressively greater analytical sensitivity has facilitated detection of myocardial injury, enhanced the overall accuracy of a diagnosis of MI, and improved risk stratification in suspected ACS. For these reasons, high-sensitivity assays are preferred over prior generation troponin assays. The greater negative predictive value of a negative troponin result with high-sensitivity assays is an advantage in the evaluation of chest pain in the ED. Rapid rule-out protocols that use serial testing and changes in troponin concentration over as short a period as 1–2 h perform well for diagnosis of ACS when using a high-sensitivity troponin assay. Troponin should be measured at presentation and repeated at 1–3 h using high-sensitivity troponin and 3–6 h using conventional troponin assays. Additional troponin measurements may be warranted beyond 3–6 h when the clinical condition still suggests possible ACS or if there is diagnostic uncer­ tainty. In patients presenting more than 2–3 h after symptom onset, a very low concentration of cardiac troponin, at the time of hospital presentation, using a high-sensitivity assay may be sufficient to exclude MI with a negative predictive value >99%. Chest Discomfort CHAPTER 15 With the use of high-sensitivity assays for troponin, myocardial injury is detected in a larger proportion of patients who have nonACS cardiopulmonary conditions than with previous, less sensitive assays. Therefore, other aspects of the clinical evaluation are criti­ cal to the practitioner’s determination of the probability that the symptoms represent ACS. In addition, observation of a change in cardiac troponin concentration between serial samples is necessary for discriminating acute causes of myocardial injury from chronic elevation due to underlying structural heart disease, end-stage renal disease, or the rare presence of interfering antibodies. The diagnosis of MI is reserved for acute myocardial injury that is marked by a rising and/or falling pattern—with at least one value exceeding the 99th percentile reference limit—and that is caused by ischemia. Other nonischemic insults, such as myocarditis, may result in acute myocardial injury but should not be labeled MI (Fig. 15-3). Other laboratory assessments may include the D-dimer test to aid in exclusion of pulmonary embolism (Chap. 290). Measure­ ment of a B-type natriuretic peptide is useful when considered in conjunction with the clinical history and exam for the diagnosis of heart failure. Elevated cTn Concentration Stable cTn Dynamic cTn (significant rise or fall) Ischemia No ischemia Myocardial infarction Acute myocardial injury Chronic myocardial injury Type 1 MI Type 2 MI FIGURE 15-3  Clinical classification of patients with elevated cardiac troponin (cTn). MI, myocardial infarction.

INTEGRATIVE DECISION-AIDS Multiple clinical algorithms have been developed to aid in decisionmaking during the evaluation and disposition of patients with acute nontraumatic chest pain. Such decision-aids estimate either of two closely related but not identical probabilities: (1) the prob­ ability of a final diagnosis of ACS and (2) the probability of major cardiac events during short-term follow-up. Use of clinical decision pathways (CDPs) is recommended to categorize patients as low, intermediate, and high risk. Evidence-based CDPs may be used to identify patients with a low clinical probability of ACS who are can­ didates for discharge from the ED without additional noninvasive testing. Two CDPs used commonly in current practice are shown in Fig. 15-4. Elements common across multiple risk stratification tools are (1) symptoms typical for ACS; (2) older age; (3) risk factors for or known atherosclerosis; (4) ischemic ECG abnormalities; and (5) elevated cardiac troponin level. Clinical application of such inte­ grated CDPs incorporating ECGs and serial high-sensitivity cardiac troponin has been reported to achieve overall “miss rates” for ACS of <0.5% and are useful for identifying patients who are reasonable to discharge home without admission or urgent cardiac testing. In some studies, provision of such protocol-driven care in dedicated chest pain units has decreased costs and overall duration of hospital evaluation with no detectable excess of adverse clinical outcomes. PART 2 Cardinal Manifestations and Presentation of Diseases Clinicians should differentiate between the algorithms discussed above and risk scores derived for stratification of prognosis (e.g., the TIMI and GRACE risk scores, Chap. 286) in patients who already have an established diagnosis of ACS. The latter risk scores were not designed to be used for diagnostic assessment. CORONARY AND MYOCARDIAL STRESS IMAGING Among patients for whom other life-threatening causes of chest pain have been reasonably excluded and serial biomarker and HEART Score (without cTn) History Highly suspicious Moderately suspicious Slightly suspicious

ECG Significant ST depression Nonspecific abnormality Normal

Age ≥65 y 45–<65 y <45 y

Risk factors ≥3 risk factors 1–2 risk factors None

TOTAL Low risk: 0–3 Not low risk: ≥4 AND cardiac troponin < the limit of quantification. Captured as low risk (%) 51.8 NPV 99.55 FIGURE 15-4  Examples of decision-aids used in conjunction with serial measurement of cardiac troponin (cTn) for evaluation of acute chest pain. The HEART score was modified by the authors in the presented study and omitting the assignment of 0, 1, or 2 points based on troponin. The negative predictive value (NPV) reported is for the composite endpoint of myocardial infarction (MI), cardiogenic shock, cardiac arrest, and all-cause mortality by 60 days. CABG, coronary artery bypass graft; CAD, coronary artery disease; ECG, electrocardiogram; PCI, percutaneous coronary intervention. (Figure prepared from data in DG Mark et al: J Am Coll Cardiol 13:606, 2018.)

clinical assessment have determined the patient to remain eligible for further testing because of intermediate or undetermined risk, diagnostic coronary imaging with coronary computed tomographic (CT) angiography or functional testing, preferably with nuclear or echocardiographic imaging, is recommended. Patient characteris­ tics (e.g., body habitus and renal function), prior cardiac testing, history of known coronary artery disease, existing contraindica­ tions for a given test modality, and patient preferences are consid­ erations when choosing among these diagnostic tests (Chaps. 248 and A9). CT Angiography (See Chap. 248)  CT angiography has emerged as a preferred modality for the evaluation of such patients. Coronary CT angiography is a sensitive technique for detection of obstructive coronary disease. CT appears to enhance the speed to disposition of patients with a low-intermediate probability for ACS, with its major strength being the negative predictive value of a finding of no significant stenosis or coronary plaque. At the same time, CT angiography can exclude aortic dissection, pericardial effusion, and pulmonary embolism. Stress Nuclear Perfusion Imaging or Stress Echocardiography (See Chaps. 248 and A9)  Functional testing with stress nuclear perfusion imaging and stress echocardiography are alternatives for the evaluation of patients with acute chest pain who are candidates for further testing and are preferred over coronary CT angiography in patients with known obstructive epicardial disease. The selec­ tion of stress test modality may depend on institutional availability and expertise. Stress testing with myocardial imaging, either with nuclear perfusion imaging or echocardiography, offers superior diagnostic performance over exercise ECG. In patients selected for stress myocardial imaging who are able to exercise, exercise stress testing is preferred over pharmacologic testing. When available, EDACS Score Age 86+ y 81–85 y 76–80 y Step down by 5-y increments 46–50 y 18–45 y

(–2)

Known CAD or risk factors Known CAD (prior MI, PCI, or CABG) or ≥3 cardiac risk factors in patient aged ≤50 y

Sex Male Female

Symptoms Radiation to arm, shoulder, neck, or jaw Diaphoresis Pain with inspiration Reproduced by palpation

–4 –6 TOTAL Low risk: 0–15 Not low risk: ≥16 60.6 99.49

04 - 16 Abdominal Pain

16 Abdominal Pain

positron emission tomography offers advantages of improved diag­ nostic performance and fewer nondiagnostic studies than singlephoton emission CT. EXERCISE ELECTROCARDIOGRAPHY Exercise electrocardiography has historically been commonly employed for completion of risk stratification of patients who have undergone an initial evaluation that has not revealed a specific cause of chest discomfort and has identified a low risk of ACS. Early exercise testing is safe in patients without ongoing chest pain or high-risk findings and may assist in refining their prognostic assessment. However, for patients with chest pain for whom both cardiac troponin and clinical risk stratification have determined the patient to have low probability of ACS, there is insufficient evidence that stress testing or cardiac imaging improves their outcomes. This evolution in evidence supports a change from past practice in which stress testing within 72 hours was broadly used for patients with acute chest pain. Exercise ECG is an alternative for patients without known coronary artery disease who remain eligible for additional testing based on intermediate risk of ACS but should be performed with cardiac imaging in patients with known coronary atherosclerosis. OTHER NONINVASIVE STUDIES Other noninvasive imaging studies of the chest can be used selec­ tively to provide additional diagnostic and prognostic information in patients with chest discomfort. Echocardiography  Echocardiography (nonstress) is not routinely necessarily in patients with chest discomfort. However, in patients with an uncertain diagnosis, particularly those with nondiagnos­ tic ST elevation, ongoing symptoms, or hemodynamic instability, detection of abnormal regional wall motion provides evidence of possible ischemic dysfunction. Echocardiography is diagnostic in patients with mechanical complications of MI or in patients with pericardial tamponade. Transthoracic echocardiography is poorly sensitive for aortic dissection, although an intimal flap may some­ times be detected in the ascending aorta. MRI (See Chap. 248)  Cardiac magnetic resonance (CMR) imaging is a versatile technique for structural and functional evaluation of the heart and the vasculature of the chest. CMR can be performed as a modality for pharmacologic stress perfusion imaging and is an alternative for completing risk assessment in patients with interme­ diate risk of ACS. Gadolinium-enhanced CMR can provide early detection of MI, defining areas of myocardial necrosis accurately, and can delineate patterns of myocardial disease that are often useful in discriminating ischemic from nonischemic myocardial injury. Although not practical in some institutions for the urgent evaluation of acute chest discomfort, CMR can be a useful modality for cardiac structural evaluation of patients with elevated cardiac troponin levels in the absence of definite coronary artery disease. CMR coronary angiography is in its early stages. MRI also permits highly accurate assessment for aortic dissection but is infrequently used as the first test because CT and transesophageal echocardiog­ raphy are usually more practical. ■ ■OUTPATIENT EVALUATION OF

CHEST DISCOMFORT Chest pain is common in outpatient practice, with a lifetime preva­ lence of 20–40% in the general population. More than 25% of patients with MI have had a related visit with a primary care physician in the previous month. The diagnostic principles are the same as in the ED. However, the pretest probability of acute cardiopulmonary cause is significantly lower. Therefore, testing paradigms are less intense, with an emphasis on the history, physical examination, and ECG. Moreover, decision-aids developed for settings with a high prevalence of sig­ nificant cardiopulmonary disease have lower positive predictive value when applied in the practitioner’s office. However, in general, if the

level of clinical suspicion of ACS is sufficiently high to consider tro­ ponin testing, the patient should be referred to the ED for evaluation.

■ ■FURTHER READING Anand A et al: High-sensitivity cardiac troponin on presentation to rule out myocardial infarction: A stepped-wedge cluster randomized controlled trial. Circulation 153:2215, 2021. Fanaroff AC et al: Does this patient with chest pain have acute coro­ nary syndrome? JAMA 315:1955, 2015. Gulati M et al: 2021 AHA/ACC/ASE/CHEST/SAEM/SCCT/SCMR guideline for the evaluation and diagnosis of chest pain: A report of the American College of Cardiology/American Heart Asso­ ciation Joint Committee on Clinical Practice Guidelines. Circulation 154:e368, 2021. Hsia RY et al: A national study of the prevalence of life-threatening Abdominal Pain CHAPTER 16 diagnoses in patients with chest pain. JAMA Intern Med 176:1029, 2016. Kontos MC et al: 2022 ACC expert consensus decision pathway on the evaluation and disposition of acute chest pain in the emergency department. J Am Coll Cardiol 80:1925, 2022. Mahler SA et al: Safely identifying emergency department patients with acute chest pain for early discharge: HEART pathway acceler­ ated diagnostic protocol. Circulation 138:2456, 2018. Danny O. Jacobs

Abdominal Pain Correctly diagnosing acute abdominal pain can be quite challenging. Few clinical situations require greater judgment, because the most catastrophic of events may be heralded by the subtlest of symptoms and signs. In every instance, the clinician must distinguish those conditions that require urgent intervention from those that do not and are best managed nonoperatively. A meticulously executed, detailed history and physical examination are critically important for focusing the dif­ ferential diagnosis and allowing the diagnostic evaluation to proceed expeditiously (Table 16-1). The etiologic classification in Table 16-2, although not complete, provides a useful framework for evaluating patients with abdominal pain. Any patient with abdominal pain of recent onset requires an early and thorough evaluation. The most common causes of abdominal pain on admission are nonspecific abdominal pain, acute appendicitis, pain of urologic origin, and intestinal obstruction. A diagnosis of “acute or surgical abdomen” is not acceptable because of its often mislead­ ing and erroneous connotations. Although most patients who present with acute abdominal pain will have self-limited disease processes, it is important to remember that pain severity does not necessarily TABLE 16-1  Some Key Components of the Patient’s History Age Time and mode of onset of the pain Pain characteristics Duration of symptoms Location of pain and sites of radiation Associated symptoms and their relationship to the pain Nausea, emesis, and anorexia Diarrhea, constipation, or other changes in bowel habits Menstrual history

TABLE 16-2  Some Important Causes of Abdominal Pain Pain Originating in the Abdomen Parietal peritoneal inflammation   Bacterial contamination     Perforated appendix or other Vascular disturbances   Embolism or thrombosis   Vascular rupture   Pressure or torsional occlusion   Sickle cell anemia Abdominal wall   Distortion or traction of mesentery   Trauma or infection of muscles Distension of visceral surfaces, e.g., by hemorrhage   Hepatic or renal capsules Inflammation   Appendicitis   Typhoid fever   Neutropenic enterocolitis or perforated viscus     Pelvic inflammatory disease   Chemical irritation     Perforated ulcer     Pancreatitis     Mittelschmerz Mechanical obstruction of hollow viscera   Obstruction of the small or large PART 2 Cardinal Manifestations and Presentation of Diseases intestine   Obstruction of the biliary tree   Obstruction of the ureter “typhlitis” Pain Referred from Extraabdominal Source Cardiothoracic   Acute myocardial infarction   Myocarditis, endocarditis,   Pleurodynia   Pneumothorax   Empyema   Esophageal disease, including pericarditis   Congestive heart failure   Pneumonia (especially lower lobes)   Pulmonary embolus spasm, rupture, or inflammation Genitalia   Torsion of the testis Metabolic Causes Diabetes Uremia Hyperlipidemia Hyperparathyroidism Acute adrenal insufficiency Familial Mediterranean fever Porphyria C1 esterase inhibitor deficiency (angioneurotic edema) Neurologic/Psychiatric Causes Herpes zoster Tabes dorsalis Causalgia Radiculitis from infection or arthritis Spinal cord or nerve root compression Functional disorders Psychiatric disorders Toxic Causes Lead poisoning Insect or animal envenomation   Black widow spider bites   Snake bites   Uncertain Mechanisms Narcotic withdrawal Heat stroke   correlate with the severity of the underlying condition. In addition, the presence or absence of various degrees of “hunger” is unreliable as a sole indicator of the severity of intraabdominal disease. The most obvious of “acute abdomens” may not require operative intervention, but the mildest of abdominal pain could. ■ ■SOME MECHANISMS OF PAIN ORIGINATING IN THE ABDOMEN Inflammation of the Parietal Peritoneum  The pain of pari­ etal peritoneal inflammation is steady and aching in character and is located directly over the inflamed area and is transmitted by somatic nerves. The intensity of the pain is dependent on the type and amount of material to which the peritoneal surfaces are exposed in a given time period. For example, the sudden release of a small quantity of sterile acidic gastric juice into the peritoneal cavity causes much more pain than the same amount of grossly contaminated pH neutral feces.

Enzymatically active pancreatic juice incites more pain and inflamma­ tion than does the same amount of sterile bile containing no potent enzymes. Because blood is normally only a mild irritant, and the response to urine is also typically bland, exposure of blood and urine to the peritoneal cavity may go unnoticed unless it is sudden and massive. Bacterial contamination, such as may occur with pelvic inflammatory disease or perforated distal intestine, causes low-intensity pain until multiplication causes significant amounts of inflammatory mediators to be released. Patients with perforated upper gastrointestinal ulcers may present entirely differently depending on how quickly gastric juices enter the peritoneal cavity and their pH. Thus, the rate at which any inflammatory material irritates the peritoneum is important. The pain of peritoneal inflammation is invariably accentuated by pressure or changes in tension of the peritoneum, whether produced by palpation or by movement such as with coughing or sneezing. The patient with peritonitis characteristically lies quietly in bed, preferring to avoid motion, in contrast to the patient with colic, who may be thrashing in discomfort. Another characteristic feature of peritoneal irritation is tonic reflex spasm of the abdominal musculature, localized to the involved body segment. Its intensity depends on the integrity of the nervous system, the location of the inflammatory process, and the rate at which it devel­ oped. Spasm over a perforated retrocecal appendix or perforation into the lesser peritoneal sac may be minimal or absent because of the pro­ tective effect of overlying viscera. Catastrophic abdominal emergencies may be associated with minimal or no detectable pain or muscle spasm in obtunded, seriously ill, debilitated, immunosuppressed, or psychotic patients. A slowly developing process also often greatly attenuates the degree of muscle spasm. Obstruction of Hollow Viscera  Intraluminal obstruction clas­ sically elicits intermittent or colicky abdominal pain that is not as well localized as the pain of parietal peritoneal irritation. However, the absence of cramping discomfort can be misleading because distention of a hollow viscus may also produce steady pain with only rare paroxysms. Small-bowel obstruction often presents as poorly localized, inter­ mittent periumbilical or supraumbilical pain. As the intestine progres­ sively dilates and loses muscular tone, the colicky nature of the pain may diminish. With superimposed strangulating obstruction, pain may spread to the lower lumbar region if there is traction on the root of the mesentery. The colicky pain of colonic obstruction is of lesser intensity, is commonly located in the infraumbilical area, and may often radiate to the lumbar region. Sudden distention of the biliary tree produces a steady rather than colicky type of pain; hence, the term biliary colic is misleading. Acute distention of the gallbladder typically causes pain in the right upper quadrant with radiation to the right posterior region of the thorax or to the tip of the right scapula, but discomfort is also not uncommonly found near the midline. Distention of the common bile duct often causes epigastric pain that may radiate to the upper lumbar region. Considerable variation is common, however, so that differentiation between gallbladder or disease affecting the common bile duct may be impossible. Gradual dilatation of the biliary tree, as can occur with carcinoma of the head of the pancreas, may cause no pain or only a mild aching sen­ sation in the epigastrium or right upper quadrant. The pain of disten­ tion of the pancreatic ducts is similar to that described for distention of the common bile duct but, in addition, is very frequently accentuated by recumbency and relieved by the upright position. Obstruction of the urinary bladder usually causes dull, low-

intensity pain in the suprapubic region. Restlessness, without a specific complaint of pain, may be the only sign of a distended bladder in an obtunded patient. In contrast, acute obstruction of the intravesicular portion of the ureter is characterized by severe suprapubic and flank pain that radiates to the penis, scrotum, or inner aspect of the upper thigh. Obstruction of the ureteropelvic junction manifests as pain near the costovertebral angle, whereas obstruction of the remainder of the ureter is associated with flank pain that often extends into the same side of the abdomen.

Vascular Disturbances  A frequent misconception is that pain due to intraabdominal vascular disturbances is sudden and catastrophic in nature. Certain disease processes, such as embolism or thrombosis of the superior mesenteric artery or impending rupture of an abdominal aortic aneurysm, can certainly be associated with diffuse, severe pain. Yet, just as frequently, the patient with occlusion of the superior mes­ enteric artery only has mild continuous or cramping diffuse pain for 2 or 3 days before vascular collapse or findings of peritoneal inflamma­ tion appear. The early, seemingly insignificant discomfort is caused by hyperperistalsis rather than peritoneal inflammation. Indeed, absence of tenderness and rigidity in the presence of continuous, diffuse pain (e.g., “pain out of proportion to physical findings”) in a patient likely to have vascular disease is quite characteristic of occlusion of the superior mesenteric artery. Abdominal pain with radiation to the sacral region, flank, or genitalia should always signal the possible presence of a rup­ turing abdominal aortic aneurysm. This pain may persist over a period of several days before rupture and collapse occur. Abdominal Wall  Pain arising from the abdominal wall is usually constant and aching. Movement, prolonged standing, and pressure accentuate the discomfort and associated muscle spasm. In the rela­ tively rare case of hematoma of the rectus sheath, now most frequently encountered in association with anticoagulant therapy, a mass may be present in the lower quadrants of the abdomen. Simultaneous involve­ ment of muscles in other parts of the body usually serves to differenti­ ate myositis of the abdominal wall from other processes that might cause pain in the same region. ■ ■REFERRED PAIN IN ABDOMINAL DISEASE Pain referred to the abdomen from the thorax, spine, or genitalia may present a diagnostic challenge because diseases of the upper part of the abdominal cavity such as acute cholecystitis or perforated ulcer may be associated with intrathoracic complications. A most important, yet often forgotten, dictum is that the possibility of intrathoracic disease must be considered in every patient with abdominal pain, especially if the pain is in the upper abdomen. Systematic questioning and examination directed toward detect­ ing myocardial or pulmonary infarction, pneumonia, pericarditis, or esophageal disease (the intrathoracic diseases that most often mas­ querade as abdominal emergencies) will often provide sufficient clues to establish the proper diagnosis. Diaphragmatic pleuritis resulting from pneumonia or pulmonary infarction may cause pain in the right upper quadrant and pain in the supraclavicular area, the latter radia­ tion to be distinguished from the referred subscapular pain caused by acute distention of the extrahepatic biliary tree. The ultimate decision as to the origin of abdominal pain may require deliberate and planned observation over a period of several hours, during which repeated questioning and examination will provide the diagnosis or suggest the appropriate studies. Referred pain of thoracic origin is often accompanied by splinting of the involved hemithorax with respiratory lag and a decrease in excur­ sion more marked than that seen in the presence of intraabdominal disease. In addition, apparent abdominal muscle spasm caused by referred pain will diminish during inspiration, whereas it persists throughout both respiratory phases if it is of abdominal origin. Palpa­ tion over the area of referred pain in the abdomen also does not usually accentuate the pain and, in many instances, actually seems to relieve it. Thoracic disease and abdominal disease frequently coexist and may be difficult or impossible to differentiate. For example, the patient with known biliary tract disease often has epigastric pain during myocardial infarction, or biliary colic may be referred to the precordium or left shoulder in a patient who has suffered previously from angina pectoris. For an explanation of the radiation of pain to a previously diseased area, see Chap. 14. Referred pain from the spine, which usually involves compression or irritation of nerve roots, is characteristically intensified by certain motions such as cough, sneeze, or strain and is associated with hyper­ esthesia over the involved dermatomes. Pain referred to the abdomen from the testes or seminal vesicles is generally accentuated by the

slightest pressure on either of these organs. The abdominal discomfort experienced is of dull, aching character and is poorly localized.

■ ■METABOLIC ABDOMINAL CRISES Pain of metabolic origin may simulate almost any other type of intraabdominal disease. Several mechanisms may be at work. In cer­ tain instances, such as hyperlipidemia, the metabolic disease itself may be accompanied by an intraabdominal process such as pancreatitis, which can lead to unnecessary laparotomy unless recognized. C1 esterase deficiency associated with angioneurotic edema is often asso­ ciated with episodes of severe abdominal pain. Whenever the cause of abdominal pain is obscure, a metabolic origin always must be consid­ ered. Abdominal pain is also the hallmark of familial Mediterranean fever (Chap. 381). Rarely, some patients with COVID-19 may present with severe abdominal pain in the absence of pulmonary symptoms. Abdominal Pain CHAPTER 16 The pain of porphyria and of lead colic is usually difficult to dis­ tinguish from that of intestinal obstruction because severe hyperperi­ stalsis is a prominent feature of both. The pain of uremia or diabetes is nonspecific, and the pain and tenderness frequently shift in location and intensity. Diabetic acidosis may be precipitated by acute appendi­ citis or intestinal obstruction, so if prompt resolution of the abdominal pain does not result from correction of the metabolic abnormalities, an underlying organic problem should be suspected. Black widow spider bites produce intense pain and rigidity of the abdominal muscles and back, an area infrequently involved in intraabdominal disease. ■ ■IMMUNOCOMPROMISE Evaluating and diagnosing causes of abdominal pain in immunosup­ pressed or otherwise immunocompromised patients is very difficult. This includes those who have undergone organ transplantation; who are receiving immunosuppressive treatments for autoimmune dis­ eases, chemotherapy, or glucocorticoids; who have AIDS; and who are very old. In these circumstances, normal physiologic responses may be absent or masked. In addition, unusual infections may cause abdominal pain where the etiologic agents include cytomegalovirus, mycobacteria, protozoa, and fungi. These pathogens may affect all gastrointestinal organs, including the gallbladder, liver, and pancreas, as well as the gastrointestinal tract, causing occult or overtly symp­ tomatic perforations of the latter. Splenic abscesses due to Candida or Salmonella infection should also be considered, especially when evalu­ ating patients with left upper quadrant or left flank pain. Acalculous cholecystitis may be observed in immunocompromised patients or those with AIDS, where it is often associated with cryptosporidiosis or cytomegalovirus infection. Neutropenic enterocolitis (typhlitis) is often identified as a cause of abdominal pain and fever in some patients with bone marrow sup­ pression due to chemotherapy. Acute graft-versus-host disease should be considered in this circumstance. Optimal management of these patients requires meticulous follow-up including serial examinations to assess the need for more surgical intervention, for example, to address perforation. ■ ■NEUROGENIC CAUSES Diseases that injure sensory nerves may cause causalgic pain. This pain has a burning character and is usually limited to the distribution of a given peripheral nerve. Stimuli that are normally not painful such as touch or a change in temperature may be causalgic and are often pres­ ent even at rest. The demonstration of irregularly spaced cutaneous “pain spots” may be the only indication that an old nerve injury exists. Even though the pain may be precipitated by gentle palpation, rigidity of the abdominal muscles is absent, and the respirations are not usually disturbed. Distention of the abdomen is uncommon, and the pain has no relationship to food intake. Pain arising from spinal nerves or roots comes and goes suddenly and is of a lancinating type (Chap. 18). It may be caused by herpes zoster, impingement by arthritis, tumors, a herniated nucleus pulposus, diabetes, or syphilis. It is not associated with food intake, abdominal distention, or changes in respiration. Severe muscle spasms, when pres­ ent, may be relieved by, but are usually not accentuated by, abdominal

palpation. The pain is made worse by movement of the spine and is usually confined to a few dermatomes. Hyperesthesia is very common.

Pain due to functional causes conforms to none of the aforemen­ tioned patterns. Here mechanisms of disease are not as clearly estab­ lished. For example, irritable bowel syndrome (IBS) is a functional gastrointestinal disorder characterized by abdominal pain and altered bowel habits. The diagnosis is made on the basis of clinical criteria (Chap. 338) and after exclusion of demonstrable structural abnormali­ ties. The episodes of abdominal pain may be brought on by stress, and the pain varies considerably in type and location. Nausea and vomiting are rare. Localized tenderness and muscle spasm are inconsistent or absent. The causes of IBS or related functional disorders are not yet fully understood, although proinflammatory cells and lipotoxic lipids likely play a role. PART 2 Cardinal Manifestations and Presentation of Diseases APPROACH TO THE PATIENT Abdominal Pain Few abdominal conditions require such urgent operative interven­ tion that an orderly approach needs to be abandoned, no matter how ill the patient is. Only patients with exsanguinating intraab­ dominal hemorrhage (e.g., ruptured aneurysm) must be rushed to the operating room immediately, but in such instances, only a few minutes are required to assess the critical nature of the prob­ lem. Under these circumstances, all obstacles must be swept aside, adequate venous access for fluid replacement obtained, and the operation begun. Unfortunately, many of these patients may die in the radiology department or the emergency room while awaiting unnecessary examinations. There are no absolute contraindications to operation when massive intraabdominal hemorrhage is present. Fortunately, this situation is relatively rare. This statement does not necessarily apply to patients with intraluminal gastrointestinal hemorrhage, who can often be managed by other means (Chap. 51). In these patients, obtaining a detailed history when possible can be extremely helpful even though it can be laborious and timeconsuming. Decision-making regarding next steps is facilitated and a reasonably accurate diagnosis can be made before any further diagnostic testing is undertaken. In cases of acute abdominal pain, a diagnosis can be readily established in most instances, whereas success is not so frequent in patients with chronic pain. IBS is one of the most common causes of abdominal pain and must always be kept in mind (Chap. 338). The location of the pain can assist in narrowing the differential diagno­ sis (Table 16-3); however, the chronological sequence of events in the patient’s history is often more important than the pain’s location. Careful attention should be paid to the extraabdominal regions. Narcotics or analgesics should not be withheld until a definitive diagnosis or a definitive plan has been formulated; obfuscation of the diagnosis by adequate analgesia is unlikely. An accurate menstrual history in a female patient is essential. It is important to remember that normal anatomic relationships can be significantly altered by the gravid uterus. Abdominal and pelvic pain may occur during pregnancy due to conditions that do not require operation. Lastly, some otherwise noteworthy laboratory values (e.g., leukocytosis) may represent the normal physiologic changes of pregnancy. In the examination, simple critical inspection of the patient, for example, of facies, position in bed, and respiratory activity, provides valuable clues. The amount of information to be gleaned is directly proportional to the gentleness and thoroughness of the examiner. Once a patient with peritoneal inflammation has been examined brusquely, accurate assessment by the next examiner becomes almost impossible. Eliciting rebound tenderness by sudden release of a deeply palpating hand in a patient with suspected peritonitis is cruel and unnecessary. The same information can be obtained by gentle percussion of the abdomen (rebound tenderness on a minia­ ture scale), a maneuver that can be far more precise and localizing. Asking the patient to cough will elicit true rebound tenderness

TABLE 16-3  Differential Diagnoses of Abdominal Pain by Usual Location Right Upper Quadrant Epigastric Left Upper Quadrant Cholecystitis Cholangitis Pancreatitis Pneumonia/empyema Pleurisy/pleurodynia Subdiaphragmatic abscess Hepatitis Budd-Chiari syndrome Peptic ulcer disease Gastritis GERD Pancreatitis Myocardial infarction Pericarditis Ruptured aortic aneurysm Esophagitis Splenic infarct Splenic rupture Splenic abscess Gastritis Gastric ulcer Pancreatitis Subdiaphragmatic abscess Right Lower Quadrant Periumbilical Left Lower Quadrant Appendicitis Salpingitis Inguinal hernia Ectopic pregnancy Nephrolithiasis Inflammatory bowel disease Mesenteric lymphadenitis Typhlitis Early appendicitis Gastroenteritis Bowel obstruction Ruptured aortic aneurysm Diverticulitis Salpingitis Inguinal hernia Ectopic pregnancy Nephrolithiasis Irritable bowel syndrome Inflammatory bowel disease Diffuse Nonlocalized Pain Gastroenteritis Mesenteric ischemia Bowel obstruction Irritable bowel syndrome Peritonitis Diabetes Malaria Familial Mediterranean fever Metabolic diseases Psychiatric disease   Abbreviation: GERD, gastroesophageal reflux disease. without the need for placing a hand on the abdomen. Furthermore, the forceful demonstration of rebound tenderness will startle and induce protective spasm in a nervous or worried patient in whom true rebound tenderness is not present. A palpable gallbladder will be missed if palpation is so aggressive that voluntary muscle spasm becomes superimposed on involuntary muscular rigidity. As with history taking, sufficient time should be spent in the examination. Abdominal signs may be minimal but, nevertheless, if accompanied by consistent symptoms, may be exceptionally meaningful. Abdominal signs may be virtually or totally absent in cases of pelvic peritonitis, so careful pelvic and rectal examinations are mandatory in every patient with abdominal pain. Tenderness on pelvic or rectal examination in the absence of other abdominal signs can be caused by operative indications such as perforated appendicitis, diverticulitis, twisted ovarian cyst, and many oth­ ers. Much attention has been paid to the presence or absence of peristaltic sounds, their quality, and their frequency. Auscultation of the abdomen is one of the least revealing aspects of the physi­ cal examination of a patient with abdominal pain. Catastrophes such as a strangulating small-intestinal obstruction or perforated appendicitis may occur in the presence of normal peristaltic sounds. Conversely, when the proximal part of the intestine above obstruction becomes markedly distended and edematous, peristal­ tic sounds may lose the characteristics of borborygmi and become weak or absent, even when peritonitis is not present. It is usually the severe chemical peritonitis of sudden onset that is associated with the truly silent abdomen. Laboratory examinations may be valuable in assessing the patient with abdominal pain, yet, with few exceptions, they rarely establish a diagnosis. Leukocytosis should never be the single deciding fac­ tor as to whether or not operation is indicated. A white blood cell count >20,000/μL may be observed with perforation of a viscus, but pancreatitis, acute cholecystitis, pelvic inflammatory disease, and intestinal infarction may also be associated with marked leu­ kocytosis. A normal white blood cell count is not rare in cases of

05 - 17 Headache

17 Headache

perforation of abdominal viscera. A diagnosis of anemia may be more helpful than the white blood cell count, especially when com­ bined with the history. The urinalysis may reveal the state of hydration or rule out severe renal disease, diabetes, or urinary infection. Blood urea nitrogen, glucose, and serum bilirubin levels and liver function tests may be helpful. Serum amylase levels may be increased by many diseases other than pancreatitis, for example, perforated ulcer, strangulating intestinal obstruction, and acute cholecystitis; thus, elevations of serum amylase do not rule in or rule out the need for an operation. Plain and upright or lateral decubitus radiographs of the abdo­ men have limited utility and may be unnecessary in some patients who have substantial evidence of some diseases such as acute appendicitis or strangulated external hernia. Where the indica­ tions for surgical or medical intervention are not clear, low-dose computed tomography is preferred to abdominal radiography when evaluating nontraumatic acute abdominal pain. Very rarely, barium or water-soluble contrast study of the upper part of the gastrointestinal tract is an appropriate radiographic investigation and may demonstrate partial intestinal obstruction that may elude diagnosis by other means. If there is any question of obstruction of the colon, oral administration of barium sul­ fate should be avoided. On the other hand, in cases of suspected colonic obstruction (without perforation), a contrast enema may be diagnostic. In the absence of trauma, peritoneal lavage has been replaced as a diagnostic tool by CT scanning and laparoscopy. Ultrasonogra­ phy has proved to be useful in detecting an enlarged gallbladder or pancreas, the presence of gallstones, an enlarged ovary, or a tubal pregnancy. Laparoscopy is especially helpful in diagnosing pelvic conditions, such as ovarian cysts, tubal pregnancies, salpingitis, acute appendicitis, and other disease processes. Laparoscopy has a particular advantage over imaging in that the underlying etiologic condition can often be definitively addressed. Radioisotopic hepatobiliary iminodiacetic acid scans (HIDAs) may help differentiate acute cholecystitis or biliary colic from acute pancreatitis. A CT scan may demonstrate an enlarged pan­ creas, ruptured spleen, or thickened colonic or appendiceal wall and streaking of the mesocolon or mesoappendix characteristic of diverticulitis or appendicitis. Sometimes, even under the best circumstances with all available aids and with the greatest of clinical skill, a definitive diagnosis cannot be established at the time of the initial examination. And, in some cases, operation may be indicated based on clinical grounds alone. Should that decision be questionable, watchful waiting with repeated questioning and examination will often elucidate the true nature of the illness and indicate the proper course of action. Acknowledgment The author gratefully acknowledges the enormous contribution to this chapter and the approach it espouses to William Silen, who authored this chapter for many previous editions. ■ ■FURTHER READING Bhangu A et al: Acute appendicitis: Modern understanding of pathogenesis, diagnosis and management. Lancet 386:1278, 2015. Cartwright SL, Knudson MP: Diagnostic imaging of acute abdominal pain in adults. Am Fam Phys 91:452, 2015. Huckins DS et al: Diagnostic performance of a biomarker panel as a negative predictor for acute appendicitis in acute emergency department patients with abdominal pain. Am J Emerg Med 35:418, 2017. Nayor J et al: Tracing the cause of abdominal pain. N Engl J Med 375:e8, 2016. Phillips MT: Clinical yield of computed tomography scans in the emergency department for abdominal pain. J Invest Med 64:542, 2016. Silen W, Cope Z: Cope’s Early Diagnosis of the Acute Abdomen, 22nd ed. New York, Oxford University Press, 2010.

Peter J. Goadsby

Headache Headache is among the most common reasons patients seek medi­ cal attention and is responsible, on a global basis, for more disability than any other neurologic problem. Diagnosis and management are based on a careful clinical approach augmented by an understanding of the anatomy, physiology, and pharmacology of the nervous system pathways mediating the various headache syndromes. This chapter will focus on the general approach to a patient with headache; migraine and other primary headache disorders are discussed in Chap. 441. Headache CHAPTER 17 ■ ■GENERAL PRINCIPLES A classification system developed by the International Headache Society (www.ihs-headache.org/en/resources/guidelines/) characterizes headache disorders as primary or secondary (Table 17-1). Primary headaches are those in which headache and its associated features form the disorder itself, whereas secondary headaches are those caused by exogenous disorders (Headache Classification Committee of the International Headache Society, 2018). Primary headache often results in considerable disability and a decrease in the patient’s quality of life. Mild secondary headache, such as that seen in association with upper respiratory tract infections, is common but rarely worrisome. Lifethreatening headache is relatively uncommon, with vigilance required to recognize and appropriately treat such patients. ■ ■ANATOMY AND PHYSIOLOGY OF HEADACHE Pain usually occurs when peripheral nociceptors are stimulated in response to tissue injury, visceral distension, or other factors (Chap. 14). In such situations, pain perception is a normal physiologic response mediated by a healthy nervous system. Pain can also result when painproducing pathways of the peripheral or central nervous system (CNS) are damaged or activated inappropriately. Headache may originate from either or both mechanisms. Relatively few cranial structures are pain-producing; these include the scalp, meningeal arteries, dural sinuses, falx cerebri, and proximal segments of the large pial arteries. The ventricular ependyma, choroid plexus, pial veins, and much of the brain parenchyma are not pain-producing. The key structures involved in primary headache appear to be: • The large intracranial vessels and dura mater and the peripheral terminals of the trigeminal nerve that innervate these structures • The caudal portion of the trigeminal nucleus, which extends into the dorsal horns of the upper cervical spinal cord and receives input from the first and second cervical nerve roots (the trigeminocervi­ cal complex) • Rostral pain-processing regions, such as the ventroposteromedial thalamus and the cortex • The pain-modulatory systems in the brain that modulate input from trigeminal nociceptors at all levels of the pain-processing pathways and influence vegetative functions, such as hypothalamus and brain­ stem structures TABLE 17-1  Common Causes of Headache PRIMARY HEADACHE SECONDARY HEADACHE TYPE % TYPE % Tension-type

Systemic infection

Migraine

Head injury

Idiopathic stabbing

Vascular disorders

Exertional

Subarachnoid hemorrhage <1 Cluster 0.1 Brain tumor 0.1 Source: After J Olesen et al: The Headaches. Philadelphia, Lippincott Williams & Wilkins, 2005.

The innervation of the large intracranial vessels and dura mater by the trigeminal nerve is known as the trigeminovascular system. Cranial autonomic symptoms, such as lacrimation, conjunctival injection, nasal congestion, rhinorrhea, periorbital swelling, aural fullness, and ptosis, are prominent in the trigeminal autonomic cephalalgias (TACs), includ­ ing cluster headache and paroxysmal hemicrania, and are often seen in migraine, even in children. These cranial autonomic symptoms reflect activation of cranial parasympathetic pathways, and functional imaging studies indicate that vascular changes in migraine and cluster headache, when present, are similarly driven by these cranial auto­ nomic systems. Thus, they are secondary, and not causative, events in the headache cascade. Moreover, they can often be mistaken for symptoms or signs of cranial sinus inflammation, which is then over­ diagnosed and inappropriately managed. Migraine and other primary headache disorders are not “vascular headaches”; these disorders do not reliably manifest vascular changes, and treatment outcomes cannot be predicted by vascular effects. Migraine is a brain disorder and is best understood and managed as such.

PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■CLINICAL EVALUATION OF ACUTE,

NEW-ONSET HEADACHE The patient who presents with a new, severe headache has a differen­ tial diagnosis that is quite different from the patient with recurrent headaches over many years. In new-onset and severe headache, the probability of finding a potentially serious cause is considerably greater than in recurrent headache. Patients with recent onset of pain require prompt evaluation and appropriate treatment. Serious causes to be considered include meningitis, subarachnoid hemorrhage, epidural or subdural hematoma, glaucoma, tumor, and purulent sinusitis. When worrisome symptoms and signs are present (Table 17-2), rapid diag­ nosis and management are critical. A careful neurologic examination is an essential part of the first step evaluation. In most cases, patients with an abnormal examination, or a history of recent-onset headache, should be evaluated by a computed tomography (CT) or magnetic resonance imaging (MRI) study of the brain. As an initial screening procedure for intracranial pathology in this setting, CT and MRI methods appear to be equally sensitive. In some circumstances, a lumbar puncture (LP) is also required, unless a benign etiology can be otherwise established. A general evaluation of acute headache might include cranial arteries by palpation; cervical spine by the effect of passive movement of the head and by imaging; the investigation of cardiovascular and renal status by blood pressure monitoring and urine examination; and eyes by funduscopy, intraocu­ lar pressure measurement, and refraction. The psychological state of the patient should also be evaluated because a relationship exists between head pain, depression, and anxiety. This is intended to identify comorbidity rather than provide an explanation for the headache, because troublesome headache is seldom simply caused by mood change. Although it is notable that some medi­ cines with antidepressant actions are also effective in the preventive TABLE 17-2  Headache Symptoms That Suggest a Serious Underlying Disorder Sudden-onset headache First severe headache Vomiting that precedes headache Subacute worsening over days or weeks Pain induced by bending, lifting, cough Pain that disturbs sleep or presents immediately upon awakening Known systemic illness “Worst” headache ever Onset after age 55 Fever or unexplained systemic signs Abnormal neurologic examination Pain associated with local tenderness, e.g., region of temporal artery

treatment of both tension-type headache and migraine, each symptom must be treated optimally. Underlying recurrent headache disorders may be activated by pain that follows otologic or endodontic surgical procedures. Thus, pain about the head as the result of diseased tissue or trauma may reawaken an otherwise quiescent migraine syndrome. Treatment of the head­ ache is largely ineffective until the cause of the primary problem is addressed. Serious underlying conditions that are associated with headache are described below. Brain tumor is a rare cause of isolated headache and even less commonly a cause of severe pain. The vast majority of patients presenting with severe headache have a benign cause, usually migraine. SECONDARY HEADACHE The management of secondary headache focuses on diagnosis and treatment of the underlying condition. ■ ■MENINGITIS Acute, severe headache with stiff neck and fever suggests meningitis. LP is mandatory. Often there is striking accentuation of pain with eye movement. Meningitis can be easily mistaken for migraine in that the cardinal symptoms of pounding headache, photophobia, nausea, and vomiting are frequently present, perhaps reflecting the underlying biol­ ogy of some of the patients. Meningitis is discussed in Chaps. 143 and 144. ■ ■INTRACRANIAL HEMORRHAGE Acute, maximal in <5 min, severe headache lasting >5 min with stiff neck but without fever suggests subarachnoid hemorrhage. A ruptured aneurysm, arteriovenous malformation, or intraparenchymal hemor­ rhage may also present with headache alone. Rarely, if the hemorrhage is small or below the foramen magnum, the head CT scan can be normal. Therefore, LP may be required to diagnose definitively sub­ arachnoid hemorrhage. Subarachnoid hemorrhage is discussed in Chap. 440, and intra­ cranial hemorrhage in Chap. 439. ■ ■BRAIN TUMOR Approximately 30% of patients with brain tumors consider headache to be their chief complaint. The head pain is usually nondescript—an intermittent deep, dull aching of moderate intensity, which may worsen with exertion or change in position and may be associated with nausea and vomiting. This pattern of symptoms results from migraine far more often than brain tumor. The headache of brain tumor disturbs sleep in about 10% of patients. Vomiting that precedes the appearance of headache by weeks is highly characteristic of posterior fossa brain tumors. A history of amenorrhea or galactorrhea with headache sug­ gests a possible prolactin-secreting pituitary adenoma or the polycystic ovary syndrome. Headache arising de novo in a patient with known malignancy suggests either cerebral metastases or carcinomatous men­ ingitis. Head pain appearing abruptly after bending, lifting, or cough­ ing can be due to a posterior fossa mass, a Chiari malformation, or low cerebrospinal fluid (CSF) volume. Brain tumors are discussed in Chap. 95. ■ ■TEMPORAL ARTERITIS (See also Chaps. 34 and 375) Temporal (giant cell) arteritis is an inflammatory disorder of arteries that frequently involves the extra­ cranial carotid circulation. It is a common disorder of the elderly; its annual incidence is 77 per 100,000 individuals aged ≥50. The average age of onset is 70 years, and women account for 65% of cases. About half of patients with untreated temporal arteritis develop blindness due to involvement of the ophthalmic artery and its branches; indeed, isch­ emic optic neuropathy induced by giant cell arteritis is the major cause of rapidly developing bilateral blindness in patients >60 years. Because treatment with glucocorticoids is effective in preventing this complica­ tion, prompt recognition of the disorder is important. Typical presenting symptoms include headache, polymyalgia rheu­ matica (Chap. 375), jaw claudication, fever, and weight loss. Headache

is the dominant symptom and often appears in association with mal­ aise and muscle aches. Head pain may be unilateral or bilateral and is located temporally in 50% of patients but may involve any and all aspects of the cranium. Pain usually appears gradually over a few hours before peak intensity is reached; occasionally, it is explosive in onset. The quality of pain is infrequently throbbing; it is almost invariably described as dull and boring, with superimposed episodic stabbing pains similar to the sharp pains that appear in migraine. Most patients can recognize that the origin of their head pain is superficial, external to the skull, rather than originating deep within the cranium (the pain site usually identified by migraineurs). Scalp tenderness is present, often to a marked degree; brushing the hair or resting the head on a pillow may be impossible because of pain. Headache is usually worse at night and often aggravated by exposure to cold. Additional findings may include reddened, tender nodules or red streaking of the skin overlying the temporal arteries, and tenderness of the temporal or, less commonly, the occipital arteries. The erythrocyte sedimentation rate (ESR) is often, although not always, elevated; a normal ESR does not exclude giant cell arteritis. A temporal artery biopsy followed by immediate treatment with prednisone 80 mg daily for the first 4–6 weeks should be initiated when clinical suspicion is high. The prevalence of migraine among the elderly is substantial, considerably higher than that of giant cell arteritis. Migraineurs often report amelioration of their headaches with prednisone; thus, caution must be used when interpreting the therapeutic response. ■ ■GLAUCOMA Glaucoma may present with a prostrating headache associated with nausea and vomiting. The headache often starts with severe eye pain. On physical examination, the eye is often red with a fixed, moderately dilated pupil. Glaucoma is discussed in Chap. 34. PRIMARY HEADACHE DISORDERS Primary headaches disorders generally manifest as headache and asso­ ciated features occurring in the absence of any exogenous cause. The most common are migraine, tension-type headache, and the trigeminal autonomic cephalalgias (TACs), notably cluster headache. These enti­ ties are discussed in detail in Chap. 441. ■ ■CHRONIC DAILY OR NEAR-DAILY HEADACHE The broad description of chronic daily headache (CDH) can be applied when a patient experiences headache on 15 days or more per month. CDH is not a single entity, nor a diagnosis; it encompasses a number of different headache syndromes, both primary and secondary (Table 17-3). TABLE 17-3  Classification of Daily or Near-Daily Headache Primary

4 H DAILY <4 H DAILY SECONDARY Chronic migrainea Chronic cluster headacheb Posttraumatic   Head injury   Iatrogenic   Postinfectious Chronic tension-type headachea Chronic paroxysmal hemicrania Inflammatory, such as   Giant cell arteritis   Sarcoidosis   Behçet’s syndrome Hemicrania continuaa SUNCT/SUNA Chronic CNS infection New daily persistent headachea Hypnic headache Medication-overuse headachea aMay be complicated by medication overuse. bSome patients may have headache 4 h/d. Abbreviations: CNS, central nervous system; SUNA, short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms; SUNCT, shortlasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

In aggregate, this group presents considerable disability and is thus spe­ cially mentioned here. Population-based estimates suggest that about 4% of adults have daily or near-daily headache.

APPROACH TO THE PATIENT Chronic Daily Headache The first step in the management of patients with CDH is to diagnose any secondary headache and treat that problem (Table 17-3). This can sometimes be a challenge when the underlying cause triggers worsening of a primary headache. For patients with primary headache disorders, diagnosis of the headache type will guide therapy. Preventive treatments such as tricyclics, either ami­ triptyline or nortriptyline at doses up to 1 mg/kg, are very useful in patients with CDH arising from migraine or tension-type headache or where the secondary cause has activated the underlying primary headache. Tricyclics are started in low doses (10–25 mg) daily and may be given 12 h before the expected time of awakening in order to avoid excessive morning sleepiness. Medicines including topiramate, valproate, propranolol, flunarizine (not available in the United States), candesartan, and the newer calcitonin gene-related peptide (CGRP) pathway monoclonal antibodies and CGRP recep­ tor antagonists (gepants; see Chap. 441) are also useful when the underlying issue is migraine. Headache CHAPTER 17 MANAGEMENT OF MEDICALLY INTRACTABLE DISABLING PRIMARY HEADACHE The management of medically intractable headache is difficult, although recent developments in therapy have proved effective. Monoclonal antibodies to CGRP or its receptor, or CGRP receptor antagonists (gepants), are effective and well-tolerated in chronic migraine and licensed for use in clinical practice. Noninvasive neu­ romodulatory approaches, such as single-pulse transcranial mag­ netic stimulation and remote electrical neuromodulation, which appear to modulate thalamic processing or brainstem mechanisms, respectively, in migraine have been used in clinical practice with success (Chap. 441). Noninvasive vagal nerve stimulation has also shown promise, particularly in cluster headache, chronic par­ oxysmal hemicrania, and hemicrania continua, and possibly in short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) and short-lasting unilateral neural­ giform headache attacks with conjunctival injection and tearing (SUNCT) (Chap. 441). Other modalities are discussed in Chap. 441. MEDICATION-RELATED AND MEDICATION-OVERUSE HEADACHE Overuse of analgesic medication for headache can aggravate head­ ache frequency, markedly impair the effect of preventive medicines, and induce a state of refractory daily or near-daily headache called medication-overuse headache. A proportion of patients who stop taking analgesics will experience substantial improvement in the severity and frequency of their headache. However, even after ces­ sation of analgesic use, many patients continue to have headache, although they may feel clinically improved in some way, especially if they have been using opioids or barbiturates regularly. The residual symptoms probably represent the underlying primary headache disorder, and most commonly, this issue occurs in patients prone to migraine. Management of Medication Overuse: Outpatients  For patients who overuse analgesic medications, it is often helpful to reduce and eliminate them, although this strategy is far from universally effective. One approach is to reduce the medication dose by 10% every 1–2 weeks. Immediate cessation of analgesic use is possible for some patients, provided there is no contraindication. Both approaches are facilitated by use of a medication diary maintained during the month or two before cessation; this helps to identify the scope of the problem. A small dose of a nonsteroidal anti-

inflammatory drug (NSAID) such as naproxen, 500 mg bid, if tolerated, will help relieve residual pain as analgesic use is reduced.

NSAID overuse is not usually a problem for patients with daily headache when a NSAID with a longer half-life is taken once or twice daily. Once the patient has substantially reduced analgesic use, a preventive medication should be introduced. Another widely used approach is to commence the preventive at the same time the analgesic reduction is started; both approaches are supported by controlled trial data. A common cause of unresponsiveness to treatment is the use of a preventive when analgesics continue to be used regularly. For some patients, discontinuing analgesics is very difficult; often the best approach is to inform the patient that some degree of pain is inevitable during this initial period. PART 2 Cardinal Manifestations and Presentation of Diseases Management of Medication Overuse or Treatment-Refractory Headache: Inpatients  Some patients will require hospitalization for detoxification and management. Such patients have typically failed efforts at outpatient withdrawal or have a significant medi­ cal condition, such as diabetes mellitus or epilepsy, that would complicate withdrawal as an outpatient. Following admission to the hospital, medications are withdrawn completely on the first day, in the absence of a contraindication. Antiemetics and fluids are administered as required; clonidine is used for opioid withdrawal symptoms. For acute intolerable pain during the waking hours, aspirin, 1 g IV (not approved in United States), is useful. IM chlorpromazine can be helpful at night; patients must be adequately hydrated. Three to five days into the admission, as the effect of the withdrawn substance wears off, a course of IV dihydroergotamine (DHE) can be used. DHE, administered every 8 h for 5 consecutive days, a treatment that is not stopped short if headache settles, can induce a significant remission that allows a preventive treatment to be established. Serotonin 5-HT3 receptor antagonists, such as ondansetron or granisetron, or the neuroki­ nin receptor antagonist aprepitant may be required with DHE to prevent significant nausea, and domperidone (not approved in the United States) orally or by suppository can be very helpful. Avoid­ ing sedating or otherwise side effect–prone antiemetics is helpful. Alternatives include a 7- to 10-day course of IV lidocaine or IV divalproex sodium or use of the CGRP antagonist eptinezumab intravenously (Table 441-6). NEW DAILY PERSISTENT HEADACHE New daily persistent headache (NDPH) is a clinically distinct syn­ drome with important secondary causes; these are listed in Table 17-4. Clinical Presentation  NDPH presents with headache on most if not all days, and the patient can clearly, and often vividly, recall the moment of onset. The headache usually begins abruptly, but onset may be more gradual; evolution over 3 days has been proposed as the upper limit for this syndrome. Patients typically recall the exact day and circumstances of the onset of headache; the new, persis­ tent head pain does not remit. The first priority is to distinguish between a primary and a secondary cause of this syndrome. Sub­ arachnoid hemorrhage is the most serious of the secondary causes and must be excluded either by history or appropriate investigation (Chap. 440). Secondary NDPH  •  Low CSF Volume Headache  In these syndromes, head pain is positional: it begins when the patient sits TABLE 17-4  Differential Diagnosis of New Daily Persistent Headache PRIMARY SECONDARY Migrainous-type Subarachnoid hemorrhage Featureless (tension-type) Low cerebrospinal fluid (CSF) volume headache   Raised CSF pressure headache   Posttraumatic headachea   Chronic meningitis aIncludes postinfectious forms.

or stands upright and resolves upon reclining. The pain, which is occipitofrontal, is usually a dull ache but may be throbbing. Patients with chronic low CSF volume headache typically present with a history of headache from one day to the next that is generally not present on waking but worsens during the day. Recumbency usu­ ally improves the headache within minutes, and it can take only minutes to an hour for the pain to return when the patient resumes an upright position. The most common cause of headache due to persistent low CSF volume is CSF leak following LP (Chap. S3). Post-LP headache usually begins within 48 h but may be delayed for up to 12 days. Its incidence is between 10 and 30%. Beverages with caffeine may provide temporary relief. Besides LP, index events may include epidural injection or a vigorous Valsalva maneuver, such as from lifting, straining, coughing, clearing the eustachian tubes in an airplane, or multiple orgasms. Spontaneous CSF leaks are well recognized, and the diagnosis should be considered whenever the headache history is typical, even when there is no obvious index event. As time passes from the index event, the postural nature may become less apparent; cases in which the index event occurred several years before the eventual diagnosis have been recognized. Symptoms appear to result from low volume rather than low pressure: although low CSF pressures, typically 0–50 mm CSF, are usually identified, a pressure as high as 140 mm CSF has been noted with a documented leak. Postural orthostatic tachycardia syndrome (POTS; Chap. 451) can present with orthostatic headache similar to low CSF vol­ ume headache and is a diagnosis that needs consideration in this setting. When imaging is indicated to identify the source of a presumed leak, an MRI with gadolinium is the initial study of choice (Fig. 17-1). A striking pattern of diffuse meningeal enhancement is so typical that in the appropriate clinical context the diagnosis is established. Chiari malformations may sometimes be noted on MRI; in such cases, surgery to decompress the posterior fossa is not indicated and usually worsens the headache. Spinal MRI with T2 weighting may reveal a leak, and spinal MRI may demonstrate spinal men­ ingeal cysts whose role in these syndromes is yet to be elucidated. The source of CSF leakage may be identified by spinal MRI with appropriate sequences, or by CT, preferably lateral decubitus digital subtraction, myelography. In the absence of a directly identified site of leakage, 111In-DTPA CSF studies may demonstrate early empty­ ing of the tracer into the bladder or slow progress of tracer across POST CONTRAST POST CONTRAST FIGURE 17-1  Magnetic resonance image showing diffuse meningeal enhancement after gadolinium administration in a patient with low cerebrospinal fluid (CSF) volume headache.

the brain suggesting a CSF leak; this procedure is now only rarely employed. Initial treatment for low CSF volume headache is bed rest. For patients with persistent pain, IV caffeine (500 mg in 500 mL of saline administered over 2 h) can be very effective. An electro­ cardiogram (ECG) to screen for arrhythmia should be performed before administration. It is reasonable to administer at least two infusions of caffeine before embarking on additional tests to iden­ tify the source of the CSF leak. Because IV caffeine is safe and can be curative, it spares many patients the need for further investiga­ tions. If unsuccessful, an abdominal binder may be helpful. If a leak can be identified, an autologous blood patch is usually curative. A blood patch is also effective for post-LP headache; in this setting, the location is empirically determined to be the site of the LP. In patients with intractable headache, oral theophylline is a useful alternative that can take some months to be effective. CSF-venous fistulas require closure. Raised CSF Pressure Headache  Raised CSF pressure is well rec­ ognized as a cause of headache. Brain imaging can often reveal the cause, such as a space-occupying lesion. Idiopathic Intracranial Hypertension (Pseudotumor Cerebri)   NDPH due to raised CSF pressure can be the presenting symptom for patients with idiopathic intracranial hypertension, a disorder asso­ ciated with obesity, female gender, and, on occasion, pregnancy. The syndrome can also occur without visual problems, particularly when the fundi are normal. These patients typically present with a history of generalized headache that is present on awaken­ ing, improves as the day goes on, and worsens with recumbency. Transient visual obscurations are frequent and may occur when the headaches are most severe. The diagnosis is relatively straight­ forward when papilledema is present, but the possibility must be considered even in patients without funduscopic changes. Formal visual field testing should be performed even in the absence of overt ophthalmic involvement. Partial obstructions of the cerebral venous sinuses are found in a small number of cases. In addition, persistently raised intracranial pressure can trigger a syndrome of chronic migraine. Other conditions that characteristically produce headache on rising in the morning or nocturnal headache are obstructive sleep apnea or poorly controlled hypertension. Evaluation of patients suspected to have raised CSF pressure requires brain imaging. It is most efficient to obtain an MRI, including an MR venogram, as the initial study. If there are no contraindications, the CSF pressure should be measured by LP; this should be done when the patient is symptomatic so that both the pressure and the response to removal of 20–30 mL of CSF can be determined. An elevated opening pressure and improvement in headache following removal of CSF are diagnostic in the absence of fundal changes. Initial treatment is with acetazolamide (250–500 mg bid); the headache may improve within weeks. A plan for weight loss should also be instituted when required. If ineffective, topiramate is the next treatment of choice; it has many actions that may be useful in this setting, including carbonic anhydrase inhibition, weight loss, and neuronal membrane stabilization, likely mediated via effects on phosphorylation pathways. Severely disabled patients who do not respond to medical treatment require intracranial pressure monitoring and may require shunting. Posttraumatic Headache  A traumatic event can trigger a head­ ache process that lasts for many months or years after the event. The term trauma is used here in a very broad sense: headache can develop following an injury to the head, but it can also develop after an infectious episode, typically viral meningitis, a flulike illness (see below), or a parasitic infection. Complaints of dizziness, vertigo, and impaired memory can accompany the headache. Symptoms may remit after several weeks or persist for months and even years

after the injury. Typically, the neurologic examination is normal and CT or MRI studies are unrevealing. Chronic subdural hematoma may on occasion mimic this disorder. Posttraumatic headache may also be seen after carotid dissection and subarachnoid hemorrhage and after intracranial surgery. The underlying theme appears to be that a traumatic event involving the pain-producing meninges can trigger a headache process that lasts for many years. Other Causes  In one series, one-third of patients with NDPH reported headache beginning after a transient flulike illness charac­ terized by fever, neck stiffness, photophobia, and marked malaise. Evaluation typically reveals no apparent cause for the headache. There is no convincing evidence that persistent Epstein-Barr virus infection plays a role in NDPH. A complicating factor is that many patients undergo LP during the acute illness; iatrogenic low CSF volume headache must be considered in these cases. Post-COVID-19 onset of NDPH is now well documented. Headache CHAPTER 17 Treatment  Treatment is largely empirical and directed at the head­ ache phenotype. Tricyclic antidepressants, notably amitriptyline, and anticonvulsants, such as topiramate, valproate, candesartan, and gabapentin, have been used with reported benefit, as have CGRP pathway blockers (monoclonal antibodies and gepants). The monoamine oxidase inhibitor phenelzine may also be useful in carefully selected patients. The headache usually resolves within 3–5 years, but it can be quite disabling. PRIMARY CARE AND HEADACHE MANAGEMENT Most patients with headache will be seen first in a primary care setting. The challenging task of the primary care physician is to identify the very few worrisome secondary headaches from the very great majority of primary and less dangerous secondary headaches (Table 17-2). Absent any warning signs, a reasonable approach is to treat when a diagnosis is established. As a general rule, the investigation should focus on identifying worrisome causes of headache or on helping the patient to gain confidence if no primary headache diagnosis can be made. After treatment has been initiated, follow-up care is essential to identify whether progress has been made against the headache com­ plaint. Not all headaches will respond to treatment, but, in general, worrisome headaches will progress and will be easier to identify. When a primary care physician feels the diagnosis is a primary headache disorder, it is worth noting that >90% of patients who pres­ ent to primary care with a complaint of headache will have migraine (Chap. 441). In general, patients who do not have a clear diagnosis, have a pri­ mary headache disorder other than migraine or tension-type headache, or are unresponsive to two or more standard therapies for the consid­ ered headache type should be referred to a specialist. In a practical sense, the threshold for referral is also determined by the experience of the primary care physician in headache medicine and the availability of secondary care options. ■ ■FURTHER READING Headache Classification Committee of the International Headache Society: The International Classification of Headache Disorders, 3rd ed. Cephalalgia 38:1, 2018. Kernick D, Goadsby PJ: Headache: A Practical Manual, 2nd ed. Oxford, Oxford University Press, 2024. Lance JW, Goadsby PJ: Mechanism and Management of Headache, 7th ed. New York, Elsevier, 2005. Olesen J et al: The Headaches. Philadelphia, Lippincott, Williams & Wilkins, 2005. Silberstein SD et al: Wolff’s Headache and Other Head Pain, 9th ed. New York, Oxford University Press, 2021.

06 - 18 Low Back Pain

18 Low Back Pain

Steven P. Cohen, Eric J. Wang

Low Back Pain EPIDEMIOLOGY Low back pain (LBP) is among the leading causes of years lived with disability worldwide and the principal cause of work-related disability in nearly all industrialized countries. Between 28 and 34% of Americans experienced LBP in the past 3 months, with LBP accounting for

57 million unique patient visits. The all-cause medical costs in the United States are estimated to exceed $300 billion per year. Risk factors for chronic LBP include female sex, African-American race, older age, being unemployed, obesity, and sedentary lifestyle. PAIN CATEGORIZATION The categorization of pain is important because it predicates treatment decisions at all levels of care. PART 2 Cardinal Manifestations and Presentation of Diseases Nociceptive pain is the most common form of chronic pain in gen­ eral and LBP in particular and results from activity in neural pathways secondary to actual or potentially tissue-damaging stimuli. Nocicep­ tive LBP typically worsens with activities that stress the structures responsible for pain, is usually secondary to degenerative changes that occur over time, and with the exception of myofascial pain, tends to be progressive in nature. Mechanical pain can radiate to the upper and sometimes lower leg depending on the structure and level(s) involved and the magnitude of the stimulus (greater stimulation results in more distal radiation). However, referral patterns of mechanical pain tend to be more variable and more proximal than for radicular pain, and do not follow a dermatomal distribution. TABLE 18-1  Distinguishing Characteristics of Nociceptive, Neuropathic, and Nociplastic Low Back Pain CLINICAL CHARACTERISTIC NOCICEPTIVE PAIN NEUROPATHIC PAIN NOCIPLASTIC PAIN Etiology Cumulative stress Usually preceded by spine degeneration; herniated disk may sometimes occur after inciting event Onset Insidious Usually insidious Usually insidious Examples/causes Degenerative spondylosis, myofascial pain Herniated disk, spinal stenosis Nonspecific back pain; may present as mechanical or radicular pain Descriptors Aching, deep, throbbing Sharp, shooting, lancinating Usually similar to neuropathic descriptors, but may include nociceptive ones as well Sensory deficits Uncommon Common Occur sometimes, but often outside of any dermatomal distribution Motor deficits May be pain-induced Frequent Pain-induced weakness, fatigue common Hypersensitivity Occasionally, with myofascial pain Common Extremely common Pain pattern May be referred into leg (usually proximally) in nondermatomal distribution Reflects dermatomal pattern Diffuse, often outside of any anatomic pain patterns Precipitating/relieving factors Worse with activities that stress structure More unpredictable; spinal stenosis may be alleviated by forward flexion Autonomic signs Uncommon Present in up to 25% of patients Sympathetic nervous system hyperactivity and postural orthostatic tachycardia syndrome (POTS) very common Accompanying symptoms Co-existing psychopathology common, and increased rate of neck pain Higher levels of psychological stress and quality of life decrements than in nociceptive pain Diagnosis Imaging correlated with history and physical exam and diagnostic blocks History and neurologic exam, instruments such as s-LANSS and painDETECTa aS-LANSS (self-report version of the Leeds Assessment of Neuropathic Symptoms and Signs) and painDETECT are patient-reported questionnaires used to distinguish neuropathic from nonneuropathic pain. Developed before the term nociplastic pain was proposed, individuals scoring in the predominantly or likely “neuropathic pain” range in the absence of identifiable nerve damage are often presumed to have nociplastic pain.

Neuropathic pain is defined as pain caused by injury or disease affecting the somatosensory nervous system. In contrast to nociceptive pain, neuropathic pain is often accompanied by sensory abnormali­ ties such as paresthesias, numbness, and sometimes allodynia; is more unpredictable and associated with wide fluctuations and paroxysms; and often presents with focal neurologic findings (e.g., loss of senso­ rimotor functions or reflexes). It is important to recognize that radicu­ lopathy can occur without pain, and radicular pain frequently occurs in the absence of neurologic deficits. The newest recognized category of pain is nociplastic, which is pain that develops due to abnormal processing of pain signals without evidence of tissue damage or pathology involving the somatosensory system (e.g., central sensitization). Nociplastic back pain, often termed “nonspecific LBP,” is characterized by diffuse pain, superficial ten­ derness, and pain patterns that deviate from normal neuroanatomy. Patients may experience pain-induced weakness, multiple concomitant pain conditions, and sensory deficits outside of classic dermatomal maps. Table 18-1 provides a summary of the distinguishing character­ istics among nociceptive, neuropathic, and nociplastic pain conditions. Clinical studies estimate that more than one-third (range <10–55%) of patients with chronic LBP report neuropathic qualities, with 10–20% of the overall back pain population having nociplastic pain. However, different pain categories may occur simultaneously. For example, the predisposing pathology that results in herniated disks (disk degen­ eration with annular tears) and spinal stenosis (bulging, degenerative disks, facet joint and ligamentum flavum hypertrophy, spondylolisthe­ sis [e.g., anterior (anterolisthesis) or posterior (retrolisthesis) displace­ ment of a vertebral body, decreasing the diameter of the spinal canal]) frequently results in concomitant nociceptive pain, and individuals with central sensitization often experience neuropathic and nocicep­ tive pain at lower thresholds than other people. Studies performed in Usually insidious, but sometimes occurs after physically or psychologically traumatic event Unpredictable, typically worse with stress Very high levels of psychological distress and sleep abnormalities; generally co-prevalent with other nociplastic conditions History (e.g., multiple concomitant nociplastic and nonnociplastic conditions), physical exam (e.g., diffuse tenderness), instruments (central sensitization inventory), and psychophysical tests (conditioned pain modulation)

orthopedic populations suggest that over half of individuals may have mixed pain phenotypes. NATURAL COURSE ■ ■MECHANICAL LBP The distinction between acute (<3 months’ duration) and chronic LBP is important as it is the major factor in determining prognosis. In one systematic review involving 11 studies with acute nonradicular pain, 80% (95% confidence interval [CI], 61–100%), 67% (95% CI, 50–83%), 57% (95% CI, 46–68%), and 65% (95% CI, 54–75%) of patients experi­ enced pain at 1, 3, 6, and 12 months, respectively. In systematic reviews evaluating patients with predominantly chronic LBP, stagnant rates of improvement in pain were reported, with few patients improving dra­ matically after 6 months and a small percentage worsening. ■ ■RADICULAR LBP In patients with radicular pain, between 15 and 40% of individuals experience persistent symptoms at 6 months to 1 year, with most stud­ ies also finding that herniated disks typically resorb within 2 years but often reherniate. For spinal stenosis, most patients also remain stable, with a small percentage progressing, although unlike disk hernia­ tions, the underlying pathology does not recede. Risk factors for pain persistence and poor outcomes for both axial and radicular symptoms include greater disease burden, older age, psychopathology, poor job satisfaction, and secondary gain. ETIOLOGIES ■ ■NOCICEPTIVE PAIN Myofascial Pain  Muscles, ligaments, and fascia may be sources of mechanical pain, as they are imbued with nociceptors, collectively comprise a large surface area within spinal structures, are heavily involved in loadbearing and movements, and provide structural sup­ port to other potential pain generators. Studies examining muscle histology have found higher levels of neuropeptides (substance P, bra­ dykinin), neurotransmitters (norepinephrine, 5-hydroxytryptamine), and inflammatory cytokines (e.g., tumor necrosis factor α, interleu­ kins); lower pH levels; and more numerous vascular abnormalities in active trigger points than in latent trigger points and normal muscle. Studies using electromyography have also found higher myoelectric tone in patients with back pain compared to controls. Back muscles can be divided into deep intrinsic muscles that con­ nect to the vertebral column (semispinalis, rotatores, multifidus), intermediate muscles (erector spinae), and superficial muscles (e.g., latissimus dorsi). Although trigger points are frequently associated with muscle pain, these are more challenging to palpate in the low back compared to the mid-back and neck. Often co-prevalent with other etiologies or misdiagnosed as nonspecific (or nociplastic) pain, individuals with myofascial pain may present with focal or diffuse tenderness (and occasionally discrete trigger points), limited range of motion, increased muscle tension (and functional scoliosis in severe cases), and normal neurologic exams. Discogenic Pain  Disk degeneration is reported to account for 26–42% of patients with axial LBP, although selection bias (i.e., only those with suspected discogenic pain are included in discography prevalence studies), concomitant pain generators (e.g., disk degenera­ tion predisposes to facet degeneration), the lack of a reference standard for identifying painful disks (high false-positive rate of discography), and flaws in studies utilizing diagnostic tests to identify painful disks (lack of multiple diagnostic tests with adequate controls) limit the pre­ cision of prevalence estimates. In healthy disks, nerve fibers are limited to the outer annulus, but in those with disk degeneration, they populate the inner annulus and even the nucleus pulposus. Disk degeneration is associated with upregulation of inflammatory cytokines and other molecules, which may sensitize intradiscal nerve endings and cause hypermobility, which increases the mechanical stress on disks. Macro­ scopically, the tearing and degeneration of annular fibers increases the

stress on intact annular rings to the point of exceeding the mechanical pain threshold and facilitates contact between intradiscal cytokines and sensitized nerve endings.

Clinically, discogenic pain manifests as pain worsened with sitting or bending forward. It is more likely to be bilateral than facet or sacroil­ iac (SI) joint pain and frequently radiates into the upper and sometimes lower leg in a nondermatomal distribution. Since most individuals have evidence of disk degeneration by their fourth decade of life and a majority of individuals will experience LBP at least once, it can be chal­ lenging to establish a cause–effect relationship between pathology and symptoms. Provocative and analgesic discography are sometimes used to correlate degenerated disks with pain but are characterized by high false-positive rates in some populations (e.g., those with psychiatric morbidities, somatization, multiple other pain conditions) (Fig. 18-1). Low Back Pain CHAPTER 18 Facet Joint Pain  Facet joint pain affects approximately 10–15% of individuals with axial LBP, increasing with age. It may arise from the synovial lining, fibrous capsule, and bone, all of which are innervated with nociceptors. Disk degeneration generally precedes facet degen­ eration and increases loadbearing on the joints. Individuals with facet joint pain are more likely to experience unilateral, paraspinal pain and tenderness than those with predominantly discogenic pain, although the referral patterns overlap and advanced disease is usually bilateral. Individuals with facet joint arthritis may experience morning stiffness, and unlike those with discogenic pain, sitting may alleviate their symp­ toms. The diagnosis of facet joint pain is made via anesthetic blocks of the medial branches innervating the joints or the joints themselves, but anesthetic blocks are subject to high false-positive rates. Sacroiliac Joint Pain  Pain arising from the SI complex may be secondary to pathology involving the ligaments connecting the ilia and sacrum posteriorly and anteriorly (extraarticular) or the joint itself (intraarticular, e.g., internal bony structures, capsule, synovial lining). The SI joint is a true synovial joint, with the upper third being a syn­ desmosis, the lower two-thirds lined by synovium, and the lower third containing an anteriorly situated joint capsule, all of which contain nociceptors. Studies have found equal prevalence rates between extraar­ ticular and intraarticular pathology, with the former being more com­ mon in younger individuals, after trauma, and in those with prominent tenderness and less degeneration on imaging. Pain from the SI joint is more likely to be unilateral than discogenic or facetogenic pain and is generally most marked inferior to the L5 vertebral level, with about half of patients experiencing nondermatomal pain radiating into the leg(s), including below the knee in about a quarter of cases. Depend­ ing on the pathology, pain from the SI joint may also be referred into the groin and be mistaken for hip pathology. The reference standard Healthy intervertebral disk Degenerated intervertebral disk Extension of nucleus pulposus into degenerated annulus fibrosus, with inflammation Notochord cells (decrease in number as disks mature) Neovascularization and nerve ingrowth Intact annulus fibrosus Bulging disk Inflammatory cytokines (increase in number with disk degeneration) Osteophyte formation Endplate fractures FIGURE 18-1  Schematic drawing of a coronal view demonstrating a healthy intervertebral disc (left) and a degenerated disc (right). (Redrawn with permission from Seffrah Jin.)

for diagnosis is low-volume anesthetic blocks, although some studies have found that a battery of three or more provocative tests on physical examination (e.g., Patrick’s test [external rotation of the hip with the patient supine and the knee flexed], Gaenslen’s test [leg hyperextension off the edge of the exam table in the supine position, with the other leg flexed at the knee toward the chest], SI joint distraction [dorsolateral pressure on the anterior superior iliac spines of the iliac crests with the patient supine], or compression [downward pressure on the front side of the iliac crest in the lateral position with the affected side up and the hips and knees flexed]) has high sensitivity and specificity for detecting intra-articular SI joint pain (Table 18-2).

PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■RADICULAR PAIN Herniated Disc  The annual incidence of symptomatic lumbar disk herniation is about 1%, with a point prevalence between 1.5 and 4%. However, the prevalence of asymptomatic disk herniation is much higher, ranging from 29 to 43%, increasing with age. Between 38 and 56% of symptomatic individuals report an inciting event, with falls, lift­ ing, and motor vehicle collisions being the three most common causes. Persons with a herniated disk typically present with LBP radiating into the lower leg following a dermatomal distribution, although there is significant overlap and variability in dermatomes, and up to 40% of individuals have multilevel involvement. Patients frequently report sensory deficits and neurologic motor deficits (25–30%) and occa­ sionally are found to have asymmetrical or diminished reflexes, most pronounced when L4 or S1 is involved (<20%). The sensitivity of the straight leg raising test (Table 18-2) is ~80% for L5 and more caudad nerve roots, with the sensitivity of the femoral stretch test (Table 18-2) exceeding 50% for mid-lumbar nerve root involvement. Spinal Stenosis  Spinal stenosis affects approximately 11% of the U.S. population, with the prevalence dramatically increasing with age. Stenosis may be central (<10 mm anteroposterior diameter) or involve the lateral recesses or foramina (<3 mm). Anatomic etiologies include bulging or herniated disks, facet joint hypertrophy, spondylolisthesis, and ligamentum flavum buckling and hypertrophy, all of which can also independently cause axial pain. Neurogenic claudication, which has a sensitivity of 88% (95% CI, 78–98%), is a hallmark of spinal stenosis but has low specificity. Symptoms of neurogenic claudication include back pain radiating into the legs that is exacerbated by activity and improved by rest, especially sitting. The most common levels affected by spinal ste­ nosis are L4–5 (92%) and L3–4 (66%), with most people having multiple nerve root involvement. Typically, leaning forward (e.g., shopping cart sign) alleviates symptoms. Other signs and symptoms of spinal stenosis include a wide-based gait, poor balance, pain worsened by lumbar exten­ sion, and diminished vibratory perception. As with radicular symptoms secondary to a herniated disk, the diagnosis of lumbosacral stenosis (with or without neurogenic claudication) is made by a combination of history, physical examination, and imaging (e.g., magnetic resonance imaging [MRI]); see Figs. 18-2 through 18-4. HISTORY AND PHYSICAL EXAM (SEE ALSO CHAP. V8) History and physical examination may be used to identify patients who require further diagnostic workup and have indications for advanced therapies, including surgery, but are rarely pathognomonic. Inspection may provide clues of congenital or unusual pathology (e.g., birthmarks and doughy lipomas can indicate spina bifida, and an unusual patch of hair over the spine may indicate underlying bony pathology), while observation of gait can suggest nonspinal pathology (e.g., Parkinson’s disease or antipsychotic drug use causing propulsive gait; a central lesion causing spastic gait; muscular dystrophy, spinal or gluteal muscle weakness, or hip pathology causing waddling gait; peroneal neuropa­ thy, a large herniated disk, Guillain-Barré syndrome, multiple sclerosis, or another neurologic condition causing steppage gait or foot drop). Paraspinal tenderness overlying an area of “fullness” or increased muscle tension can indicate muscle spasm or a muscle tear, which can sometimes be distinguished through ultrasound, while midline tender­ ness may indicate ligamentous injury.

Spine alignment should be viewed from multiple dimensions. Scoliosis can predispose patients to disk and facet joint degeneration. Scoliosis, defined as a sideways curvature of the spine, or curvature in a coronal plane, can predispose patients to disk and facet joint degen­ eration. Functional scoliosis or decreased lordosis (natural inward or anterior curvature of the spine) can indicate muscle spasm or postural dysfunction (which may disappear with flexion), and exaggerated lor­ dosis can be secondary to a tethered spinal cord or abdominal muscle weakness. Range of motion can indicate specific pathology but is most frequently associated with nonspecific pain-induced limitations. For example, decreased extension can indicate spinal stenosis or spondylo­ listhesis, diminished forward flexion can suggest discogenic pain, and pain when rising from sitting or with transitional movements might warrant workup for SI joint pain. True or apparent leg length discrep­ ancies (20% have a clinically relevant leg length discrepancy exceeding 9 mm), which can be distinguished by measurements from the umbi­ licus, anterior superior iliac spine, or greater trochanter to the medial malleolus, may predispose patients to a host of biomechanical prob­ lems including SI joint pain, accelerated disk and facet joint degenera­ tion, and myofascial strain. Nonorganic signs (e.g., overreaction, pain with sham stimulation) may signify underlying psychopathology and are associated with treatment failure. Specific tests are generally more specific for radicular than axial pain. Clinical studies have found that older age, positive treadmill test (a decrease in ambulatory capacity and an increase in pain with progressively greater grades of inclination), positive Romberg’s test (Chap. 433), pain that disappears with sitting, and perineal numbness have strong predictive value for lumbosacral stenosis. For detecting a herniated disk, the straight leg raising test (with the patient prone, the examiner gently straightens and raises the leg of the affected side by flexing the hip, reproducing radicular pain at an elevation between 30° and 70°) has high sensitivity but widely variable specificity for L5–S2 (L5–S1 are most commonly affected) nerve root involvement, with the femoral stretch test (the knee is passively flexed to the thigh while the hip is gently extended, reproducing radicular pain in the anterior thigh) being less studied but reasonably sensitive for mid-lumbar nerve root involvement. In contrast, the crossed straight leg raising test (elicit­ ing radicular pain on the affected side when raising the leg on the unaffected, contralateral side) demonstrates consistently high (>85%) specificity but low sensitivity. For mechanical back pain, centralization (referred pain that is perceived as receding toward the midline with repeated movements), pain worse with sitting, and midline tenderness suggest discogenic pain, whereas paraspinal tenderness is weakly associ­ ated with injection-confirmed (e.g., lumbar medial branch nerve block) facet joint pain. An array of at least three positive SI provocation tests (e.g., Patrick’s, Gaenslen’s, compression, distraction; Table 18-2) is asso­ ciated with accurately identifying the intraarticular SI joint as the prin­ cipal pain generator. Compared to other sources of LBP, pain below L5 and radiation into the groin are also more likely to indicate SI joint pain. A neurologic exam can indicate nerve root involvement (i.e., radicu­ lar pain), with reflexes (patellar reflex indicating L4 and sometimes L2 or L3 involvement, Achilles reflex indicating S1 pathology) being the most objective measure. However, these too must be considered in context as about 5% of younger individuals but over one-third of older individuals have absent reflexes and about one-quarter of people have asymmetrical reflexes. Although tenderness over the sciatic notch with internal rotation of the extended hip (Freiberg’s test) may suggest piri­ formis syndrome, tenderness elicited on rectal or pelvic examination may improve selection for diagnostic injections. When cauda equina syndrome is suspected, assessing sensation in the perianal area and a rectal exam to evaluate sphincter tone is necessary, and urgent confir­ mation through MRI might be needed. Table 18-3 summarizes the main etiologies of LBP and their usual clinical features, diagnostic tests, and treatments. RED FLAGS The term “red flags” has been used to denote signs or symptoms that suggest the potential presence of serious spinal (e.g., cauda equina syndrome) or nonspinal pathology (e.g., infectious, visceral [pelvic and

TABLE 18-2  Summary of Common Physical Exam Maneuvers for the Low Back TEST DESCRIPTION COMMENTS Lumbar Radiculopathy Straight leg raising (SLR) The patient is in a supine position. The examiner passively flexes the leg of the affected side at the hip, reproducing radicular pain. Crossed SLR The patient is in a supine position. The examiner passively flexes the leg of the nonaffected (contralateral) side at the hip, reproducing radicular pain in the affected leg. Femoral stretch The patient is in a prone position. The examiner passively extends the leg of the affected side at the hip, reproducing radicular pain in the thigh. Sacroiliac (SI) Joint Provocation Compression The patient is in a lateral decubitus position with the affected side up, with hips and knees flexed; the examiner exerts downward pressure on the superior border of the iliac crest. Thigh thrust (posterior shear test [POSH]; femoral shear test) The patient extends their unaffected leg while in a supine position. On the affected side, the examiner flexes the patient’s hip to 90° and simultaneously flexes the ipsilateral knee while applying downward pressure along the longitudinal axis of the femur. Distraction (gapping test) The patient is in a supine position. On the affected side, the examiner applies downward (dorsolateral) pressure on the ipsilateral anterior superior iliac spine (ASIS). Flexion, abduction, and external rotation (FABER; Patrick’s test) The patient is in a supine position. On the affected side, the examiner flexes the patient’s hip and knee and positions the foot under the contralateral knee (abduction). While stabilizing the contralateral ASIS with one hand, the examiner uses their other hand to apply downward pressure on the knee of the affected side (external rotation). Pelvic torsion (Gaenslen’s test) The patient is in a supine position, usually on the edge of an examining table. The examiner hyperextends the leg of the affected side while maximally flexing the hip and knee of the unaffected side against the patient’s abdomen. SI Joint Mobility/Alignment Standing hip flexion test (SHFT; Gillet’s test; Stork test) The patient stands upright with both feet on level ground. The patient is instructed to lift one leg by flexing their hip and knee toward the chest. The examiner stands behind the patient and observes the spine and pelvis. The test is repeated in the other leg for comparison. Deep Gluteal Syndrome/Piriformis Syndrome Freiberg’s sign The patient is in a supine position. The examiner passively extends, adducts, and internally rotates the thigh and calf (“log roll”) on the affected side. Flexion, adduction, and internal rotation (FADIR; FAIR test) The patient is in a supine position. On the affected side, the examiner flexes the patient’s hip and knee, and while maximally adducting the thigh, internally rotates the hip. Pace test In a sitting position, the patient is asked to abduct and externally rotate their hip, eliciting pain. Beatty test The patient is positioned in a lateral decubitus position with the affected side up. Elevating the affected leg elicits pain in the buttocks. Spondyloarthropathy/Ankylosing Spondylitis Schober test The patient stands upright, and horizontal lines are drawn across L5 and 10 cm superior to L5. The patient is asked to bend forward and touch their toes. If the distance between the drawn lines increases <5 cm, this indicates decreased range of motion and is a positive result. Nonorganic Signs/Functional Disorders (Neurologic and/or psychiatric consultations potentially indicated prior to interventional procedures) Hoover’s sign The patient is in a supine position. The examiner asks the patient to flex the leg of the affected side at the hip, against resistance. If an organic source of neuropathy or paresis is present, with normal effort, the unaffected leg will involuntarily push downward on the examination table. Tripod sign With the patient in a seated position, elevating the affected leg may result in pain in the leg and back. Waddell signs Five categories of signs: (1) nonanatomic distribution of tenderness; (2) pain from sham stimulation (i.e., lumbar pain from gentle downward force on the shoulders); (3) distraction (i.e., positive SLR test in supine position but not while sitting, or while preoccupied); (4) regional disturbances (i.e., motor or sensory findings that do not correlate with areas of pathology); and (5) overreaction (i.e., disproportionate physical or emotional responses on exam).

SLR has greatest sensitivity (80%) for impingement of the L5 or S1 nerve roots; sensitivity markedly decreases for nerve roots cephalad to L4. Unreliable for eliciting radicular symptoms from spinal stenosis. High specificity (>85%) but low sensitivity. Low Back Pain CHAPTER 18 Modest sensitivity (50%) for L2–L4 nerve root impingement. There are no physical examination maneuvers that reliably distinguish between intraarticular and extraarticular pathologies, but most tests have been studied based on blocks diagnosing intraarticular pathology. Estimated sensitivities and specificities for individual tests vary greatly. The thigh thrust, FABER, and pelvic torsion tests have relatively greater sensitivities (up to 50–80%), whereas the compression and distraction tests have relatively greater specificities (up to 70–80%). A battery of ≥3 tests is generally accepted as having the greatest overall sensitivity (potentially ≥90%) and specificity (potentially ≥80%). During hip flexion, the ipsilateral ASIS should rise slightly while the posterior superior iliac spine (PSIS) drops slightly. If these motions are paradoxical (i.e., PSIS rises with hip flexion) or asymmetrical, this suggests SI joint mobility dysfunction. Assesses potential impingement of the sciatic nerve by nonspine structures (e.g., piriformis muscle, gluteal muscles) by stretching the piriformis and associated (e.g., gemelli) muscles, which can produce symptoms similar to those of lumbar radiculopathy. There are variants in which the patient lies supine with the hips and knees flexed. Unlike the FAIR test and Freiberg’s sign, this test causes contraction of the piriformis muscle and thus may not reliably elicit sciatic nerve entrapment symptoms. Numerous modifications exist regarding the location of the drawn lines. Nonspecific for inflammatory spinal arthritis (i.e., other conditions such as discogenic pain associated with decreased forward flexion can lead to a positive result). A discordant response might suggest malingering or the presence of a functional neurologic disorder (e.g., conversion disorder). Leaning back and resting both hands on the table should reduce the pain. Failure to do this may suggest nonorganic pathology or malingering. A greater number of positive signs is associated with a greater risk of treatment failure.

L3 Spondylolisthesis Spinal stenosis secondary to spondylolisthesis, bulging disk, and facet hypertrophy L4 PART 2 Cardinal Manifestations and Presentation of Diseases Annulus fibrosus Disk extrusion with extension of nucleus pulposus into central canal Nucleus pulposus L5 Sacrum FIGURE 18-2  Sagittal view of the lumbar spine depicting L4-5 spinal stenosis secondary to spondylolisthesis, a bulging disc and facet joint hypertrophy, and an L5-S1 herniated nucleus pulposus. (Redrawn with permission from Seffrah Jin.) FIGURE 18-3  In this T2-weighted sagittal lumbar MRI, severe central canal stenosis secondary to a disk herniation is visualized at L4–5 (arrowhead). This patient appears to also have partial lumbarization of the sacrum, a risk factor for back pain.

FIGURE 18-4  In this T2-weighted axial lumbar MRI, bilateral neuroforaminal narrowing secondary to protrusion of the L4–5 disk (arrowheads) and severe bilateral facet joint hypertrophy (asterisks) are visualized. retroperitoneal organs], traumatic, vascular, neoplastic, inflammatory, or endocrine) that may lead to permanent neurologic deficits if not urgently treated. In one review of 9940 patients with a chief complaint of LBP, 92.6% of patients endorsed at least one red flag, with the most common being night pain (58.1%); although the presence of one or more red flags could predict that a neurologic emergency was present, their absence did not meaningfully decrease the likelihood. Table 18-4 summarizes red flag findings and their potential causes. ANCILLARY TESTS ■ ■IMAGING Advanced imaging is often used to associate symptoms with a poten­ tial etiology, but lacks specificity, with most studies demonstrating no significant correlation between imaging and symptoms, and a high per­ centage of abnormalities in populations without back pain. For acute LBP, red flags and serious or progressive neurologic deficits warrant imaging. For chronic LBP, MRI can be considered on a case-to-case basis, especially when considering invasive interventions such as sur­ gery. For lumbar epidural steroid injections (ESIs), a randomized trial failed to demonstrate that MRI improved outcomes or meaningfully affected decision-making. MRI is considered the gold standard for detecting soft tissue abnor­ malities including herniation, and can reveal active inflammation on certain sequences (Chap. 434). Although MRI is superior for contrast resolution between structures, computed tomography (CT) can pro­ vide better spatial contrast, is more sensitive for some bone abnormali­ ties, and has sensitivity >90% for identifying most lumbar pathology including disk herniations. Plain films can be used to evaluate scoliosis and spondylolisthesis and detect fractures (including pars interarticu­ laris), although MRI is needed to determine acuity and chronicity (e.g., presence or absence of edema). As a general principle, when pain symptoms persist or worsen despite optimal nonpharmacologic and pharmacologic treatments or if red flag symptoms arise, dedicated imaging (e.g., x-ray, CT, MRI) can clarify potential diagnoses. Focal lesions on radiologic exams that are physiologically or anatomically plausible sources of pain (e.g., disk her­ niation with nerve root impingement) might be targets for subsequent interventional pain procedures or surgical management, but because symptom severity does not always correlate with imaging findings, a thorough history and physical examination remain the foundation for accurate contextualization. Treatment decisions should rarely be predi­ cated on imaging findings alone.

duloxetine); topical analgesics (e.g., diclofenac, lidocaine) only if superimposed soft tissue pain. Pharmacologic: NSAIDs; antidepressants (e.g., Pharmacologic: NSAIDs; antidepressants (e.g., Judicious use of opioids can be considered for considered, but evidence for long-term benefit analgesics (e.g., diclofenac, lidocaine in those is mixed and disk puncture may increase risk electromyography Pharmacologic: NSAIDs; nonbenzodiazepine of future disk degeneration; the benefit for intradiscal corticosteroid injections or ESI Interventional: biacuplasty or IDET can be duloxetine, tricyclic compounds); topical muscle relaxants; antidepressants (e.g., Interventional: trigger point injections  with irritable nociceptors or allodynia) ETIOLOGY RISK FACTORS TYPICAL ONSET CLINICAL PRESENTATION PHYSICAL EXAM DIAGNOSTIC TESTS TREATMENTSa duloxetine) unclear  test; MRI generally nonspecific abnormalities and acuity, plain films for acute fractures. Bony vibration test sometimes used. positive rate), bony vibration correlates with discography Occasionally ultrasound or upper leg, worsened with activities Midline tenderness MRI to identify endplate Discography (high falsebut high-intensity zone results indicate ligamentous occasionally trigger Midline tenderness, motion (especially reduced range of between spinous forward flexion) processes may points. Midline tenderness in Tenderness, injury. bilateral than SI or facet joint pain, Axial pain, occasionally referred insidious Axial pain that may radiate into Often superimposed with other into thigh, mid-back, or groin. extremities, more likely to be Axial pain, may radiate into worse with sitting etiologies. TABLE 18-3  Clinical Evaluation, Diagnosis, and Treatment of Low Back Pain Etiologies occasionally abrupt Vertebrogenic Advanced age/osteoporosis, trauma Abrupt (trauma) or (e.g., annular tear) sometimes acute abrupt movements (sneezing) Usually insidious (muscle tear or (chronic) but Insidious, spasm) disks Advanced age (although patients younger Myofascial pain Strenuous activities, sedentary lifestyle, than those with facet joint pain), acute (torsional event) or repetitive trauma, genetic predisposition Mechanical Pain Intervertebral

(Continued) Interventional: RFA of the relevant medial branch invasive fusion of the SI joint in refractory cases type 1 or type 2 vertebral endplate/bone marrow duloxetine); topical analgesics (e.g., diclofenac, nerves when preceded by a positive diagnostic structures are less likely to be the predominant Pharmacologic: NSAIDs; antidepressants (e.g., Pharmacologic: NSAIDs; antidepressants (e.g., source of pain, basivertebral nerve RFA can be Interventional: In acute vertebral compression lidocaine) only if superimposed soft tissue pain joint injection; RFA of the sacral lateral branch In patients with chronic axial pain with Modic Interventional: Intra- and/or extra-articular SI augmentation (vertebroplasty or kyphoplasty) nerves for extraarticular pathology; minimally can be considered. The benefit for vertebral augmentation in chronic fractures is mixed. changes on MRI and in whom other lumbar severe pain secondary to acute fracture(s). involving joint degeneration or instability fracture(s) (<6 weeks) with severe pain or disability, percutaneous vertebral block (e.g., ≥50% reduction in pain)  Low Back Pain CHAPTER 18 considered.  duloxetine) provocative tests correlate well medial branch or intraarticular CT) may indicate intraarticular Advanced imaging (especially CT or MRI generally reveals with diagnostic injections. degeneration. Diagnostic pathology. Battery of injections. tenderness, improved Tenderness below L5; positive provocative tests. Most painful posterior superior area located near Paraspinal with sitting iliac spine. and occasionally lower legs. About genetic predisposition Insidious Axial pain may radiate into upper individuals, intraarticular). About Unilateral (younger individuals, post-trauma) or bilateral (older half of cases radiate into leg, sometimes below knee. half are bilateral. extraarticular, intraarticular. insidious for Abrupt for with bilateral intraarticular pathology). True (intraarticular), and lumbar spine surgery SI joint Bimodal prevalence (younger individuals often secondary to trauma, older people and apparent leg length discrepancies, with unilateral extraarticular pathology Facet joints Increases with age, repetitive strain, hip pathology, inflammatory arthritis are predisposing factors.

secondary to disk herniation. ESIs might confer a (gabapentin, pregabalin), but systematic reviews weak but potentially meaningful surgery-sparing duloxetine). Gabapentinoids are commonly used harms, especially in the elderly (e.g., dizziness, used (gabapentin, pregabalin), but systematic when balanced against potential harms (e.g., effective in the acute phase of radicular pain Interventional: ESIs commonly used and may Pharmacologic: NSAIDs; nonbenzodiazepine MRI or CT scan Pharmacologic: NSAIDs; nonbenzodiazepine reviews and meta-analyses suggest minimal and meta-analyses suggest minimal benefit duloxetine). Gabapentinoids are commonly Interventional: ESIs, which are likely most dizziness, somnolence, gait disturbance). benefit when balanced against potential muscle relaxants; antidepressants (e.g., muscle relaxants; antidepressants (e.g., somnolence, gait disturbance). ETIOLOGY RISK FACTORS TYPICAL ONSET CLINICAL PRESENTATION PHYSICAL EXAM DIAGNOSTIC TESTS TREATMENTSa PART 2 Cardinal Manifestations and Presentation of Diseases effect.  selective nerve root blocks may MRI or CT scan, myelography Electrodiagnostic tests or when contraindicated. be confirmatory. neurologic weakness ability when bending diminished reflexes. test usually positive Straight leg raising Sensory and motor Most patients also Improved walking Sensory loss and common; may be usually negative. deficits; SLR test for lower lumbar associated with have back pain. forward. levels. Usually insidious Usually unilateral for lateral recess disability may wax and wane, the Although the severity of pain and bilateral. Wide-based gait, often Pain often improves with sitting. radiating into leg in dermatomal spondylolisthesis, degenerative causes of spinal stenosis (e.g., (large, central herniation) pain or foraminal stenosis; central affects multiple dermatomes. be insidious May be unilateral or bilateral stenosis may be unilateral or TABLE 18-3  Clinical Evaluation, Diagnosis, and Treatment of Low Back Pain Etiologies (Continued) distribution Often abrupt, may Herniated disk Peak prevalence 30–50 years, preexisting predisposition, lifestyle (heavy lifting, spondylolisthesis, facet hypertrophy) disk degeneration, trauma, genetic Spinal stenosis Advanced age, concomitant spinal pathology (disk degeneration, smoking), obesity Predominantly Radicular Pain

therapy, targeted exercise) should be prioritized.  analgesics (e.g., diclofenac, lidocaine, menthol). term benefit, but evidence for long-term benefit lamotrigine) are occasionally used, but minimal confer short-term and sometimes intermediateTCAs), topical local anesthetics (e.g., lidocaine Pharmacologic: gabapentinoids (gabapentin, Interventional: peripheral nerve blocks might Pharmacologic: NSAIDs; nonbenzodiazepine confer analgesia, but evidence for long-term Nonpharmacologic therapies (e.g., physical Other anticonvulsants (e.g., oxcarbazepine, pregabalin), antidepressants (e.g., SNRIs, is mixed given the progressive pathology.  duloxetine); gabapentinoids (gabapentin, benefit is minimal or negative for certain muscle relaxants; antidepressants (e.g., patches or creams), topical capsaicin. pregabalin); over-the-counter topical conditions (e.g., PHN).  evidence is available. advanced imaging may rule out Based on clinical presentation. Workup for underlying cause; conditioned pain modulation sensitization inventory and “neuropathic” range on Patients often score in (painDETECT); central validated instruments may confirm central disk pathology sensitization. Sensory and motor provocative tests neurologic exam but nonspecific, loss, diminished Marked diffuse often positive tenderness, nonfocal reflexes nociplastic and nonnociplastic pain into legs. Most patients have other bilateral (advanced neuropathies). spinal regions, frequently radiates rate of mood disorders and sleep common with herpes zoster than thoracic dermatomes. Unilateral Advanced neuropathies usually changes/osteophyte formation) conditions. High co-prevalence Lumbosacral dermatomes less Bilateral, often involves other (herpes zoster), occasionally often progress with age. multidermatomal. dysfunction. herpes zoster, diabetic amyotrophy) Generally insidious, Usually insidious, acute for herpes but >20% report psychological inciting event a physical or zoster Neuropathy Underlying neuropathic pain condition (e.g., pain Central sensitization, more common in females, peak age 20s to 50s, genetic predisposition Nociplastic Pain Nonspecific back

be considered in individuals with epidural scar Interventional: Epidural lysis of adhesions can cases, especially those in whom neuropathic Pharmacologic: NSAIDs; nonbenzodiazepine tissue. SCS can be considered in refractory aNonpharmacologic treatments such as physical therapy, along with the management of concomitant mood disorders and maladaptive coping mechanisms (e.g., via pain psychology or CBT), should be considered for all patients with Most neuropathic conditions have concomitant mechanical pain (e.g., spinal stenosis may be from facet hypertrophy or degenerated/herniated disks, which in themselves can cause mechanical pain); herpes zoster can cause gabapentinoids (depending on whether neuropathic or nociceptive symptoms muscle relaxants; antidepressants; symptoms predominate. predominate) (e.g., discography, facet blocks) myelography. Diagnostic blocks MRI with gadolinium, or even are associated with a high false-positive rate. common in individuals dermatomes. Muscle with nociplastic pain. weakness common. wasting and/or loss may be in multiple pain in a multidermatomal fashion Sensory loss and Neurologic signs be appreciated. or lordosis may tenderness is Superficial Often involves axial and radicular Epidural scar tissue, result in no benefit.

1 year to manifest. Adjacent segment arachnoiditis, and pseudoarthroses, disease can take

may present with weeks or months muscle wasting surgical levels), worsening pain fragments may selection (e.g., after surgery. and retained Poor patient irrelevant greater presurgical disease burden, more concurrent pain conditions (e.g., baseline syndrome Younger age, female sex, opioid use, central sensitization) cutaneous inflammatory pain. Mixed Pain Phenotypes Postlaminectomy chronic pain.

Abbreviations: CBT, cognitive-based therapy; CT, computed tomography; ESI, epidural steroid injection; IDET, intradiscal electrothermal therapy; MRI, magnetic resonance imaging; NSAID, nonsteroidal anti-inflammatory drug; PHN, Low Back Pain CHAPTER 18 postherpetic neuralgia; RFA, radiofrequency ablation; SCS, spinal cord stimulation; SI, sacroiliac; SLR, straight leg raise; SNRI, serotonin-norepinephrine reuptake inhibitor; TCA, tricyclic antidepressant.

TABLE 18-4  “Red Flag” Symptoms and Corresponding Pathology Demographics Age ≤18 years Congenital defect, tumor, spondylolysis, or spondylolisthesis Age >50 years Tumor, fracture, vascular abnormality (aortic aneurysm) Social and Treatment Related Intravenous drug use Infection Anticoagulant use Hematoma Recent procedure Hematoma (complication after spine procedure) or infection PART 2 Cardinal Manifestations and Presentation of Diseases Immunocompromised state Infection Trauma Fracture, hematoma History of cancer Tumor Symptoms Fever, night sweats, chills Infection, tumor Weight loss Tumor, infection Saddle anesthesia Cauda equina syndrome Urinary or rectal incontinence, sexual dysfunction Cauda equina syndrome Rapidly progressive or severe neurologic symptoms Cauda equina syndrome Pain not relieved by rest or at night Tumor, infection Physical Exam Signs Saddle anesthesia Cauda equina syndrome Decreased rectal tone Cauda equina syndrome ■ ■ELECTRODIAGNOSTIC TESTING Electromyography and nerve conduction studies are often used to iden­ tify peripheral sources of nerve and muscle injury. This determination is particularly pertinent in cases of multiple dermatomal involvement or atypical extremity pain, when symptoms and imaging findings are conflicting, and in cases of transitional anatomy or aberrant innervation. Transitional anatomy, which includes variations of “lumbarization” of the S1 spinal segment (i.e., a sixth vertebral body is present), or more commonly “sacralization” of L5 (i.e., a partial or complete anatomic fusion of L5 with S1), is present in 15–35% of the population and is asso­ ciated with an increased prevalence of back pain. Studies have generally found sensitivity rates ranging from 36 to 64% for radicular pain in the absence of focal neurologic findings and from 51 to 86% in patients with an abnormal neurologic examination. The specificity of electrodiagnos­ tic testing is also variable, ranging between 50 and 60%. ■ ■SELECTIVE NERVE ROOT BLOCKS Selective nerve root blocks (SNRBs) can also be used to identify a symp­ tomatic nerve root in ambiguous cases. SNRBs are performed in a man­ ner similar to that of transforaminal ESIs but, by definition, involve the blockade of only a single nerve root (i.e., avoidance of epidural spread), with studies finding that high-volume injections (>0.5 mL) undermine specificity. There have been no randomized studies evaluating the effect of SNRB on postsurgical decompression outcomes, although retrospec­ tive studies have generally found a modest correlation between pain relief after SNRB and surgery. One systematic review assessing the accuracy of SNRB in detecting radiculopathy in patients with LBP and lower limb pain found 93% sensitivity and 26% specificity based on very low-quality studies and concluded that the addition of SNRB to routine presurgical workup is not cost-effective. TREATMENT Low Back Pain MULTIMODAL AND INTERDISCIPLINARY STRATEGIES Contemporary strategies for managing acute and chronic LBP prioritize the optimization of nonpharmacologic modalities (e.g.,

physical therapy, exercise, cognitive-behavioral therapy, heat, mas­ sage) with a graded, patient-centered incorporation of pharma­ cologic, interventional (e.g., fluoroscopic injections), and surgical treatments for increasingly refractory symptoms. Because most cases of acute LBP resolve within 6 weeks, over-the-counter anal­ gesics in addition to nonpharmacologic treatments such as targeted physical therapy, core-strengthening exercises, and education fre­ quently suffice without the need for imaging or prescription anal­ gesics. The biopsychosocial model recognizes that psychological (e.g., underlying mood disorders) and social factors (e.g., systemic barriers to care) contribute to the overall perception and experience of pain, and these issues should be identified and addressed when possible. An interdisciplinary team that involves specialists from pain medicine, orthopedic, and/or neurosurgical spine surgery, physical therapy, and psychology/psychiatry can facilitate a more nuanced, individualized, and comprehensive treatment plan. Stud­ ies have found that interdisciplinary treatment programs involving these specialties provide better improvements in pain, function, and quality of life, but restrictions in coverage from health care payors have hindered widespread implementation. Pharmacotherapy  Around a quarter of patients with acute LBP develop chronic symptoms. Chronic LBP is defined by symptoms that persist for >3 months. Pharmacologic options include non­ steroidal anti-inflammatory drugs (NSAIDs), nonbenzodiazepine muscle relaxants, and antidepressants (e.g., duloxetine, a serotonin and norepinephrine reuptake inhibitor, or tricyclic antidepressants) (Chap. 14). Although frequently used, acetaminophen is unlikely to provide significant analgesia for back pain and is no longer recommended as a first-line agent. There is insufficient evidence for gabapentinoids (gabapentin or pregabalin) for either axial or radicular back pain. Opioids have not demonstrated significant long-term benefits for analgesia or function, but a temporary course may be considered on a case-by-case basis for debilitating acute pain or severe exacerbations of chronic LBP. Opioids are associated with risks of serious potential harms (e.g., respiratory depression, addiction, endocrinologic disturbances). If used, opioids should be prescribed at the lowest effective dose for the shortest duration of time feasible and with clearly defined treatment goals collab­ oratively made with the patient. Concomitant use of opioids with benzodiazepines should be avoided due to the increased risk of respiratory depression. Psychological Therapies  There is a high co-prevalence between psychopathology (e.g., depression, anxiety disorders, catastrophiza­ tion, poor coping skills, somatic symptom disorder, fear avoidance, posttraumatic stress disorder, substance use disorders) and chronic back pain. Studies have found co-prevalence rates for depression ranging between 33 and 67%, for anxiety between 10 and 30%, for substance misuse disorders between 13 and 40%, and for axis II disorders (e.g., personality disorders), >50% in some studies. The lifetime co-prevalence rates of axis I and axis II conditions in indi­ viduals with chronic back pain are even higher. It is important to rec­ ognize that psychiatric conditions are not binary (present or absent), but rather exist along a continuum (Chap. 463). Many chronic pain sufferers may still benefit from precision psychotherapies despite not formally meeting contemporaneous diagnostic criteria. It is therefore important to identify and address underlying psychiatric and mood conditions. Studies have shown that targeted education, mindfulness-based stress reduction, operant therapy, biofeedback, progressive relaxation, and cognitive-behavioral thera­ pies may benefit patients with back pain from various etiologies, with evidence generally being greatest for patients with chronic pain. No individual psychological therapy has demonstrated con­ sistent superiority, and it is likely that the effectiveness of these therapies is greatly dependent upon the provider-specific and patient-specific characteristics that undergird the therapeutic rela­ tionships of psychiatric care. There is stronger and more consistent evidence for short-term than long-term benefit on pain and func­ tion, with the benefits waning without ongoing follow-up.

Physical Therapies  Physical therapies have been a cornerstone of back pain treatment for decades. Physical therapists evaluate and educate patients regarding kinesiologic or functional abnormalities that contribute to pain and provide minimally invasive procedural interventions to help reduce symptoms and dysfunction. Physical therapists develop exercise regimens to address underlying causes of pain (e.g., correcting gait abnormalities) and provide treatments (e.g., hot and cold packs, manual therapies including manipulation, massage, neuromuscular reeducation). Exercise has been shown to reduce pain and increase function for radicular and nonradicular back pain, although the effects diminish over time if exercises cease. For acute back pain, although early resumption of activities including exercise (within 2 weeks of symptom onset) is widely recommended, studies are mixed regarding its long-term effect on pain and function. Most studies have failed to demonstrate one type of exercise as more beneficial than another, with yoga and Tai Chi being two of the more commonly studied therapies. Integrative Medicine  The use of integrative treatments for back pain has grown substantially but continues to be characterized by low-quality studies. Integrative medicine therapies can be pro­ vided via specialists (e.g., acupuncturists, chiropractors), physical therapies, and physicians. Although there are no trials comparing therapies stratified by specialty, specialists (acupuncturists, chiro­ practors) may have a greater knowledge base and more experience than generalists, which could theoretically be helpful for refractory cases. Massage may be beneficial in individuals with acute and chronic pain with prominent soft tissue symptoms (e.g., spasmodic or tension-based pain), but the analgesic benefits tend to be shortlived. Spinal manipulation may provide small benefits for acute and chronic back pain and physical function compared to the absence of therapy, but the effects diminish over time. Spinal manipulation is noninferior to other recommended physical therapies; there is mixed evidence for its benefit compared to sham or as an add-on treatment to other physical therapies. Acupuncture has been shown to be effective for pain and, to a lesser degree, several second­ ary outcomes in patients with acute and chronic LBP, although the effects tend to be modest and short-lived without continued therapy. Reviews have found similar effects for a wide variety of different types of acupuncture (e.g., electroacupuncture, moxibus­ tion, auricular, cupping), with true acupuncture being slightly more effective than sham acupuncture (e.g., needles placed outside standard acupoints or applying pressure that fails to penetrate the skin). In turn, sham acupuncture is more effective than the absence of treatment, although this is likely due to placebo effects. There is no evidence to support one form of integrative treatment compared to others. INTERVENTIONAL PAIN PROCEDURES Most cases of LBP cannot be attributed to one anatomic source (nonspecific LBP). However, a thorough history and physical examination and the appropriate use of imaging can help identify potential targets for interventional procedures, which may provide analgesia and improve physical function when surgical indications have not been met or if contraindications for surgery exist. Most interventional pain procedures are performed fluoroscopically or with ultrasound in some cases. LBP Without Radicular Symptoms (Axial LBP)  Axial LBP most commonly involves the facet joints (e.g., zygapophyseal joint, or Z-joint, referring to the paired posterolateral articulations between the inferior articular process of a vertebra with the superior articu­ lar process of the subjacent vertebra), SI joints, intervertebral disks, vertebrae, or the paraspinal muscles and ligaments. It is important to recognize that patients can have pain from more than one of these structures simultaneously. However, estimating the preva­ lence of concomitant sources of spine pain remains challenging; among several structural abnormalities that may be present, only a few might be contributing to a patient’s overall pain symptoms. Patients with similar radiologic findings frequently experience

different severities and locations of pain from one another, likely as a consequence of each individual’s confluence of biopsychosocial factors. LUMBAR MEDIAL BRANCH NERVE BLOCKS AND ABLATION Facet joint pain comprises 10–15% of cases of axial LBP, with prevalence increasing with age. The diagnosis of facetogenic pain can only be established through diagnostic medial branch blocks, which entail the administration of local anesthetic onto the medial branch nerves that innervate the facet joints thought to be contrib­ uting to the patient’s axial pain. If the patient experiences significant improvement in pain and physical function, the diagnosis of face­ togenic pain is confirmed and the same nerves can be ablated via radiofrequency ablation (RFA). SI JOINT INTERVENTIONS The SI joints are confirmed as the primary etiology in 20–35% of suspected cases of lower axial LBP. SI pain manifests predominantly inferior to the L5 vertebral level and is more likely to be unilateral than facetogenic pain or discogenic pain. The source of SI pain may be intraarticular, which is more likely to occur bilaterally and in older individuals, or extraarticular, which is frequently unilateral, more common in younger individuals (especially after trauma), and can be associated with unremarkable imaging. As noted earlier, the likelihood of SI pain is greatly increased when there are three or more positive provocative physical exam maneuvers (Table 18-2). In addition to being therapeutic, a low-volume intraarticular SI joint injection is the reference standard for diagnosis. Although the prevalence of intraarticular and extraarticular pathology is similar, the treatments are different. RFA of the sacral lateral branch nerves that innervate the extraarticular SI joint ligaments can be consid­ ered if intraarticular SI joint injections provide only transient relief, whereas minimally invasive fusion techniques may be indicated in refractory cases of intraarticular pathology or joint malalignment.

Low Back Pain CHAPTER 18 INTRADISCAL INJECTIONS AND THERMAL-BASED THERAPIES Discogenic pain is the main pain generator in 26–42% of individu­ als with chronic, axial LBP. The diagnosis is suggested by certain physical exam findings, such as increased pain with forward lum­ bar flexion, sitting, or Valsalva maneuver. Provocative discogra­ phy, which entails the administration of contrast into the nucleus pulposus to increase intradiscal pressure and reproduce the patient’s symptoms, is purported to identify the specific disks contributing to the patient’s pain. However, discography is characterized by high false-positive rates in certain populations (e.g., those with somatiza­ tion and other psychiatric conditions; patients who have undergone prior spine surgery or have multifocal pain symptoms), and based on both animal and clinical studies, the procedure is associated with concerns regarding subsequent accelerated disk degeneration or injury. If the relevant disk(s) have not fragmented and there is no extrusion of intradiscal contents, intradiscal electrothermal therapy (IDET) or biacuplasty, which entails ablating the nervous tissue in the disk, might be considered, but the evidence for intermediateterm benefit is mixed. Intradiscal administration of corticosteroids or ESIs has also demonstrated mixed efficacy for short-term ben­ efit. The intradiscal administration of bone marrow concentrate is a topic of emerging study, but concerns regarding hastened disk degeneration secondary to disk penetration with a large-bore needle and theoretical risks of tumor formation led to a 2019 U.S. Food and Drug Administration warning about stem cell therapies. VERTEBRAL AUGMENTATION AND BASIVERTEBRAL

NERVE ABLATION Vertebrogenic pain can result from vertebral compression frac­ tures (most commonly due to osteoporosis) or vertebral endplate inflammation. The vertebral endplates are anatomically discrete structures composed of an epiphyseal bone ring surrounding a cartilaginous interior that form the interface between verte­ brae and adjacent disks. Due to the transition from the rigid,

rib-bearing thoracic spine to the more flexible lumbar spine, most fractures occur at the thoracolumbar junction (T11–L2), with the lower lumbar region being the second most common location. Most vertebral compression fractures are associated with mild to moderate pain that improves within 6–8 weeks of conservative therapy (e.g., physical therapy, oral analgesics), but up to 40% of cases might result in chronic pain. Infrequently (<10%), posterior lumbar compression fractures may be associated with nerve root impingement or spinal cord injury, in which case surgical consul­ tation is warranted.

Although evidence is conflicting, vertebral augmentation via the percutaneous administration of cement into the fracture (vertebro­ plasty or kyphoplasty) can be considered for patients with severe pain or disability due to an acute (<6 weeks) compression fracture. This may work not only by stabilizing the fracture but also possibly by denervating nociceptive fibers. Posterior compression fractures may also cause facetogenic pain as the superior and inferior articu­ lar processes collapse on themselves. PART 2 Cardinal Manifestations and Presentation of Diseases Vertebral endplate inflammation due to trauma or degenerative changes may be present (though not necessarily be the primary etiology of pain) in up to 40% of patients with chronic axial lumbar pain. Vertebrogenic pain from endplate fractures or degeneration presents similarly to discogenic pain (e.g., worsened pain with bending forward, sitting, or activity), also occurs most frequently in the lower lumbar area, and can co-occur with discogenic pain. For patients in whom other structures of the spine (e.g., facet joints) are less likely to be the predominant source of their symptoms, and in whom Modic type 1 (hypointense signal on T1-weighted and hyperintense signal on T2-weighted MRI, indicating marrow edema) or type 2 changes (hyperintense signal on T1-weighted and isointense on T2-weighted MRI, signifying conversion of red hemo­ poietic bone marrow into yellow fatty marrow due to ischemia) are demonstrated on MRI, RFA of the basivertebral nerves that inner­ vate the vertebral endplates can be considered. TRIGGER POINT INJECTIONS OF MYOFASCIAL

TAUT BANDS Pain from paraspinal ligaments and muscles is frequently due to spasmodic activity that results in myofascial taut bands. Trigger point injections can relieve spasmodic activity by improving local blood flow via vasodilation and facilitate the removal of inflamma­ tory mediators and cytokines. Evidence has not demonstrated the superiority of any specific injectate (e.g., saline, higher concentra­ tions of local anesthetic with or without steroids, botulinum toxin), suggesting that the mechanism of action of trigger point injections is independent of the medication(s) administered. LBP WITH RADICULAR SYMPTOMS (RADICULAR LBP) Epidural Steroid Injections  Radicular LBP is usually from spinal stenosis (e.g., central canal, lateral recess, or neuroforaminal) or disk pathology (e.g., bulge, herniation, extrusion) causing com­ pression or irritation of one or more spinal nerve roots. Although most patients with acute radicular pain due to a herniated disk will clinically improve within 3 months with conservative management (e.g., over-the-counter analgesics and physical therapy), the natural history of pain from lumbar stenosis is more guarded. Whereas over two-thirds of herniated disks will retract within 2 years, the causes of spinal stenosis (e.g., spondylolisthesis, facet hypertrophy, liga­ mentum flavum hypertrophy) often progress with age. Although some studies have reported that spinal stenosis is less responsive to ESI than herniated disks, most studies have failed to show any dif­ ferences in response rates, with several showing a poorer response rate for noncompressive (e.g., degenerative disks causing chemical irritation of nerve roots) pathologies. There is also some evidence for a weak but potentially meaningful surgery-sparing effect from ESIs for radicular pain. Surgery  Lumbar surgeries can be broadly categorized as entail­ ing fusion of adjacent vertebral bodies, decompression of spinal nerve roots (i.e., diskectomy or laminectomy), or a combination.

Lumbar interbody fusion is commonly performed for spinal insta­ bility (i.e., symptomatic or severe spondylolisthesis) or severe axial pain refractory to nonsurgical management and associated with severe functional disability. The precise indications for lumbar fusion remain controversial. Data are mixed regarding the effec­ tiveness for axial back pain and disability based on randomized trials and observational cohorts, with the strongest evidence being for spondylolisthesis, which is often associated with instability. In individuals with single-level and sometimes two-level discogenic pain without posterior element involvement, the less invasive disk arthroplasty procedure has been shown to be at least as effective as circumferential or anterior fusion for pain and function with better preservation of motion; however, the quality of these studies has generally been poor, with most being industry funded. Adjacent segment disease (e.g., subsequent accelerated degeneration of adja­ cent disks and facet joints) can occur following both procedures but is more likely after a fusion, while the risk of postsurgical instability is greater following disk arthroplasty. Lumbar nerve root decompression is indicated for severe or progressive neurologic deficits (i.e., loss of motor or sensory func­ tion or reflexes, indicating progressive radiculopathy) or for severe radicular pain refractory to interventional treatments (e.g., ESIs), medications, and physical therapy. The role of lumbar interbody fusion in addition to decompression is controversial, but studies have generally shown higher complication rates without greater benefit for nerve root compression without instability. Studies are mixed regarding whether surgical decompression is superior to conservative management for spinal stenosis, with meta-analyses generally finding a small benefit that diminishes after 2 years. For herniated disk, randomized trials have generally shown greater short-term reduction in pain and disability, but small and question­ ably meaningful benefits after 1 year. Minimally invasive surgical techniques are available for both lumbar stenosis (e.g., interspinal spacers, minimally invasive lumbar decompression) and herni­ ated disks (e.g., chemonucleolysis, endoscopic discectomy), with low-quality data supporting at least short-term benefit for these procedures in well-selected patients. ■ ■FURTHER READING Brinjikji W et al: Systematic literature review of imaging features of spinal degeneration in asymptomatic populations. AJNR Am J Neu­ roradiol 36:811, 2015. Cohen SP et al: Effect of MRI on treatment results or decision mak­ ing in patients with lumbosacral radiculopathy referred for epidural steroid injections: A multicenter, randomized controlled trial. Arch Intern Med 172:134, 2012. Cohen SP et al: Chronic pain: An update on burden, best practices, and new advances. Lancet 397:2082, 2021. Cohen SP et al: Multicenter study evaluating factors associated with treatment outcome for low back pain injections. Reg Anesth Pain Med 47:89, 2022. Cook CJ et al: Systematic review of diagnostic accuracy of patient his­ tory, clinical findings, and physical tests in the diagnosis of lumbar spinal stenosis. Eur Spine J 29:93, 2020. Itz CJ et al: Clinical course of non-specific low back pain: A systematic review of prospective cohort studies set in primary care. Eur J Pain 17:5, 2013. Kasch R et al: Association of lumbar MRI findings with current and future back pain in a population-based cohort study. Spine (Phila Pa 1976) 47:201, 2022. Katz JN et al: Diagnosis and management of lumbar spinal stenosis: A review. JAMA 327:1688, 2022. Knezevic NN et al: Low back pain. Lancet 398:78, 2021. Lo J et al: A systematic review of the incidence, prevalence, costs, and activity and work limitations of amputation, osteoarthritis, rheuma­ toid arthritis, back pain, multiple sclerosis, spinal cord injury, stroke, and traumatic brain injury in the United States: A 2019 Update. Arch Phys Med Rehabil 102:115, 2021.

07 - 19 Neck Pain

19 Neck Pain

Fan Jiang, Soichiro Takamiya,

Michael G. Fehlings

Neck Pain Neck pain is a highly prevalent global problem. In the United States, it is the fourth leading cause of disability and can affect people of all ages, genders, and professions. The lifetime prevalence is nearly 50%, women appear to be at a higher risk than men, and the incidence increases with age, peaking in late middle life. It is associated with sport- and work-related injuries, with low job satisfaction and poor work support having been found to play a role in work-related neck pain. Other risk factors include genetics, headaches, sleep disorders, smoking, obesity, sedentary lifestyle, secondary gain, history of neck pain, trauma, back pain, and poor overall physical or mental health. Neck pain usually arises from diseases of the cervical spine and soft tissues of the neck, is typically precipitated by movement, and may be accompanied by focal tenderness and limitation of motion. Pain arising from the brachial plexus, shoulder, or peripheral nerves can sometimes be confused with cervical spine disease, but the history and examina­ tion usually identify a more distal origin for the pain (discussed later). The underlying causes of neck pain are diverse, and patients often present with nonspecific and vague symptoms; occipital headache is a common complaint. It is especially important to develop a system­ atic approach to evaluation and management, as well as to recognize dangerous etiologies including infection, malignancy, or spinal cord involvement from any cause. When a patient presents with neck pain, the clinician should iden­ tify if the pain has a neuropathic component, indicating that the pain originates from identifiable nerves producing cervical radiculopathy. Causes of neuropathic neck pain include compression or irritation of cervical spinal nerves secondary to disk herniation, ligamentous hyper­ trophy, or facet overgrowth, among other etiologies, discussed below. APPROACH TO THE PATIENT Neck Pain A complete clinical history is essential to gain an appreciation of the patient’s chief complaints and to look for red flags. A patient’s TABLE 19-1  Cervical Radiculopathy: Neurologic Features EXAMINATION FINDINGS CERVICAL NERVE ROOT PAIN DISTRIBUTION REFLEX SENSORY MOTOR C5 Biceps Lateral deltoid Rhomboidsa (elbow extends backward with hand on hip) Lateral arm, medial scapula       Infraspinatusa (arm rotates externally with elbow flexed at the side)       Deltoida (arm raised laterally 30°–45° from the side)   C6 Biceps Palmar thumb/index finger Bicepsa (arm flexed at the elbow in supination) Lateral forearm, thumb/ index fingers     Dorsal hand/lateral forearm Pronator teres (forearm pronated)   C7 Triceps Middle finger Tricepsa (forearm extension, flexed at elbow) Posterior arm, dorsal forearm, dorsal hand     Dorsal forearm Wrist/finger extensorsa   C8 Finger flexors Palmar surface of little finger Abductor pollicis brevis (abduction of thumb) Fourth and fifth fingers, medial hand and forearm     Medial hand and forearm First dorsal interosseous (abduction of index finger)         Abductor digiti minimi (abduction of little finger)   T1 Finger flexors Axilla, medial arm, anteromedial forearm Abductor pollicis brevis (abduction of thumb) Medial arm, axilla       First dorsal interosseous (abduction of index finger)         Abductor digiti minimi (abduction of little finger)   aThese muscles receive the majority of innervation from this root. Source: From JW Engstrom: Back and neck pain, in Harrison’s Principles of Internal Medicine, 21st ed. New York, NY: McGraw Hill; 2022, Table 17-4, p. 127.

occupation, general health, and past medical history are impor­ tant to identify likely pain generators and risk factors. A history of cancer, fever, and weight loss should prompt investigations to rule out malignancy and infectious etiologies. Characteristics of the pain (dull, sharp, electric, stabbing, spasms) and aggravating and alleviating factors should be determined. Any radiating pain into the occiput, arms, or hands can raise concern for radiculopa­ thy. Patients should be specifically asked if they have experienced numbness or tingling in extremities; clumsiness in hands; change in handwriting; difficulty with buttons; unsteady gait; saddle pares­ thesia; and bladder or bowel incontinence. Neck Pain CHAPTER 19 Physical examination of the patient begins with observation. The head, neck, and shoulder should be examined for any deformity, mass, skin changes, or signs of trauma. Determining the location of the pain is imperative, as well as the quantity of pain and whether it is interfering with daily function and activities. The range of motion of the neck and shoulder should be assessed, and any restriction or guarding against movement noted. Fifty percent of cervical motion (flexion, extension, and rotation) originates from the atlantoaxial joint (C1-C2) and 50% from the subaxial (C3-C7); in general, any motion restriction needs to be further investigated to rule out underlying pathologies. Radicular pain in the arms typically follows dermatomal distribu­ tions (Table 19-1). Obtaining a precise description of the pain pattern can assist in determining if the pain is neuropathic and where the problem might originate. If a patient describes radiculopathy-like or other neuropathic pain, a complete neurologic examination is required, including assessment of the cranial nerves, motor strength, sensation, coordination, reflexes, and gait (Chaps. 433, V6, and V7). A few bedside tests are of particular value when assessing for radiculopathy or possible spinal cord involvement in patients present­ ing with neck pain. Spurling’s maneuver is a test for radiculopathy originating from the cervical spine. It is performed by passively rotat­ ing and flexing a patient’s neck laterally and performing axial compres­ sion to the top of the head. A test is considered positive if it triggers or worsens symptoms of upper extremity radiculopathy. Lhermitte’s sign is elicited by gently flexing a patient’s neck. It is considered posi­ tive and signifies underlying cervical spinal pathology if the maneuver reproduces electric pain down the spine or extremities. Also useful is Hoffmann’s test, which should be performed whenever there is any suspicion of cervical spinal cord pathology. It is a sign of hyperreflexia

whereby a patient involuntarily flexes and adducts the thumb and index finger while the examiner snaps the distal phalanx of the middle finger. Similarly, the presence of more than three beats of ankle clonus when the ankle is briskly dorsiflexed and held under pressure by the examiner is an upper motor neuron sign signifying underlying spinal cord pathology. Patients should also be observed for tandem or heel-totoe gait, the integrity of which is dependent on proprioception, as well as coordination and strength. Patients are asked to walk in a straight line with one foot in front of the other. If there are any signs of imbal­ ance (i.e., the patient is not able to complete this task), the possibility of spinal cord compression should be considered.

Imaging and additional tests are often necessary to finalize the diagnosis and should be guided by the patient’s history and physical examination findings. Cervical spine x-rays are simple diagnostic tools that are readily accessible and can provide an excellent initial assessment for spinal column pathologies. Performed in the anteriorposterior, lateral, and flexion-extension views, these radiographs are useful tools to screen for fractures, instability, and osteoarthritis, and can often prompt further investigations. Computed tomography (CT) scan is usually indicated if there are any concerns for fractures in the spinal column or if there have been previous surgical instrumentations to assess for any hardware complications. However, due to the poor visualization of soft tissues, CT is not very helpful when evaluating the spinal cord or ruling out intervertebral disk pathologies. Magnetic resonance imaging (MRI) is the gold standard for assessing these soft tissue structures. MRI is indicated for patients presenting with radicu­ lopathy symptoms or signs of myelopathy or other neurologic deficits. PART 2 Cardinal Manifestations and Presentation of Diseases MRI is also the imaging modality of choice when ruling out malig­ nancy or infectious causes of neck pain. However, given the high rate of abnormal findings on MRI in asymptomatic individuals, and degenerative changes in particular, it should be performed with caution and only in subjects with strong indications based on history, physi­ cal exam, and other screening radiographs. Finally, for individuals in whom MRI is contraindicated (Chap. 434), CT myelography, whereby contrast is injected into the spinal canal prior to the CT scan, can be used to assess the spinal cord and surrounding structures. Electromyography (EMG) and nerve conduction studies (NCS) are diagnostic studies often utilized in evaluating a patient with neck pain and associated neuropathic symptoms. While these electrodiagnostic studies are typically unnecessary when the diagnosis is clear, they can be helpful when a patient’s symptoms do not correlate with the MRI findings. By measuring the electrical response to nerve stimulation in the muscles and the speed by which an electrical impulse travels, the combination of EMG and NCS can distinguish radiculopathy arising from the spine from peripheral neuropathy and brachial plexopathy (Chap. 457). Referral to a neurologist is recommended in the setting of high clinical suspicion and negative electrodiagnostic findings. Routine laboratory tests have limited value in assessment of most patients with neck pain. However, if there is clinical suspicion of an underlying infection, malignancy, inflammatory arthritis, or neuro­ muscular disorder, appropriate blood panels should be obtained. While the differential diagnosis of neck pain is very broad, the most important goal of the clinical evaluation is recognizing nonmuscular causes of pain and identifying clinically dangerous underlying pathol­ ogy. Table 19-2 summarizes clinical findings that should prompt a clinician to conduct further investigations to rule out dangerous under­ lying etiologies. The following section will provide an overview and discussion of various causes of clinically important neck pain. CAUSES OF NECK PAIN ■ ■DEGENERATIVE Cervical radiculopathy occurs when a cervical spinal nerve root is compressed. Herniated cervical disks cause about 25% of cervical radiculopathy, whereas protruding cervical disks and the narrowing intervertebral foramen due to osteophytic spurs, hypertrophic facet joints, and uncovertebral joints can be solely or jointly responsible for ~70% of cervical radiculopathy. Although the mechanisms underly­ ing radiculopathy are not fully understood, ischemia and hypoxia of

TABLE 19-2  Clinical Features Suggesting a Need for Further Investigation in Patients With Neck Pain HISTORY PHYSICAL EXAM History of congenital disorders Fever History of cancer Neck stiffness History of substance abuse Severe neck pain and tenderness History of inflammatory arthritis Torticollis Recent trauma to the head and neck Motor weakness in upper or lower extremities Signs or symptoms of infection Sensory changes in upper or lower extremities Family history of spinal conditions Upper motor neuron signs: Hoffman, clonus, Babinski Unexplained weight loss Hyperreflexia Progressive neurologic deficits Unsteady gait Saddle anesthesia Difficulty with tandem or heel-to-toe walk Bladder or bowel incontinence   the affected nerve root appear to contribute to injury and subsequent symptoms. The nerve root most frequently affected is C7, followed by C6. Besides neck pain, cervical radiculopathy is commonly accom­ panied by symptoms such as pain, sensory disturbance, and motor weakness in the shoulder, interscapular, or upper limb, depending on the affected nerve root; however, neck pain can be the only symptom, especially when arising from nerve roots at C4 or higher. Degenerative cervical disk disease is a relatively common pathology. Degenerative disks contain inflammatory mediators, including proin­ flammatory cytokines, that can lead to stimulation of inflammation-

responsive sensory nerve fibers, which innervate intervertebral disks, resulting in nociceptive or “discogenic” pain. When cervical disks are her­ niated, they can cause radiculopathy and myelopathy (Fig. 19-1 A, B). Neck pain in patients with cervical disk herniation is often caused by a combination of the mechanisms mentioned above—ischemia of the compressed root and/or spinal cord and inflammation arising from degenerative disks. Degenerative cervical myelopathy, which is the comprehensive term used to describe the various degenerative diseases causing symptom­ atic cervical spine narrowing such as cervical spondylosis, ossification of the posterior longitudinal ligament, degenerative disk disease, and ossification of the ligamentum flavum, is also a common cause of neck pain. In degenerative cervical myelopathy, the conditions listed above can compress the cervical spinal cord and lead to spinal cord injury (Fig. 19-1 C, D). Clinicians need to understand this condition well, given that the initial presenting symptoms can often be vague and misleading. It has been reported that the delay in obtaining a diagnosis of degenerative cervical myelopathy can be up to 2 years after the onset of symptoms. Given the shifting demographics of an aging society, this will become more and more relevant at the primary care level, where these patients are typically first encountered. The early signs of cervical myelopathy can be extremely mild, such as paresthesia, minor loss of hand dexterity, or feelings of “clumsiness.” These can easily be overlooked during the initial clinical encounter, especially when the chief presenting complaint is neck pain. Severe dysfunction, including gait disturbance, quadriparesis, and bowel or bladder incontinence, often presents at a later stage. However, prompt diagnosis and timely surgical intervention at the initial phase of the disease often result in better clinical outcomes in these individuals, hence the importance of early recognition and prompt referral for definitive treatment. Fortunately, the deterioration in degenerative cer­ vical myelopathy is typically slow and occurs in a stepwise progressive fashion. Spinal cord disorders are discussed in Chap. 454. ■ ■NEOPLASTIC Spinal tumors can cause neck pain when they occur in the cervical spine. Metastases are the most common extradural spinal tumors. Although the cervical spine is involved in <20% of patients with spinal

A B C D FIGURE 19-1  Cases of degenerative cervical disk disease and degenerative cervical myelopathy. Cervical x-ray shows a disk height reduction at the C5/C6 level (arrowhead) (A), and cervical magnetic resonance imaging (MRI) shows a herniated disk compressing the spinal cord (arrow) (B) in a case of degenerative cervical disk disease. Cervical x-ray shows osteophytic spurs at C5/C6 and C6/C7 levels (dotted arrow) (C), and cervical MRI shows a protruded disk (asterisk) and thickened ligamentum flavum (double arrows) (D) in a case of degenerative cervical myelopathy. metastatic tumors, neck pain is the most common symptom in such patients. This pain tends to be unrelieved by rest and worse at night. Metastases sometimes cause pathological fractures, which can also be responsible for neck pain (Fig. 19-2 A, B). Primary spinal cord tumors including schwannomas, meningiomas, and intramedullary tumors can induce neuropathic neck pain, whereas primary spinal bone tumors, such as hemangiomas or chordomas, typically cause nociceptive neck pain. Systemic tumors such as multiple myeloma or lymphoma may also be responsible for neck pain when the cervical spine is involved. ■ ■INFECTIOUS Cervical vertebral osteomyelitis and diskitis, which is less common com­ pared with thoracic or lumbar regions, can cause constant neck pain (Chap. 136). Although fever is present in some patients, it is absent in many others, which can lead to a delay in diagnosis. Whenever patients present with neck pain and unidentified fever, physicians should always consider these etiologies, especially in patients with a history A B C D FIGURE 19-2  Cases of cervical metastasis and cervical epidural abscess. Cervical computed tomography shows osteolytic lesions at C6 and C7 that protrude into the spinal canal (arrow) (A, B) in a case of cervical metastasis. Sagittal (C) and axial (D) views of cervical fat-suppressed contrast-enhanced magnetic resonance imaging show enhanced epidural lesions at C2/3–C4/5, which compress the spinal cord drastically (dotted arrows) in this case of cervical epidural abscess.

Neck Pain CHAPTER 19 of intravenous drug abuse, immunocompromised status, diabetes mel­ litus, or other disorders that predispose to infection. Cervical epidural abscess (Chap. 145) can cause severe neck pain and progressive neurologic deterioration due to cord compression (Fig. 19-2 C, D), often requiring urgent surgical intervention. Meningitis (Chap. 143) is another important cause of neck pain, usually accompanied by fever and headache. ■ ■VASCULAR Neck pain associated with vascular pathologies often occurs suddenly. Vertebral and carotid artery dissections can cause sudden neck pain as well as headache. Acute coronary syndromes may present as a referred neck pain. Cervical arteriovenous malformations and other vascular pathologies can cause acute neck pain when they bleed. Cervical epi­ dural hematomas typically present with sudden neck pain and neuro­ logic deficits. They can be misdiagnosed as stroke; however, the neck pain aggravated by palpation of the spinous process can be a helpful distinguishing sign.

■ ■CONGENITAL Chiari type 1 malformations (Chap. 453) can cause headache and neck pain aggravated by cough. The pathophysiology remains unclear, but dissociation between intracranial and intraspinal pressures or traction on pain-sensitive nerves of the dura mater may be responsible.

■ ■AUTOIMMUNE/INFLAMMATORY Rheumatoid arthritis (Chap. 370) commonly affects the cervical spine and produces neck pain most often due to cervical instability. Approxi­ mately 50% of patients with rheumatoid arthritis have atlantoaxial subluxation, which may lead to neurologic deterioration. Polymyalgia rheumatica (Chap. 375) presents with pain and stiffness in the neck, shoulder, and pelvic girdle and is accompanied by other systemic symptoms. Ankylosing spondylitis (Chap. 374) also causes neck pain, though chronic back pain is more common, and these pains typically worsen with rest or inactivity. Crowned dens syndrome, also known as periodontoid calcium pyrophosphate dihydrate crystal deposition disease, is another cause of severe neck pain and neck stiffness. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■ENDOCRINE/METABOLIC Paget’s disease (Chap. 424) is a bone disorder characterized by an imbalance in bone modeling and remodeling. Paget’s disease in the cer­ vical spine is less common compared with the thoracolumbar regions but can cause neck pain that tends to be worse at rest. Osteoporosis (Chap. 423), which is sometimes induced by hyperparathyroidism and glucocorticoid therapy, and osteomalacia due to abnormal vitamin D metabolism (Chap. 421), can produce pathological bone fractures. Although these disorders usually affect lumbar or lower thoracic verte­ brae, neck pain can occur when the cervical spine is affected. ■ ■TRAUMATIC Traumatic fracture and dislocation of the cervical spine are lifethreatening conditions when accompanied by injury to the cervical spinal cord. Nociceptive and neuropathic neck pains can be combined, and immobilization of the neck is essential to reduce neck pain and prevent further cervical cord injury due to spinal instability. Whiplash injury is also responsible for neck pain. It is usually caused by motor vehicle collisions, and injury to the facet joints is believed to underlie this pain syndrome. Approximately 50% of patients with whiplash injury will have had persistent neck pain for 1 year. ■ ■OTHER CAUSES Cervical myofascial pain is a very common clinical condition that can involve diffuse areas around the neck and shoulder. Restriction of motions of the cervical spine can cause this nonspecific neck pain. Myofascial trigger points, which are palpable nodules housed inside taut muscle bands, are regarded as a hallmark of myofascial pain. TREATMENT Neck Pain Given the broad differential diagnosis of neck pain, the manage­ ment and treatment should be tailored toward the underlying condition. Most important is to recognize red flags that indicate the possible presence of myelopathy, malignancy, infection, or a severe spinal column injury; in such cases, urgent assessment is required. The discussion below will focus on the management of the common causes of neck pain seen in general medical practice. In general, the evidence regarding treatment for neck pain is less comprehensive than that for low back pain (Chap. 18), but the approach is similar in many respects. NECK PAIN WITHOUT RADICULOPATHY OR OTHER NEUROLOGIC FINDINGS For many patients with acute neck pain, spontaneous improvement is the norm, and the usual goals of therapy are to promote a rapid return to normal function and provide pain relief while healing proceeds. Acute neck pain is often treated with nonsteroidal antiinflammatory drugs (NSAIDs), acetaminophen, cold packs, or heat,

alone or in combination while awaiting recovery. Patients should be specifically educated regarding the favorable natural history of acute neck pain to avoid unrealistic fear and inappropriate requests for imaging and other tests. For patients kept awake by symptoms, cyclobenzaprine (5–10 mg) at night can help relieve muscle spasm and promote drowsiness. A trial of physiotherapy such as super­ vised exercise with or without mobilization appears to be effective. Exercises often include shoulder rolls and neck stretches. The McKenzie method of physical therapy is one option in widespread use. Some patients obtain modest pain relief using a soft neck col­ lar; there is little risk or cost. Massage can produce temporary pain relief. For patients with chronic neck pain, supervised exercise pro­ grams can provide symptom relief and improve function. Acupunc­ ture provided short-term benefit for some patients when compared to a sham procedure and is an option. Spinal manipulation alone has not been shown to be effective and carries a risk for injury. Surgery plays a very limited role in patients with acute and chronic neck pain without neurologic findings, spine instability, or fractures. For individuals with pain refractory to conservative man­ agement, referral to a pain specialist can be of benefit. The literature shows that neck pain originating from cervical facet joints can be effectively treated with fluoroscopically guided radiofrequency ablation. However, careful patient selection is essential to ensure optimal outcomes, and the procedure is not available in many cen­ ters. Referral to a specialist for diagnostic and treatment guidance is highly recommended for any patient in whom such procedures are considered. NECK PAIN WITH RADICULOPATHY OR OTHER NEUROLOGIC FINDINGS The natural history of acute neck pain with radiculopathy due to disk disease is also favorable, and many patients will improve without specific therapy. Although there are no randomized trials of NSAIDs for neck pain, a course of NSAIDs, acetaminophen, or both, with or without muscle relaxants, and avoidance of activi­ ties that trigger symptoms are reasonable as initial therapy. Gentle supervised exercise and avoidance of inactivity are reasonable as well. A short course of high-dose oral glucocorticoids with a rapid taper or epidural steroids administered under imaging guid­ ance can be effective for acute or subacute disk-related cervical radicular pain but have not been subjected to rigorous trials. The risk of injection-related complications is higher in the neck than the low back; vertebral artery dissection, dural puncture, spinal cord injury, and embolism in the vertebral arteries have all been reported. Opioid analgesics can be used in the emergency depart­ ment and for short courses as an outpatient. Soft cervical collars can be modestly helpful by limiting spontaneous and reflex neck movements that exacerbate pain; hard collars are in general poorly tolerated. If cervical radiculopathy is due to bony compression from cervi­ cal spondylosis with foraminal narrowing, periodic follow-up to assess for progression is indicated and consideration of surgical decompression is reasonable. Surgical treatment can produce rapid pain relief, although it is unclear if long-term functional outcomes are improved over nonsurgical therapy. Indications for cervical disk surgery include a progressive motor deficit due to nerve root compression, functionally limiting pain that fails to respond to conservative management, or spinal cord compression. In other circumstances, clinical improvement over time regardless of thera­ peutic intervention is common. Surgical treatments include anterior cervical diskectomy/

corpectomy and fusion, posterior cervical laminectomy, laminoplasty or laminectomy with fusion. The risk of subsequent radiculopathy or myelopathy at cervical segments adjacent to a fusion is ~3% per year and 26% per decade. Although this risk is sometimes portrayed as a late complication of surgery, it may also reflect the natural his­ tory of degenerative cervical disk disease.

08 - SECTION 2 Alterations in Body Temperature

SECTION 2 Alterations in Body Temperature

PAIN ARISING IN THE SHOULDER REGION ■ ■THORACIC OUTLET SYNDROMES The thoracic outlet contains the first rib, the subclavian artery and vein, the brachial plexus, the clavicle, and the lung apex. Injury to these structures may result in postural or movement-induced pain around the shoulder and supraclavicular region, classified as follows. True neurogenic thoracic outlet syndrome (TOS) is an uncommon disorder resulting from compression of the lower trunk of the brachial plexus or ventral rami of the C8 or T1 nerve roots, caused most often by an anomalous band of cartilaginous tissue connecting an elongate transverse process at C7 with the first rib. Pain is mild or may be absent. Signs include weakness and wasting of intrinsic muscles of the hand and diminished sensation on the palmar aspect of the fifth digit. An anteroposterior cervical spine x-ray will show an elongate C7 trans­ verse process (an anatomic marker for the anomalous cartilaginous band), and EMG and NCSs confirm the diagnosis. Treatment consists of surgical resection of the anomalous band. The weakness and wasting of intrinsic hand muscles typically do not improve, but surgery halts the insidious progression of weakness. Arterial TOS results from compression of the subclavian artery by a cervical rib, resulting in poststenotic dilatation of the artery and in some cases secondary thrombus formation. Blood pressure is reduced in the affected limb, and signs of emboli may be present in the hand. Neurologic signs are absent. Ultrasound can confirm the diagnosis noninvasively. Treatment is with thrombolysis or anticoagulation (with or without embolectomy) and surgical excision of the cervical rib com­ pressing the subclavian artery. Venous TOS is due to subclavian vein thrombosis resulting in swell­ ing of the arm and pain. The vein may be compressed by a cervical rib or anomalous scalene muscle. Venography is the diagnostic test of choice. Disputed TOS accounts for 95% of patients diagnosed with TOS; chronic arm and shoulder pain are prominent and of unclear cause. The lack of sensitive and specific findings on physical examination or specific markers for this condition results in diagnostic uncertainty. The role of surgery in disputed TOS is controversial. Multidisciplinary pain management is a conservative approach, although treatment is often unsuccessful. ■ ■BRACHIAL PLEXUS AND NERVES Pain from injury to the brachial plexus or peripheral nerves of the arm can occasionally mimic referred pain of cervical spine origin, includ­ ing cervical radiculopathy, but the pain typically begins distal to the posterior neck region in the shoulder girdle or upper arm. Neoplastic infiltration of the lower trunk of the brachial plexus may produce shoulder or supraclavicular pain radiating down the arm, numbness of the fourth and fifth fingers or medial forearm, and weakness of intrinsic hand muscles innervated by the lower trunk and medial cord of the brachial plexus. Delayed radiation injury may produce weak­ ness in the upper arm or numbness of the lateral forearm or arm due to involvement of the upper trunk and lateral cord of the plexus. Pain is less common and less severe than with neoplastic infiltration. A Pancoast tumor of the lung (Chap. 83) is another cause of injury to the brachial plexus and should be considered especially when a concurrent Horner’s syndrome is present. Acute brachial neuritis is often confused with radiculopathy; the acute onset of severe shoulder or scapular pain is followed typically over days by weakness of the proximal arm and shoulder girdle muscles innervated by the upper brachial plexus. The onset may be preceded by an infection, vaccination, or minor surgi­ cal procedure. The long thoracic nerve may be affected, resulting in a winged scapula. Brachial neuritis may also present as an isolated paralysis of the diaphragm with or without involvement of other nerves of the upper limb. Recovery may take up to several years, and full func­ tional recovery can be expected in the majority of patients. Occasional cases of carpal tunnel syndrome produce pain and paresthesias extending into the forearm, arm, and shoulder resem­ bling a C5 or C6 root lesion. Lesions of the radial or ulnar nerve can also mimic radiculopathy at C7 or C8, respectively. EMG and NCSs

can accurately localize lesions to the nerve roots, brachial plexus, or peripheral nerves.

For further discussion of peripheral nerve disorders, see Chap. 457. SHOULDER Pain arising from the shoulder can also on occasion mimic pain from the spine. If symptoms and signs of radiculopathy are absent, then the differential diagnosis includes mechanical shoulder pain (bicipital tendonitis, frozen shoulder, bursitis, rotator cuff tear, dislocation, adhe­ sive capsulitis, or rotator cuff impingement under the acromion) and referred pain (subdiaphragmatic irritation, angina, or Pancoast tumor). Mechanical pain is often worse at night, associated with local shoulder tenderness, and aggravated by passive abduction, internal rotation, or extension of the arm. Demonstrating normal passive full range of motion of the arm at the shoulder without worsening of the pain can help exclude mechanical shoulder pathology as a cause of neck region pain. Pain from shoulder disease may radiate into the arm or hand, but focal neurologic signs (sensory, motor, or reflex changes) are absent. Fever CHAPTER 20 Acknowledgment The authors acknowledge the contributions of John W. Engstrom to ear­ lier editions of this chapter. ■ ■FURTHER READING Cohen SP, Hooten WM: Advances in the diagnosis and management of neck pain. BMJ 358:j3221, 2017. Popescu A, Lee H: Neck pain and lower back pain. Med Clin North Am 104:279, 2020. Rupp R et al: International standards for neurological classification of spinal cord injury: Revised 2019. Top Spinal Cord Inj Rehabil 27:1, 2021. Shin DW et al: Global, regional, and national neck pain burden in the general population, 1990-2019: An analysis of the global burden of disease study 2019. Front Neurol 13:955367, 2022. Vazirizadeh-Mahabadi M, Yarahmadi M: Canadian C-spine Rule versus NEXUS in screening of clinically important traumatic cervi­ cal spine injuries: A systematic review and meta-analysis. Arch Acad Emerg Med 11:e5, 2023. Section 2 Alterations in Body Temperature Charles A. Dinarello, Neeraj K. Surana

Fever Body temperature is controlled by the hypothalamus. Neurons in both the preoptic anterior hypothalamus and the posterior hypothalamus receive two kinds of signals: one from peripheral nerves that transmit information from warmth/cold receptors in the skin and the other from the temperature of the blood bathing the region. These two types of signals are integrated by the thermoregulatory center of the hypo­ thalamus to maintain normal temperature. In a neutral temperature environment, the human metabolic rate produces more heat than is necessary to maintain the core body temperature in the range of 36.5–37.5°C (97.7–99.5°F). NORMAL BODY TEMPERATURES A normal body temperature is ordinarily maintained despite environ­ mental variations because the hypothalamic thermoregulatory center balances the excess heat production derived from metabolic activity

09 - 20 Fever

20 Fever

PAIN ARISING IN THE SHOULDER REGION ■ ■THORACIC OUTLET SYNDROMES The thoracic outlet contains the first rib, the subclavian artery and vein, the brachial plexus, the clavicle, and the lung apex. Injury to these structures may result in postural or movement-induced pain around the shoulder and supraclavicular region, classified as follows. True neurogenic thoracic outlet syndrome (TOS) is an uncommon disorder resulting from compression of the lower trunk of the brachial plexus or ventral rami of the C8 or T1 nerve roots, caused most often by an anomalous band of cartilaginous tissue connecting an elongate transverse process at C7 with the first rib. Pain is mild or may be absent. Signs include weakness and wasting of intrinsic muscles of the hand and diminished sensation on the palmar aspect of the fifth digit. An anteroposterior cervical spine x-ray will show an elongate C7 trans­ verse process (an anatomic marker for the anomalous cartilaginous band), and EMG and NCSs confirm the diagnosis. Treatment consists of surgical resection of the anomalous band. The weakness and wasting of intrinsic hand muscles typically do not improve, but surgery halts the insidious progression of weakness. Arterial TOS results from compression of the subclavian artery by a cervical rib, resulting in poststenotic dilatation of the artery and in some cases secondary thrombus formation. Blood pressure is reduced in the affected limb, and signs of emboli may be present in the hand. Neurologic signs are absent. Ultrasound can confirm the diagnosis noninvasively. Treatment is with thrombolysis or anticoagulation (with or without embolectomy) and surgical excision of the cervical rib com­ pressing the subclavian artery. Venous TOS is due to subclavian vein thrombosis resulting in swell­ ing of the arm and pain. The vein may be compressed by a cervical rib or anomalous scalene muscle. Venography is the diagnostic test of choice. Disputed TOS accounts for 95% of patients diagnosed with TOS; chronic arm and shoulder pain are prominent and of unclear cause. The lack of sensitive and specific findings on physical examination or specific markers for this condition results in diagnostic uncertainty. The role of surgery in disputed TOS is controversial. Multidisciplinary pain management is a conservative approach, although treatment is often unsuccessful. ■ ■BRACHIAL PLEXUS AND NERVES Pain from injury to the brachial plexus or peripheral nerves of the arm can occasionally mimic referred pain of cervical spine origin, includ­ ing cervical radiculopathy, but the pain typically begins distal to the posterior neck region in the shoulder girdle or upper arm. Neoplastic infiltration of the lower trunk of the brachial plexus may produce shoulder or supraclavicular pain radiating down the arm, numbness of the fourth and fifth fingers or medial forearm, and weakness of intrinsic hand muscles innervated by the lower trunk and medial cord of the brachial plexus. Delayed radiation injury may produce weak­ ness in the upper arm or numbness of the lateral forearm or arm due to involvement of the upper trunk and lateral cord of the plexus. Pain is less common and less severe than with neoplastic infiltration. A Pancoast tumor of the lung (Chap. 83) is another cause of injury to the brachial plexus and should be considered especially when a concurrent Horner’s syndrome is present. Acute brachial neuritis is often confused with radiculopathy; the acute onset of severe shoulder or scapular pain is followed typically over days by weakness of the proximal arm and shoulder girdle muscles innervated by the upper brachial plexus. The onset may be preceded by an infection, vaccination, or minor surgi­ cal procedure. The long thoracic nerve may be affected, resulting in a winged scapula. Brachial neuritis may also present as an isolated paralysis of the diaphragm with or without involvement of other nerves of the upper limb. Recovery may take up to several years, and full func­ tional recovery can be expected in the majority of patients. Occasional cases of carpal tunnel syndrome produce pain and paresthesias extending into the forearm, arm, and shoulder resem­ bling a C5 or C6 root lesion. Lesions of the radial or ulnar nerve can also mimic radiculopathy at C7 or C8, respectively. EMG and NCSs

can accurately localize lesions to the nerve roots, brachial plexus, or peripheral nerves.

For further discussion of peripheral nerve disorders, see Chap. 457. SHOULDER Pain arising from the shoulder can also on occasion mimic pain from the spine. If symptoms and signs of radiculopathy are absent, then the differential diagnosis includes mechanical shoulder pain (bicipital tendonitis, frozen shoulder, bursitis, rotator cuff tear, dislocation, adhe­ sive capsulitis, or rotator cuff impingement under the acromion) and referred pain (subdiaphragmatic irritation, angina, or Pancoast tumor). Mechanical pain is often worse at night, associated with local shoulder tenderness, and aggravated by passive abduction, internal rotation, or extension of the arm. Demonstrating normal passive full range of motion of the arm at the shoulder without worsening of the pain can help exclude mechanical shoulder pathology as a cause of neck region pain. Pain from shoulder disease may radiate into the arm or hand, but focal neurologic signs (sensory, motor, or reflex changes) are absent. Fever CHAPTER 20 Acknowledgment The authors acknowledge the contributions of John W. Engstrom to ear­ lier editions of this chapter. ■ ■FURTHER READING Cohen SP, Hooten WM: Advances in the diagnosis and management of neck pain. BMJ 358:j3221, 2017. Popescu A, Lee H: Neck pain and lower back pain. Med Clin North Am 104:279, 2020. Rupp R et al: International standards for neurological classification of spinal cord injury: Revised 2019. Top Spinal Cord Inj Rehabil 27:1, 2021. Shin DW et al: Global, regional, and national neck pain burden in the general population, 1990-2019: An analysis of the global burden of disease study 2019. Front Neurol 13:955367, 2022. Vazirizadeh-Mahabadi M, Yarahmadi M: Canadian C-spine Rule versus NEXUS in screening of clinically important traumatic cervi­ cal spine injuries: A systematic review and meta-analysis. Arch Acad Emerg Med 11:e5, 2023. Section 2 Alterations in Body Temperature Charles A. Dinarello, Neeraj K. Surana

Fever Body temperature is controlled by the hypothalamus. Neurons in both the preoptic anterior hypothalamus and the posterior hypothalamus receive two kinds of signals: one from peripheral nerves that transmit information from warmth/cold receptors in the skin and the other from the temperature of the blood bathing the region. These two types of signals are integrated by the thermoregulatory center of the hypo­ thalamus to maintain normal temperature. In a neutral temperature environment, the human metabolic rate produces more heat than is necessary to maintain the core body temperature in the range of 36.5–37.5°C (97.7–99.5°F). NORMAL BODY TEMPERATURES A normal body temperature is ordinarily maintained despite environ­ mental variations because the hypothalamic thermoregulatory center balances the excess heat production derived from metabolic activity

in muscle and the liver with heat dissipation from the skin and lungs. According to a study of >35,000 individuals ≥18 years of age seen in routine medical visits, the mean oral temperature is 36.6°C (95% confidence interval, 35.7–37.3°C). In light of this study, a temperature of >37.7°C (>99.9°F), which represents the 99th percentile for healthy individuals, defines a fever. Importantly, higher ambient temperatures are linked to higher baseline body temperatures. Additionally, body temperatures have diurnal and seasonal variation, with low levels at 8 a.m. and during summer and higher levels at 4 p.m. and during winter. Baseline temperatures are also affected by age (lower by 0.02°C for every 10-year increase in age), demographics (African-American women have temperatures 0.052°C higher than white men), and comorbid conditions (cancer is associated with 0.02°C higher tempera­ tures; hypothyroidism is linked to temperatures lower by 0.01°C). After controlling for age, sex, race, vital signs, and comorbidities, an increase in baseline temperature of 0.15°C (or 1 standard deviation) intriguingly translates into a 0.52% absolute increase in 1-year mortality.

PART 2 Cardinal Manifestations and Presentation of Diseases Rectal temperatures are generally 0.4°C (0.7°F) higher than oral readings. The lower oral readings are probably attributable to mouth breathing, which is a factor in patients with respiratory infections and rapid breathing. Lower-esophageal temperatures closely reflect core temperature. Tympanic membrane thermometers measure radiant heat from the tympanic membrane and nearby ear canal and display that absolute value (unadjusted mode) or a value automatically calculated from the absolute reading on the basis of nomograms relating the radiant temperature measured to actual core temperatures obtained in clinical studies (adjusted mode). These measurements, although convenient, may be more variable than directly determined oral or rectal values. Studies in adults show that readings are lower with unadjusted-mode than with adjusted-mode tympanic membrane ther­ mometers and that unadjusted-mode tympanic membrane values are 0.8°C (1.6°F) lower than rectal temperatures. In women who menstruate, the a.m. temperature is generally lower during the 2 weeks before ovulation; it then rises by ~0.6°C (1°F) with ovulation and stays at that level until menses occur. During the luteal phase, the amplitude of the circadian rhythm remains the same. FEVER VERSUS HYPERTHERMIA Fever is an elevation of body temperature that exceeds the normal daily variation and occurs in conjunction with an increase in the hypotha­ lamic set point (e.g., from 37°C to 39°C). This shift of the set point from “normothermic” to febrile levels very much resembles the resetting of the home thermostat to a higher level in order to raise the ambient temperature in a room. Once the hypothalamic set point is raised, neurons in the vasomotor center are activated and vasoconstriction commences. The individual first notices vasoconstriction in the hands and feet. Shunting of blood away from the periphery to the internal organs essentially decreases heat loss from the skin, and the person feels cold. For most fevers, body temperature increases by 1–2°C. Shivering, which increases heat production from the muscles, may begin at this time; however, shivering is not required if mechanisms of heat conservation raise blood temperature sufficiently. Nonshiver­ ing heat production from the liver also contributes to increasing core temperature. Behavioral adjustments (e.g., putting on more clothing or bedding) help raise body temperature by decreasing heat loss. The processes of heat conservation (vasoconstriction) and heat production (shivering and increased nonshivering thermogenesis) continue until the temperature of the blood bathing the hypothalamic neurons matches the new “thermostat setting.” Once that point is reached, the hypothalamus maintains the temperature at the febrile level by the same mechanisms of heat balance that function in the afe­ brile state. When the hypothalamic set point is again reset downward (in response to either a reduction in the concentration of pyrogens or the use of antipyretics), the processes of heat loss through vasodilation and sweating are initiated. Loss of heat by sweating and vasodila­ tion continues until the blood temperature at the hypothalamic level matches the lower setting. Behavioral changes (e.g., removal of cloth­ ing) facilitate heat loss.

A fever of >41.5°C (>106.7°F) is called hyperpyrexia. This extraor­ dinarily high fever can develop in patients with severe infections but most commonly occurs in patients with central nervous system (CNS) hemorrhages. In the preantibiotic era, fever due to a variety of infec­ tious diseases rarely exceeded 106°F, and there has been speculation that this natural “thermal ceiling” is mediated by neuropeptides func­ tioning as central antipyretics. In rare cases, the hypothalamic set point is elevated as a result of local trauma, hemorrhage, tumor, or intrinsic hypothalamic mal­ function. The term hypothalamic fever is sometimes used to describe elevated temperature caused by abnormal hypothalamic function. However, most patients with hypothalamic damage have subnormal, not supranormal, body temperatures. Although most patients with elevated body temperature have fever, there are circumstances in which elevated temperature represents not fever but hyperthermia (heat stroke). Hyperthermia is characterized by an uncontrolled increase in body temperature that exceeds the body’s ability to lose heat. The setting of the hypothalamic thermoregulatory center is unchanged. In contrast to fever in infections, hyperthermia does not involve pyrogenic molecules. Exogenous heat exposure and endogenous heat production are two mechanisms by which hyperther­ mia can result in dangerously high internal temperatures. Excessive heat production can easily cause hyperthermia despite physiologic and behavioral control of body temperature. For example, work or exercise in hot environments can produce heat faster than peripheral mechanisms can lose it. For a detailed discussion of hyperthermia, see Chap. 478. It is important to distinguish between fever and hyperthermia since hyperthermia can be rapidly fatal and characteristically does not respond to antipyretics. In an emergency situation, however, making this distinction can be difficult. For example, in systemic sepsis, fever (hyperpyrexia) can be rapid in onset, and temperatures can exceed 40.5°C (104.9°F). Hyperthermia is often diagnosed on the basis of the events immediately preceding the elevation of core temperature—e.g., heat exposure or treatment with drugs that interfere with thermo­ regulation. In patients with heat stroke syndromes and in those taking drugs that block sweating, the skin is hot but dry, whereas in fever, the skin can be cold as a consequence of vasoconstriction. Antipyretics do not reduce the elevated temperature in hyperthermia, whereas in fever—and even in hyperpyrexia—adequate doses of either aspirin or acetaminophen usually result in some decrease in body temperature. PATHOGENESIS OF FEVER ■ ■PYROGENS The term pyrogen (Greek pyro, “fire”) is used to describe any substance that causes fever. Exogenous pyrogens are derived from outside the patient; most are microbial products, microbial toxins, or whole micro­ organisms (including viruses). The classic example of an exogenous pyrogen is the lipopolysaccharide (endotoxin) produced by all gramnegative bacteria. Endotoxin is a highly pyrogenic molecule in humans: when injected intravenously into volunteers, a dose of 2–3 ng/kg produces fever, leukocytosis, acute-phase proteins, and generalized symptoms of malaise. While cell wall components of gram-positive organisms are less pyrogenic than endotoxin, these organisms often produce toxins that act as superantigens and induce fever (e.g., Staphylococcus aureus toxic shock syndrome toxin-1, staphylococcal enterotoxins, streptococcal pyrogenic exotoxins). These products of staphylococci and strepto­ cocci cause fever in experimental animals when injected intravenously at concentrations of 1–10 μg/kg. ■ ■PYROGENIC CYTOKINES Cytokines are small proteins (molecular mass, 10,000–20,000 Da) that regulate immune, inflammatory, and hematopoietic processes. For example, the elevated leukocytosis seen in several infections with an absolute neutrophilia is attributable to the cytokines interleukin (IL) 1 and IL-6. Some cytokines also cause fever; formerly referred to as endogenous pyrogens, they are now called pyrogenic cytokines. The pyrogenic cytokines include IL-1, IL-6, tumor necrosis factor (TNF),

and ciliary neurotropic factor, a member of the IL-6 family. Fever is a prominent side effect of interferon α therapy. Each pyrogenic cytokine is encoded by a separate gene, and each has been shown to cause fever in laboratory animals and in humans. When injected into humans at low doses (10–100 ng/kg), IL-1 and TNF produce fever; in contrast, for IL-6, a dose of 1–10 μg/kg is required for fever production. A wide spectrum of bacterial and fungal products induce the synthesis and release of pyrogenic cytokines. However, fever can be a manifestation of disease in the absence of microbial infection. For example, inflammatory processes such as pericarditis, trauma, stroke, and routine immunizations induce the production of IL-1, TNF, and/ or IL-6; individually or in combination, these cytokines trigger the hypothalamus to raise the set point to febrile levels. ■ ■ELEVATION OF THE HYPOTHALAMIC SET POINT BY CYTOKINES During fever, levels of prostaglandin E2 (PGE2) are elevated in hypo­ thalamic tissue and the third cerebral ventricle. The concentrations of PGE2 are highest near the circumventricular vascular organs (organum vasculosum of lamina terminalis)—networks of enlarged capillaries surrounding the hypothalamic regulatory centers. Destruction of these organs reduces the ability of pyrogens to produce fever. Most studies in animals have failed to show, however, that pyrogenic cytokines pass from the circulation into the brain itself. Thus, it appears that both exogenous pyrogens and pyrogenic cytokines interact with the endo­ thelium of these capillaries and that this interaction is the first step in initiating fever—i.e., in raising the set point to febrile levels. The key events in the production of fever are illustrated in Fig. 20-1. Myeloid and endothelial cells are the primary cell types that produce pyrogenic cytokines. Pyrogenic cytokines such as IL-1, IL-6, and TNF are released from these cells and enter the systemic circulation. Although these circulating cytokines lead to fever by inducing the synthesis of PGE2, they also induce PGE2 in peripheral tissues. The increase in PGE2 in the periphery accounts for the nonspecific myal­ gias and arthralgias that often accompany fever. It is thought that some systemic PGE2 escapes destruction by the lung and gains access to the hypothalamus via the internal carotid. However, it is the elevation of PGE2 in the brain that starts the process of raising the hypothalamic set point for core temperature. There are four receptors for PGE2, and each signals the cell in differ­ ent ways. Of the four receptors, the third (EP-3) is essential for fever: when the gene for this receptor is deleted in mice, no fever follows the injection of IL-1 or endotoxin. Deletion of the other PGE2 receptor genes leaves the fever mechanism intact. Although PGE2 is essential for fever, it is not a neurotransmitter. Rather, the release of PGE2 from the brain side of the hypothalamic endothelium triggers the PGE2 receptor Infection, microbial toxins, mediators of inflammation, immune reactions Microbial toxins Fever Heat conservation, heat production Cyclic AMP Monocytes/macrophages, endothelial cells, others Elevated thermoregulatory set point PGE2 Hypothalamic endothelium Pyrogenic cytokines IL-1, IL-6, TNF, IFN Circulation FIGURE 20-1  Chronology of events required for the induction of fever. AMP, adenosine 5′-monophosphate; IFN, interferon; IL, interleukin; PGE2, prostaglandin E2; TNF, tumor necrosis factor.

on glial cells, and this stimulation results in the rapid release of cyclic adenosine 5′-monophosphate (cAMP), which is a neurotransmitter. As shown in Fig. 20-1, the release of cAMP from glial cells activates neuronal endings from the thermoregulatory center that extend into the area. The elevation of cAMP is thought to account for changes in the hypothalamic set point either directly or indirectly (by inducing the release of neurotransmitters). Distinct receptors for microbial products are located on the hypothalamic endothelium. These receptors are called Toll-like receptors and are similar in many ways to IL-1 receptors. IL-1 receptors and Toll-like receptors share the same signal-transducing mechanism. Thus, the direct activation of Toll-like receptors or IL-1 receptors results in PGE2 production and fever.

Fever CHAPTER 20 ■ ■PRODUCTION OF CYTOKINES IN THE CNS Cytokines produced in the brain may account for the hyperpyrexia of CNS hemorrhage, trauma, or infection. Viral infections of the CNS induce microglial and possibly neuronal production of IL-1, TNF, and IL-6. In experimental animals, the concentration of a cytokine required to cause fever is several orders of magnitude lower with direct injec­ tion into the brain substance or brain ventricles than with systemic injection. Therefore, cytokines produced in the CNS can raise the hypothalamic set point, bypassing the circumventricular organs. CNS cytokines likely account for the hyperpyrexia of CNS hemorrhage, trauma, or infection. APPROACH TO THE PATIENT Fever HISTORY AND PHYSICAL EXAMINATION There are a range of disease processes that present with fever as a cardinal manifestation, and a thorough history can help distinguish between these broad categories (Table 20-1). The chronology of events preceding fever, including exposure to other symptomatic individuals or to vectors of disease, should be ascertained. Elec­ tronic devices for measuring oral, tympanic membrane, or rectal temperatures are reliable, but the same site should be used consis­ tently to monitor a febrile disease. Moreover, physicians should be aware that newborns, elderly patients, patients with chronic hepatic or renal failure, and patients taking glucocorticoids or being treated with an anticytokine may have active disease in the absence of fever because of a blunted febrile response. LABORATORY TESTS The workup should include a complete blood count; a differential count should be performed manually or with an instrument sensi­ tive to the identification of neutrophil juvenile or band forms, toxic granulations, and Döhle bodies, which are suggestive of bacterial infection. Neutropenia may be present with some viral infections. Measurement of circulating cytokines in patients with fever is not helpful since levels of cytokines such as IL-1 and TNF in the circulation often are below the detection limit of the assay or do not coincide with fever. However, in patients with low-grade fevers or with suspected occult disease, the most valuable measurements are the C-reactive protein (CRP) level and the erythrocyte sedimenta­ tion rate. These markers of inflammatory processes are particularly helpful in detecting occult disease. Measurement of circulating IL-6, which induces CRP, can be useful. However, whereas IL-6 TABLE 20-1  Disease Categories That Present with Fever as a Cardinal Sign Infectious diseases Autoimmune and noninfectious inflammatory disorders Cancer Medication related (e.g., vaccines, drug fever) Endocrine disorders (e.g., hyperthyroidism) Intrinsic hypothalamic malfunction

levels may vary during a febrile disease, CRP levels remain elevated. Acute-phase reactants are discussed in Chap. 315. FEVER IN PATIENTS RECEIVING ANTICYTOKINE THERAPY Patients receiving long-term treatment with anticytokine-based regimens are at increased risk of infection because of lowered host defenses. For example, latent Mycobacterium tuberculosis infection can disseminate in patients receiving anti-TNF therapy. With the increasing use of anticytokines to reduce the activity of IL-1, IL-6, IL-12/23, IL-17, or TNF in patients with Crohn disease, rheumatoid arthritis, or psoriasis, the possibility that these therapies blunt the febrile response should be kept in mind. PART 2 Cardinal Manifestations and Presentation of Diseases The blocking of cytokine activity has the distinct clinical draw­ back of lowering the level of host defenses against both routine bacterial and opportunistic infections such as M. tuberculosis and fungal infections. The use of monoclonal antibodies to reduce IL-17 in psoriasis increases the risk of systemic candidiasis. In nearly all reported cases of infection associated with anticy­ tokine therapy, fever is among the presenting signs. However, the extent to which the febrile response is blunted in these patients remains unknown. Therefore, low-grade fever in patients receiving anticytokine therapies is of considerable concern. The physician should conduct an early and rigorous diagnostic evaluation in these cases. The febrile response is also blunted in patients receiving chronic glucocorticoid therapy or anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs (NSAIDs). TREATMENT Fever THE DECISION TO TREAT FEVER In deciding whether to treat fever, it is important to remember that fever itself is not an illness: it is an ordinary response to a pertur­ bation of normal host physiology. Most fevers are associated with self-limited infections, such as common viral diseases. The use of antipyretics is not contraindicated in these infections: no significant clinical evidence indicates either that antipyretics delay the resolu­ tion of viral or bacterial infections or that fever facilitates recovery from infection or acts as an adjuvant to the immune system. In short, treatment of fever and its symptoms with routine antipyretics does no harm and does not slow the resolution of common viral and bacterial infections. However, in bacterial infections, the withholding of antipyretic therapy can be helpful in evaluating the effectiveness of a particular antibiotic, especially in the absence of positive cultures of the infect­ ing organism, and the routine use of antipyretics can mask an inad­ equately treated bacterial infection. Withholding antipyretics in some cases may facilitate the diagnosis of an unusual febrile disease. Temperature–pulse dissociation (relative bradycardia) occurs in typhoid fever, brucellosis, leptospirosis, some drug-induced fevers, and factitious fever. As stated earlier, in newborns, elderly patients, patients with chronic liver or kidney failure, and patients taking glucocorticoids, fever may not be present despite infection. Hypo­ thermia can develop in patients with septic shock. Some infections have characteristic patterns in which febrile epi­ sodes are separated by intervals of normal temperature. For example, Plasmodium vivax causes fever every third day, whereas fever occurs every fourth day with Plasmodium malariae. Another relapsing fever is related to Borrelia infection, with days of fever followed by a several-day afebrile period and then a relapse into additional days of fever. In the Pel-Ebstein pattern, fever lasting 3–10 days is fol­ lowed by afebrile periods of 3–10 days; this pattern can be classic for Hodgkin disease and other lymphomas. In cyclic neutropenia, fevers occur every 21 days and accompany the neutropenia. There are also a number of periodic fever syndromes (e.g., familial Mediterranean fever, TNF receptor–associated periodic syndrome [TRAPS]) that differ in their periodicity, duration of attack, constellation of clinical

features, genetic causes, and therapies (Chap. 381). Understanding these clinical differences can help tailor diagnostic testing to confirm the diagnosis and guide therapy. ANTICYTOKINE THERAPY TO REDUCE FEVER IN AUTOIMMUNE AND AUTOINFLAMMATORY DISEASES Recurrent fever is documented at some point in most autoimmune diseases and many autoinflammatory diseases, which include the periodic fever syndromes as well as disorders of inflammasomes (e.g., NLRP3, pyrin) and other components of the innate immune system (Chap. 360). Although fever can be a manifestation of auto­ immune diseases, recurrent fevers are characteristic of autoinflam­ matory diseases, including uncommon diseases such as adult and juvenile Still disease, familial Mediterranean fever, and hyper-IgD syndrome but also common diseases such as idiopathic pericarditis and gout. In addition to recurrent fevers, neutrophilia and serosal inflammation characterize autoinflammatory diseases. The fevers associated with many of these illnesses are dramatically reduced by blocking of IL-1 activity with anakinra or canakinumab. Anticyto­ kines therefore reduce fever in autoimmune and autoinflammatory diseases. Although fevers in autoinflammatory diseases are medi­ ated by IL-1β, patients also respond to antipyretics. MECHANISMS OF ANTIPYRETIC AGENTS The reduction of fever by lowering of the elevated hypothalamic set point is a direct function of reduction of the PGE2 level in the thermoregulatory center. The synthesis of PGE2 depends on the constitutively expressed enzyme cyclooxygenase. The substrate for cyclooxygenase is arachidonic acid released from the cell mem­ brane, and this release is the rate-limiting step in the synthesis of PGE2. Therefore, inhibitors of cyclooxygenase are potent antipyret­ ics. The antipyretic potency of various drugs is directly correlated with the inhibition of brain cyclooxygenase. Acetaminophen is a poor cyclooxygenase inhibitor in peripheral tissue and lacks note­ worthy anti-inflammatory activity; in the brain, however, acetamin­ ophen is oxidized by the P450 cytochrome system, and the oxidized form inhibits cyclooxygenase activity. Moreover, in the brain, the inhibition of another enzyme, COX-3, by acetaminophen may account for the antipyretic effect of this agent. However, COX-3 is not found outside the CNS. Oral aspirin and acetaminophen are equally effective in reducing fever in humans. NSAIDs such as ibuprofen and specific inhibi­ tors of COX-2 also are excellent antipyretics. Chronic, high-dose therapy with antipyretics such as aspirin or any NSAID does not reduce normal core body temperature. Thus, PGE2 appears to play no role in normal thermoregulation. As effective antipyretics, glucocorticoids act at two levels. First, similar to the cyclooxygenase inhibitors, glucocorticoids reduce PGE2 synthesis by inhibiting the activity of phospholipase A2, which is needed to release arachidonic acid from the cell membrane. Sec­ ond, glucocorticoids block the transcription of the mRNA for the pyrogenic cytokines. Limited experimental evidence indicates that ibuprofen and COX-2 inhibitors reduce IL-1-induced IL-6 produc­ tion and may contribute to the antipyretic activity of NSAIDs. REGIMENS FOR THE TREATMENT OF FEVER The objectives in treating fever are first to reduce the elevated hypo­ thalamic set point and second to facilitate heat loss. Reducing fever with antipyretics also reduces systemic symptoms of headache, myalgias, and arthralgias. Oral aspirin and NSAIDs effectively reduce fever but can adversely affect platelets and the gastrointestinal tract. Therefore, acetaminophen is preferred as an antipyretic. In children, acetamin­ ophen or oral ibuprofen must be used because aspirin increases the risk of Reye syndrome with certain viral infections. If the patient cannot take oral antipyretics, parenteral preparations of NSAIDs and rectal suppositories of various antipyretics can be used. Treatment of fever in some patients is highly recommended. Fever increases the demand for oxygen (i.e., for every increase of 1°C over 37°C, there is a 13% increase in oxygen consumption) and

10 - 21 Fever and Rash

21 Fever and Rash

can aggravate the condition of patients with preexisting impairment of cardiac, pulmonary, or CNS function. Children with a history of febrile or nonfebrile seizure should be aggressively treated to reduce fever. However, it is unclear what triggers the febrile seizure, and there is no correlation between absolute temperature elevation and onset of a febrile seizure in susceptible children. In hyperpyrexia, the use of cooling blankets facilitates the reduc­ tion of temperature; however, cooling blankets should not be used without oral antipyretics. In hyperpyretic patients with CNS disease or trauma (CNS bleeding), reducing core temperature mitigates the detrimental effects of high temperature on the brain. For a discussion of treatment for hyperthermia, see Chap. 478. ■ ■FURTHER READING Dinarello CA et al: Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Rev 11:633, 2012. Gattorno M et al: Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 78:1025, 2019. Kullenberg T et al: Long-term safety profile of anakinra in patients with severe cryopyrin-associated periodic syndromes. Rheumatology 55:1499, 2016. Sakkat A et al: Temperature control in critically ill patients with fever: A meta-analysis of randomized controlled trials. J Crit Care 61:89, 2021. Elaine T. Kaye, Kenneth M. Kaye

Fever and Rash The acutely ill patient with fever and rash often presents a diagnostic challenge for physicians, yet the distinctive appearance of an eruption in concert with a clinical syndrome can facilitate a prompt diagnosis and the institution of life-saving therapy or critical infection-control interventions. Representative images of many of the rashes discussed in this chapter are included in Chap. A1. APPROACH TO THE PATIENT Fever and Rash A thorough history of patients with fever and rash includes the following relevant information: immune status, medications taken within the previous month, specific travel history, immunization status, exposure to domestic pets and other animals, history of animal (including arthropod) bites, recent dietary exposures, exis­ tence of cardiac abnormalities, presence of prosthetic material, recent exposure to ill individuals, and sexual exposures. The history should also include the site of onset of the rash and its direction and rate of spread. PHYSICAL EXAMINATION A thorough physical examination entails close attention to the rash, with an assessment and precise identification of its salient features. First, it is critical to determine what type of lesions make up the eruption. Macules are flat lesions defined by an area of changed color (i.e., a blanchable erythema). Papules are raised, solid lesions <5 mm in diameter; plaques are lesions >5 mm in diameter with a flat, plateau-like surface; and nodules are lesions >5 mm in diameter with a more rounded configuration. Wheals (urticaria, hives) are papules or plaques that are pale pink and may appear annular (ring­ like) as they enlarge; classic (nonvasculitic) wheals are transient, lasting only 24 h in any defined area. Vesicles (<5 mm) and bullae

(>5 mm) are circumscribed, elevated lesions containing fluid. Pus­ tules are raised lesions containing purulent exudate; vesicles such as due to varicella or herpes simplex may evolve to pustules. Nonpal­ pable purpura is a flat lesion that is due to bleeding into the skin. If <3 mm in diameter, the purpuric lesions are termed petechiae; if

3 mm, they are termed ecchymoses. Palpable purpura is a raised lesion that is due to inflammation of the vessel wall (vasculitis) with subsequent hemorrhage. An ulcer is a defect in the skin extending at least into the upper layer of the dermis, and an eschar (tâche noire) is a necrotic lesion covered with a black crust. Fever and Rash CHAPTER 21 Other pertinent features of rashes include their configuration (i.e., annular or target), the arrangement of their lesions, and their distribution (i.e., central or peripheral). For further discussion, see Chaps. 59, 61, 127, and 134. ■ ■CLASSIFICATION OF RASH This chapter reviews rashes that reflect systemic disease, but it does not include localized skin eruptions (i.e., cellulitis, impetigo) that may also be associated with fever (Chap. 134). The chapter is not intended to be all-inclusive, but it covers the most important and most common diseases associated with fever and rash. Rashes are classified herein on the basis of lesion morphology and distribution. For practical pur­ poses, this classification system is based on the most typical disease presentations. However, morphology may vary as rashes evolve, and the presentation of diseases with rashes is subject to many variations (Chap. 61). For instance, the classic petechial rash of Rocky Mountain spotted fever (Chap. 192) may initially consist of blanchable ery­ thematous macules distributed peripherally; at times, however, the rash associated with this disease may not be predominantly acral, or no rash may develop at all. Diseases with fever and rash may be classified by type of eruption: centrally distributed maculopapular, peripheral, confluent desquama­ tive erythematous, vesiculobullous, urticaria-like, nodular, purpuric, ulcerated, or with eschars. Diseases are listed by these categories in Table 21-1, and many are highlighted in the text. However, for a more detailed discussion of each disease associated with a rash, the reader is referred to the chapter dealing with that specific disease. (Reference chapters are cited in the text and listed in Table 21-1.) ■ ■CENTRALLY DISTRIBUTED MACULOPAPULAR ERUPTIONS Centrally distributed rashes, in which lesions are primarily truncal, are the most common type of eruption. The rash of rubeola (measles) starts at the hairline 2–3 days into the illness and moves down the body, typically sparing the palms and soles (Fig. 21-1; see also Fig. A1-3) (Chap. 211). It begins as discrete erythematous lesions, which become confluent as the rash spreads. Koplik’s spots (1- to 2-mm white or blu­ ish lesions with an erythematous halo on the buccal mucosa) (Fig. A1-2) are pathognomonic for measles and are generally seen during the first 2 days of symptoms. They should not be confused with Fordyce’s spots (ectopic sebaceous glands), which have no erythematous halos and are found in the mouth of healthy individuals. Koplik’s spots may briefly overlap with the measles exanthem. Rubella (German measles) (Fig. A1-4) also spreads from the hairline downward; unlike that of measles, however, the rash of rubella tends to clear from originally affected areas as it migrates, and it may be pruritic (Chap. 212). Forchheimer spots (palatal petechiae) may develop but are nonspecific because they also develop in infectious mononucleosis (Chap. 199), scarlet fever (Chap. 153), and Zika virus infection (Chap. 215) (Fig. A1-51A-D). Postauricular and suboccipital adenop­ athy and arthritis are common among adults with rubella. Exposure of pregnant women to ill individuals should be avoided, as rubella causes severe congenital abnormalities. Numerous strains of enteroviruses (Chap. 210), primarily echoviruses and coxsackieviruses, cause non­ specific syndromes of fever and eruptions that may mimic rubella or measles. Patients with infectious mononucleosis caused by Epstein-Barr virus (Chap. 199) or with primary HIV infection (Fig. A1-6; see also

TABLE 21-1  Diseases Associated with Fever and Rash DISEASE ETIOLOGY DESCRIPTION Centrally Distributed Maculopapular Eruptions Acute meningococcemiaa — — — —

Drug reaction with eosinophilia and systemic symptoms (DRESS); also termed drug-induced hypersensitivity syndrome (DIHS)b; Chikungunyac; COVID-19c — — — —

PART 2 Cardinal Manifestations and Presentation of Diseases Rubeola (measles, first disease) (Fig. 21-1,

Fig. A1-2, Fig. A1-3) Paramyxovirus Discrete lesions that become confluent as rash spreads from hairline downward, usually sparing palms and soles; lasts

≥3 days; Koplik’s spots Rubella (German measles, third disease) (Fig. A1-4) Togavirus Spreads from hairline downward, clearing as it spreads; Forchheimer spots (palatal petechiae) Erythema infectiosum (fifth disease) (Fig. A1-1) Human parvovirus B19 Bright-red “slapped-cheeks” appearance followed by lacy reticular rash that waxes and wanes over 3 weeks; rarely, papularpurpuric “gloves-and-socks” syndrome on hands and feet Exanthem subitum (roseola, sixth disease) (Fig. A1-5) Human herpesvirus 6 or, less commonly, the closely related human herpesvirus 7 Diffuse maculopapular eruption over trunk and neck; resolves within 2 days Primary HIV infection

(Fig. A1-6) HIV Nonspecific diffuse macules and papules most commonly on upper thorax, face, collar region; less commonly, urticarial or vesicular lesions; oral or genital ulcers Infectious mononucleosis Epstein-Barr virus Diffuse maculopapular eruption historically in ~5% of cases increasing to ~90% of cases when antibiotics, particularly ampicillin, given, but recent observed rates of ~20% without antibiotics and little increase with antibiotics; urticaria, petechiae in some cases; periorbital edema (50%); palatal petechiae (25%) Other viral exanthems Echoviruses 2, 4, 9, 11, 16, 19, 25; coxsackieviruses A9, B1, B5; etc. Wide range of skin findings that may mimic rubella or measles Exanthematous druginduced eruption

(Fig. A1-7) Drugs (antibiotics, anticonvulsants, diuretics, etc.) Intensely pruritic, bright-red macules and papules, symmetric on trunk and extremities; may become confluent Epidemic typhus Rickettsia prowazekii Maculopapular eruption appearing in axillae, spreading to trunk and later to extremities; usually spares face, palms, soles; evolves from blanchable macules to confluent eruption with petechiae; rash evanescent in recrudescent typhus

(Brill-Zinsser disease) Endemic (murine) typhus Rickettsia typhi Maculopapular eruption, usually sparing palms, soles Scrub typhus Orientia tsutsugamushi Diffuse macular rash starting on trunk; eschar at site of mite bite

GROUP AFFECTED/ EPIDEMIOLOGIC FACTORS CLINICAL SYNDROME CHAPTER Nonimmune individuals Cough, conjunctivitis, coryza, severe prostration

Nonimmune individuals Adenopathy, arthritis

Most common among children 3–12 years old; occurs in winter and spring Mild fever; arthritis in adults; rash following resolution of fever

Usually affects children <3 years old Rash following resolution of fever; similar to Boston exanthem (echovirus 16); febrile seizures may occur

Individuals recently infected with HIV Pharyngitis, adenopathy, arthralgias

Adolescents, young adults Hepatosplenomegaly, pharyngitis, cervical lymphadenopathy, atypical lymphocytosis, heterophile antibody

Affects children more commonly than adults Nonspecific viral syndromes

Occurs 2–3 days after exposure in previously sensitized individuals; otherwise, after 2–3 weeks (but can occur anytime, even shortly after drug is discontinued) Variable findings: fever and eosinophilia

Exposure to body lice; occurrence of recrudescent typhus as relapse after

30–50 years Headache, myalgias; mortality rates 10–40% if untreated; milder clinical presentation in recrudescent form

Exposure to rat or cat fleas Headache, myalgias

Endemic in South Pacific, Australia, Asia; transmitted by mites Headache, myalgias, regional adenopathy; mortality rates up to 30% if untreated

(Continued)

(Continued) TABLE 21-1  Diseases Associated with Fever and Rash DISEASE ETIOLOGY DESCRIPTION Rickettsial spotted fevers (Fig. 21-8) Rickettsia conorii (boutonneuse fever), Rickettsia australis (North Queensland tick typhus), Rickettsia sibirica (Siberian tick typhus), Rickettsia africae (African tick-bite fever), and others Eschar common at bite site; maculopapular (rarely, vesicular and petechial) eruption on proximal extremities, spreading to trunk and face Human monocytotropic ehrlichiosisd Ehrlichia chaffeensis Maculopapular eruption (40% of cases), involves trunk and extremities; may be petechial Leptospirosis Leptospira interrogans and other Leptospira species Maculopapular eruption; conjunctivitis; scleral hemorrhage in some cases Lyme disease (Fig. A1-8) Borrelia burgdorferi (sole cause in U.S.), Borrelia afzelii, Borrelia garinii Papule expanding to erythematous

annular lesion with central clearing (erythema migrans; average diameter,

15 cm), sometimes with concentric rings, sometimes with indurated or vesicular center; multiple secondary erythema migrans lesions in some cases Southern tick-associated rash illness (STARI, Master’s disease) Unknown (possibly Borrelia lonestari or other Borrelia spirochetes) Similar to erythema migrans of Lyme disease with several differences, including: multiple secondary lesions less likely; lesions tending to be smaller (average diameter, ~8 cm); central clearing more likely Typhoid fever (Fig. A1-9) Salmonella typhi Transient, blanchable erythematous macules and papules, 2–4 mm, usually on trunk (rose spots) Dengue fevere (Fig. A1-53) Dengue virus

(4 serotypes; flaviviruses) Rash in 50% of cases; initially diffuse flushing; midway through illness, onset of maculopapular rash, which begins on trunk and spreads centrifugally to extremities and face; pruritus, hyperesthesia in some cases; after defervescence, petechiae on extremities may occur Rat-bite fever (sodoku) Spirillum minus Eschar at bite site; then blotchy violaceous or red-brown rash involving trunk and extremities Relapsing fever Borrelia species Central rash at end of febrile episode; petechiae in some cases Erythema marginatum (rheumatic fever) Group A Streptococcus Erythematous annular papules and plaques occurring as polycyclic lesions in waves over trunk, proximal extremities; evolving and resolving within hours Systemic lupus erythematosus (SLE)

(Fig. A1-10, Fig. A1-11,

Fig. A1-12) Autoimmune disease Macular and papular erythema, often in sun-exposed areas; discoid lupus lesions (local atrophy, scale, pigmentary changes); periungual telangiectasis; malar rash; vasculitis sometimes causing urticaria, palpable purpura; oral erosions in some cases Still’s disease (Fig. A1-13) Autoimmune disease Transient 2- to 5-mm erythematous papules appearing at height of fever on trunk, proximal extremities; lesions evanescent

GROUP AFFECTED/ EPIDEMIOLOGIC FACTORS CLINICAL SYNDROME CHAPTER Exposure to ticks; R. conorii in Mediterranean region, India, Africa; R. australis in Australia; R. sibirica in Siberia, Mongolia; R. africae in Africa, Caribbean Headache, myalgias, regional adenopathy

Fever and Rash CHAPTER 21 Tick-borne; most common in U.S. Southeast, southern Midwest, and midAtlantic regions Headache, myalgias, leukopenia

Exposure to water contaminated with animal urine Myalgias; aseptic meningitis; fulminant form: icterohemorrhagic fever (Weil’s disease)

Bite of Ixodes tick vector Headache, myalgias, chills, photophobia occurring acutely; CNS disease, myocardial disease, arthritis weeks to months later in some cases

Bite of tick vector Amblyomma americanum (Lone Star tick); often found in regions where Lyme disease is uncommon, including southern United States Compared with Lyme disease: fewer constitutional symptoms, tick bite more likely to be recalled; other Lyme disease sequelae lacking

Ingestion of contaminated food or water (rare in U.S.) Variable abdominal pain and diarrhea; headache, myalgias, hepatosplenomegaly

Occurs in tropics and subtropics; transmitted by mosquito Headache; musculoskeletal pain (“breakbone fever”); leukopenia; occasionally biphasic (“saddleback”) fever

Rat bite; primarily found in Asia; rare in U.S. Regional adenopathy; recurrent fevers if untreated

Exposure to ticks or body lice Recurrent fever, headache, myalgias, hepatosplenomegaly

Patients with rheumatic fever Pharyngitis preceding polyarthritis, carditis, subcutaneous nodules, chorea

Most common in young to middleaged women; flares precipitated by sun exposure Arthritis; cardiac, pulmonary, renal, hematologic, and vasculitic disease

Children and young adults High spiking fever, polyarthritis, splenomegaly; erythrocyte sedimentation rate

100 mm/h — (Continued)

TABLE 21-1  Diseases Associated with Fever and Rash (Continued) DISEASE ETIOLOGY DESCRIPTION African trypanosomiasis (Fig. A1-47) Trypanosoma brucei rhodesiense/gambiense Blotchy or annular erythematous macular and papular rash (trypanid), primarily on trunk; pruritus; chancre at site of tsetse fly bite may precede rash by several weeks Arcanobacterial pharyngitis Arcanobacterium (Corynebacterium) haemolyticum Diffuse, erythematous, maculopapular eruption involving trunk and proximal extremities; may desquamate PART 2 Cardinal Manifestations and Presentation of Diseases West Nile virus infection West Nile virus Maculopapular eruption involving the trunk, extremities, and head or neck; rash in 20–50% of cases Zika virus infection

(Fig. A1-51) Zika virus Pruritic macular and papular erythema; rash may begin on trunk and descend to lower body; conjunctival injection; palatal petechiae may occur Peripheral Eruptions Chronic meningococcemia, disseminated gonococcal infection,a human parvovirus B19 infection,f RIMEg — — — — 160, 161, 202 Rocky Mountain spotted fever (Fig. 21-2, Fig. A1-16) Rickettsia rickettsii Rash beginning on wrists and ankles and spreading centripetally; appears on palms and soles later in disease; lesion evolution from blanchable macules to petechiae Secondary syphilis

(Fig. A1-18, Fig. A1-19,

Fig. A1-20, Fig. A1-21) Treponema pallidum Coincident primary chancre in 10% of cases; copper-colored, scaly papular eruption, diffuse but prominent on palms and soles; rash never vesicular in adults; condyloma latum, mucous patches, and alopecia in some cases Chikungunya fever

(Fig. A1-54) Chikungunya virus Maculopapular eruption; typically occurs on trunk, but also occurs on extremities and face Hand-foot-and-mouth disease (Fig. A1-22) Coxsackievirus A16 and enterovirus 71 most common causes; coxsackievirus A6 associated with atypical syndrome Tender vesicles, erosions in mouth; 0.25- to 1-cm papules on hands and feet with rim of erythema evolving into tender vesicles; shedding of nails (onychomadesis) can occur 1–2 months after acute illness; coxsackievirus A6 lesions may also be maculopapular, petechial, purpuric, or erosive; atypical form often extends to perioral area, extremities, trunk, buttocks, genitals, and areas affected by eczema (eczema coxsackium) Erythema multiforme (EM) (Fig. A1-24) Infection, drugs, idiopathic causes Target lesions (central erythema surrounded by area of clearing and another rim of erythema) up to 2 cm; symmetric on knees, elbows, palms, soles; spreads centripetally; papular, sometimes vesicular; when extensive and involving mucous membranes, termed EM major

GROUP AFFECTED/ EPIDEMIOLOGIC FACTORS CLINICAL SYNDROME CHAPTER Tsetse fly bite in eastern (T. brucei rhodesiense) or western (T. brucei gambiense) Africa Hemolymphatic disease followed by meningoencephalitis; Winterbottom’s sign (posterior cervical lymphadenopathy)

(T. brucei gambiense)

Children and young adults Exudative pharyngitis, lymphadenopathy

Mosquito bite; rarely, blood transfusion or transplanted organ Headache, weakness, malaise, myalgia, neuroinvasive disease (encephalitis, meningitis, flaccid paralysis)

Mosquito bite; sexual transmission or blood transfusion less common Arthralgia (especially of small joints), myalgia, lymphadenopathy, headache, low-grade fever; illness in pregnancy may cause severe birth defects, including microcephaly; neurologic complications, including Guillain-Barré, may occur

Tick vector; widespread but more common in southeastern and southwest-central U.S. Headache, myalgias, abdominal pain; mortality rates up to 40% if untreated

Sexually transmitted Fever, constitutional symptoms

Aedes aegypti and A. albopictus mosquito bites; tropical and subtropical regions Severe polyarticular, migratory arthralgias, especially involving small joints (e.g., hands, wrists, ankles)

Summer and fall; primarily children

<10 years old; multiple family members; coxsackievirus A6 infection also occurs in young adults Transient fever; enterovirus 71 can be associated with brainstem encephalitis, flaccid paralysis resembling polio, or aseptic meningitis

Herpes simplex virus or Mycoplasma pneumoniae infection; drug intake (i.e., sulfa, phenytoin, penicillin) 50% of patients <20 years old; fever more common in most severe form, EM major, which can be confused with StevensJohnson syndrome (but EM major lacks prominent skin sloughing) —h (Continued)

(Continued) TABLE 21-1  Diseases Associated with Fever and Rash DISEASE ETIOLOGY DESCRIPTION Rat-bite fever (Haverhill fever) Streptobacillus moniliformis Maculopapular eruption over palms, soles, and extremities; tends to be more severe at joints; eruption sometimes becoming generalized; may be purpuric; may desquamate Bacterial endocarditis (Fig. A1-23) Streptococcus, Staphylococcus, etc. Subacute course (e.g., viridans streptococci): Osler’s nodes (tender pink nodules on finger or toe pads); petechiae on skin and mucosa; splinter hemorrhages. Acute course (e.g., Staphylococcus aureus): Janeway lesions (painless erythematous or hemorrhagic macules, usually on palms and soles) COVID-19 (Fig. A1-57) SARS-CoV-2 Mild or asymptomatic COVID-19: Pernio (macules, papules, or plaques that are tender, erythematous/violaceous; acral, feet more common than hands). Moderate/ severe COVID-19: Vesicles, urticaria, maculopapular erythema; often pruritic; occur on trunk, extremities. Severe

COVID-19: Retiform purpura (net-like, purple patches/plaques often with necrosis); lesions often asymptomatic; occur on extremities, buttocks. Multisystem inflammatory syndrome in children (MIS-C): Findings similar to Kawasaki disease Confluent Desquamative Erythemas Scarlet fever (second disease) (Fig. A1-25) Group A Streptococcus (pyrogenic exotoxins

A, B, C) Diffuse blanchable erythema beginning on face and spreading to trunk and extremities; circumoral pallor; “sandpaper” texture to skin; accentuation of linear erythema in skin folds (Pastia’s lines); enanthem of white evolving into red “strawberry” tongue; desquamation in second week Kawasaki disease

(Fig. A1-29) Idiopathic Rash similar to scarlet fever (scarlatiniform) or EM; fissuring of lips, strawberry tongue; conjunctivitis; edema of hands, feet; desquamation later in disease Streptococcal toxic shock syndrome Group A Streptococcus (associated with pyrogenic exotoxin A and/or B or certain

M types) When present, rash often scarlatiniform May occur in setting of severe group A streptococcal infections (e.g., necrotizing fasciitis, bacteremia, pneumonia) Staphylococcal toxic shock syndrome S. aureus (toxic shock syndrome toxin 1, enterotoxins B and others) Diffuse erythema involving palms; pronounced erythema of mucosal surfaces; conjunctivitis; desquamation 7–10 days into illness Staphylococcal scaldedskin syndrome (Fig. A1-28) S. aureus, phage group II Diffuse tender erythema, often with bullae and desquamation; Nikolsky’s sign Exfoliative erythroderma syndrome (Fig. A1-27) Underlying psoriasis, eczema, drug eruption, mycosis fungoides Diffuse erythema (often scaling) interspersed with lesions of underlying condition

GROUP AFFECTED/ EPIDEMIOLOGIC FACTORS CLINICAL SYNDROME CHAPTER Rat bite, ingestion of contaminated food Myalgias; arthritis (50%); fever recurrence in some cases

Abnormal heart valve (e.g., viridans streptococci), intravenous drug use New or changing heart murmur

Fever and Rash CHAPTER 21 Infection with SARSCoV-2; MIS-C in older children/adolescents Ranging from asymptomatic to mild/ moderate with loss of taste/smell, pharyngitis, cough, fever, to severe with dyspnea, ARDS; complications include thrombosis, especially with retiform purpura; lesions may be delayed compared to other COVID-19 symptoms; MIS-C occurs ~2-6 weeks following acute (often asymptomatic) infection   Most common among children 2–10 years old; usually follows group A streptococcal pharyngitis Fever, pharyngitis, headache

Children <8 years old Cervical adenopathy, pharyngitis, coronary artery vasculitis 61, 375 Multiorgan failure, hypotension; mortality rate 30%

Colonization with toxin-producing

S. aureus Fever >39°C (>102°F), hypotension, multiorgan dysfunction

Colonization with toxin-producing

S. aureus; occurs in children <10 years old (termed Ritter’s disease in neonates) or adults with renal dysfunction Irritability; nasal or conjunctival secretions

Usually occurs in adults over age 50; more common among men Fever, chills (i.e., difficulty with thermoregulation); lymphadenopathy 61, 63 (Continued)

TABLE 21-1  Diseases Associated with Fever and Rash (Continued) DISEASE ETIOLOGY DESCRIPTION DRESS (drug reaction with eosinophilia and systemic symptoms; also known as drug-induced hypersensitivity syndrome [DIHS]) (Fig. A1-48) Aromatic anticonvulsants; other drugs, including sulfonamides, minocycline Maculopapular eruption (mimicking exanthematous drug rash), sometimes progressing to exfoliative erythroderma; profound edema, especially facial; pustules may occur PART 2 Cardinal Manifestations and Presentation of Diseases Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) (Fig. 21-3,

Fig. A1-26) Drugs (80% of cases; often allopurinol, anticonvulsants, antibiotics), infection, idiopathic factors Erythematous and purpuric macules, sometimes targetoid, or diffuse erythema progressing to bullae, with sloughing and necrosis of entire epidermis; Nikolsky’s sign; involves mucosal surfaces; TEN (>30% epidermal necrosis) is maximal form; SJS involves <10% of epidermis; SJS/ TEN overlap involves 10–30% of epidermis Vesiculobullous or Pustular Eruptions Hand-foot-andmouth syndromec; staphylococcal scaldedskin syndromeb; TENb; DRESS/DIHSb; COVID-19c — — — — —h Varicella (chickenpox) (Fig. 21-4, Fig. A1-30) Varicella-zoster virus (VZV) Macules (2–3 mm) evolving into papules, then vesicles (sometimes umbilicated), on an erythematous base (“dewdrops on a rose petal”); pustules then forming and crusting; lesions appearing in crops; may involve scalp, mouth; intensely pruritic Pseudomonas “hot-tub” folliculitis (Fig. A1-55) Pseudomonas aeruginosa Pruritic erythematous follicular, papular, vesicular, or pustular lesions that may involve axillae, buttocks, abdomen, and especially areas occluded by bathing suits; can manifest as tender isolated nodules on palmar or plantar surfaces (the latter designated “Pseudomonas hot-foot syndrome”) Variola (smallpox)

(Fig. A1-50) Variola major virus Red macules on tongue and palate evolving to papules and vesicles; skin macules evolving to papules, then vesicles, then pustules over 1 week, with subsequent lesion crusting; lesions initially appearing on face and spreading centrifugally from trunk to extremities; differs from varicella in that (1) skin lesions in any given area are at same stage of development and (2) there is a prominent distribution of lesions on face and extremities (including palms, soles) Mpox (Fig. A1-59) Monkeypox virus Classically, lesions similar in morphology and distribution to those of variola (smallpox); 2022 outbreak: macules evolve to papules, vesicles, and pustules, with subsequent crusting over 1–2 weeks; often umbilicated; unlike traditional Mpox, lesions may be in different stages of development and typically number fewer than 20; lesions often painful; mucosal lesions (anorectal, oropharyngeal, ocular) may occur at sites of inoculation; disease may be severe and progressive in advanced HIV

GROUP AFFECTED/ EPIDEMIOLOGIC FACTORS CLINICAL SYNDROME CHAPTER Individuals genetically unable to detoxify arene oxides (anticonvulsant metabolites), patients with slow N-acetylating capacity (sulfonamides) Lymphadenopathy, multiorgan failure (especially hepatic), eosinophilia, atypical lymphocytes; HHV6 viremia; mimics sepsis

Uncommon among children; more common among people living with HIV systemic lupus erythematosus, certain HLA types, or slow acetylators Dehydration, sepsis sometimes resulting from lack of normal skin integrity; mortality rates up to 30%

Usually affects children; 10% of adults susceptible; most common in late winter and spring; incidence down by 90% in U.S. as a result of varicella vaccination Malaise; generally mild disease in healthy children; more severe disease with complications in adults and immunocompromised children

Bathers in hot tubs or swimming pools; occurs in outbreaks Earache, sore eyes and/ or throat; fever may be absent; generally self-limited

Nonimmune individuals exposed to smallpox Prodrome of fever, headache, backache, myalgias; vomiting in 50% of cases S4 Nonimmune individuals exposed to monkeypox; virus endemic to Central and West Africa; 2022 outbreak: among nonendemic countries including Europe, U.S.; most cases in men who have sex with men Classically, similar to smallpox, though with lymphadenopathy and typically milder; 2022 outbreak: fever, lymphadenopathy, headache, proctitis, or pharyngitis

(Continued)

(Continued) TABLE 21-1  Diseases Associated with Fever and Rash DISEASE ETIOLOGY DESCRIPTION Primary herpes simplex virus (HSV) infection (Fig. A1-58) HSV Erythema rapidly followed by hallmark painful grouped vesicles that may evolve into pustules that ulcerate, especially on mucosal surfaces; lesions at site of inoculation: commonly gingivostomatitis for HSV-1 and genital lesions for HSV-2; recurrent disease milder (e.g., herpes labialis typically does not involve oral mucosa) Disseminated herpesvirus infection (Fig. A1-31,

Fig. A1-58D) VZV or HSV Generalized nongrouped vesicles that can evolve to pustules and ulcerations; individual lesions similar for VZV and HSV. Zoster cutaneous dissemination:

25 lesions extending outside involved dermatome. HSV: extensive, progressive mucocutaneous lesions may occur in absence of dissemination; HSV may disseminate in eczematous skin (eczema herpeticum); HSV visceral dissemination may occur with only localized mucocutaneous disease; in disseminated HSV neonatal disease, skin lesions diagnostically helpful when present, but rash absent in a substantial minority of cases Rickettsialpox (Fig. A1-33) Rickettsia akari Eschar found at site of mite bite; generalized rash involving face, trunk, extremities; may involve palms and soles; <100 papules and plaques (2–10 mm); centers of papules develop vesicles or pustules Acute generalized exanthematous pustulosis (Fig. A1-49) Drugs (mostly anticonvulsants or antimicrobials); also viral Tiny, sterile, nonfollicular pustules on erythematous, edematous skin; begins on face and in body folds, then becomes generalized Disseminated Vibrio vulnificus infection V. vulnificus Erythematous lesions evolving into hemorrhagic bullae and then into necrotic ulcers Ecthyma gangrenosum (Fig. A1-34) P. aeruginosa, other gram-negative rods, fungi Indurated plaque evolving into hemorrhagic bulla or pustule that sloughs, resulting in eschar formation; erythematous halo; most common in axillary, groin, perianal regions Reactive infectious mucocutaneous eruption (RIME) (this generalized term encompasses multiple infectious etiologies, and includes Mycoplasma pneumoniae–induced rash and mucositis [MIRM]) M. pneumoniae, Chlamydia pneumoniae, human metapneumovirus, parainfluenzavirus 2, rhinovirus, influenza B virus, SARS-CoV-2 Severe mucositis of at least two sites (e.g., oropharynx, ocular, genital) with nearly universal hemorrhagic crusting of lips; sparse, vesiculobullous, or atypical targetoid rash over <10% of body; lesions typically on extremities but can be truncal; rash sometimes absent Urticaria-Like Eruptions COVID-19c           Urticarial vasculitis

(Fig. 21-5, Fig. A1-35) Serum sickness, often due to infection (including acute hepatitis B, enteroviral, parasitic), drugs; connective tissue disease Erythematous, edematous “urticarialike” plaques, pruritic or burning; unlike urticaria: typical lesion duration >24 h (up to 5 days) and lack of complete lesion blanching with compression due to hemorrhage

GROUP AFFECTED/ EPIDEMIOLOGIC FACTORS CLINICAL SYNDROME CHAPTER Primary infection most common among children and young adults for HSV-1 and among sexually active young adults for HSV-2; no fever in recurrent infection Regional lymphadenopathy

Fever and Rash CHAPTER 21 Patients with immunosuppression, eczema; neonates Visceral organ involvement (e.g., liver, lungs) in some cases; neonatal disease particularly severe 143, 197, 198 Seen in urban settings; transmitted by mouse mites Headache, myalgias, regional adenopathy; mild disease

Appears 2–21 days after start of drug therapy, depending on whether patient has been sensitized Acute fever, pruritus, leukocytosis

Patients with cirrhosis, diabetes, renal failure; exposure by ingestion of contaminated saltwater, seafood Hypotension; mortality rate 50%

Usually affects neutropenic patients; occurs in up to 28% of individuals with Pseudomonas bacteremia Clinical signs of sepsis

More common in males; usually children (mean age 11–12 years old) Cough, respiratory infection symptoms often precede rash by ~1 week, good prognosis; distinct from SJS/TEN Patients with serum sickness (including acute hepatitis B), connective tissue disease Fever variable; arthralgias/ arthritis 375h (Continued)

TABLE 21-1  Diseases Associated with Fever and Rash (Continued) DISEASE ETIOLOGY DESCRIPTION Nodular Eruptions Disseminated infection (Fig. 21-6, Fig. A1-36,

Fig. A1-37, Fig. A1-38) Fungal infections (e.g., candidiasis, histoplasmosis, cryptococcosis, sporotrichosis, coccidioidomycosis); mycobacteria Subcutaneous nodules (up to 3 cm); fluctuance, draining common with mycobacteria; necrotic nodules (extremities, periorbital or nasal regions) common with Aspergillus, Mucor PART 2 Cardinal Manifestations and Presentation of Diseases Erythema nodosum (septal panniculitis)

(Fig. A1-39) Infections (e.g., streptococcal, fungal, mycobacterial, yersinial); drugs (e.g., sulfas, penicillins, oral contraceptives); sarcoidosis; idiopathic causes Large, violaceous, nonulcerative, subcutaneous nodules; exquisitely tender; usually on lower legs but also on upper extremities Sweet syndrome (acute febrile neutrophilic dermatosis) (Fig. A1-40) Yersinia infection; upper respiratory infection; inflammatory bowel disease; pregnancy; malignancy (usually hematologic); drugs (G-CSF) Tender red or blue edematous nodules giving impression of vesiculation; usually on face, neck, upper extremities; when on lower extremities, may mimic erythema nodosum Bacillary angiomatosis Bartonella henselae,

B. quintana Many forms, including erythematous, smooth vascular nodules; friable, exophytic lesions; erythematous plaques (may be dry, scaly); subcutaneous nodules (may be erythematous) Purpuric Eruptions Rocky Mountain spotted fever, rat-bite fever, endocarditisc; epidemic typhusf; dengue fevere,f; human parvovirus B19 infectionf; COVID-19c — — — — —h Acute meningococcemia Neisseria meningitidis Initially pink maculopapular lesions evolving into petechiae; petechiae rapidly becoming numerous, sometimes enlarging and becoming vesicular; trunk, extremities most commonly involved; may appear on face, hands, feet; may include purpura fulminans (see below) reflecting DIC Purpura fulminans

(Fig. A1-41) Severe DIC Large ecchymoses with sharply irregular shapes evolving into hemorrhagic bullae and then into black necrotic lesions Chronic meningococcemia

(Fig. A1-42) N. meningitidis Variety of recurrent eruptions, including pink maculopapular; nodular (usually on lower extremities); petechial (sometimes developing vesicular centers); purpuric areas with pale blue-gray centers Disseminated gonococcal infection (Fig. A1-43) Neisseria gonorrhoeae Papules (1–5 mm) evolving over 1–2 days into hemorrhagic pustules with gray necrotic centers; hemorrhagic bullae occurring rarely; lesions (usually <40) distributed peripherally near joints (more commonly on upper extremities) Enteroviral petechial rash Usually echovirus 9 or coxsackievirus A9 Disseminated petechial lesions (may also be maculopapular, vesicular, or urticarial) Viral hemorrhagic fever Arenaviruses, bunyaviruses, filoviruses (including Ebola), flaviviruses (including dengue) Petechial rash Residence in or travel to endemic areas, other virus exposure

GROUP AFFECTED/ EPIDEMIOLOGIC FACTORS CLINICAL SYNDROME CHAPTER Immunocompromised hosts (e.g., bone marrow transplant recipients, patients undergoing chemotherapy, HIVinfected patients) Features vary with organism —h More common among females 15–30 years old Arthralgias (50%); features vary with associated condition —h More common among women and among persons 30–60 years old; 20% of cases associated with malignancy (men and women equally affected in this group) Headache, arthralgias, leukocytosis

Immunosuppressed individuals, especially those with advanced HIV infection Peliosis of liver and spleen in some cases; lesions sometimes involving multiple organs; bacteremia

Most common among children, individuals with asplenia or terminal complement component deficiency (C5–C8) Hypotension, meningitis (sometimes preceded by upper respiratory infection)

Individuals with sepsis (e.g., involving N. meningitidis), malignancy, or massive trauma; asplenic patients at high risk for sepsis Hypotension 160, 315 Individuals with complement deficiencies Fevers, sometimes intermittent; arthritis, myalgias, headache

Sexually active individuals (more often females), some with complement deficiency Low-grade fever, tenosynovitis, arthritis

Often occurs in outbreaks Pharyngitis, headache; aseptic meningitis with echovirus 9

Triad of fever, shock, hemorrhage from mucosa or gastrointestinal tract 215, 216 (Continued)

(Continued) TABLE 21-1  Diseases Associated with Fever and Rash DISEASE ETIOLOGY DESCRIPTION Thrombotic thrombocytopenic purpura/hemolytic-uremic syndrome Idiopathic, bloody diarrhea caused by Shiga toxin– generating bacteria (e.g., Escherichia coli O157:H7), deficiency in ADAMTS13 (cleaves von Willebrand factor), drugs (e.g., quinine, chemotherapy, immunosuppression) Petechiae Individuals with Shiga toxin producing bacterial (commonly E. coli O157:H7) gastroenteritis (especially children), cancer chemotherapy, HIV infection, autoimmune diseases, pregnant/postpartum women, those with ADAMTS13 deficiency Cutaneous smallvessel vasculitis (leukocytoclastic vasculitis) (Fig. 21-7,

Fig. A1-44) Infections (including group A streptococcal infection, hepatitis B or C), drugs, idiopathic factors Palpable purpuric lesions appearing in crops on legs or other dependent areas; may become vesicular or ulcerative Eruptions with Ulcers and/or Eschars Scrub typhus, rickettsial spotted fevers, ratbite fever, African trypanosomiasisf; rickettsialpox, ecthyma gangrenosumg — — — — —h Tularemia (Fig. A1-45,

Fig. A1-46) Francisella tularensis Ulceroglandular form: erythematous, tender papule evolves into necrotic, tender ulcer with raised borders; in 35% of cases, eruptions (maculopapular, vesiculopapular, acneiform, or urticarial; erythema nodosum; or EM) may occur Anthrax (Fig. A1-52) Bacillus anthracis Pruritic papule enlarging and evolving into a 1- by 3-cm painless ulcer surrounded by vesicles and then developing a central eschar with edema; residual scar aSee “Purpuric Eruptions.” bSee “Confluent Desquamative Erythemas.” cSee “Peripheral Eruptions.” dRash is rare in human granulocytotropic ehrlichiosis or anaplasmosis (caused by Anaplasma phagocytophilum; most common in the upper midwestern and northeastern United States). eSee “Viral hemorrhagic fever” under “Purpuric Eruptions” for dengue hemorrhagic fever/dengue shock syndrome. fSee “Centrally Distributed Maculopapular Eruptions.” gSee “Vesiculobullous or Pustular Eruptions.” hSee etiology-specific chapters. Abbreviations: ARDS, acute respiratory distress syndrome; CNS, central nervous system; DIC, disseminated intravascular coagulation; G-CSF, granulocyte colonystimulating factor; HLA, human leukocyte antigen. Chapter 208) may exhibit pharyngitis, lymphadenopathy, and a non­ specific maculopapular exanthem. The rash of erythema infectiosum (fifth disease), which is caused by human parvovirus B19, primarily affects children 3–12 years old; it develops after fever has resolved as a bright blanchable erythema on the cheeks (“slapped cheeks”) (Fig. A1-1A) with perioral pallor (Chap. 202). A more diffuse rash (often pruritic) appears the next day on the trunk and extremities and then rapidly develops into a lacy reticular eruption (Fig. A1-1B) that may wax and wane (especially with temperature change) over 3 weeks. Adults with fifth disease often have arthritis, and fetal hydrops can develop in association with this condi­ tion in pregnant women. Exanthem subitum (roseola) is caused by human herpesvirus 6, or less commonly by the closely related human herpesvirus 7, and is most common among children <3 years of age (Chap. 200). As in erythema infectiosum, the rash usually appears after fever has subsided. It con­ sists of 2- to 3-mm rose-pink macules and papules that coalesce only rarely, occur initially on the trunk (Fig. A1-5) and sometimes on the extremities (sparing the face), and fade within 2 days. Although drug reactions have many manifestations, including urti­ caria, exanthematous drug-induced eruptions (Chap. 63) (Fig. A1-7) are most common and are often difficult to distinguish from viral

GROUP AFFECTED/ EPIDEMIOLOGIC FACTORS CLINICAL SYNDROME CHAPTER Fever (not always present), microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, neurologic dysfunction; coagulation studies normal 61, 105, 120, 166, 172 Fever and Rash CHAPTER 21 Occurs in a wide spectrum of diseases, including connective tissue disease, cryoglobulinemia, malignancy, HenochSchönlein purpura (HSP); more common among children Fever (not always present), malaise, arthralgias, myalgias; systemic vasculitis in some cases; renal, joint, and gastrointestinal involvement common in HSP

Exposure to ticks, biting flies, infected animals Fever, headache, lymphadenopathy

Exposure to infected animals or animal products, other exposure to anthrax spores Lymphadenopathy, headache S4 exanthems. Eruptions elicited by drugs are usually more intensely erythematous and pruritic than viral exanthems, but this distinction is not reliable. A history of new medications and an absence of prostra­ tion may help to distinguish a drug-related rash from an eruption of another etiology. Rashes may persist for up to 2 weeks after admin­ istration of the offending agent is discontinued. Certain populations are more prone than others to drug rashes. Of people living with HIV, 50–60% develop a rash in response to sulfa drugs. Rickettsial illnesses (Chap. 192) should be considered in the evalua­ tion of individuals with centrally distributed maculopapular eruptions. The usual setting for epidemic typhus is a site of war or natural disaster in which people are exposed to body lice. Endemic typhus or leptospirosis (the latter caused by a spirochete) (Chap. 189) may be seen in urban environments where rodents proliferate. Outside the United States, other rickettsial diseases cause a spotted-fever syndrome and should be consid­ ered in residents of or travelers to endemic areas. Similarly, typhoid fever, a nonrickettsial disease caused by Salmonella typhi (Chap. 171) (Fig. A1-9), is usually acquired during travel outside the United States. Dengue fever (Fig. A1-53), caused by a mosquito-transmitted flavivirus, occurs in tropical and subtropical regions of the world (Chap. 215). Some centrally distributed maculopapular eruptions have distinc­ tive features. Erythema migrans (Fig. A1-8), the rash of Lyme disease

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 21-1  Centrally distributed, maculopapular eruption on the trunk in a patient with measles. (From EJ Mayeaux Jr et al: Measles, in Usatine RP et al [eds]: Color Atlas and Synopsis of Family Medicine, 3rd ed. New York, McGraw-Hill, 2019, p. 797, Figure 132-2. Reproduced with permission from Richard P. Usatine, MD.) (Chap. 191), typically manifests as single or multiple annular lesions. Untreated erythema migrans lesions usually fade within a month but may persist for more than a year. Southern tick-associated rash illness (STARI) (Chap. 191) has an erythema migrans–like rash but is less severe than Lyme disease and often occurs in regions where Lyme is not endemic. Erythema marginatum, the rash of acute rheumatic fever (Chap. 371), has a distinctive pattern of enlarging and shifting tran­ sient annular lesions. Collagen vascular diseases may cause fever and rash. Patients with systemic lupus erythematosus (Chap. 368) typically develop a sharply defined, erythematous eruption in a butterfly distribution on the cheeks (malar rash) (Fig. A1-10) as well as many other skin manifes­ tations (Figs. A1-11, A1-12). Still’s disease presents as an evanescent, salmon-colored rash on the trunk and proximal extremities that coin­ cides with fever spikes (Fig. A1-13). Hemophagocytic lymphohistiocytosis may be familial or triggered by infection, autoimmunity, or neoplasia. Cutaneous manifestations are protean and can present as an erythematous maculopapular erup­ tion, pyoderma gangrenosum, purpura, panniculitis, or Stevens-Johnson syndrome. Zika virus is a mosquito-transmitted flavivirus that is associated with severe birth defects (Chap. 215). Zika is widespread among tropi­ cal and subtropical regions of the world. The eruption of Zika virus infection (Fig. A1-51A, A1-51B) is typically pruritic and often accom­ panied by conjunctival injection (Fig. A1-51C). ■ ■PERIPHERAL ERUPTIONS These rashes are alike in that they are most prominent peripherally or begin in peripheral (acral) areas before spreading centripetally. Early diagnosis and therapy are critical in Rocky Mountain spotted fever (Chap. 192) because of its grave prognosis if untreated. Lesions (Fig. 21-2; see also Fig. A1-16) evolve from macular to petechial, start on the wrists and ankles, spread centripetally, and appear on the palms and soles only later in the disease. The rash of secondary syphilis (Chap. 187), which may be generalized (Fig. A1-18) but is prominent on the palms and soles (Fig. A1-19), should be considered in the differ­ ential diagnosis of pityriasis rosea, especially in sexually active patients.

FIGURE 21-2  Peripheral eruption on the wrist and palm exhibiting erythematous macules in the process of evolving into petechial lesions in a patient with Rocky Mountain spotted fever. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 562, Figure 25-50; with permission.) Chikungunya fever (Chap. 215), which is transmitted by mosquito bite in tropical and subtropical regions, is associated with a maculopapular eruption (Fig. A1-54) and severe polyarticular small-joint arthralgias. Hand-foot-and-mouth disease (Chap. 210), most commonly caused by coxsackievirus A16 or enterovirus 71, is distinguished by tender vesicles distributed on the hands and feet and in the mouth (Fig. A1-22); coxsackievirus A6 causes an atypical syndrome with more extensive lesions. The classic target lesions of erythema multiforme (Fig. A1-24A) appear symmetrically on the elbows, knees, palms, soles, and face. In severe cases, these lesions spread diffusely and involve mucosal surfaces (Fig. A1-24B, C). Lesions may develop on the hands and feet in endocarditis (Fig. A1-23) (Chap. 133). Pernio, tender violaceous lesions that are acral (Fig. A1-57), occur most commonly on the feet in asymptomatic or mild COVID-19. Vesicles, urticaria, or maculopapu­ lar eruptions, often pruritic, may occur on the trunk and extremities in moderate or severe disease, whereas retiform purpura occurs on the extremities and buttocks in severe COVID-19. ■ ■CONFLUENT DESQUAMATIVE ERYTHEMAS These eruptions consist of diffuse erythema frequently followed by desquamation. The eruptions caused by group A Streptococcus or Staphylococcus aureus are toxin-mediated. Scarlet fever (Chap. 153) (Fig. A1-25) usually follows pharyngitis; patients have a facial flush, a “strawberry” tongue, and accentuated petechiae in body folds (Pastia’s lines). Kawasaki disease (Fig. A1-29) (Chaps. 61 and 375) presents in the pediatric population as fissuring of the lips, a strawberry tongue, conjunctivitis, adenopathy, and sometimes cardiac abnormalities. Streptococcal toxic shock syndrome (Chap. 153) manifests with hypo­ tension, multiorgan failure, and, often, a severe group A streptococ­ cal infection (e.g., necrotizing fasciitis). Staphylococcal toxic shock syndrome (Chap. 152) also presents with hypotension and multiorgan failure, but usually only S. aureus colonization—not a severe S. aureus infection—is documented. Staphylococcal scalded-skin syndrome (Fig. A1-28) (Chap. 152) is seen primarily in children and in immu­ nocompromised adults. Generalized erythema is often evident during the prodrome of fever and malaise; profound tenderness of the skin is distinctive. In the exfoliative stage, the skin can be induced to form bul­ lae with light lateral pressure (Nikolsky’s sign) (Fig. A1-28B). In a mild form, a scarlatiniform eruption mimics scarlet fever, but the patient

FIGURE 21-3  Confluent desquamation in a patient with toxic epidermal necrolysis. (From KS-M Kane et al: Color Atlas & Synopsis of Pediatric Dermatology, 3rd ed. New York, McGraw Hill, 2017, Figure 15-6; with permission.) does not exhibit a strawberry tongue or circumoral pallor. In contrast to the staphylococcal scalded-skin syndrome, in which the cleavage plane is superficial in the epidermis, toxic epidermal necrolysis (Chap. 63), a maximal variant of Stevens-Johnson syndrome, involves sloughing of the entire epidermis (Fig. 21-3, see also Fig. A1-26), resulting in severe disease. Exfoliative erythroderma syndrome (Chaps. 61 and 63) is a serious reaction associated with systemic toxicity that is often due to eczema, psoriasis (Fig. A1-27), a drug reaction, or mycosis fungoides. Drug reaction with eosinophilia and systemic symptoms (DRESS) (also termed drug-induced hypersensitivity syndrome [DIHS]), often due to antiepileptic or antibiotic agents (Chap. 63), initially appears similar to an exanthematous drug reaction (Fig. A1-48) but may progress to exfoliative erythroderma; it is accompanied by multiorgan failure and has an associated mortality rate of ~10%. ■ ■VESICULOBULLOUS OR PUSTULAR ERUPTIONS Varicella (Chap. 198) is highly contagious, often occurring in winter or spring, and is characterized by pruritic lesions that, within a given region of the body, are in different stages of development at any point in time (Fig. 21-4; see also Fig. A1-30). In immunocompromised FIGURE 21-4  Vesicular and pustular lesions on the chest in a patient with varicella. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 695, Figure 27-48; with permission.)

hosts, varicella vesicles may lack the characteristic erythematous base or may appear hemorrhagic. Lesions of Pseudomonas “hot-tub” folliculi­ tis (Chap. 170) are also pruritic and may appear similar to those of varicella (Fig. A1-55). However, hot-tub folliculitis generally occurs in outbreaks after bathing in hot tubs or swimming pools, and lesions occur in regions occluded by bathing suits. Lesions of variola (smallpox) (Chap. S4) also appear similar to those of varicella but are all at the same stage of development in a given region of the body (Figs. A1-50B and A1-50C). Variola lesions are most prominent on the face (Fig. A1-50A) and extremities, while varicella lesions are most promi­ nent on the trunk. Mpox, endemic to Africa, can present similarly to variola, although with lower mortality. A 2022 Mpox outbreak in nonendemic nations was characterized by presence of fewer lesions (Fig. A1-59) and milder disease. Herpes simplex virus infection (Chap. 197) is characterized by hallmark grouped vesicles on an erythematous base. Primary herpes infection (Fig. A1-58A, B) is accompanied by fever and toxicity, while recurrent disease (Fig. A1-58C) is milder. Rickettsialpox (Chap. 192) is often documented in urban settings and is characterized by vesicles followed by pustules (Figs. A1-33B, A1-33C). It can be distinguished from varicella by an eschar at the site of the mouse-mite bite (Fig. A1-33A) and the papule/plaque base of each vesicle. Acute generalized exanthematous pustulosis (Fig. A1-49) should be considered in individuals who are acutely febrile and are taking new medications, especially anticonvulsant or antimicrobial agents (Chap. 63). Disseminated Vibrio vulnificus infection (Chap. 173) or ecthyma gangrenosum due to Pseudomonas aeruginosa (Fig. A1-34) (Chap. 170) should be considered in immunosuppressed individuals with sepsis and hemorrhagic bullae. In children, reactive infectious mucocutaneous eruption (RIME, encompasses MIRM) can occur with Mycoplasma pneumoniae or other respiratory pathogen infection

(Fig. A1-56) and is characterized by a sparse, often vesiculobullous eruption with prominent oral, ocular, or urogenital mucositis.

Fever and Rash CHAPTER 21 ■ ■URTICARIA-LIKE ERUPTIONS Individuals with classic urticaria (“hives”) (Fig. 21-5; see also Fig. A1-35) usually have a hypersensitivity reaction without associated fever. In the presence of fever, urticaria-like eruptions are most often due to urticarial vasculitis (Chap. 375). Unlike individual lesions of classic urticaria, which last up to 24 h, these lesions may last 3–5 days. Etiologies include serum sickness (often induced by drugs such as penicillins, sulfas, salicylates, or FIGURE 21-5  Urticarial eruption. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 299, Figure 14-2; with permission.)

barbiturates), connective-tissue disease (e.g., systemic lupus erythema­ tosus or Sjögren’s syndrome), and infection (e.g., with hepatitis B virus, enteroviruses, or parasites). Malignancy, especially lymphoma, may be associated with fever and chronic urticaria (Chap. 61).

■ ■NODULAR ERUPTIONS In immunocompromised hosts, nodular lesions often represent dis­ seminated infection. Patients with disseminated candidiasis (Fig. A1-37) (often due to Candida tropicalis) may have a triad of fever, myalgias, and eruptive nodules (Chap. 222). Disseminated cryptococcosis lesions (Fig. 21-6; see also Fig. A1-36) (Chap. 221) may resemble molluscum contagiosum (Chap. 201). Necrosis of nodules should raise the sus­ picion of aspergillosis (Fig. A1-38) (Chap. 223) or mucormycosis (Chap. 224). Erythema nodosum presents with exquisitely tender nodules on the lower extremities (Fig. A1-39). Sweet syndrome (Chap. 61) should be considered in individuals with multiple nod­ ules and plaques, often so edematous (Fig. A1-40) that they give the appearance of vesicles or bullae. Sweet syndrome may occur in indi­ viduals with infection, inflammatory bowel disease, or malignancy and can also be induced by drugs. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■PURPURIC ERUPTIONS Acute meningococcemia (Chap. 160) classically presents in children as a petechial eruption, but initial lesions may appear as blanchable mac­ ules or urticaria. Rocky Mountain spotted fever should be considered in the differential diagnosis of acute meningococcemia. Echovirus 9 infection (Chap. 210) may mimic acute meningococcemia; patients should be treated as if they have bacterial sepsis because prompt dif­ ferentiation of these conditions may be impossible. Large ecchymotic areas of purpura fulminans (Fig. A1-41) (Chaps. 160 and 315) reflect severe underlying disseminated intravascular coagulation, which may be due to infectious or noninfectious causes. The lesions of chronic meningococcemia (Fig. A1-42) (Chap. 160) may have a variety of morphologies, including petechial. Purpuric nodules may develop on the legs and resemble erythema nodosum but lack its exquisite tender­ ness. Lesions of disseminated gonococcemia (Chap. 161) are distinctive, sparse, countable hemorrhagic pustules (Fig. A1-43), usually located near joints. The lesions of chronic meningococcemia and those of gonococcemia may be indistinguishable in terms of appearance and FIGURE 21-6  Nodular eruption on the face due to disseminated Cryptococcus in a patient living with HIV. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 641, Figure 26-57. Used with permission from Loïc Vallant, MD.)

FIGURE 21-7  Purpuric lesions of cutaneous small vessel vasculitis in a patient with Henoch-Schonlein purpura. (Courtesy of Peter Lio, MD; with permission) distribution. Viral hemorrhagic fever (Chaps. 215 and 216) should be considered in patients with an appropriate travel history and a pete­ chial rash. Thrombotic thrombocytopenic purpura (Chaps. 61, 105, and 120) and hemolytic-uremic syndrome (Chaps. 120, 166, and 172) are closely related and are noninfectious causes of fever and petechiae. Cutaneous small-vessel vasculitis (leukocytoclastic vasculitis) typically manifests as palpable purpura (Fig. 21-7, see also Fig. A1-44) and has a wide variety of causes (Chap. 61). ■ ■ERUPTIONS WITH ULCERS OR ESCHARS The presence of an ulcer or eschar (Fig. 21-8) in the setting of a more widespread eruption can provide an important diagnostic clue. For FIGURE 21-8  Eschar with surrounding erythema at the site of a tick bite in a patient with African tick-bite fever. (From K Wolff et al [eds]: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017, p. 561, Figure 25-49; with permission.)

11 - 22 Fever of Unknown Origin

22 Fever of Unknown Origin

example, an eschar may suggest the diagnosis of scrub typhus or rickett­ sialpox (Fig. A1-33A) (Chap. 192) in the appropriate setting. In other illnesses (e.g., anthrax) (Fig. A1-52) (Chap. S4), an ulcer or eschar may be the only skin manifestation. ■ ■FURTHER READING Cherry JD: Cutaneous manifestations of systemic infections, in Feigin and Cherry’s Textbook of Pediatric Infectious Diseases, 8th ed. JD Cherry et al (eds). Philadelphia, Elsevier, 2019, pp 539–559. Juliano JJ et al: The acutely ill patient with fever and rash, in Mandell, Douglas, and Bennett’s Principles and Practice of Infectious Diseases, vol 1, 10th ed. MJ Blaser et al (eds). Philadelphia, Elsevier, 2025. Kang S et al (eds): Fitzpatrick’s Dermatology, 9th ed. New York, McGraw-Hill, 2019. Saavedra AP et al: Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 9th ed. New York, McGraw Hill, 2023. Catharina M. Mulders-Manders,

Chantal P. Rovers

Fever of Unknown Origin ■ ■DEFINITION Clinicians commonly refer to any febrile illness without an initially obvious etiology as fever of unknown origin (FUO). Most febrile ill­ nesses either resolve before a diagnosis can be made or develop distin­ guishing characteristics that lead to a diagnosis. The term FUO should be reserved for prolonged febrile illnesses without an established etiol­ ogy despite intensive evaluation and diagnostic testing. This chapter focuses on FUO in the adult patient. FUO was originally defined by Petersdorf and Beeson in 1961 as an illness of at least 3 weeks’ duration with fever of ≥38.3°C (≥101°F) on two occasions and an uncertain diagnosis despite 1 week of inpatient evaluation. Since then, several modifications of the definition have been proposed to better reflect outpatient-based health care and to exclude immunocompromised patients, who require a different and more aggressive approach. To reduce heterogeneity between cohorts, inclusion of qualitative criteria of minimal diagnostic testing are neces­ sary. Accordingly, FUO is now defined as:

1. Fever ≥38.3°C (≥101°F) on at least two occasions
2. Illness duration of at least 3 weeks
3. No known immunocompromised state TABLE 22-1  Etiology of FUO: Pooled Results of Large Studies Published in the Past 20 Years (2003–2023) NO. OF COHORTS (INCLUSION PERIOD) NO. OF PATIENTS INFECTIONS, MEDIAN % (RANGE) GEOGRAPHIC AREA Western Europe

(1995–2020)

15.5 (4–36) Other European and Turkey

(1984–2019)

(26–74) Middle East

(2009–2010)a

(42–79) Asia

(1994–2021)a

(3–58) Note: No studies from the Americas, Africa, or Oceania have been reported. Studies aimed at diagnostic methods were excluded. aSome studies did not report an inclusion period. For references, see supplementary material at accessmedicine.com/harrisons.

4. Diagnosis that remains uncertain after a thorough history-taking,

physical examination, and the following obligatory investigations: determination of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) level; platelet count; leukocyte count and differential; measurement of levels of hemoglobin, electrolytes, creatinine, total protein, alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, creatine kinase, ferritin, antinuclear antibodies, and rheumatoid factor; protein electropho­ resis; urinalysis; blood cultures (n = 3); urine culture; chest x-ray; abdominal ultrasonography; and tuberculin skin test (TST) or inter­ feron γ release assay (IGRA) Fever of Unknown Origin CHAPTER 22 Closely related to FUO is inflammation of unknown origin (IUO), which has the same definition as FUO, except for the body tempera­ ture criterion: IUO is defined as the presence of elevated inflamma­ tory parameters (CRP or ESR) on multiple occasions for a period of at least 3 weeks in an immunocompetent patient with normal body temperature, for which a final explanation is lacking despite historytaking, physical examination, and the obligatory tests listed above. It has been shown in multiple cohorts that the causes for IUO and FUO are the same and that their workup should be identical. Therefore, for convenience, the term FUO will refer to both FUO and IUO within the remainder of this chapter. ■ ■ETIOLOGY AND EPIDEMIOLOGY The prevalence of FUO is largely unknown and will likely vary between different geographic regions and different health care settings. In the 1990s, Japan reported a prevalence of 2.9% in admitted patients, and a recent Danish registry study reported 6220 patients in a 10-year time frame. Table 22-1 summarizes the findings of large studies on FUO conducted over the past 20 years. Since the 1960s, the range of FUO etiologies has evolved as a result of changes in the definition, local disease epidemiology, the wide­ spread use of antibiotics, and especially the availability of new diag­ nostic techniques. The proportion of cases caused by intraabdominal abscesses and tumors, for example, has decreased because of earlier detection by CT and ultrasound. In addition, infective endocarditis is a less frequent cause because blood culture and echocardiographic techniques have improved. Conversely, some diagnoses, such as acute HIV infection or autoinflammatory diseases, were unknown six decades ago. Data on the outcome of FUO are difficult to compare between studies because of variability in patient selection and variability in workup between cohorts. Study outcome strongly depends on study design and the origin of the cohort. The chance of a final diagnosis is higher when (older) time-based criteria are used versus when (newer) criteria including a standard basic workup are used for patient selec­ tion. The chance of remaining without a final diagnosis is two to five times higher in patients from Europe compared to patients from Asia. NONINFECTIOUS INFLAMMATORY DISEASES, MEDIAN % (RANGE) NO DIAGNOSIS, MEDIAN % (RANGE) MALIGNANCY, MEDIAN % (RANGE) MISCELLANEOUS, MEDIAN % (RANGE)

(17–33)

(3–30) 7.5 (0–16) 39.5 (26–54)

(12–38)

(4–19)

(2–18)

(0–35)

(7–17)

(1–30)

(0–12)

(2–12)

(7–57)

(6–23) 6.5 (0–15)

(0–81)

Roughly comparable to 60 years ago, infections remain the most common cause of FUO in non-Western cohorts. Compared to Europe, the risk of having an infection is over four times higher in patients from Southern Asia and three times higher in far East Asia. Up to half of all infections in patients with FUO outside Western nations are caused by Mycobacterium tuberculosis, which is a less common cause in Western Europe and probably also in the United States. Recent data on FUO from the latter, however, have not been reported. In Western cohorts, noninfectious inflammatory diseases (NIIDs), including autoimmune, autoinflammatory, and granulomatous diseases, as well as vasculitides, form the most common cause of FUO. Up to one-third of Western patients with FUO have a diagnosis that falls within the category of NIIDs. The number of FUO patients diagnosed with NIIDs probably will not decrease in the near future, as inflammation may precede more typical manifestations or laboratory evidence of these diseases by months. Moreover, NIIDs may only be diagnosed after prolonged observation and exclusion of other diseases, and an increasing num­ ber of genetic inflammatory syndromes have been described in more recent years.

PART 2 Cardinal Manifestations and Presentation of Diseases Especially in Western cohorts, where the proportion of undiagnosed patients can be up to >50%, the proportion of patients remaining without a final diagnosis is much higher than 60 years ago despite technical advantages. This is called “the FUO paradox” and can be explained by the fact that in patients with fever, a diagnosis is often established before 3 weeks have elapsed because these patients tend to seek medical advice earlier and because diagnostic techniques such as CT, MRI, and positron emission tomography (PET)/CT, are now widely available. Therefore, only the cases that are most difficult to diagnose continue to meet the criteria for FUO. Furthermore, most patients who have FUO without a diagnosis currently do well. A less aggressive diagnostic approach may be used in clinically stable patients once diseases with immediate therapeutic or prognostic consequences have been ruled out. No clinical parameters or tools that can help identify patients with a high risk of remaining undiagnosed have been identified. Recurrent inflammation (defined as repeated episodes of fever or inflammation interspersed with fever-free intervals of at least 2 weeks and apparent remission of the underlying disease) reduces the chance of finding a final explanation and is associated with a lower, but not zero, preva­ lence of infections. A symptom duration of >12 months is significantly associated with a lower chance of finding a final explanation, and infec­ tions and malignancy are less common, but still a possibility, in patients with such extensive symptom duration. It is important to note that even in patients with symptom duration >3 months, more common infections such as tuberculosis, spondylodiscitis, and endocarditis have been described and that lymphoma has been reported in patients with symptom duration >12 months. Normal PET/CT has also been associ­ ated with a lower chance of a final diagnosis. Artificial intelligence, using computer models to predict the final diagnosis in patients with FUO, may be able to shorten diagnostic delay and may guide specific diagnostic testing, but only limited data are available. Its exact value on a larger scale, especially in different geographic regions, is difficult to estimate at this moment. ■ ■DIFFERENTIAL DIAGNOSIS The differential diagnosis for FUO is extensive. It is important to note that patients with FUO most often suffer from an atypical presentation of a more common disease, rather than from a rare disease. Unsurpris­ ingly, the distribution of causes of FUO is influenced by local epide­ miology. Table 22-2 presents an overview of possible causes of FUO. Endocarditis, diverticulitis, vertebral osteomyelitis, and extrapulmo­ nary tuberculosis are the more common infectious disease diagnoses. Q fever (Coxiella burnetii) and Whipple’s disease (Tropheryma whipplei infection) are quite rare but should always be kept in mind as causes of FUO since the presenting symptoms can be nonspecific. Serologic test­ ing for Q fever, which results from exposure to animals or animal prod­ ucts, should be performed by immunofluorescence assay (IFA) when the patient lives in a rural area or has a history of heart valve disease, an

aortic aneurysm, or a vascular prosthesis. In patients with unexplained symptoms localized to the central nervous system, gastrointestinal tract, or joints, polymerase chain reaction testing for T. whipplei should be performed on stool and blood early in the diagnostic process. Travel to or (former) residence in tropical countries or the American Southwest should lead to consideration of endemic infectious diseases such as malaria, leishmaniasis, histoplasmosis, or coccidioidomycosis. Fever with signs of endocarditis and negative blood culture results poses a special problem. Culture-negative endocarditis (Chap. 133) may be due to difficult-to-culture bacteria such as nutritionally vari­ ant bacteria, HACEK organisms (including Haemophilus parainflu­ enzae, H. paraphrophilus, Aggregatibacter actinomycetemcomitans, A. aphrophilus, A. paraphrophilus, Cardiobacterium hominis, C. valvarum, Eikenella corrodens, and Kingella kingae), Coxiella burnetii, T. whipplei, and Bartonella species. Marantic endocarditis is a sterile thrombotic disease that occurs as a paraneoplastic phenomenon, especially with adenocarcinomas. Sterile endocarditis is also seen in the context of sys­ temic lupus erythematosus and antiphospholipid syndrome. The use of next-generation sequencing for rapid detection of infecting microbes may be valuable in patients with FUO, but its exact value and exact application are yet to be determined. Of the NIIDs, adult-onset Still’s disease, large-vessel vasculitis, polymyalgia rheumatica, systemic lupus erythematosus (SLE), and sarcoidosis are rather common diagnoses in patients with FUO. Autoinflammatory syndromes are rare (with the exception of familial Mediterranean fever in specific geographic regions), and most can only be diagnosed on clinical criteria. Schnitzler’s syndrome, which can present at any age, can often be diagnosed easily in a patient with FUO who presents with urticaria, bone pain, and monoclonal gammopa­ thy. A new autoinflammatory syndrome called vacuoles, E1 enzyme, X-linked autoinflammatory syndrome (VEXAS) has been described in

300 patients since 2020. VEXAS is an adult-onset multisystem auto­ inflammatory syndrome with predominance in middle-aged to elderly males and is characterized, among others, by recurrent inflammation, skin lesions, chondritis, lung disease, venous thrombosis, arthritis, and myelodysplastic syndrome. The presence of vacuoles in myeloid precursors in bone marrow biopsy is very suspicious for VEXAS in a patient with inflammatory symptoms. The disease is caused by somatic mosaicism for pathogenic variants in UBA1. Although most malignancies can present with fever, malignant lymphoma is by far the most common diagnosis of FUO among the neoplasms. Sometimes the fever even precedes lymphadenopathy detectable by physical examination. Apart from drug-induced fever and exercise-induced or benign hyperthermia, none of the miscellaneous causes of fever is found very frequently in patients with FUO. Virtually all drugs can cause fever, even after long-term use. Drug-induced fever, including DRESS (drug reaction with eosinophilia and systemic symptoms; now more generally referred to as drug-induced hypersensitivity syndrome [DIHS]; Fig. A1-48), is often accompanied by eosinophilia and also by lymphadenopathy, which can be extensive. More common causes of drug-induced fever are allopurinol, carbamazepine, lamotrigine, phenytoin, sulfasalazine, furosemide, and antimicrobial drugs (espe­ cially sulfonamides, minocycline, vancomycin, β-lactam antibiotics, and isoniazid). Benign hyperthermia or exercise-induced hyperthermia (Chaps. 20 and 478) is characterized by an elevated body tempera­ ture without an increase in CRP or ESR or other signs of inflamma­ tion; these may be postinfectious in origin. Infectious triggers for benign hyperthermia are possibly the same as for chronic fatigue syndrome, such as Epstein-Barr virus, Q-fever, and COVID-19. Factitious fever (fever artificially induced by the patient—for exam­ ple, by IV injection of contaminated water) should be considered in all patients, especially those with easy access to medical equipment. In fraudulent fever, the patient is normothermic but manipulates the thermometer. Simultaneous measurements at different body sites (rectum, ear, mouth) should rapidly identify this diagnosis. Another clue to fraudulent fever is dissociation between pulse rate and temperature.

Fever of Unknown Origin CHAPTER 22 TABLE 22-2  Reported Causes of Fever of Unknown Origin (FUO)a Infections Bacterial, nonspecific Abdominal abscess, adnexitis, aortitis, apical granuloma, appendicitis, bacterial translocation, bronchiectasis, cholangitis, cholecystitis, diverticulitis, endocarditis, endometritis, epididymitis, epidural abscess, infected joint prosthesis, infected vascular catheter, infected vascular prosthesis, infectious arthritis, infective myonecrosis, intracranial abscess, liver abscess, lung abscess, malakoplakia, mastitis, mastoiditis, mediastinitis, muscle abscess, mycotic aneurysm, osteomyelitis, pelvic inflammatory disease, prostatitis, pyelonephritis, pylephlebitis, pyomyoma, renal abscess, septic arthritis, septic phlebitis, sinusitis, spondylodiscitis, xanthogranulomatous urinary tract infection Bacterial, specific Actinomycosis, Bacteroides, bartonellosis, brucellosis, Bacillus Calmette-Guérin infection, Burkholderia spp., Campylobacter infection, Chlamydia pneumoniae infection, chronic meningococcemia, ehrlichiosis, enterococci, Escherichia coli, Gemella infection, gonococcus, Klebsiella spp., Lactobacillus, legionellosis, leptospirosis, listeriosis, louse-borne relapsing fever (Borrelia recurrentis), Lyme disease (Borrelia burgdorferi), melioidosis (Burkholderia pseudomallei), Mycoplasma infection, nocardiosis, nontuberculous mycobacteria, Prevotella infection, Pseudomonas spp., psittacosis, Q fever (Coxiella burnetii), rickettsiosis, Rhodococcus spp., Salmonella spp., Spirillum minor infection, Sphingobacterium infection, Staphylococcus aureus, Streptobacillus moniliformis infection, syphilis, tick-borne relapsing fever (Borrelia duttonii, Borrelia hermsi), tuberculosis, tularemia, typhoid fever and other salmonelloses, Whipple disease (Tropheryma whipplei), yersiniosis Fungal Aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, cryptococcosis, histoplasmosis, Malassezia furfur infection, mucormycosis, paracoccidioidomycosis, Penicillium spp., Pneumocystis jirovecii pneumonia, sporotrichosis, Talaromyces infection Parasitic Amebiasis, babesiosis, echinococcosis, fascioliasis, malaria, schistosomiasis, strongyloidiasis, toxocariasis, toxoplasmosis, trichinellosis, trypanosomiasis, visceral leishmaniasis Viral Colorado tick fever, coxsackievirus infection, cytomegalovirus infection, chikungunya, dengue, Epstein-Barr virus infection, hantavirus infection, hepatitis (A, B, C, D, E), herpes simplex, HIV infection, human herpesvirus 6 infection, parvovirus infection, West Nile virus infection Noninfectious Inflammatory Diseases Systemic rheumatic and autoimmune diseases Ankylosing spondylitis, antiphospholipid syndrome, autoimmune hemolytic anemia, autoimmune hepatitis, Behçet’s disease, cryoglobulinemia, dermatomyositis, Felty syndrome, gout, mixed connective tissue disease, neuromyelitis optica, polymyositis, pseudogout, reactive arthritis, psoriatic arthritis, relapsing polychondritis, rheumatic fever, rheumatoid arthritis, Sjögren’s syndrome, systemic lupus erythematosus, systemic sclerosis, Vogt-Koyanagi-Harada syndrome Vasculitis Allergic vasculitis, antineutrophil cytoplastic antibody (ANCA) vasculitis, Cogan’s syndrome, eosinophilic granulomatosis with polyangiitis, giant cell vasculitis/polymyalgia rheumatica, granulomatosis with polyangiitis, hypersensitivity vasculitis, IgA vasculitis, Kawasaki disease, polyarteritis nodosa, Takayasu arteritis, urticarial vasculitis Granulomatous diseases Idiopathic granulomatous hepatitis, sarcoidosis Autoinflammatory syndromes Blau syndrome, CAPSb (cryopyrin-associated periodic syndromes), Crohn’s disease, DIRA (deficiency of the interleukin 1 receptor antagonist), deficiency of adenosine deaminase 2 (DADA2), familial Mediterranean fever, hyper-IgD syndrome (HIDS, due to mevalonate kinase deficiency), juvenile idiopathic arthritis, macrophage activation syndrome, NLRP12-related disease, PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne), PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis, adenitis), recurrent idiopathic pericarditis, SAPHO (synovitis, acne, pustulosis, hyperostosis, osteomyelitis), Schnitzler’s syndrome, Still’s disease, TRAPS (tumor necrosis factor receptor– associated periodic syndrome), VEXAS (vacuoles, E1 enzyme, X-linked autoinflammatory syndrome) Neoplasms Hematologic malignancies Amyloidosis, angioimmunoblastic lymphoma, Castleman’s disease, hemophagocytic syndrome (hemophagocytic lymphohistiocytosis), Hodgkin’s disease, hypereosinophilic syndrome, leukemia, lymphomatoid granulomatosis, malignant histiocytosis, multiple myeloma, myelodysplastic syndrome, myelofibrosis, non-Hodgkin’s lymphoma, plasmacytoma, systemic mastocytosis, vaso-occlusive crisis in sickle cell disease Solid tumors Most solid tumors and metastases can cause fever. Those most common causing FUO are breast, colon, hepatocellular, lung, pancreatic, and renal cell carcinomas. Benign tumors Angiomyolipoma, cavernous hemangioma of the liver, craniopharyngioma, necrosis of dermoid tumor in Gardner’s syndrome, tumoral calcinosis Miscellaneous Causes   ADEM (acute disseminated encephalomyelitis), adrenal insufficiency, alcoholic steatohepatitis, allergic purpura, aneurysms, anal fistula, antiNMDA encephalitis, antisynthetase syndrome, anomalous thoracic duct, aortic dissection, aortic-enteral fistula, aseptic meningitis (Mollaret’s syndrome), atrial myxoma, brewer’s yeast ingestion, calcium pyrophosphate deposition, Caroli’s disease, cholesterol emboli, cirrhosis, complex partial status epilepticus, crowned dense syndrome, cyclic neutropenia, cryptogenic organizing pneumonia, drug fever, Erdheim-Chester disease, extrinsic allergic alveolitis, Fabry’s disease, factitious disease, fire-eater’s lung, fraudulent fever, Dressler’s syndrome, ganglioneuroma, extrinsic allergic alveolitis, Gaucher’s disease, hemolytic uremic syndrome, Hamman-Rich syndrome (acute interstitial pneumonia), Hashimoto’s encephalopathy, hematoma, heparin-induced thrombocytopenia, histiocytic necrotizing lymphadenitis, hypersensitivity pneumonitis, hypertriglyceridemia, hypogammaglobulinemia/subclass deficiency, hypothalamic hypopituitarism, idiopathic inflammatory myopathy, idiopathic normal-pressure hydrocephalus, IgG4 disease, inflammatory pseudotumor, interstitial nephritis, Kikuchi’s disease, limbic encephalitis, linear IgA dermatosis, mesenteric fibromatosis, metal fume fever, microaspiration, milk protein allergy, Mollaret’s meningitis, myotonic dystrophy, nonbacterial osteitis, obstructive suppurative pancreatic ductitis, organic dust toxic syndrome, panniculitis, POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes), obstructive sleep apnea syndrome, organizing pneumonia, polymer fume fever, post–cardiac injury syndrome, primary biliary cirrhosis, primary hyperparathyroidism, pseudomembranous colitis, pulmonary embolism, pulmonary nodular lymphoid hyperplasia, pyoderma gangrenosum, recurrent large bowel ischemia, retroperitoneal fibrosis, Rosai-Dorfman disease, sclerosing mesenteritis, silicone embolization, subacute thyroiditis (de Quervain’s), Sweet’s syndrome (acute febrile neutrophilic dermatosis), thrombosis, TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly) tubulointerstitial nephritis and uveitis syndrome (TINU), ulcerative colitis, XIAP deficiency (X-linked inhibitor of apoptosis deficiency) Thermoregulatory Disorders Central Brain tumor, cerebrovascular accident, encephalitis, hypothalamic dysfunction Peripheral Anhidrotic ectodermal dysplasia, benign hyperthermia, exercise-induced hyperthermia, heat stroke, hyperthyroidism, paroxysmal sympathetic hyperactivity, pheochromocytoma aThis table includes causes of FUO that have been described in the literature. bCAPS includes chronic infantile neurologic cutaneous and articular syndrome (CINCA, also known as neonatal-onset multisystem inflammatory disease, or NOMID), familial cold autoinflammatory syndrome (FCAS), and Muckle-Wells syndrome.

Fever ≥38.3°C (101°F) AND illness ≥3 weeks AND no known immunocompromised state History and physical examination Stop antibiotic treatment and corticosteroids Obligatory investigations: CRP or ESR, hemoglobin, platelet count, leukocyte count and differentiation, electrolytes, creatinine, total protein, protein electrophoresis, alkaline phosphatase, AST, ALT, LDH, creatine kinase, antinuclear antibodies, rheumatoid factor, urinalysis, blood cultures (n = 3), urine culture, chest X-ray, abdominal ultrasonography, and tuberculin skin test or IGRA PART 2 Cardinal Manifestations and Presentation of Diseases Exclude manipulation with thermometer Exclude drug fever (stop or replace medication) PDCs present PDCs absent or misleading Guided diagnostic tests Diagnosis No diagnosis 18F-FDG-PET/CT* Abnormal Normal Confirmation of abnormality (e.g., biopsy, culture) Repeat history and physical examination PDC driven invasive testing Diagnosis No diagnosis Diagnosis No diagnosis Follow up for new PDCs Consider NSAID FIGURE 22-1  Structured approach to patients with FUO. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; 18F-FDG-PET/CT, 18F-fluorodeoxyglucose positron emission tomography combined with low-dose CT; IGRA, interferon γ release assay; LDH, lactate dehydrogenase; NSAID, nonsteroidal anti-inflammatory drug; PDCs, potentially diagnostic clues (all localizing signs, symptoms, and abnormalities potentially pointing toward a diagnosis). *If not available, gallium scintigraphy or labeled leukocyte scintigraphy is an acceptable alternative. APPROACH TO THE PATIENT A Structured Diagnostic Approach Figure 22-1 shows a structured approach to patients presenting with FUO. The most important step in the diagnostic workup is the search for potentially diagnostic clues (PDCs) through com­ plete and repeated history-taking and physical examination and the obligatory investigations listed above and in the figure. PDCs are defined as all localizing signs, symptoms, and abnormalities potentially pointing toward a diagnosis. Although PDCs are often misleading, only with their help can a concise list of probable diagnoses be made. The history should include information about the fever pattern (continuous or recurrent) and duration, previous

Cryoglobulin and fundoscopy Stable condition Deterioration Further diagnostic tests Consider therapeutic trial medical history, present and recent drug use, family history, sexual history, country of origin, recent and remote travel, environmental exposures associated with travel or hobbies, and animal contacts. A complete physical examination should be performed, with spe­ cial attention to the eyes, lymph nodes, temporal arteries, liver, spleen, sites of previous surgery, entire skin surface, and mucous membranes. Before further diagnostic tests are initiated, antibiotic and glucocorticoid treatment, which can mask many diseases, should be stopped. For example, sterile blood and other cultures are not completely reliable when samples are obtained during antibiotic treatment, and the size of enlarged lymph nodes usually decreases during glucocorticoid treatment, regardless of the cause of lymphadenopathy. Despite the high percentage of false-positive

ultrasounds and the relatively low sensitivity of chest x-rays, the performance of these simple, low-cost diagnostic tests remains obligatory in all patients with FUO in order to separate cases that are caused by easily diagnosed diseases from those that are not. Abdominal ultrasound and conventional chest radiography have been preferred to thoracic and abdominal CT as an obligatory test because of their relatively low cost, lower radiation burden, and absence of side effects. After identification of all PDCs retrieved from the history, physical examination, and obligatory tests, a limited list of the most probable diagnoses should be made. Since most investigations are helpful only for patients who have PDCs for the diagnoses sought, further diagnostic procedures should be limited to specific inves­ tigations aimed at confirming or excluding diseases on this list. In FUO, the diagnostic pointers are numerous and diverse but may be missed on initial examination, often being detected only by subse­ quent careful examinations. In the absence of PDCs, the history and physical examination should be repeated regularly. In patients with recurrent inflammation, the diagnostic workup is the same as for patients with continuous inflammation. Patients should be asked to return during a febrile episode so that the history, physical exami­ nation, and laboratory tests can be repeated during a symptomatic phase. Further diagnostic tests should be performed only during an inflammatory episode because abnormalities may be absent between episodes. One of the first steps should be to rule out benign hyperthermia or factitious or fraudulent fever, particularly in patients without signs of inflammation in laboratory tests. All medications, includ­ ing nonprescription drugs and nutritional supplements, should be discontinued early in the evaluation to exclude drug fever. If fever persists beyond 72 h after discontinuation of the suspected drug, it is unlikely that this drug is the cause. Only rarely do biochemical tests (beyond the obligatory tests needed to classify a patient’s fever as FUO) lead directly to a definitive diagnosis in the absence of PDCs. The diagnostic yield of immuno­ logic serologies other than those included in the obligatory tests is relatively low. These tests more often yield false-positive rather than true-positive results and are of little use without PDCs pointing to specific disorders. Given the absence of specific symptoms in many patients and the relatively low cost of the test, investigation of cryo­ globulins appears to be a valuable screening test in patients with FUO. Multiple blood samples should be cultured in the laboratory long enough to ensure ample time for any fastidious organisms, such as those of the HACEK group. It is critical to inform the laboratory of the intent to test for unusual organisms. Specialized media should be used when the history suggests uncommon microorganisms, such as Histoplasma or Legionella. Performing more than three blood cultures or more than one urine culture is useless in patients with FUO in the absence of PDCs (e.g., a high level of clinical suspicion of endocarditis). Repeating blood or urine cultures is useful only when previously cultured samples were collected dur­ ing antibiotic treatment or within 1 week after its discontinuation. FUO with headache should prompt microbiologic examination of cerebrospinal fluid (CSF) for organisms including herpes simplex virus (especially type 2), Cryptococcus neoformans and C. gattii, and Mycobacterium tuberculosis. Microbiologic serology should not be included in the diagnostic workup of patients without PDCs for specific infections. A tuber­ culin skin test (TST) or interferon γ (IFNγ) release assay (IGRA) is included in the obligatory investigations, but it may yield indetermi­ nate results in patients with miliary tuberculosis, with malnutrition, receiving immunosuppression, or with anti-IFNγ autoantibodies. Although the IGRA is less influenced by prior vaccination with bacille Calmette-Guérin (BCG) or by infection with most nontu­ berculous mycobacteria, its sensitivity is similar to that of the TST; a negative TST or IGRA does not exclude a diagnosis of tuberculosis. Miliary tuberculosis is especially difficult to diagnose. Granuloma­ tous disease in liver or bone marrow biopsy samples, for example,

should always lead to a (re)consideration of this diagnosis. If miliary tuberculosis is suspected, liver biopsy for acid-fast smear, culture, and polymerase chain reaction probably still has the highest diagnostic yield; however, biopsies of bone marrow, lymph nodes, or other involved organs also can be considered. Mycobacterial polymerase chain reaction (PCR) testing together with cultures may shorten the time to diagnosis compared to mycobacterial cultures alone. The diagnostic yield of echocardiography, sinus radiography, radiologic or endoscopic evaluation of the gastrointestinal tract, bone marrow biopsy, liver biopsy, and bronchoscopy is very low in the absence of PDCs. Fever of Unknown Origin CHAPTER 22 In patients without PDCs or with only misleading PDCs, fundos­ copy by an ophthalmologist may be useful early in the diagnostic workup to exclude retinal vasculitis. Several studies have shown a high prevalence of giant cell arte­ ritis among patients with FUO, with rates up to 17% among elderly patients. Giant cell arteritis often involves large arteries and, in most cases, can be diagnosed by 18F-fluordeoxyglucose (18F-FDG) positron emission tomography (PET) with combined CT. However, temporal artery biopsy is still recommended for patients ≥55 years. 18F-FDG-PET/CT may be confounded in vasculitis limited to the temporal arteries because of the small diameter of these vessels and the high levels of FDG uptake in the brain. When PDC-guided diagnostic tests do not lead to a diagnosis, 18F-FDG-PET/CT should be performed, preferably at a time point with elevated ESR or CRP to increase the chance of positive find­ ings. This is especially important in patients with episodic FUO. 18F-FLUORDEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY 18F-FDG-PET has become an established imaging procedure in FUO. FDG accumulates in tissues with a high rate of glycolysis, which occurs not only in malignant cells but also in activated leu­ kocytes and thus permits the imaging of acute and chronic inflam­ matory processes. Compared with conventional scintigraphy (see below), 18F-FDG-PET/CT offers the advantages of higher resolu­ tion, greater sensitivity in chronic low-grade infections, and a high degree of accuracy in the central skeleton. Furthermore, vascular uptake of FDG is increased in patients with vasculitis (Fig. 22-2). The mechanisms responsible for FDG uptake do not allow differ­ entiation among infection, sterile inflammation, and malignancy, but because all of these can cause FUO, this is an overall advantage. It is important to realize that physiologic uptake or concentration of FDG may obscure pathologic foci in the brain, heart, bowel, kid­ neys, and bladder. FDG uptake in the heart, which obscures endo­ carditis, may be prevented by consumption of a low-carbohydrate diet before the PET investigation. FDG uptake in the brain may obscure local temporal large vessel vasculitis. In patients with fever, bone marrow uptake is frequently increased in a nonspecific way due to cytokine activation, which upregulates glucose transporters in bone marrow cells. In recent years, many cohort studies and several meta-analyses have focused on the diagnostic yield of PET/CT in FUO. These studies are highly variable in terms of the selection of patients, the follow-up, and the selection of a gold-standard reference. Indirect comparisons of test performance suggested that 18F-FDG-PET/ CT outperformed gallium scintigraphy and leukocyte scintigraphy. Similarly, indirect comparisons of diagnostic yields suggested that 18F-FDG-PET/CT was more likely than alternative tests to correctly identify the cause of FUO. Meta-analyses report a high diagnostic yield of PET/CT in the workup of FUO patients, with total diag­ nostic yield (i.e., the proportion of scans helpful in finding the final explanation for the inflammation) of ~50% for PET/CT. As many patients with FUO present with periodic fever, the correct timing of PET/CT increases its diagnostic value. Few studies on the use of biomarkers, such as elevated CRP or ESR, as contributors to outcome of PET/CT have been performed. When both CRP and ESR are normal at the time of 18F-FDG-PET/CT, the outcome may only be contributory if a patient does have fever at the time of the scan.

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 22-2  18F-FDG-PET/CT in a patient with FUO. This 72-year-old woman presented with a low-grade fever and severe fatigue of almost 3 months’ duration. An extensive history was taken, but the patient had no specific complaints and had not traveled recently. Her previous history was unremarkable, and she did not use any drugs. Physical examination, including palpation of the temporal arteries, yielded completely normal results. Laboratory examination showed normocytic anemia, a C-reactive protein level of 43 mg/L, an erythrocyte sedimentation rate of 87 mm/h, and mild hypoalbuminemia. Results of the other obligatory tests were all normal. 18F-FDG-PET/CT showed increased FDG uptake in all major arteries (carotid, jugular, and subclavian arteries; thoracic and abdominal aorta; iliac, femoral, and popliteal arteries) and in the soft tissue around the shoulders, hips, and knees—findings compatible with large-vessel vasculitis and polymyalgia rheumatica. Within 1 week after the initiation of treatment with prednisone (60 mg once daily), the patient completely recovered. After 1 month, the prednisone dose was slowly tapered. Although PET/CT and other scintigraphic techniques do not directly provide a definitive diagnosis (with the exception of some patients with, for instance, large vessel vasculitis), they often iden­ tify the anatomic location of a particular ongoing metabolic pro­ cess. With the help of other techniques such as biopsy and culture, a timely diagnosis and treatment can be facilitated. Pathologic FDG uptake is quickly eradicated by treatment with glucocorticoids in many diseases, including vasculitis and lymphoma; therefore, glucocorticoid use should be stopped or postponed until after 18F-FDG-PET/CT is performed. 18F-FDG-PET/CT is a relatively expensive procedure whose avail­ ability is still limited in some regions. Nevertheless, 18F-FDG-PET/CT can be cost-effective in the FUO diagnostic workup if used early, helping to establish an early diagnosis, reducing days of hospital­ ization for diagnostic purposes, and obviating unnecessary and unhelpful tests. When 18F-FDG-PET/CT has been made under the right conditions (i.e., during active inflammation) but has not contributed to the final diagnosis, repeating PET/CT is probably of little value, unless new signs or symptoms appear. ALTERNATIVES TO POSITRON EMISSION TOMOGRAPHY/ COMPUTED TOMOGRAPHY When PET/CT is unavailable, other whole-body imaging modali­ ties should be considered. Compared to CT, scintigraphy provides the location of active inflammation. Conventional scintigraphic methods in clinical practice are 67Ga-citrate scintigraphy and 111In- or 99mTc-labeled leukocyte scintigraphy. The diagnostic yields of these conventional scintigraphic studies are lower than for PET/ CT: the diagnostic yield of gallium scintigraphy ranges from 21% to 54%, and on average, the location of a source of fever can correctly be localized in approximately one-third of patients. The diagnostic value of leukocyte scintigraphy ranges from 8% to 31%, and overall, the cause of FUO can correctly be identified in one-fifth of patients. Recently, one study of full-body MRI as an alternative for PET/CT reported a diagnostic yield comparable to PET/CT. Further studies are needed to confirm this finding.

LATER-STAGE DIAGNOSTIC TESTS Later-stage diagnostic testing should always be PDC driven and may come from repeated history-taking, physical examination, or PET/CT. Biopsies for pathology and/or microbiology evaluation will often be necessary. Diagnostic delay frequently results from a failure to recognize PDCs in the available information. When all PDCs have been thoroughly evaluated but no final explanation has been found, waiting for new PDCs to appear probably is better than ordering more screening investigations. Only when a patient’s condition deteriorates without providing new PDCs should further diagnostic workup be performed. SECOND OPINION IN AN EXPERT CENTER When no explanation for FUO is found despite the workup described above, a second opinion from an FUO expert center should be considered. The single study on the value of second opinion in FUO reported that in over half of patients with unexplained FUO, a diagnosis could be found in an expert center. Additionally, of all patients who remained without a diagnosis after second opinion, 1 in 10 became fever-free upon empirical treatment, adding up to a ben­ eficial outcome in a little under 70% of patients. One of the reasons for the higher diagnostic rate in expert centers is the fact that FUO is often an atypical presentation of a common disease, making pattern recognition informed by high exposure an important diagnostic tool. TREATMENT Fever of Unknown Origin Rational treatment is based on the final diagnosis. In FUO patients remaining with unexplained FUO, the large majority may sponta­ neously become symptom-free. Empirical therapeutic trials should be avoided, except in cases in which a patient’s condition is rapidly deteriorating. Drugs that are commonly used for therapeutic tri­ als are antibiotics, antituberculars, nonsteroidal anti-inflammatory drugs, colchicine, and interleukin-1 inhibitors.

12 - SECTION 3 Nervous System Dysfunction

SECTION 3 Nervous System Dysfunction

ANTIBIOTICS AND ANTITUBERCULOUS THERAPY Antibiotic or antituberculous therapy may irrevocably diminish the ability to culture bacteria. However, hemodynamic instability or neutropenia is a good indication for empirical antibiotic therapy. If the TST or IGRA is positive, or if granulomatous disease is pres­ ent with anergy and sarcoidosis seems unlikely, or in any patient coming from an endemic region with a clinical picture fitting extrapulmonary tuberculosis, a trial of antituberculous therapy may be started, but not before mycobacterial cultures and, if avail­ able, mycobacterial PCR testing have been performed on material collected from the suspected location of inflammation. Especially in miliary tuberculosis, it may be very difficult to obtain a rapid diagnosis. If the fever does not respond after 6 weeks of empirical antituberculous treatment, another diagnosis should be considered. COLCHICINE, NONSTEROIDAL ANTI-INFLAMMATORY DRUGS, AND GLUCOCORTICOIDS If the fever persists and the source remains elusive after comple­ tion of investigations, supportive treatment with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful. The response of Still’s disease to NSAIDs is dramatic in some cases. Colchicine is highly effective in preventing attacks of familial Medi­ terranean fever (FMF) but is not always effective once an attack is underway. When FMF is suspected, the response to colchicine is not a completely reliable diagnostic tool in the acute phase, but within weeks to months of continuous colchicine treatment, most patients show remarkable improvements in the frequency and severity of subsequent febrile episodes. Therefore, colchicine may be tried in patients with features compatible with FMF, especially when these patients originate from a high-prevalence region. In patients suffer­ ing from pericarditis as one of the main associated symptoms, col­ chicine may also be effective to prevent recurrent attacks. If Behçet’s disease is considered likely, colchicine may also have favorable effect. The effects of glucocorticoids on giant cell arteritis and polymy­ algia rheumatica are impressive. Early empirical trials with gluco­ corticoids, however, decrease the chances of reaching a diagnosis for which more specific, less morbid, and sometimes life-saving treatment might be more appropriate, such as malignant lym­ phoma. The ability of glucocorticoids to mask fever while permitting the spread of infection or lymphoma dictates that their use should be avoided unless infectious diseases and malignant lymphoma have been sufficiently ruled out and inflammatory disease is prob­ able and is likely to be debilitating or threatening. INTERLEUKIN-1 INHIBITION Interleukin (IL) 1 is a key cytokine in local and systemic inflammation and the febrile response. The availability of specific IL-1-targeting agents has revealed a pathologic role of IL-1-mediated inflamma­ tion in a growing list of diseases. Anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra), blocks the activity of both IL-1α and IL-1β. Anakinra is extremely effec­ tive in the treatment of many autoinflammatory syndromes, such as FMF, cryopyrin-associated periodic syndrome, tumor necrosis factor receptor–associated periodic syndrome, mevalonate kinase deficiency (hyper-IgD syndrome), Schnitzler’s syndrome, and Still’s disease. There are many other chronic inflammatory disorders in which anti-IL-1 therapy is highly effective. A therapeutic trial with anakinra can be considered in patients whose FUO has not been diagnosed after later-stage diagnostic tests and show signs of IL1-driven inflammation, such as serositis, elevated CRP, and elevated ferritin. When autoinflammation is considered in the differential diagnosis, IL-1 inhibition is preferred over corticosteroids to pre­ vent the metabolic, immunologic, and gastrointestinal side effects of glucocorticoid administration, and because IL-1 inhibition has superior efficacy. ■ ■PROGNOSIS The prognosis of patients with FUO mostly depends on the underly­ ing disease. In patients in whom FUO remains unexplained despite

extensive evaluation, the prognosis is favorable. The risk of FUO-related mortality is probably highest during the early phases of the diagnostic process: in a cohort study including 168 patients without a final diag­ nosis, all four patients who died did so during the index admission; in two of them, diagnoses were made upon autopsy (intravascular lym­ phoma and bilateral pneumonia).

Large cohort studies in patients remaining without a diagnosis report high percentages of spontaneous resolution of fever and a mor­ tality of 8% or less during several years of follow-up. 18F-FDG-PET/CT may be helpful to predict which patients will resolve because normal 18F-FDG-PET/CT scans are associated with higher rates of spontane­ ous resolution. Syncope CHAPTER 23 ■ ■FURTHER READING Betrains A et al: update on imaging in fever and inflammation of unknown origin: Focus on infectious disorders. Clin Microbiol Infect 18:S1198, 2023. Erdem H et al: Classical fever of unknown origin in 21 countries with different economic development: An international ID-IRI study. Eur J Clin Microbiol Infect Dis 42:387, 2023. Mulders-Manders C et al: Fever of unknown origin. Clin Med 15:280, 2015. van Rijsewijk N et al: Molecular imaging of fever of unknown origin: An update. Semin Nucl Med 53:4, 2023. Wright WF et al: Fever of unknown origin (FUO): A call for new research standards and updated clinical management. Am J Med 135:173, 2022. Section 3 Nervous System Dysfunction Roy Freeman, Satish R. Raj

Syncope Syncope is a transient, self-limited loss of consciousness due to acute global impairment of cerebral blood flow. The onset is rapid, dura­ tion brief, and recovery spontaneous and complete. Other causes of transient loss of consciousness need to be distinguished from syncope; these include seizures, vertebrobasilar ischemia, hypoxemia, and hypo­ glycemia. A syncopal prodrome (presyncope) is common, although loss of consciousness may occur without any warning symptoms. Typical presyncopal symptoms include lightheadedness or faintness, dizziness, weakness, fatigue, and visual and auditory disturbances. The causes of syncope can be divided into three general categories: (1) neurally medi­ ated syncope (also called reflex or vasovagal syncope), (2) orthostatic hypotension, and (3) cardiac syncope. Neurally mediated syncope comprises a heterogeneous group of disorders that are characterized by a transient change in the reflexes responsible for maintaining cardiovascular homeostasis. Episodic vasodilation (or loss of vasoconstrictor tone), decreased cardiac output, and bradycardia occur in varying combinations, resulting in tempo­ rary failure of blood pressure control. In contrast, in patients with orthostatic hypotension due to autonomic failure, these cardiovascular homeostatic reflexes are chronically impaired. Cardiac syncope may be due to arrhythmias or structural cardiac diseases that cause a decrease in cardiac output. The clinical features, underlying pathophysiologic mechanisms, therapeutic interventions, and prognoses differ markedly among these three causes. ■ ■EPIDEMIOLOGY AND NATURAL HISTORY Syncope is a common presenting problem, accounting for ~3% of all emergency department (ED) visits and 1% of all hospital admissions. The annual cost for syncope-related hospitalization in the United States

13 - 23 Syncope

23 Syncope

ANTIBIOTICS AND ANTITUBERCULOUS THERAPY Antibiotic or antituberculous therapy may irrevocably diminish the ability to culture bacteria. However, hemodynamic instability or neutropenia is a good indication for empirical antibiotic therapy. If the TST or IGRA is positive, or if granulomatous disease is pres­ ent with anergy and sarcoidosis seems unlikely, or in any patient coming from an endemic region with a clinical picture fitting extrapulmonary tuberculosis, a trial of antituberculous therapy may be started, but not before mycobacterial cultures and, if avail­ able, mycobacterial PCR testing have been performed on material collected from the suspected location of inflammation. Especially in miliary tuberculosis, it may be very difficult to obtain a rapid diagnosis. If the fever does not respond after 6 weeks of empirical antituberculous treatment, another diagnosis should be considered. COLCHICINE, NONSTEROIDAL ANTI-INFLAMMATORY DRUGS, AND GLUCOCORTICOIDS If the fever persists and the source remains elusive after comple­ tion of investigations, supportive treatment with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs) can be helpful. The response of Still’s disease to NSAIDs is dramatic in some cases. Colchicine is highly effective in preventing attacks of familial Medi­ terranean fever (FMF) but is not always effective once an attack is underway. When FMF is suspected, the response to colchicine is not a completely reliable diagnostic tool in the acute phase, but within weeks to months of continuous colchicine treatment, most patients show remarkable improvements in the frequency and severity of subsequent febrile episodes. Therefore, colchicine may be tried in patients with features compatible with FMF, especially when these patients originate from a high-prevalence region. In patients suffer­ ing from pericarditis as one of the main associated symptoms, col­ chicine may also be effective to prevent recurrent attacks. If Behçet’s disease is considered likely, colchicine may also have favorable effect. The effects of glucocorticoids on giant cell arteritis and polymy­ algia rheumatica are impressive. Early empirical trials with gluco­ corticoids, however, decrease the chances of reaching a diagnosis for which more specific, less morbid, and sometimes life-saving treatment might be more appropriate, such as malignant lym­ phoma. The ability of glucocorticoids to mask fever while permitting the spread of infection or lymphoma dictates that their use should be avoided unless infectious diseases and malignant lymphoma have been sufficiently ruled out and inflammatory disease is prob­ able and is likely to be debilitating or threatening. INTERLEUKIN-1 INHIBITION Interleukin (IL) 1 is a key cytokine in local and systemic inflammation and the febrile response. The availability of specific IL-1-targeting agents has revealed a pathologic role of IL-1-mediated inflamma­ tion in a growing list of diseases. Anakinra, a recombinant form of the naturally occurring IL-1 receptor antagonist (IL-1Ra), blocks the activity of both IL-1α and IL-1β. Anakinra is extremely effec­ tive in the treatment of many autoinflammatory syndromes, such as FMF, cryopyrin-associated periodic syndrome, tumor necrosis factor receptor–associated periodic syndrome, mevalonate kinase deficiency (hyper-IgD syndrome), Schnitzler’s syndrome, and Still’s disease. There are many other chronic inflammatory disorders in which anti-IL-1 therapy is highly effective. A therapeutic trial with anakinra can be considered in patients whose FUO has not been diagnosed after later-stage diagnostic tests and show signs of IL1-driven inflammation, such as serositis, elevated CRP, and elevated ferritin. When autoinflammation is considered in the differential diagnosis, IL-1 inhibition is preferred over corticosteroids to pre­ vent the metabolic, immunologic, and gastrointestinal side effects of glucocorticoid administration, and because IL-1 inhibition has superior efficacy. ■ ■PROGNOSIS The prognosis of patients with FUO mostly depends on the underly­ ing disease. In patients in whom FUO remains unexplained despite

extensive evaluation, the prognosis is favorable. The risk of FUO-related mortality is probably highest during the early phases of the diagnostic process: in a cohort study including 168 patients without a final diag­ nosis, all four patients who died did so during the index admission; in two of them, diagnoses were made upon autopsy (intravascular lym­ phoma and bilateral pneumonia).

Large cohort studies in patients remaining without a diagnosis report high percentages of spontaneous resolution of fever and a mor­ tality of 8% or less during several years of follow-up. 18F-FDG-PET/CT may be helpful to predict which patients will resolve because normal 18F-FDG-PET/CT scans are associated with higher rates of spontane­ ous resolution. Syncope CHAPTER 23 ■ ■FURTHER READING Betrains A et al: update on imaging in fever and inflammation of unknown origin: Focus on infectious disorders. Clin Microbiol Infect 18:S1198, 2023. Erdem H et al: Classical fever of unknown origin in 21 countries with different economic development: An international ID-IRI study. Eur J Clin Microbiol Infect Dis 42:387, 2023. Mulders-Manders C et al: Fever of unknown origin. Clin Med 15:280, 2015. van Rijsewijk N et al: Molecular imaging of fever of unknown origin: An update. Semin Nucl Med 53:4, 2023. Wright WF et al: Fever of unknown origin (FUO): A call for new research standards and updated clinical management. Am J Med 135:173, 2022. Section 3 Nervous System Dysfunction Roy Freeman, Satish R. Raj

Syncope Syncope is a transient, self-limited loss of consciousness due to acute global impairment of cerebral blood flow. The onset is rapid, dura­ tion brief, and recovery spontaneous and complete. Other causes of transient loss of consciousness need to be distinguished from syncope; these include seizures, vertebrobasilar ischemia, hypoxemia, and hypo­ glycemia. A syncopal prodrome (presyncope) is common, although loss of consciousness may occur without any warning symptoms. Typical presyncopal symptoms include lightheadedness or faintness, dizziness, weakness, fatigue, and visual and auditory disturbances. The causes of syncope can be divided into three general categories: (1) neurally medi­ ated syncope (also called reflex or vasovagal syncope), (2) orthostatic hypotension, and (3) cardiac syncope. Neurally mediated syncope comprises a heterogeneous group of disorders that are characterized by a transient change in the reflexes responsible for maintaining cardiovascular homeostasis. Episodic vasodilation (or loss of vasoconstrictor tone), decreased cardiac output, and bradycardia occur in varying combinations, resulting in tempo­ rary failure of blood pressure control. In contrast, in patients with orthostatic hypotension due to autonomic failure, these cardiovascular homeostatic reflexes are chronically impaired. Cardiac syncope may be due to arrhythmias or structural cardiac diseases that cause a decrease in cardiac output. The clinical features, underlying pathophysiologic mechanisms, therapeutic interventions, and prognoses differ markedly among these three causes. ■ ■EPIDEMIOLOGY AND NATURAL HISTORY Syncope is a common presenting problem, accounting for ~3% of all emergency department (ED) visits and 1% of all hospital admissions. The annual cost for syncope-related hospitalization in the United States

is ~$2.4 billion. Syncope has a lifetime cumulative incidence of up to 40% in the general population. A bimodal age distribution exists; the peak incidence in the young occurs between ages 10 and 30 years, with a median peak around 15 years. Neurally mediated syncope is the etiol­ ogy in the vast majority of these cases. In older adults, there is a sharp rise in the incidence of syncope after 70 years of age.

In population-based studies, neurally mediated syncope is the most common cause of syncope. The incidence is higher in women than men. In young subjects, there is often a family history in first-degree relatives. Cardiovascular disease due to structural disease or arrhythmias is the next most common cause in most series, particularly in ED settings and in older patients. Orthostatic hypotension also increases in prevalence with age because of the reduced baroreflex responsiveness, decreased cardiac compliance, and attenuation of the vestibulosympathetic reflex associated with aging. Other contributors are reduced fluid intake and vasoactive medications, also more likely in this age group. In the elderly, orthostatic hypotension is more common in institutionalized than community-dwelling individuals, most likely explained by a greater prevalence of predisposing neurologic disorders, physiologic impair­ ment, and vasoactive medication use among institutionalized patients. PART 2 Cardinal Manifestations and Presentation of Diseases Syncope of noncardiac and unexplained origin in younger indi­ viduals has an excellent prognosis; life expectancy is unaffected. By contrast, syncope due to a cardiac cause, either structural heart disease or a primary arrhythmic disorder, is associated with an increased risk of sudden cardiac death and mortality from other causes. Similarly, the mortality rate is increased in individuals with syncope due to ortho­ static hypotension related to age and the associated comorbid condi­ tions (Table 23-1). The likelihood of hospitalization and mortality risk are higher in older adults. ■ ■PATHOPHYSIOLOGY The upright posture imposes a unique physiologic stress upon humans; most, although not all, syncopal episodes occur from a standing posi­ tion. Standing results in pooling of 500–1000 mL of blood in the lower extremities, buttocks, and splanchnic circulation. The dependent pooling leads to a decrease in venous return to the heart and reduced ventricular filling that result in diminished cardiac output and blood pressure. These hemodynamic changes provoke a compensatory reflex response, initiated by the baroreceptors in the carotid sinus and aortic arch, resulting in increased sympathetic outflow and decreased vagal nerve activity (Fig. 23-1). The reflex increases peripheral resistance, venous return to the heart, and cardiac output and thus limits the fall in blood pressure. If this response fails, as is the case chronically in orthostatic hypotension and transiently in neurally mediated syncope, hypotension and cerebral hypoperfusion occur. TABLE 23-1  High-Risk Features Indicating Hospitalization or Intensive Evaluation of Syncope Chest pain suggesting coronary ischemia Features of congestive heart failure Moderate or severe valvular disease Moderate or severe structural cardiac disease Electrocardiographic features of ischemia History of ventricular arrhythmias Prolonged QT interval (>500 ms) Repetitive sinoatrial block or sinus pauses Persistent sinus bradycardia Bi- or trifascicular block or intraventricular conduction delay with QRS duration ≥120 ms Atrial fibrillation Nonsustained ventricular tachycardia Family history of sudden death Preexcitation syndromes Brugada pattern on electrocardiogram Palpitations at time of syncope Syncope at rest or during exercise

Syncope is a form of transient loss of consciousness (TLOC) that is a consequence of global cerebral hypoperfusion. It represents a failure of cerebral blood flow autoregulatory mechanisms. Myogenic factors, local metabolites, and to a lesser extent autonomic neurovascular control are responsible for the autoregulation of cerebral blood flow (Chap. 318). The latency of the autoregulatory response is 5–10 s. Typically, cerebral blood flow ranges from 50–60 mL/min per 100 g brain tissue and remains relatively constant over perfusion pressures ranging from 50–150 mmHg. Cessation of blood flow for 6–8 s will result in loss of consciousness, while impairment of consciousness ensues when blood flow decreases to 25 mL/min per 100 g brain tissue. From the clinical standpoint, a fall in systemic systolic blood pres­ sure to ~50 mmHg or lower will usually result in syncope. A decrease in cardiac output and/or systemic vascular resistance—the determinants of blood pressure—thus underlies the pathophysiology of syncope. Common causes of impaired cardiac output include decreased effec­ tive circulating blood volume, increased thoracic pressure, massive pulmonary embolus, cardiac brady- and tachyarrhythmias, valvular heart disease, and myocardial dysfunction. Systemic vascular resis­ tance may be decreased by central and peripheral autonomic nervous system diseases, sympatholytic medications, and transiently during neurally mediated syncope. Increased cerebral vascular resistance, most frequently due to hypocarbia induced by hyperventilation, may also contribute to the pathophysiology of syncope. Two patterns of electroencephalographic (EEG) changes occur in syncopal subjects. The first is a “slow-flat-slow” pattern in which nor­ mal background activity is replaced with high-amplitude slow delta waves. This is followed by sudden flattening of the EEG—a cessation or attenuation of cortical activity—followed by the return of slow waves, and then normal activity. A second pattern, the “slow pattern,” is char­ acterized by increasing and decreasing slow wave activity only. The EEG flattening that occurs in the slow-flat-slow pattern is a marker of more severe cerebral hypoperfusion. Despite the presence of myoclonic movements and other motor activity during some syncopal events, EEG seizure discharges are not detected. CLASSIFICATION ■ ■NEURALLY MEDIATED SYNCOPE Neurally mediated (reflex; vasovagal) syncope is the final pathway of a complex central and peripheral nervous system reflex arc. There is a transient change in autonomic efferent activity with increased parasympathetic outflow, plus sympathoinhibition, resulting in brady­ cardia, vasodilation, and/or reduced vasoconstrictor tone (the vasode­ pressor response) and reduced cardiac output. The resulting fall in systemic blood pressure can then reduce cerebral blood flow to below the compensatory limits of autoregulation (Fig. 23-2). In order to develop neurally mediated syncope, a functioning autonomic nervous system is necessary, in contrast to syncope resulting from autonomic failure (discussed below). Multiple triggers of the afferent limb of the reflex arc can result in neurally mediated syncope. In some situations, these can be clearly defined, e.g., orthostatic stress, and stimulation of the carotid sinus, the gastrointestinal tract, or the bladder. Often, however, the trigger is less easily recognized and the cause is multifactorial. Under these circumstances, it is likely that different afferent pathways converge on the central autonomic network within the medulla that integrates the neural impulses and mediates the vasodepressor-bradycardic response. Classification of Neurally Mediated Syncope  Neurally mediated syncope may be subdivided based on the afferent pathway and pro­ vocative trigger. Vasovagal syncope (the common faint) is provoked by intense emotion, pain, and/or orthostatic stress, whereas the situational reflex syncopes have specific localized stimuli that provoke the reflex vasodilation and bradycardia that leads to syncope. The underlying mechanisms have been identified and pathophysiology delineated for most of these situational reflex syncopes. The afferent trigger may originate in the pulmonary system, gastrointestinal system, urogenital system, heart, and carotid sinus in the carotid artery (Table 23-2).

FIGURE 23-1  The baroreflex. A decrease in arterial pressure unloads the baroreceptors—the terminals of afferent fibers of the glossopharyngeal and vagus nerves—that are situated in the carotid sinus and aortic arch. This leads to a reduction in the afferent impulses that are relayed from these mechanoreceptors through the glossopharyngeal and vagus nerves to the nucleus of the tractus solitarius (NTS) in the dorsomedial medulla. The reduced baroreceptor afferent activity produces a decrease in vagal nerve input to the sinus node that is mediated via connections of the NTS to the nucleus ambiguus (NA). There is an increase in sympathetic efferent activity that is mediated by the NTS projections to the caudal ventrolateral medulla (CVLM) (an excitatory pathway) and from there to the rostral ventrolateral medulla (RVLM) (an inhibitory pathway). The activation of RVLM presympathetic neurons in response to hypotension is thus predominantly due to disinhibition. In response to a sustained fall in blood pressure, vasopressin release is mediated by projections from the A1 noradrenergic cell group in the ventrolateral medulla. This projection activates vasopressin-synthesizing neurons in the magnocellular portion of the paraventricular nucleus (PVN) and the supraoptic nucleus (SON) of the hypothalamus. Blue denotes sympathetic neurons, and green denotes parasympathetic neurons. (From R Freeman: Neurogenic orthostatic hypotension. N Engl J Med 358:615, 2008. Copyright © 2008 Massachusetts Medical Society. Reprinted with permission.)

HR (bpm)

BP (mm Hg)

A B Time (s) FIGURE 23-2  A. The paroxysmal hypotensive-bradycardic response that is characteristic of neurally mediated syncope. Noninvasive beat-to-beat blood pressure and heart rate are shown >5 min (from 60 to 360 s) of an upright tilt on a tilt table. B. The same tracing expanded to show 80 s of the episode (from 80 to 200 s). BP, blood pressure; bpm, beats per minute; HR, heart rate.

Syncope CHAPTER 23

HR (bpm)

BP (mm Hg)

Time (s)

TABLE 23-2  Causes of Syncope A. Neurally Mediated Syncope   Vasovagal syncope     Provoked fear, pain, anxiety, intense emotion, sight of blood, unpleasant sights and odors, orthostatic stress   Situational reflex syncope     Pulmonary       Cough syncope, wind instrument player’s syncope, weightlifter’s syncope, “mess trick”a and “fainting lark,”b sneeze syncope, airway instrumentation     Urogenital PART 2 Cardinal Manifestations and Presentation of Diseases       Postmicturition syncope, urogenital tract instrumentation, prostatic massage     Gastrointestinal       Swallow syncope, glossopharyngeal neuralgia, esophageal stimulation, gastrointestinal tract instrumentation, rectal examination, defecation syncope     Cardiac       Bezold-Jarisch reflex, cardiac outflow obstruction     Carotid sinus       Carotid sinus sensitivity, carotid sinus massage     Ocular       Ocular pressure, ocular examination, ocular surgery B. Orthostatic Hypotension   Primary autonomic failure due to idiopathic central and peripheral neurodegenerative diseases—the “synucleinopathies”     Lewy body diseases       Parkinson’s disease       Lewy body dementia       Pure autonomic failure     Multiple system atrophy (Shy-Drager syndrome)   Secondary autonomic failure due to autonomic peripheral neuropathies     Diabetes     Hereditary amyloidosis (familial amyloid polyneuropathy)     Primary amyloidosis (AL amyloidosis; immunoglobulin light chain associated)     Hereditary sensory and autonomic neuropathies (HSAN) (especially type III—familial dysautonomia)     Idiopathic immune-mediated autonomic neuropathy     Autoimmune autonomic ganglionopathy     Sjögren’s syndrome     Paraneoplastic autonomic neuropathy     HIV neuropathy   Postprandial hypotension   Iatrogenic (drug-induced)   Volume depletion C. Cardiac Syncope   Arrhythmias     Sinus node dysfunction     Atrioventricular dysfunction     Supraventricular tachycardias     Ventricular tachycardias     Inherited channelopathies   Cardiac structural disease     Valvular disease     Myocardial ischemia     Obstructive and other cardiomyopathies     Atrial myxoma     Pericardial effusions and tamponade aHyperventilation for ~1 min, followed by sudden chest compression. bHyperventilation (~20 breaths) in a squatting position, rapid rise to standing, then Valsalva maneuver.

Hyperventilation, leading to hypocarbia and cerebral vasoconstriction, and raised intrathoracic pressure that impairs venous return to the heart play a central role in many of the situational reflex syncopes. The affer­ ent pathway of the reflex arc differs among these disorders, but the efferent response via the vagus and sympathetic pathways is similar. Alternately, neurally mediated syncope may be subdivided based on the predominant efferent pathway. Vasodepressor syncope describes syncope predominantly due to efferent, sympathetic, vasoconstrictor failure; cardioinhibitory syncope describes syncope predominantly associated with bradycardia or asystole due to increased vagal outflow; and mixed response syncope describes syncope in which there are both vagal and sympathetic reflex changes. Features of Neurally Mediated Syncope  In addition to symp­ toms of orthostatic intolerance such as dizziness, lightheadedness, and fatigue, premonitory features of autonomic activation may be present in patients with neurally mediated syncope. These include diaphoresis, pallor, palpitations, nausea, hyperventilation, and yawning. During the syncopal event, proximal and distal myoclonus (typically arrhythmic and multifocal) may occur, raising the possibility of a seizure. The eyes typically remain open and usually deviate upward. Pupils are usually dilated. Roving eye movements may occur. Grunting, moaning, snort­ ing, and stertorous breathing may be present. Urinary incontinence may occur. Fecal incontinence is very rare, however. Postictal confu­ sion is also rare, although visual and auditory hallucinations and neardeath and out-of-body experiences are sometimes reported. Although some predisposing factors and provocative stimuli are well established (for example, motionless upright posture, warm ambi­ ent temperature, intravascular volume depletion, alcohol ingestion, hypoxemia, anemia, pain, the sight of blood, venipuncture, and intense emotion), the underlying basis for the widely different thresholds for syncope among individuals exposed to the same provocative stimulus is not known. A genetic basis for neurally mediated syncope may exist. Several studies have reported an increased incidence of syncope in first-degree relatives of fainters, and some candidate genes have been identified with sex-specific associations. These have not been repro­ duced in other large cohorts. It is likely that environmental, social, and cultural factors play a large role. TREATMENT Neurally Mediated Syncope Reassurance, education, avoidance of provocative stimuli, and plasma volume expansion with fluid and salt are the cornerstones of the management of neurally mediated syncope. Isometric coun­ terpressure maneuvers of the limbs (tensing of the abdominal and leg muscles, handgrip and arm tensing, and leg crossing) may raise blood pressure by increasing central blood volume and cardiac output. Of these, abdominal and leg muscle tensing is the most effective. By maintaining pressure in the autoregulatory zone, these maneuvers, which may be particularly helpful in patients with a long prodrome, avoid or delay the onset of syncope. A randomized controlled trial supports this intervention. Fludrocortisone, vasoconstricting agents, and β-adrenoreceptor antagonists are widely used by experts to treat refractory patients. Of these, only midodrine has been shown to be effective in interna­ tional, multicenter randomized controlled trials. Because vasodila­ tion, decreased central blood volume, decreased stroke volume, and cardiac output are the dominant pathophysiologic syncopal mecha­ nisms in most patients, use of a cardiac pacemaker is rarely beneficial. In patients with a cardioinhibitory syncope response during tilt-table testing, however, recent sham-controlled randomized clinical trial data have shown that a dual-chamber pacemaker with a closed-loop stimulation algorithm can decrease syncope recurrence. These stud­ ies restricted enrollment to older patients (>40 years) with frequent recurrence of syncope and a cardioinhibitory response on tilt-table test. In these patients, dual-chamber pacing may be helpful, although this continues to be an area of uncertainty.

■ ■ORTHOSTATIC HYPOTENSION Orthostatic hypotension, defined as a reduction in systolic blood pressure of at least 20 mmHg or diastolic blood pressure of at least 10 mmHg after 3 min of standing or head-up tilt on a tilt table, is a manifestation of sympathetic vasoconstrictor (autonomic) fail­ ure (Fig. 23-3). In many (but not all) cases, there is no compensatory increase in heart rate despite hypotension; with partial autonomic fail­ ure, heart rate may increase to some degree but is insufficient to main­ tain cardiac output. A variant of orthostatic hypotension is “delayed” orthostatic hypotension, which occurs beyond 3 min of standing; this may reflect a mild or early form of sympathetic adrenergic dysfunc­ tion. In some cases, orthostatic hypotension can occur within 15 s of standing with full resolution within 45 s (so-called initial orthostatic hypotension), a finding that may reflect a transient mismatch between cardiac output and peripheral vascular resistance and does not repre­ sent autonomic failure. Characteristic symptoms of orthostatic hypotension include lightheadedness, dizziness, and presyncope (near-faintness) occurring in response to sudden postural change. However, symptoms may be absent or nonspecific such as generalized weakness, fatigue, cognitive slowing, leg buckling, or headache. Visual blurring may occur, likely due to retinal or occipital lobe ischemia. Neck pain, typically in the suboccipital, posterior cervical, and shoulder region (the “coat-hanger headache”), most likely due to neck muscle ischemia, may be the only symptom. Patients may report orthostatic dyspnea (thought to reflect ventilation-perfusion mismatch due to inadequate perfusion of ventilated lung apices) or angina (attributed to impaired myocardial perfusion even with normal coronary arteries). Symptoms may be exacerbated by exertion, prolonged standing, increased ambient tem­ perature, or meals. Syncope is usually preceded by warning symptoms, but may occur suddenly, suggesting the possibility of a seizure or car­ diac cause. Some patients have profound decreases in blood pressure, sometimes without symptoms but placing them at risk for falls and injuries if the autoregulatory threshold is crossed with ensuing cerebral hypoperfusion. Supine hypertension is common in patients with orthostatic hypo­ tension due to autonomic failure, affecting >50% of patients in some series. Orthostatic hypotension may present after initiation of therapy for hypertension, and supine hypertension may follow treatment of orthostatic hypotension. However, in other cases, the association of the

HR (bpm)

BP (mm Hg)

A B Time (s) FIGURE 23-3  A. The gradual fall in blood pressure without a compensatory heart rate increase that is characteristic of orthostatic hypotension due to autonomic failure. Blood pressure and heart rate are shown >5 min (from 60 to 360 s) of an upright tilt on a tilt table. B. The same tracing expanded to show 40 s of the episode (from 180 to 220 s). BP, blood pressure; bpm, beats per minute; HR, heart rate.

two conditions is unrelated to therapy; it may in part be explained by baroreflex dysfunction in the presence of residual sympathetic outflow, particularly in patients with central autonomic degeneration.

Causes of Neurogenic Orthostatic Hypotension  Causes of neurogenic orthostatic hypotension include central and peripheral autonomic nervous system dysfunction (Chap. 451). Autonomic dysfunction of other organ systems (including the bladder, bowels, sexual organs, and sudomotor system) of varying severity frequently accompanies orthostatic hypotension in these disorders (Table 23-2). The primary autonomic degenerative disorders are multiple sys­ tem atrophy (Shy-Drager syndrome; Chap. 451), Parkinson’s disease (Chap. 446), dementia with Lewy bodies (Chap. 445), and pure autonomic failure (Chap. 451). These are often grouped together as “synucleinopathies” due to the presence of α-synuclein, a protein that aggregates predominantly in the cytoplasm of neurons in the Lewy body disorders (Parkinson’s disease, dementia with Lewy bodies, and pure autonomic failure) and in the glia in multiple system atrophy. Syncope CHAPTER 23 Peripheral autonomic dysfunction may also accompany small-fiber peripheral neuropathies such as those associated with diabetes melli­ tus, acquired and hereditary amyloidosis, immune-mediated neuropa­ thies, and hereditary sensory and autonomic neuropathies (HSAN; particularly HSAN type III, familial dysautonomia) (Chaps. 457 and 458). Less frequently, orthostatic hypotension is associated with the peripheral neuropathies that accompany vitamin B12 deficiency, neuro­ toxin exposure, HIV and other infections, and porphyria. Patients with autonomic failure and the elderly are susceptible to falls in blood pressure associated with meals. The magnitude of the blood pressure fall is exacerbated by large meals, meals high in carbo­ hydrate, and alcohol intake. The mechanism of postprandial hypoten­ sion, and resultant syncope, is not fully elucidated. Orthostatic hypotension is often iatrogenic. Drugs from several classes may lower peripheral resistance (e.g., α-adrenoreceptor antago­ nists used to treat hypertension and prostatic hypertrophy; diuretics, nitrates and other venodilators and vasodilators; other antihyperten­ sive agents of several classes; tricyclic agents and phenothiazines). Iatrogenic volume depletion due to diuresis and volume depletion due to medical causes (hemorrhage, vomiting, diarrhea, or decreased fluid intake) may also result in decreased effective circulatory volume, orthostatic hypotension, and syncope.

HR (bpm)

BP (mm Hg)

Time (s)

TREATMENT Orthostatic Hypotension The first step is to remove reversible causes—usually vasoactive medications (see Table 451-6). Next, nonpharmacologic inter­ ventions should be introduced. These include patient education regarding staged moves from supine to upright; warnings about the hypotensive effects of large meals; instructions about the isometric counterpressure maneuvers that increase intravascular pressure (see above); and raising the head of the bed to reduce supine hypertension and nocturnal diuresis. Intravascular volume should be expanded by increasing dietary fluid and salt. The rapid ingestion of 500 mL of plain water can often effect a short-term pressor response in these patients. If these nonpharmacologic measures fail, pharmacologic intervention with fludrocortisone acetate and vasoconstricting agents such as midodrine or l-dihy­ droxyphenylserine (droxidopa) should be introduced. Some patients with intractable symptoms require additional therapy with supplementary agents that include pyridostigmine, atomox­ etine, yohimbine, octreotide, desmopressin acetate (DDAVP), and erythropoietin (Chap. 451). PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■CARDIAC SYNCOPE Cardiac (or cardiovascular) syncope is caused by arrhythmias and structural heart disease. These may occur in combination because structural disease renders the heart more vulnerable to abnormal elec­ trical activity. Arrhythmias  Bradyarrhythmias that cause syncope include those due to severe sinus node dysfunction (e.g., sinus arrest or sinoatrial block) and atrioventricular (AV) block (e.g., Mobitz type II, highgrade, and complete AV block). The bradyarrhythmias due to sinus node dysfunction are often associated with an atrial tachyarrhythmia, a disorder known as the tachycardia-bradycardia syndrome. A pro­ longed pause following the termination of a tachycardic episode is a frequent cause of syncope in patients with the tachycardia-bradycardia syndrome. Medications of several classes may also cause bradyarrhyth­ mias of sufficient severity to cause syncope. Syncope due to bradycar­ dia or asystole has been referred to as a Stokes-Adams attack. Ventricular tachyarrhythmias frequently cause syncope. The likeli­ hood of syncope with ventricular tachycardia is in part dependent on the ventricular rate (rates <200 beats/min are less likely to cause syncope) and ventricular function (a patient with poor ventricular function is more likely to have syncope at a given ventricular rate). The compromised hemodynamic function during ventricular tachycardia is caused by ineffective ventricular contraction, reduced diastolic filling due to abbreviated filling periods, loss of AV synchrony, and concur­ rent myocardial ischemia. Several disorders associated with cardiac electrophysiologic instabil­ ity and arrhythmogenesis are due to mutations in ion channel subunit genes. These include the long QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. The long QT syndrome is a genetically heterogeneous disorder associated with prolonged cardiac repolarization and a predisposition to ventricular arrhythmias. Syncope and sudden death in patients with long QT syndrome result from a unique polymorphic ventricular tachycardia called torsades des pointes that may degenerate into ventricular fibril­ lation. The long QT syndrome has been linked to genes encoding K+ channel α-subunits, K+ channel β-subunits, voltage-gated Na+ channel, and a scaffolding protein, ankyrin B (ANK2). Brugada syndrome is characterized by syncope, polymorphic ventricular tachycardia, and idiopathic ventricular fibrillation in association with right ventricu­ lar electrocardiogram (ECG) abnormalities without structural heart disease. This disorder is also genetically heterogeneous, although it is most frequently linked to mutations in the Na+ channel α-subunit, SCN5A. Catecholaminergic polymorphic tachycardia is an inherited, genetically heterogeneous disorder often involving cardiac calcium handling that is associated with exercise- or stress-induced ventricular

arrhythmias, syncope, or sudden death. Acquired QT interval prolon­ gation, most commonly due to drugs, may also result in ventricular arrhythmias and syncope. These disorders are discussed in detail in Chap. 262. Structural Disease  Structural heart disease (e.g., valvular disease, myocardial ischemia, hypertrophic and other cardiomyopathies, car­ diac masses such as atrial myxoma, and pericardial effusions) may lead to syncope by compromising cardiac output. Structural disease may also contribute to other pathophysiologic mechanisms of syncope. For example, cardiac structural disease may predispose to arrhythmogen­ esis; aggressive treatment of cardiac failure with diuretics and/or vaso­ dilators may lead to orthostatic hypotension; and inappropriate reflex vasodilation may occur with structural disorders such as aortic stenosis and hypertrophic cardiomyopathy, possibly provoked by increased ventricular contractility. TREATMENT Cardiac Syncope Treatment of cardiac disease depends on the underlying disorder. Therapies for arrhythmias consist of cardiac pacing for brady­ cardia, including sinus node disease and AV block, and ablation, antiarrhythmic drugs, and cardioverter-defibrillators for atrial and ventricular tachyarrhythmias. These disorders are best managed by physicians with specialized skills in this area. APPROACH TO THE PATIENT Syncope DIFFERENTIAL DIAGNOSIS Syncope is easily diagnosed when the characteristic features are present; however, several disorders with real or apparent transient loss of consciousness may create diagnostic confusion. Generalized and partial seizures (Chap. 436) may be confused with syncope; however, there are a number of differentiating fea­ tures. Whereas tonic-clonic movements are the hallmark of a gen­ eralized seizure, myoclonic and other movements also may occur in up to 90% of syncopal episodes. Myoclonic jerks associated with syncope may be multifocal or generalized. They are typically arrhythmic and of short duration (<30 s). Mild flexor and extensor posturing also may occur. Partial or partial-complex seizures with secondary generalization are usually preceded by an aura, com­ monly an unpleasant smell; fear; anxiety; abdominal discomfort; or other visceral sensations. These phenomena should be differenti­ ated from the premonitory features of syncope. Autonomic manifestations of seizures (autonomic epilepsy) may provide a more difficult diagnostic challenge. Autonomic sei­ zures have cardiovascular, gastrointestinal, pulmonary, urogenital, pupillary, and cutaneous manifestations that are similar to the premonitory features of syncope. Furthermore, the cardiovascular manifestations of autonomic epilepsy include clinically significant tachycardias and bradycardias that may be of sufficient magnitude to cause loss of consciousness. The presence of accompanying non­ autonomic auras may help differentiate these episodes from syncope. Loss of consciousness associated with a seizure usually lasts

5 min and is associated with prolonged postictal drowsiness and disorientation, whereas reorientation occurs almost immediately after a syncopal event. Muscle aches may occur after both syncope and seizures, although they tend to last longer and be more severe following a seizure. Seizures, unlike syncope, are rarely provoked by emotions or pain. Incontinence of urine may occur with both seizures and syncope; however, fecal incontinence occurs only very rarely with syncope. Hypoglycemia may cause transient loss of consciousness, typi­ cally in individuals with type 1 or type 2 diabetes (Chap. 415) treated with insulin. The clinical features associated with impending

or actual hypoglycemia include tremor, palpitations, anxiety, dia­ phoresis, hunger, and paresthesias. These symptoms are due to autonomic activation to counter the falling blood glucose. Hunger, in particular, is not a typical premonitory feature of syncope. Hypo­ glycemia also impairs neuronal function, leading to fatigue, weak­ ness, dizziness, and cognitive and behavioral symptoms. Diagnostic difficulties may occur in individuals in strict glycemic control; repeated hypoglycemia impairs the counterregulatory response and leads to a loss of the characteristic warning symptoms that are the hallmark of hypoglycemia. Patients with cataplexy (Chap. 33) experience an abrupt partial or complete loss of muscular tone triggered by strong emotions, typically anger or laughter. Unlike syncope, consciousness is main­ tained throughout the attacks, which typically last between 30 s and 2 min. There are no premonitory symptoms. Cataplexy occurs in 60–75% of patients with narcolepsy. The clinical interview and interrogation of eyewitnesses (and ancillary cellphone video of the spell, when available) usually allow differentiation of syncope from falls due to vestibular dysfunction, cerebellar disease, extrapyramidal system dysfunction, and other gait disorders. A diagnosis of syncope can be particularly challeng­ ing in patients with dementia who experience repeated falls and are unable to provide a clear history of the episodes. If the fall is accompanied by head trauma, a postconcussive syndrome, amnesia for the precipitating events, and/or a loss or alteration of conscious­ ness, this may also contribute to diagnostic difficulty. Apparent loss of consciousness can be a manifestation of psychi­ atric disorders such as generalized anxiety, panic disorders, major depression, and somatization disorder. These possibilities should be considered in individuals who faint frequently without prodromal symptoms. Such patients are rarely injured despite numerous falls. There are no clinically significant hemodynamic changes concur­ rent with these episodes. In contrast, transient loss of consciousness due to vasovagal syncope precipitated by fear, stress, anxiety, and emotional distress is accompanied by hypotension and sometimes bradycardia. INITIAL EVALUATION The goals of the initial evaluation are to determine whether the transient loss of consciousness was due to syncope; to identify the cause; and to assess risk for future episodes and serious harm (Table 23-1). The initial evaluation should include a detailed history, thorough questioning of eyewitnesses, and a complete physical and neurologic examination. Blood pressure and heart rate should be measured in the supine position and after 3 min of standing to determine whether orthostatic hypotension is present. High-risk features on history include the new onset of chest discomfort, abdominal pain, shortness of breath, or head­ ache; syncope during exertion or while supine; sudden onset of palpitations followed by syncope; and severe coronary artery or structural heart disease. High-risk features on examination include an unexplained sys­ tolic blood pressure of <90 mmHg; suggestion of gastrointestinal hemorrhage; persistent bradycardia (<40 beats/min); and an undi­ agnosed systolic murmur. An ECG should be performed if there is suspicion of syncope due to an arrhythmia or underlying cardiac disease. Relevant electrocardiographic abnormalities include bradyarrhythmias or tachyarrhythmias, AV block, acute myocardial ischemia, old myo­ cardial infarction, long QT, and bundle branch block. This initial assessment will lead to the identification of a cause of syncope in ~50% of patients and also allows stratification of patients at risk for cardiac mortality. Laboratory Tests  Baseline laboratory blood tests are rarely help­ ful in identifying the cause of syncope. Blood tests should be per­ formed when specific disorders, e.g., myocardial infarction, anemia, and secondary autonomic failure, are suspected (Table 23-2).

Autonomic Nervous System Testing (Chap. 451)  Autonomic test­ ing, including tilt-table testing, can be performed in specialized centers. Autonomic testing is helpful to uncover objective evidence of autonomic failure and also to demonstrate a predisposition to neurally mediated syncope. Autonomic testing includes assess­ ments of parasympathetic autonomic nervous system function (e.g., heart rate variability to deep respiration and a Valsalva maneuver), sympathetic cholinergic function (e.g., thermoregula­ tory sweat response and quantitative sudomotor axon reflex test), and sympathetic adrenergic function (e.g., blood pressure response to a Valsalva maneuver and a tilt-table test with beat-to-beat blood pressure measurement). The hemodynamic abnormalities demon­ strated on the tilt-table test (Figs. 23-2 and 23-3) may be useful in distinguishing orthostatic hypotension due to autonomic failure from the hypotensive bradycardic response of neurally mediated syncope. Similarly, the tilt-table test may help identify patients with syncope due to immediate or delayed orthostatic hypotension. Syncope CHAPTER 23 Carotid sinus massage should be considered in patients with symptoms suggestive of carotid sinus syncope and in patients

40 years with recurrent syncope of unknown etiology. This test should ideally be carried out under continuous ECG and blood pressure monitoring and should be avoided in patients with carotid bruits, possible or known plaques, or stenosis. Cardiac Evaluation  ECG monitoring is indicated for patients with a high pretest probability of arrhythmia causing syncope. Patients should be monitored in the hospital if the likelihood of a lifethreatening arrhythmia is high, e.g., patients with severe coronary artery or structural heart disease, nonsustained ventricular tachy­ cardia, supraventricular tachycardia, paroxysmal atrial fibrillation, trifascicular heart block, prolonged QT interval, Brugada syndrome ECG pattern, syncope during exertion, syncope while seated or supine, and family history of sudden cardiac death (Table 23-1). Continuous ambulatory electrocardiographic (Holter) monitoring is recommended for patients who experience frequent syncopal episodes (e.g., daily or almost daily), whereas loop recorders, which continually record and erase cardiac rhythm, are indicated for patients with suspected arrhythmias with low risk of sudden car­ diac death. Loop recorders may be external (e.g., for evaluation of episodes that occur at a frequency of >1 per month) or implantable (e.g., if syncope occurs less frequently). The monitoring duration should ideally be at least twice the interspell duration. Echocardiography should be performed in patients with a his­ tory of cardiac disease or if abnormalities are found on physical examination or the ECG. Echocardiographic diagnoses that may be responsible for syncope include aortic stenosis, hypertrophic cardiomyopathy, cardiac tumors, aortic dissection, and pericardial tamponade. Echocardiography also has a role in risk stratification for sudden cardiac death based on the left ventricular ejection fraction. Treadmill exercise testing with ECG and blood pressure moni­ toring should be performed in patients who have experienced syncope during or shortly after exercise. Treadmill testing may help identify exercise-induced arrhythmias (e.g., tachycardia-related AV block) and exercise-induced exaggerated vasodilation. Invasive electrophysiologic studies are indicated in patients with structural heart disease and ECG abnormalities in whom noninvasive investigations have failed to yield a diagnosis. Elec­ trophysiologic studies have low sensitivity and specificity and should only be performed when a high pretest probability exists. Currently, these tests are rarely performed to evaluate patients with syncope. Psychiatric Evaluation  Screening for psychiatric disorders may be appropriate in patients with recurrent unexplained syncope episodes. Tilt-table testing, with demonstration of symptoms in the absence of hemodynamic change, may be useful in reproducing syncope in patients with suspected psychogenic syncope.

14 - 24 Dizziness and Vertigo

24 Dizziness and Vertigo

■ ■FURTHER READING Brignole M et al: 2018 ESC Guidelines for the diagnosis and manage­

ment of syncope. Eur Heart J 39:1883, 2018. Brignole M et al: Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole. Eur Heart J 42:508, 2021. Cheshire WP et al: Electrodiagnostic assessment of the autonomic nervous system: A consensus statement endorsed by the American Autonomic Society, American Academy of Neurology, and the Inter­ national Federation of Clinical Neurophysiology. Clin Neurophysiol 132:666, 2021. Freeman R et al: Consensus statement on the definition of orthostatic hypotension, neurally mediated syncope and the postural tachycardia syndrome. Auton Neurosci 161:46, 2011. Freeman R et al: Orthostatic Hypotension: JACC state-of-the-art PART 2 Cardinal Manifestations and Presentation of Diseases review. J Am Coll Cardiol 72:1294, 2018. Gibbons CH et al: The recommendations of a consensus panel for the screening, diagnosis, and treatment of neurogenic orthostatic hypotension and associated supine hypertension. J Neurol 264:1567, 2017. Sheldon RS, Raj SR: Pacing and vasovagal syncope: Back to our physi­ ologic roots. Clin Auton Res 27:213, 2017. Sheldon R et al: Midodrine for the prevention of vasovagal syncope: A randomized clinical trial. Ann Intern Med 74:1349, 2021. Shen WK et al: 2017 ACC/AHA/HRS guideline for the evaluation and management of patients with syncope: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circula­ tion 136:e60, 2017. Mark F. Walker, Robert B. Daroff*

Dizziness and Vertigo Dizziness is an imprecise symptom used to describe a variety of com­ mon sensations that include vertigo, light-headedness, faintness, and imbalance. Vertigo refers to a sense of spinning or other motion that may be physiological, occurring during or after a sustained head rota­ tion, or pathological, due to vestibular dysfunction. The term lightheadedness is classically applied to presyncopal sensations resulting from brain hypoperfusion but as used by patients has little specificity, as it may also refer to other symptoms such as disequilibrium and imbalance. A challenge to diagnosis is that patients often have dif­ ficulty distinguishing among these various symptoms, and the words they choose do not reliably indicate the underlying etiology. There are many causes of dizziness. Vestibular dizziness (vertigo or imbalance) may be due to peripheral disorders that affect the laby­ rinths or vestibular nerves, or it may result from disruption of central vestibular pathways. It may be paroxysmal or due to a fixed unilateral or bilateral vestibular deficit. Acute unilateral lesions cause vertigo due to a sudden imbalance in vestibular inputs from the two labyrinths. Bilateral lesions cause imbalance and instability of vision when the head moves (oscillopsia) due to loss of normal vestibular reflexes. Ocular Motility   The range of eye movements and whether they are equal in each eye should be observed. Peripheral eye move­ ment disorders (e.g., cranial neuropathies, eye muscle weakness) are usually disconjugate (different in the two eyes). One should check pursuit (the ability to follow a smoothly moving target) and saccades (the ability to look back and forth accurately between two targets). Poor pursuit or inaccurate (dysmetric) saccades usually indicate central pathology, often involving the cerebellum. Align­ ment of the two eyes can be checked with a cover test: while the patient is looking at a target, alternately cover the eyes and observe for corrective saccades. A vertical misalignment may indicate a brainstem or cerebellar lesion. Finally, one should look for spon­ taneous nystagmus, an involuntary back-and-forth movement of the eyes. Nystagmus is most often of the jerk type, in which a slow drift (slow phase) in one direction alternates with a rapid saccadic movement (quick phase or fast phase) in the opposite direction that resets the position of the eyes in the orbits. Except in the case of acute vestibulopathy (e.g., vestibular neuritis), if nystagmus is ∗Deceased. Presyncopal dizziness occurs when cardiac dysrhythmia, ortho­ static hypotension, medication effects, or another cause leads to brain hypoperfusion. Such presyncopal sensations vary in duration; they may increase in severity until loss of consciousness occurs, or they may resolve before loss of consciousness if the cerebral ischemia is corrected. Faintness and syncope, which are discussed in detail in Chap. 23, should always be considered when one is evaluating patients with brief episodes of dizziness or dizziness that occurs with upright posture. Other causes of dizziness include nonvestibular balance and

gait disorders (e.g., loss of proprioception from sensory neuropathy, parkinsonism) and anxiety. When evaluating patients with dizziness, questions to consider include the following: (1) Is it dangerous (e.g., arrhythmia, transient ischemic attack/stroke)? (2) Is it vestibular? (3) If vestibular, is it peripheral or central? A careful history and examination often pro­ vide sufficient information to answer these questions and determine whether additional studies or referral to a specialist is necessary. APPROACH TO THE PATIENT HISTORY When a patient presents with dizziness, the first step is to delineate more precisely the nature of the symptom. In the case of vestibular disorders, the physical symptoms depend on whether the lesion is unilateral or bilateral, and whether it is acute or chronic. Vertigo, an illusion of self or environmental motion, implies an acute asym­ metry of vestibular inputs from the two labyrinths or in their cen­ tral pathways. Symmetric bilateral vestibular hypofunction causes imbalance but no vertigo. Because of the ambiguity in patients’ descriptions of their symptoms, diagnosis based simply on symp­ tom characteristics is typically unreliable. Thus, the history should focus closely on other features, including whether this is the first attack, the duration of this and any prior episodes, provoking fac­ tors, and accompanying symptoms. Timing   Dizziness can be divided into episodes that last for sec­ onds, minutes, hours, or days. Common causes of brief dizziness (seconds) include benign paroxysmal positional vertigo (BPPV) and orthostatic hypotension, both of which typically are provoked by changes in head and/or body position relative to gravity. Attacks of vestibular migraine and Ménière’s disease often last hours. When episodes are of intermediate duration (minutes), transient ischemic attacks of the posterior circulation should be considered, although migraine and other causes are also possible. Associated Symptoms   Symptoms that accompany vertigo may be helpful in distinguishing peripheral vestibular lesions from central causes. Unilateral hearing loss and other acute aural symp­ toms (ear pain, pressure, fullness, new tinnitus) typically point to a peripheral cause. Because the auditory pathways quickly become bilateral upon entering the brainstem, central lesions are unlikely to cause unilateral hearing loss unless the lesion lies near the root entry zone of the auditory nerve. Symptoms such as double vision, numbness, and limb ataxia suggest a brainstem or cerebellar lesion. EXAMINATION Because dizziness and imbalance can be a manifestation of a variety of neurologic disorders, the neurologic examination is essential in the evaluation of these patients. Focus should be given to assess­ ment of eye movements, vestibular function, and hearing.

TABLE 24-1  Features of Peripheral and Central Vertigo • Nystagmus from an acute peripheral lesion is unidirectional, with fast phases beating away from the ear with the lesion. Nystagmus that changes direction with gaze is due to a central lesion. • Transient mixed vertical-torsional nystagmus occurs in benign paroxysmal positional vertigo (BPPV), but pure vertical or pure torsional nystagmus is a central sign. • Nystagmus from a peripheral lesion may be inhibited by visual fixation, whereas central nystagmus is not suppressed. • Absence of a head impulse sign in a patient with acute prolonged vertigo should suggest a central cause. • Unilateral hearing loss suggests peripheral vertigo. Findings such as diplopia, dysarthria, and limb ataxia suggest a central disorder. easily seen in the light, it is probably due to a central cause. Two forms of nystagmus that are characteristic of lesions of the cere­ bellar pathways are vertical nystagmus with downward fast phases (downbeat nystagmus) and horizontal nystagmus that changes direction with gaze (gaze-evoked nystagmus). By contrast, periph­ eral lesions typically cause unidirectional horizontal nystagmus. Use of Frenzel eyeglasses (self-illuminated goggles with convex lenses that blur the patient’s vision but allow the examiner to see the eyes greatly magnified) or infrared video goggles can aid in the detection of peripheral vestibular nystagmus, because they reduce the patient’s ability to use visual fixation to suppress nystagmus. Table 24-1 outlines key findings that help distinguish peripheral from central causes of vertigo. Head Impulse Test   The most useful bedside test of peripheral vestibular function is the head impulse test, in which the vestibuloocular reflex (VOR) is assessed with small-amplitude (~20 degrees) rapid head rotations. While the patient fixates on a target, the head is rotated quickly to the left or right. If the VOR is deficient, the rotation is followed by a catch-up saccade in the opposite direc­ tion (e.g., a leftward saccade after a rightward rotation). The head impulse test can identify both unilateral (catch-up saccades after rotations toward the weak side) and bilateral (catch-up saccades after rotations in both directions) vestibular hypofunction. Positioning Maneuvers   All patients with episodic dizziness, especially if provoked by positional change, should be tested with the Dix-Hallpike maneuver. The patient begins in a sitting position with the head turned 45 degrees; holding the back of the head, the examiner then lowers the patient into a supine position with the head extended backward by about 20 degrees while watching the eyes. Posterior canal BPPV can be diagnosed confidently if transient upbeating-torsional nystagmus is seen. If no nystagmus is observed after 15–20 s, the patient is raised to the sitting position, and the procedure is repeated with the head turned to the other side. Again, Frenzel goggles may improve the sensitivity of the test. Dynamic Visual Acuity   This is a functional test that can be useful in assessing vestibular function. Visual acuity is measured with the head still and when the head is rotated back and forth by the exam­ iner (about 1–2 Hz). A drop in visual acuity during head motion of more than one line on a near card or Snellen chart is abnormal and indicates vestibular dysfunction. ANCILLARY TESTING The choice of ancillary tests should be guided by the history and examination findings. Audiometry should be performed whenever a vestibular disorder is suspected. Unilateral sensorineural hear­ ing loss supports a peripheral disorder (e.g., vestibular schwan­ noma). Predominantly low-frequency hearing loss is characteristic of Ménière’s disease. Videonystagmography includes recordings of spontaneous nystagmus (if present) and measurement of posi­ tional nystagmus. Caloric testing compares the responses of the two horizontal semicircular canals, while video head-impulse test­ ing measures the integrity of each of the six semicircular canals.

Vestibular evoked potentials assess otolith reflexes. The test battery often includes recording of saccades and pursuit to evaluate central ocular motor function. Neuroimaging is important if a central ves­ tibular disorder is suspected. In addition, patients with unexplained unilateral hearing loss or vestibular hypofunction should undergo MRI of the internal auditory canals, including administration of gadolinium, to rule out a schwannoma. ■ ■DIFFERENTIAL DIAGNOSIS AND TREATMENT Treatment of vestibular symptoms should be driven by the underlying diagnosis. Simply treating dizziness with vestibular suppressant medi­ cations is often not helpful and may prolong recovery. The diagnostic and specific treatment approaches for the most commonly encoun­ tered vestibular disorders are discussed below. Dizziness and Vertigo CHAPTER 24 ■ ■ACUTE PROLONGED VERTIGO

(VESTIBULAR NEURITIS) An acute unilateral vestibular lesion causes constant vertigo, nausea, vomiting, oscillopsia (motion of the visual scene), and imbalance. These symptoms are due to a sudden asymmetry of inputs from the two labyrinths or in their central connections, simulating a continuous rotation of the head. Unlike BPPV, continuous vertigo persists even when the head remains still. History and Examination   When a patient presents with an acute vestibular syndrome, the most important question is whether the lesion is central (e.g., a cerebellar or brainstem infarct or hemorrhage), which may be life-threatening, or peripheral, affecting the vestibular nerve or labyrinth (vestibular neuritis). Attention should be given to any symp­ toms or signs that point to central dysfunction (diplopia, weakness or numbness, dysarthria). The pattern of spontaneous nystagmus, if present, may be helpful (Table 24-1). If the head impulse test is normal, an acute peripheral vestibular lesion is unlikely. A central lesion cannot always be excluded with certainty based on symptoms and examination alone; thus, older patients with vascular risk factors who present with an acute vestibular syndrome should be evaluated for the possibility of stroke even when there are no specific findings that indicate a central lesion. Treatment   Most patients with vestibular neuritis recover sponta­ neously, although chronic dizziness, motion sensitivity, and disequilib­ rium may persist. The role of early glucocorticoid therapy is uncertain, as studies have yielded disparate results. Antiviral medications are of no proven benefit and are not typically given unless there is evidence to suggest herpes zoster oticus (Ramsay Hunt syndrome). Vestibular suppressant medications may reduce acute symptoms but should be avoided after the first several days because they may impede central compensation and recovery. Patients should be encouraged to resume a normal level of activity as soon as possible, and directed vestibular rehabilitation therapy may accelerate improvement. ■ ■BENIGN PAROXYSMAL POSITIONAL VERTIGO BPPV is a common cause of recurrent vertigo. Episodes are brief (<1 min and typically 15–20 s) and are always provoked by changes in head position relative to gravity, such as lying down, rising from a supine position, and extending the head to look upward. Rolling over in bed is a common trigger that may help to distinguish BPPV from orthostatic hypotension. The attacks are caused by free-floating oto­ conia (calcium carbonate crystals) that have been dislodged from the utricular macula and have moved into one of the semicircular canals, usually the posterior canal. When head position changes, gravity causes the otoconia to move within the canal, producing vertigo and nystag­ mus. With posterior canal BPPV, the nystagmus beats upward and torsionally (the upper poles of the eyes beat toward the affected lower ear). Less commonly, the otoconia enter the horizontal canal, result­ ing in a horizontal nystagmus when the patient is lying with either ear down. Superior (also called anterior) canal involvement is rare. BPPV is treated with repositioning maneuvers that use gravity to remove the otoconia from the semicircular canal. For posterior canal BPPV, the Epley maneuver (Fig. 24-1) is the most commonly used procedure. For

Step 1 Step 2 Step 3 Step 4 Step 5 Nose is pointed 45° PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 24-1  Modified Epley maneuver for treatment of benign paroxysmal positional vertigo of the right (top panels) and left (bottom panels) posterior semicircular canals. Step 1. With the patient seated, turn the head 45 degrees toward the affected ear. Step 2. Keeping the head turned, lower the patient to the head-hanging position and hold for at least 30 s and until nystagmus disappears. Step 3. Without lifting the head, turn it 90 degrees toward the other side. Hold for another 30 s. Step 4. Rotate the patient onto their side while turning the head another 90 degrees, so that the nose is pointed down 45 degrees. Hold again for 30 s. Step 5. Have the patient sit up on the side of the table. After a brief rest, the maneuver should be repeated to confirm successful treatment. (Reproduced with permission from Chicago Dizziness and Hearing (CDH). Figure adapted from http://www.dizziness-and-balance.com/disorders/bppv/movies/Epley-480x640.avi.) more refractory cases of BPPV, patients can be taught a variant of this maneuver that they can perform alone at home. A demonstration of the Epley maneuver is available online (http://www.dizziness-and-balance. com/disorders/bppv/bppv.html). ■ ■VESTIBULAR MIGRAINE Vestibular migraine is a common yet underdiagnosed cause of episodic vertigo. Vertigo sometimes precedes a typical migraine headache but more often occurs without headache or with only a mild headache. Some patients who have had frequent migraine headaches in the past present later in life with vestibular migraine as the predominant prob­ lem. In vestibular migraine, the duration of vertigo may be from min­ utes to hours, and some migraineurs also experience more prolonged periods of disequilibrium (lasting days to weeks). Motion sensitivity and sensitivity to visual motion (e.g., movies) are common. Even in the absence of headache, other migraine features may be present, such as photophobia, phonophobia, or a visual aura. Although data from controlled studies are generally lacking, vestibular migraine typically is treated with medications that are used for prophylaxis of migraine headaches (Chap. 441). Antiemetics may be helpful to relieve symp­ toms at the time of an attack. ■ ■MÉNIÈRE’S DISEASE Attacks of Ménière’s disease consist of vertigo and hearing loss, as well as pain, pressure, and/or fullness in the affected ear. Low-frequency hearing loss and aural symptoms are key features that distinguish Ménière’s disease from other peripheral vestibulopathies and from vestibular migraine. Audiometry at the time of an attack shows a characteristic asymmetric low-frequency hearing loss; hearing com­ monly improves between attacks, although permanent hearing loss may eventually occur. Ménière’s disease is associated with excess endo­ lymph fluid in the inner ear; hence the term endolymphatic hydrops. The exact pathophysiological mechanism, however, remains unclear. Patients suspected of having Ménière’s disease should be referred to an otolaryngologist for further evaluation. Diuretics and sodium restric­ tion are typically the initial treatments. If attacks persist, injections of glucocorticoids or gentamicin into the middle ear may be considered. Nonablative surgical options include decompression and shunting of

Nose is pointed 45° the endolymphatic sac. Full ablative procedures (vestibular nerve sec­ tion, labyrinthectomy) are seldom required. ■ ■VESTIBULAR SCHWANNOMA Vestibular schwannomas (sometimes termed acoustic neuromas) and other tumors at the cerebellopontine angle cause slowly progressive unilateral sensorineural hearing loss and vestibular hypofunction. These patients typically do not have vertigo because the gradual vestib­ ular deficit is compensated centrally as it develops. The diagnosis often is not made until there is sufficient hearing loss to be noticed. The ves­ tibular examination will show a deficient response to the head impulse test when the head is rotated toward the affected side, but nystagmus will not be prominent. As noted above, patients with unexplained uni­ lateral sensorineural hearing loss or vestibular hypofunction require MRI of the internal auditory canals to look for a schwannoma. ■ ■BILATERAL VESTIBULAR HYPOFUNCTION Patients with bilateral loss of vestibular function also typically do not have vertigo, because vestibular function is lost on both sides simul­ taneously, and there is no asymmetry of vestibular input. Symptoms include loss of balance, particularly in the dark, where vestibular input is most critical, and oscillopsia during head movement, such as while walking or riding in a car. Bilateral vestibular hypofunction may be (1) idiopathic and progressive, (2) part of a neurodegenerative disor­ der, or (3) iatrogenic due to medication ototoxicity (most commonly gentamicin or other aminoglycoside antibiotics). Other causes include bilateral vestibular schwannomas (neurofibromatosis type 2), autoim­ mune disease, superficial siderosis, and meningeal-based infection or tumor. It also may occur in patients with peripheral polyneuropathy; in these patients, both vestibular loss and impaired proprioception may contribute to poor balance. Finally, unilateral processes such as vestibular neuritis and Ménière’s disease may involve both ears sequen­ tially, resulting in bilateral vestibulopathy. Examination findings include diminished dynamic visual acu­ ity (see above) due to loss of stable vision when the head is moving, abnormal head impulse responses in both directions, and a Romberg sign. Responses to caloric testing are reduced. Patients with bilateral vestibular hypofunction should be referred for vestibular rehabilitation

15 - 25 Fatigue

25 Fatigue

therapy. Vestibular suppressant medications should not be used, as they will increase the imbalance. Evaluation by a neurologist is important not only to confirm the diagnosis but also to consider any other associ­ ated neurologic abnormalities that may clarify the etiology. ■ ■CENTRAL VESTIBULAR DISORDERS Central lesions causing vertigo typically involve vestibular pathways in the brainstem and/or cerebellum. They may be due to discrete lesions, such as from ischemic or hemorrhagic stroke (Chaps. 437–439), demyelination (Chap. 455), or tumors (Chap. 95), or they may be due to neurodegenerative conditions that include the vestibulocerebellum (Chaps. 442–445). Subacute cerebellar degeneration may be due to immune, including paraneoplastic, processes (Chaps. 99 and 450). Table 24-1 outlines important features of the history and examination that help to identify central vestibular disorders. Acute central vertigo is a medical emergency, due to the possibility of life-threatening stroke or hemorrhage. All patients with suspected central vestibular disorders should undergo brain MRI, and the patient should be referred for full neurologic evaluation. ■ ■FUNCTIONAL DIZZINESS Psychological factors play an important role in chronic dizziness. First, dizziness may be a somatic manifestation of a psychiatric condition such as major depression, anxiety, or panic disorder (Chap. 463). Second, patients may develop anxiety and autonomic symptoms as a consequence or comorbidity of an independent vestibular disorder. One particular form of this has been termed variously phobic postural vertigo, psychophysiologic vertigo, or chronic subjective dizziness, but is now referred to as persistent postural-perceptual dizziness (PPPD). These patients have a chronic feeling (3 months or longer) of fluctuat­ ing dizziness and disequilibrium that is present at rest but worse while standing. There is an increased sensitivity to self-motion and visual motion (e.g., watching movies) and a particular intensification of symptoms when moving through complex visual environments such as supermarkets. Although there may be a past history of an acute vestib­ ular disorder (e.g., vestibular neuritis), the neuro-otologic examination and vestibular testing are normal or indicative of a compensated ves­ tibular deficit, indicating that the ongoing subjective dizziness cannot be explained by a primary vestibular pathology. Anxiety disorders are particularly common in patients with chronic dizziness; when present, TABLE 24-2  Treatment of Vertigo AGENTa DOSEb Antihistamines     Meclizine 25–50 mg 3 times daily   Dimenhydrinate 50 mg 1–2 times daily   Promethazine 25 mg 2–3 times daily (also can be given rectally and IM) Benzodiazepines     Diazepam 2.5 mg 1–3 times daily   Clonazepam 0.25 mg 1–3 times daily Anticholinergic     Scopolamine transdermalc Patch Physical therapy     Repositioning maneuversd     Vestibular rehabilitation   Other     Diuretics and/or low-sodium (1000 mg/d) diete     Antimigrainous drugsf     Selective serotonin reuptake inhibitorsg   aAll listed drugs are approved by the U.S. Food and Drug Administration, but most are not approved for the treatment of vertigo. bUsual oral (unless otherwise stated) starting dose in adults; a higher maintenance dose can be reached by a gradual increase. cFor motion sickness only. dFor benign paroxysmal positional vertigo. eFor Ménière’s disease. fFor vestibular migraine. gFor persistent postural-perceptual vertigo and anxiety.

they contribute substantially to the morbidity. Treatment approaches for PPPD include pharmacological therapy with selective serotonin reuptake inhibitors (SSRIs), cognitive-behavioral psychotherapy, and vestibular rehabilitation. Vestibular suppressant medications generally should be avoided.

■ ■TREATMENT Table 24-2 provides a list of commonly used medications for suppres­ sion of vertigo. As noted, these medications should be reserved for short-term control of active vertigo, such as during the first few days of acute vestibular neuritis, or for acute attacks of Ménière’s disease. They are less helpful for chronic dizziness and, as previously stated, may hin­ der central compensation. An exception is that benzodiazepines may attenuate psychosomatic dizziness and the associated anxiety, although SSRIs are generally preferable in such patients. Fatigue CHAPTER 25 Vestibular rehabilitation therapy promotes central adaptation pro­ cesses that compensate for vestibular loss and also may help habituate motion sensitivity and other symptoms of perceptual dizziness. The general approach is to use a graded series of exercises that progressively challenge gaze stabilization and balance. For patients with bilateral vestibular hypofunction, an implanted vestibular prosthesis has shown promise as a future option. ■ ■FURTHER READING Altissimi G et al: Drugs inducing hearing loss, tinnitus, dizziness and vertigo: An updated guide. Eur Rev Med Pharmacol Sci 24:7946, 2020. Kim JS, Zee DS: Benign paroxysmal positional vertigo. N Engl J Med 370:1138, 2014. Smyth D et al: Vestibular migraine treatment: A comprehensive practical review. Brain 145:3741, 2022. Staab JP: Persistent postural-perceptual dizziness. Neurol Clin 41:647, 2023. Jeffrey M. Gelfand, Vanja C. Douglas

Fatigue Fatigue is one of the most common symptoms in clinical medicine. It is a prominent manifestation of a number of systemic, neurologic, and psychiatric syndromes, although a precise cause will not be identified in a substantial minority of patients. Fatigue refers to the subjective experience of physical and mental weariness, sluggishness, low energy, and exhaustion. In the context of clinical medicine, fatigue is most practically defined as difficulty initiating or maintaining voluntary mental or physical activity. Nearly everyone who has ever been ill with a self-limited infection has experienced this near-universal symptom, and fatigue is usually brought to medical attention only when it is either of unclear cause, fails to remit, or the severity is out of propor­ tion with what would be expected for the associated trigger. Fatigue should be distinguished from muscle weakness, a reduction of neuromuscular power (Chap. 26); most patients complaining of fatigue are not truly weak when direct muscle power is tested. Fatigue is also distinct from somnolence, which refers to sleepiness in the context of disturbed sleep-wake physiology (Chap. 33), and from dyspnea on exertion, although patients may use the word fatigue to describe any of these symptoms. The task facing clinicians when a patient presents with fatigue is to identify the underlying cause and develop a therapeu­ tic alliance, the goal of which is to spare patients expensive and fruitless diagnostic workups and steer them toward effective therapy.

■ ■EPIDEMIOLOGY AND GLOBAL CONSIDERATIONS Variability in the definitions of fatigue and the survey instruments used in different studies makes it difficult to arrive at precise figures about the global burden of fatigue. The point prevalence of fatigue was 6.7% and the lifetime prevalence was 25% in a large National Institute of Mental Health survey of the U.S. general population. In primary care clinics in Europe and the United States, between 10 and 25% of patients surveyed endorsed symptoms of prolonged (present for >1 month) or chronic (present for >6 months) fatigue, but in only a minority was fatigue the primary reason for seeking medical attention. In a com­ munity survey of women in India, 12% reported chronic fatigue. By contrast, the prevalence of myalgic encephalomyelitis/chronic fatigue syndrome (Chap. 461), as defined by the U.S. Centers for Disease Control and Prevention, is low.

PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■DIFFERENTIAL DIAGNOSIS Psychiatric Disease  Fatigue is a common somatic manifestation of many major psychiatric syndromes, including depression, anxiety, and somatoform disorders (Chap. 463). Psychiatric symptoms are reported in more than three-quarters of patients with unexplained chronic fatigue. Even in patients with systemic or neurologic disorders in which fatigue is independently recognized as a symptom, comorbid psychiatric disease may still be an important contributor. Neurologic Disease  Patients with fatigue often say they feel weak, but upon careful examination, objective muscle weakness is rarely discernible. If found, muscle weakness must then be localized to the central nervous system, peripheral nervous system, neuromuscular junction, or muscle, and appropriate follow-up studies obtained (Chap. 26). Fatigability of muscle power is a cardinal manifestation of some neuromuscular disorders such as myasthenia gravis and is distinguished from fatigue by finding clinically evident diminution of the amount of force that a muscle generates upon repeated contrac­ tion (Chap. 459). Fatigue is one of the most common and bothersome symptoms reported in multiple sclerosis (MS) (Chap. 455), affecting nearly 90% of patients; fatigue in MS can persist between MS attacks and does not necessarily correlate with magnetic resonance imag­ ing (MRI) disease activity. Fatigue is also increasingly identified as a troublesome feature of many neurodegenerative diseases, including Parkinson’s disease (Chap. 446), amyotrophic lateral sclerosis (Chap. 448), and central nervous system dysautonomias (Chap. 451). Fatigue after stroke (Chap. 437) is a well-described but poorly understood entity with a widely varying prevalence. Episodic fatigue can be a pre­ monitory symptom of migraine (Chap. 441). Fatigue is also a frequent consequence of traumatic brain injury (Chap. 454), often occurring in association with depression and sleep disorders. Sleep Disorders  Obstructive sleep apnea is an important cause of excessive daytime sleepiness in association with fatigue and should be investigated using overnight polysomnography, particularly in those with prominent snoring, obesity, or other predictors of obstructive sleep apnea (Chap. 308). Whether the cumulative sleep deprivation that is common in modern society contributes to clinically apparent fatigue is not known (Chap. 33). Endocrine Disorders  Fatigue, sometimes in association with true muscle weakness, can be a heralding symptom of hypothyroid­ ism (Chap. 395), particularly in the context of hair loss, dry skin, cold intolerance, constipation, and weight gain. Fatigue associated with heat intolerance, sweating, and palpitations is typical of hyperthyroidism (Chap. 396). Adrenal insufficiency (Chap. 398) can also manifest with unexplained fatigue as a primary or prominent symptom, often with anorexia, weight loss, nausea, myalgias, and arthralgias; hyponatremia, hyperkalemia, and hyperpigmentation may be present at time of diag­ nosis. Mild hypercalcemia can cause fatigue, which may be relatively vague, whereas severe hypercalcemia can lead to lethargy, stupor, and coma (Chap. 422). Both hypoglycemia and hyperglycemia can cause lethargy, often in association with confusion; diabetes mellitus, in particular type 1 diabetes, is also associated with fatigue independent

of glucose levels (Chap. 415). Fatigue may also accompany Cushing’s disease, hypoaldosteronism, and hypogonadism. Low vitamin D status has also been associated with fatigue. Liver and Kidney Disease  Both chronic liver failure and chronic kidney disease can cause fatigue. Over 80% of hemodialysis patients complain of fatigue, which makes it one of the most common symp­ toms reported by patients in chronic kidney disease (Chap. 322). Obesity  Obesity (Chap. 413) is associated with fatigue and sleepi­ ness independent of the presence of obstructive sleep apnea. Obese patients undergoing bariatric surgery experience improvement in daytime sleepiness sooner than would be expected if the improvement were solely the result of weight loss and resolution of sleep apnea. A number of other factors common in obese patients are likely contribu­ tors as well, including physical inactivity, diabetes, and depression. Physical Inactivity  Physical inactivity is associated with fatigue, and increasing physical activity can improve fatigue in some patients. Malnutrition  Although fatigue can be a presenting feature of malnutrition (Chap. 345), nutritional status may also be an impor­ tant comorbidity and contributor to fatigue in other chronic illnesses, including cancer-associated fatigue. Infection  Both acute and chronic infections commonly lead to fatigue as part of the broader infectious syndrome. Evaluation for undi­ agnosed infection as the cause of unexplained fatigue, and particularly prolonged or chronic fatigue, should be guided by the history, physical examination, and infectious risk factors, with particular attention to risk for tuberculosis, HIV, chronic hepatitis, and endocarditis. Infectious mononucleosis may cause prolonged fatigue that persists for weeks to months following the acute illness, but infection with the Epstein-Barr virus is only very rarely the cause of unexplained chronic fatigue. Postin­ fectious fatigue may also occur following a variety of acute infections. For example, a substantial minority of patients who have recovered from SARS-CoV-1, SARS-CoV-2, Dengue, and Ebola virus experience persistent fatigue. Almost one-third of patients report fatigue 3 or more months following SARS-CoV-2 (COVID-19) diagnosis. Drugs  Many medications, drugs, drug withdrawal, and chronic alcohol use can all lead to fatigue. Medications that are more likely to be causative include antidepressants, antipsychotics, anxiolytics, opi­ ates, antispasticity agents, antiseizure agents, and beta blockers. Cardiovascular and Pulmonary Disorders  Fatigue is one of the most taxing symptoms reported by patients with congestive heart failure and chronic obstructive pulmonary disease and negatively affects quality of life. In a population-based cohort study in Norfolk, United Kingdom, fatigue was associated with an increased hazard of all-cause mortality in the general population, but particularly for deaths related to cardiovascular disease. Malignancy  Fatigue, particularly in association with unexplained weight loss, can be a sign of occult malignancy, but cancer is rarely identified in patients with unexplained chronic fatigue in the absence of other telltale signs or symptoms. Cancer-related fatigue is experi­ enced by 40% of patients at the time of diagnosis and by >80% at some time in the disease course. Hematologic Disorders  Chronic or progressive anemia may present with fatigue, sometimes in association with exertional tachy­ cardia and breathlessness. Anemia may also contribute to fatigue in chronic illness. Low serum ferritin in the absence of anemia may also cause fatigue that is reversible with iron replacement. Immune-Mediated Disorders  Fatigue is a prominent complaint in many chronic inflammatory disorders, including systemic lupus erythematosus, polymyalgia rheumatica, rheumatoid arthritis, inflam­ matory bowel disease, antineutrophil cytoplasmic antibody (ANCA)– associated vasculitis, sarcoidosis, and Sjögren’s syndrome, but is not usually an isolated symptom. Fatigue is also associated with primary immunodeficiency diseases.

Pregnancy  Fatigue is very commonly reported by women during all stages of pregnancy and postpartum. Disorders of Unclear Cause  Myalgic encephalomyelitis (ME)/ chronic fatigue syndrome (CFS) (Chap. 461) and fibromyalgia (Chap. 385) incorporate chronic fatigue as part of the syndromic definition when fatigue is present in association with other criteria, as discussed in the respective chapters. Chronic multisymptom illness, also known as Gulf-War syndrome, is another symptom complex with prominent fatigue; it is most commonly, although not exclusively, observed in veterans of the 1991 Gulf War conflict (Chap. S8). Idio­ pathic chronic fatigue is used to describe the syndrome of unexplained chronic fatigue in the absence of enough additional clinical features to meet the diagnostic criteria for ME/CFS. APPROACH TO THE PATIENT Fatigue A detailed history focusing on the quality, pattern, time course, associated symptoms, and alleviating factors of fatigue is neces­ sary to define the syndrome and help direct further evaluation and treatment. It is important to determine if fatigue is the appropriate designation, whether symptoms are acute or chronic, and if the impairment is primarily mental, physical, or a combination of the two. The review of systems should attempt to distinguish fatigue from excessive sleepiness, dyspnea on exertion, exercise intoler­ ance, and muscle weakness. The presence of fever, chills, night sweats, or weight loss should raise suspicion for an occult infection or malignancy. A careful review of prescription, over-the-counter, herbal, and recreational drug and alcohol use is required. Circum­ stances surrounding the onset of symptoms and potential triggers should be investigated. The social history is important, with atten­ tion paid to life stressors and adverse experiences, workhours, the social support network, and domestic affairs including a screen for intimate partner violence. Sleep habits and sleep hygiene should be questioned. The impact of fatigue on daily functioning is important to understand the patient’s experience and gauge recovery and the success of treatment. The physical examination of patients with fatigue is guided by the history and differential diagnosis. A detailed mental status examination should be performed with particular attention to symptoms of depression and anxiety. A formal neurologic exami­ nation is required to determine whether objective muscle weak­ ness is present. This is usually a straightforward exercise, although occasionally patients with fatigue have difficulty sustaining effort against resistance and sometimes report that generating full power requires substantial mental effort. On confrontational testing, full power may be generated for only a brief period before the patient suddenly gives way to the examiner. This type of weakness is often referred to as breakaway weakness and may or may not be associated with pain. This is contrasted with weakness due to lesions in the motor tracts or lower motor unit, in which the patient’s resistance can be overcome in a smooth and steady fashion and full power can never be generated. Occasionally, a patient may demonstrate fatigable weakness, in which power is full when first tested but becomes weak upon repeat evaluation without interval rest. Fati­ gable weakness, which usually indicates a problem of neuromuscu­ lar transmission, never has the sudden breakaway quality that one occasionally observes in patients with fatigue. If the presence or absence of muscle weakness cannot be determined with the physi­ cal examination, electromyography with nerve conduction studies can be a helpful ancillary test. The general physical examination should screen for signs of cardiopulmonary disease, malignancy, lymphadenopathy, organo­ megaly, infection, liver failure, kidney disease, malnutrition, endo­ crine abnormalities, and connective tissue disease. In patients with associated widespread musculoskeletal pain, assessment of tender points may help to reveal fibromyalgia. Although the diagnostic

yield of the general physical examination may be relatively low in the context of evaluation of unexplained chronic fatigue, elucidat­ ing the cause of only 2% of cases in one prospective analysis, the yield of a detailed neuropsychiatric and mental status evaluation is likely to be much higher, revealing a potential explanation for fatigue in up to 75–80% of patients in some series. Furthermore, a complete physical examination demonstrates a serious and system­ atic approach to the patient’s complaint and helps build trust and a therapeutic alliance. Laboratory testing is likely to identify the cause of chronic fatigue in only about 5% of cases. Beyond a few standard screening tests, laboratory evaluation should be guided by the history and physical examination; extensive testing is likely to lead to incidental findings that require explanation and unnecessary follow-up investigation and should be avoided in lieu of frequent clinical follow-up. A reasonable approach to screening includes a complete blood count with differential (to screen for anemia, infection, and malignancy), electrolytes (including sodium, potassium, and calcium), glucose, renal function, liver function, and thyroid function. Testing for HIV and adrenal function can also be considered. Published guidelines for ME/CFS also recommend an erythrocyte sedimentation rate (ESR) as part of the evaluation for mimics, but unless the value is very high, such nonspecific testing in the absence of other features is unlikely to clarify the situation. Routine screening with an anti­ nuclear antibody (ANA) test is also unlikely to be informative in isolation and is frequently positive at low titers in otherwise healthy adults. Additional unfocused studies, such as whole-body imaging scans, are usually not indicated; in addition to their inconvenience, potential risk, and cost, they often reveal unrelated incidental find­ ings that can prolong the workup unnecessarily. Fatigue CHAPTER 25 TREATMENT Fatigue The first priority is to address the underlying disorder or disor­ ders that account for fatigue, because this can be curative in select contexts and palliative in others. Unfortunately, in many chronic illnesses, fatigue may be refractory to traditional disease-modifying therapies, but it is nevertheless important in such cases to evaluate for other potential contributors because the cause may be multifac­ torial. Antidepressants (Chap. 463) may be helpful for treatment of chronic fatigue when symptoms of depression are present and are generally most effective as part of a multimodal approach. However, antidepressants can also cause fatigue and should be discontinued if they are not clearly effective. Cognitive-behavioral therapy has also been demonstrated to be helpful in ME/CFS as well as cancer-associated fatigue. Both cognitive-behavioral therapy and graded exercise therapy, in which physical exercise, most typically walking, is gradually increased with attention to target heart rates to avoid overexertion, were shown to modestly improve walking times and self-reported fatigue measures when compared to stan­ dard medical care in patients in the United Kingdom with chronic fatigue. These benefits were maintained after a median follow-up of 2.5 years. Exercise as an intervention has also demonstrated some benefit for patients with fatigue related to cancer, MS, and diabetes, among other conditions. Psychostimulants such as amphetamines, modafinil, and armodafinil can help increase alertness and concen­ tration and reduce excessive daytime sleepiness in certain clinical contexts, which may in turn help with symptoms of fatigue in a minority of patients, but they have generally proven to be unhelp­ ful in randomized trials for treating fatigue in posttraumatic brain injury, Parkinson’s disease, cancer, and MS. In patients with low vitamin D status, vitamin D replacement may lead to improvement in fatigue. Development of more effective therapy for fatigue is hampered by limited knowledge of the biologic basis of this symptom, includ­ ing how fatigue is detected and registered in the nervous system.

17 - 27 Numbness, Tingling, and Sensory Loss

27 Numbness, Tingling, and Sensory Loss

weakness usually is due to lower motor neuron or peripheral nerve dis­ ease, such as in a facial palsy. Weakness of part of a limb is commonly due to a peripheral nerve lesion such as an entrapment neuropathy. Relatively symmetric weakness of extraocular or bulbar muscles fre­ quently is due to a myopathy (Chap. 460) or neuromuscular junction disorder (Chap. 459). Bilateral facial palsy with areflexia suggests Guillain-Barré syndrome (Chap. 458). Worsening of relatively sym­ metric weakness with fatigue is characteristic of neuromuscular junc­ tion disorders. Asymmetric bulbar weakness usually is due to motor neuron disease. Weakness limited to respiratory muscles is uncommon and usually is due to motor neuron disease, myasthenia gravis, or polymyositis/dermatomyositis (Chap. 377).

PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■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. O’Brien M on behalf of the Guarantors of Brain: Aids to the Examination of the Peripheral Nervous System, 6th ed. Amsterdam, Elsevier, 2023. Stephen L. Hauser

Numbness, Tingling,

and Sensory Loss Normal somatic sensation reflects a continuous monitoring process, little of which reaches consciousness under ordinary conditions. By contrast, disordered sensation, particularly when experienced as painful, is alarming and dominates the patient’s attention. Physicians should be able to recognize abnormal sensations by how they are described, know their type and likely site of origin, and understand their implications. Pain is considered separately in Chap. 14. ■ ■POSITIVE AND NEGATIVE SYMPTOMS Abnormal sensory symptoms can be divided into two categories: positive and negative. The prototypical positive symptom is tingling (pins and needles); other positive sensory phenomena include itch and altered sensations that are described as pricking, bandlike, lightninglike shooting feelings (lancinations), aching, knifelike, twisting, draw­ ing, pulling, tightening, burning, searing, electrical, or raw feelings. Such symptoms are often painful. Positive phenomena usually result from trains of impulses gener­ ated at sites of lowered threshold or heightened excitability along a peripheral or central sensory pathway. The nature and severity of the abnormal sensation depend on the number, rate, timing, and distribu­ tion of ectopic impulses and the type and function of nervous tissue in which they arise. Because positive phenomena represent excessive activity in sensory pathways, they are not necessarily associated with a sensory deficit (loss) on examination. Negative phenomena represent loss of sensory function and are characterized by diminished or absent feeling that often is experienced as numbness and by abnormal findings on sensory examination. In disorders affecting peripheral sensation, at least one-half of the affer­ ent axons innervating a particular site are probably lost or functionless before a sensory deficit can be demonstrated by clinical examination. If the rate of loss is slow, however, lack of cutaneous feeling may be unno­ ticed by the patient and difficult to demonstrate on examination, even though few sensory fibers are functioning; if it is rapid, both positive and negative phenomena are usually conspicuous. Subclinical degrees

of sensory dysfunction may be revealed by sensory nerve conduction studies or somatosensory-evoked potentials. Whereas sensory symptoms may be either positive or negative, sensory signs on examination are always a measure of negative phenomena. ■ ■TERMINOLOGY Paresthesias and dysesthesias are general terms used to denote positive sensory symptoms. The term paresthesias typically refers to tingling or pins-and-needles sensations but may include a wide variety of other abnormal sensations, except pain; it sometimes implies that the abnor­ mal sensations are perceived spontaneously. The more general term dysesthesias denotes all types of abnormal sensations, including painful ones, regardless of whether a stimulus is evident. Another set of terms refers to sensory abnormalities found on exam­ ination. Hypesthesia or hypoesthesia refers to a reduction of cutaneous sensation to a specific type of testing such as pressure, light touch, and warm or cold stimuli; anesthesia, to a complete absence of skin sensa­ tion to the same stimuli plus pinprick; and hypalgesia or analgesia, to reduced or absent pain perception (nociception). Hyperesthesia means pain or increased sensitivity in response to touch. Similarly, allodynia describes the situation in which a nonpainful stimulus, once perceived, is experienced as painful, even excruciating. An example is elicitation of a painful sensation by application of a vibrating tuning fork. Hyperal­ gesia denotes severe pain in response to a mildly noxious stimulus, and hyperpathia, a broad term, encompasses all the phenomena described by hyperesthesia, allodynia, and hyperalgesia. With hyperpathia, the threshold for a sensory stimulus is increased and perception is delayed, but once felt, it is unduly painful. Disorders of deep sensation arising from muscle spindles, tendons, and joints affect proprioception (position sense). Manifestations include imbalance (particularly with eyes closed or in the dark), clum­ siness of precision movements, and unsteadiness of gait, which are referred to collectively as sensory ataxia. Other findings on examina­ tion usually, but not invariably, include reduced or absent joint posi­ tion and vibratory sensation and absent deep tendon reflexes in the affected limbs. The Romberg sign is positive, which means that the patient sways markedly or topples when asked to stand with feet close together and eyes closed. In severe states of deafferentation involving deep sensation, the patient cannot walk or stand unaided or even sit unsupported. Continuous involuntary movements (pseudoathetosis) of the outstretched hands and fingers occur, particularly with eyes closed. ■ ■ANATOMY OF SENSATION Cutaneous receptors are classified by the type of stimulus that opti­ mally excites them. They consist of naked nerve endings (nociceptors, which respond to tissue-damaging stimuli, and thermoreceptors, which respond to noninjurious thermal stimuli) and encapsulated terminals (several types of mechanoreceptor, activated by physical deformation of the skin or stretch of muscles). Each type of receptor has its own set of sensitivities to specific stimuli, size and distinctness of receptive fields, and adaptational qualities. Afferent peripheral nerve fibers conveying somatosensory informa­ tion from the limbs and trunk traverse the dorsal roots and enter the dorsal horn of the spinal cord (Fig. 27-1); the cell bodies of first-order neurons are located in the dorsal root ganglia (DRG). In an analogous fashion, sensations from the face and head are conveyed through the trigeminal system (Fig. 452-2). Once fiber tracts enter the spinal cord, the polysynaptic projections of the smaller fibers (unmyelinated and small myelinated), which subserve mainly nociception, itch, tempera­ ture sensibility, and touch, cross and ascend in the opposite anterior and lateral columns of the spinal cord, through the brainstem, to the ventral posterolateral (VPL) nucleus of the thalamus and ultimately project to the postcentral gyrus of the parietal cortex and other cortical areas (Chap. 14). This is the spinothalamic pathway or anterolateral system. The larger fibers, which subserve tactile and position sense and kinesthesia, project rostrally in the posterior and posterolateral columns on the same side of the spinal cord and make their first syn­ apse in the gracile or cuneate nucleus of the lower medulla. Axons of

Leg Trunk Post-central cortex Arm Thalamus Face Internal capsule Ventral posterolateral nucleus of thalamus MIDBRAIN Principal sensory nucleus of V PONS Medial lemniscus Nucleus of funiculus gracilis Nucleus of funiculus cuneatus MEDULLA Spinothalamic tract Nucleus of spinal tract V Posterior column fibers SPINAL CORD Spinothalamic tract FIGURE 27-1  The main somatosensory pathways. The spinothalamic tract (pain, thermal sense) and the posterior column–lemniscal system (touch, pressure, joint position) are shown. Offshoots from the ascending anterolateral fasciculus (spinothalamic tract) to nuclei in the medulla, pons, and mesencephalon and nuclear terminations of the tract are indicated. (Reproduced with permission from AH Ropper, MA Samuels: Adams and Victor’s Principles of Neurology, 9th ed. New York, McGraw-Hill, 2009.) second-order neurons decussate and ascend in the medial lemniscus located medially in the medulla and in the tegmentum of the pons and midbrain and synapse in the VPL nucleus; third-order neurons project to parietal cortex as well as to other cortical areas. This large-fiber system is referred to as the posterior column–medial lemniscal pathway (lemniscal, for short). Although the fiber types and functions that make up the spinothalamic and lemniscal systems are relatively well known, many other fibers, particularly those associated with touch, pressure, and position sense, ascend in a diffusely distributed pattern both ipsilaterally and contralaterally in the anterolateral quadrants of the spinal cord. This explains why a complete lesion of the posterior columns of the spinal cord may be associated with little sensory deficit on examination. APPROACH TO THE PATIENT Clinical Examination of Sensation The main components of the sensory examination are tests of pri­ mary sensation (pain, touch, vibration, joint position, and thermal sensation) (Table 27-1). The examiner must depend on patient responses, and this complicates interpretation. Further, examina­ tion may be limited in some patients. In a stuporous patient, for

example, sensory examination is reduced to observing the briskness of withdrawal in response to a pinch or another noxious stimulus. Comparison of responses on the two sides of the body is essential. In an alert but uncooperative patient, it may not be possible to examine cutaneous sensation, but some idea of proprioceptive function may be gained by noting the patient’s best performance of movements requiring balance and precision. In patients with sensory complaints, testing should begin in the center of the affected region and proceed radially until sensa­ tion is perceived as normal. The distribution of any abnormality is defined and compared to root and peripheral nerve territories (Figs. 27-2 and 27-3). Some patients present with sensory symp­ toms that do not fit an anatomic localization and are accompanied by either no abnormalities or gross inconsistencies on examination. The examiner should consider in such cases the possibility of a psychological cause (see “Psychogenic Symptoms,” below). Sensory examination of a patient who has no neurologic complaints can be brief and consist of pinprick, touch, and vibration testing in the hands and feet plus evaluation of stance and gait, including the Romberg maneuver (Chap. V6). Evaluation of stance and gait also tests the integrity of motor and cerebellar systems. Numbness, Tingling, and Sensory Loss CHAPTER 27 PRIMARY SENSATION The sense of pain usually is tested with a clean pin, which is then discarded. The patient is asked to close the eyes and focus on the pricking or unpleasant quality of the stimulus, not just the pressure or touch sensation elicited. Areas of hypalgesia should be mapped by proceeding radially from the most hypalgesic site. Temperature sensation to both hot and cold is best tested with small containers filled with water of the desired temperature. An alternative way to test cold sensation is to touch a metal object, such as a tuning fork at room temperature, to the skin. For testing warm temperatures, the tuning fork or another metal object may be held under warm water of the desired temperature and then used. The appreciation of both cold and warmth should be tested because different receptors respond to each. Touch usually is tested with a wisp of cotton, mini­ mizing pressure on the skin. In general, it is better to avoid testing touch on hairy skin because of the profusion of the sensory endings that surround each hair follicle. The patient is tested with the eyes closed and should respond as soon as the stimulus is perceived, indicating its location. Joint position testing is a measure of proprioception. With the patient’s eyes closed, joint position is tested in the distal inter­ phalangeal joint of the great toe and fingers. The digit is held by its sides, distal to the joint being tested, and moved passively while more proximal joints are stabilized—the patient indicates the change in position or direction of movement. If errors are made, more proximal joints are tested. A test of proximal joint position sense, primarily at the shoulder, is performed by asking the patient to bring the two index fingers together with arms extended and eyes closed. Normal individuals can do this accurately, with errors of 1 cm or less. The sense of vibration is tested with an oscillating tuning fork that vibrates at 128 Hz. Vibration is tested over bony points, begin­ ning distally; in the feet, it is tested over the dorsal surface of the distal phalanx of the big toes and at the malleoli of the ankles, and in the hands, it is tested dorsally at the distal phalanx of the fingers. If abnormalities are found, more proximal sites should be examined. Vibratory thresholds at the same site in the patient and the exam­ iner may be compared for control purposes. CORTICAL SENSATION The most commonly used tests of cortical function are two-point discrimination, touch localization, and bilateral simultaneous stim­ ulation, and tests for graphesthesia and stereognosis. Abnormalities of these sensory tests, in the presence of normal primary sensation in an alert cooperative patient, signify a lesion of the parietal cortex or thalamocortical projections. If primary sensation is altered, these

TABLE 27-1  Testing Primary Sensation SENSE TEST DEVICE ENDINGS ACTIVATED FIBER SIZE MEDIATING CENTRAL PATHWAY Pain Pinprick Cutaneous nociceptors Small SpTh, also D Temperature, heat Warm metal object Cutaneous thermoreceptors for hot Small SpTh Temperature, cold Cold metal object Cutaneous thermoreceptors for cold Small SpTh Touch Cotton wisp, fine brush Cutaneous mechanoreceptors, also naked endings Vibration Tuning fork, 128 Hz Mechanoreceptors, especially pacinian corpuscles Joint position Passive movement of specific joints Joint capsule and tendon endings, muscle spindles PART 2 Cardinal Manifestations and Presentation of Diseases Abbreviations: D, diffuse ascending projections in ipsilateral and contralateral anterolateral columns; Lem, posterior column and lemniscal projection, ipsilateral; SpTh, spinothalamic projection, contralateral. cortical discriminative functions usually will be abnormal also. Comparisons should always be made between analogous sites on the two sides of the body because the deficit with a specific parietal lesion is likely to be unilateral. Two-point discrimination can be tested with calipers, the points of which may be set from 2 mm to several centimeters apart and then applied simultaneously to the test site. On the fingertips, a nor­ mal individual can distinguish about a 3-mm separation of points. Touch localization is performed by light pressure for an instant with the examiner’s fingertip or a wisp of cotton wool; the patient, whose eyes are closed, is asked to identify the site of touch. Bilateral simultaneous stimulation at analogous sites (e.g., the dorsum of I II Great auricular n. III Ant. cut. n. of neck Supraclavicular n’s. Axillary n. (circumflex) T2

Ant. Med. cut. n. of arm & intercostobrachial n. cut. Lower lat. cut. n. of arm (from radial n.) Lat. rami of cut. thor. Med. cut. n. of forearm Lat. cut. of forearm (from musculocut. n.) n’s. rami Iliohypogastric n. Iliohypogastric n. Radial n. Ilioinguinal n. Ilioinguinal n. Median n. Genital branch of genitofem. n. Femoral branch of genito- femoral n. (lumbo-inguinal n.)
Ulnar n. Dorsal n. of penis Lat. cut. n. of thigh Intermed. & med. cut. n’s. of thigh (from femoral n.) Scrotal branch of perineal n. Obturator n. Saphenous n. (from femoral n.) Lat. cut. n. of calf (from common peroneal n.) Superficial peroneal n. (from common peroneal n.) Deep peroneal n. (from common peroneal n.) Med. & lat. plantar n’s. (from posttibial n.) Sural n. (from tibial n.) FIGURE 27-2  The cutaneous fields of peripheral nerves. (Reproduced with permission from W Haymaker, B Woodhall: Peripheral Nerve Injuries, 2nd ed. Philadelphia, Saunders, 1953.)

Large and small Lem, also D and SpTh Large Lem, also D Large Lem, also D both hands) can be carried out to determine whether the percep­ tion of touch is extinguished consistently on one side (extinction or neglect). Graphesthesia refers to the capacity to recognize, with eyes closed, letters or numbers drawn by the examiner’s fingertip on the palm of the hand. Once again, side-to-side comparison is of prime importance. Inability to recognize numbers or letters is termed agraphesthesia. Stereognosis refers to the ability to identify common objects by palpation, recognizing their shape, texture, and size. Common standard objects such as keys, paper clips, and coins are best used. Patients with normal stereognosis should be able to distinguish a dime from a penny and a nickel from a quarter without looking. Greater Lesser n. occipital nerves Great auricular n. Ant. cut. n. of neck C5 C6 Supraclavicular n’s. T1 T2

5 6 7 8 9 10 11 12 Post. cut. rami of thor. n’s. Axillary n. (circumflex) Lat. cut.
rami
Med. cut. n. of arm & intercostobrachial n. Post cut. n. of arm (from radial n.) Post. cut. n. of forearm (from radial n.) Lower Lat. cut. of arm (from radial n.) L1 Lat. cut. n. of forearm (from musculocut n.) Med. cut. n. of forearm S1 Post. rami of lumbar sacral & coccygeal n’s. Radial n. Iliohypogastric n. Ulnar n. Inf. med. cluneal n. Inf. lat. cluneal n’s. Median n. Inf. med. n. of thigh Obturator n. Post cut. n. of thigh Med. cut. n. of thigh (from femoral n.) Lat. cut. n.of calf (from common femoral n.) Lat. plantar n. Med. plantar n. Lat. plantar n. Saphenous n. (from femoral n.) Superficial peroneal n. Superficial peroneal n. (from common peroneal n.) Saphenous n. Sural n. (from tibial n.) Sural n. Calcanean branches of tibial & sural n’s. Calcanean branches of sural & tibial n’s.

FIGURE 27-3  Distribution of the sensory spinal roots on the surface of the body (dermatomes). (Reproduced with permission from Receptors of the somatosensory system. In ER Kandel, JD Koester, SH Mack, SA Siegelbaum. Principles of Neural science, 6th ed. New York: McGraw Hill; 2021.) Patients should feel the object with only one hand at a time. If they are unable to identify it in one hand, it should be placed in the other for comparison. Individuals who are unable to identify common objects and coins in one hand but can do so in the other are said to have astereognosis of the abnormal hand. QUANTITATIVE SENSORY TESTING Effective sensory testing devices are commercially available. Quan­ titative sensory testing is particularly useful for serial evaluation of cutaneous sensation in clinical trials. Threshold testing for touch and vibratory and thermal sensation is the most widely used application. ELECTRODIAGNOSTIC STUDIES AND NERVE BIOPSY Nerve conduction studies and nerve biopsy are important means of investigating the peripheral nervous system, but they do not evalu­ ate the function or structure of cutaneous receptors and free nerve endings or of unmyelinated or thinly myelinated nerve fibers in the nerve trunks. Skin biopsy can be used to evaluate these structures in the dermis and epidermis. ■ ■LOCALIZATION OF SENSORY ABNORMALITIES Sensory symptoms and signs can result from lesions at many different levels of the nervous system from the parietal cortex to the peripheral sensory receptor. Noting their distribution and nature is the most important way to localize their source. Their extent, configuration, symmetry, quality, and severity are the key observations.

Numbness, Tingling, and Sensory Loss CHAPTER 27 Dysesthesias without sensory findings by examination may be difficult to interpret. To illustrate, tingling dysesthesias in an acral distribution (hands and feet) can be systemic in origin, for example, secondary to hyperventilation, or induced by a medication such as acetazolamide. Distal dysesthesias can also be an early event in an evolving polyneuropathy or may herald a myelopathy, such as from vitamin B12 deficiency. Sometimes, distal dysesthesias have no defin­ able basis. In contrast, dysesthesias that correspond in distribution to that of a particular peripheral nerve structure denote a lesion at that site. For instance, dysesthesias restricted to the fifth digit and the adja­ cent one-half of the fourth finger on one hand reliably point to disorder of the ulnar nerve, most commonly at the elbow. Nerve and Root  In focal nerve trunk lesions, sensory abnormalities are readily mapped and generally have discrete boundaries (Figs. 27-2 and 27-3). Root (“radicular”) lesions frequently are accompanied by deep, aching pain along the course of the related nerve trunk. With compression of a fifth lumbar (L5) or first sacral (S1) root, as from a ruptured intervertebral disk, sciatica (radicular pain relating to the sciatic nerve trunk) is a common manifestation (Chap. 18). With a lesion affecting a single root, sensory deficits may be minimal or absent because adjacent root territories overlap extensively. Isolated mononeuropathies may cause symptoms beyond the terri­ tory supplied by the affected nerve, but abnormalities on examination typically are confined to expected anatomic boundaries. In multiple mononeuropathies, symptoms and signs occur in discrete territories supplied by different individual nerves and—as more nerves are

affected—may simulate a polyneuropathy if deficits become confluent. With polyneuropathies, sensory deficits are generally graded, distal, and symmetric in distribution (Chap. 457). Dysesthesias, followed by numbness, begin in the toes and ascend symmetrically. When dysesthesias reach the knees, they usually also have appeared in the fingertips. The process is nerve length–dependent, and the deficit is often described as “stocking glove” in type. Involvement of both hands and feet also occurs with lesions of the upper cervical cord or the brainstem, but an upper level of the sensory disturbance may then be found on the trunk and other evidence of a central lesion may be pres­ ent, such as sphincter involvement or signs of an upper motor neuron lesion (Chap. 26). Although most polyneuropathies are pansensory and affect all modalities of sensation, selective sensory dysfunction according to nerve fiber size may occur. Small-fiber polyneuropathies are characterized by burning, painful dysesthesias with reduced pin­ prick and thermal sensation but with sparing of proprioception, motor function, and deep tendon reflexes. Touch is involved variably; when it is spared, the pattern is referred to as a dissociated sensory loss. Impor­ tantly, sensory dissociation may occur also with spinal cord lesions (Chap. 453, and below). Large-fiber polyneuropathies are character­ ized by vibration and position sense deficits, imbalance, absent tendon reflexes, and variable motor dysfunction but preservation of most cutaneous sensation. Dysesthesias, if present at all, tend to be tingling or bandlike in quality.

PART 2 Cardinal Manifestations and Presentation of Diseases Sensory neuronopathy (or ganglionopathy) is characterized by widespread but asymmetric sensory loss occurring in a non-length-

dependent manner so that it may occur proximally or distally, and in the arms, legs, or both. Pain and numbness progress to sensory ataxia and impairment of all sensory modalities over time. This condition is usually paraneoplastic or idiopathic in origin (Chaps. 99 and 457) or related to an autoimmune disease, particularly Sjögren’s syndrome (Chap. 373). Spinal Cord  (See also Chap. 453) If the spinal cord is transected, all sensation is lost below the level of transection. Bladder and bowel function also are lost, as is motor function. Lateral hemisection of the spinal cord produces the Brown-Séquard syndrome, with absent pain and temperature sensation contralaterally and loss of proprioceptive sensation and power ipsilaterally below the lesion (see Figs. 27-1 and 453-1); ipsilateral pain or hyperesthesia may also occur. Numbness or paresthesias in both feet may arise from a spinal cord lesion; this is especially likely when the upper level of the sensory loss extends to the trunk. When all extremities are affected, the lesion is probably in the cervical region or brainstem unless a peripheral neuropathy is responsible. The presence of upper motor neuron signs (Chap. 26) supports a central lesion; a hyperesthetic band on the trunk may suggest the level of involvement. A dissociated sensory loss can reflect spinothalamic tract involve­ ment in the spinal cord, especially if the deficit is unilateral and has an upper level on the torso. Bilateral spinothalamic tract involvement occurs with lesions affecting the center of the spinal cord, such as in syringomyelia. There is a dissociated sensory loss with impairment of pinprick and temperature appreciation but relative preservation of light touch, position sense, and vibration appreciation. Dysfunction of the posterior columns in the spinal cord or of the posterior root entry zone may lead to a bandlike sensation around the trunk or a feeling of tight pressure in one or more limbs. Flexion of the neck sometimes leads to an electric shock–like sensation that radiates down the back and into the legs (Lhermitte’s sign) in patients with a cervical lesion affecting the posterior columns, such as from multiple sclerosis, cervical spondylosis, or following irradiation to the cervical region. Brainstem  Crossed patterns of sensory disturbance, in which one side of the face and the opposite side of the body are affected, local­ ize to the lateral medulla. Here a small lesion may damage both the ipsilateral descending trigeminal tract and trigeminal nucleus, plus the ascending spinothalamic fibers subserving the opposite arm, leg, and

hemitorso (see “Lateral medullary syndrome” in Fig. 437-7). A lesion in the tegmentum of the pons and midbrain, where the lemniscal and spinothalamic tracts merge, causes pansensory loss contralaterally. Thalamus  Hemisensory disturbance with tingling numbness from head to foot is often thalamic in origin but also can arise from the ante­ rior parietal region. If abrupt in onset, the lesion is likely to be due to a small stroke (lacunar infarction), particularly if localized to the thala­ mus. Occasionally, with lesions affecting the VPL nucleus or adjacent white matter, a syndrome of thalamic pain, also called Déjerine-Roussy syndrome, may ensue. The severe, persistent, unrelenting unilateral pain often is described in dramatic terms. Cortex  With lesions of the parietal lobe involving either the cortex or subjacent white matter, the most prominent symptoms are contra­ lateral hemineglect, hemi-inattention, and a tendency not to use the affected hand and arm. On cortical sensory testing (e.g., two-point discrimination, graphesthesia), abnormalities are often found, but pri­ mary sensation is usually intact. Anterior parietal infarction may pres­ ent as a pseudothalamic syndrome with contralateral loss of primary sensation from head to toe. Dysesthesias or a sense of numbness and, rarely, a painful state may also occur. Focal Sensory Seizures  These seizures generally are due to lesions in the area of the postcentral or precentral gyrus. The principal symptom of focal sensory seizures is tingling, but additional, more complex sensations may occur, such as a rushing feeling, a sense of warmth, or a sense of movement without detectable motion. Symptoms typically are unilateral; commonly begin in the arm or hand, face, or foot; and often spread in a manner that reflects the cortical represen­ tation of different bodily parts, a pattern referred to as a Jacksonian march. Their duration is variable; seizures may be transient, lasting only for seconds, or persist for an hour or more. Focal motor features may supervene, often becoming generalized with loss of consciousness and tonic-clonic jerking. Psychogenic Symptoms  Sensory symptoms can have a psycho­ genic basis. Such symptoms may be generalized or have an anatomic boundary that is difficult to explain neurologically, for example, cir­ cumferentially at the groin or shoulder or around a specific joint. Pain is common, but the nature and intensity of any sensory disturbances are variable. The diagnosis should not be one of exclusion but based on suggestive findings that are otherwise difficult to explain, such as mid­ line splitting of impaired vibration, pinprick, or light touch apprecia­ tion; variability or poor reproducibility of sensory deficits; or normal performance of tasks requiring sensory input that is seemingly abnor­ mal on formal testing, such as good performance with eyes closed of the finger-to-nose test despite an apparent loss of position sense in the upper limb. The side with abnormal sensation may be confused when the limbs are placed in an unusual position, such as crossed behind the back. Sensory complaints should not be regarded as psychogenic simply because they are unusual. ■ ■TREATMENT Management is based on treatment of the underlying condition. Symp­ tomatic treatment of acute and chronic pain is discussed in Chap. 14. Dysesthesias, when severe and persistent, may respond to anticonvul­ sants (carbamazepine, 100–1000 mg/d; gabapentin, 300–3600 mg/d; or pregabalin, 50–300 mg/d), antidepressants (amitriptyline, 25–150 mg/d; nortriptyline, 25–150 mg/d; desipramine, 100–300 mg/d; or venlafax­ ine, 75–225 mg/d). ■ ■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. Waxman S: Clinical Neuroanatomy, 30th ed. New York, McGraw Hill Education, 2024.

18 - 28 Gait Disorders, Imbalance, and Falls

28 Gait Disorders, Imbalance, and Falls

Jessica M. Baker, Gerald Pankratz

Gait Disorders,

Imbalance, and Falls PREVALENCE, MORBIDITY,

AND MORTALITY Gait and balance problems are common in the elderly and contribute to the risk of falls and injury. Gait disorders have been described in 15% of individuals aged >65. By age 80, one person in four will use a mechanical aid to assist with ambulation. Among those aged ≥85, the prevalence of gait abnormality approaches 40%. In epidemiologic studies, gait disorders are consistently identified as a major risk factor for falls and injury. ANATOMY AND PHYSIOLOGY An upright bipedal gait depends on the successful integration of postural control and locomotion. These functions are widely distributed in the central nervous system. The biomechanics of bipedal walking are com­ plex, and the performance is easily compromised by a neurologic deficit at any level. Command and control centers in the brainstem, cerebellum, and forebrain modify the action of spinal pattern generators to promote stepping. While a form of “fictive locomotion” can be elicited from qua­ drupedal animals after spinal transection, this capacity is limited in pri­ mates. Step generation in primates is dependent on locomotor centers in the pontine tegmentum, midbrain, and subthalamic region. Locomotor synergies are executed through the reticular formation and descending pathways in the ventromedial spinal cord. Cerebral control provides a goal and purpose for walking and is involved in avoidance of obstacles and adaptation of locomotor programs to context and terrain. Postural control requires the maintenance of the center of mass over the base of support through the gait cycle. Unconscious postural adjustments maintain standing balance: long latency responses are measurable in the leg muscles, beginning 110 milliseconds after a per­ turbation. Forward motion of the center of mass provides propulsive force for stepping, but failure to maintain the center of mass within sta­ bility limits results in falls. The anatomic substrate for dynamic balance has not been well defined, but the vestibular nucleus and midline cer­ ebellum contribute to balance control in animals. Patients with damage to these structures have impaired balance while standing and walking. TABLE 28-1  Prevalence of Neurologic Gait Disorders NEUROLOGIC GAIT DISORDER NO. (%)a TOTAL NUMBERb CAUSES (NO.) Single neurologic gait disorder 81 (69%)       Sensory ataxic 22 (18%)

Peripheral sensory neuropathy (46)   Parkinsonian 19 (16%)

Parkinson’s disease (18), drug-induced parkinsonism (8), dementia with parkinsonism (4), parkinsonism (4)   Higher level 9 (8%)

Vascular encephalopathy (20), normal pressure hydrocephalus (1), severe dementia (7), hypoxic ischemic encephalopathy (1), unknown (1)   Cerebellar ataxic 7 (6%)

Cerebellar stroke (3), cerebellar lesion due to multiple sclerosis (1), severe essential tremor (3), postvaccinal cerebellitis (1), chronic alcohol abuse (1), multiple system atrophy (1)   Cautious 7 (6%)

Idiopathic, associated fear of falling (7)   Paretic/hypotonic 6 (5%)

Neurogenic claudication (7), diabetic neuropathy (1), nerve lesion due to trauma or surgery (4), distal paraparesis after Guillain-Barré syndrome (1), unknown (2)   Spastic 6 (5%)

Ischemic stroke (3), intracerebral hemorrhage (3), congenital (1)   Vestibular ataxic 4 (3%)

Bilateral vestibulopathy (3), recent vestibular neuronitis (1), recent Ménière’s attack (1), acoustic neuroma with surgery (1)   Dyskinetic 1 (1%)

Levodopa-induced dyskinesia (3), chorea (1) Multiple neurologic gait disorders 36 (30%)     Total

aPercentage of individuals with a single gait disorder. bIncludes individuals with multiple gait disorders. Note: Of 117 patients with a neurologic gait disorder, 81 had a single neurologic gait disorder; the remainder (36) had multiple neurologic gait disorders. Source: Reproduced from P Mahlknecht et al: PLoS One 8:e69627, 2013.

Standing balance depends on good-quality sensory information about the position of the body center with respect to the environment, sup­ port surface, and gravitational forces. Sensory information for postural control is primarily generated by the visual system, the vestibular system, and proprioceptive receptors in the muscle spindles and joints. A healthy redundancy of sensory afferent information is generally available, but loss of two of the three pathways is sufficient to compromise standing balance. Balance disorders in older individuals sometimes result from multiple insults in the peripheral sensory systems (e.g., visual loss, ves­ tibular deficit, peripheral neuropathy) that critically degrade the quality of afferent information needed for balance stability.

Gait Disorders, Imbalance, and Falls CHAPTER 28 Older patients with cognitive impairment appear to be particularly prone to falls and injury. There is a growing body of literature on the use of attentional resources to manage gait and balance. Walking is generally considered to be unconscious and automatic, but the ability to walk while attending to a cognitive task (dual-task walking) may be compromised in the elderly. Older patients with deficits in executive function may have particular difficulty in managing the attentional resources needed for dynamic balance when distracted. Decline in gait speed and memory are increasingly associated with risk for dementia in older adults. DISORDERS OF GAIT Disorders of gait may be attributed to neurologic and nonneurologic causes, although significant overlap often exists. The antalgic gait results from avoidance of pain associated with weight bearing and is commonly seen in osteoarthritis. Asymmetry is a common feature of gait disorders due to contractures and other orthopedic deformities. Impaired vision rounds out the list of common nonneurologic causes of gait disorders. Neurologic gait disorders are disabling and equally important to address. The heterogeneity of gait disorders observed in clinical prac­ tice reflects the large network of neural systems involved in the task. Walking is vulnerable to neurologic disease at every level. Gait disor­ ders have been classified descriptively on the basis of abnormal physi­ ology and biomechanics. One problem with this approach is that many failing gaits look fundamentally similar. This overlap reflects common patterns of adaptation to threatened balance stability and declining performance. The gait disorder observed clinically must be viewed as the product of a neurologic deficit and a functional adaptation. Unique features of the failing gait are often overwhelmed by the adaptive response. Some common patterns of abnormal gait are summarized next. Gait disorders can also be classified by etiology (Table 28-1). Analy­ sis of gait remains primarily observational in clinical settings, though

quantitative gait analysis, with devices such as instrumented walkways, motion capture systems and wearables, is standard in research settings and has the potential to inform diagnosis and treatment of gait disor­ ders when more widely adopted in clinical settings.

■ ■CAUTIOUS GAIT The term cautious gait is used to describe the patient who walks with an abbreviated stride, widened base, and lowered center of mass, as if walking on a slippery surface. Arms are often held abducted. This disorder is both common and nonspecific. It is, in essence, an adapta­ tion to a perceived postural threat. There may be an associated fear of falling. This disorder can be observed in more than one-third of older patients with gait impairment. Physical therapy often improves walk­ ing to the degree that follow-up observation may reveal a more specific underlying disorder. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■STIFF-LEGGED GAIT Spastic gait is characterized by stiffness in the legs, an imbalance of muscle tone, and a tendency to circumduct and scuff the feet. The disorder reflects compromise of corticospinal command and overac­ tivity of spinal reflexes. The patient may walk on the toes. In extreme instances, the legs cross due to increased tone in the adductors (“scis­ soring” gait). Upper motor neuron signs are present on physical exami­ nation. The disorder may be cerebral or spinal in origin. Myelopathy from cervical spondylosis is a common cause of spastic or spastic-ataxic gait in the elderly. Demyelinating disease and trauma are the leading causes of myelopathy in younger patients. In chronic progressive myelopathy of unknown cause, a workup with laboratory and imaging tests may establish a diagnosis. A structural lesion, such as a tumor or a spinal vascular malformation, should be excluded with appropriate testing. Spinal cord disorders are discussed in detail in Chap. 453. With cerebral spasticity, asymmetry is common, the upper extremities are usually involved, and dysarthria is often an associated feature. Com­ mon causes include vascular disease (stroke), multiple sclerosis, motor neuron disease, and perinatal nervous system injury (cerebral palsy). Other stiff-legged gaits include dystonia (Chap. 447) and stiff-person syndrome (Chap. 99). Dystonia is a disorder characterized by sus­ tained muscle contractions resulting in repetitive twisting movements and abnormal posture. It often has a genetic basis, though asymmetric dystonia, particularly involving gait, may be a sign of Parkinson’s dis­ ease in younger adults. Dystonic spasms can produce plantar flexion and inversion of the feet, sometimes with torsion of the trunk. In autoimmune stiff-person syndrome, exaggerated lordosis of the lum­ bar spine and overactivation of antagonist muscles restrict trunk and lower-limb movement and result in a wooden or fixed posture. ■ ■PARKINSONISM, FREEZING GAIT,

AND OTHER MOVEMENT DISORDERS Parkinson’s disease (Chap. 446) is common, affecting 1% of the population >65 years of age. The stooped posture, shuffling gait, and decreased arm swing are characteristic and distinctive features. Patients sometimes accelerate (festinate) with walking, display retropulsion, or exhibit a tendency to turn en bloc. Falls are a major source of morbid­ ity, particularly later in the disease course, as balance becomes progres­ sively impaired. Dopamine replacement improves step length, arm swing, turning speed, and gait initiation. There is increasing evidence that deficits in cholinergic circuits in the pedunculopontine nucleus and cortex contribute to the gait disorder of Parkinson’s disease. Cho­ linesterase inhibitors such as donepezil and rivastigmine may decrease fall frequency, even in the absence of cognitive impairment, perhaps through improvement in attention. Freezing is defined as a brief, episodic absence of forward progres­ sion of the feet, despite the intention to walk. Freezing may be triggered by approaching a narrow doorway or crowd and contributes to fall risk. Gait freezing is present in approximately one-quarter of Parkinson’s patients within 5 years of onset, and its frequency increases further over time. In patients with motor fluctuations, freezing of gait occur­ ring in the “on” state often fails to respond to changes in levodopa;

auditory and visual cueing strategies may be used to overcome freez­ ing. End-of-dose gait freezing may improve with optimization of dopa­ minergic drugs or with use of monoamine oxidase type B inhibitors such as rasagiline or selegiline (Chap. 446). Freezing of gait is also common in other neurodegenerative disor­ ders associated with parkinsonism, including progressive supranuclear palsy (PSP) (Chap. 443), multiple-system atrophy (Chap. 451), and corticobasal degeneration (Chap. 443). Patients with these disorders frequently present with axial stiffness, postural instability, and a shuf­ fling, freezing gait while lacking the characteristic pill-rolling tremor of Parkinson’s disease. The gait of PSP is typically more erect compared with the stooped posture of typical Parkinson’s disease, and falls within the first year also suggest the possibility of PSP. The gait of vascular parkinsonism tends to be broad-based and shuffling with reduced arm swing bilaterally; disproportionate involvement of gait early in the dis­ ease course differentiates this entity from Parkinson’s disease. Hyperkinetic movement disorders also produce characteristic and recognizable disturbances in gait. In Huntington’s disease (Chap. 447), the unpredictable occurrence of choreic movements gives the gait a dancing quality. Tardive dyskinesia is the cause of many stereotypic gait disorders seen in patients chronically exposed to antipsychotics and other drugs that block the D2 dopamine receptor. Orthostatic tremor is a high-frequency, low-amplitude tremor predominantly involving the lower extremities. Patients often report shakiness or unsteadiness on standing and improvement with sitting or walking. Falls are common. The tremor is often only appreciable by palpating the legs while standing. ■ ■FRONTAL GAIT DISORDER Frontal gait disorder, also known as higher-level gait disorder, is com­ mon in the elderly and has a variety of causes. The term is used to describe a shuffling, freezing gait with imbalance, and other signs of higher cerebral dysfunction. Typical features include a wide base of support, a short stride, shuffling along the floor, and difficulty with starts and turns. Many patients exhibit a difficulty with gait initiation that is descriptively characterized as the “slipping clutch” syndrome or gait ignition failure. The term lower-body parkinsonism is also used to describe such patients. Strength is generally preserved, and patients are able to make stepping movements when not standing and maintaining their balance at the same time. This disorder is best considered a higher-level motor control disorder, as opposed to an apraxia (Chap. 32), though the term gait apraxia persists in the literature. The most common cause of frontal gait disorder is vascular disease, particularly subcortical small-vessel disease in the deep frontal white matter and centrum ovale. Over three-quarters of patients with sub­ cortical vascular dementia demonstrate gait abnormalities; decreased arm swing and a stooped posture are particularly prevalent features. The clinical syndrome also includes dysarthria, pseudobulbar affect (emotional disinhibition), increased tone, and hyperreflexia in the lower limbs (Chap. 444). Normal pressure (communicating) hydrocephalus (NPH) in adults also presents with a similar gait disorder (Chap. 442). Other features of the diagnostic triad (mental changes, incontinence) may be absent in a substantial number of patients. Magnetic resonance imaging (MRI) demonstrates ventricular enlargement, an enlarged flow void about the aqueduct, periventricular white matter change, and highconvexity tightness (disproportionate widening of the sylvian fissures versus the cortical sulci). A lumbar puncture or dynamic test is neces­ sary to confirm a diagnosis of NPH. Neurodegenerative dementias and mass lesions of the frontal lobes cause a similar clinical picture and can be differentiated from vascular disease and hydrocephalus by neuroimaging. ■ ■CEREBELLAR GAIT ATAXIA Disorders of the cerebellum (Chap. 450) have a dramatic impact on gait and balance. Cerebellar gait ataxia is characterized by a wide base of support, lateral instability of the trunk, erratic foot placement, and decompensation of balance when attempting to walk on a narrow base. Difficulty maintaining balance when turning is often an early feature. Patients are unable to walk tandem heel to toe and display truncal sway

TABLE 28-2  Features of Cerebellar Ataxia, Sensory Ataxia, and Frontal Gait Disorders FEATURE CEREBELLAR ATAXIA SENSORY ATAXIA FRONTAL GAIT Base of support Wide-based Wide-based, looks down Wide-based Velocity Variable Slow Very slow Stride Irregular, lurching Regular with path deviation Short, shuffling Romberg test +/– Unsteady, falls +/– Heel → shin Abnormal +/– Normal Initiation Normal Normal Hesitant Turns Unsteady +/– Hesitant, multistep Postural instability + +++ ++++ Poor postural synergies rising from a chair Falls Late event Frequent Frequent in narrow-based or tandem stance. They show considerable variation in their tendency to fall in daily life. Causes of cerebellar ataxia in older patients include stroke, trauma, tumor, and neurodegenerative disease such as multiple-system atrophy (Chap. 451) and various forms of hereditary cerebellar degeneration (Chap. 450). A short expansion at the site of the fragile X mutation (fragile X premutation) has been associated with gait ataxia in older men. Alcohol causes acute and chronic cerebellar ataxia. In patients with ataxia due to cerebellar degeneration, MRI demonstrates the extent and topography of cerebellar atrophy. ■ ■SENSORY ATAXIA As reviewed earlier in this chapter, balance depends on high-quality afferent information from the visual and the vestibular systems and proprioception. When this information is lost or degraded, balance during locomotion is impaired and instability results. The sensory ataxia of tabetic neurosyphilis is a classic example. The contemporary equivalent is the patient with neuropathy affecting large fibers. Vitamin B12 deficiency is a treatable cause of large-fiber sensory loss in the spinal cord and peripheral nervous system. Joint position and vibration sense are diminished in the lower limbs. The stance in such patients is desta­ bilized by eye closure; they often look down at their feet when walking and do poorly in the dark. Table 28-2 compares sensory ataxia with cerebellar ataxia and frontal gait disorder. ■ ■NEUROMUSCULAR DISEASE Patients with neuromuscular disease often have an abnormal gait, occasionally as a presenting feature. With distal weakness (peripheral neuropathy), the step height is increased to compensate for foot drop, and the sole of the foot may slap on the floor during weight accep­ tance, termed the steppage gait. Patients with myopathy or muscular dystrophy more typically exhibit proximal weakness. Weakness of the hip girdle may result in some degree of excess pelvic sway during locomotion. The stooped posture of lumbar spinal stenosis ameliorates pain from the compression of the cauda equina occurring with a more upright posture while walking and may mimic early parkinsonism. ■ ■TOXIC AND METABOLIC DISORDERS Chronic toxicity from medications and metabolic disturbances can impair motor function and gait. Examination may reveal mental status changes, asterixis, or myoclonus. Static equilibrium is disturbed, and such patients are easily thrown off balance. Disequilibrium is par­ ticularly evident in patients with chronic renal disease and those with hepatic failure, in whom asterixis may impair postural support. Seda­ tive drugs, especially neuroleptics and long-acting benzodiazepines, affect postural control and increase the risk for falls. These disorders are especially important to recognize because they are often treatable. ■ ■FUNCTIONAL GAIT DISORDER Functional neurologic disorders (formerly “psychogenic”) are common in practice, and the presentation often involves gait. Sudden onset, inconsistent deficits, waxing and waning course, incongruence of symptoms with an organic lesion, and improvement with distraction are key features. Phenomenology is variable; extreme slow motion, an inappropriately overcautious gait, gyrations of posture with wastage of

Gait Disorders, Imbalance, and Falls CHAPTER 28 muscular energy, astasia–abasia (inability to stand and walk), bounc­ ing, and foot stiffness (dystonia) have been described. Falls are rare, and there are often discrepancies between examination findings and the patient’s functional status. Preceding stress or trauma is variably present, and its absence does not preclude the diagnosis of a functional gait disorder. Functional gait disorders may be challenging to diagnose and should be differentiated from the slowness and psychomotor retar­ dation seen in certain patients with major depression. APPROACH TO THE PATIENT Slowly Progressive Disorder of Gait When reviewing the history, it is helpful to inquire about the onset and progression of disability. Initial awareness of an unsteady gait often follows a fall. Stepwise evolution or sudden progression sug­ gests vascular disease. Gait disorder may be associated with urinary urgency and incontinence, particularly in patients with cervical spine disease or hydrocephalus. It is always important to review the use of alcohol and medications that affect gait and balance. Infor­ mation on localization derived from the neurologic examination can be helpful in narrowing the list of possible diagnoses. Gait observation provides an immediate sense of the patient’s degree of disability. Arthritic and antalgic gaits are recognized by observation, although neurologic and orthopedic problems may coexist. Characteristic patterns of abnormality are sometimes seen, although, as stated previously, failing gaits often look fundamentally similar. Cadence (steps per minute), velocity, and stride length can be recorded by timing a patient over a fixed distance. Watching the patient rise from a chair provides a good functional assessment of balance. Brain imaging studies may be informative in patients with an undiagnosed disorder of gait. MRI is sensitive for cerebral lesions of vascular or demyelinating disease and is a good screening test for occult hydrocephalus. Patients with recurrent falls are at risk for subdural hematoma. As mentioned earlier, many elderly patients with gait and balance difficulty have white matter abnormali­ ties in the periventricular region and centrum semiovale. While these lesions may be an incidental finding, a substantial burden of white matter disease will ultimately impact cerebral control of locomotion. DISORDERS OF BALANCE ■ ■DEFINITION, ETIOLOGY, AND MANIFESTATIONS Balance is the ability to maintain equilibrium—a dynamic state in which one’s center of mass is controlled with respect to the lower extremities, gravity, and the support surface despite external perturba­ tions. The reflexes required to maintain upright posture require input from cerebellar, vestibular, and somatosensory systems; the premotor cortex and corticospinal and reticulospinal tracts mediate output to axial and proximal limb muscles. These responses are physiologi­ cally complex, and the anatomic representation they entail is not well

understood. Failure can occur at any level and presents as difficulty maintaining posture while standing and walking.

The history and physical examination may differentiate underlying causes of imbalance. Patients with cerebellar ataxia do not generally complain of dizziness, although balance is visibly impaired. Neurologic examination reveals a variety of cerebellar signs. Postural compensa­ tion may prevent falls early on, but falls are inevitable with disease progression. The progression of neurodegenerative ataxia is often mea­ sured by the number of years to loss of stable ambulation. Vestibular disorders (Chap. 24) have symptoms and signs that fall into three categories: (1) vertigo (the subjective inappropriate percep­ tion or illusion of movement); (2) nystagmus (involuntary eye move­ ments); and (3) impaired standing balance. Not every patient has all manifestations. Patients with vestibular deficits related to ototoxic drugs may lack vertigo or obvious nystagmus, but their balance is impaired on standing and walking, and they cannot navigate in the dark. Laboratory testing is available to investigate vestibular deficits. PART 2 Cardinal Manifestations and Presentation of Diseases Somatosensory deficits also produce imbalance and falls. There is often a subjective sense of insecure balance and fear of falling. Postural control is compromised by eye closure (Romberg’s sign); these patients also have difficulty navigating in the dark. A dramatic example is pro­ vided by the patient with autoimmune subacute sensory neuronopathy, which is sometimes a paraneoplastic disorder (Chap. 99). Compensa­ tory strategies enable such patients to walk in the virtual absence of proprioception, but the task requires active visual monitoring. Patients with higher-level disorders of equilibrium have difficulty maintaining balance in daily life and may present with falls. Their awareness of balance impairment may be reduced. Patients taking sedating medications are in this category. ■ ■FALLS Falls are common in the elderly. Over one-third of people aged >65 who are living in the community fall each year, and this number is even higher in nursing homes and hospitals. Elderly people are not only at higher risk for falls but are also more likely to suffer serious complications due to medical comorbidities such as osteoporosis. Hip fractures result in hospitalization, can lead to nursing home admission, and are associated with a substantially increased mortality risk in the subsequent year. Falls may result in brain or spinal injury, the history of which may be difficult for the patient to provide. The proportion of spinal cord injuries due to falls in individuals aged >65 years has doubled in the past decade, perhaps due to increasing activity in this age group. Some falls result in a prolonged time lying on the ground increasing risk for dehydration and rhabdomyolysis. For each person who is physically disabled, there are others whose functional independence is limited by anxiety and fear of falling. Nearly one in five elderly individuals voluntarily restricts their activity because of fear of falling. With loss of ambulation, the quality of life diminishes, and rates of morbidity and mortality increase. ■ ■RISK FACTORS FOR FALLS Risk factors for falls may be intrinsic (e.g., gait and balance disorders, visual impairment) or extrinsic (e.g., wet surfaces, improper footwear); some risk factors are modifiable. The presence of multiple risk factors is associated with a substantially increased risk of falls. Polypharmacy (use of four or more prescription medications) has also been identified as an important risk factor. Table 28-3 summarizes the principal risk factors for falls. ■ ■ASSESSMENT OF THE PATIENT WITH FALLS The most productive approach is to identify the high-risk patient prospectively, before there is a serious injury. All community-dwelling adults should be asked annually about falls and whether or not fear of falling limits daily activities. The Timed Up and Go (TUG) test involves timing a patient as they stand up from a chair, walk 10 feet, turn, and then sit down. Patients with a history of falls or those requir­ ing >12 seconds to complete the TUG test are at high risk for falls and should undergo further assessment. History  The history surrounding a fall is often problematic or incomplete, and the underlying mechanism or cause may be difficult

TABLE 28-3  Common Risk Factors for Falls in Older Adults RISK FACTOR History of falls Gait and/or balance disorder Visual deficits Physical disability • Includes muscle weakness, use of assistive devices, osteoarthritis of the knee Orthostatic hypotension Depression Cognitive impairment Medications • Polypharmacy, use of antipsychotics, antidepressants, benzodiazepines, anticholinergics, antihypertensives, and diuretics to establish in retrospect. A report from an attentive observer to the fall can be invaluable. If a sudden drop without provocation is reported, suspicion for syncope, seizure, or other neurologic event should rise. Gait freezing and festination should raise concern for parkinsonism. Falling after arising from a chair or after a minor perturbation suggests a muscular strength issue. Falls occurring in changing footing situa­ tions or in poor lighting suggest somatosensory, visual, or vestibular deficits as causes. Patients should be queried about any provoking factors (including head turn, standing, carrying an object) or prodromal symptoms, such as dizziness, vertigo, presyncopal symptoms, or focal weakness. A his­ tory of baseline mobility and medical comorbidities should be elicited. Patients at particular risk include those with mental status changes or dementia. Medications should be reviewed, with particular attention to benzodiazepines, opioids, antipsychotics, antiepileptics, antidepres­ sants, antiarrhythmics, and diuretics, all of which are associated with an increased risk of falls. It is equally important to distinguish mechani­ cal falls (those caused by tripping or slipping) due to purely extrinsic or environmental factors from those in which a possibly modifiable intrinsic factor contributes. Recurrent falls suggest an underlying gait or balance disorder. Falls associated with loss of consciousness (syncope, seizure) may require appropriate cardiac (Chap. 243) or neurologic (Chaps. 23 and 436) evaluation and intervention, although a patient’s report of change in consciousness may be unreliable. Physical Examination  Examination of the patient with falls should include a cardiac examination looking for rhythm irregulari­ ties or murmurs. Supine blood pressure should be compared both to standing pressures shortly after arising and after 3 minutes to evaluate for immediate or delayed orthostasis (Chap. 451). A systolic drop of

20 mmHg, a diastolic drop >10 mmHg, or a marked increase in heart rate should be investigated. Visual acuity can be assessed with a pocket or wall eye chart and performed with eyewear that the patient typically wears when walk­ ing. Peripheral fields can be assessed if suspicion for a visual field cut is present. Bilateral hearing assessments can be pursued, especially if a vestibular problem is suspected. The patient’s standing posture should be evaluated for spinal defor­ mity (kyphosis, lordosis, scoliosis). Orthopedic complications such as arthritis can cause knee alignment deformity and overpronation at the ankle/hindfoot. Feet should be inspected for calluses, great toe deformation like hallux valgus, hammertoes, and loss of the arch. Foot­ wear should be evaluated for fit to the top of the mid foot, attachment behind the calcaneus, and depth of tread and wear pattern on the sole. Mental status is easily assessed while obtaining a history from the patient. Motor function in the lower extremities should be done with particular attention paid to hip abductors and flexors, knee extensors and flexors, and ankle dorsiflexors and plantar flexors. Tone assessment in these muscle groups can be useful when neuromuscular disease is suspected. A sensory exam is useful to determine if the patient has developed a neuropathy impacting how they feel the surface they are standing and walking upon. Monofilament testing, during which

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29 Confusion and Delirium

pressure applied to a small nylon filament is used to assess sensation over the plantar aspect of the foot, can be used to screen for neuropathy in patients with diabetes. Sensory testing should also include proprio­ ceptive awareness at the great toe and ankle. A heel-to-shin test can assess cerebellar input on the lower extremity. The remainder of the neurologic examination should assess gait and balance as described earlier in this chapter. Fall Patterns  The description of a fall event may provide further clues to the underlying etiology. While there is no standard nosology of falls, some common clinical patterns may emerge and provide a clue. DROP ATTACKS AND COLLAPSING FALLS  Drop attacks and collapsing falls are associated with a sudden loss of postural tone. Patients may report that their legs just “gave out” underneath them or that they “col­ lapsed in a heap.” Syncope or orthostatic hypotension may be a factor in some such falls. Neurologic causes are relatively rare but include atonic seizures, myoclonus, and intermittent obstruction of the fora­ men of Monro by a colloid cyst of the third ventricle causing acute obstructive hydrocephalus. An emotional trigger suggests cataplexy. While collapsing falls are more common among older patients with vascular risk factors, drop attacks should not be confused with verte­ brobasilar ischemic attacks. TOPPLING FALLS  Some patients maintain tone in antigravity muscles but fall over like a tree trunk, as if postural defenses had disengaged. Causes include cerebellar pathology and lesions of the vestibular sys­ tem. There may be a consistent direction to such falls. Toppling falls are an early feature of PSP, and a late feature of Parkinson’s disease, once postural instability has developed. Thalamic lesions causing truncal instability (thalamic astasia) may also contribute to this type of fall. FALLS DUE TO GAIT FREEZING  Freezing of gait is seen in Parkinson’s disease and related disorders. The feet stick to the floor and the center of mass keeps moving, resulting in a disequilibrium from which the patient has difficulty recovering, resulting in a forward fall. Similarly, patients with Parkinson’s disease and festinating gait may find their feet unable to keep up and may thus fall forward. FALLS RELATED TO SENSORY LOSS  Patients with somatosensory, visual, or vestibular deficits are prone to falls. These patients have particular difficulty dealing with poor illumination or walking on uneven ground. They often report subjective imbalance, apprehension, and fear of falling. These patients may be especially responsive to a rehabilitation-based intervention. FALLS RELATED TO WEAKNESS  Patients who lack strength in antigrav­ ity muscles have difficulty rising from a chair or maintaining their bal­ ance after a perturbation. These patients are often unable to get up after a fall and may have to remain on the floor for a prolonged period until help arrives. If due to deconditioning, this is often treatable. Resistance strength training can increase muscle mass and leg strength, even for people in their eighties and nineties. TREATMENT Interventions to Reduce the Risk of Falls and Injury Efforts should be made to define the mechanism underlying falls in a given patient, as specific treatment may be possible once a diag­ nosis is established. Exercise should be recommended for everyone. Home- and group-based exercise programs focusing on leg strength and balance, physical therapy, and use of assistive devices reduce fall risk in individuals with a history of falls or disorders of gait and bal­ ance. Rehabilitative interventions aim to improve muscle strength and balance stability and to make the patient more resistant to injury and fracture. Resistance training with weights and machines is useful to improve muscle mass, even in frail older patients. Improvements realized in posture and gait should translate to reduced risk of falls and injury. Sensory balance training is another approach to improving balance stability. Measurable gains can be made in a few weeks of training, and benefits can be maintained over 6 months by a 10- to 20-min home exercise program. This

strategy is particularly successful in patients with vestibular and somatosensory balance disorders. The Centers for Disease Control and Prevention’s STEADI program (Stopping Elderly Accidents, Deaths and Injuries) is freely available online and contains tools for use by clinicians, patients, and their families to screen, assess, and offer interventions to minimize the risk of falls in older adults.

Orthostatic changes in blood pressure and pulse should be recorded. Contributory medications should be scrutinized and behavioral modifications initiated. Medications (including overthe-counter) should be reviewed, reevaluating benefits and burdens of medications that might increase fall risk. Treatment of cataracts and avoidance of multifocal lenses could be considered for patients whose falls may result from vision impairment. A home visit (often by an occupational therapist) to look for environmental hazards can be helpful. A variety of modifications may be recom­ mended to improve safety, including improved lighting, installation of grab bars and nonslip surfaces, and use of adaptive equip­ ment like walkers. Cognitive training, including dual-task training, may improve mobility in older adults with cognitive impairment. Adequate supervision appears to be most essential in this high-risk population. Confusion and Delirium CHAPTER 29 ■ ■FURTHER READING American Geriatrics Society, British Geriatrics Society, American Academy of Orthopedic Surgeons Panel on Falls Prevention: Guideline for the prevention of falls in older persons. J Am Geriatr Soc 49:664, 2001. Centers for Disease Control and Prevention: STEADI: Older Adult Fall Prevention. Available from https://www.cdc.gov/steadi/ index.html.  Accessed January 2, 2024. Colón-Emeric CS et al: Risk assessment and prevention of falls in older community-dwelling adults: A review. JAMA 331:1397, 2024. Nutt JG: Classification of gait and balance disorders. Adv Neurol 87:135, 2001. Pirker W, Katzenschlager R: Gait disorders in adults and the elderly. Wien Klin Wochenschr 129:81, 2017. S. Andrew Josephson, Bruce L. Miller

Confusion and Delirium Confusion, a mental and behavioral state of reduced comprehen­ sion, coherence, and capacity to reason, is one of the most common problems encountered in medicine, accounting for a large number of emergency department visits, hospital admissions, and inpatient con­ sultations. Delirium, a term used to describe an acute confusional state, remains a major cause of morbidity and mortality, costing billions of dollars yearly in health care costs in the United States alone. Despite increased efforts targeting awareness of this condition, delirium often goes unrecognized despite evidence that it is often the cognitive mani­ festation of serious underlying medical or neurologic illness. ■ ■CLINICAL FEATURES OF DELIRIUM A multitude of terms are used to describe patients with delirium, including encephalopathy, acute brain failure, acute altered mental status, acute confusional state, and postoperative or intensive care unit (ICU) psychosis. Delirium has many clinical manifestations, but it is defined as a relatively acute decline in cognition that fluctuates over hours or days. The hallmark of delirium is a deficit of attention, although all cognitive domains—including memory, executive func­ tion, visuospatial tasks, and language—are variably involved. Associ­ ated symptoms that may be present in some cases include altered

sleep-wake cycles, perceptual disturbances such as hallucinations or delusions, affect changes, and autonomic findings that include heart rate and blood pressure instability.

Delirium is a clinical diagnosis that is made only at the bedside. Two subtypes have been described—hyperactive and hypoactive—based on differential psychomotor features. The cognitive syndrome associ­ ated with severe alcohol withdrawal (i.e., “delirium tremens”) remains the classic example of the hyperactive subtype, featuring prominent hallucinations, agitation, and hyperarousal, often accompanied by lifethreatening autonomic instability. In striking contrast is the hypoactive subtype, exemplified by benzodiazepine intoxication, in which patients are withdrawn and quiet, with prominent apathy and psychomotor slowing. PART 2 Cardinal Manifestations and Presentation of Diseases This dichotomy between subtypes of delirium is a useful construct, but patients often fall somewhere along a spectrum between the hyperactive and hypoactive extremes, sometimes fluctuating from one to the other. Therefore, clinicians must recognize this broad range of presentations of delirium to identify all patients with this potentially reversible cognitive disturbance. Hyperactive patients are often easily recognized by their characteristic severe agitation, tremor, hallucina­ tions, and autonomic instability. Patients who are quietly hypoactive are more often overlooked and underdiagnosed on the medical wards and in the ICU. The reversibility of delirium is emphasized because many etiologies, such as infection and medication effects, can be treated easily. The long-term cognitive consequences of delirium remain an area of active research. Some episodes of delirium continue for weeks, months, or even years. The persistence of delirium in some patients and its high recurrence rate may be due to inadequate initial treatment of the underlying etiology, including neurodegenerative diseases. In other instances, delirium appears to cause permanent neuronal damage and long-term cognitive decline. Therefore, prevention strategies are important to implement. Even if an episode of delirium completely resolves, there may be lingering effects of the disorder; a patient’s recall of events after delirium varies widely, ranging from complete amnesia to repeated reexperiencing of the frightening period of confusion, similar to what is seen in patients with posttraumatic stress disorder. ■ ■RISK FACTORS An effective primary prevention strategy for delirium begins with identification of high-risk patients. Some hospital systems have initi­ ated comprehensive delirium programs that screen most or all patients upon admission or before elective surgery; positive screens trigger a host of focused prevention measures. Multiple validated scoring sys­ tems have been developed as a screen for asymptomatic patients, many of which emphasize well-established risk factors for delirium. The two most consistently identified risk factors are older age and baseline cognitive dysfunction. Individuals who are aged >65 or exhibit low scores on standardized tests of cognition develop delirium upon hospitalization at a rate approaching 50%. Whether age and baseline cognitive dysfunction are truly independent risk factors or are related is uncertain. Other predisposing factors include sensory deprivation, such as preexisting hearing and visual impairment, as well as indices for poor overall health, including baseline immobility, malnutrition, and underlying medical or neurologic illness. In-hospital risks for delirium include the use of physical restraints, bladder catheterization, sleep and sensory deprivation, and the addi­ tion of three or more new medications. Avoiding such risks remains a key component of delirium prevention as well as treatment. Surgi­ cal and anesthetic risk factors for the development of postoperative delirium include procedures such as those involving cardiopulmonary bypass, inadequate or excessive treatment of pain in the immediate postoperative period, and perhaps specific agents such as inhalational anesthetics or benzodiazepines. The relationship between delirium and dementia (Chap. 31) is com­ plicated by significant overlap between the two conditions, and it is not always simple to distinguish between them. Dementia and preexisting cognitive dysfunction serve as major risk factors for delirium, and at least two-thirds of cases of delirium occur in patients with coexisting

underlying dementia. A form of dementia with parkinsonism, demen­ tia with Lewy bodies (Chap. 445), is characterized by a fluctuating course, prominent visual hallucinations, parkinsonism, and an atten­ tional deficit that clinically resembles hyperactive delirium; patients with this condition are particularly vulnerable to delirium. Delirium in the elderly often reflects an insult to a brain that is vulnerable due to an underlying neurodegenerative condition. Therefore, the development of delirium sometimes heralds the onset of a previously unrecognized brain disorder, and after the acute delirious episode has cleared, careful screening for an underlying condition should occur in the outpatient setting. ■ ■EPIDEMIOLOGY Delirium is common, but its reported incidence has varied widely with the criteria used to define this disorder. Estimates of delirium in hospi­ talized patients range from 10% to >50%, with higher rates reported for elderly patients and patients undergoing hip surgery. Older patients in the ICU have especially high rates of delirium that approach 75%. The condition is not recognized in up to one-third of delirious inpatients, and the diagnosis is especially problematic in the ICU environment, where cognitive dysfunction is often difficult to appreciate in the setting of serious systemic illness and sedation. Delirium in the ICU should be viewed as an important manifestation of organ dysfunction not unlike liver, kidney, or heart failure. Outside the acute hospital setting, delirium occurs in nearly one-quarter of patients in nurs­ ing homes and in 50–80% of those at the end of life. These estimates emphasize the remarkably high frequency of this cognitive syndrome in older patients, a population that continues to grow. An episode of delirium was previously viewed as a transient condi­ tion that carried a benign prognosis. It is now recognized as a disorder with substantial morbidity and mortality that often represents the first manifestation of a serious underlying illness. Estimates of in-hospital mortality rates among delirious patients range from 25% to 33%, similar to mortality rates due to sepsis. Patients with an in-hospital episode of delirium have a fivefold higher mortality rate in the months after their illness compared with age-matched nondelirious hospital­ ized patients. Delirious hospitalized patients also have a longer length of stay, are more likely to be discharged to a nursing home, have a higher frequency of readmission, and are more likely to experience subsequent episodes of delirium and cognitive decline; as a result, this condition has an enormous economic cost. ■ ■PATHOGENESIS The pathogenesis and anatomy of delirium are incompletely under­ stood. The attentional deficit that serves as the neuropsychological hallmark of delirium has a diffuse localization within the brainstem, thalamus, prefrontal cortex, and parietal lobes. Rarely, focal lesions such as ischemic strokes have led to delirium in otherwise healthy persons; right parietal and medial dorsal thalamic lesions have been reported most commonly, pointing to the importance of these areas in delirium pathogenesis. In most cases, however, delirium results from widespread disturbances in cortical and subcortical regions of the brain. Electroencephalogram (EEG) often reveals symmet­ ric slowing, a nonspecific finding that supports diffuse cerebral dysfunction. Multiple neurotransmitter abnormalities, proinflammatory factors, and specific genes likely play a role in the pathogenesis of delirium. Deficiency of acetylcholine may play a key role, and medications with anticholinergic properties can commonly precipitate delirium. As noted earlier, patients with preexisting dementia are particularly susceptible to episodes of delirium. Alzheimer’s disease (Chap. 442), dementia with Lewy bodies (Chap. 445), and Parkinson’s disease dementia (Chap. 446) are all associated with cholinergic deficiency due to degeneration of acetylcholine-producing neurons in the basal forebrain. In addition, other neurotransmitters are also likely to be involved in this diffuse cerebral disorder. For example, increases in dopamine can lead to delirium, and patients with Parkinson’s disease treated with dopaminergic medications can develop a delirium-like state that features visual hallucinations, fluctuations, and confusion.

Not all individuals exposed to the same insult will develop signs of delirium. A low dose of an anticholinergic medication may have no cognitive effects on a healthy young adult but produce a florid delirium in an elderly person with known underlying dementia, although even healthy young persons develop delirium with very high doses of anticholinergic medications. This concept of delirium developing as the result of an insult in predisposed individuals is currently the most widely accepted pathogenic construct. Therefore, if a previously healthy individual with no known history of cognitive illness develops delirium in the setting of a relatively minor insult such as elective surgery, a urinary tract infection, or hospitalization, an unrecognized underlying neurologic illness such as a neurodegenerative disease, multiple previous strokes, or another diffuse cerebral cause should be considered. In this context, delirium can be viewed as a “stress test for the brain” whereby exposure to known inciting factors such as systemic infection and offending drugs can unmask a decreased cerebral reserve and herald a serious underlying and potentially treatable illness. New blood-based biomarkers for specific dementias may soon be available to help predict people at risk for delirium prior to surgical procedures or hospitalization. APPROACH TO THE PATIENT Delirium Because the diagnosis of delirium is clinical and is made at the bedside, a careful history and physical examination are necessary in evaluating patients with possible confusional states. Screening tools can aid physicians and nurses in identifying patients with delirium, including the Confusion Assessment Method (CAM); the Nursing Delirium Screening Scale (NuDESC); the Organic Brain Syndrome Scale; the Delirium Rating Scale; and, in the ICU, the ICU version of the CAM and the Delirium Detection Score. Using the well-

validated CAM, a diagnosis of delirium is made if there is (1) an acute onset and fluctuating course and (2) inattention accompanied by either (3) disorganized thinking or (4) an altered level of conscious­ ness. These scales may not identify the full spectrum of patients with delirium, and all patients who are acutely confused should be presumed delirious regardless of their presentation due to the wide variety of possible clinical features. A course that fluctuates over hours or days and may worsen at night (termed sundowning) is typical but not essential for the diagnosis. Observation will usu­ ally reveal an altered level of consciousness or a deficit of attention. Other features that are only sometimes present include alteration of sleep-wake cycles, thought disturbances such as hallucinations or delusions, autonomic instability, and changes in affect. HISTORY It may be difficult to elicit an accurate history in delirious patients who have altered levels of consciousness or impaired attention. Information from a collateral source such as a spouse or another family member is therefore invaluable. The three most important pieces of history are the patient’s baseline cognitive function, the time course of the present illness, and current medications. Premorbid cognitive function can be assessed through the col­ lateral source or, if needed, via a review of outpatient records. Delir­ ium by definition represents a change from a cognitive baseline that is relatively acute and usually develops over hours to days. An acute confusional state is nearly impossible to diagnose without some knowledge of baseline cognitive function. Without this informa­ tion, many patients with dementia or longstanding depression may be mistaken as delirious during a single initial evaluation. Patients with a more hypoactive, apathetic presentation with psychomotor slowing may be identified as being different from baseline only through conversations with family members. A number of vali­ dated instruments have been shown to diagnose cognitive dysfunc­ tion accurately using a collateral source, including the modified Blessed Dementia Rating Scale and the Clinical Dementia Rating (CDR). Baseline cognitive impairment is common in patients with

delirium. Even when no such history of cognitive impairment is elicited, there should still be a high suspicion for a previously unrec­ ognized underlying neurologic disorder. Establishing the time course of cognitive change is important not only to make a diagnosis of delirium but also to correlate the onset of the illness with potentially treatable etiologies such as recent medication changes or systemic infection. Medications remain a common cause of delirium, especially compounds with anticholinergic or sedative properties. It is esti­ mated that nearly one-third of all cases of delirium are secondary to medications, especially in the elderly. Medication histories should include all prescription as well as over-the-counter and herbal substances taken by the patient and any recent changes in dosing or formulation, including substitution of generics for brand-name medications. Confusion and Delirium CHAPTER 29 Other important elements of the history include screening for symptoms of organ failure or systemic infection, which often con­ tributes to delirium in the elderly. A history of illicit drug use, alcoholism, or toxin exposure is important, particularly in younger delirious patients. Finally, asking the patient and collateral source about other symptoms that may accompany delirium, such as depression or anxiety, may help identify potential therapeutic targets. PHYSICAL EXAMINATION The general physical examination in a delirious patient should include careful screening for signs of infection such as fever, tachy­ pnea, pulmonary consolidation, heart murmur, and meningismus. The patient’s fluid status should be assessed; both dehydration and fluid overload with resultant hypoxemia have been associated with delirium, and each is usually easily rectified. The appearance of the skin can be helpful, showing jaundice in hepatic encephalopathy, cyanosis in hypoxemia, or needle tracks in patients using intrave­ nous drugs. The neurologic examination requires a careful assessment of mental status. Patients with delirium often present with a fluctuat­ ing course; therefore, the diagnosis can be missed when one relies on a single time point of evaluation. For patients who worsen in the evening (sundowning), assessment only during morning rounds may be falsely reassuring. An altered level of consciousness ranging from hyperarousal to lethargy to coma is present in most patients with delirium and can be assessed easily at the bedside. In a patient with a relatively normal level of consciousness, a screen for an attentional deficit is in order, because this deficit is the classic neuropsychological hall­ mark of delirium. Attention can be assessed while taking a history from the patient. Tangential speech, a fragmentary flow of ideas, or inability to follow complex commands often signifies an attentional problem. There are formal neuropsychological tests to assess atten­ tion, but a simple bedside test of digit span forward is quick and fairly sensitive. In this task, patients are asked to repeat successively longer random strings of digits beginning with two digits in a row, said to the patient at one per second intervals. Healthy adults can repeat a string of five to seven digits before faltering; a digit span of four or less usually indicates an attentional deficit unless hearing or language barriers are present, and many patients with delirium have forward digit spans of three or fewer digits. More formal neuropsychological testing can be helpful in assess­ ing a delirious patient, but it is usually too cumbersome and time-consuming in the inpatient setting. A Mini-Mental State Examination (MMSE) provides information regarding orientation, language, and visuospatial skills (Chap. 31); however, performance of many tasks on the MMSE, including the spelling of “world” back­ ward and serial subtraction of digits, will be impaired by delirious patients’ attentional deficits, rendering the test unreliable. The remainder of the screening neurologic examination should focus on identifying new focal neurologic deficits. Focal strokes or mass lesions in isolation are rarely the cause of delirium, but patients with underlying extensive cerebrovascular disease or neurodegenerative

conditions may not be able to cognitively tolerate even relatively small new insults. Patients should be screened for other signs of neurode­ generative conditions such as parkinsonism, which is seen not only in idiopathic Parkinson’s disease but also in other dementing conditions including Alzheimer’s disease, dementia with Lewy bodies, and pro­ gressive supranuclear palsy. The presence of multifocal myoclonus or asterixis on the motor examination is nonspecific but usually indicates a metabolic or toxic etiology of the delirium. ETIOLOGY Some etiologies can be easily discerned through a careful history and physical examination, whereas others require confirmation with laboratory studies, imaging, or other ancillary tests. A large, diverse group of insults can lead to delirium, and the cause in many patients is multifactorial. Common etiologies are listed in Table 29-1. PART 2 Cardinal Manifestations and Presentation of Diseases Prescribed, over-the-counter, and herbal medications all can pre­ cipitate delirium. Drugs with anticholinergic properties, narcotics, and benzodiazepines are particularly common offenders, but nearly any compound can lead to cognitive dysfunction in a predisposed patient. Whereas an elderly patient with baseline dementia may become delirious upon exposure to a relatively low dose of a medi­ cation, in less susceptible individuals, delirium occurs only with very high doses of the same medication. This observation empha­ sizes the importance of correlating the timing of recent medication changes, including dose and formulation, with the onset of cogni­ tive dysfunction. In younger patients, illicit drugs and toxins are common causes of delirium. In addition to more classic drugs of abuse, the avail­ ability of fentanyl (Chap. 467), synthetic cannabis (Chap. 466), “bath salts,” methylenedioxymethamphetamine (MDMA, ecstasy), γ-hydroxybutyrate (GHB), and the phencyclidine (PCP)-like agent ketamine has led to an increase in delirious young persons present­ ing to acute care settings (Chap. 468). Many common prescription drugs such as oral narcotics and benzodiazepines are often abused and readily available on the street. Alcohol abuse leading to high serum levels causes confusion, but more commonly, it is withdrawal from alcohol that leads to a hyperactive delirium (Chap. 464). Alcohol and benzodiazepine withdrawal should be considered in all cases of delirium, including in the elderly, because even patients who drink only a few servings of alcohol every day can experience relatively severe withdrawal symptoms upon hospitalization. Metabolic abnormalities such as electrolyte disturbances of sodium, calcium, magnesium, or glucose can cause delirium, and mild derangements can lead to substantial cognitive disturbances in susceptible individuals. Other common metabolic etiologies include liver and renal failure, hypercarbia and hypoxemia, vitamin deficiencies of thiamine and B12, autoimmune disorders including central nervous system (CNS) vasculitis, and endocrinopathies such as thyroid and adrenal disorders. Systemic infections often cause delirium, especially in the elderly. A common scenario involves the development of an acute cogni­ tive decline in the setting of a urinary tract infection in a patient with baseline dementia. Pneumonia, skin infections such as cel­ lulitis, and frank sepsis also lead to delirium. This so-called septic encephalopathy, often seen in the ICU, is probably due to the release of proinflammatory cytokines and their diffuse cerebral effects. CNS infections such as meningitis, encephalitis, and abscess are less common etiologies of delirium, as are cases of autoimmune or para­ neoplastic encephalitis; however, in light of the high morbidity and mortality rates associated with these conditions when they are not treated, clinicians must always maintain a high index of suspicion. In some susceptible individuals, exposure to the unfamiliar envi­ ronment of a hospital itself can contribute to delirium. This etiology usually occurs as part of a multifactorial delirium and should be considered a diagnosis of exclusion after all other causes have been thoroughly investigated. Many primary prevention and treatment strategies for delirium involve relatively simple methods to address the aspects of the inpatient setting that are most confusing.

TABLE 29-1  Differential Diagnosis of Delirium Toxins Prescription medications: especially those with anticholinergic properties, narcotics, and benzodiazepines Drugs of abuse: alcohol intoxication and alcohol withdrawal, opiates, ecstasy, LSD, GHB, PCP, ketamine, cocaine, “bath salts,” marijuana and its synthetic forms Poisons: inhalants, carbon monoxide, ethylene glycol, pesticides Metabolic Conditions Electrolyte disturbances: hypoglycemia, hyperglycemia, hyponatremia, hypernatremia, hypercalcemia, hypocalcemia, hypomagnesemia Hypothermia and hyperthermia Pulmonary failure: hypoxemia and hypercarbia Liver failure/hepatic encephalopathy Renal failure/uremia Cardiac failure Vitamin deficiencies: B12, thiamine, folate, niacin Dehydration and malnutrition Anemia Infections Systemic infections: urinary tract infections, pneumonia and other respiratory infections, skin and soft tissue infections, sepsis CNS infections: meningitis, encephalitis, brain abscess Endocrine Conditions Hyperthyroidism, hypothyroidism Hyperparathyroidism Adrenal insufficiency Cerebrovascular Disorders Global hypoperfusion states Hypertensive encephalopathy Focal ischemic strokes and hemorrhages (rare): especially nondominant parietal and thalamic lesions Autoimmune Disorders CNS vasculitis Cerebral lupus Neurologic paraneoplastic and autoimmune encephalitis Seizure-Related Disorders Nonconvulsive status epilepticus Intermittent seizures with prolonged postictal states Neoplastic Disorders Diffuse metastases to the brain Diffuse glioma Carcinomatous meningitis CNS lymphoma Hospitalization Terminal end-of-life delirium Abbreviations: CNS, central nervous system; GHB, γ-hydroxybutyrate; LSD, lysergic acid diethylamide; PCP, phencyclidine. Cerebrovascular etiologies of delirium are usually due to global hypoperfusion in the setting of systemic hypotension from heart failure, septic shock, dehydration, or anemia. Focal strokes in the right parietal lobe and medial dorsal thalamus rarely can lead to a delirious state. A more common scenario involves a new focal stroke or hemorrhage causing confusion in a patient who has decreased cerebral reserve. In these individuals, it is sometimes difficult to distinguish between cognitive dysfunction resulting from the new neurovascular insult itself and delirium due to the infectious, metabolic, and pharmacologic complications that can accompany hospitalization after stroke.

Because a fluctuating course often is seen in delirium, intermit­ tent seizures may be overlooked when one is considering potential etiologies. Both nonconvulsive status epilepticus and recurrent focal or generalized seizures followed by postictal confusion can cause delirium; EEG remains essential for this diagnosis and should be considered whenever the etiology of delirium remains unclear following initial workup. Seizure activity spreading from an electri­ cal focus in a mass or infarct can explain global cognitive dysfunc­ tion caused by relatively small lesions. It is extremely common for patients to experience delirium at the end of life in palliative care settings. This condition must be identi­ fied and treated aggressively because it is an important cause of patient and family discomfort at the end of life. It should be remem­ bered that these patients also may be suffering from more common etiologies of delirium such as systemic infection. LABORATORY AND DIAGNOSTIC EVALUATION A cost-effective approach allows the history and physical examina­ tion to guide further tests after initial screening laboratory studies are obtained. No single algorithm will fit all delirious patients due to the staggering number of potential etiologies, but one stepwise approach is detailed in Table 29-2. If a clear precipitant such as an offending medication is identified, further testing may not be required. If, how­ ever, no likely etiology is uncovered with initial evaluation, an aggres­ sive search for an underlying cause should be initiated. TABLE 29-2  Stepwise Evaluation of a Patient with Delirium Initial Evaluation History with special attention to medications (including over-the-counter and herbals) General physical examination and neurologic examination Complete blood count Electrolyte panel including calcium, magnesium, phosphorus Liver function tests, including albumin Renal function tests First-Tier Further Evaluation Guided by Initial Evaluation Systemic infection screen   Urinalysis and culture   Chest radiograph and tests for respiratory pathogens   Blood cultures Electrocardiogram Arterial blood gas Serum and/or urine toxicology screen (perform earlier in young persons) Brain imaging with MRI with diffusion and gadolinium (preferred) or CT Suspected CNS infection or other inflammatory disorder: lumbar puncture after brain imaging Suspected seizure-related etiology: electroencephalogram (EEG) (if high suspicion, should be performed immediately) Second-Tier Further Evaluation Vitamin levels: B12, folate, thiamine Endocrinologic laboratories: thyroid-stimulating hormone (TSH) and free T4; cortisol Serum ammonia Sedimentation rate Autoimmune serologies: antinuclear antibodies (ANA), complement levels; p-ANCA, c-ANCA, consider paraneoplastic/autoimmune encephalitis testing in the serum and CSF Infectious serologies: rapid plasmin reagin (RPR); fungal and viral serologies if high suspicion; HIV antibody Lumbar puncture (if not already performed) Brain MRI with and without gadolinium (if not already performed) Abbreviations: c-ANCA, cytoplasmic antineutrophil cytoplasmic antibody; CNS, central nervous system; CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging; p-ANCA, perinuclear antineutrophil cytoplasmic antibody.

Basic screening lab tests, including a complete blood count, electrolyte panel, and tests of liver and renal function, should be obtained in all patients with delirium. In elderly patients, screen­ ing for systemic infection, including chest radiography, urinalysis and culture, and possibly blood cultures, is important. In younger individuals, serum and urine drug and toxicology screening may be appropriate earlier in the workup. Additional laboratory tests addressing other autoimmune, endocrinologic, metabolic, and infectious etiologies should be reserved for patients in whom the diagnosis remains unclear after initial testing. Confusion and Delirium CHAPTER 29 Multiple studies have demonstrated that brain imaging in patients with delirium is often unhelpful. If, however, the ini­ tial workup is unrevealing, most clinicians quickly move toward imaging of the brain to exclude structural causes. A noncontrast computed tomography (CT) scan can identify large masses and hemorrhages but is otherwise unlikely to help determine an etiol­ ogy of delirium. The ability of magnetic resonance imaging (MRI) to identify nearly all acute ischemic strokes as well as to provide neuroanatomic detail that gives clues to possible infectious, inflam­ matory, neurodegenerative, and neoplastic conditions makes it the test of choice. Because MRI techniques are limited by availability, speed of imaging, patient’s cooperation, and contraindications, many clinicians begin with CT scanning and proceed to MRI if the etiology of delirium remains elusive. Lumbar puncture (LP) must be obtained immediately after neuroimaging for all patients in whom CNS infection is suspected. Spinal fluid examination can also be useful in identifying autoim­ mune, other inflammatory, and neoplastic conditions. As a result, LP should be considered in any delirious patient with a negative workup. EEG remains invaluable if seizures are considered or if there is no cause readily identified. TREATMENT Delirium Management of delirium begins with treatment of the underlying inciting factor (e.g., patients with systemic infections should be given appropriate antibiotics, and underlying electrolyte distur­ bances should be judiciously corrected). These treatments often lead to prompt resolution of delirium. Blindly targeting the symp­ toms of delirium pharmacologically only serves to prolong the time patients remain in the confused state and may mask important diagnostic information. Relatively simple methods of supportive care can be highly effective (Fig. 29-1). Reorientation by the nursing staff and fam­ ily combined with visible clocks, calendars, and outside-facing windows can reduce confusion. Sensory isolation should be pre­ vented by providing glasses and hearing aids to patients who need them. Sundowning can be addressed to a large extent through vigilance to appropriate sleep-wake cycles. During the day, a well-lit room should be accompanied by activities or exercises to prevent napping. At night, a quiet, dark environment with limited interruptions by staff can assure proper rest; melatonin can be considered before bed to promote sleep. These sleep-wake cycle interventions are especially important in the ICU setting as the usual constant 24-h activity commonly provokes delirium. Attempting to mimic the home environment as much as possible also has been shown to help treat and even prevent delirium. Visits from friends and family throughout the day minimize the anxiety associated with the constant flow of new faces of staff and physicians. Allowing hospitalized patients to have access to home bedding, clothing, and nightstand objects makes the hospital environment less foreign and therefore less confusing. Simple standard nursing practices such as maintaining proper nutri­ tion and volume status as well as managing pain, incontinence, and skin breakdown also help alleviate discomfort and resulting confusion.

20 - 30 Coma

30 Coma

PROMOTE WAKEFULNESS AM Delirium Reduction Care Shades up. Lights on. Write date and staff names on board to orient patient. Patient out of bed to chair for all 3 meals. Walk patient 3x/ day. Engage patient in conversation. PART 2 Cardinal Manifestations and Presentation of Diseases Hi, my name is... Make sure your patient has water within reach at all times. Dehydration is the #1 complaint in the hospital. Each visit, introduce yourself; remind patient where they are, what day and time it is. Patient is wearing hearing aids/glasses (if needed) to hear and see appropriately. Provide activities like games and reading materials to keep patient’s mind active while awake. Make sure family members have been provided information about delirium and discuss any questions they have. It is ok to refer to the nurse or doctor if you are unsure.
Discuss with the nurse at each shift if the patient truly needs the following: nasal cannula, Foley catheter, telemetry, and CPO. These “tethers” make it difficult for the patient to move and can contribute to confusion. PCA RN A PROMOTE SLEEP PM Minimize caffeine intake. Offer eye mask, ear plugs to help with sleep. Shades closed. Lights off. TV off. Make room as dark and quiet as possible. Hi, my name is... If you communicate with the patient during the night, make sure glasses and hearing aids are on. Remember to introduce yourself, remind the patient where they are. Group nighttime tasks so staff are entering the room and waking the patient as few times as possible. Discuss each shift if they need vital signs done overnight. B FIGURE 29-1  Delirium management and prevention: a checklist for hospitalized patients. Effective management of delirium relies on broad efforts to promote wakefulness (A) and sleep (B). CPO, continuous pulse oximetry. In some instances, patients pose a threat to their own safety or to the safety of staff members, and acute management is required. Bed alarms and personal sitters are more effective and much less disorienting than physical restraints. Chemical restraints should be avoided, but when necessary, very-low-dose typical or atypical antipsychotic medications administered on an as-needed basis can be used, recognizing that multiple clinical trials have consistently shown that these medications are ineffective in preventing or treating delirium. Therefore, they should be reserved for patients who display severe agitation and significant potential to harm themselves or staff. The association of antipsychotic drug use in the elderly with increased mortality rates underscores the importance of using these medications judiciously and only as a last resort. Ben­ zodiazepines often worsen confusion through their sedative prop­ erties. Although many clinicians use benzodiazepines to treat acute confusion, their use should be limited to cases in which delirium is caused by alcohol or benzodiazepine withdrawal.

■ ■PREVENTION In light of the high morbidity associated with delirium and the tre­ mendously increased health care costs that accompany it, development of an effective strategy to prevent delirium in hospitalized patients is extremely important. Successful identification of high-risk patients is the first step, followed by initiation of appropriate interventions. Increasingly, hospitals are using nursing or physician-administered tools to screen for high-risk individuals, triggering simple standardized protocols used to manage risk factors for delirium, including sleepwake cycle reversal, immobility, visual impairment, hearing impair­ ment, sleep deprivation, and dehydration. No specific medications have been definitively shown to be effective for delirium prevention, including trials of cholinesterase inhibitors and antipsychotic agents. Melatonin and its agonist ramelteon have shown some promising results in small preliminary trials. Recent studies in the ICU have focused both on identifying sedatives, such as dexmedetomidine, that are less likely to lead to delirium in critically ill patients and on devel­ oping protocols for daily awakenings in which infusions of sedative medications are interrupted and the patient is reorientated by the staff. All hospitals and health care systems should work toward decreasing the incidence of delirium and promptly recognizing and treating the disorder when it occurs. ■ ■FURTHER READING Goldberg TE et al: Association of delirium with long-term cognitive decline: A meta-analysis. JAMA Neurol 77:1, 2020. Kunicki ZJ et al: Six-year cognitive trajectory in older adults following major surgery and delirium. JAMA Int Med 183:442, 2023. Livingston G et al: Dementia prevention, intervention, and care: 2020 report of the Lancet Commission. Lancet 396:413, 2020. Ng KT et al: The effect of dexmedetomidine on delirium and agitation in patients in intensive care: Systematic review and meta-analysis with trial sequential analysis. Anesthesia 74:380, 2019. Smit L et al: Efficacy of haloperidol to decrease the burden of delirium in adult critically ill patients: The EuRIDICE randomized clinical trial. Crit Care 27:413, 2023. S. Andrew Josephson, Allan H. Ropper,

Stephen L. Hauser

Coma Coma is among the most common neurologic emergencies encoun­ tered in general medicine and requires an organized approach. It accounts for a substantial portion of emergency department visits and occurs on all services in the hospital. There exists a continuum of states of reduced alertness, the most severe form being coma, defined as a deep sleeplike state with eyes closed, from which the patient cannot be aroused. Stupor refers to a lower threshold for arousability, in which the patient can be transiently awakened by vigorous stimuli, accompanied by motor behavior that leads to avoidance or withdrawal from noxious stimuli. Drowsiness simulates light sleep and is characterized by easy arousal that may per­ sist for brief periods. Stupor and drowsiness are usually accompanied by some degree of confusion when the patient is alerted (Chap. 29). A precise narrative description of the level of arousal and of the type of responses evoked by various stimuli as observed at the bedside is preferable to use of more ambiguous terms such as lethargy, semicoma, or obtundation. Several conditions that render patients unresponsive and simulate coma are considered separately because of their special significance. The vegetative state signifies an awake-appearing but nonresponsive

state, usually encountered in a patient who has emerged from coma. In the vegetative state, the eyelids typically open periodically, giving the appearance of wakefulness. Respiratory and autonomic functions are retained. Yawning, coughing, swallowing, and limb and head move­ ments persist, but there are few, if any, meaningful responses to the external and internal environment. There are typically accompanying signs that indicate extensive damage in both cerebral hemispheres, e.g., decerebrate or decorticate limb posturing and absent responses to visual stimuli (see below). In the related but less severe minimally con­ scious state, the patient displays rudimentary vocal or motor behaviors, often spontaneous, but sometimes in response to touch, visual stimuli, or command. Cardiac arrest with cerebral hypoperfusion and head trauma are the most common causes of the vegetative and minimally conscious states (Chap. 318). The prognosis for regaining meaningful mental faculties once the vegetative state has supervened for several months is poor, and after a year, almost nil; hence the term persistent vegetative state. Most reports of dramatic recovery, when investigated carefully, are found to yield to the usual rules for prognosis, but there have been rare instances in which recovery has occurred to a severely disabled condition and, particularly in childhood cases, to an even better state. Patients in the minimally conscious state carry a better prognosis for some recovery compared to those in a persistent vegetative state, but even in these patients, dramatic recovery after 12 months is unusual. The possibility of incorrectly attributing meaningful behavior to patients in the vegetative and minimally conscious states creates problems and anguish for families and physicians. The question of whether some of these patients have the capability for cognition has been investigated by functional MRI and electroencephalogram (EEG) studies that have demonstrated cerebral activation that is temporally consistent in response to verbal and other stimuli, as discussed in more detail below. This finding suggests at a minimum that some of these patients could in the future be able to communicate using technologi­ cal advances and that further research could shed light on treatment approaches targeting areas of the brain and their connections that appear to be preserved in such individuals. Several syndromes that affect alertness are prone to be misinter­ preted as stupor or coma, and clinicians should be aware of these pitfalls when diagnosing coma at the bedside. Akinetic mutism refers to a partially or fully awake state in which the patient remains virtually immobile and mute but can form impressions and think, as demon­ strated by later recounting of events. This condition results from dam­ age in the regions of the medial thalamic nuclei or the frontal lobes (particularly lesions situated deeply or on the orbitofrontal surfaces) or from extreme hydrocephalus. The term abulia describes a milder form of akinetic mutism characterized by mental and physical slowness and diminished ability to initiate activity. It is also usually the result of damage to the medial frontal lobes and their connections (Chap. 32). Catatonia is a hypomobile and mute syndrome that occurs usually as part of a major psychiatric disorder, typically schizophrenia or major depression. Catatonic patients make few voluntary or responsive move­ ments, although they blink, swallow, and may not appear distressed. There are nevertheless signs that the patient is responsive, although it takes a careful examination to demonstrate these features. For example, eyelid elevation is often actively resisted, blinking occurs in response to a visual threat, and the eyes move concomitantly with head rotation, all of which are inconsistent with the presence of a brain lesion caus­ ing unresponsiveness. The limbs may retain postures in which they have been placed by the examiner (“waxy flexibility,” or catalepsy). There may be remarkable reversal, albeit sometimes brief, of the signs of catatonia when lorazepam is administered, validating the diagno­ sis. With appropriate medical therapy and recovery from catatonia, patients often have some memory of events that occurred during their stupor. Catatonia is superficially similar to akinetic mutism, but clinical evidence of cerebral damage such as hyperreflexia and hypertonicity of the limbs is lacking in the former. The locked-in state describes a type of pseudocoma in which an awake but paralyzed patient has no means of producing speech or voli­ tional limb movement but retains voluntary vertical eye movements

and lid elevation, thus allowing the patient to communicate. The pupils are normally reactive. The usual cause is an infarction (e.g., basilar artery thrombosis) or hemorrhage of the ventral pons bilaterally that transects all descending motor (corticospinal and corticobulbar) path­ ways and those that control horizontal eye movements. Another awake but de-efferented state occurs as a result of total paralysis of the mus­ culature in severe cases of neuromuscular weakness such as in forms of Guillain-Barré syndrome (Chap. 458), critical illness neuropathy (Chap. 318), or pharmacologic neuromuscular blockade.

■ ■THE ANATOMY AND PHYSIOLOGY OF COMA Almost all instances of coma can be traced to either (1) widespread abnormalities of both cerebral hemispheres or (2) reduced activity of the thalamocortical alerting system, the reticular activating system (RAS), which is an assemblage of neurons located diffusely in the upper brainstem and thalamus. The proper functioning of this sys­ tem, its ascending projections to the cortex, and the cortex itself are required to maintain alertness and coherence of thought. In addition to structural damage to either or both of these systems, suppression of reticulocerebral function commonly occurs by drugs, toxins, or meta­ bolic derangements such as hypoglycemia, anoxia, uremia, and hepatic failure, or by seizures; these types of metabolic causes of coma are far more common than structural injuries. Coma CHAPTER 30 Coma Due to Cerebral Mass Lesions and Herniation Syn­ dromes  The skull prevents outward expansion of the brain, and infoldings of the dura create compartments that restrict displacement of brain tissue within the cranium. The two cerebral hemispheres are sepa­ rated by the falx and the anterior and posterior fossae by the tentorium. Herniation refers to displacement of brain tissue by an intracerebral or overlying mass into a contiguous compartment that it normally does not occupy. Coma from mass lesions, and many of its associated signs, are attributable to these tissue shifts, and certain clinical features are charac­ teristic of specific configurations of herniation (Fig. 30-1). In the most common form of herniation, brain tissue is displaced from the supratentorial to the infratentorial compartment through the tentorial opening, referred to as transtentorial herniation. The cause is often a mass hemispheral lesion that is evident by contra­ lateral hemiparesis and other cerebral signs. Uncal transtentorial herniation refers to impaction of the anterior medial temporal gyrus (the uncus) into the tentorial opening anterior to and adjacent to the midbrain (Fig. 30-1A). The uncus can compress the third nerve as the nerve traverses the subarachnoid space, causing enlargement of the ipsilateral pupil as the first sign (the fibers subserving parasym­ pathetic pupillary function are located peripherally in the nerve). The C B A D FIGURE 30-1  Types of cerebral herniation: (A) uncal; (B) central; (C ) transfalcial; and (D) foraminal.

PART 2 Cardinal Manifestations and Presentation of Diseases A B FIGURE 30-2  Axial (A) and coronal (B) T2-weighted magnetic resonance images from a stuporous patient with a left third nerve palsy from a large left-sided meningioma. A. The upper midbrain is compressed and displaced horizontally away from the mass, and there is transtentorial herniation of the medial temporal lobe structures, including the uncus. B. The lateral ventricle opposite to the mass has become enlarged as a result of compression of the third ventricle. coma that typically follows is due to vertical and lateral displacement of the midbrain (and therefore the RAS) against the opposite tento­ rial edge by the displaced parahippocampal gyrus (Fig. 30-2). An additional feature of lateral displacement can be compression of the opposite cerebral peduncle, producing a Babinski sign and hemipa­ resis ipsilateral to the supratentorial mass (the Kernohan-Woltman sign). Herniation may also compress the anterior and posterior cere­ bral arteries as they pass over the tentorial reflections, with resultant brain infarction. These distortions may also entrap portions of the ventricular system, causing hydrocephalus. Central transtentorial herniation denotes a symmetric downward movement of the thalamic structures through the tentorial opening with compression of the upper midbrain (Fig. 30-1B). Miotic pupils and drowsiness are the heralding signs, in contrast to a unilaterally enlarged pupil of the uncal syndrome. Both uncal and central trans­ tentorial herniations cause progressive compression of the brainstem and RAS, with initial damage to the rostral structures in midbrain, then the pons, and finally the most caudal medulla. The result is an approximate sequence of neurologic signs that corresponds to each affected level, with respiratory centers in the brainstem often spared until late in the herniation syndrome. This orderly sequential appear­ ance of signs is not always respected, and rapid deterioration reflecting disruption of many brainstem functions can occur. Other forms of her­ niation include transfalcial herniation (displacement of the cingulate gyrus under the falx and across the midline, Fig. 30-1C) and foraminal herniation (downward forcing of the cerebellar tonsils into the foramen magnum, Fig. 30-1D), which causes early compression of the medulla and respiratory arrest. Coma Due to Metabolic, Drug, and Toxic Disorders  Many systemic metabolic abnormalities cause coma by interrupting the deliv­ ery of energy substrates (e.g., oxygen, glucose) or by altering neuronal excitability (drugs and alcohol, anesthetics, and epilepsy). These are the most common causes of coma in general practice and in large case series. The metabolic abnormalities that produce coma in milder forms may induce a confusional state (metabolic encephalopathy). Cerebral neurons are dependent on cerebral blood flow (CBF) and the delivery of oxygen and glucose. Brain stores of glucose are able to provide energy for ~2 min after blood flow is interrupted, and oxy­ gen stores last 8–10 s after the cessation of blood flow. Simultaneous hypoxia and ischemia exhaust glucose more rapidly. The EEG rhythm

in these circumstances becomes diffusely slowed, typical of metabolic encephalopathies, and as substrate delivery worsens, eventually brain electrical activity ceases. Unlike systemic hypoxia-ischemia, which first causes a metabolic encephalopathy due to reduced energy substrate but ultimately causes neuronal destruction, most metabolic disorders such as hypoglyce­ mia, hyponatremia, hyperosmolarity, hypercapnia, hypercalcemia, and hepatic and renal failure cause no or only minor neuropathologic changes in the brain. The reversible effects of these conditions are not fully understood but may result from impaired energy supplies, changes in ion fluxes across neuronal membranes, and neurotransmit­ ter abnormalities. In hepatic encephalopathy (HE), high ammonia concentrations have been proposed to lead to increased synthesis of glutamine in astrocytes and osmotic swelling of the cells, mitochon­ drial energy failure, production of reactive nitrogen and oxygen spe­ cies, increases in the inhibitory neurotransmitter γ-aminobutyric acid (GABA), and synthesis of putative “false” neurotransmitters, none of which has provided a fully adequate explanation for confusion and stupor. Over time, development of a diffuse astrocytosis is typical of chronic HE. Which, if any, of these is mainly responsible for hepatic coma is not known. The mechanism of the encephalopathy of renal failure is also uncer­ tain and likely to be multifactorial; unlike ammonia, urea does not produce central nervous system (CNS) depression when infused into normal persons. Contributors to uremic encephalopathy may include accumulation of neurotoxic substances such as creatinine, guanidine, and related compounds; depletion of catecholamines; altered glutamate and GABA tone; increases in brain calcium; and inflammation with disruption of the blood-brain barrier. Coma and seizures are common accompaniments of large shifts in sodium and water balance in the brain. These changes in osmolarity arise from systemic medical disorders, including diabetic ketoacidosis, the nonketotic hyperosmolar state, and hyponatremia from any cause (e.g., water intoxication, excessive secretion of antidiuretic hormone, or atrial natriuretic peptides). Sodium levels <125 mmol/L, especially if achieved quickly, induce confusion, and levels <119 mmol/L, when arrived at acutely, are typically associated with coma and convulsions. In hyperosmolar coma, the serum osmolarity is generally >350 mosmol/L. Hypercapnia depresses the level of consciousness in proportion to the rise in carbon dioxide (CO2) in the blood. In all of these metabolic encephalopathies, the degree of neurologic change depends on the

rapidity with which the serum changes occur. The pathophysiology of other metabolic encephalopathies such as those due to hypercalcemia, hypothyroidism, vitamin B12 deficiency, and hypothermia are incom­ pletely understood but must reflect derangements of synaptic function, cellular biochemistry, membrane function, or neurotransmitters. Coma due to drugs and toxins is typically reversible and leaves no residual damage provided there has not been hypoxia or severe hypotension. Many drugs and toxins are capable of depressing ner­ vous system function. Some produce coma by affecting both the RAS and the cerebral cortex. The combination of cortical and brainstem signs, which occurs occasionally in certain drug overdoses, may lead to an incorrect diagnosis of structural brainstem disease. Overdose of medications that have atropinic actions produces signs such as dilated pupils, tachycardia, and dry skin; opiate overdose produces pinpoint pupils <1 mm in diameter. Some drug intoxications, typified by barbi­ turates, can mimic all of the signs of brain death; thus, toxic etiologies must be excluded prior to making a diagnosis of brain death. Epileptic Coma  Generalized electrical seizures are associated with coma, even in the absence of motor convulsions (a condition termed “nonconvulsive status epilepticus”). As a result, EEG monitor­ ing is often used in the evaluation of unexplained coma to exclude this potentially treatable etiology. The self-limited coma that follows a seizure, the postictal state, may be due to exhaustion of energy reserves or effects of locally toxic molecules that are the by-product of seizures. The postictal state produces continuous, generalized slowing of the background EEG activity similar to that of metabolic encephalopathies. It typically lasts for a few minutes but in some cases can be prolonged for hours or, even rarely, for days. Coma Due to Widespread Structural Damage to the Cerebral Hemispheres  This category, comprising several unrelated disor­ ders, results from extensive bilateral structural cerebral damage. The clinical appearance simulates a metabolic encephalopathy. Hypoxia-

ischemia is perhaps the best characterized form of this type of injury, in which it is not possible initially to distinguish the acute reversible effects of oxygen deprivation of the brain from the subsequent effects of neuronal damage. Similar cerebral damage may be produced by disorders that occlude widespread small blood vessels throughout the brain; examples include thrombotic thrombocytopenic purpura, hyperviscosity, and cerebral malaria. Diffuse white matter damage from cranial trauma, the delayed effects of some opioid intoxications, or inflammatory demyelinating diseases can cause a similar coma syndrome. APPROACH TO THE PATIENT Coma Acute respiratory and cardiovascular problems should be attended to prior to neurologic assessment. In most instances, a com­ plete medical evaluation, except for vital signs, fundoscopy, sys­ temic trauma survey, and examination for nuchal rigidity, may be deferred until the neurologic evaluation has established the severity and nature of coma. A video examination of the comatose patient is shown in Chap. V4. The approach to the patient with coma from cranial trauma is discussed in Chap. 454. HISTORY The cause of coma may be immediately evident as in cases of trauma, cardiac arrest, or observed drug ingestion. In the remain­ der, certain points are useful: (1) the circumstances and rapidity with which neurologic symptoms developed; (2) antecedent symp­ toms (confusion, weakness, headache, fever, seizures, dizziness, double vision, or vomiting); (3) the use of medications, drugs, or alcohol; and (4) chronic liver, kidney, lung, heart, or other medical disease. Direct interrogation of family, observers, and emergency medical technicians on the scene, in person or by telephone, is an important part of the evaluation when possible.

GENERAL PHYSICAL EXAMINATION Signs of head trauma raise the possibility of coexisting spinal cord injury, and in such cases, immobilization of the cervical spine is essential to prevent further injury. Fever suggests a systemic infec­ tion, bacterial meningitis, encephalitis, heat stroke, neuroleptic malignant syndrome, malignant hyperthermia due to anesthetics, or anticholinergic drug intoxication. Only rarely is fever attribut­ able to a lesion that has disturbed hypothalamic temperatureregulating centers (“central fever”), and this diagnosis should only be considered after an exhaustive search for other causes fails to reveal an alternative explanation. A slight elevation in temperature may follow vigorous convulsions. Hypothermia is observed with exposure to cold ambient temperature, drowning, alcohol, barbitu­ rate, sedative, or phenothiazine intoxication; hypoglycemia; periph­ eral circulatory failure; or extreme hypothyroidism. Hypothermia itself causes coma when the temperature is <31°C (87.8°F) regard­ less of the underlying etiology; less dramatically, low body tem­ peratures can also cause coma in some instances. Tachypnea may indicate systemic acidosis or pneumonia. Aberrant respiratory pat­ terns that reflect brainstem disorders are discussed below. Marked hypertension suggests hypertensive encephalopathy, cerebral hem­ orrhage, large cerebral infarction, or head injury. Hypotension is characteristic of coma from alcohol or barbiturate intoxication, internal hemorrhage or myocardial infarction causing poor delivery of blood to the brain, sepsis, profound hypothyroidism, or Addi­ sonian crisis. The funduscopic examination can detect increased intracranial pressure (ICP) (papilledema), subarachnoid hemor­ rhage (subhyaloid hemorrhages), and hypertensive encephalopa­ thy (exudates, hemorrhages, vessel-crossing changes, papilledema). Cutaneous petechiae suggest thrombotic thrombocytopenic pur­ pura, meningococcemia, or a bleeding diathesis associated with an intracerebral hemorrhage. Cyanosis and reddish or anemic skin coloration are other indications of an underlying systemic disease or carbon monoxide as responsible for the coma. Coma CHAPTER 30 NEUROLOGIC EXAMINATION The patient is ideally first observed without intervention by the examiner. Spontaneously moving about the bed, reaching up toward the face, crossing legs, yawning, swallowing, coughing, and moan­ ing reflect a drowsy state that is close to normal awakeness. Lack of restless movements on one side or an externally rotated leg suggests hemiplegia (or hip fracture). Subtle, intermittent twitching move­ ments of a foot, finger, or facial muscle may be the only sign of sei­ zures. Multifocal myoclonus usually indicates a metabolic disorder, particularly uremia, hypoxemia, drug intoxication, or rarely a prion disease (Chap. 449). In a drowsy and confused patient, bilateral asterixis is a sign of metabolic encephalopathy or drug intoxication. Decorticate rigidity and decerebrate rigidity, or “posturing,” describe stereotyped arm and leg movements occurring spontane­ ously or elicited by sensory stimulation. Flexion of the elbows and wrists and supination of the arm (decorticate posturing) classically suggest bilateral damage rostral to the midbrain, whereas extension of the elbows and wrists with pronation (decerebrate posturing) indicates damage to motor tracts caudal to the midbrain. However, these localizations have been adapted from animal work and can­ not be applied with precision to coma in humans. In fact, acute and widespread cerebral disorders of any type, regardless of location, frequently cause limb extension. LEVEL OF AROUSAL A sequence of increasingly intense stimuli is first used to determine the threshold for arousal and the motor response of each side of the body. The results of testing may vary from minute to minute, and serial examinations are useful. Tickling the nostrils with a cotton wisp is a moderate stimulus to arousal—all but deeply stuporous and comatose patients will move the head away and arouse to some degree. An even greater degree of responsiveness is present if the patient uses the hand to remove an offending stimulus. Pressure

on bony prominences and pinprick stimulation, when necessary, are humane forms of noxious stimuli; pinching the skin causes ecchymoses and is generally not performed but may be useful in eliciting abduction withdrawal movements of the limbs. Posturing in response to noxious stimuli indicates severe damage to the corti­ cospinal system, whereas abduction-avoidance movement of a limb is usually purposeful and denotes an intact corticospinal system. Posturing may also be unilateral and coexist with purposeful limb movements, reflecting incomplete damage to the motor system. BRAINSTEM REFLEXES Assessment of brainstem function allows localization of the lesion in coma (Fig. 30-3). Patients with preserved brainstem reflexes typically have a bihemispheric localization to coma, including toxic or drug intoxication, whereas patients with abnormal brainstem reflexes either have a lesion in the brainstem or a herniation syn­ drome from a cerebral mass lesion impacting the brainstem second­ arily. The most important brainstem reflexes are pupillary size and reaction to light, spontaneous and elicited eye movements, corneal responses, and the respiratory pattern. PART 2 Cardinal Manifestations and Presentation of Diseases Pupillary Signs  Pupillary reactions are examined with a bright, diffuse light. Reactive and round pupils of midsize (2.5–5 mm) essentially exclude upper midbrain damage, either primary or sec­ ondary to compression from herniation. A response to light may be difficult to appreciate in pupils <2 mm in diameter, and bright room lighting may mute pupillary reactivity. One enlarged (>6 mm) Pupillary light reflex III III Pons M L F V Vll Vl Vlll Medulla Reflex conjugate eye movements Corneal-blink reflex Respiratory neurons FIGURE 30-3  Examination of brainstem reflexes in coma. Midbrain and third nerve function are tested by pupillary reaction to light, pontine function by spontaneous and reflex eye movements and corneal responses, and medullary function by respiratory and pharyngeal responses. Reflex conjugate, horizontal eye movements are dependent on the medial longitudinal fasciculus (MLF) interconnecting the sixth and contralateral third nerve nuclei. Head rotation (oculocephalic reflex) or caloric stimulation of the labyrinths (oculovestibular reflex) elicits contraversive eye movements (for details, see text).

and poorly reactive pupil signifies compression of the third nerve from the effects of a cerebral mass above. Enlargement of the pupil contralateral to a hemispheral mass may occur but is infrequent. An oval and slightly eccentric pupil is a transitional sign that accompa­ nies early midbrain–third nerve compression. The most extreme pupillary sign, bilaterally dilated and unreactive pupils, indicates severe midbrain damage, usually from compression by a supra­ tentorial mass. Ingestion of drugs with anticholinergic activity, the use of mydriatic eye drops, nebulizer treatments that inadvertently spray into the eye, and direct ocular trauma are other causes of pupillary enlargement. Reactive and bilaterally small (1–2.5 mm) but not pinpoint pupils are seen in metabolic encephalopathies or in deep bilateral hemispheral lesions such as hydrocephalus or thalamic hemor­ rhage. Even smaller reactive pupils (<1 mm) characterize opioid overdoses but also occur with extensive pontine hemorrhage. The response to naloxone and the presence of reflex eye movements (see below) assist in distinguishing between these. Unilateral miosis in coma has been attributed to dysfunction of sympathetic efferents originating in the posterior hypothalamus and descending in the tegmentum of the brainstem to the cervical cord. It is an occasional finding in patients with a large cerebral hemorrhage that affects the thalamus. Ocular Movements  The eyes are first observed by elevating the lids and observing the resting position and spontaneous move­ ments of the globes. Horizontal divergence of the eyes at rest is nor­ mal in drowsiness. As coma deepens, the ocular axes may become parallel again. Spontaneous eye movements in coma often take the form of con­ jugate horizontal roving. This finding alone exonerates extensive damage in the midbrain and pons and has the same significance as normal reflex eye movements (see below). Conjugate horizontal ocular deviation to one side indicates damage to the frontal lobe on the same side or less commonly the pons on the opposite side. This phenomenon is summarized by the following maxim: The eyes look toward a hemispheral lesion and away from a brainstem lesion. Sei­ zures involving the frontal lobe drive the eyes to the opposite side, simulating a pontine destructive lesion. The eyes may occasionally turn paradoxically away from the side of a deep hemispheral or thalamic lesion (“wrong-way eyes”). The eyes more often turn down and inward with thalamic and upper midbrain lesions, typically thalamic hemorrhage. “Ocular bobbing” describes brisk downward and slow upward movements of the eyes associated with loss of horizontal eye movements and is diagnostic of bilateral pontine damage, usually from thrombosis of the basilar artery. “Ocular dip­ ping” is a slower, arrhythmic downward movement followed by a faster upward movement in patients with normal reflex horizontal gaze; it usually indicates diffuse cortical anoxic damage. The oculocephalic reflex, elicited after establishing there is no cervical spinal cord injury, is examined by moving the head from side to side or vertically and observing eye movements in the direction opposite to the head movement. The reflex depends on the integrity of the ocular motor nuclei and their interconnecting tracts that extend from the midbrain to the pons and medulla (Fig. 30-3). The movements, called somewhat inaccurately “doll’s eyes,” are normally suppressed in the awake patient with intact frontal lobes. The ability to elicit an oculocephalic reflex therefore reflects both reduced cortical influence on the brainstem and intact brain­ stem pathways. The opposite, an absence of reflex eye movements, usually signifies damage within the brainstem but can result from overdoses of certain drugs. In this circumstance, normal pupillary size and light reaction distinguishes most drug-induced comas from structural brainstem damage. Thermal, or “caloric,” stimulation of the vestibular apparatus (oculovestibular response) provides a more intense stimulus for the oculocephalic reflex but provides essentially the same information. The test is performed by irrigating the external auditory canal with

cold water in order to induce convection currents in the labyrinths. After a brief latency, the result is tonic deviation of both eyes to the side of cold-water irrigation. In comatose patients, nystagmus in the opposite direction may not occur. The acronym “COWS” has been used to remind generations of medical students of the direction of nystagmus—cold water opposite, warm water same—but since nystagmus is often absent in the opposite direction due to frontal lobe dysfunction in coma, this mnemonic does not often hold true in this situation. The corneal reflex, elicited by touching the cornea with a wisp of cotton and observing bilateral lid closure, depends on the integrity of pontine pathways between the fifth (afferent) and both seventh (efferent) cranial nerves; it is a useful test of pontine function. CNS-depressant drugs diminish or eliminate the corneal responses soon after reflex eye movements are paralyzed but before the pupils become unreactive to light. The corneal response may be lost for a time on the side of an acute hemiplegia. Respiratory Patterns  These are of less localizing value in compar­ ison to other brainstem signs. Shallow, slow, but regular breathing suggests metabolic or drug-induced depression of the medullary respiratory centers. Cheyne-Stokes respiration in its typical cyclic form, ending with a brief apneic period, signifies bihemispheral damage or metabolic suppression and commonly accompanies light coma. Rapid, deep (Kussmaul) breathing usually implies metabolic acidosis but may also occur with pontomesencephalic lesions. Ago­ nal gasps are the result of lower brainstem (medullary) damage and are recognized as the terminal respiratory pattern of severe brain damage. Other cyclic breathing patterns have been described but are of lesser significance. ■ ■LABORATORY STUDIES AND IMAGING The studies that are most useful in the diagnosis of coma are chem­ ical-toxicologic analyses of blood and urine, cranial CT or MRI, EEG, and cerebrospinal fluid (CSF) examination. Arterial blood gas analysis is helpful in patients with lung disease and acid-base disor­ ders. The metabolic aberrations commonly encountered in clinical practice are usually revealed by measurement of electrolytes, glucose, calcium, magnesium, osmolarity, and renal (blood urea nitrogen) and hepatic (including NH3) function. Toxicologic analysis may be neces­ sary in cases of acute coma when the diagnosis is not immediately clear. However, the presence of exogenous drugs or toxins, especially alcohol, does not exclude the possibility that other factors, including head trauma, are contributing to the clinical state. An ethanol level of 43 mmol/L (0.2 g/dL) in nonhabituated patients generally causes impaired mental activity; a level of >65 mmol/L (0.3 g/dL) is asso­ ciated with stupor. The development of tolerance may allow some individuals who chronically ingest alcohol to remain awake at levels

87 mmol/L (0.4 g/dL). The availability of cranial CT and MRI has focused attention on causes of coma that are detectable by imaging (e.g., hemorrhage, tumor, or hydrocephalus). Resorting primarily to this approach, although at times expedient, is imprudent because most cases of coma (and confu­ sion) are metabolic or toxic in origin. Furthermore, a normal CT scan does not exclude an anatomic lesion as the cause of coma; for example, early bilateral hemisphere infarction, acute brainstem infarction, encephalitis, meningitis, mechanical shearing of axons as a result of closed head trauma, sagittal sinus thrombosis, hypoxic injury, and sub­ dural hematoma isodense to adjacent brain are some of the disorders that may not be detected. Sometimes imaging results can be mislead­ ing such as when small subdural hematomas or old strokes are found, but the patient’s coma is due to intoxication. Additional imaging with CT angiography or MRI can be obtained if acute posterior circulation stroke is considered. The EEG (Chap. 436) provides clues in metabolic or drug-induced states but is rarely diagnostic in these disorders. However, it is the essential test to reveal coma due to nonconvulsive seizures and shows fairly characteristic patterns in some conditions including herpesvirus

encephalitis and prion disease. The EEG may be further helpful in disclosing generalized slowing of the background activity, a reflection of the severity of an encephalopathy. Predominant high-voltage slow­ ing (δ or triphasic waves) in the frontal regions is typical of metabolic coma, as from hepatic failure, and widespread fast (β) activity impli­ cates overdose with sedative drugs (e.g., benzodiazepines). A special pattern of “alpha coma,” defined by widespread, variable, 8- to 12-Hz activity, superficially resembles the normal α rhythm of waking but, unlike normal α activity, is not altered by environmental stimuli. Alpha coma results from pontine or diffuse cortical damage and is associated with a poor prognosis. A unique EEG pattern in adults of “extreme delta brush” is characteristic of the anti–N-methyl-d-aspartate (NMDA) recep­ tor form of autoimmune encephalitis. Normal α activity on the EEG, which is suppressed by stimulating the patient, also alerts the clinician to the locked-in syndrome, functional disorder, or catatonia.

Coma CHAPTER 30 Lumbar puncture should be performed if no cause is readily appar­ ent, as examination of the CSF remains indispensable in the diagnosis of various forms of meningitis and encephalitis. An imaging study is generally performed prior to lumbar puncture to exclude a large intracranial mass lesion, which could lead to herniation with lumbar puncture. Blood cultures and administration of antimicrobials should precede the imaging study if infectious meningitis is suspected (Chap. 143). ■ ■DIFFERENTIAL DIAGNOSIS OF COMA (Table 30-1) The causes of coma can be divided into three broad categories: those without focal neurologic signs (e.g., metabolic and toxic encephalopathies); those with prominent focal signs (e.g., stroke, cerebral hemorrhage); and meningitis syndromes, character­ ized by fever or stiff neck and an excess of cells in the spinal fluid (e.g., bacterial meningitis, subarachnoid hemorrhage, infectious or TABLE 30-1  Differential Diagnosis of Coma

1. Diseases that cause no focal brainstem or lateralizing neurologic signs

(CT scan is often normal) a. Intoxications: alcohol, sedative drugs, opiates, etc. b. Metabolic disturbances: anoxia, hyponatremia, hypernatremia, hypercalcemia, diabetic acidosis, nonketotic hyperosmolar hyperglycemia, hypoglycemia, uremia, hepatic coma, hypercarbia, Addisonian crisis, hypo- and hyperthyroid states, profound nutritional deficiency c. Severe systemic infections: pneumonia, septicemia, typhoid fever, malaria, Waterhouse-Friderichsen syndrome d. Shock from any cause e. Status epilepticus, nonconvulsive status epilepticus, postictal states f. Hyperperfusion syndromes including hypertensive encephalopathy, eclampsia, posterior reversible encephalopathy syndrome (PRES) g. Severe hyperthermia, hypothermia h. Concussion i. Acute hydrocephalus 2. Diseases that cause focal brainstem or lateralizing cerebral signs

(CT scan is typically abnormal) a. Hemispheral hemorrhage (basal ganglionic, thalamic) or infarction (large middle cerebral artery territory) with secondary brainstem compression b. Brainstem infarction due to basilar artery thrombosis or embolism c. Brain abscess, subdural empyema d. Epidural and subdural hemorrhage, brain contusion e. Brain tumor with surrounding edema f. Cerebellar and pontine hemorrhage and infarction g. Widespread traumatic brain injury h. Metabolic coma (see above) in the setting of preexisting focal damage 3. Diseases that cause meningeal irritation with or without fever, and with an excess of white blood cells or red blood cells in the CSF a. Subarachnoid hemorrhage from ruptured aneurysm, arteriovenous malformation, trauma b. Infectious meningitis and meningoencephalitis c. Paraneoplastic and autoimmune encephalitis d. Carcinomatous and lymphomatous meningitis

autoimmune/paraneoplastic encephalitis). Causes of sudden coma include drug ingestion, cerebral hemorrhage, trauma, cardiac arrest, epilepsy, and basilar artery occlusion. Coma that appears subacutely is usually related to a preexisting medical or neurologic problem or, less often, to secondary brain swelling surrounding a mass such as tumor or cerebral infarction.

The diagnosis of coma due to cerebrovascular disease can be dif­ ficult but is generally disclosed by cerebral imaging (Chap. 437). The most common diseases in this category are (1) basal ganglia and thalamic hemorrhage (acute but not instantaneous onset, vomiting, headache, hemiplegia, and characteristic eye signs); (2) pontine hemor­ rhage (sudden onset, pinpoint pupils, loss of reflex eye movements and corneal responses, ocular bobbing, posturing, and hyperventilation); (3) cerebellar hemorrhage (occipital headache, vomiting, gaze paresis, and inability to stand and walk); (4) basilar artery thrombosis (neuro­ logic prodrome or transient ischemic attack warning spells, diplopia, dysarthria, vomiting, eye movement and corneal response abnormali­ ties, and asymmetric limb paresis); and (5) subarachnoid hemorrhage (precipitous coma after sudden severe headache and vomiting). The most common large-vessel stroke, unilateral infarction in the terri­ tory of the middle cerebral artery, does not cause coma, but edema surrounding large infarctions may expand over several days and cause coma from mass effect. PART 2 Cardinal Manifestations and Presentation of Diseases The syndrome of acute hydrocephalus accompanies many intracra­ nial diseases, particularly subarachnoid hemorrhage. It is characterized by headache and sometimes vomiting that may progress quickly to coma with extensor posturing of the limbs, bilateral Babinski signs, small unreactive pupils, and impaired oculocephalic movements in the vertical direction. At times, the coma may be featureless without lateralizing signs, although papilledema is often present. ■ ■BRAIN DEATH Brain death is a state of irreversible cessation of all cerebral and brain­ stem function with preservation of cardiac activity and maintenance of respiratory and somatic function by artificial means. It is the only type of brain damage recognized as morally, ethically, and legally equivalent to death. Criteria have been advanced for the diagnosis of brain death, and it is essential to adhere to consensus standards as multiple studies have shown variability in local practice. Given the implications of the diagnosis, clinicians must be thorough and precise in determining brain death. It is advisable to delay clinical testing for at least 24 h if a cardiac arrest has caused brain death or if the inciting disease is not known. Some centers advocate a brief period of observation between two examiners’ tests during which the clinical signs of brain death are sustained. Established criteria contain two essential elements, after assuring that no confounding factors (e.g., hypothermia, drug intoxication) are present: (1) widespread cortical destruction that is reflected by deep coma and unresponsiveness to all forms of stimulation; and (2) global brainstem damage as demonstrated by absent pupillary light reaction, absent corneal reflexes, loss of oculovestibular reflexes, and destruc­ tion of the medulla, manifested by complete and irreversible apnea. Diabetes insipidus is often present but may only develop hours or days after the other clinical signs of brain death appear and is not used as a criterion. The pupils are usually midsized but may be enlarged. Loss of deep tendon reflexes is not required because the spinal cord remains functional. Occasionally, other reflexes that originate from the spine may be present and should not preclude a diagnosis of brain death. Demonstration that apnea is due to medullary damage requires that the Pco2 be high enough to stimulate respiration during a test of spontaneous breathing. Apnea testing can be done by the use of pre­ oxygenation with 100% oxygen prior to and following removal of the ventilator. CO2 tension increases ~0.3–0.4 kPa/min (2–3 mmHg/min) during apnea. Apnea is confirmed if no respiratory effort has been observed in the presence of a sufficiently elevated Pco2. The apnea test is usually stopped if there is cardiovascular instability and alternative means of testing can be employed. An isoelectric EEG may be used as an optional confirmatory test for total cerebral damage. Radionuclide brain scanning, cerebral

angiography, or transcranial Doppler measurements may be used to demonstrate the absence of blood flow when a confirmatory study is desired. It is largely accepted in Western society that the ventilator can be disconnected from a brain-dead patient and that organ donation is subsequently possible. Good communication between the physician and the family is important with appropriate preparation of the family for brain death testing and diagnosis. TREATMENT Coma The immediate goal in a comatose patient is prevention of further nervous system damage. Hypotension, hypoglycemia, hypercalce­ mia, hypoxia, hypercapnia, and hyperthermia should be corrected rapidly. Hyponatremia should be corrected slowly to avoid injury from osmotic demyelination (Chap. 318). An oropharyngeal air­ way is adequate to keep the pharynx open in a drowsy patient who is breathing normally. Tracheal intubation is indicated if there is apnea, upper airway obstruction, hypoventilation, or emesis, or if the patient is at risk for aspiration. Mechanical ventilation is required if there is hypoventilation or a need to induce hypo­ capnia in order to lower ICP. The management of raised ICP is discussed in Chap. 318. IV access is established and naloxone and dextrose are administered if opioid overdose or hypoglycemia are possibilities; thiamine is given along with glucose to avoid provok­ ing Wernicke’s encephalopathy in malnourished patients. In cases of suspected ischemic stroke including basilar thrombosis with brainstem ischemia, IV tissue plasminogen activator or mechani­ cal embolectomy is often used after cerebral hemorrhage has been excluded and when the patient presents within established time windows for these interventions (Chap. 438). Physostigmine may awaken patients with anticholinergic-type drug overdose but should be used only with careful monitoring; many physicians believe that it should only be used to treat anticholinergic over­ dose–associated cardiac arrhythmias. The use of benzodiazepine antagonists offers some prospect of improvement after overdose; however, these drugs are not commonly used empirically in part due to their tendency to provoke seizures. Certain other toxic and drug-induced comas have specific treatments such as fomepizole for ethylene glycol ingestion. Administration of hypotonic IV solutions should be monitored carefully in any serious acute brain illness because of the potential for exacerbating brain swelling. Cervical spine injuries must not be overlooked, particularly before attempting intubation or evalu­ ation of oculocephalic responses. Fever and meningismus indicate an urgent need for examination of the CSF to diagnose meningi­ tis. Whenever acute bacterial meningitis is suspected, antibiotics including at least vancomycin and a third-generation cephalospo­ rin are typically administered rapidly along with dexamethasone (see Chap. 143). ■ ■PROGNOSIS Some patients, especially children and young adults, may have omi­ nous early clinical findings such as abnormal brainstem reflexes and yet recover; early prognostication outside of brain death therefore is unwise. Metabolic comas have a far better prognosis than traumatic or ischemic ones. Systems for estimating prognosis in adults should be taken as approximations, and medical judgments must be tem­ pered by factors such as age, underlying systemic disease, and general medical condition. In an attempt to collect prognostic information from large numbers of patients with head injury, the Glasgow Coma Scale was devised; it has predictive value in cases of brain trauma (Chap. 454), but not in most other causes of coma. For anoxic coma, clinical signs such as the pupillary and motor responses after 1 day, 3 days, and 1 week have predictive value; however, in the setting of therapeutic hypothermia, these prediction rules are less reliable,

21 - 31 Dementia

31 Dementia

and therefore, serial examinations and multimodal prognostication approaches are advised. For example, the absence of the cortical responses of the somatosensory evoked potentials has been shown to be a strong indicator of poor outcome following hypoxic injury, as has high elevations of serum neuron-specific enolase drawn at estab­ lished intervals after anoxia. The poor outcome of persistent vegetative and minimally conscious states has already been mentioned, but reports of a small number of patients displaying cortical activation on functional MRI in response to salient stimuli have begun to alter the perception of such individu­ als. In one series, about 10% of vegetative patients (mainly following traumatic brain injury) could activate their frontal or temporal lobes in response to requests by an examiner to imagine certain visuospatial tasks. Another series demonstrated that up to 15% of patients with various forms of acute brain injury and absence of behavioral responses to motor commands showed EEG activation in response to these com­ mands. It is prudent to avoid generalizations from these findings, but the need for future studies of novel techniques to help communication and possibly recovery is needed. ■ ■FURTHER READING Claasen J et al: Detection of brain activation in unresponsive patients with acute brain injury. N Engl J Med 380:2497, 2019. Edlow JA et al: Recovery from disorders of consciousness: Mechanisms, prognosis and emerging therapies. Nat Rev Neurol 17:135, 2021. Greer DM et al: Pediatric and adult brain death/death by neurologic criteria consensus guideline: Report of the AAN guidelines subcom­ mittee, AAP, CNS, and SCCM. Neurology 101:1112, 2023. Posner JB et al: Plum and Posner’s Diagnosis of Stupor and Coma, 5th ed. New York, Oxford University Press, 2019. Wijdicks EFM: Predicting the outcome of a comatose patient at the bedside. Pract Neurol 20:26, 2020. Gil D. Rabinovici, William W. Seeley,

Bruce L. Miller

Dementia Dementia, a syndrome with many causes, affects over 6 million people in the United States and results in a total annual health care cost in excess of $300 billion. Dementia is defined as an acquired deterioration in cognitive abilities that impairs the successful performance of activi­ ties of daily living. Episodic memory, the ability to recall events specific in time and place, is the cognitive function most commonly lost; 10% of persons age >70 years and 20–40% of individuals age >85 years have clinically identifiable memory loss. In addition to memory, dementia may erode other mental faculties, including language, visuospatial, praxis, calculation, judgment, and problem-solving abilities. Neuropsy­ chiatric and social deficits also arise in many dementia syndromes, manifesting as depression, apathy, anxiety, hallucinations, delusions, agitation, insomnia, sleep disturbances, compulsions, or disinhibition. The clinical course may be slowly progressive, as in Alzheimer’s disease (AD); static, as in anoxic encephalopathy; or may fluctuate from day to day or minute to minute, as in dementia with Lewy bodies (DLB). Most patients with AD, the most prevalent form of dementia, begin with episodic memory impairment, but in other dementias, such as fron­ totemporal dementia (FTD), memory loss is not typically a presenting feature. When dementia is caused by a progressive neurodegenerative disease, it is preceded by a prodromal clinical stage called mild cogni­ tive impairment (MCI), in which individuals experience cognitive decline but remain independent in most daily activities. Increasingly,

a preclinical stage is recognized for AD and other dementing illnesses, in which brain pathology is present but clinical symptoms are not yet manifest. Focal cerebral disorders are discussed in Chap. 32 and illustrated in a video library in Chap. V2; detailed discussions of AD can be found in Chap. 442; FTD and related disorders in Chap. 443; vascular dementia in Chap. 444; DLB in Chap. 445; Huntington’s disease (HD) in Chap. 447; and prion diseases in Chap. 449.

FUNCTIONAL ANATOMY OF THE DEMENTIAS Dementia syndromes result from the disruption of specific large-scale neuronal networks by initially focal brain lesions, including neurode­ generative changes and vascular injury. Ultimately, the location and severity of synaptic and neuronal loss combine to produce the clinical features (Chap. 32). Behavior, mood, and attention are also modu­ lated by ascending noradrenergic, serotonergic, and dopaminergic pathways, whereas cholinergic signaling is critical for attention and memory functions. The dementias differ in the underlying molecular pathology and relative neurotransmitter deficit profiles; accordingly, accurate diagnosis guides effective therapy. Dementia CHAPTER 31 AD typically begins in the entorhinal region of the medial temporal lobe, spreads to the hippocampus and other limbic structures, moves through the basal temporal areas, and then into lateral and posterior temporal and parietal neocortex, eventually causing a more widespread degeneration. Vascular dementia is associated with focal damage in a variable patchwork of cortical and subcortical regions or white matter tracts that disconnects nodes within distributed networks. In keeping with its anatomy, AD typically presents with episodic memory loss accompanied later by aphasia, executive dysfunction, or navigational problems. In contrast, dementias that begin in frontal or subcortical regions, such as FTD or HD, are less likely to begin with memory prob­ lems and more likely to present with difficulties with judgment, mood, executive control, movement, and behavior. Lesions of frontal-striatal1 pathways produce specific and predict­ able effects on behavior. The dorsolateral prefrontal cortex has con­ nections with a central band of the caudate nucleus. Lesions of either the caudate or dorsolateral prefrontal cortex, or their connecting white matter pathways, may result in executive dysfunction, manifesting as poor organization and planning, decreased cognitive flexibility, and impaired working memory. The lateral orbital frontal cortex connects with the ventromedial caudate, and lesions of this system cause impulsiveness, distractibility, and disinhibition. The anterior cingulate cortex and adjacent medial prefrontal cortex project to the nucleus accumbens, and interruption of this system produces apathy, poverty of speech, emotional blunting, or even akinetic mutism. All corticostriatal systems also include topographically organized projec­ tions through the globus pallidus and thalamus, and damage to these nodes can likewise reproduce the clinical syndrome associated with the corresponding cortical or striatal injuries. Lesions in nodes of the dominant hemisphere speech and language networks can present as a primary progressive aphasia, with deficits in naming, word retrieval, motor speech, grammar, and comprehension of single words or more complex phrases (Chap. 443). Involvement of brainstem nuclei and cerebellar structures can further contribute to cognitive, behavioral, motor and autonomic manifestations. ■ ■THE CAUSES OF DEMENTIA The single strongest risk factor for dementia is increasing age. The prevalence of disabling memory loss increases with each decade over age 50 and is usually associated with the microscopic changes of AD at autopsy. Yet some centenarians have intact memory function and no evidence of clinically significant dementia. Whether dementia is an inevitable consequence of normal human aging remains controversial, although the prevalence increases with every decade of life. The many causes of dementia are listed in Table 31-1. The frequency of each condition depends on the age group under study, access of the 1The striatum comprises the caudate/putamen.

TABLE 31-1  Differential Diagnosis of Dementia Most Common Causes of Dementia Alzheimer’s disease Alcoholisma Vascular dementia PDD/LBD spectrum   Multi-infarct Drug/medication intoxicationa’   Diffuse white matter disease Limbic-predominant age-related TDP-43 encephalopathy (Binswanger’s) Less Common Causes of Dementia Vitamin deficiencies   Thiamine (B1): Wernicke’s Toxic disorders   Drug, medication, and narcotic PART 2 Cardinal Manifestations and Presentation of Diseases encephalopathya poisoninga   B12 (subacute combined   Heavy metal intoxicationa degeneration)a   Organic toxins Psychiatric   Depression (pseudodementia)a   Nicotinic acid (pellagra)a Endocrine and other organ failure   Hypothyroidisma   Schizophreniaa   Adrenal insufficiency and Cushing’s   Conversion disordera syndromea Degenerative disorders   Huntington’s disease   Multisystem atrophy   Hereditary ataxias (some forms)   Frontotemporal lobar degeneration   Hypo- and hyperparathyroidisma   Renal failurea   Liver failurea   Pulmonary failurea Chronic infections   HIV   Neurosyphilisa spectrum   Multiple sclerosis   Adult Down’s syndrome with   Papovavirus (JC virus) (progressive Alzheimer’s disease   ALS-parkinsonism-dementia multifocal leukoencephalopathy)   Tuberculosis, fungal, and protozoala complex of Guam   Prion (Creutzfeldt-Jakob and   Whipple’s diseasea Gerstmann-Sträussler-Scheinker diseases) Miscellaneous   Sarcoidosisa Head trauma and diffuse brain damage   Chronic traumatic encephalopathy   Chronic subdural hematomaa   Postanoxia   Postencephalitis   Normal-pressure hydrocephalusa   Vasculitisa   CADASIL, etc.   Acute intermittent porphyriaa Intracranial hypotension Neoplastic   Primary brain tumora   Recurrent nonconvulsive seizuresa Additional conditions in children or adolescents   Pantothenate kinase–associated   Metastatic brain tumora   Paraneoplastic/autoimmune limbic neurodegeneration   Subacute sclerosing panencephalitis   Metabolic disorders (e.g., Wilson’s and encephalitisa Leigh’s diseases, leukodystrophies, lipid storage diseases, mitochondrial mutations) aPotentially reversible dementia. Abbreviations: ALS, amyotrophic lateral sclerosis; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; LBD, Lewy body disease; PDD, Parkinson’s disease dementia. group to medical care, country of origin, and perhaps racial or ethnic background. AD is the most common cause of dementia in Western countries, accounting for more than half of all patients. Vascular dis­ ease is the second most frequent cause for dementia and is particularly common in elderly patients or populations with limited access to medi­ cal care, where vascular risk factors are undertreated. Often, vascular brain injury is mixed with neurodegenerative disorders, particularly AD, making it difficult, even for the neuropathologist, to estimate the contribution of cerebrovascular disease to the cognitive disorder in an individual patient. Dementias associated with Parkinson’s disease (PD) are common and may develop years after onset of a parkinsonian disorder, as seen with PD-related dementia (PDD), or can occur con­ currently with or preceding the motor syndrome, as in DLB. A recently characterized dementia is limbic-predominant aging-related TDP-43

encephalopathy (LATE), which is common after age 70 and has been linked to declining episodic memory function. Chronic traumatic encephalopathy (CTE), a unique disease found in individuals with high exposure to repetitive head impacts (e.g., professional athletes in collision or fighting sports, military veterans exposed to multiple blasts), presents with changes in cognition, mood, behavior, or motor function. Mixed pathology is common, especially in older individuals. In patients under the age of 65, FTD rivals AD as the most common cause of dementia. Chronic intoxications, including those resulting from alcohol and prescription drugs, are an important and often treat­ able cause of dementia. Other disorders listed in Table 31-1 are uncom­ mon but important because many are reversible. The classification of dementing illnesses into reversible and irreversible disorders is a useful approach to differential diagnosis. In a study of 1000 persons attending a memory disorders clinic, 19% had a potentially reversible cause of the cognitive impairment and 23% had a potentially reversible concomitant condition that may have contributed to the patient’s impairment. The three most com­ mon potentially reversible diagnoses were depression, normal pres­ sure hydrocephalus (NPH), and alcohol dependence; medication side effects are also common and should be considered in every patient (Table 31-1). The term rapidly progressive dementia (RPD) is applied to illnesses that progress from initial symptom onset to dementia within a year or less; confusional states related to toxic/metabolic conditions are excluded. Although the prion proteinopathy Creutzfeldt-Jakob disease (CJD) (Chap. 449) is the classic cause of a rapidly progressive demen­ tia, especially when associated with myoclonus, more often cases of RPD are due to AD or another neurodegenerative disorder, or to an autoimmune encephalitis (Chap. 99). Subtle cumulative decline in episodic memory is a common part of aging. This frustrating experience, often the source of jokes and humor, has historically been referred to as benign forgetfulness of the elderly. Benign means that it is not so progressive or serious that it impairs successful and productive daily functioning, although the distinction between benign and significant memory loss can be subtle. At age 85, the average person is able to learn and recall approximately one-half of the items (e.g., words on a list) that they could at age 18. The term sub­ jective cognitive decline is used to refer to individuals who experience a subjective decline from their cognitive baseline but perform within normal limits for their age and educational attainment on formal neu­ ropsychological testing. As noted earlier, MCI is defined as a decline in cognition that is confirmed on objective cognitive testing but does not disrupt normal daily activities. MCI can be further subcategorized based on the presenting complaints and deficits (e.g., amnestic MCI, dysexecutive MCI). Factors that predict progression from MCI to an AD dementia include a prominent memory deficit, family history of dementia, presence of an apolipoprotein ε4 (Apo ε4) allele, small hippocampal volumes on brain imaging, and positive AD biofluid or imaging biomarkers (see below). The term mild behavioral impairment (MBI) refers to the emergence of sustained and impactful neuropsychi­ atric symptoms in older adults (e.g., apathy, emotional dysregulation, impulse control, social inappropriateness, hallucinations, or delusions). Like its cognitive counterpart (MCI), MBI can reflect a neuropsychiat­ ric prodrome to a neurodegenerative dementia. The major degenerative dementias include AD, DLB, LATE, FTD and related disorders, HD, and prion diseases, including CJD. These disorders are all associated with the abnormal aggregation of a specific protein: Aβ and tau in AD; α-synuclein in DLB; TAR DNA-binding protein of 43 kDa (TDP-43) in LATE; tau, TDP-43, or the FET fam­ ily of proteins (fused in sarcoma [FUS], Ewing sarcoma [EWS], and TBP-associated factor 15 [TAF15]) in FTD; huntingtin in HD; and misfolded prion protein (PrPsc) in CJD (Table 31-2). The risk of developing dementia in late life is associated with numerous exposures that can happen across the lifespan. Modifi­ able risk factors based on large-scale epidemiologic studies include low education, hearing loss, social isolation, traumatic brain injury, hypertension, diabetes mellitus, obesity, heavy alcohol use, smoking, depression, physical inactivity, and air pollution exposure. Improved

TABLE 31-2  The Molecular Basis for Degenerative Dementia DEMENTIA MOLECULAR BASIS CAUSAL GENES (CHROMOSOME) SUSCEPTIBILITY GENES PATHOLOGIC FINDINGS AD Aβ/tau APP (21), PS-1 (14), PS-2 (1) (<2% carry these mutations, most often in PS-1) DLB α-Synuclein Very rare SNCA (4) Unknown α-Synuclein neuronal inclusions (Lewy bodies) LATE TDP-43 None identified TMEM106B, GRN TDP-43 neuronal “inclusion bodies” and neurites in neurons and glia, with or without hippocampal sclerosis FTD Tau MAPT exon and intron mutations (17) (~10% of familial cases) TDP-43 GRN (10% of familial cases), C9ORF72 (20–30% of familial cases), rare VCP, very rare TARDBP, TBK1, TIA1 FUS Very rare FUS FUS neuronal and glial inclusions varying in morphology and distribution CJD PrPSC PRNP (20) (up to 15% of patients carry these

dominant mutations) Abbreviations: AD, Alzheimer’s disease; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FTD, frontotemporal dementia; LATE, limbic-predominant age-related TDP-43 encephalopathy. management of mid-life cardiovascular risk factors has been credited with a decreasing incidence of dementia noted in North America and western European countries. APPROACH TO THE PATIENT Dementias Three major issues should be kept at the forefront: (1) What is the clinical diagnosis? (2) What component of the dementia syndrome is treatable or reversible? (3) Can the physician help to alleviate the burden on caregivers? A broad overview of the approach to demen­ tia is shown in Table 31-3. The major degenerative dementias can usually be distinguished by the initial symptoms; neuropsycho­ logical, neuropsychiatric, and neurologic findings; neuroimaging features; and other biomarkers (Table 31-4). HISTORY The history should concentrate on the onset, duration, and tempo of progression. An acute or subacute onset of confusion may be due to delirium (Chap. 29) and should trigger a search for intoxi­ cation, infection, or metabolic derangement. An elderly person with slowly progressive memory loss over several years is likely to suffer from AD and/or LATE. Nearly 75% of patients with AD begin with memory symptoms, but other early symptoms include anxiety or depression and difficulty with managing money, driv­ ing, shopping, following instructions, finding words, or navigating. Personality change, disinhibition, and weight gain or compulsive eating suggest FTD, not AD. FTD is also suggested by prominent apathy, compulsivity, loss of empathy for others, or progressive loss of speech fluency or single-word comprehension with relative spar­ ing of memory and visuospatial abilities. The diagnosis of DLB is suggested by early visual hallucinations; parkinsonism; proneness to delirium or sensitivity to psychoactive medications; rapid eye movement (REM) behavior disorder (RBD; dramatic, sometimes violent, limb movements during dreaming [Chap. 33]); or Capgras syndrome, the delusion that a familiar person has been replaced by an impostor. A history of stroke with irregular stepwise progression suggests vascular dementia. Vascular dementia is also commonly seen in the setting of hypertension, atrial fibrillation, peripheral vascular dis­ ease, smoking, and diabetes. In patients suffering from cerebrovas­ cular disease, it can be difficult to determine whether the dementia is due to AD, vascular disease, or a mixture of the two because many of the risk factors for vascular dementia, including diabetes, high cholesterol, elevated homocysteine, and low exercise, are also

Apo ε4 (19) Amyloid plaques, neurofibrillary tangles, and neuropil threads H1 MAPT haplotype Tau neuronal and glial inclusions varying in morphology and distribution Dementia CHAPTER 31 TDP-43 neuronal and glial inclusions varying in morphology and distribution Codon 129 homozygosity for methionine or valine PrPSC deposition, panlaminar spongiosis TABLE 31-3  Evaluation of the Patient with Dementia OPTIONAL FOCUSED TESTS OCCASIONALLY HELPFUL TESTS ROUTINE EVALUATION History Physical examination Laboratory tests   Thyroid function (TSH)   Vitamin B12   Complete blood count   Complete metabolic panel   CT/MRI Psychometric testing HIV, RPR, or VDRL Lumbar puncture PET (FDG, amyloid, tau) Chest x-ray Urine toxin screen Apolipoprotein E Blood-based AD biomarkers EEG Parathyroid function Adrenal function Urine heavy

metals RBC sedimentation rate Lab screen for autoantibodies Angiogram Brain biopsy Diagnostic Categories IRREVERSIBLE/ DEGENERATIVE DEMENTIAS PSYCHIATRIC DISORDERS REVERSIBLE CAUSES Examples   Hypothyroidism   Thiamine deficiency   Vitamin B12 deficiency   Normal-pressure Examples   Alzheimer’s   Frontotemporal Depression Schizophrenia Conversion reaction dementia   Huntington’s   Dementia with Lewy hydrocephalus   Subdural hematoma   Chronic infection   Brain tumor   Drug intoxication   Autoimmune bodies   Vascular   Leukoencephalopathies   Parkinson’s   LATE encephalopathy Associated Treatable Conditions Depression Seizures Insomnia Agitation Caregiver “burnout” Drug side effects Abbreviations: CT, computed tomography; EEG, electroencephalogram; LATE, limbic-predominant age-related TDP-43 encephalopathy; MRI, magnetic resonance imaging; PET, positron emission tomography; RBC, red blood cell; RPR, rapid plasma reagin (test); TSH, thyroid-stimulating hormone; VDRL, Venereal Disease Research Laboratory (test for syphilis).

TABLE 31-4  Clinical Differentiation of the Major Dementias DISEASE FIRST SYMPTOM MENTAL STATUS NEUROPSYCHIATRY NEUROLOGY IMAGING AD Memory loss Episodic memory loss Executive, language, and visuospatial functions variably affected Vascular Often but not always sudden; variable; apathy, falls, focal weakness Frontal/executive, cognitive slowing; can spare memory DLB Visual hallucinations, REM sleep behavior disorder, delirium, Capgras syndrome, parkinsonism Drawing and frontal/ executive; spares memory; delirium-prone PART 2 Cardinal Manifestations and Presentation of Diseases LATE Memory loss Episodic memory loss Mild semantic deficits FTD Apathy; poor judgment/insight, speech/language; hyperorality Frontal/executive and/or language; spares drawing CJD Dementia, mood, anxiety, movement disorders Variable, frontal/executive, focal cortical, memory Abbreviations: AD, Alzheimer’s disease; CBD, cortical basal degeneration; CJD, Creutzfeldt-Jakob disease; DLB, dementia with Lewy bodies; FLAIR, fluid-attenuated inversion recovery; FTD, frontotemporal dementia; LATE, limbic-predominant age-related TDP-43 encephalopathy; MND, motor neuron disease; MRI, magnetic resonance imaging; PSP, progressive supranuclear palsy; REM, rapid eye movement. risk factors for AD. Moreover, many patients with a major vascular contribution to their dementia lack a history of stepwise decline. The age at symptom onset can also aid in the differential diag­ nosis of dementia. AD and FTD are the most common neuro­ degenerative causes of “early-onset” (age at symptom onset <65) dementia. The most common causes of “late-onset” dementia (age at symptom onset >65) are AD, DLB, and vascular dementia. LATE neuropathological changes are increasingly common with older age and are found in ~20% of individuals with dementia who die at age <70 versus >50% of individuals with dementia who die at age

90. Most late-onset dementia is associated with multiple patho­ logical entities; it is common for individuals who suffered from dementia to show three or four different pathologies at autopsy. In one large community-based autopsy cohort of individuals who presented with an amnestic dementia during life (mean age at death 89.7 years), 39% of the attributable risk for dementia was explained by AD neuropathology, 25% by cerebrovascular disease, 17% by LATE, and 12% by Lewy body disease. Rapid progression with motor rigidity and myoclonus suggests CJD (Chap. 449). Seizures may indicate strokes or neoplasm but also occur in AD, particularly early-age-of-onset AD. Gait distur­ bance is common in vascular dementia, PD/DLB, or NPH. A history of high-risk sexual behaviors or intravenous drug use should trig­ ger a search for central nervous system (CNS) infection, especially HIV or syphilis. A history of recurrent head trauma could indicate chronic subdural hematoma, CTE, intracranial hypotension, or NPH. Subacute onset of severe amnesia and psychosis with mesial temporal T2/fluid-attenuated inversion recovery (FLAIR) hyperin­ tensities on magnetic resonance imaging (MRI) should raise con­ cern for autoimmune (paraneoplastic) encephalitis, sometimes in long-term smokers or other patients at risk for cancer. The spectrum of autoimmune etiologies producing RPD has rapidly expanded and includes antibodies targeting leucine-rich glioma-inactivated 1 (LGI1; faciobrachial dystonic seizures); contactin-associated protein-like 2 (Caspr2; insomnia, ataxia, myotonia); N-methyl-d-

aspartate (NMDA) receptor (psychosis, insomnia, dyskinesias); and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor (limbic encephalitis with relapses), among others (Chap. 99). Alcohol abuse creates risk for malnutrition and thiamine deficiency. Pernicious anemia, veganism, bowel irradiation, a remote history

Irritability, anxiety, depression Initially normal Entorhinal cortex and hippocampal atrophy; posterior-predominant cortical atrophy Apathy, delusions, anxiety Usually motor slowing, spasticity; can be normal Cortical and/or subcortical infarctions, confluent white matter disease Visual hallucinations, depression, sleep disorder, delusions Parkinsonism Posterior parietal atrophy; hippocampi larger than in AD None described Normal Medial temporal and hippocampal atrophy, anterior predominant Apathy, disinhibition, overeating, compulsivity May have vertical gaze palsy, axial rigidity, dystonia, alien hand, or MND Frontal, insular, and/or temporal atrophy; usually spares posterior parietal lobe Depression, anxiety, psychosis in some Myoclonus, rigidity, parkinsonism Cortical ribboning and basal ganglia or thalamus hyperintensity on diffusion/ FLAIR MRI of gastric surgery, and chronic therapy with histamine H2-receptor antagonists for dyspepsia or gastroesophageal reflux are causes of B12 deficiency. Certain occupations, such as working in a battery or chemical factory, might indicate heavy metal intoxication. Careful review of medication intake, especially for sedatives and analgesics, may raise the issue of chronic drug intoxication. An autosomal dominant family history is found in HD and in familial forms of AD, FTD, DLB, or prion disorders. A history of mood disorder, the recent death of a loved one, or depressive signs such as insomnia or weight loss raise the possibility of depression-related cognitive impairment. PHYSICAL AND NEUROLOGIC EXAMINATION A thorough general and neurologic examination is essential, in the setting of dementia, to look for signs of nervous system involvement and to search for clues suggesting a systemic disease that might be responsible for the cognitive disorder. Typical AD spares motor sys­ tems until later in the course. In contrast, patients with FTD often develop axial rigidity, supranuclear gaze palsy, or a motor neuron disease reminiscent of amyotrophic lateral sclerosis (ALS). In DLB, the initial symptoms may include the new onset of a parkinsonian syndrome (resting tremor, cogwheel rigidity, bradykinesia, festinat­ ing gait), but DLB often starts with visual hallucinations or cogni­ tive impairment, and symptoms referable to the lower brainstem (RBD, gastrointestinal or autonomic problems) may arise years or even decades before parkinsonism or dementia. Corticobasal syn­ drome (CBS) features asymmetric akinesia and rigidity, dystonia, myoclonus, alien limb phenomena, pyramidal signs, and prefrontal deficits such as nonfluent aphasia with or without motor speech impairment, executive dysfunction, apraxia, or a behavioral disor­ der. Progressive supranuclear palsy (PSP) is associated with unex­ plained falls, axial rigidity, dysphagia, and vertical gaze deficits. CJD is suggested by the presence of diffuse rigidity, an akinetic-mute state, and prominent, often startle-sensitive myoclonus. Hemiparesis or other focal neurologic deficits suggest vascu­ lar dementia or brain tumor. Dementia with a myelopathy and peripheral neuropathy suggests vitamin B12 deficiency. Peripheral neuropathy could also indicate another vitamin deficiency, heavy metal intoxication, thyroid dysfunction, Lyme disease, or vasculitis. Dry cool skin, hair loss, and bradycardia suggest hypothyroidism.

Fluctuating confusion associated with repetitive stereotyped move­ ments may indicate ongoing limbic, temporal, or frontal seizures. In the elderly, hearing impairment or visual loss may produce confusion and disorientation misinterpreted as dementia. Profound bilateral sensorineural hearing loss in a younger patient with short stature or myopathy, however, should raise concern for a mitochon­ drial disorder. COGNITIVE AND NEUROPSYCHIATRIC EXAMINATION Brief screening tools such as the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MOCA) can be used to capture dementia and follow progression. None of these tests is highly sensitive to early-stage dementia or reliably discrimi­ nates between dementia syndromes. The MMSE is a 30-point test of cognitive function, with each correct answer being scored as 1 point. It includes tests of orientation (e.g., identify season/date/ month/year/floor/hospital/town/state/country); registration (e.g., name and restate three objects); recall (e.g., remember the same three objects 5 min later); and language (e.g., name pencil and watch; repeat “no ifs, ands, or buts”; follow a three-step command; obey a written command; and write a sentence and copy a design). In most patients with MCI and some with clinically apparent AD, bedside screening tests may be normal, and a more challenging and comprehensive set of neuropsychological tests will be required. When the etiology for the dementia syndrome remains in doubt, a specially tailored evaluation should be performed that includes tasks of working and episodic memory, executive function, lan­ guage, and visuospatial and perceptual abilities. In AD, the early deficits involve episodic memory, category generation (“Name as many animals as you can in 1 minute”), and visuoconstructive abil­ ity. Usually deficits in verbal or visual episodic memory are the first neuropsychological abnormalities detected, and tasks that require the patient to recall a long list of words or a series of pictures after a predetermined delay will demonstrate deficits in most patients. Patients with LATE also present with prominent deficits in epi­ sodic memory and can be identified by sparing of other cognitive domains and relatively slow progression. Patients with PDD or DLB have more severe deficits in executive and visuospatial function but do better on episodic memory tasks than patients with AD. Patients with vascular dementia often demonstrate a mixture of executive and visuospatial deficits, with prominent psychomotor slowing. In delirium, the most prominent deficits involve attention, working memory, and executive function, making the assessment of other cognitive domains challenging and often uninformative. In FTD, the earliest deficits on cognitive testing involve executive control or language (speech or naming) function, but some patients lack either finding despite profound social-emotional deficits. A functional assessment should also be performed to help the physician determine the day-to-day impact of the disorder on the patient’s memory, community affairs, hobbies, judgment, dressing, and eating. Knowledge of the patient’s functional abilities will help the clinician and the family to organize a therapeutic approach. Neuropsychiatric assessment is important for diagnosis, prog­ nosis, and treatment. In the early stages of AD, mild depressive features, social withdrawal, and irritability or anxiety are the most prominent psychiatric changes, but patients often maintain core social graces into the middle or late stages, when delusions, agita­ tion, and sleep disturbance may emerge. In FTD, dramatic person­ ality changes with apathy, overeating, compulsions, disinhibition, and loss of empathy are early and common. DLB is associated with visual hallucinations, delusions related to person or place identity, RBD, and excessive daytime sleepiness. Dramatic fluctuations occur not only in cognition but also in arousal. Vascular dementia can present with psychiatric symptoms such as depression, anxiety, delusions, disinhibition, or apathy. LABORATORY TESTS The choice of laboratory tests in the evaluation of dementia is com­ plex and should be tailored to the individual patient. The physician

must take measures to avoid missing a reversible or treatable cause, yet no single treatable etiology is common; thus, a screen must use multiple tests, each of which has a low yield. Cost/benefit ratios are difficult to assess, and many laboratory screening algorithms for dementia discourage multiple tests. Nevertheless, even a test with only a 1–2% positive rate is worth undertaking if the alterna­ tive is missing a treatable cause of dementia. Table 31-3 lists most screening tests for dementia. The American Academy of Neurol­ ogy recommends the routine measurement of a complete blood count; electrolytes; glucose; renal, liver, and thyroid functions; a vitamin B12 level; and a structural neuroimaging study (MRI or computed tomography [CT]). Dementia CHAPTER 31 Neuroimaging studies, especially MRI, help to rule out primary and metastatic neoplasms, locate areas of infarction or inflam­ mation, detect subdural hematomas, and suggest NPH or diffuse white matter disease. They also help to establish a regional pattern of atrophy. Support for the diagnosis of AD includes hippocampal atrophy in addition to posterior-predominant cortical atrophy (Fig. 31-1). Marked hippocampal and medial temporal lobe atrophy is also the MRI signature of LATE. Focal frontal, insular, and/or anterior temporal atrophy suggests FTD (Chap. 443). DLB often features less prominent atrophy, with greater involvement of amygdala than hippocampus. In CJD, magnetic resonance diffusion-weighted imaging reveals restricted diffusion within the cortical ribbon and/or basal ganglia in most patients. Extensive multifocal white matter abnormalities suggest a vascular etiology (Fig. 31-2). Communicating hydrocephalus with vertex efface­ ment (crowding of dorsal convexity gyri/sulci), gaping Sylvian fissures despite minimal cortical atrophy, and additional features shown in Fig. 31-3 suggest NPH. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning shows temporal-pari­ etal or hypometabolism in AD, often with early and prominent involvement of the posterior cingulate cortex and precuneus. Conversely, patients with FTD show hypometabolism in frontal and anterior temporal cortices. The FDG signature of DLB fea­ tures hypometabolism in the occipital cortex and precuneus with sparing of the posterior cingulate (“cingulate island sign”), while LATE is characterized by severe medial temporal hypometabo­ lism with sparing of association cortices. Single-photon emission computed tomography (SPECT) demonstrates spatial patterns of hypoperfusion that mirror the FDG hypometabolic patterns described above. Amyloid and tau PET imaging can support the diagnosis of AD by directly detecting amyloid plaques and neurofibrillary tangles, the neuropathological lesions that define the disease. There are cur­ rently three amyloid PET ligands (18F-florbetapir, 18F-florbetaben, 18F-flutametamol) and one tau PET ligand (18F-flortaucipir) approved by the U.S. Food and Drug Administration (FDA) for clinical use. Amyloid PET ligands bind to diffuse and neuritic amyloid plaques as well as to vascular amyloid deposits (cerebral amyloid angiopathy), while tau PET ligands bind to the paired helical filaments of tau characteristic of neurofibrillary tangles in AD. Current tau PET ligands do not reliably detect tau deposits in non-AD conditions. Because amyloid plaques are also commonly found in cognitively normal older persons (~25% of individuals at age 70), the main clinical value of amyloid imaging is to exclude AD as the likely cause of dementia in patients who have negative scans. In older patients presenting with a progressive amnestic disorder and hippocampal atrophy, a negative amyloid PET scan strongly suggests LATE as the underlying neuropathology. The spread of tau is more tightly linked to cognitive state (Chap. 442), and thus tau PET may be more useful for “ruling in” AD, as well as for disease staging. Amyloid PET is also useful to identify can­ didates for novel anti-Aβ monoclonal antibodies (e.g., lecanemab, donanemab) that reduce amyloid plaque load and slow cognitive decline in patients in early clinical stages of AD. Amyloid and tau PET can also assist with prognosis, as patients who are positive on both modalities show the most rapid decline in cognition and

62 y.o. HC 60 y.o. AD PART 2 Cardinal Manifestations and Presentation of Diseases A B C D FIGURE 31-1  Alzheimer’s disease (AD). Axial T1-weighted MRI and 18F-florbetapir amyloid PET images from a 62-year-old healthy control (left) and 60-year-old with dementia due to AD (right panels). Note the reduction in medial temporal volumes and prominent sulci on MRI in the patient with AD. Amyloid PET demonstrates a white matter only binding pattern in the healthy control (negative scan), whild the patient with AD demonstrates diffuse neocortical binding and blurring of gray/white matter contrast (positive scan). (Images courtesy of Gil Rabinovici, University of California, San Francisco.) function. Use of amyloid and tau PET in cognitively unimpaired older adults should for now be restricted to research studies and clinical trials testing interventions aimed at reducing the risk of MCI and dementia in asymptomatic individuals who are positive for AD biomarkers. Lumbar puncture is indicated when CNS infection or inflamma­ tion is a credible diagnostic possibility or to assess molecular bio­ markers for AD in lieu of PET imaging. A cerebrospinal fluid (CSF) pattern that shows low levels of Aβ42 (or a low Aβ42/Aβ40 ratio), mild to moderately elevated CSF total tau, and elevated CSF phosphory­ lated tau (p-Tau at residues 181 or 217) is highly suggestive of AD and sufficient for selecting patients for anti-Aβ antibody treatment. Novel fully automated CSF Aβ and tau assays perform comparably to amyloid PET, with the Aβ42/Aβ40 or p-Tau181/Aβ42 ratios show­ ing higher concordance with amyloid PET and neuropathology than any single CSF AD biomarker. Blood-based AD biomarkers, such as plasma Aβ42/Aβ40, p-Tau181 and p-Tau217 measured with FIGURE 31-2  Diffuse white matter disease. Axial fluid-attenuated inversion recovery (FLAIR) magnetic resonance image through the lateral ventricles reveals multiple areas of hyperintensity (arrows) involving the periventricular white matter as well as the corona radiata and striatum. Although seen in some individuals with normal cognition, this appearance is more pronounced in patients with dementia of a vascular etiology.

mass spectrometry or highly sensitive immunoassays, are evolving rapidly and are likely to be approved for clinical use in the near future, greatly enhancing the scalability and cost effectiveness of biomarker testing in patients with suspected AD (Chap. 442). Recently, there has been significant progress in developing bio­ markers of α-synuclein pathology, enabling a molecular diagnosis of PD or DLB. A CSF seed amplification assay for α-synuclein shows high sensitivity and specificity in clinically diagnosed PD patients and also detects pathology in a subset of individuals at risk for PD based on the presence of anosmia or RBD. α-Synuclein can also be detected with high sensitivity and specificity in living patients with PD and DLB with skin biopsies immunostained for phosphorylated α-synuclein colocalizing with nerve fiber bundles. While still in early stages of validation, these biomarkers hold A B FIGURE 31-3  Normal-pressure hydrocephalus. A. Sagittal T1-weighted magnetic resonance image (MRI) demonstrates dilation of the lateral ventricle and stretching of the corpus callosum (arrows), depression of the floor of the third ventricle (single arrowhead), and enlargement of the aqueduct (double arrowheads). Note the diffuse dilation of the lateral, third, and fourth ventricles with a patent aqueduct, typical of communicating hydrocephalus. B. Axial T2-weighted MRIs demonstrate dilation of the lateral ventricles. This patient underwent successful ventriculoperitoneal shunting.

great promise for enhancing diagnostic accuracy and accelerating drug development for α-synuclein disorders. Active work is being done to develop PET tracers for α-synuclein and to discover both imaging and fluid-based biomarkers for other aggregated disease proteins underlying neurodegenerative dementias, such as non-AD tau and TDP-43. Electroencephalogram (EEG) is not routinely used but can help to suggest CJD (repetitive bursts of diffuse high-amplitude sharp waves, or “periodic complexes”) or an underlying nonconvulsive seizure disorder (epileptiform discharges). Brain biopsy (including meninges) is not advised except to diagnose vasculitis, potentially treatable neoplasms, or unusual infections when the diagnosis is uncertain. Systemic disorders with CNS manifestations, such as sarcoidosis, can often be confirmed through biopsy of lymph node or solid organ rather than brain. Magnetic resonance angiography should be considered when cerebral vasculitis or cerebral venous thrombosis is a possible cause of the dementia. ■ ■GLOBAL CONSIDERATIONS Vascular dementia (Chap. 444) is more common in Asian countries, due to the higher prevalence of intracranial atherosclerosis. Rates of vascular dementia are also on the rise in developing countries as vascular risk factors such as hypertension, hypercholesterolemia, and diabetes mellitus become more widespread. CNS infections, HIV (and associated opportunistic infections), syphilis, cysticercosis, and tuberculosis likewise represent major contributors to dementia in the developing world. Systemic infection with SARS-CoV-2 may, in some individuals, have lasting effects on cognition due to involvement of brain microvasculature or due to immunologically mediated white matter injury (acute disseminated encephalomyelitis [ADEM]) (Chap. 456). Some individuals infected with SARS-CoV-2 complain of lasting fatigue, changes in mood, and cognitive difficulties, but the long-term prognosis for SARS-CoV-2–related cognitive impairment remains unknown. Isolated populations have also contributed to our understanding of neurodegenerative dementia. Kuru, the cannibalismassociated rapidly progressive dementia seen in tribal New Guinea, played a role in the discovery of human prion disease. ALS-parkin­ sonism-dementia complex of Guam (or lytico-bodig disease) is a poly­ proteinopathy, often with tau, TDP-43, and α-synuclein aggregation. The root cause of the disease remains uncertain, but its incidence has declined sharply over the past 60 years. TREATMENT Dementia The major goals of dementia management are to treat reversible causes and to provide comfort and support to the patient and their caregivers. Treatment of underlying causes includes thyroid replacement for hypothyroidism; vitamin therapy for thiamine or B12 deficiency or for elevated serum homocysteine; antimicrobials for opportunistic infections or antiretrovirals for HIV; ventricular shunting for NPH; or surgical, radiation, and/or chemotherapeutic treatment for CNS neoplasms. Removal of cognition-impairing drugs or medications is critical when appropriate. If the patient’s cognitive complaints stem from a psychiatric disorder, vigorous treatment of the condition should be sought to eliminate the cogni­ tive complaint or to confirm that it persists despite adequate resolu­ tion of the mood or anxiety symptoms. Patients with degenerative diseases may also be depressed or anxious, and those aspects of their condition often respond to therapy, while not necessarily improving cognition. Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) (Chap. 463), which feature anxiolytic properties but few cognitive side effects, provide the mainstay of treatment when necessary. Anticonvulsants are used to control seizures, with levetiracetam and lamotrigine being the preferred agents based on their efficacy in animal models of AD and favorable cognitive side

effect profiles. Furthermore, a small clinical trial found a potential cognitive benefit for levetiracetam over placebo in AD patients found to have epileptiform activity on electroencephalogram or magnetoencephalography.

Agitation, hallucinations, delusions, and confusion are difficult to treat. These behavioral problems represent major causes for nursing home placement and institutionalization. Before treating these behaviors with medications, the clinician should aggres­ sively seek out modifiable environmental or metabolic factors. Hunger, lack of exercise, toothache, constipation, urinary tract or respiratory infection, electrolyte imbalance, and drug toxicity all represent easily correctable causes that can be remedied without psychoactive drugs. Drugs such as phenothiazines and benzodiaz­ epines may ameliorate the behavior problems but have untoward side effects such as sedation, rigidity, dyskinesia, and occasion­ ally paradoxical disinhibition (benzodiazepines). Despite their unfavorable side effect profile, second-generation antipsychotics such as quetiapine (starting dose, 12.5–25 mg daily) can be used for patients with agitation, aggression, and psychosis, although the risk profile for these compounds is significant, including increased mortality in patients with dementia. Brexpiprazole, an atypical antipsychotic that acts on noradrenergic, serotonergic, and dopaminergic neurotransmitter systems, recently became the first FDA-approved drug for the treatment of agitation in patients with AD dementia based on evidence of short-term efficacy and safety in a 12-week, double-blind, placebo-controlled randomized clini­ cal trial. When patients do not respond to treatment, it is usually a mistake to advance to higher doses or to use anticholinergic drugs (e.g., diphenhydramine) or sedatives (e.g., barbiturates or ben­ zodiazepines). It is important to recognize and treat depression; treatment can begin with a low dose of an SSRI (e.g., escitalopram, starting dose 5 mg daily, target dose 5–10 mg daily) while monitor­ ing for efficacy and toxicity. Sometimes apathy, visual hallucina­ tions, depression, and other psychiatric symptoms respond to the cholinesterase inhibitors, especially in DLB, obviating the need for other more toxic therapies. Dementia CHAPTER 31 Cholinesterase inhibitors are being used to treat AD (donepezil, rivastigmine, galantamine) and PDD (rivastigmine). Memantine, which acts on N-methyl-D-aspartate (NMDA) glutamate receptors, proves useful when treating some patients with moderate to severe AD; its major benefit relates to decreasing caregiver burden, most likely by decreasing resistance to dressing and grooming support. In moderate to severe AD, the combination of memantine and a cholinesterase inhibitor delayed nursing home placement in several studies, although other studies have not supported the efficacy of adding memantine to the regimen. Memantine should be used with great caution, or not at all, in patients with DLB, due to risk of worsening agitation and confusion. In recent years, a novel class of drugs, monoclonal antibod­ ies that target Aβ, have been approved for the treatment of MCI and mild dementia due to AD. These drugs reduce amyloid plaque burden as measured by PET, and some have been found to modestly slow clinical decline. In 2021, aducanumab became the first anti-Aβ monoclonal antibody to receive accelerated FDA approval, based on strong biomarker evidence of amyloid plaque lowering on PET. However, clinical benefits were ques­ tionable based on discordant results in two identically designed phase 3 randomized clinical trials (RCTs). In 2023, lecanemab received traditional FDA approval based on evidence of clinical efficacy in a phase 3 RCT, with treated patients showing 27% less decline over 18 months compared to placebo on the Clinical Dementia Rating–Sum of Boxes, a clinical scale that measures changes in cognition and function. A third antibody, donanemab, reported similar positive clinical results in a phase 3 RCT, and was approved by the FDA in 2024. All three drugs are infused intrave­ nously every 2 weeks (lecanemab) or monthly (aducanumab and donanemab). Significant side effects of this class of medications include infusion reactions and amyloid-related imaging abnor­ malities (ARIA), which manifest as edema or sulcal effusions

23 - 33 Sleep Disorders

33 Sleep Disorders

avoid making a diagnosis of “frontal lobe syndrome” in a patient with no evidence of frontal cortex disease, it is advisable to use the diag­ nostic term frontal network syndrome, with the understanding that the responsible lesions can lie anywhere within this distributed network. A patient with frontal lobe disease raises potential dilemmas in differ­ ential diagnosis, especially if the cause is neurodegenerative: the abulia and blandness may be misinterpreted as depression, and the disinhibi­ tion as idiopathic mania or acting out. CARING FOR PATIENTS WITH DEFICITS

OF HIGHER CEREBRAL FUNCTION Spontaneous improvement of cognitive deficits following stroke or trauma is common. It is most rapid in the first few weeks but may continue for up to 2 years, especially in young individuals with single brain lesions. Some of the initial deficits in such cases appear to arise from remote dysfunction (diaschisis) in brain regions that are inter­ connected with the site of initial injury. Improvement in these patients may reflect, at least in part, a normalization of the remote dysfunction. Other mechanisms may involve functional reorganization in surviving neurons adjacent to the injury or the compensatory use of homologous structures. In contrast, neurodegenerative diseases show a progression of impairment but at rates that vary greatly from patient to patient. Pharmacologic and Nonpharmacologic Interventions  Some of the deficits described in this chapter are so complex that they may bewilder not only the patient and family but also the physician. The care of patients with such deficits requires a careful evaluation of the history, cognitive test results, and diagnostic procedures. Each piece of information needs to be interpreted cautiously and placed in context. A complaint of “poor memory,” for example, may reflect an anomia; poor scores on a learning task may reflect a weakness of attention rather than explicit memory; a report of depression or indifference may reflect impaired prosody rather than a change in mood or empa­ thy; jocularity may arise from poor insight rather than good mood. Treatment plans should encompass two levels: a symptomatic level that can be addressed by pharmacologic or nonpharmacologic means and a disease level that needs to be addressed through pharmacologic or molecular interventions. Although there are few well-controlled stud­ ies, several nonpharmacologic interventions have been used to treat higher cortical deficits. These include speech therapy for aphasias, behavioral modification for compartmental disorders, and cogni­ tive training for visuospatial disorientation and amnestic syndromes. More practical interventions, usually delivered through occupational therapy, aim to improve daily living activities through assistive devices and modifications of the home environment. Determining driving competence is challenging, especially in the early stages of dementing diseases. An on-the-road driving test and reports from family mem­ bers may help time decisions related to this very important activity. In neurodegenerative conditions such as PPA, transcranial magnetic (or direct current) stimulation has had mixed success in eliciting symp­ tomatic improvement. The goal is to activate remaining neurons at sites of atrophy or in unaffected regions of the contralateral hemisphere. Depression and sleep disorders can intensify the cognitive disorders and should be treated with appropriate modalities. If neuroleptics become necessary for the control of agitation, atypical neuroleptics are preferable because of their lower extrapyramidal side effects. Treatment with neuroleptics in elderly patients with dementia requires weighing the potential benefits against the potentially serious side effects. This is especially relevant to the case of patients with Lewy body dementia, who can be unusually sensitive to side effects. As in all other branches of medicine, a crucial step in patient care is to identify the underlying cause of the impairment. This is easily done in cases of CVA, head trauma, or encephalitis but becomes particularly challenging in neurodegenerations because the same progressive clinical syndrome can be caused by one of several neuropathologic entities. The advent of imaging, blood, and cerebrospinal fluid biomarkers now makes it possible to address this question with reasonable success and to make specific diagnoses of AD, LBD, CJD, and FTLD. A specific etiologic diagnosis allows the physician to recommend medications or clinical

trials that are the most appropriate for the underlying disease process. A clinical assessment that identifies the principal domain of behavioral and cognitive impairment followed by the judicious use of biomarker information to surmise the nature of the underlying disease allows a personalized approach to patients with higher cognitive impairment.

■ ■FURTHER READING Carretero RG et al: Behavioral changes as the first manifestation of a silent frontal lobe stroke. BMJ Case Rep 12:bcr-2018-227617, 2019. Mesulam M-M: Behavioral neuroanatomy: Large-scale networks, association cortex, frontal syndromes, the limbic system and hemi­ spheric specialization, in Principles of Behavioral and Cognitive Neurology, M-M Mesulam (ed). New York, Oxford University Press, 2000, pp 1–120. Mesulam M-M et al: Frontotemporal degeneration with transactive Sleep Disorders CHAPTER 33 response DNA-binding protein type C at the anterior temporal lobe. Ann Neurol 94:1, 2023. Ricken G et al: Autoimmune global amnesia as manifestation of AMPAR encephalitis and neuropathologic findings. Neurol Neuro­ immunol Neuroinflamm 8:e1019, 2021. Singh NR, Leff AP: Advances in the rehabilitation of hemispatial inat­ tention. Curr Neurol Neurosci Rep 23:33, 2023. Ulugut H, Pijnenburg YAL: Frontotemporal dementia: Past, present, and future. Alzheimers Dement 19:5253, 2023. Ulugut H et al: Right temporal variant frontotemporal dementia is pathologically heterogeneous: A case-series and systematic review. Acta Neuropathol Commun 9:131, 2021. Thomas E. Scammell, Clifford B. Saper,

Charles A. Czeisler

Sleep Disorders Disturbed sleep is one of the most common health complaints that physicians encounter. More than one-half of adults in the United States experience at least intermittent sleep disturbance, and only 30% of adult Americans report consistently obtaining a sufficient amount of sleep. The National Academy of Medicine has estimated that 50–70 million Americans suffer from a chronic disorder of sleep and wakefulness, which can adversely affect daytime functioning as well as physical and mental health. A high prevalence of sleep disorders across all cultures is also now increasingly recognized, and these problems are expected to further increase in the years ahead as the global population ages. Over the past 40 years, the field of sleep medicine has emerged as a distinct specialty in response to the impact of sleep disorders and sleep deficiency on overall health. Nonetheless, >80% of patients with sleep disorders remain undiagnosed and untreated—costing the U.S. economy >$400 billion annually in increased health care costs, lost productivity, accidents, and injuries, and leading to the development of workplace-based sleep health education and sleep disorders screening programs designed to address this unmet medical need. PHYSIOLOGY OF SLEEP AND WAKEFULNESS Most adults need 7–9 h of sleep per night to promote optimal health, although the timing, duration, and internal structure of sleep vary among individuals. In the United States, adults tend to have one consolidated sleep episode each night, although in some cultures, sleep may be divided into a mid-afternoon nap and a shortened night sleep. This pattern changes considerably over the life span, as infants and young children sleep considerably more than older people, while

individuals >70 years of age sleep on average about an hour less than young adults.

The stages of human sleep are defined on the basis of characteristic patterns in the electroencephalogram (EEG), the electrooculogram (EOG—a measure of eye-movement activity), and the surface elec­ tromyogram (EMG) measured on the chin and legs. The continuous recording of these electrophysiologic parameters to define sleep and wakefulness is termed polysomnography. Polysomnographic profiles define two basic states of sleep: (1) rapid eye movement (REM) sleep and (2) non–rapid eye movement (NREM) sleep. NREM sleep is further subdivided into three stages: N1, N2, and N3, characterized by an increasing threshold for arousal and slowing of the cortical EEG. REM sleep is distinguished by a low-amplitude, mixed-frequency EEG, similar to NREM stage N1 sleep, and an EOG pattern of REMs that tend to occur in flurries or bursts. EMG activ­ ity is absent in nearly all skeletal muscles except those involved in respiration, reflecting the brainstem-mediated muscle paralysis that is characteristic of REM sleep. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■ORGANIZATION OF HUMAN SLEEP Normal nocturnal sleep in adults displays a consistent organization from night to night (Fig. 33-1). After sleep onset, sleep usually pro­ gresses through NREM stages N1–N3 sleep within 45–60 min. NREM stage N3 sleep (also known as slow-wave sleep) predominates in the first third of the night and comprises 15–25% of total nocturnal sleep time in young adults. Sleep deprivation increases the rapidity of sleep onset and both the intensity and amount of slow-wave sleep. The first REM sleep episode usually occurs in the second hour of sleep. NREM and REM sleep alternate through the night with an aver­ age period of 60–160 min (the “ultradian” sleep cycle). Overall, in a healthy young adult, REM sleep constitutes 20–25% of total sleep, and NREM stages N1 and N2 constitute 50–60%. Age has a profound impact on sleep state organization (Fig. 33-1). N3 sleep is most intense and prominent during childhood, decreasing with puberty and across the second and third decades of life. In older adults, N3 sleep may be completely absent, and the remaining NREM sleep typically becomes more fragmented, with frequent awakenings from NREM sleep. Older people spend more time awake during their sleep episode, mainly due to more awakenings, rather than a decreased ability to fall back asleep. While REM sleep may account for 50% of total sleep time in infancy, the percentage falls off sharply over the first postnatal year as a mature REM-NREM cycle develops; in young adults, REM sleep occupies about 25% of total sleep time. Sleep deprivation degrades cognitive performance, particularly on tests that require continual vigilance. Young adults are particularly sus­ ceptible to slowed reaction times and difficulty maintaining vigilance during sleep deprivation, which may in part account for the large num­ ber of motor vehicle accidents in this age group late at night. Age 23 N2 N1 REM Awake N3 Age 68 N3 N2 N1 REM Awake 02.00 04.00 06.00 08.00 Clock time 00.00 FIGURE 33-1  Wake-sleep architecture. Alternating stages of wakefulness, the three stages of non–rapid eye movement sleep (N1–N3), and rapid eye movement (REM) sleep (solid bars) occur over the course of the night for representative young and older adult men. Characteristic features of sleep in older people include reduction of N3 slow-wave sleep, frequent spontaneous awakenings, early sleep onset, and early morning awakening.

After sleep deprivation, NREM sleep generally recovers first, fol­ lowed by REM sleep. However, because REM sleep tends to be most prominent in the second half of the night, sleep truncation (e.g., by an alarm clock) results in selective REM sleep deprivation. This may increase REM sleep pressure to the point where the first REM sleep may occur much earlier in the nightly sleep episode. To avoid these influences, it is important that the patient have sufficient sleep oppor­ tunity (at least 8 h per night) for several nights prior to a diagnostic polysomnogram. Beyond impaired cognition, chronic sleep deficiency is associated with glucose intolerance that may contribute to the development of diabetes, obesity, and the metabolic syndrome, as well as impaired immune responses, accelerated atherosclerosis, and increased risk of cardiac disease, cognitive impairment, Alzheimer’s disease, and stroke. For these reasons, the National Academy of Medicine declared sleep deficiency and sleep disorders “an unmet public health problem.” ■ ■WAKE AND SLEEP ARE REGULATED

BY BRAIN CIRCUITS Two principal neural systems govern the expression of sleep and wake­ fulness. The ascending arousal system, illustrated in green in Fig. 33-2, consists of clusters of nerve cells extending from the upper pons to the hypothalamus and basal forebrain that activate the cerebral cortex, thalamus (which is necessary to relay sensory information to the cor­ tex), and other forebrain regions. The ascending arousal neurons use monoamines (norepinephrine, dopamine, serotonin, and histamine), glutamate, or acetylcholine as neurotransmitters to activate their tar­ get neurons. Some basal forebrain neurons use γ-aminobutyric acid (GABA) to inhibit cortical inhibitory interneurons, thus promoting arousal. Additional wake-promoting neurons in the hypothalamus use the peptide neurotransmitter orexin (also known as hypocretin, shown in Fig. 33-2 in blue) to reinforce activity in the other arousal-promoting cell groups. Damage to the arousal system at the level of the rostral pons and lower midbrain causes coma, indicating that the ascending arousal influence from this level is critical in maintaining wakefulness. Injury to the arousal system in the midbrain or hypothalamus causes pro­ found sleepiness. Specific loss of the orexin neurons produces the sleep disorder narcolepsy (see below). Isolated damage to the thalamus causes loss of the content of wakefulness, known as a persistent vegeta­ tive state, but wake-sleep cycles are largely preserved. The arousal system is turned off during sleep by inhibitory inputs from cell groups in the sleep-promoting system, shown in Fig. 33-2 in red. These neurons in the preoptic area and pons use GABA to inhibit the arousal system. Additional neurons in the lateral hypothalamus containing the peptide melanin-concentrating hormone promote REM sleep. Many sleep-promoting neurons are themselves inhibited by inputs from the arousal system. This mutual inhibition between the arousal- and sleep-promoting systems forms a neural circuit akin to what electrical engineers call a “flip-flop switch.” A switch of this type tends to promote rapid transitions between the on (wake) and off (sleep) states, while avoiding intermediate states. The relatively rapid transitions between waking and sleeping states, as seen in the EEG of humans and animals, is consistent with this model. Neurons in the ventrolateral preoptic nucleus, one of the key sleep-promoting sites, are lost during normal human aging, correlating with reduced ability to maintain sleep (sleep fragmentation). The ventrolateral preoptic neurons are also injured in Alzheimer’s disease, which may in part account for the poor sleep quality in those patients. Transitions between NREM and REM sleep appear to be governed by a similar switch in the brainstem. GABAergic REM-Off neurons have been identified in the lower mid­ brain that inhibit REM-On neurons in the upper pons. The REM-On group contains both GABAergic neurons that inhibit the REM-Off group (thus satisfying the conditions for a REM sleep flip-flop switch) as well as glutamatergic neurons that project widely in the central nervous system

Inhibitors of arousal systems: H1 antagonists Alpha-2 agonists Muscarinic antagonists Orexin antagonists Thalamus Hypothalamus Ascending arousal system GABAergic arousal inhibiting system Potentiators of GABA inhibition: Benzodiazepines Barbiturates Ethanol Chloral hydrate Orexin (hypocretin) system FIGURE 33-2  Relationship of drugs for insomnia with wake-sleep systems. The arousal system in the brain (green) includes monoaminergic, glutamatergic, and cholinergic neurons in the brainstem that activate neurons in the hypothalamus, thalamus, basal forebrain, and cerebral cortex. Orexin neurons (blue) in the hypothalamus, which are lost in narcolepsy, reinforce and stabilize arousal by activating other components of the arousal system. The sleep-promoting system (red) consists of GABAergic neurons in the preoptic area and brainstem that inhibit the components of the arousal system, thus allowing sleep to occur. Drugs used to treat insomnia include those that block the effects of arousal system neurotransmitters (green and blue) and those that enhance the effects of γ-aminobutyric acid (GABA) produced by the sleep system (red). to cause the key phenomena associated with REM sleep. REM-On neurons that project to the medulla and spinal cord activate inhibitory (GABA and glycine-containing) interneurons, which in turn hyper­ polarize the motor neurons, producing the paralysis of REM sleep. REM-On neurons that project to the forebrain may be important in producing dreams. The REM sleep switch receives cholinergic input, which favors transitions to REM sleep, and monoaminergic (norepinephrine and serotonin) input that prevents REM sleep. As a result, drugs that increase monoamine tone (e.g., serotonin or norepinephrine reuptake inhibitors) tend to reduce the amount of REM sleep. Damage to the neurons that promote REM sleep paralysis can produce REM sleep behavior disorder, a condition in which patients act out their dreams (see below). ■ ■SLEEP-WAKE CYCLES ARE DRIVEN BY HOMEOSTATIC, ALLOSTATIC, AND

CIRCADIAN INPUTS The gradual increase in sleep drive with prolonged wakefulness, fol­ lowed by deeper slow-wave sleep and prolonged sleep episodes, dem­ onstrates that there is a homeostatic mechanism that regulates sleep. The neurochemistry of sleep homeostasis is only partially understood, but with prolonged wakefulness, adenosine levels rise in parts of the brain. Adenosine may act through A1 receptors to directly inhibit many arousal-promoting brain regions. In addition, adenosine pro­ motes sleep through A2a receptors; blockade of these receptors by caffeine is one of the chief ways in which people fight sleepiness. Other humoral factors, such as prostaglandin D2, have also been implicated in this process. Both adenosine and prostaglandin D2 activate the sleeppromoting neurons in the ventrolateral preoptic nucleus. Allostasis is the physiologic response to a challenge such as physical danger or psychological threat that cannot be managed by homeostatic mechanisms. These stress responses can severely impact the need for and ability to sleep. For example, insomnia is very common in patients with anxiety and other psychiatric disorders. Intermittent stress-induced insomnia is even more common, affecting most people at some time

in their lives. Positron emission tomography (PET) studies in patients with chronic insomnia show hyperactivation of components of the ascending arousal system, as well as their limbic system targets in the forebrain (e.g., cingulate cortex and amygdala). The limbic areas are not only targets for the arousal system, but they also send excitatory outputs back to the arousal system, which contributes to a vicious cycle of anxiety about insomnia that makes it more difficult to sleep. Approaches to treating insomnia may employ drugs that either inhibit the output of the ascending arousal system (green and blue in Fig. 33-2) or potentiate the output of the sleep-promoting system (red in Fig. 33-2). However, behavioral approaches (cognitive behavioral therapy [CBT] and sleep hygiene) that may reduce forebrain limbic activity at bedtime are often the best long-term treatment.

Sleep Disorders CHAPTER 33 Wakefulness and sleep are also regulated by a strong circadian tim­ ing signal, driven by the suprachiasmatic nuclei (SCN) of the hypo­ thalamus, as described below. The SCN sends outputs to key sites in the hypothalamus, which impose 24-h rhythms on a wide range of behaviors and body systems, including the wake-sleep cycle. ■ ■PHYSIOLOGY OF CIRCADIAN RHYTHMICITY The wake-sleep cycle is the most evident of many 24-h rhythms in humans. Prominent daily variations also occur in endocrine, thermo­ regulatory, cardiac, pulmonary, renal, immune, gastrointestinal, and neurobehavioral functions. In evaluating daily rhythms in humans, it is important to distinguish between diurnal components passively evoked by periodic environmental or behavioral changes (e.g., the increase in blood pressure and heart rate that occurs upon assumption of the upright posture) and circadian rhythms actively driven by an endogenous oscillatory process (e.g., the circadian variations in adrenal cortisol and pineal melatonin secretion that persist across a variety of environmental and behavioral conditions). At the cellular level, endogenous circadian rhythmicity is driven by self-sustaining molecular genetic feedback loops. These clock gene feedback loops of approximately 24 h duration are found in most if not all cells in the body and regulate diverse physiologic processes. However, when cells in most tissues are placed in isolation, they soon fall out of synchrony with each other and can no longer produce useful 24-h rhythms of tissue function. The only tissue that maintains this rhythm in isolation is the SCN, whose neurons are interconnected with one another in such a way as to produce a near-24-h synchronous rhythm of neural activity even in prolonged slice culture. SCN neurons are located just above the optic chiasm in the hypothalamus, from which they receive visual input to synchronize them with the external world, and they have outputs to transmit circadian timing signals to the rest of the body. Bilateral destruction of the SCN results in a loss of most endogenous circadian rhythms including wake-sleep behavior and rhythms in endocrine and metabolic systems. The genetically determined period of this endogenous neural oscillator, which aver­ ages ~24.15 h in humans, is normally synchronized to the 24-h period of the environmental light-dark cycle through direct input to the SCN from intrinsically photosensitive ganglion cells in the retina. Humans are exquisitely sensitive to the resetting effects of light, particularly the shorter wavelengths (~460–500 nm) in the blue part of the visible spec­ trum. Small differences in circadian period contribute to variations in diurnal preference. For example, people with short circadian cycles (e.g., 23.5 h) due to mutations of circadian clock genes prefer an early bedtime and wake up in the early morning hours (known as advanced sleep phase disorder). The timing and internal architecture of sleep are directly coupled to the output of the endogenous circadian pacemaker. Paradoxically, the endogenous circadian rhythm for wake propensity peaks just before the habitual bedtime, whereas that of sleep propensity peaks near the habitual wake time. These rhythms are thus timed to oppose the rise of homeostatic sleep tendency throughout the usual waking day and the decline of sleep propensity during the habitual sleep episode, respectively, thus promoting consolidated sleep and wakefulness. Mis­ alignment of the endogenous circadian pacemaker with the desired wake-sleep cycle can, therefore, induce insomnia (especially diffi­ culty initiating sleep or waking earlier than desired in the morning),

decrease alertness, and impair performance, posing health problems for night-shift workers and airline travelers. In addition, mounting evidence indicates that sleep regularity may be as important as sleep duration in terms of physical and mental health outcomes.

Participants awakened from REM sleep recall vivid dream imagery

80% of the time, especially later in the night. Less vivid imagery may also be reported after NREM sleep interruptions. Certain disorders may occur during specific sleep stages and are described below under “Parasomnias.” These include sleepwalking, night terrors, and enuresis (bed wetting), which occur most commonly in children during deep (N3) NREM sleep. In contrast, REM sleep behavior disorder occurs mainly among older people who fail to main­ tain full paralysis during REM sleep, and often call out, thrash around, or even act out fragments of dreams. PART 2 Cardinal Manifestations and Presentation of Diseases All major physiologic systems are influenced by sleep. Blood pres­ sure and heart rate decrease during NREM sleep, particularly during N3 sleep. During REM sleep, bursts of eye movements are associated with large variations in both blood pressure and heart rate mediated by the autonomic nervous system. Cardiac dysrhythmias may occur selec­ tively during REM sleep. Respiratory function also changes. In com­ parison to relaxed wakefulness, respiratory rate becomes slower and more regular during NREM sleep (especially N3 sleep) and becomes irregular during bursts of eye movements in REM sleep. Decreases in minute ventilation during sleep are out of proportion to the decrease in metabolic rate, resulting in a slightly higher PCO2. Within the brain itself, neurotransmission is supported by ion gra­ dients across the cell membranes of neurons and astrocytes. These ion flows are accompanied by increases in intracellular volume, so that during wake there is very little extracellular space in the brain. During sleep, intracellular volume is reduced, resulting in increased extracel­ lular space, which has higher calcium and lower potassium concentra­ tions, supporting hyperpolarization and reduced firing of neurons. This expansion of the extracellular space during sleep increases dif­ fusion of substances that accumulate extracellularly, like β-amyloid peptide, enhancing their clearance from the brain via cerebrospinal fluid (CSF) flow. Recent evidence suggests that lack of adequate sleep may contribute to extracellular accumulation of β-amyloid peptide, a key step in the pathogenesis of Alzheimer’s disease. Endocrine function also varies with sleep. N3 sleep is associated with secretion of growth hormone in men, while sleep in general is associated with augmented secretion of prolactin in both men and women. Sleep has a complex effect on the secretion of luteinizing hormone (LH): during puberty, sleep is associated with increased LH secretion, whereas sleep in postpubertal women inhibits LH secretion in the early follicular phase of the menstrual cycle. Sleep onset (and probably N3 sleep) is associated with inhibition of thyroid-stimulating hormone and of the adrenocorticotropic hormone–cortisol axis, an effect that is superimposed on the prominent circadian rhythms in the two systems. The hormone melatonin is secreted from the pineal gland pre­ dominantly at night in both day- and night-active species, under the control of the SCN. Melatonin secretion does not require sleep, but melatonin secretion is inhibited by ambient light, an effect mediated by the neural connection from the retina to the SCN and then on to the pineal gland via the sympathetic nervous system. In humans, sleep efficiency is highest when sleep coincides with endogenous melatonin secretion. When endogenous melatonin levels are low, such as during the biological day or at the desired bedtime in people with delayed sleep-wake phase disorder (DSWPD), administration of exogenous melatonin can hasten sleep onset and increase sleep efficiency, but it does not increase sleep efficiency if administered when endogenous melatonin levels are elevated. This may explain why melatonin is often ineffective in the treatment of patients with primary insomnia. On the other hand, patients with sympathetic denervation of the pineal gland, such as occurs in cervical spinal cord injury or in patients with Parkin­ son’s disease, often have low melatonin levels, and administration of melatonin (3 mg 30 min before bedtime) may help them sleep. Sleep is accompanied by alterations of thermoregulatory func­ tion. Warming the skin is associated with an increase in the firing of

warm-responsive neurons in the preoptic area, which cause a fall in body temperature and promote onset of NREM sleep. REM sleep is associated with reduced thermoregulatory responsiveness. DISORDERS OF SLEEP AND WAKEFULNESS APPROACH TO THE PATIENT Sleep Disorders Patients may seek help from a physician because of: (1) sleepiness or tiredness during the day; (2) difficulty initiating or maintaining sleep at night (insomnia); or (3) unusual behaviors during sleep itself (parasomnias). Obtaining a careful history is essential. In particular, the dura­ tion, severity, and consistency of the symptoms are important, along with the patient’s estimate of the consequences of the sleep disorder on waking function. Information from a bed partner or family member is often helpful because some patients may be unaware of symptoms such as heavy snoring or may underreport symptoms such as falling asleep at work or while driving. Physicians should inquire about when the patient typically goes to bed, when they fall asleep and wake up, whether they awaken during sleep, whether they feel rested in the morning, and whether they nap during the day. Depending on the primary complaint, it may be useful to ask about snoring, witnessed apneas, restless sensations in the legs, movements during sleep, depression, anxiety, and behaviors around the sleep episode. The physical examination may provide evidence of a small airway, large tonsils, or a neurologic or medical disorder that contributes to the main complaint. It is important to remember that, rarely, seizures may occur exclusively during sleep, mimicking a primary sleep disorder; such sleep-related seizures typically occur during episodes of NREM sleep and may take the form of generalized tonic-clonic movements (sometimes with urinary incontinence or tongue biting) or stereo­ typed movements in partial complex epilepsy (Chap. 436). It is often helpful for the patient to complete a daily sleep log for 1–2 weeks to define the timing and amounts of sleep. When relevant, the log can also include information on levels of alert­ ness, work times, and drug and alcohol use, including caffeine and hypnotics. Polysomnography is necessary for the diagnosis of several disor­ ders such as sleep apnea, narcolepsy, and periodic limb movement disorder (PLMD). A conventional polysomnogram performed in a clinical sleep laboratory allows measurement of sleep stages, respiratory effort and airflow, oxygen saturation, limb movements, heart rhythm, and additional parameters. A home sleep test usually focuses on just respiratory measures and is helpful in patients with a moderate to high likelihood of having obstructive sleep apnea. The multiple sleep latency test (MSLT) is used to measure a patient’s propensity to sleep during the day and can provide crucial evidence for diagnosing narcolepsy and some other causes of sleepiness. The maintenance of wakefulness test is used to measure a patient’s ability to sustain wakefulness during the daytime and can provide important evidence for evaluating the efficacy of therapies for improving sleepiness in conditions such as narcolepsy and obstruc­ tive sleep apnea. ■ ■EVALUATION OF DAYTIME SLEEPINESS Up to 25% of the adult population has persistent daytime sleepiness that impairs an individual’s ability to perform optimally in school, at work, while driving, and in other conditions that require alertness. Sleepy students often have trouble staying alert and performing well in school, and sleepy adults struggle to stay awake and focused on their work. More than half of Americans have fallen asleep while driving. An estimated 1.2 million motor vehicle crashes per year are due to drowsy drivers, causing about 20% of all serious crash injuries and deaths. One need not fall asleep to have a motor vehicle crash, as the inatten­ tion and slowed responses of drowsy drivers are major contributors.

Twenty-four hours of continuous wakefulness impairs reaction time as much as a blood alcohol concentration of 0.10 g/dL (which is legally drunk in all 50 states). Identifying and quantifying sleepiness can be challenging. First, patients may describe themselves as “sleepy,” “fatigued,” or “tired,” and the meanings of these words may differ between patients. For clinical purposes, it is best to use the term “sleepiness” to describe a propen­ sity to fall asleep, whereas “fatigue” is best used to describe a feeling of low physical or mental energy but without a tendency to actually sleep. Sleepiness is usually most evident when the patient is sedentary, whereas fatigue may interfere with more active pursuits. Sleepiness generally occurs with disorders that reduce the quality or quantity of sleep or that interfere with the neural mechanisms of arousal, whereas fatigue is more common in inflammatory disorders such as cancer, multiple sclerosis (Chap. 455), post-COVID syndrome (Chap. 205), fibromyalgia (Chap. 385), myalgic encephalomyelitis/chronic fatigue syndrome (Chap. 461), or endocrine deficiencies such as hypothyroid­ ism (Chap. 395) or Addison’s disease (Chap. 398). Second, sleepiness can affect judgment in a manner analogous to ethanol, such that patients may have limited insight into the condition and the extent of their functional impairment. Finally, patients may be reluctant to admit that sleepiness is a problem because they may have become unfamiliar with feeling fully alert, and because sleepiness is sometimes viewed pejoratively as reflecting poor motivation or bad sleep habits. Table 33-1 outlines the diagnostic and therapeutic approach to the patient with a complaint of excessive daytime sleepiness. To determine the extent and impact of sleepiness on daytime func­ tion, it is helpful to ask patients about the occurrence of sleepiness and sleep episodes during normal waking hours, both intentional and unintentional. Specific areas to be addressed include the occurrence of inadvertent sleep episodes while driving or in other safety-related settings, sleepiness while at work or school (and its impact on perfor­ mance), and the effect of sleepiness on social and family life. Standard­ ized questionnaires such as the Epworth Sleepiness Scale are often used clinically to measure sleepiness. Eliciting a history of daytime sleepiness is usually adequate, but objective quantification is sometimes necessary. The MSLT measures a patient’s propensity to sleep under quiet conditions. An overnight poly­ somnogram should precede the MSLT to establish that the patient has had an adequate amount of good-quality nighttime sleep. The MSLT consists of five 20-min nap opportunities every 2 h across the day. The patient is instructed to try to fall asleep, and the major endpoints are the average latency to sleep and the occurrence of REM sleep during the naps. An average sleep latency across the naps of <8 min is con­ sidered objective evidence of excessive daytime sleepiness. REM sleep normally occurs only during nighttime sleep, and the occurrence of REM sleep in two or more of the MSLT daytime naps provides support for the diagnosis of narcolepsy. TABLE 33-1  Evaluation of the Patient with Excessive Daytime Sleepiness FINDINGS ON HISTORY AND PHYSICAL EXAMINATION DIAGNOSTIC EVALUATION DIAGNOSIS THERAPY Difficulty waking in the morning, rebound sleep on weekends and vacations with improvement in sleepiness Sleep log Insufficient sleep Sleep education and behavioral modification to increase amount of sleep Obesity, snoring, hypertension Polysomnogram or home sleep test Cataplexy, hypnagogic hallucinations, sleep paralysis Polysomnogram and multiple sleep latency test Restless legs, kicking movements during sleep Assessment for predisposing medical conditions (e.g., iron deficiency or renal failure) Sedating medications, stimulant withdrawal, head trauma, systemic inflammation, Parkinson’s disease and other neurodegenerative disorders, hypothyroidism, encephalopathy Thorough medical history and examination including detailed neurologic examination

For the safety of the individual and the general public, physicians have a responsibility to help manage issues around driving in patients with sleepiness. Legal reporting requirements vary between states and countries, but at a minimum, physicians should inform sleepy patients about their increased risk of having an accident and advise such patients not to drive a motor vehicle until their sleepiness has been treated effectively. This discussion is especially important for com­ mercial drivers, and it should be documented in the patient’s medical record.

Sleep Disorders CHAPTER 33 ■ ■INSUFFICIENT SLEEP Insufficient sleep is probably the most common cause of excessive daytime sleepiness. The average adult needs 7.5–8 h of sleep, but on weeknights, the average U.S. adult obtains only 6.75 h of sleep. Only 30% of the U.S. adult population reports consistently obtaining suffi­ cient sleep. Insufficient sleep is especially common among shift work­ ers, individuals working multiple jobs, people in lower socioeconomic groups, and historically minority populations. Most teenagers need ≥9 h of sleep, but many fail to get enough sleep because of circadian phase delay, plus social pressures to stay up late coupled with early school start times. Late evening light exposure, homework, television view­ ing, video-gaming, social media, texting, and smartphone use often delay bedtimes, despite the fixed early wake times required for work or school. As is typical with any disorder that causes sleepiness, indi­ viduals with chronically insufficient sleep may feel inattentive, irritable, unmotivated, and depressed, and have difficulty with school, work, and driving. Individuals differ in their optimal amount of sleep, and it can be helpful to ask how much sleep the patient obtains on a quiet vacation when he or she can sleep without restrictions. Some patients may think that a short amount of sleep is normal or advantageous, and they may not appreciate their biological need for more sleep, especially if coffee and other stimulants mask the sleepiness. A 2-week sleep log documenting the timing of sleep and daily level of alertness is diagnos­ tically useful and provides helpful feedback for the patient. Extending sleep to the optimal amount on a regular basis can resolve the sleepi­ ness and other symptoms. As with any lifestyle change, extending sleep requires commitment and adjustments, but the improvements in day­ time alertness make this change worthwhile. ■ ■SLEEP APNEA SYNDROMES Respiratory dysfunction during sleep is a common, serious cause of excessive daytime sleepiness as well as of disturbed nocturnal sleep. At least 24% of middle-aged men and 9% of middle-aged women in the United States have a reduction or cessation of breathing dozens or more times each night during sleep, with 9% of men and 4% of women doing so more than a hundred times per night. These episodes may be due to an occlusion of the airway (obstructive sleep apnea), absence of respiratory effort (central sleep apnea), or a combination Obstructive sleep apnea (Chap. 308) Continuous positive airway pressure; upper airway surgery (e.g., uvulopalatopharyngoplasty); dental appliance; weight loss Narcolepsy Stimulants (e.g., modafinil, methylphenidate); rapid eye movement (REM) sleep-suppressing antidepressants (e.g., venlafaxine); pitolisant; solriamfetol; sodium oxybate Restless legs syndrome with or without periodic limb movements Treatment of predisposing condition; dopamine agonists (e.g., pramipexole, ropinirole); gabapentin; pregabalin; opiates Sleepiness due to a drug or medical condition Change medications, treat underlying condition, consider stimulants

of these factors. Failure to recognize and treat these conditions appro­ priately may reduce daytime alertness and increase the risk of sleeprelated motor vehicle crashes, depression, hypertension, myocardial infarction, diabetes, stroke, and mortality. Sleep apnea is particularly prevalent in overweight men and in the elderly, yet it is estimated to go undiagnosed in most affected individuals. This is unfortunate because several effective treatments are available. Readers are referred to Chap. 308 for a comprehensive review of the diagnosis and treat­ ment of sleep apnea.

■ ■NARCOLEPSY Narcolepsy is characterized by difficulty sustaining wakefulness, poor regulation of REM sleep, and disturbed nocturnal sleep. All patients with narcolepsy have excessive daytime sleepiness. This sleepiness is usually moderate to severe, and in contrast to patients with disrupted sleep (e.g., sleep apnea), people with narcolepsy usually feel well rested upon awakening and then feel tired throughout much of the day. They may fall asleep at inappropriate times, but then feel refreshed again after a nap. In addition, they often experience symptoms related to an intrusion of REM sleep characteristics into wakefulness. REM sleep is characterized by dreaming and muscle paralysis, and people with narcolepsy can have: (1) sudden muscle weakness without a loss of consciousness, which is usually triggered by strong emotions (cataplexy; Video 33-1); (2) dreamlike hallucinations at sleep onset (hypnagogic hallucinations) or upon awakening (hypnopompic hallucinations); and (3) muscle paralysis upon awakening (sleep paralysis). With severe cataplexy, an individual may be laughing at a joke and then suddenly collapse to the ground, immobile but awake for 1–2 min. With milder episodes, patients may have partial weakness of the face or neck. Narcolepsy is one of the more common causes of chronic sleepiness and affects about 1 in 2000 people in the United States. Narcolepsy typically begins between age 10 and 20; once established, the disease persists for life. PART 2 Cardinal Manifestations and Presentation of Diseases Narcolepsy is caused by loss of the hypothalamic neurons that pro­ duce the orexin neuropeptides (also known as hypocretins). Research in mice and dogs first demonstrated that a loss of orexin signaling due to null mutations of either the orexin neuropeptides or one of the orexin receptors causes sleepiness and cataplexy nearly identical to that seen in people with narcolepsy. Although genetic mutations rarely cause human narcolepsy, researchers soon discovered that patients with narcolepsy with cataplexy (now called type 1 narcolepsy) have very low or undetectable levels of orexins in their CSF, and autopsy studies showed a nearly complete loss of the orexin-producing neurons in the hypothalamus. The orexins normally promote long episodes of wakefulness and suppress REM sleep, and thus loss of orexin signal­ ing results in frequent intrusions of sleep during the usual waking episode, with REM sleep and elements of REM sleep at any time of day (Fig. 33-3). Patients with narcolepsy but no cataplexy (type 2 nar­ colepsy) usually have normal orexin levels and may have partial loss of the orexin neurons or other yet uncharacterized causes of their exces­ sive daytime sleepiness. Healthy N3 N2 N1 REM Awake Narcolepsy N3 N2 N1 REM Awake 20:00 00:00 04:00 08:00 12:00 16:00 FIGURE 33-3  Polysomnographic recordings of a healthy individual and a patient with narcolepsy. The healthy individual has a long period or NREM sleep before entering REM sleep, but the individual with narcolepsy enters rapid eye movement (REM) sleep quickly at night and has moderately fragmented sleep. During the day, the healthy participant stays awake from 8:00 A.M. until midnight, but the patient with narcolepsy dozes off frequently, with many daytime naps that include REM sleep.

Extensive evidence suggests that an autoimmune process likely causes this selective loss of the orexin-producing neurons. Certain human leukocyte antigens (HLAs) can increase the risk of autoimmune disorders (Chap. 361), and narcolepsy has the strongest known HLA association. HLA DQB106:02 is found in >90% of people with type 1 narcolepsy, whereas it occurs in only 12–25% of the general popula­ tion. Researchers now hypothesize that in people with DQB106:02, an immune response against influenza, Streptococcus, or other infections may also damage the orexin-producing neurons through a process of molecular mimicry. This mechanism may account for the eight- to twelvefold increase in new cases of narcolepsy among children in Europe who received a particular brand of H1N1 influenza A vaccine (Pandemrix). In support of this hypothesis, people with type 1 narco­ lepsy have heightened T-cell responses against orexin peptides. On rare occasions, narcolepsy can occur with other neurologic dis­ orders such as anti-Ma2 paraneoplastic antibodies (Chap. 99), severe traumatic brain injury, tumors, or strokes that directly damage the orexin-producing neurons in the hypothalamus or their projections. Diagnosis  Narcolepsy is most commonly diagnosed by relatively abrupt onset in a previously healthy individual of chronic sleepiness plus cataplexy or other symptoms. Narcoleptic patients report an over­ whelming desire to sleep, and often awake refreshed after a brief nap. Cataplexy is distinguished from many disorders that can cause feelings of weakness by sudden onset of postural weakness (e.g., slurred speech, dropping a cup, slumping into a chair) that is often triggered by strong emotions such as laughing at a joke, happy surprise at unexpectedly seeing a friend, or intense anger. Cataplexy occurs in about half of all narcolepsy patients, who are distinguished as narcolepsy type 1; when it occurs, cataplexy is diagnostically very helpful because it occurs in almost no other disorder. In contrast, hypnagogic hallucinations and sleep paralysis occur in both type 1 and type 2 narcolepsy patients, and occasionally in about 20% of the general population, and so are not as diagnostically specific. When narcolepsy is suspected, the diagnosis should be firmly established with a polysomnogram followed the next day by an MSLT. The polysomnogram helps rule out other causes of daytime sleepiness such as sleep apnea and establishes that the patient had adequate sleep the night before, and the MSLT provides essential, objective evidence of sleepiness plus REM sleep dysregulation. Across the five naps of the MSLT, most patients with narcolepsy will fall asleep in <8 min on average, and they will have episodes of REM sleep in at least two of the naps. Abnormal regulation of REM sleep is also manifested by the appearance of REM sleep within 15 min of sleep onset at night, which is rare in healthy individuals sleeping at their habitual bedtime. Stimu­ lants should be stopped 1 week before the MSLT, and antidepressants should be stopped 3 weeks prior, because these medications can sup­ press REM sleep. In addition, patients should be encouraged to obtain a fully adequate amount of sleep each night for the week prior to the test to eliminate any effects of insufficient sleep. Clock time

TREATMENT Narcolepsy The treatment of narcolepsy is symptomatic. Most patients with narcolepsy feel more alert after sleep, and they should be encour­ aged to get adequate sleep each night and to take a 15- to 20-min nap in the afternoon. This nap may be sufficient for occasional patients with mild narcolepsy, but most also require treatment with wake-promoting medications. Modafinil is often used because it has fewer side effects than amphetamines and a relatively long halflife; for most patients, 200–400 mg each morning is very effective. Methylphenidate (10–20 mg bid) and dextroamphetamine (10 mg bid) are also effective, but sympathomimetic side effects, anxiety, and the potential for abuse can be concerns. These medications are available in slow-release formulations, extending their duration of action and allowing easier dosing. Solriamfetol, a norepinephrine– dopamine reuptake inhibitor (75–150 mg daily), and pitolisant, a selective histamine 3 (H3) receptor antagonist (8.9–35.6 mg daily), also improve sleepiness and have relatively few side effects. Cataplexy is usually much improved with antidepressants that increase noradrenergic or serotonergic tone because these neu­ rotransmitters strongly suppress REM sleep and cataplexy. Venla­ faxine (37.5–150 mg each morning) and fluoxetine (10–40 mg each morning) are often quite effective. The tricyclic antidepressants, such as protriptyline (10–40 mg/d) or clomipramine (25–50 mg/d), are potent suppressors of cataplexy, but their anticholinergic effects, including sedation and dry mouth, make them less attractive.1 People with narcolepsy often have fragmented sleep at night, and sodium oxybate (gamma hydroxybutyrate), typically given at bed­ time and 3–4 h later, promotes more continuous slow wave sleep. Oxybates are also available in low-sodium and once-nightly ver­ sions. Oxybates are often very valuable in improving alertness and reducing cataplexy during the day, but at too high a dosage, they can produce excessive sedation, nausea, and confusion. 1No antidepressant has been approved by the U.S. Food and Drug Administration (FDA) for treating narcolepsy. ■ ■EVALUATION OF INSOMNIA Insomnia is the complaint of poor sleep and usually presents as dif­ ficulty initiating and/or maintaining sleep. People with insomnia are dissatisfied with their sleep and feel that it impairs their ability to function well in work, school, and social situations. Affected individu­ als often experience fatigue, decreased mood, irritability, malaise, and cognitive impairment. Chronic insomnia, lasting >3 months, occurs in about 10% of adults and is more common in women, older adults, people of lower socioeco­ nomic status, and individuals with medical, psychiatric, and substance abuse disorders. Acute or short-term insomnia affects >30% of adults and is often precipitated by stressful life events such as a major illness or loss, change of occupation, medications, and substance abuse. If the acute insomnia triggers maladaptive behaviors such as increased noc­ turnal light exposure, frequently checking the clock, or attempting to sleep more by napping, it can lead to chronic insomnia. Insomnia typically begins in adulthood, but many patients may be predisposed and report easily disturbed sleep predating the insomnia, suggesting that their sleep is lighter than usual. Clinical studies and animal models indicate that insomnia is associated with activation during sleep of brain areas normally active only during wakefulness. The polysomnogram is rarely used in the evaluation of insomnia, as it typically confirms the patient’s subjective report of long latency to sleep and numerous awakenings but usually adds little new informa­ tion. Many patients with insomnia have more fast (beta) activity in the EEG during sleep; this fast activity is normally present only dur­ ing wakefulness, which may explain why some patients report feeling awake for much of the night. The MSLT is rarely used in the evalu­ ation of insomnia because, despite their feelings of low energy, most

people with insomnia do not easily fall asleep during the day, and on the MSLT, their average sleep latencies are usually longer than normal.

Many factors can contribute to insomnia, and obtaining a careful history is essential so one can select therapies targeting the underly­ ing factors. The assessment should focus on identifying predisposing, precipitating, and perpetuating factors. Psychophysiological Factors  Many patients with insomnia have negative expectations and conditioned arousal that interfere with sleep. These individuals may worry about their insomnia during the day and have increasing anxiety as bedtime approaches if they anticipate a poor night of sleep. While attempting to sleep, they may frequently check the clock, which only heightens anxiety and frustration. They may find it easier to sleep in a new environment rather than their bedroom, as it lacks the negative associations. Sleep Disorders CHAPTER 33 Inadequate Sleep Hygiene  Patients with insomnia sometimes develop counterproductive behaviors that contribute to their insomnia. These can include daytime napping that reduces sleep drive at night; an irregular sleep-wake schedule that disrupts their circadian rhythms; use of wake-promoting substances (e.g., caffeine, tobacco) too close to bedtime; engaging in alerting or stressful activities close to bedtime (e.g., arguing with a partner, work-related emailing and texting while in bed, sleeping with a smartphone or tablet at the bedside); and routinely using the bedroom for activities other than sleep or sex (e.g., email, television, work), so the bedroom becomes associated with arousing or stressful feelings. Psychiatric Conditions  About 80% of patients with psychiatric disorders have sleep complaints, and about half of all chronic insomnia occurs in association with a psychiatric disorder (Chap. 463). Depres­ sion is classically associated with early morning awakening, but it can also interfere with the onset and maintenance of sleep. Mania and hypomania can disrupt sleep and often are associated with substantial reductions in the total amount of sleep. Anxiety disorders can lead to racing thoughts and rumination that interfere with sleep and can be very problematic if the patient’s mind becomes active midway through the night. Panic attacks can arise from sleep and need to be distin­ guished from other parasomnias. Insomnia is common in schizophre­ nia and other psychoses, often resulting in fragmented sleep, less deep NREM sleep, and sometimes reversal of the day-night sleep pattern. Medications and Drugs of Abuse  A wide variety of psychoactive drugs can interfere with sleep. Caffeine, which has a half-life of 6–9 h, can disrupt sleep for up to 8–14 h, depending on the dose, variations in metabolism, and an individual’s caffeine sensitivity. Insomnia can also result from use of prescription medications too close to bedtime (e.g., antidepressants, stimulants, glucocorticoids, theophylline). Conversely, withdrawal of sedating medications such as alcohol, narcotics, or ben­ zodiazepines can cause insomnia. Alcohol consumed just before bed can shorten sleep latency, but it often produces rebound insomnia 2–3 h later as it wears off. This same problem with sleep maintenance can occur with short-acting medications such as alprazolam or zolpidem. Medical Conditions  A large number of medical conditions dis­ rupt sleep. Pain from rheumatologic disorders or a painful neuropathy commonly disrupts sleep. Some patients may sleep poorly because of respiratory conditions such as asthma, chronic obstructive pulmonary disease, cystic fibrosis, congestive heart failure, or restrictive lung dis­ ease, and some of these disorders are worse at night due to circadian variations in airway resistance and postural changes in bed that can result in nocturnal dyspnea. Obstructive sleep apnea is an example of a respiratory disorder that only becomes a problem with loss of airway muscle tone during sleep. Many women experience poor sleep with the hormonal changes of menopause. Gastroesophageal reflux is also a common cause of difficulty sleeping. Approximately 60% of patients with long COVID report symptoms of insomnia. Neurologic Disorders  Dementia (Chap. 31) is often associated with poor sleep, probably due to a variety of factors, including napping during the day, altered circadian rhythms, and perhaps a weakened

output of the brain’s sleep-promoting mechanisms. In fact, insomnia and nighttime wandering are some of the most common causes for institutionalization of patients with dementia, because they place a large burden on caregivers. Conversely, in cognitively intact elderly men, fragmented sleep and poor sleep quality are associated with subsequent cognitive decline. Patients with Parkinson’s disease may sleep poorly due to rigidity, dementia, urinary frequency, REM sleep behavior disorder, restless legs syndrome, and other factors. Fatal familial insomnia is a very rare neurodegenerative condition caused by mutations in the prion protein gene (Chap. 449), and although insom­ nia is a common early symptom, most patients present with other obvious neurologic signs such as dementia, myoclonus, dysarthria, or autonomic dysfunction.

PART 2 Cardinal Manifestations and Presentation of Diseases TREATMENT Insomnia Treatment of insomnia improves quality of life and can promote long-term health. With improved sleep, patients often report less daytime fatigue, improved cognition, and more energy. Treating the insomnia can also improve comorbid disease. For example, man­ agement of insomnia at the time of diagnosis of major depression often improves the response to antidepressants and reduces the risk of relapse. Sleep loss can heighten the perception of pain, so a simi­ lar approach is warranted in acute and chronic pain management. Gabapentin (100–300 mg before bedtime) can often reduce the pain and improve sleep in patients with chronic pain. The treatment plan should target all putative contributing fac­ tors: establish good sleep hygiene, treat medical disorders, and use behavioral therapies for anxiety and negative conditioning and pharmacotherapy and/or psychotherapy for psychiatric disorders. Behavioral therapies should be the first-line treatment, followed by judicious use of sleep-promoting medications if needed. TREATMENT OF MEDICAL AND PSYCHIATRIC DISEASE If the history suggests that a medical or psychiatric disease contrib­ utes to the insomnia, then it should be addressed by, for example, treating the pain or depression, improving breathing, and switching or adjusting the timing of medications. IMPROVE SLEEP HYGIENE Attention should be paid to improving sleep hygiene and avoiding counterproductive, arousing behaviors before bedtime. Patients should establish a regular bedtime and wake time, even on weekends, to help synchronize their circadian rhythms and sleep patterns. The amount of time allocated for sleep should not be more than their actual total amount of sleep. In the 30 min before bedtime, patients should establish a relaxing “wind-down” routine that can include a warm bath, listening to music, meditation, or other relaxation techniques. The bedroom should be off-limits to computers, televisions, radios, smartphones, videogames, and tablets. If an e-reader is used, the light should be adjusted for evening use (dimmer and reduced blue light) if possible, because light itself, especially in the blue spectrum, suppresses melato­ nin secretion and is arousing. Once in bed, patients should try to avoid thinking about anything stressful or arousing such as problems with relationships or work. If they cannot fall asleep within 20 min, it often helps to get out of bed and read or listen to relaxing music in dim light as a form of distraction from any anxiety, but “blue light,” especially from a cell phone, computer, or television, should be avoided. Table 33-2 outlines some of the key aspects of good sleep hygiene to improve insomnia. COGNITIVE BEHAVIORAL THERAPY Cognitive behavioral therapy (CBT) uses a combination of the techniques above plus additional methods to improve insomnia. A trained therapist may use cognitive psychology techniques to reduce excessive worrying about sleep and to reframe faulty beliefs about

TABLE 33-2  Methods to Improve Sleep Hygiene in Insomnia Patients HELPFUL BEHAVIORS BEHAVIORS TO AVOID Use the bed only for sleep and sex • If you cannot sleep within 20 min, Avoid behaviors that interfere with sleep physiology, including: • Napping, especially after 3:00 PM • Attempting to sleep too early • Caffeine after lunchtime get out of bed and read or do other relaxing activities in dim light before returning to bed Make quality sleep a priority • Go to bed and get up at the same In the 2–3 h before bedtime, avoid: • Heavy eating • Smoking or alcohol • Vigorous exercise time each day • Ensure a restful environment (comfortable bed, bedroom quiet and dark) Develop a consistent bedtime routine. For example: • Prepare for sleep with 20–30 min When trying to fall asleep, avoid: • Solving problems • Thinking about life issues • Reviewing events of the day of relaxation (e.g., soft music, meditation, yoga, pleasant reading) • Take a warm bath the insomnia and its daytime consequences. The therapist may also teach the patient relaxation techniques, such as progressive muscle relaxation or meditation, to reduce autonomic arousal, intrusive thoughts, and anxiety. While sleep restriction may improve sleep continuity, chronic exposure to sleep restriction may have adverse effects on daytime performance. MEDICATIONS FOR INSOMNIA If insomnia persists after treatment of these contributing factors, pharmacotherapy is often used on a nightly or intermittent basis. A variety of sedatives can improve sleep. Antihistamines, such as diphenhydramine, are the primary active ingredient in most over-the-counter sleep aids. These may be of benefit when used intermittently but can produce tolerance and anticholinergic side effects such as dry mouth and constipation, which limit their use, particularly in the elderly. Benzodiazepine receptor agonists (BzRAs) are an effective and well-tolerated class of medications for insomnia (Chap. 463). BzRAs bind to the GABAA receptor and potentiate the postsynaptic response to GABA. GABAA receptors are found throughout the brain, and BzRAs may globally reduce neural activity and enhance the activity of specific sleep-promoting GABAergic pathways. Clas­ sic BzRAs include lorazepam, triazolam, and clonazepam, whereas newer agents such as zolpidem and zaleplon have more selective affinity for the α1 subunit of the GABAA receptor. Specific BzRAs are often chosen based on the desired duration of action. The most commonly prescribed agents in this family are zaleplon (5–20 mg), with a half-life of 1–2 h; zolpidem (5–10 mg) and triazolam (0.125–0.25 mg), with half-lives of 2–4 h; eszopiclone (1–3 mg), with a half-life of 5–8 h; and temazepam (15–30 mg), with a half-life of 8–20 h. Generally, side effects are uncommon when the dose is kept low and the serum concentration is minimized during the waking hours (by using the shortest-acting effective agent). For chronic insomnia, intermittent use is recommended, unless the consequences of untreated insomnia outweigh concerns regarding chronic use. The heterocyclic antidepressants (trazodone, amitriptyline,2 and doxepin) are the most commonly prescribed alternatives to BzRAs due to their lack of abuse potential and low cost (Chap. 463). Trazodone (25–100 mg) is used more commonly than the tricyclic antidepressants, because it has a much shorter half-life (5–9 h) and less anticholinergic activity. The orexin receptor antagonists suvorexant (10–20 mg), lembo­ rexant (5–10 mg), and daridorexant (25–50 mg) can also improve insomnia by blocking the wake-promoting effects of the orexin neuropeptides. These have medium to long half-lives and can pro­ duce morning sedation, and as they reduce orexin signaling, they

can rarely produce hypnagogic hallucinations and sleep paralysis (see narcolepsy section above). Medications for insomnia are now among the most commonly prescribed medications, but they should be used cautiously. All sed­ atives increase the risk of injurious falls and confusion in the elderly, and therefore, if needed, these medications should be used at the lowest effective dose. Morning sedation can interfere with driving and judgment, so when selecting a medication, one should consider the duration of action. Benzodiazepines carry a risk of addiction and abuse, especially in patients with a history of alcohol or seda­ tive abuse. In patients with depression, all sedatives can worsen the depression. Like alcohol, some sleep-promoting medications can worsen sleep apnea. Sedatives can also produce complex behaviors during sleep, such as sleepwalking and sleep eating, especially at higher doses. 2Trazodone and amitriptyline have not been approved by the FDA for treating insomnia. ■ ■RESTLESS LEGS SYNDROME Patients with restless legs syndrome (RLS) report an irresistible urge to move the legs. Many patients report a creepy-crawly, tingly, or unpleas­ ant deep ache within the thighs or calves, and those with more severe RLS may have discomfort in the arms as well. For most patients with RLS, these dysesthesias and restlessness are much worse in the evening and first half of the night. The symptoms appear with inactivity and can make sitting still when traveling or watching a movie a miserable expe­ rience. The sensations are temporarily relieved by movement, stretch­ ing, or massage. This nocturnal discomfort usually interferes with sleep, and patients may report daytime sleepiness as a consequence. RLS is very common, affecting 5–10% of adults, and is more common in women and older adults. A variety of factors can cause RLS. Iron deficiency is the most com­ mon treatable cause, and iron replacement should be considered if the ferritin level is <75 ng/mL. RLS can also occur with peripheral neurop­ athies and uremia and can be worsened by pregnancy, caffeine, alcohol, antidepressants, lithium, neuroleptics, and antihistamines. Genetic factors contribute to RLS, and polymorphisms in a variety of genes (BTBD9, MEIS1, MAP2K5/LBXCOR, and PTPRD) have been linked to RLS, although as yet, the mechanism through which they cause RLS remains unknown. Roughly one-third of patients (particularly those with an early age of onset) have multiple affected family members. RLS is treated by addressing the underlying cause such as iron deficiency if present. Otherwise, treatment is symptomatic, and alpha-2-delta calcium channel ligands or dopamine agonists are used most frequently. Alpha-2-delta calcium channel ligands such as gabapentin (300–900 mg q7PM), gabapentin enacarbil (300–600 mg q5PM), and pregabalin (150–450 mg q7PM) are quite effective, and because they are also sedating and analgesic, they can be especially helpful in patients with concomitant pain, neuropathy, or anxiety. Agonists of dopamine D2/3 receptors such as pramipexole (0.25–0.5 mg q7PM) or ropinirole (0.5–4 mg q7PM) are usually quite effective, but about 25% of patients taking dopamine agonists develop augmenta­ tion, a worsening of RLS such that symptoms begin earlier in the day and can spread to other body regions. Other possible side effects of dopamine agonists include nausea, morning sedation, and increases in rewarding behaviors such as sex and gambling. Opioids and ben­ zodiazepines may also be of therapeutic value in refractory patients. Most patients with restless legs also experience PLMD, although the reverse is not the case. ■ ■PERIODIC LIMB MOVEMENT DISORDER PLMD involves rhythmic twitches of the legs that disrupt sleep. The movements resemble a triple flexion reflex with extensions of the great toe and dorsiflexion of the foot for 0.5–5.0 s, which recur every 20–40 s during NREM sleep, in episodes lasting from minutes to hours. PLMD is diagnosed by a polysomnogram that includes recordings of the ante­ rior tibialis and sometimes additional muscles. The EEG shows that

the movements of PLMD frequently cause brief arousals that disrupt sleep, sometimes resulting in insomnia and daytime sleepiness. PLMD can be caused by the same factors that cause RLS (see above), and the frequency of leg movements improves with the same medications used for RLS, including dopamine agonists. Genetic studies identified poly­ morphisms associated with both RLS and PLMD, suggesting that they may have a common pathophysiology.

■ ■PARASOMNIAS Parasomnias are abnormal behaviors or experiences that arise from or occur during sleep. A variety of parasomnias can occur during NREM sleep, from brief confusional arousals to sleepwalking and night terrors. The presenting complaint is usually related to the behavior itself, but the parasomnias can disturb sleep continuity or lead to mild impairments in daytime alertness. Two main parasomnias occur in REM sleep: REM sleep behavior disorder (RBD) and nightmares. Sleep Disorders CHAPTER 33 Sleepwalking (Somnambulism)  Patients affected by this dis­ order carry out automatic motor activities that range from simple to complex. Individuals may walk, urinate inappropriately, eat, exit the house, or drive a car with minimal awareness. It may be difficult to arouse the patient to wakefulness, and some individuals may respond to attempted awakening with agitation or violence. In general, it is saf­ est to lead the patient back to bed, at which point they will often fall back asleep. Sleepwalking arises from NREM stage N3 sleep, usually in the first few hours of the night, and the EEG initially shows the slow cortical activity of deep NREM sleep even when the patient is mov­ ing about. Sleepwalking is most common in children and adolescents, when deep NREM sleep is most abundant. About 15% of children have occasional sleepwalking, and it persists in about 1% of adults. Episodes are usually isolated but may be recurrent in 1–6% of patients. The cause is unknown, although it has a familial basis in roughly one-third of cases. Sleepwalking can be worsened by stress, alcohol, and insufficient sleep, which subsequently causes an increase in deep NREM sleep. These should be addressed if present. Small studies have shown some efficacy of antidepressants and benzodiazepines; relaxation techniques and hypnosis can also be helpful. Patients and their families should improve home safety (e.g., replace glass doors, remove low tables to avoid tripping) to minimize the chance of injury if sleepwalking occurs. Sleep Terrors  This disorder occurs primarily in young children during the first few hours of sleep during NREM stage N3 sleep. The child often sits up during sleep and screams, exhibiting autonomic arousal with sweating, tachycardia, large pupils, and hyperventilation. The individual may be difficult to arouse and rarely recalls the episode on awakening in the morning. Treatment usually consists of reassuring parents that the condition is self-limited and benign, and like sleep­ walking, it may improve by avoiding insufficient sleep. Sleep Enuresis  Bedwetting, like sleepwalking and night terrors, is another parasomnia that occurs during sleep in the young. Before age 5 or 6 years, nocturnal enuresis should be considered a normal feature of development. The condition usually improves spontane­ ously by puberty, persists in 1–3% of adolescents, and is rare in adult­ hood. Treatment consists of bladder training exercises and behavioral therapy. Symptomatic pharmacotherapy is usually accomplished in adults with desmopressin (0.2 mg qhs), oxybutynin chloride (5 mg qhs), or imipramine (10–25 mg qhs). Important causes of nocturnal enuresis in patients who were previously continent for 6–12 months include urinary tract infections or malformations, cauda equina lesions, emotional disturbances, epilepsy, sleep apnea, and certain medications. Sleep Bruxism  Bruxism is an involuntary, forceful grinding of teeth during sleep that affects 10–20% of the population. The patient is usually unaware of the problem. The typical age of onset is 17–20 years, and spontaneous remission usually occurs by age 40. In many cases, the diagnosis is made during dental examination, damage is minor, and no treatment is indicated. In more severe cases, treatment with a mouth guard is necessary to prevent tooth injury. Stress management,

benzodiazepines, and biofeedback can be useful when bruxism is a manifestation of psychological stress.

REM Sleep Behavior Disorder (RBD)  RBD (Video 33-2) is distinct from other parasomnias in that it occurs during REM sleep. The patient or the bed partner usually reports that the patient calls out and has agitated or violent behavior during sleep. If awakened during or by the event, the patient can often report a dream that matches the accompanying movements. During normal REM sleep, nearly all nonrespiratory skeletal muscles are paralyzed, but in patients with RBD, dramatic limb movements such as punching or kicking lasting seconds to minutes occur during REM sleep, and it is not uncommon for the patient or the bed partner to be injured while enacting dream behaviors. PART 2 Cardinal Manifestations and Presentation of Diseases The prevalence of RBD increases with age, afflicting about 2% of adults aged >70, and is reported more often in men. Within 12 years of disease onset, half of RBD patients develop a synucleinopathy such as Parkinson’s disease (Chap. 446), dementia with Lewy bodies (Chap. 445), or occasionally multiple system atrophy (Chap. 451), and >90% develop a synucleinopathy by 25 years. Patients with a latent synucleinopathy can be distinguished from those with other causes of symptomatic RBD by detection of alpha-synuclein aggre­ gates in spinal fluid or in peripheral nerves in skin biopsy. RBD can occur in patients taking antidepressants, and in some, these medica­ tions may unmask this early indicator of neurodegeneration. Synucle­ inopathies probably cause neuronal loss in brainstem regions that regulate muscle paralysis during REM sleep, and loss of these neurons permits movements to break through during REM sleep. RBD also occurs in about 30% of people with narcolepsy, but the underlying cause is probably different, as they seem to be at no increased risk of a neurodegenerative disorder. Many patients with RBD have sustained improvement with melato­ nin at doses up to 10 mg nightly. Clonazepam (0.5–2.0 mg qhs)3 also prevents attacks, but as with all benzodiazepines, it can increase the risk of falls and confusion at night. ■ ■CIRCADIAN RHYTHM SLEEP DISORDERS A subset of patients presenting with either insomnia or hypersomnia may have a disorder of sleep timing rather than sleep generation. Disor­ ders of sleep timing can be either inherent (i.e., due to an abnormality of circadian pacemaker[s]) or environmental/behavioral (i.e., due to a disruption of environmental synchronizers). The therapeutic goal is to entrain the circadian rhythm of sleep propensity to the appropriate behavioral phase. Delayed Sleep-Wake Phase Disorder  DSWPD is character­ ized by: (1) sleep onset and wake times persistently later than desired; (2) actual sleep times at nearly the same clock hours daily; and (3) if conducted at the habitual delayed sleep time, essentially normal sleep on polysomnography (except for delayed sleep onset). About half of patients with DSWPD exhibit an abnormally delayed endogenous circadian phase, which can be assessed by measuring the onset of secretion of melatonin in either the blood or saliva; this is best done in a dimly lit environment as light suppresses melatonin secretion. In healthy people, dim-light melatonin onset (DLMO) typically occurs about 8:00–9:00 P.M. (i.e., about 1–2 h before habitual bedtime), but in DSWPD patients, DLMO occurs later in the evening than normal, which helps distinguish DSWPD from other forms of sleep-onset insomnia. Patients tend to be young adults. The delayed circadian phase could be due to: (1) an abnormally long, genetically determined intrinsic period of the endogenous circadian pacemaker; (2) reduced phase-advancing capacity of the pacemaker; (3) slower buildup of homeostatic sleep drive during wakefulness; or (4) an irregular prior sleep-wake schedule, characterized by frequent nights when the patient chooses to remain awake while exposed to artificial light well past mid­ night (for personal, social, school, or work reasons). In most cases, it is difficult to distinguish among these factors, as both patients with either 3No medications have been approved by the FDA for the treatment of RBD.

a behaviorally induced or biologically driven circadian phase delay may exhibit a similar circadian phase delay in DLMO, and both factors make it difficult to fall asleep at the desired hour. DSWPD is a chronic condition that can persist for years and may not respond to attempts to reestablish normal bedtime hours. Typical treatment is phototherapy with blue-enriched light during the morning hours and/or melatonin administration in the evening hours, although the relapse rate is high. Advanced Sleep-Wake Phase Disorder  Advanced sleep-wake phase disorder (ASWPD) is the converse of DSWPD. Most commonly, this syndrome occurs in older people, 15% of whom report that they cannot sleep past 5:00 A.M., with twice that number complaining that they wake up too early at least several times per week. Patients with ASWPD are sleepy during the evening hours, even in social settings. Sleep-wake timing in ASWPD patients can interfere with a normal social life. Patients with this circadian rhythm sleep disorder can be distinguished from those who have early wakening due to insomnia because ASWPD patients show early onset of dim-light melatonin secretion. In addition to age-related ASWPD, an early-onset familial variant of this condition has also been reported. In two families in which ASWPD was inherited in an autosomal dominant pattern, the syndrome was due to missense mutations in a circadian clock component (in the casein kinase binding domain of PER2 in one family, and in casein kinase I delta in the other) that shortens the circadian period. Patients with ASWPD may benefit from bright light and/or blue-enriched pho­ totherapy during the evening hours to reset the circadian pacemaker to a later hour. Non-24-h Sleep-Wake Rhythm Disorder  Non-24-h sleepwake rhythm disorder (N24SWD) most commonly occurs when the primary synchronizing input (i.e., the light-dark cycle) from the envi­ ronment to the circadian pacemaker is lost (as occurs in many blind people with no light perception), and the maximal phase-advancing capacity of the circadian pacemaker in response to nonphotic cues cannot accommodate the difference between the 24-h geophysical day and the intrinsic period of the patient’s circadian pacemaker, resulting in loss of entrainment to the 24-h day. The sleep of most blind patients with N24SWD is restricted to the nighttime hours due to social or occupational demands. Despite this regular sleep-wake schedule, affected patients with N24SWD are nonetheless unable to maintain a stable phase relationship between the output of the nonentrained circa­ dian pacemaker and the 24-h day. Therefore, most blind patients with no light perception present with intermittent bouts of insomnia. When the blind patient’s endogenous circadian rhythms are out of phase with the local environment, nighttime insomnia coexists with excessive day­ time sleepiness. Conversely, when the endogenous circadian rhythms of those same patients are in phase with the local environment, symp­ toms remit. The interval between symptomatic phases may last several weeks to several months in blind patients with N24SWD, depending on the difference between the period of the underlying nonentrained rhythm and the 24-h day. Nightly administration of low-dose (0.5 mg) melatonin or a melatonin receptor agonist may improve sleep and, in some cases, induce synchronization of the circadian pacemaker. In sighted patients, N24SWD can be caused by self-selected exposure to artificial light that inadvertently entrains the circadian pacemaker to a >24-h schedule, and these individuals present with an incremental pattern of successive delays in sleep timing, progressing in and out of phase with local time—a clinical presentation that is seldom seen in blind patients with N24SWD. Shift-Work Disorder  More than 7 million people in the United States regularly work at night, either on a permanent or rotating schedule. Many more begin the commute to work or school between 4:00 A.M. and 7:00 A.M., requiring them to commute and then work during a time of day that they would otherwise be asleep. In addition, each week, millions of “day” workers and students elect to remain awake at night or awaken very early in the morning to work or study to meet work or school deadlines, drive long distances, compete in sporting

events, or participate in recreational activities. Such schedules can result in both sleep loss and misalignment of circadian rhythms with respect to the sleep-wake cycle. The circadian timing system usually fails to adapt successfully to the inverted schedules required by overnight work or the phase advance required by early morning (4:00 A.M. to 7:00 A.M.) start times, par­ ticularly if the shift worker reverts to a normal day-night schedule on days off. This leads to a misalignment between the desired work-rest schedule and the output of the pacemaker, resulting in disturbed day­ time sleep in most such individuals. Excessive work hours (per day or per week), insufficient time off between consecutive days of work or school, and frequent travel across time zones may be contribut­ ing factors. Sleep deficiency, increased length of time awake prior to work, and misalignment of circadian phase impair alertness and performance, increase reaction time, and increase risk of performance lapses, thereby resulting in greater safety hazards among night workers and other sleep-deprived individuals. Sleep disturbance nearly doubles the risk of a fatal work accident. Similarly, the risk of sleep-related, fatal-to-the-driver highway crashes is highest in the early morning and late afternoon hours, coincident with bimodal peaks in the daily rhythm of sleep tendency. An expert consensus panel has concluded that individuals who have slept <2 h in the prior 24 h are unfit to drive a motor vehicle. In addition, long-term night-shift workers may have higher rates of breast, colorectal, and prostate cancer and of cardiac, gastrointestinal, metabolic, and reproductive disorders. The World Health Organization has added night-shift work to its list of probable carcinogens. Both circadian rhythms and sleep deficiency contribute to this risk. Physicians who work prolonged shifts, especially intermittent overnight shifts, constitute another group of workers at greater risk for accidents and other adverse consequences of lack of sleep and mis­ alignment of the circadian rhythm. Recurrent scheduling of resident physicians to work shifts of ≥24 consecutive hours impairs psychomo­ tor performance to a degree that is comparable to alcohol intoxica­ tion, doubles the risk of attentional failures among intensive care unit resident physicians working at night, and increases the risk of serious medical errors in intensive care units, including a fivefold increase in the risk of serious diagnostic mistakes. Some 20% of hospital resident physicians report making a fatigue-related mistake that injured a patient, and 5% admit making a fatigue-related mistake that resulted in the death of a patient. Moreover, working for >24 consecutive hours increases the risk of percutaneous injuries and more than doubles the risk of motor vehicle crashes during the commute home. For these reasons, a National Academy of Medicine report concluded that the practice of scheduling resident physicians to work for >16 consecutive hours without sleep is hazardous for both resident physicians and their patients. Of individuals scheduled to work at night or in the early morning hours, 5–15% have much greater-than-average difficulties remaining awake during night work and sleeping during the day; these individu­ als are diagnosed with chronic and severe shift-work disorder (SWD). Patients with this disorder have a level of excessive sleepiness during work at night or in the early morning and insomnia during day sleep that the physician judges to be clinically significant; the condition is associated with an increased risk of sleep-related accidents and with some of the illnesses associated with night-shift work. Patients with chronic and severe SWD are profoundly sleepy at work. In fact, their sleep latencies during night work average just 2 min, comparable to mean daytime sleep latency durations of patients with narcolepsy or severe sleep apnea. TREATMENT Shift-Work Disorder Caffeine is frequently used by night workers to promote wakeful­ ness. However, it cannot forestall sleep indefinitely, and it does not shield users from sleep-related performance lapses. Postural changes, exercise, and strategic placement of nap opportunities can

sometimes temporarily reduce the risk of fatigue-related perfor­ mance lapses. Properly timed exposure to blue-enriched light or bright white light can directly enhance alertness and facilitate more rapid adaptation to night-shift work.

Modafinil (200 mg) or armodafinil (150 mg) 30–60 min before the start of an 8-h overnight shift is an effective treatment for the excessive sleepiness during night work in patients with SWD. Although treatment with modafinil or armodafinil significantly improves performance and reduces sleep propensity and the risk of lapses of attention during night work, affected patients remain excessively sleepy. Sleep Disorders CHAPTER 33 Fatigue risk management programs for night-shift workers should promote education about sleep, increase awareness of the hazards associated with sleep deficiency and night work, and screen for common sleep disorders. Work schedules should be designed to minimize: (1) exposure to night work; (2) the frequency of shift rotations; (3) the number of consecutive night shifts; and (4) the duration of night shifts. Jet Lag Disorder  Each year, >60 million people fly from one time zone to another, often resulting in excessive daytime sleepiness, sleeponset insomnia, or frequent arousals from sleep, particularly in the lat­ ter half of the night. The syndrome is transient, typically lasting 2–14 d depending on the number of time zones crossed, the direction of travel, and the traveler’s age and phase-shifting capacity. Travelers who spend more time outdoors at their destination reportedly adapt more quickly than those who remain in hotel or seminar rooms, presumably due to brighter (outdoor) light exposure. Avoidance of antecedent sleep loss or napping in the afternoon prior to overnight travel can reduce the difficulties associated with extended wakefulness. Laboratory studies suggest that low doses of melatonin can enhance sleep efficiency, but only if taken when endogenous melatonin concentrations are low (i.e., during the biologic daytime). In addition to jet lag associated with travel across time zones, many patients report a behavioral pattern that has been termed social jet lag, in which bedtimes and wake times on weekends or days off occur 3–4 h or more later than during the week. Such recurrent displace­ ment of the timing of the sleep-wake cycle is common in adolescents and young adults and is associated with delayed circadian phase, sleep-onset insomnia, excessive daytime sleepiness, poorer academic performance, and increased risk of both obesity and depressive symptoms. ■ ■MEDICAL IMPLICATIONS OF CIRCADIAN RHYTHMICITY Prominent circadian variations have been reported in the incidence of acute myocardial infarction, sudden cardiac death, and stroke, the leading causes of death in the United States. Platelet aggregability is increased in the early morning hours, coincident with the peak inci­ dence of these cardiovascular events. Recurrent circadian disruption combined with chronic sleep deficiency, such as occurs during nightshift work, is associated with increased plasma glucose concentrations after a meal due to inadequate pancreatic insulin secretion. Nightshift workers with elevated fasting glucose have an increased risk of progressing to diabetes. Blood pressure of night workers with sleep apnea is higher than that of day workers. A better understanding of the possible role of circadian rhythmicity in the acute destabilization of a chronic condition such as atherosclerotic disease could improve the understanding of its pathophysiology. Diagnostic and therapeutic procedures may also be affected by the time of day at which data are collected. Examples include blood pressure, body temperature, the dexamethasone suppression test, and plasma cortisol levels. The timing of administration of drugs such as chemotherapy can affect both their toxicity and effectiveness. Anes­ thetic agents are particularly sensitive to time-of-day effects. Finally, the physician must be aware of the public health risks associated with the ever-increasing demands made by the 24/7 schedules in our roundthe-clock society.

25 - 34 Disorders of the Eye

34 Disorders of the Eye

■ ■FURTHER READING Aquino G et al: Towards the neurobiology of insomnia: A systematic

review of neuroimaging studies. Sleep Med Rev 73:101878, 2024. Cash RE et al: Association between sleep duration and ideal cardio­ vascular health among US adults, National Health and Nutrition Examination Survey. Prev Chronic Dis 17:E43, 2020. Chinoy ED et al: Unrestricted evening use of light-emitting tablet computers delays self-selected bedtime and disrupts circadian timing and alertness. Physiol Rep 6:e13692, 2018. Cribb L et al: Sleep regularity and mortality: A prospective analysis in the UK Biobank. Elife 12:RP88359, 2023. Holth JK et al: The sleep-wake cycle regulates brain interstitial fluid PART 2 Cardinal Manifestations and Presentation of Diseases tau in mice and CSF tau in humans. Science 363:880, 2019. Landrigan CP et al: Effect on patient safety of a resident physician schedule without 24-hour shifts. N Engl J Med 382:2514, 2020. Lee ML et al: High risk of near-crash driving events following nightshift work. Proc Natl Acad Sci USA 113:176, 2016. Liblau RS et al: The immunopathogenesis of narcolepsy type 1. Nat Rev Immunol 24:33, 2024. Scammell TE: Narcolepsy. N Engl J Med 373:2654, 2015. Scammell TE et al: Neural circuitry of wakefulness and sleep. Neuron 93:747, 2017. Sletten TL et al: The importance of sleep regularity: A consensus statement of the National Sleep Foundation sleep timing and vari­ ability panel. Sleep Health 9:801, 2023. VIDEO 33-1  A typical episode of severe cataplexy. The patient is joking and then falls to the ground with an abrupt loss of muscle tone. The electromyogram recordings (four lower traces on the right) show reductions in muscle activity during the period of paralysis. The electroencephalogram (top two traces) shows wakefulness throughout the episode. (Video courtesy of Giuseppe Plazzi, University of Bologna.) VIDEO 33-2  Typical aggressive movements in rapid eye movement (REM) sleep behavior disorder. (Video courtesy of Dr. Carlos Schenck, University of Minnesota Medical School.) Section 4 Disorders of Eyes, Ears, Nose, and Throat Jonathan C. Horton

Disorders of the Eye THE HUMAN VISUAL SYSTEM The visual system provides a supremely efficient means for the rapid assimilation of information from the environment to aid in the guid­ ance of behavior. The act of seeing begins with the capture of images focused by the cornea and lens on a light-sensitive membrane in the back of the eye called the retina. The retina is actually part of the brain, banished to the periphery to serve as a transducer for the conversion of patterns of light energy into neuronal signals. Light is absorbed by pigment in two types of photoreceptors: rods and cones. In the human retina, there are 100 million rods and 5 million cones. The rods operate in dim (scotopic) illumination. The cones function under daylight (photopic) conditions. The cone system is special­ ized for color perception and high spatial resolution. The majority of cones are within the macula, the portion of the retina that serves the central 10° of vision. In the middle of the macula, a small pit

termed the fovea, packed exclusively with cones, provides the best visual acuity. Photoreceptors hyperpolarize in response to light, activating bipolar, amacrine, and horizontal cells in the inner nuclear layer. After process­ ing of photoreceptor responses by this complex retinal circuit, the flow of sensory information ultimately converges on a final common path­ way: the ganglion cells. These cells translate the visual image impinging on the retina into a continuously varying barrage of action potentials that propagates along the primary optic pathway to visual centers within the brain. There are a million ganglion cells in each retina and hence a million fibers in each optic nerve. Ganglion cell axons sweep along the inner surface of the retina in the nerve fiber layer, exit the eye at the optic disc, and travel through the optic nerve, optic chiasm, and optic tract to reach targets in the brain. The majority of fibers synapse on cells in the lateral geniculate nucleus, a thalamic relay station. Cells in the lateral geniculate nucleus project in turn to the primary visual cortex. This afferent retinoge­ niculocortical sensory pathway provides the neural substrate for visual perception. Separate classes of ganglion cells project to subcortical visual nuclei involved in other functions. Pupillary constriction and circadian rhythms are governed by ganglion cells that are intrinsically light sensitive, owing to a pigment named melanopsin. Pupil reflexes are mediated by a projection to the pretectal olivary nuclei. Their output is supplied to the Edinger-Westphal nuclei, which provide para­ sympathetic innervation to the iris sphincter via an interneuron in the ciliary ganglion. Circadian rhythms are timed by melanopsin ganglion cells that project to the suprachiasmatic nucleus. Visual orientation and eye movements are served by retinal input to the superior colliculus. Gaze stabilization and optokinetic reflexes are governed by a cluster of small retinal targets known collectively as the brainstem accessory optic system. The eyes must be rotated constantly within their orbits to place and maintain targets of visual interest on the fovea. This activity, called foveation, or looking, is governed by an elaborate efferent motor system. Each eye is moved by six extraocular muscles that are supplied by cranial nerves from the oculomotor (III), trochlear (IV), and abducens (VI) nuclei. Activity in these ocular motor nuclei is coordinated by pontine and midbrain mechanisms for smooth pursuit, saccades, and gaze stabilization during head and body move­ ments. Large regions of the frontal and parietooccipital cortex con­ trol these brainstem eye movement centers by providing descending supranuclear input. CLINICAL ASSESSMENT OF VISUAL FUNCTION ■ ■REFRACTIVE STATE In approaching a patient with reduced vision, the first step is to decide whether refractive error is responsible. In emmetropia, parallel rays from infinity are focused perfectly on the retina. Sadly, this condition is enjoyed by only a minority of the population. In myopia, the globe is too long, and light rays come to a focal point in front of the retina. Near objects can be seen clearly, but distant objects require a diverging lens in front of the eye. In hyperopia, the globe is too short, and hence, a converging lens is used to supplement the refractive power of the eye. In astigmatism, the corneal surface is not spherical, necessitating a cylindrical corrective lens. Most patients elect to wear eyeglasses or contact lenses to neutralize refractive error. An alternative is to perma­ nently alter the refractive properties of the cornea by performing laser in situ keratomileusis (LASIK) or photorefractive keratectomy (PRK). With the onset of middle age, presbyopia develops as the lens within the eye becomes unable to increase its refractive power to accommo­ date on near objects. To compensate for presbyopia, an emmetropic patient must use reading glasses. A patient already wearing glasses for distance correction usually switches to bifocals. The only exception is a myopic patient, who may achieve clear vision at near simply by remov­ ing glasses containing the distance prescription. Refractive errors usually develop slowly and remain stable after ado­ lescence, except in unusual circumstances. For example, the acute onset

of diabetes mellitus can produce sudden myopia because of lens edema induced by hyperglycemia. Testing vision through a pinhole aperture is a useful way to screen quickly for refractive error. If acuity is improved by viewing through a pinhole, the patient needs a refraction to obtain best corrected visual acuity. ■ ■VISUAL ACUITY The Snellen chart is used to test acuity at a distance of 6 m (20 ft). A portable scale version of the Snellen chart called the Rosenbaum card is held at 36 cm (14 in.) from the patient (eFig. 34-1: available at accessmedicine.com/harrisons). All subjects should be able to read the 6/6 m (20/20 ft) line with each eye using their refractive correction, if any. Patients who need reading glasses because of presbyopia must wear them for accurate testing with the Rosenbaum card. If 6/6 (20/20) acuity is not present in each eye, the deficiency in vision must be explained. If it is worse than 6/240 (20/800), acuity should be recorded in terms of counting fingers, hand motions, light perception, or no light perception. Legal blindness is defined by the Internal Revenue Service as a best corrected acuity of 6/60 (20/200) or less in the better eye or a binocular visual field subtending 20° or less. Loss of vision in one eye only does not constitute legal blindness. For driving, the laws vary by state, but most require a corrected acuity of 6/12 (20/40) in at least one eye for unrestricted privileges. Patients who develop a hom­ onymous hemianopia should not drive. ■ ■PUPILS The pupils should be tested individually in dim light with the patient fixating on a distant target. There is no need to check the near response if the pupils respond briskly to light, because isolated loss of constric­ tion (miosis) to accommodation does not occur. For this reason, the ubiquitous abbreviation PERRLA (pupils equal, round, and reactive to light and accommodation) implies a wasted effort with the last step. However, it is important to test the near response if the light response is poor or absent. Light-near dissociation occurs with neurosyphilis (Argyll Robertson pupil), with lesions of the dorsal midbrain (Parinaud’s syndrome), and after aberrant regeneration (oculomotor nerve palsy, Adie’s tonic pupil). An eye with no light perception has no pupillary response to direct light stimulation. If the retina or optic nerve is only partially injured, the direct pupillary response will be weaker than the consensual pupil­ lary response evoked by shining a light into the healthy fellow eye. A relative afferent pupillary defect (Marcus Gunn pupil) is elicited with the swinging flashlight test. It is an extremely useful sign in retrobulbar optic neuritis and other optic nerve diseases, in which it may be the sole objective evidence for disease. In bilateral optic neuropathy, no afferent pupil defect is present if the optic nerves are affected equally. Subtle inequality in pupil size, up to 0.5 mm, is a fairly common finding in normal persons. The diagnosis of essential or physiologic anisocoria is secure as long as the relative pupil asymmetry remains constant as ambient lighting varies. Anisocoria that increases in dim light indicates a sympathetic paresis of the iris dilator muscle. The triad of miosis with ipsilateral ptosis and anhidrosis constitutes Horner’s syndrome, although anhidrosis is an inconstant feature. A drop of 1% apraclonidine produces no effect on the normal pupil, but the miotic pupil dilates because of denervation hypersensitivity. Brainstem stroke, carotid dissection, and neoplasm impinging on the sympathetic chain occasionally are identified as the cause of Horner’s syndrome, but most cases are idiopathic. Anisocoria that increases in bright light suggests a parasympathetic palsy. The first concern is an oculomotor nerve paresis. This possibility is excluded if the eye movements are full and the patient has no ptosis or diplopia. Acute pupillary dilation (mydriasis) can result from dam­ age to the ciliary ganglion in the orbit. Common mechanisms are infec­ tion (herpes zoster, influenza), trauma (blunt, penetrating, surgical), and ischemia (diabetes, temporal arteritis). After denervation of the iris sphincter, the pupil does not respond well to light, but the response to near is often relatively intact. When the near stimulus is removed, the pupil redilates very slowly compared with the normal pupil, hence the term tonic pupil. In Adie’s syndrome, a tonic pupil is present, sometimes

in conjunction with weak or absent tendon reflexes in the lower extremities. This benign disorder, which occurs predominantly in healthy young women, is assumed to represent a mild dysautonomia. Tonic pupils are also associated with multiple system atrophy, segmen­ tal hypohidrosis, diabetes, and amyloidosis. Occasionally, a tonic pupil is discovered incidentally in an otherwise completely normal, asymp­ tomatic individual. The diagnosis is confirmed by placing a drop of dilute (0.125%) pilocarpine into each eye. Denervation hypersensitivity produces pupillary constriction in a tonic pupil, whereas the normal pupil shows no response. Pharmacologic dilatation from accidental or deliberate instillation of anticholinergic (atropine, scopolamine) drops can produce pupillary mydriasis. Gardener’s pupil refers to mydriasis induced by exposure to tropane alkaloids, contained in plants such as deadly nightshade, jimsonweed, or angel’s trumpet. When an anticho­ linergic agent is responsible for pupil dilation, 1% pilocarpine causes no constriction.

Disorders of the Eye CHAPTER 34 Both pupils are affected equally by systemic medications. They are small with opiate use and large with anticholinergics (scopolamine). Parasympathetic agents (pilocarpine) used to treat glaucoma produce miosis. In any patient with an unexplained pupillary abnormality, a slit-lamp examination is helpful to exclude an occult foreign body, perforating injury, intraocular inflammation, adhesions (synechia), angle-closure glaucoma, and iris sphincter rupture from blunt trauma. ■ ■EYE MOVEMENTS AND ALIGNMENT Eye movements are tested by asking the patient, with both eyes open, to pursue a small target such as a pen tip into the cardinal fields of gaze. Normal ocular versions are smooth, symmetric, full, and main­ tained in all directions. Saccades, or quick refixation eye movements, are assessed by having the patient look back and forth between two stationary targets. The eyes should move rapidly and accurately in a single jump to their target. Ocular alignment can be judged by hold­ ing a penlight directly in front of the patient at about 1 m. If the eyes are straight, the corneal light reflex will be centered in the middle of each pupil. To test eye alignment more precisely, the cover test is use­ ful. The patient is instructed to look at a small fixation target in the distance. One eye is occluded with a paddle or hand, while the other eye is observed. If the viewing eye shifts position to take up fixation on the target, it was misaligned. If it remains motionless, the first eye is uncovered and the test is repeated on the second eye. If neither eye moves, the eyes are aligned orthotropically. If the eyes are orthotropic in primary gaze but the patient complains of diplopia, the cover test should be performed with the head tilted or turned in whatever direc­ tion elicits diplopia. With practice, the examiner can detect an ocular deviation (heterotropia) as small as 1° with the cover test. In a patient with vertical diplopia, a small deviation can be difficult to detect and easy to dismiss. The magnitude of the deviation can be measured by placing a prism in front of the misaligned eye to determine the power required to neutralize the fixation shift evoked by covering the other eye. Temporary press-on plastic Fresnel prisms, prism eyeglasses, or eye muscle surgery can be used to restore binocular alignment. ■ ■STEREOPSIS Stereoacuity is determined by presenting targets with retinal disparity separately to each eye by using polarized images. The most popular office tests measure a range of thresholds from 2000 to 40 s of arc. Normal stereoacuity is 40 s of arc. If a patient achieves this level of stereoacuity, one is assured that the eyes are aligned orthotropically and that vision is intact in each eye. Random dot stereograms have no mon­ ocular depth cues and provide an excellent screening test for strabismus. ■ ■COLOR VISION The retina contains three classes of cones, with visual pigments of differing peak spectral sensitivity: red (560 nm), green (530 nm), and blue (430 nm). The red and green cone pigments are encoded on the X chromosome, and the blue cone pigment on chromosome 7. Mutations of the blue cone pigment are exceedingly rare. Mutations of the red and green pigments cause congenital X-linked color blindness in 8% of males. Affected individuals are not truly color blind; rather, they differ

from normal subjects in the way they perceive color and how they combine primary monochromatic lights to match a particular color. Anomalous trichromats have three cone types, but a mutation in one cone pigment (usually red or green) causes a shift in peak spectral sen­ sitivity, altering the proportion of primary colors required to achieve a color match. Dichromats have only two cone types and therefore will accept a color match based on only two primary colors. Anomalous tri­ chromats and dichromats have 6/6 (20/20) visual acuity, but their hue discrimination is impaired. Ishihara color plates can be used to detect red-green color blindness. The test plates contain a hidden number that is visible only to subjects with color confusion from red-green color blindness. Because color blindness is almost exclusively X-linked, it is worthwhile screening only male children.

PART 2 Cardinal Manifestations and Presentation of Diseases The Ishihara plates often are used to detect acquired defects in color vision, although they are intended as a screening test for congenital color blindness. Acquired defects in color vision frequently result from disease of the macula or optic nerve. For example, patients with a history of optic neuritis often complain of color desaturation long after their visual acuity has returned to normal. Color blindness also can result from bilateral strokes involving the ventral portion of the occipital lobe (cerebral achromatopsia). Such patients can perceive only shades of gray and also may have difficulty recognizing faces (prosopagnosia) (Chap. 32). Infarcts of the dominant occipital lobe sometimes give rise to color anomia. Affected patients can discriminate colors but cannot name them. ■ ■VISUAL FIELDS Vision can be impaired by damage to the visual system anywhere from the eyes to the occipital lobes. One can localize the site of the lesion with considerable accuracy by mapping the visual field deficit by finger confrontation and then correlating it with the topographic anatomy of the visual pathway (Fig. 34-1). Quantitative visual field mapping is per­ formed by computer-driven perimeters that present a target of variable intensity at fixed positions in the visual field (Fig. 34-1A). By generat­ ing an automated printout of light thresholds, these static perimeters provide a sensitive means of detecting scotomas in the visual field. They are exceedingly useful for serial assessment of visual function in chronic diseases such as glaucoma and pseudotumor cerebri. The crux of visual field analysis is to decide whether a lesion is before, at, or behind the optic chiasm. If a scotoma is confined to one eye, it must be due to a lesion anterior to the chiasm, involving either the optic nerve or the retina. Retinal lesions produce scotomas that correspond optically to their location in the fundus. For example, a superior-nasal retinal detachment results in an inferior-temporal field cut. Damage to the macula causes a central scotoma (Fig. 34-1B). Optic nerve disease produces characteristic patterns of visual field loss. Glaucoma selectively destroys axons that enter the superotempo­ ral or inferotemporal poles of the optic disc, resulting in arcuate scoto­ mas shaped like a Turkish scimitar, which emanate from the blind spot and curve around fixation to end flat against the horizontal meridian (Fig. 34-1C). This type of field defect mirrors the arrangement of the nerve fiber layer in the temporal retina. Arcuate or nerve fiber layer scotomas also result from optic neuritis, ischemic optic neuropathy, optic disc drusen, and branch retinal artery or vein occlusion. Damage to the entire upper or lower pole of the optic disc causes an altitudinal field cut that follows the horizontal meridian (Fig. 34-1D). This pattern of visual field loss is typical of ischemic optic neuropathy but also results from retinal vascular occlusion, advanced glaucoma, and optic neuritis. About half the fibers in the optic nerve originate from ganglion cells serving the macula. Damage to papillomacular fibers causes a cecocen­ tral scotoma that encompasses the blind spot and macula (Fig. 34-1E). If the damage is irreversible, pallor eventually appears in the temporal portion of the optic disc. Temporal pallor from a cecocentral scotoma may develop in optic neuritis, nutritional optic neuropathy, toxic optic neuropathy, Leber’s hereditary optic neuropathy, Kjer’s dominant optic atrophy, and compressive optic neuropathy. It is worth mentioning that the temporal side of the optic disc is slightly paler than the nasal side in most normal individuals. Therefore, it sometimes can be difficult to

decide whether temporal pallor visible on fundus examination repre­ sents a pathologic change. Pallor of the nasal rim of the optic disc is a less equivocal sign of optic atrophy. At the optic chiasm, fibers from nasal ganglion cells decussate into the contralateral optic tract. Crossed fibers are damaged more by compression than are uncrossed fibers. As a result, mass lesions of the sellar region cause a temporal hemianopia in each eye. Tumors ante­ rior to the optic chiasm, such as meningiomas of the tuberculum sella, produce a junctional scotoma characterized by an optic neuropathy in one eye and a superior-temporal field cut in the other eye (Fig. 34-1G). More symmetric compression of the optic chiasm by a pituitary ade­ noma (see Fig. 392-1), meningioma, craniopharyngioma, glioma, or aneurysm results in a bitemporal hemianopia (Fig. 34-1H). The insidi­ ous development of a bitemporal hemianopia often goes unnoticed by the patient and will escape detection by the physician unless each eye is tested separately. It is difficult to localize a postchiasmal lesion accurately, because injury anywhere in the optic tract, lateral geniculate nucleus, optic radiations, or visual cortex can produce a homonymous hemianopia (i.e., a temporal hemifield defect in the contralateral eye and a match­ ing nasal hemifield defect in the ipsilateral eye) (Fig. 34-1I). A unilat­ eral postchiasmal lesion leaves the visual acuity in each eye unaffected, although the patient may read the letters on only the left or right half of the eye chart. Lesions of the optic radiations tend to cause poorly matched or incongruous field defects in each eye. Damage to the optic radiations in the temporal lobe (Meyer’s loop) produces a superior quadrantic homonymous hemianopia (Fig. 34-1J), whereas injury to the optic radiations in the parietal lobe results in an inferior quadrantic homonymous hemianopia (Fig. 34-1K). Lesions of the primary visual cortex give rise to dense, congruous hemianopic field defects. Occlu­ sion of the posterior cerebral artery supplying the occipital lobe is a common cause of total homonymous hemianopia. Some patients have macular sparing, because the central field representation at the tip of the occipital lobe is supplied by collaterals from the middle cerebral artery (Fig. 34-1L). Destruction of both occipital lobes produces cortical blindness. This condition can be distinguished from bilateral prechiasmal visual loss by noting that the pupil responses and optic fundi remain normal. Partial recovery of homonymous hemianopia has been reported through computer-based rehabilitation therapy. During daily train­ ing sessions, patients fixate a central target while visual stimuli are presented within the blind region. The premise of vision restoration programs is that extra stimulation can promote recovery of partially damaged tissue located at the fringe of a cortical lesion. When fixation is controlled rigorously, however, no improvement of the visual fields can be demonstrated. No effective treatment exists for homonymous hemianopia caused by permanent brain damage. DISORDERS ■ ■RED OR PAINFUL EYE Corneal Abrasions  Corneal abrasions are seen best by placing a drop of fluorescein in the eye and looking with the slit lamp, using a cobalt-blue light. A penlight with a blue filter will suffice if a slit lamp is not available. Damage to the corneal epithelium is revealed by yellow fluorescence of the basement membrane exposed by loss of the overly­ ing epithelium. It is important to check for foreign bodies. To search the conjunctival fornices, the lower lid should be pulled down and the upper lid everted. A foreign body can be removed with a moistened cotton-tipped applicator after a drop of a topical anesthetic such as proparacaine has been placed in the eye. Alternatively, it may be pos­ sible to flush the foreign body from the eye by irrigating copiously with saline or artificial tears. If the corneal epithelium has been abraded, antibiotic ointment and a patch may be applied to the eye. A drop of an intermediate-acting cycloplegic such as cyclopentolate hydrochloride 1% helps reduce pain by relaxing the ciliary body. The eye should be reexamined the next day. Minor abrasions may not require patching, antibiotics, or cycloplegia.

Monocular prechiasmal field defects: C D E F A B 30° 30° Blind spot Central scotoma Normal field right eye Nerve-fiber bundle (arcuate) scotoma Altitudinal scotoma Cecocentral scotoma Enlarged blind-spot with peripheral constriction Binocular chiasmal or postchiasmal field defects: (Left eye) (Right eye) G 30° 100° 60° Junctional scotoma H 30° Bitemporal hemianopia I 30° Optic nerve Homonymous hemianopia J Optic chiasm 30° Optic tract Superior quadrantanopia K Lateral geniculate body 30° Optic radiations Inferior quadrantanopia L 30° Primary visual cortex Homonymous hemianopia with macular sparing FIGURE 34-1  Ventral view of the brain, correlating patterns of visual field loss with the sites of lesions in the visual pathway. The visual fields overlap partially, creating 120° of central binocular field flanked by a 40° monocular crescent on either side. The visual field maps in this figure were done with a computer-driven perimeter (Humphrey Instruments, Carl Zeiss, Inc.). It plots the retinal sensitivity to light in the central 30° by using a gray scale format. Areas of visual field loss are shown in black. The examples of common monocular, prechiasmal field defects are all shown for the right eye. By convention, the visual fields are always recorded with the left eye’s field on the left and the right eye’s field on the right, just as the patient sees the world. Subconjunctival Hemorrhage  This results from rupture of small vessels bridging the potential space between the episclera and the con­ junctiva. Blood dissecting into this space can produce an impressive red eye, but vision is not affected and the hemorrhage resolves without treatment. Subconjunctival hemorrhage is usually spontaneous but can result from blunt trauma, eye rubbing, or vigorous coughing. Occa­ sionally, it is a clue to an underlying bleeding disorder. Pinguecula  Pinguecula is a small, raised conjunctival nodule, usually at the nasal limbus. In adults such lesions are extremely common and have little significance unless they become inflamed

30° 30° 30° 30° Disorders of the Eye CHAPTER 34 Right Left G H J K I L (pingueculitis). They are more apt to occur in workers with outdoor exposure. A pterygium resembles a pinguecula but has crossed the limbus to encroach on the corneal surface. Removal is justified when symptoms of irritation or blurring develop, but recurrence is common. Blepharitis  This refers to inflammation of the eyelids. The most common form occurs in association with acne rosacea or seborrheic dermatitis. The eyelid margins usually are colonized heavily by staphy­ lococci. Upon close inspection, they appear greasy, ulcerated, and crusted with scaling debris that clings to the lashes. Treatment consists of strict eyelid hygiene, applying warm compresses, and eyelash scrubs

with a cleansing agent. An external hordeolum (stye) is caused by staphylococcal infection of the superficial accessory glands of Zeis or Moll located in the eyelid margins. An internal hordeolum occurs after suppurative infection of the oil-secreting meibomian glands within the tarsal plate of the eyelid. Topical antibiotics such as bacitracin/ polymyxin B ophthalmic ointment can be applied. Systemic antibiot­ ics, usually tetracyclines or azithromycin, sometimes are necessary for treatment of meibomian gland inflammation (meibomitis) or chronic, severe blepharitis. A chalazion is a painless, chronic granulomatous inflammation of a meibomian gland that produces a pealike nodule within the eyelid. It can be incised and drained, but injection with glucocorticoids is equally effective. Basal cell, squamous cell, or mei­ bomian gland carcinoma should be suspected with any nonhealing ulcerative lesion of the eyelids.

PART 2 Cardinal Manifestations and Presentation of Diseases Dacryocystitis  An inflammation of the lacrimal drainage sys­ tem, dacryocystitis can produce epiphora (tearing) and ocular injec­ tion. Gentle pressure over the lacrimal sac evokes pain and reflux of mucus or pus from the tear puncta. Dacryocystitis usually occurs after obstruction of the lacrimal system. It is treated with topical and systemic antibiotics, followed by probing, silicone stent intubation, or surgery to reestablish patency. Entropion (inversion of the eyelid) or ectropion (sagging or eversion of the eyelid) can also lead to epiphora and ocular irritation. Conjunctivitis  Conjunctivitis is the most common cause of a red, irritated eye. Pain is minimal, and visual acuity is reduced only slightly. The most common viral etiology is adenovirus infection. It causes a watery discharge, a mild foreign-body sensation, and photophobia. Bacterial infection tends to produce a more mucopurulent exudate. Mild cases of infectious conjunctivitis usually are treated empirically with broad-spectrum topical ocular antibiotics such as sulfacetamide 10%, polymyxin-bacitracin, or a trimethoprim-polymyxin combina­ tion. Smears and cultures usually are reserved for severe, resistant, or recurrent cases of conjunctivitis. To prevent contagion, patients should be admonished to wash their hands frequently, not to touch their eyes, and to avoid direct contact with others. Allergic Conjunctivitis  This condition is extremely common and often is mistaken for infectious conjunctivitis. Itching, redness, and epiphora are typical. The palpebral conjunctiva may become hypertropic with giant excrescences called cobblestone papillae. Irrita­ tion from contact lenses or any chronic foreign body also can induce formation of cobblestone papillae. Atopic conjunctivitis occurs in sub­ jects with atopic dermatitis or asthma. Symptoms caused by allergic conjunctivitis can be alleviated with cold compresses, topical vaso­ constrictors (naphazoline), antihistamines (olopatadine), and mast cell stabilizers (cromolyn). Topical glucocorticoid solutions provide dramatic relief of immune-mediated forms of conjunctivitis, but their long-term use is ill advised because of the complications of glaucoma, cataract, and secondary infection. Topical nonsteroidal anti-inflammatory drugs (NSAIDs; ketorolac) are better alternatives. Keratoconjunctivitis Sicca  Also known as dry eye, this produces a burning foreign-body sensation, injection, and photophobia. In mild cases, the eye appears surprisingly normal, but tear production mea­ sured by wetting of a filter paper (Schirmer strip) is deficient. A variety of systemic drugs, including antihistaminic, anticholinergic, and psy­ chotropic medications, result in dry eye by reducing lacrimal secretion. Disorders that involve the lacrimal gland directly, such as sarcoidosis and Sjögren’s syndrome, also cause dry eye. Patients may develop dry eye after radiation therapy if the treatment field includes the orbits. Ocular drying is also common after lesions affecting cranial nerve V or VII. Corneal anesthesia is particularly dangerous, because the absence of a normal blink reflex exposes the cornea to injury without pain to warn the patient. Dry eye is managed by frequent and liberal applica­ tion of artificial tears and ocular lubricants. In severe cases, the tear puncta can be plugged or cauterized to reduce lacrimal outflow. Keratitis  Keratitis is a threat to vision because of the risk of corneal clouding, scarring, and perforation. Worldwide, the two leading causes

of blindness from keratitis are trachoma from chlamydial infection and vitamin A deficiency related to malnutrition. In the United States, con­ tact lenses play a major role in corneal infection and ulceration. They should not be worn by anyone with an active eye infection. In evaluat­ ing the cornea, it is important to differentiate between a superficial infection (keratoconjunctivitis) and a deeper, more serious ulcerative process. The latter is accompanied by greater visual loss, pain, photo­ phobia, redness, and discharge. Slit-lamp examination shows disrup­ tion of the corneal epithelium, a cloudy infiltrate or abscess in the stroma, and an inflammatory cellular reaction in the anterior chamber. In severe cases, pus settles at the bottom of the anterior chamber, giving rise to a hypopyon. Immediate empirical antibiotic therapy should be initiated after corneal scrapings are obtained for Gram’s stain, Giemsa stain, potassium hydroxide (KOH) prep, and cultures. Fortified topi­ cal antibiotics are most effective, supplemented with subconjunctival antibiotics as required. A fungal etiology should always be considered in a patient with keratitis. Fungal infection is common in warm humid climates, especially after penetration of the cornea by plant or vegetable material. Acanthamoeba keratitis is associated with improper disinfec­ tion of contact lenses. Herpes Simplex  The herpesviruses are a major cause of blindness from keratitis. Most adults in the United States have serum antibod­ ies to herpes simplex, indicating prior viral infection (Chap. 197). Primary ocular infection generally is caused by herpes simplex type 1 rather than type 2. It manifests as a unilateral follicular blepharocon­ junctivitis that is easily confused with adenoviral conjunctivitis, unless telltale vesicles are present on the eyelids or conjunctiva. Recurrent ocular infection arises from reactivation of latent herpesvirus. A den­ dritic pattern of corneal epithelial ulceration revealed by fluorescein staining is pathognomonic for herpes infection but often not present. Involvement of both eyes is extremely rare. Corneal stromal inflamma­ tion produces edema, vascularization, and iridocyclitis. Herpes kerati­ tis is treated with cycloplegia and either a topical antiviral (trifluridine, ganciclovir) or an oral antiviral (acyclovir, valacyclovir) agent. Topical glucocorticoids are effective in mitigating corneal scarring but gener­ ally are reserved for cases involving stromal damage. Risks include corneal melting, perforation, prolonged infection, and glaucoma. Herpes Zoster  Herpes zoster from reactivation of latent varicella (chickenpox) virus causes a dermatomal pattern of painful vesicular dermatitis (Chap. 198). Ocular symptoms can occur after zoster eruption in any branch of the trigeminal nerve but are particularly common when vesicles form on the nose, reflecting nasociliary (V1) nerve involvement (Hutchinson’s sign). Herpes zoster ophthalmicus produces corneal dendrites, which can be difficult to distinguish from those seen in herpes simplex. Stromal keratitis, anterior uveitis, raised intraocular pressure, ocular motor nerve palsies, acute retinal necrosis, and postherpetic scarring and neuralgia are other common sequelae. Herpes zoster ophthalmicus is treated with antiviral agents and cyclo­ plegics. In severe cases, topical steroids may be added to reduce corneal scarring. Shingles should be prevented by vaccination of all healthy adults aged 50 years and older. Episcleritis  This is an inflammation of the episclera, a thin layer of connective tissue between the conjunctiva and the sclera. Episcleritis resembles conjunctivitis, but it is a more localized process and discharge is absent. Most cases of episcleritis are idiopathic, but some occur in the setting of an autoimmune disease. Scleritis refers to a deeper, more severe inflammatory process that frequently is associated with a connec­ tive tissue disease such as rheumatoid arthritis, lupus erythematosus, polyarteritis nodosa, granulomatosis with polyangiitis, or relapsing polychondritis. The inflammation and thickening of the sclera can be diffuse or nodular. In anterior forms of scleritis, the globe assumes a violet hue and the patient complains of severe ocular tenderness and pain. With posterior scleritis, the pain and redness may be less marked, but there is often proptosis, choroidal effusion, reduced motility, and visual loss. Episcleritis and scleritis should be treated with NSAIDs. If these agents fail, topical or even systemic glucocorticoid therapy may be necessary, especially if an underlying autoimmune process is active.

Anterior Uveitis  Involving the anterior structures of the eye, uve­ itis was previously called iritis or iridocyclitis. The diagnosis requires slit-lamp examination to identify inflammatory cells floating in the aqueous humor or deposited on the corneal endothelium (keratic precipitates). Anterior uveitis develops in sarcoidosis, ankylosing spon­ dylitis, juvenile idiopathic arthritis, inflammatory bowel disease, pso­ riasis, reactive arthritis, and Behçet’s disease. It also is associated with herpes infections, syphilis, Lyme disease, onchocerciasis, tuberculosis, and leprosy. Although anterior uveitis can occur in conjunction with many diseases, no cause is found to explain the majority of cases. For this reason, laboratory evaluation usually is reserved for patients with recurrent or severe anterior uveitis. Treatment is aimed at reducing inflammation and scarring by judicious use of topical glucocorticoids. Dilatation of the pupil reduces pain and prevents the formation of synechiae. Posterior Uveitis  This diagnosis is made by observing inflam­ mation of the vitreous, retina, or choroid on fundus examination. It is more likely than anterior uveitis to be associated with an identifiable systemic disease. Some patients have panuveitis, or inflammation of both the anterior and posterior segments of the eye. Posterior uve­ itis is a manifestation of autoimmune diseases such as sarcoidosis, Behçet’s disease, Vogt-Koyanagi-Harada syndrome, and inflammatory bowel disease. It also accompanies diseases such as toxoplasmosis, onchocerciasis, cysticercosis, coccidioidomycosis, toxocariasis, and histoplasmosis; infections caused by organisms such as Candida, Pneu­ mocystis carinii, Cryptococcus, Aspergillus, herpes, and cytomegalovirus (see Fig. 200-1); and other diseases, such as syphilis, Lyme disease, tuberculosis, cat-scratch disease, Whipple’s disease, and brucellosis. In multiple sclerosis, chronic inflammatory changes can develop in the extreme periphery of the retina (pars planitis or intermediate uveitis). Glucocorticoids have been the mainstay of treatment for noninfectious uveitis. Biologic agents that target proinflammatory cytokines, such as the tumor necrosis factor alpha (TNF-α) inhibitor adalimumab, are effective at preventing vision loss in chronic uveitis. Acute Angle-Closure Glaucoma  This is an unusual but fre­ quently misdiagnosed cause of a red, painful eye. Asian populations have a particularly high risk of angle-closure glaucoma. Susceptible eyes have a shallow anterior chamber because the eye has either a short axial length (hyperopia) or a lens enlarged by the gradual development of cataract. When the pupil becomes mid-dilated, the peripheral iris blocks aqueous outflow via the anterior chamber angle and the intraocular pressure rises abruptly, producing pain, injection, corneal edema, obscurations, and blurred vision. In some patients, ocular symptoms are overshadowed by nausea, vomiting, or headache, prompting a fruitless workup for abdominal or neurologic disease. The diagnosis is made by measuring the intraocular pressure during an acute attack or by performing gonioscopy, a procedure that allows one to observe a narrow chamber angle with a mirrored contact lens. Acute angle closure is treated with acetazolamide (PO or IV), topical beta blockers, prostaglandin analogues, α2-adrenergic agonists, and pilocarpine to induce miosis. If these measures fail, a laser can be used to create a hole in the peripheral iris to relieve pupillary block. Many physicians are reluctant to dilate patients routinely for fundus examination because they fear precipitating an angle-closure glaucoma. The risk is actually remote and more than outweighed by the potential benefit to patients of discovering a hid­ den fundus lesion visible only through a fully dilated pupil. Moreover, a single attack of angle closure after pharmacologic dilatation rarely causes any permanent damage to the eye and serves as an inadvertent provocative test to identify patients with narrow angles who would benefit from prophylactic laser iridectomy. Endophthalmitis  This results from bacterial, viral, fungal, or parasitic infection of the internal structures of the eye. It usually is acquired by hematogenous seeding from a remote site. Chronically ill, diabetic, or immunosuppressed patients, especially those with a history of indwelling IV catheters or positive blood cultures, are at greatest risk for endogenous endophthalmitis. Although most patients have ocular

Disorders of the Eye CHAPTER 34 FIGURE 34-2  Roth’s spot, cotton-wool spot, and retinal hemorrhages in a 48-yearold liver transplant patient with candidemia from immunosuppression. pain and injection, visual loss is sometimes the only symptom. Septic emboli from a diseased heart valve or a dental abscess that lodge in the retinal circulation can give rise to endophthalmitis. White-centered retinal hemorrhages known as Roth’s spots (Fig. 34-2) are considered pathognomonic for subacute bacterial endocarditis, but they also appear in leukemia, diabetes, and many other conditions. Endophthal­ mitis occurs as a complication of ocular surgery, especially glaucoma filtering, occasionally months or even years after the operation. An occult penetrating foreign body or unrecognized trauma to the globe should be considered in any patient with unexplained intraocular infection or inflammation. ■ ■TRANSIENT OR SUDDEN VISUAL LOSS Amaurosis Fugax  This term refers to a transient ischemic attack of the retina (Chap. 438). Because neural tissue has a high rate of metabolism, interruption of blood flow to the retina for more than a few seconds results in transient monocular blindness, a term used interchangeably with amaurosis fugax. Patients describe a rapid fading of vision like a curtain descending, sometimes affecting only a portion of the visual field. Amaurosis fugax usually results from an embolus that becomes stuck within a retinal arteriole (Fig. 34-3). If the embolus breaks up or passes, flow is restored and vision returns quickly to nor­ mal without permanent damage. With prolonged interruption of blood flow, the inner retina suffers infarction. Ophthalmoscopy reveals zones of whitened, edematous retina following the distribution of branch retinal arterioles. Complete occlusion of the central retinal artery pro­ duces arrest of blood flow and a milky retina with a cherry-red fovea (Fig. 34-4). Emboli are composed of cholesterol (Hollenhorst plaque), calcium, or platelet-fibrin debris. The most common source is an ath­ erosclerotic plaque in the carotid artery or aorta, although emboli can also arise from the heart, especially in patients with diseased valves, atrial fibrillation, or wall motion abnormalities. Urgent evaluation is appropriate, because of the risk of stroke. In rare instances, amaurosis fugax results from low central retinal artery perfusion pressure in a patient with a critical stenosis of the ipsi­ lateral carotid artery and poor collateral flow via the circle of Willis. In this situation, amaurosis fugax develops when there is a dip in systemic blood pressure or a slight worsening of the carotid stenosis. Sometimes there is contralateral motor or sensory loss, indicating concomitant hemispheric cerebral ischemia. Retinal arterial occlusion also occurs rarely in association with retinal migraine, lupus erythematosus, anticardiolipin antibodies, anticoagulant deficiency states (protein S, protein C, and antithrombin

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 34-3  Hollenhorst plaque lodged at the bifurcation of a retinal arteriole proves that a patient is shedding emboli from the carotid artery, great vessels, or heart. deficiency), Susac’s syndrome, pregnancy, IV drug abuse, blood dys­ crasias, dysproteinemias, and temporal arteritis. Marked systemic hypertension causes sclerosis of retinal arteri­ oles, splinter hemorrhages, focal infarcts of the nerve fiber layer (cotton-wool spots), and leakage of lipid and fluid (hard exudate) into the macula (Fig. 34-5). In hypertensive crisis, sudden visual loss can result from ischemia induced by vasospasm of retinal arterioles. In addition, visual loss can occur from ischemic optic disc swelling. Patients with acute hypertensive retinopathy should be treated by low­ ering the blood pressure. However, the blood pressure should not be reduced precipitously, because there is a danger of optic disc infarction from sudden hypoperfusion. Impending branch or central retinal vein occlusion can produce pro­ longed visual obscurations that resemble those described by patients with amaurosis fugax. The veins appear engorged and phlebitic, with numerous retinal hemorrhages (Fig. 34-6). In some patients, venous FIGURE 34-4  Central retinal artery occlusion in a 78-year-old man reducing acuity to counting fingers in the right eye. Note the splinter hemorrhage on the optic disc and the slightly milky appearance to the macula with a cherry-red fovea.

FIGURE 34-5  Hypertensive retinopathy with blurred optic disc, scattered hemorrhages, cotton-wool spots (nerve fiber layer infarcts), and foveal exudate in a 62-year-old man with chronic renal failure and a systolic blood pressure of 220. blood flow recovers spontaneously, whereas others evolve a frank obstruction with extensive retinal bleeding (“blood and thunder” appearance), infarction, and visual loss. Venous occlusion of the retina is often idiopathic, but hypertension, diabetes, and glaucoma are prominent risk factors. Polycythemia, thrombocythemia, or other factors leading to an underlying hypercoagulable state should be cor­ rected; aspirin treatment may be beneficial. Anterior Ischemic Optic Neuropathy (AION)  This is caused by insufficient blood flow through the posterior ciliary arteries that supply the optic disc. It produces painless monocular visual loss that is sudden in onset, followed sometimes by stuttering progression. The optic disc is edematous and usually bordered by nerve fiber layer splin­ ter hemorrhages (Fig. 34-7). AION is divided into two forms: arteritic and nonarteritic. The nonarteritic form is most common. No specific cause is known, although diabetes, renal failure, and hypertension are FIGURE 34-6  Central retinal vein occlusion can produce massive retinal hemorrhage (“blood and thunder”), ischemia, and vision loss.

FIGURE 34-7  Anterior ischemic optic neuropathy from temporal arteritis in a 64-year-old woman with acute disc swelling, splinter hemorrhages, visual loss, and an erythrocyte sedimentation rate of 60 mm/h. common risk factors. Case reports have linked erectile dysfunction drugs to AION, but a causal association is doubtful. Evidence is strong that a crowded disc architecture and small optic cup predispose to the development of nonarteritic AION. In patients with such a “disc-at-risk,” the advent of AION in one eye increases the likelihood of the same event occurring in the other eye. No treatment is available for nonar­ teritic AION; glucocorticoids should not be prescribed. About 5% of patients, especially Caucasian females aged >60, have the arteritic form of AION in conjunction with giant cell (temporal) arteritis (Chap. 375). It is urgent to recognize arteritic AION so that high doses of glucocorticoids can be instituted immediately to prevent blindness in the second eye. Tocilizumab, a monoclonal antibody against interleukin 6 receptor, is an effective alternative to glucocor­ ticoids for sustained suppression of giant cell arteritis. Symptoms of polymyalgia rheumatica may be present; the sedimentation rate and C-reactive protein level are usually elevated. In a patient with visual loss from suspected arteritic AION, temporal artery biopsy is manda­ tory to confirm the diagnosis. Administer glucocorticoids immediately, without waiting for the biopsy to be completed. The biopsy should be obtained as soon as practical, because prolonged glucocorticoid treat­ ment can hide inflammatory changes. It is important to harvest a long arterial segment and to examine a sufficient number of tissue sections. The histologic features of granulomatous inflammation are often quite subtle in temporal artery specimens. If an adequate biopsy is declared negative by an experienced pathologist, the diagnosis of arteritic AION is highly unlikely and glucocorticoids should usually be discontinued. Posterior Ischemic Optic Neuropathy  This is an uncommon cause of acute visual loss, induced by the combination of severe anemia and hypotension. Cases have been reported after major blood loss dur­ ing surgery (especially in patients undergoing cardiac or lumbar spine operation), shock, gastrointestinal bleeding, and renal dialysis. The fundus usually appears normal, although optic disc swelling develops if the process extends anteriorly far enough to reach the globe. Vision can be salvaged in some patients by immediate blood transfusion and reversal of hypotension. Optic Neuritis  This is a common inflammatory disease of the optic nerve. In the Optic Neuritis Treatment Trial (ONTT), the mean age of patients was 32 years, 77% were female, 92% had ocular pain (especially with eye movements), and 35% had optic disc swelling. In most patients, the demyelinating event was retrobulbar and the ocular fundus appeared normal on initial examination (Fig. 34-8), although optic disc pallor slowly developed over subsequent months.

Disorders of the Eye CHAPTER 34 FIGURE 34-8  Retrobulbar optic neuritis is characterized by a normal fundus examination initially, hence the rubric “the doctor sees nothing, and the patient sees nothing.” Optic atrophy develops after severe or repeated attacks. Virtually all patients experience a gradual recovery of vision after a single episode of optic neuritis, even without treatment. This rule is so reliable that failure of vision to improve after a first attack of optic neuritis casts doubt on the original diagnosis. Treatment with highdose IV methylprednisolone (250 mg every 6 h for 3 days) followed by oral prednisone (1 mg/kg per day for 11 days) makes no difference in ultimate acuity 6 months after the attack, but the recovery of visual function occurs more rapidly. Therefore, when visual loss is severe (worse than 20/100), IV followed by PO glucocorticoids are often recommended. For some patients, optic neuritis remains an isolated event. How­ ever, the ONTT showed that the 15-year cumulative probability of developing clinically definite multiple sclerosis after optic neuritis is 50%. A brain magnetic resonance (MR) scan is advisable in every patient with a first attack of optic neuritis. If two or more plaques are present on initial imaging, treatment should be considered to prevent the development of additional demyelinating lesions (Chap. 455). A particularly severe optic neuritis, often involving a long segment of nerve, occurs in neuromyelitis optica (NMO); it may be bilateral and associated with myelitis. NMO can occur as a primary disorder, in the setting of systemic autoimmune disease, or rarely, as a paraneoplastic condition. Detection of circulating antibodies directed against aqua­ porin-4 or myelin oligodendrocyte glycoprotein (MOG) is diagnostic. Treatment for acute episodes consists of glucocorticoids followed by satralizumab, eculizumab, or inebilizumab to prevent relapse. Neuro­ myelitis optica is discussed in detail in Chap. 456. ■ ■LEBER’S HEREDITARY OPTIC NEUROPATHY This disease usually affects young men, causing progressive, painless, severe central visual loss in one eye, followed weeks to years later by the same process in the other eye. Acutely, the optic disc appears mildly plethoric with surface capillary telangiectasias but no vascular leakage on fluorescein angiography. Eventually, optic atrophy ensues. Leber’s optic neuropathy is caused by a point mutation at codon 11778 in the mitochondrial gene encoding nicotinamide adenine dinucleotide dehy­ drogenase (NADH) subunit 4. Additional mutations responsible for the disease have been identified, most in mitochondrial genes that encode proteins involved in electron transport. Mitochondrial mutations that cause Leber’s neuropathy are maternally inherited by all children, but for unknown reasons, only 10% of cases occur in females. Clinical trials of gene therapy for this condition have been unsuccessful. Toxic Optic Neuropathy  This can result in acute visual loss with bilateral optic disc swelling and cecocentral scotomas. Cases have been

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 34-9  Optic atrophy is not a specific diagnosis but refers to the combination of optic disc pallor, arteriolar narrowing, and nerve fiber layer destruction produced by a host of eye diseases, especially optic neuropathies. FIGURE 34-10  Papilledema in a young, obese woman with idiopathic intracranial hypertension (top), showing resolution after placement of a lumboperitoneal shunt (bottom). reported from exposure to methyl alcohol (moonshine) and ethylene glycol (antifreeze). More commonly, visual loss develops gradually and produces optic atrophy (Fig. 34-9) without a phase of acute optic disc edema. Ethambutol causes a dose-dependent toxic optic neuropathy in 2% of patients. Other agents have been implicated in toxic optic neuropathy, but supporting evidence is often weak. The following is a partial list of potential offending drugs or toxins: disulfiram, carbon monoxide, ethchlorvynol, chloramphenicol, amiodarone, monoclonal anti-CD3 antibody, ciprofloxacin, digitalis, streptomycin, lead, arse­ nic, thallium, d-penicillamine, isoniazid, emetine, and sulfonamides. Metallosis (chromium, cobalt, nickel) from hip implant failure is a rare cause of toxic optic neuropathy. Deficiency states induced by starva­ tion, malabsorption, alcoholism, or gastric bypass can lead to insidious visual loss. Thiamine, vitamin B12, and folate levels should be checked in any patient with unexplained bilateral central scotomas and optic pallor. Papilledema  This connotes bilateral optic disc swelling from raised intracranial pressure (Fig. 34-10). Headache is a common but not invariable accompaniment. All other forms of optic disc swelling (e.g., from optic neuritis or ischemic optic neuropathy) should be called “optic disc edema.” This convention is arbitrary but serves to avoid confusion. Often it is difficult to differentiate papilledema from other forms of optic disc edema by fundus examination alone. Transient

visual obscurations are a classic symptom of papilledema. They occur in only one eye or simultaneously in both eyes. They usually last seconds but can persist longer. Obscurations follow abrupt shifts in posture or happen spontaneously. When obscurations are prolonged or spontaneous, the papilledema is more threatening. Visual acuity is not affected by papilledema unless the papilledema is severe, longstanding, or accompanied by macular edema and hemorrhage. Visual field testing shows enlarged blind spots and peripheral constriction (Fig. 34-1F). With unremitting papilledema, peripheral visual field loss progresses in an insidious fashion while the optic nerve develops atrophy. In this setting, reduction of optic disc swelling is an ominous sign of a dying nerve rather than an encouraging indication of resolv­ ing papilledema. Evaluation of papilledema requires neuroimaging to exclude an intracranial lesion. Noninvasive MR vascular imaging may be useful in selected cases to search for a dural venous sinus thrombosis or an arteriovenous shunt. If neuroradiologic studies are negative, the sub­ arachnoid opening pressure should be measured in the lateral decu­ bitus position by lumbar puncture. Inaccurate pressure readings are a common pitfall. An elevated pressure, with normal cerebrospinal fluid, points by exclusion to the diagnosis of pseudotumor cerebri (idiopathic intracranial hypertension). Almost all patients are female, and most are obese. Treatment with a carbonic anhydrase inhibitor such as acet­ azolamide lowers intracranial pressure by reducing the production of cerebrospinal fluid and improves the visual fields. Weight reduction is vital: treatment with a glucagon-like peptide-1 receptor agonist is rec­ ommended in patients who cannot lose weight by diet control. If vision loss is severe or progressive, a shunt (preferably lumboperitoneal) should be performed without delay to prevent blindness. Endovascular placement of a stent across the junction of the transverse and sigmoid dural sinuses, where stenosis is usually present, has emerged as a new treatment option. Optic nerve sheath fenestration is a less effective approach and does not address other neurologic symptoms, such as headache. Occasionally, fulminant papilledema produces rapid onset of blindness. In such patients, emergency surgery should be performed to install a shunt. Optic Disc Drusen  These are refractile, glittering particles within the substance of the optic nerve head (Fig. 34-11). They are unrelated to drusen of the retina, which occur in age-related macular degen­ eration. Optic disc drusen are most common in people of northern European descent. Their diagnosis is obvious when they are visible on the surface of the optic disc. However, in many patients, they are hid­ den beneath the surface, producing pseudopapilledema. It is important FIGURE 34-11  Optic disc drusen are calcified, mulberry-like deposits of unknown etiology within the optic disc, giving rise to “pseudopapilledema.”

to recognize optic disc drusen to avoid an unnecessary evaluation for papilledema. When optic disc drusen are buried, B-ultrasound is the most sensitive way to detect them. They appear hyperechoic because they contain calcium. They are also visible on computed tomography (CT) or optical coherence tomography (OCT), a technique for acquir­ ing cross-section images of the retina. In most patients, optic disc dru­ sen are an incidental, innocuous finding, but they can produce visual obscurations. On perimetry, they give rise to enlarged blind spots and arcuate scotomas from damage to the optic disc. With increasing age, drusen tend to become more exposed on the disc surface as optic atrophy develops. Hemorrhage, choroidal neovascular membrane, and AION are more likely to occur in patients with optic disc drusen. No treatment is available.

Disorders of the Eye CHAPTER 34 Vitreous Degeneration  This occurs in all individuals with advancing age, leading to visual symptoms. Opacities develop in the vitreous, casting annoying shadows on the retina. As the eye moves, these distracting “floaters” move synchronously, with a slight lag caused by inertia of the vitreous gel. Vitreous traction on the retina causes mechanical stimulation, resulting in perception of flashing lights. Photopsia is brief and is confined to one eye, in contrast to the bilateral, prolonged scintillations of cortical migraine. Contraction of the vitreous can result in sudden separation from the retina, heralded by an alarming shower of floaters and photopsia. This process, known as vitreous detachment, is a common involutional event in the elderly. It is not harmful unless it damages the retina. A careful examination of the dilated fundus is important in any patient complaining of floaters or photopsia to search for peripheral tears or holes. If such a lesion is found, laser application can forestall a retinal detachment. Occasion­ ally a tear ruptures a retinal blood vessel, causing vitreous hemorrhage and sudden loss of vision. On attempted ophthalmoscopy the fundus is hidden by a dark haze of blood. Ultrasound is required to examine the interior of the eye for a retinal tear or detachment. If the hemorrhage does not resolve spontaneously, the vitreous can be removed surgically. Vitreous hemorrhage also results from the fragile neovascular vessels that proliferate on the surface of the retina in diabetes, sickle cell ane­ mia, and other ischemic ocular diseases. Retinal Detachment  This produces symptoms of floaters, flashing lights, and a scotoma in the peripheral visual field corresponding to the detachment (Fig. 34-12). If the detachment includes the fovea, there is an afferent pupil defect and the visual acuity is reduced. In most eyes, retinal detachment starts with a hole, flap, or tear in the peripheral retina (rhegmatogenous retinal detachment). Patients with peripheral FIGURE 34-12  Retinal detachment appears as an elevated sheet of retinal tissue with folds. In this patient, the fovea was spared, so acuity was normal, but an inferior detachment produced a superior scotoma.

retinal thinning (lattice degeneration) are particularly vulnerable to this process. Once a break has developed in the retina, liquefied vit­ reous is free to enter the subretinal space, separating the retina from the pigment epithelium. The combination of vitreous traction on the retinal surface and passage of fluid behind the retina leads inexorably to detachment. Patients with a history of myopia, trauma, or prior cata­ ract extraction are at greatest risk for retinal detachment. The diagnosis is confirmed by ophthalmoscopic examination of the dilated eye.

Classic Migraine  (See also Chap. 441) This usually occurs with a visual aura lasting about 20 min. In a typical attack, a small central disturbance in the field of vision marches toward the periphery, leav­ ing a transient scotoma in its wake. The expanding border of migraine scotoma has a scintillating, dancing, or zigzag edge, resembling the bastions of a fortified city, hence the term fortification spectra. Descrip­ tions of fortification spectra vary widely and can be confused with amaurosis fugax. Migraine patterns usually last longer and are per­ ceived in both eyes, whereas amaurosis fugax is briefer and occurs in only one eye. Migraine phenomena also remain visible in the dark or with the eyes closed. Generally, they are confined to either the right or the left visual hemifield, but sometimes, both fields are involved simultaneously. Patients often have a long history of stereotypic attacks. After the visual symptoms recede, headache develops in most patients. PART 2 Cardinal Manifestations and Presentation of Diseases Transient Ischemic Attacks  Vertebrobasilar insufficiency may result in acute homonymous visual symptoms. Many patients mis­ takenly describe symptoms in the left or right eye when, in fact, symptoms are occurring in the left or right hemifield of both eyes. Interruption of blood supply to the visual cortex causes a sudden fogging or graying of vision, occasionally with flashing lights or other positive phenomena that mimic migraine. Cortical ischemic attacks are briefer in duration than migraine, occur in older patients, and are not followed by headache. There may be associated signs of brainstem ischemia, such as diplopia, vertigo, numbness, weakness, and dysarthria. Stroke  Permanent vision loss occurs when interruption of blood supply from the posterior cerebral artery to the visual cortex is pro­ longed. The only finding on examination is a homonymous visual field defect that stops abruptly at the vertical meridian. Occipital lobe stroke usually is due to thrombotic occlusion of the vertebrobasilar system, embolus, or dissection. Lobar hemorrhage, tumor, abscess, and arterio­ venous malformation are other common causes of hemianopic cortical visual loss. Factitious (Functional, Nonorganic) Visual Loss  This is claimed by hysterics or malingerers. The latter account for the vast majority, seeking sympathy, special treatment, or financial gain by feigning loss of sight. The diagnosis is suspected when the history is atypical, physical findings are lacking or contradictory, inconsisten­ cies emerge on testing, and a secondary motive can be identified. In our litigious society, the fraudulent pursuit of recompense often drives factitious visual symptoms. ■ ■CHRONIC VISUAL LOSS Cataract  Cataract is a clouding of the lens sufficient to affect vision. Most cataracts develop slowly as a result of aging, leading to gradual impairment. The formation of cataract occurs more rapidly in patients with a history of uveitis, diabetes mellitus, ocular trauma, or vitrectomy. Cataracts are acquired in a variety of genetic diseases, such as myotonic dystrophy, neurofibromatosis type 2, and galactosemia. Radiation therapy and glucocorticoid treatment can induce cataract as a side effect. Such cataracts typically have a posterior subcapsular loca­ tion. Cataract can be detected by noting an impaired red reflex when viewing light reflected from the fundus with an ophthalmoscope or by examining the dilated eye with the slit lamp. The only treatment for cataract is surgical extraction of the opaci­ fied lens. Thirty million cataract operations are performed each year around the globe. The operation generally is done under local anesthe­ sia on an outpatient basis. A plastic or silicone intraocular lens is placed

within the empty lens capsule in the posterior chamber, substituting for the natural lens and leading to rapid recovery of sight. More than 95% of patients who undergo cataract extraction can expect an improve­ ment in vision. In some patients, the lens capsule remaining in the eye after cataract extraction eventually turns cloudy, causing secondary loss of vision. A small opening, called a posterior capsulotomy, is made in the lens capsule with a laser to restore clarity. Glaucoma  Glaucoma is a slowly progressive, insidious optic neu­ ropathy that usually is associated with chronic elevation of intraocu­ lar pressure. After cataract, it is the most common cause of blindness in the world. It is especially prevalent in people of African descent. The mechanism by which raised intraocular pressure injures the optic nerve is not understood. Axons entering the inferotemporal and superotemporal aspects of the optic disc are damaged first, producing typical nerve fiber bundle defects called arcuate scotomas. As fibers are destroyed, the neural rim of the optic disc shrinks and the physi­ ologic cup within the optic disc enlarges (Fig. 34-13). This process is referred to as pathologic “cupping.” The cup-to-disc diameter is expressed as a fraction (e.g., 0.2). The cup-to-disc ratio ranges widely in normal individuals, making it difficult to diagnose glaucoma reliably simply by observing an unusually large or deep optic cup. Careful documentation of serial examinations is helpful. In a patient with physiologic cupping, the large cup remains stable, whereas in a patient with glaucoma, it expands relentlessly over the years. Obser­ vation of progressive cupping and detection of an arcuate scotoma or a nasal step on computerized visual field testing is sufficient to establish the diagnosis of glaucoma. OCT reveals corresponding loss of fibers along the arcuate pathways in the nerve fiber layer and thin­ ning of the ganglion cell complex. Most patients with glaucoma have open anterior chamber angles. The cause of elevated intraocular pressure is usually unknown. Although a positive family history is a risk factor, genetic mutations impairing aqueous filtration from the eye have been identified in only a minority of cases. Surprisingly, a third of patients with open-angle glaucoma have an intraocular pressure within the normal range of 10–20 mmHg. Among patients with this normal-tension form of glau­ coma, high myopia is more common. Chronic angle-closure glaucoma and chronic open-angle glaucoma are usually asymptomatic. Only acute angle-closure glaucoma causes a red or painful eye, from abrupt elevation of intraocular pressure. In all forms of glaucoma, foveal acuity is spared until end-stage disease is reached. For these reasons, severe and irreversible damage can occur FIGURE 34-13  Glaucoma results in “cupping” as the neural rim is destroyed and the central cup becomes enlarged and excavated. The cup-to-disc ratio is about 0.8 in this patient.

before either the patient or the physician recognizes the diagnosis. Screening of patients for glaucoma by noting the cup-to-disc ratio on ophthalmoscopy and by measuring the intraocular pressure is vital. Glaucoma is treated with topical adrenergic agonists, cholinergic ago­ nists, beta blockers, prostaglandin analogues, and carbonic anhydrase inhibitors. Occasionally, systemic absorption of beta blocker from eyedrops can be sufficient to cause side effects of bradycardia, hypoten­ sion, heart block, bronchospasm, or depression. Laser treatment of the trabecular meshwork in the anterior chamber angle improves aqueous outflow from the eye. If medical or laser treatments fail to halt optic nerve damage from glaucoma, a filter must be constructed surgically (trabeculectomy) or a drainage device placed to release aqueous from the eye in a controlled fashion. Macular Degeneration  This is a major cause of gradual, painless, bilateral central visual loss in the elderly. It occurs in a nonexudative (dry) form and an exudative (wet) form. Inflammation may be impor­ tant in both forms of macular degeneration; susceptibility is associated with variants in the gene for complement factor H, an inhibitor of the alternative complement pathway. The nonexudative process begins with the accumulation of extracellular deposits called drusen under­ neath the retinal pigment epithelium. On ophthalmoscopy, they are pleomorphic but generally appear as small discrete yellow lesions clus­ tered in the macula (Fig. 34-14). With time, they become larger, more numerous, and confluent. The retinal pigment epithelium becomes focally detached and atrophic, causing visual loss by interfering with photoreceptor function. Treatment with vitamins C and E, beta-carotene, and zinc may slightly retard dry macular degeneration. Exudative macular degeneration, which develops in only a minority of patients, occurs when neovascular vessels from the choroid grow through defects in Bruch’s membrane and proliferate underneath the retinal pigment epithelium or the retina. Leakage from these vessels produces elevation of the retina, with distortion (metamorphopsia) and blurring of vision. Although the onset of these symptoms is usually gradual, bleeding from a subretinal choroidal neovascular membrane sometimes causes acute visual loss. Neovascular membranes can be difficult to see on fundus examination because they are located beneath the retina. Fluorescein angiography and OCT are extremely useful for their detection. Major or repeated hemorrhage under the retina from neovascular membranes results in fibrosis, development of a round (disciform) macular scar, and permanent loss of central vision. Exudative macular degeneration can be treated with intraocu­ lar injection of antagonists to vascular endothelial growth factor. FIGURE 34-14  Age-related macular degeneration consisting of scattered yellow drusen in the macula (dry form) and a crescent of fresh hemorrhage temporal to the fovea from a subretinal neovascular membrane (wet form).

Bevacizumab, ranibizumab, aflibercept, or brolucizumab is admin­ istered by direct injection into the vitreous cavity, beginning on a monthly basis. These antibodies cause the regression of neovascular membranes by blocking the action of vascular endothelial growth fac­ tor, thereby improving visual acuity.

Central Serous Chorioretinopathy  This primarily affects males between the ages of 20 and 50 years. Leakage of serous fluid from the choroid causes small, localized detachment of the retinal pigment epithelium and the neurosensory retina. These detachments produce acute or chronic symptoms of metamorphopsia and blurred vision when the macula is involved. They are difficult to visualize with a direct ophthalmoscope because the detached retina is transparent and only slightly elevated. OCT shows fluid beneath the retina, and fluores­ cein angiography shows dye streaming into the subretinal space. The cause of central serous chorioretinopathy is unknown. Symptoms may resolve spontaneously if the retina reattaches, but recurrent detach­ ment is common. Laser photocoagulation has benefited some patients with this condition. Disorders of the Eye CHAPTER 34 Diabetic Retinopathy  A rare disease until 1921, when the discov­ ery of insulin resulted in a dramatic improvement in life expectancy for patients with diabetes mellitus, diabetic retinopathy is now a leading cause of blindness in the United States. The retinopathy takes years to develop but eventually appears in nearly all cases. Regular surveil­ lance of the dilated fundus is crucial for any patient with diabetes. In advanced diabetic retinopathy, the proliferation of neovascular vessels leads to blindness from vitreous hemorrhage, retinal detachment, and glaucoma (Fig. 34-15). These complications can be avoided in most patients by administration of panretinal laser photocoagulation at the appropriate point in the evolution of the disease. Antivascular endothelial growth factor antibody treatment is equally effective, but intraocular injections must be given repeatedly. For further discussion of the manifestations and management of diabetic retinopathy, see Chaps. 415–417. Retinitis Pigmentosa  This is a general term for a disparate group of rod-cone dystrophies characterized by progressive night blindness, visual field constriction with a ring scotoma, loss of acuity, and an abnormal electroretinogram (ERG). It occurs sporadically or in an autosomal recessive, dominant, or X-linked pattern. Irregular black deposits of clumped pigment in the peripheral retina, called bone spicules because of their vague resemblance to the spicules of FIGURE 34-15  Proliferative diabetic retinopathy in a 25-year-old man with an 18-year history of diabetes, showing neovascular vessels emanating from the optic disc, retinal and vitreous hemorrhage, cotton-wool spots, and macular exudate. Round spots in the periphery represent recently applied panretinal photocoagulation.

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 34-16  Retinitis pigmentosa with black clumps of pigment known as “bone spicules.” The patient had peripheral visual field loss with sparing of central (macular) vision. cancellous bone, give the disease its name (Fig. 34-16). The name is actually a misnomer because retinitis pigmentosa is not an inflamma­ tory process. Genetic testing usually identifies a mutation in the gene for rhodopsin, the rod photopigment, or in the gene for peripherin, a glycoprotein located in photoreceptor outer segments. Leber’s congenital amaurosis, a rare cone dystrophy, has been treated by replacement of the missing RPE65 protein through gene therapy, resulting in slight improvement in visual function. Some forms of retinitis pigmentosa occur in association with rare, hereditary systemic diseases (olivopontocerebellar degeneration, Bassen-Kornzweig dis­ ease, Kearns-Sayre syndrome, Refsum’s disease). Chronic treatment with chloroquine, hydroxychloroquine, and phenothiazines (especially thioridazine) can produce visual loss from a toxic retinopathy that resembles retinitis pigmentosa. Patients receiving long-term treat­ ment with hydroxychloroquine require regular eye examinations and screening by OCT to monitor for potential development of a bull’s eye maculopathy. Epiretinal Membrane  This is a fibrocellular tissue that grows across the inner surface of the retina, causing metamorphopsia and reduced visual acuity from distortion of the macula. A crinkled, cello­ phane-like membrane is visible on the retinal examination. Epiretinal membrane is most common in patients aged >50 years and is usually unilateral. Most cases are idiopathic, but some occur as a result of hypertensive retinopathy, diabetes, retinal detachment, or trauma. When visual acuity is reduced to the level of about 6/24 (20/80), vitrectomy and surgical peeling of the membrane to relieve macular puckering are recommended. Contraction of an epiretinal membrane sometimes gives rise to a macular hole. Most macular holes, however, are caused by local vitreous traction within the fovea. Vitrectomy can improve acuity in selected cases. Melanoma and Other Tumors  Melanoma is the most common primary intraocular tumor (Fig. 34-17). Approximately 3500 cases occur annually in the United States. It causes photopsia, an enlarg­ ing scotoma, and loss of vision. A small melanoma is often difficult to differentiate from a benign choroidal nevus. Serial examinations are required to document a malignant pattern of growth. Risk factors include light skin, hair, and eyes. Uveal origin accounts for 85% of cases. GNAQ and GNA11 mutations are common. About half metas­ tasize, mainly to the liver. Small and medium-sized tumors may be treated with radiation therapy; enucleation is the best treatment for large tumors. Metastatic tumors to the eye outnumber primary tumors.

FIGURE 34-17  Melanoma of the choroid, appearing as an elevated dark mass in the inferior fundus, with overlying hemorrhage. The black line denotes the plane of the optical coherence tomography scan (below) showing the subretinal tumor. Breast and lung carcinomas have a special propensity to spread to the choroid or iris. Leukemia and lymphoma also commonly invade ocular tissues. Sometimes the only sign on eye examination is cellular debris in the vitreous, which can masquerade as a chronic posterior uveitis. In a patient with vision loss, CT or MR scanning should be consid­ ered if the cause remains unknown after careful review of the history, visual fields, and thorough examination of the eye. Optic nerve sheath meningioma is a common retrobulbar tumor. It produces the classic triad of optociliary shunt vessels, optic atrophy, and progressive visual loss. Optic disc swelling and proptosis are also frequent signs. Optic nerve glioma in young patients is usually a pilocytic astrocytoma and has a good prognosis for preservation of vision, especially in neurofi­ bromatosis type 1 (Chap. 95). In adults, optic nerve glioma is rare and highly malignant. Chiasmal tumors (pituitary adenoma, meningioma, craniopharyngioma) produce visual loss with few objective findings except for optic disc pallor. Loss of the temporal visual field in each eye is typical, but usually patients complain of vision loss in just one eye. OCT shows loss of the retinal nerve fiber layer entering the nasal and temporal sides of the optic discs, as well as thinning of the ganglion cell complex in each nasal retina (Fig. 34-18). A high degree of vigilance is necessary to avoid missing chiasmal tumors. Although symptoms progress gradually, in rare instances, the sudden expansion of a pitu­ itary adenoma from infarction and bleeding (pituitary apoplexy) causes acute severe retrobulbar visual loss, with headache, nausea, and ocular motor nerve palsies. ■ ■PROPTOSIS When the globes appear asymmetric, the clinician must first decide which eye is abnormal. Is one eye recessed within the orbit (enophthal­ mos), or is the other eye protuberant (exophthalmos, or proptosis)? A small globe or Horner’s syndrome can give the appearance of enoph­ thalmos. True enophthalmos occurs commonly after trauma, from atrophy of retrobulbar fat, or from fracture of the orbital floor. The position of the eyes within the orbits is measured by using a Hertel exophthalmometer, a handheld instrument that records the position of the anterior corneal surface relative to the lateral orbital rim. If this instrument is not available, relative eye position can be judged by

FIGURE 34-18  Bitemporal hemianopia (top), with corresponding thinning of the ganglion cell complex in the nasal maculae bilaterally (middle) and reduced retinal nerve fiber layer thickness along the temporal and nasal edges of the optic discs (red zone <1%) from compression of the optic chiasm by a pituitary adenoma (bottom). bending the patient’s head forward and looking down upon the orbits. A proptosis of only 2 mm in one eye is detectable from this perspective. The development of proptosis implies a space-occupying lesion in the orbit and may warrant CT or MR imaging. Graves’ Ophthalmopathy  This is the leading cause of proptosis in adults (Chap. 394). The proptosis is often asymmetric and can even appear to be unilateral. Orbital inflammation and engorgement of the extraocular muscles, particularly the medial rectus and the inferior rectus, account for protrusion of the globe. Corneal exposure, lid retrac­ tion, lid lag on downgaze, conjunctival injection, restriction of gaze, diplopia, and visual loss from optic nerve compression are cardinal symptoms. Graves’ eye disease is a clinical diagnosis, but laboratory testing can be useful. The serum level of thyroid-stimulating immu­ noglobulins is often elevated. Orbital imaging usually reveals enlarged extraocular eye muscles, but not always. Topical lubricants, taping the eyelids closed at night, and moisture chambers are helpful to limit exposure of ocular tissues. Graves’ ophthalmopathy can be treated with oral prednisone (60 mg/d) for 1 month, followed by a taper over several months, but worsening of symptoms upon glucocorticoid withdrawal is common. Infusions of teprotumumab, an inhibitor of the insulinlike growth factor I receptor, reduce proptosis and diplopia. Radiation therapy is not effective. Orbital decompression should be performed for severe, symptomatic exophthalmos or if visual function is reduced by optic nerve compression. In patients with diplopia, prisms or eye muscle surgery can be used to restore ocular alignment in primary gaze. Orbital Pseudotumor  Also known as idiopathic orbital inflam­ matory syndrome, orbital pseudotumor is distinguished from Graves’ ophthalmopathy by the prominent complaint of pain. Other symptoms include diplopia, ptosis, proptosis, and orbital congestion. Evaluation for sarcoidosis, granulomatosis with polyangiitis, IgG4-related disease, and other types of orbital vasculitis or collagen-vascular pathology is negative. Imaging often shows swollen eye muscles (orbital myosi­ tis) with enlarged tendons. By contrast, in Graves’ ophthalmopathy, the tendons of the eye muscles usually are spared. The Tolosa-Hunt syndrome (Chap. 452) may be regarded as an extension of orbital pseudotumor through the superior orbital fissure into the cavernous

sinus. The diagnosis of orbital pseudotumor is difficult. Biopsy of the orbit frequently yields nonspecific evidence of fat infiltration by lymphocytes, plasma cells, and eosinophils. A dramatic response to a therapeutic trial of systemic glucocorticoids indirectly provides the best confirmation of the diagnosis.

Orbital Cellulitis  This causes pain, lid erythema, proptosis, con­ junctival chemosis, restricted motility, decreased acuity, afferent pupil­ lary defect, fever, and leukocytosis. It often arises from the paranasal sinuses, especially by contiguous spread of infection from the ethmoid sinus through the lamina papyracea of the medial orbit. A history of recent upper respiratory tract infection, chronic sinusitis, thick mucus secretions, or dental disease is significant in any patient with suspected orbital cellulitis. Blood cultures should be obtained, but they are usually negative. Most patients respond to empirical therapy with broadspectrum IV antibiotics. Occasionally, orbital cellulitis follows an over­ whelming course, with massive proptosis, blindness, septic cavernous sinus thrombosis, and meningitis. To avert this disaster, orbital celluli­ tis should be managed aggressively in the early stages, with immediate imaging of the orbits and antibiotic therapy that includes coverage of methicillin-resistant Staphylococcus aureus (MRSA). Prompt surgical drainage of an orbital abscess or paranasal sinusitis is indicated if optic nerve function deteriorates despite antibiotics. Disorders of the Eye CHAPTER 34 Tumors  Tumors of the orbit cause painless, progressive propto­ sis. The most common primary tumors are cavernous hemangioma, lymphangioma, neurofibroma, schwannoma, dermoid cyst, adenoid cystic carcinoma, optic nerve glioma, optic nerve meningioma, and benign mixed tumor of the lacrimal gland. Metastatic tumor to the orbit occurs frequently in breast carcinoma, lung carcinoma, and lym­ phoma. Diagnosis by fine-needle aspiration followed by urgent radia­ tion therapy sometimes can preserve vision. Carotid Cavernous Fistulas  With anterior drainage through the orbit, these fistulas produce proptosis, diplopia, glaucoma, and cork­ screw, arterialized conjunctival vessels. Direct fistulas usually result from trauma. They are easily diagnosed because of the prominent signs produced by high-flow, high-pressure shunting. Indirect fistulas, or dural arteriovenous malformations, are more likely to occur spontane­ ously, especially in older women. The signs are more subtle, and the diagnosis frequently is missed. The combination of slight proptosis, diplopia, enlarged muscles, and an injected eye often is mistaken for thyroid ophthalmopathy. A bruit heard upon auscultation of the head or reported by the patient is a valuable diagnostic clue. Imaging shows an enlarged superior ophthalmic vein in the orbits. Carotid cavernous shunts can be eliminated by endovascular embolization. ■ ■PTOSIS Blepharoptosis  This is an abnormal drooping of the eyelid. Unilateral or bilateral ptosis can be congenital, from dysgenesis of the levator palpebrae superioris, or from abnormal insertion of its aponeurosis into the eyelid. Acquired ptosis can develop so gradually that the patient is unaware of the problem. Inspection of old photo­ graphs is helpful in dating the onset. A history of prior trauma, eye surgery, contact lens use, diplopia, systemic symptoms (e.g., dysphagia or peripheral muscle weakness), or a family history of ptosis should be sought. Fluctuating ptosis that worsens late in the day is typical of myasthenia gravis. Ptosis evaluation should focus on evidence for pro­ ptosis, eyelid masses or deformities, inflammation, pupil inequality, or limitation of motility. The width of the palpebral fissures and distance from the upper eyelid margin to corneal light reflex are measured in primary gaze to determine the degree of ptosis. The ptosis will be underestimated if the patient compensates by lifting the brow with the frontalis muscle. Mechanical Ptosis  This occurs in many elderly patients from stretching and redundancy of eyelid skin and subcutaneous fat (dermato­ chalasis). The extra weight of these sagging tissues causes the lid to droop. Enlargement or deformation of the eyelid from infection, tumor, trauma, or inflammation also results in ptosis on a purely mechanical basis.

Aponeurotic Ptosis  This is an acquired dehiscence or stretching of the aponeurotic tendon, which connects the levator muscle to the tarsal plate of the eyelid. It occurs commonly in older patients, presum­ ably from loss of connective tissue elasticity. Aponeurotic ptosis is also a common sequela of eyelid swelling from infection or blunt trauma to the orbit, cataract surgery, or contact lens use.

Myogenic Ptosis  The causes of myogenic ptosis include myasthenia gravis (Chap. 459) and a number of rare myopathies that manifest with ptosis. The term chronic progressive external ophthalmoplegia refers to a spectrum of systemic diseases caused by mutations of mitochondrial DNA. As the name implies, the most prominent findings are symmet­ ric, slowly progressive ptosis and limitation of eye movements. In gen­ eral, diplopia is a late symptom because all eye movements are reduced equally. In the Kearns-Sayre variant, retinal pigmentary changes and abnormalities of cardiac conduction develop. Peripheral muscle biopsy shows characteristic “ragged-red fibers.” Oculopharyngeal dystrophy is a distinct autosomal dominant disease with onset in middle age, charac­ terized by ptosis, limited eye movements, and trouble swallowing. Myo­ tonic dystrophy, another autosomal dominant disorder, causes ptosis, ophthalmoparesis, cataract, and pigmentary retinopathy. Patients have muscle wasting, myotonia, frontal balding, and cardiac abnormalities. PART 2 Cardinal Manifestations and Presentation of Diseases Neurogenic Ptosis  This results from a lesion affecting the inner­ vation to either of the two muscles that open the eyelid: Müller’s muscle or the levator palpebrae superioris. Examination of the pupil helps distinguish between these two possibilities. In Horner’s syndrome, the eye with ptosis has a smaller pupil and the eye movements are full. In an oculomotor nerve palsy, the eye with the ptosis has a larger or a normal pupil. If the pupil is normal but there is limitation of adduc­ tion, elevation, and depression, a pupil-sparing oculomotor nerve palsy is likely (see next section). Rarely, a lesion affecting the small, central subnucleus of the oculomotor complex will cause bilateral ptosis with normal eye movements and pupils. ■ ■DOUBLE VISION (DIPLOPIA) The first point to clarify is whether diplopia persists in either eye after the opposite eye is covered. If it does, the diagnosis is monocular dip­ lopia. The cause is usually intrinsic to the eye and therefore has no dire implications for the patient. Corneal aberrations (e.g., keratoconus, pterygium), uncorrected refractive error, cataract, or foveal traction may give rise to monocular diplopia. Occasionally, it is a symptom of malingering or psychiatric disease. Diplopia alleviated by covering one eye is binocular diplopia and is caused by disruption of ocular align­ ment. Inquiry should be made into the nature of the double vision (purely side-by-side vs partial vertical displacement of images), mode of onset, duration, intermittency, diurnal variation, and associated neu­ rologic or systemic symptoms. If the patient has diplopia while being examined, motility testing should reveal a deficiency corresponding to the patient’s symptoms. However, subtle limitation of ocular excur­ sions is often difficult to detect. For example, a patient with a slight left abducens nerve paresis may appear to have full eye movements despite a complaint of horizontal diplopia upon looking to the left. In this situ­ ation, the cover test provides a more sensitive method for demonstrat­ ing the ocular misalignment. It should be conducted in primary gaze and then with the head turned and tilted in each direction while the patient fixates a central, distant target. In the above example, a cover test with the head turned to the right bringing the eyes into left gaze will maximize the fixation shift evoked by the cover test. Occasionally, a cover test performed in an asymptomatic patient during a routine examination will reveal an ocular deviation. If the eye movements are full and the ocular misalignment is equal in all direc­ tions of gaze (comitant deviation), the diagnosis is strabismus. In this condition, which affects about 1% of the population, fusion is disrupted in infancy or early childhood. To avoid diplopia, retinal input from the nonfixating eye may be partially suppressed. In some children, this leads to impaired vision (amblyopia, or “lazy” eye) in the deviated eye. Binocular diplopia results from a wide range of processes: infec­ tious, neoplastic, metabolic, degenerative, inflammatory, and vascular. One must decide whether the diplopia is neurogenic in origin or is

due to restriction of globe rotation by local disease in the orbit. Orbital pseudotumor, myositis, infection, tumor, thyroid disease, and muscle entrapment (e.g., from a blowout fracture) cause restrictive diplopia. The diagnosis of restriction is usually made by recognizing other associated signs and symptoms of local orbital disease. Dedicated, high-resolution orbital imaging with fat saturation and gadolinium enhancement is helpful when the cause of diplopia is not evident. Myasthenia Gravis  (See also Chap. 459) This is a major cause of painless diplopia. The diplopia is often intermittent, variable, and not confined to any single ocular motor nerve distribution. The pupils are always normal. Serial observation of a fatigable ptosis, often accompa­ nied by diplopia from fluctuating ocular misalignment, establishes the diagnosis. Many patients have a purely ocular form of the disease, with no evidence of systemic muscular weakness. Classically, the diagnosis was confirmed by an IV edrophonium injection, which produces a transient reversal of eyelid or eye muscle weakness, but this drug is discontinued in the United States. Blood tests for antibodies against the acetylcholine receptor or the MuSK protein are frequently negative in the purely ocular form of myasthenia gravis. Botulism from food or wound poisoning can mimic ocular myasthenia. If restrictive orbital disease and myasthenia gravis are excluded, a lesion of a cranial nerve supplying innervation to the extraocular muscles is the most likely cause of binocular diplopia. Oculomotor Nerve  The third cranial nerve innervates the medial, inferior, and superior recti; inferior oblique; levator palpebrae superi­ oris; and the iris sphincter. Total palsy of the oculomotor nerve causes ptosis, a dilated pupil, and leaves the eye “down and out” because of the unopposed action of the lateral rectus and superior oblique. This combination of findings is obvious. More challenging is the diagnosis of early or partial oculomotor nerve palsy. In this setting, any com­ bination of ptosis, pupil dilation, and weakness of the eye muscles supplied by the oculomotor nerve may be encountered. Frequent serial examinations during the rapidly evolving phase of the palsy help ensure that the diagnosis is not missed. The advent of an oculomotor nerve palsy with pupil involvement, especially when accompanied by pain, suggests a compressive lesion, such as a tumor or circle of Willis aneurysm. Urgent neuroimaging should be obtained, along with a CT or MR angiogram. The resolution of these noninvasive techniques has advanced to the point that catheter angiography is rarely necessary to exclude an aneurysm. A lesion of the oculomotor nucleus in the rostral midbrain produces signs that differ from those caused by a lesion of the nerve itself. There is bilateral ptosis because the levator muscle is innervated by a single central subnucleus. There is also weakness of the contralateral superior rectus, because it is supplied by the oculomotor nucleus on the other side. Occasionally both superior recti are weak. Isolated nuclear oculo­ motor palsy is rare. Usually, neurologic examination reveals additional signs that suggest brainstem damage from infarction, hemorrhage, tumor, or infection. Injury to structures surrounding fascicles of the oculomotor nerve descending through the midbrain has given rise to a number of classic eponymic designations. In Nothnagel’s syndrome, injury to the superior cerebellar peduncle causes ipsilateral oculomotor palsy and contralat­ eral cerebellar ataxia. In Benedikt’s syndrome, injury to the red nucleus results in ipsilateral oculomotor palsy and contralateral tremor, chorea, and athetosis. Claude’s syndrome incorporates features of both of these syndromes, by injury to both the red nucleus and the superior cerebel­ lar peduncle. Finally, in Weber’s syndrome, injury to the cerebral pedun­ cle causes ipsilateral oculomotor palsy with contralateral hemiparesis. In the subarachnoid space, the oculomotor nerve is vulnerable to aneurysm, meningitis, tumor, infarction, and compression. In cerebral herniation, the nerve becomes trapped between the edge of the tento­ rium and the uncus of the temporal lobe. Oculomotor palsy also can result from midbrain torsion and hemorrhage during herniation. In the cavernous sinus, oculomotor palsy arises from carotid aneurysm, carotid cavernous fistula, cavernous sinus thrombosis, tumor (pituitary adenoma, meningioma, metastasis), herpes zoster infection, and the Tolosa-Hunt syndrome.

The etiology of an isolated, pupil-sparing oculomotor palsy often remains an enigma even after neuroimaging and extensive laboratory testing. Most cases are thought to result from microvascular ischemia of the nerve somewhere along its course from the brainstem to the orbit. Usually, the patient complains of pain. Diabetes, hypertension, and vascular disease are major risk factors. Spontaneous recovery over a period of months is the rule. If this fails to occur or if new findings develop, the diagnosis of microvascular oculomotor nerve palsy should be reconsidered. Aberrant regeneration is common when the oculo­ motor nerve is injured by trauma or compression (tumor, aneurysm). Miswiring of sprouting fibers to the levator muscle and the rectus mus­ cles results in elevation of the eyelid upon downgaze or adduction. The pupil also constricts upon attempted adduction, elevation, or depres­ sion of the globe. Aberrant regeneration is not seen after oculomotor palsy from microvascular infarct and hence vitiates that diagnosis. Trochlear Nerve  The fourth cranial nerve originates in the mid­ brain, just caudal to the oculomotor nerve complex. Fibers exit the brainstem dorsally and cross to innervate the contralateral superior oblique. The principal actions of this muscle are to depress and intort the globe. A palsy therefore results in hypertropia and excyclotorsion. The cyclotorsion seldom is noticed by patients. Instead, they complain of vertical diplopia, especially upon reading or looking down. Vertical diplopia is exacerbated by tilting the head toward the side with the muscle palsy and alleviated by tilting it away. This “head tilt test” is a cardinal diagnostic feature. Review of old photographs will sometimes reveal a habitual head tilt, signifying a patient with a decompensated, congenital trochlear nerve palsy. New, isolated trochlear nerve palsy results from all the causes listed above for the oculomotor nerve except aneurysm. The trochlear nerve is particularly apt to suffer injury after closed head trauma. The free edge of the tentorium impinges on the nerve during a concussive blow. Most isolated trochlear nerve palsies are idiopathic and hence are diagnosed by exclusion as “microvascular.” Spontaneous improvement occurs over a period of months in most patients. A base-down prism (conveniently applied to the patient’s glasses as a stick-on Fresnel lens) may serve as a temporary measure to alleviate diplopia. If the palsy does not resolve, the eyes can be realigned by weakening the inferior oblique muscle. Abducens Nerve  The sixth cranial nerve innervates the lateral rectus muscle. A palsy produces horizontal diplopia, worse on gaze to the side of the lesion. A nuclear lesion has different consequences, because the abducens nucleus contains interneurons that project via the medial longitudinal fasciculus to the medial rectus subnucleus of the contralateral oculomotor complex. Therefore, an abducens nuclear lesion produces a complete lateral gaze palsy from weakness of both the ipsilateral lateral rectus and the contralateral medial rectus. Foville’s syndrome after dorsal pontine injury includes lateral gaze palsy, ipsilat­ eral facial palsy, and contralateral hemiparesis incurred by damage to descending corticospinal fibers. Millard-Gubler syndrome from ventral pontine injury is similar except for the eye findings. There is lateral rec­ tus weakness only, instead of gaze palsy, because the abducens fascicle is injured rather than the nucleus. Infarct, tumor, hemorrhage, vascular malformation, and multiple sclerosis are the most common etiologies of brainstem abducens palsy. After leaving the ventral pons, the abducens nerve runs forward along the clivus to pierce the dura at the petrous apex, where it enters the cavernous sinus. Along its subarachnoid course, it is susceptible to meningitis, tumor (meningioma, chordoma, carcinomatous meningitis), subarachnoid hemorrhage, trauma, and compression by aneurysm or dolichoectatic vessels. At the petrous apex, mastoiditis can produce deaf­ ness, pain, and ipsilateral abducens palsy (Gradenigo’s syndrome). In the cavernous sinus, the nerve can be affected by carotid aneurysm, carotid cavernous fistula, tumor (pituitary adenoma, meningioma, nasopharyn­ geal carcinoma), herpes infection, and Tolosa-Hunt syndrome. Unilateral or bilateral abducens palsy is a classic sign of raised intracranial pressure. The diagnosis can be confirmed if papilledema is observed on fundus examination. The mechanism is still debated but probably is related to rostral-caudal displacement of the brainstem. The

same phenomenon accounts for abducens palsy from Chiari malfor­ mation or low intracranial pressure (e.g., after lumbar puncture, spinal anesthesia, or spontaneous dural cerebrospinal fluid leak).

Treatment of abducens palsy is aimed at prompt correction of the underlying cause. However, the cause remains obscure in many instances despite diligent evaluation. As was mentioned above for isolated trochlear or oculomotor palsy, most cases are assumed to rep­ resent microvascular infarcts because they often occur in the setting of diabetes or other vascular risk factors. Some cases may develop as a postinfectious mononeuritis (e.g., after a viral flu). Patching one eye, occluding one eyeglass lens with tape, or applying a temporary prism will provide relief of diplopia until the palsy resolves. If recovery is incomplete, eye muscle surgery nearly always can realign the eyes, at least in primary position. A patient with an abducens palsy that fails to improve should be reevaluated for an occult etiology (e.g., chordoma, carcinomatous meningitis, carotid cavernous fistula, myasthenia gra­ vis). Skull base tumors are easily missed even on contrast-enhanced neuroimaging studies. Disorders of the Eye CHAPTER 34 Multiple Ocular Motor Nerve Palsies  These should not be attributed to spontaneous microvascular events affecting more than one cranial nerve at a time. This remarkable coincidence does occur, especially in diabetic patients, but the diagnosis is made only in ret­ rospect after all other diagnostic alternatives have been exhausted. Neuroimaging should focus on the cavernous sinus, superior orbital fissure, and orbital apex, where all three ocular motor nerves are in close proximity. In a diabetic or immunocompromised host, fungal infection (Aspergillus, Mucorales, Cryptococcus) is a common cause of multiple nerve palsies. In a patient with systemic malignancy, carcino­ matous meningitis is a likely diagnosis. Cytologic examination may be negative despite repeated sampling of the cerebrospinal fluid. The can­ cer-associated Lambert-Eaton myasthenic syndrome also can produce ophthalmoplegia. Giant cell (temporal) arteritis occasionally manifests as diplopia from ischemic palsies of extraocular muscles. Fisher’s syn­ drome, an ocular variant of Guillain-Barré, produces ophthalmoplegia with areflexia and ataxia. Often the ataxia is mild, and the reflexes are normal. Antiganglioside antibodies (GQ1b) can be detected in about 50% of cases. Supranuclear Disorders of Gaze  These are often mistaken for multiple ocular motor nerve palsies. For example, Wernicke’s encepha­ lopathy can produce nystagmus and a partial deficit of horizontal and vertical gaze that mimics a combined abducens and oculomotor nerve palsy. The disorder occurs in patients who are malnourished, alco­ holic, or following bariatric surgery, and can be reversed by thiamine. Infarct, hemorrhage, tumor, multiple sclerosis, encephalitis, vasculitis, and Whipple’s disease are other important causes of supranuclear gaze palsy. Disorders of vertical gaze, especially downward saccades, are an early feature of progressive supranuclear palsy. Smooth pursuit is affected later in the course of the disease. Parkinson’s disease, Huntington’s disease, and olivopontocerebellar degeneration also can affect vertical gaze. The frontal eye field of the cerebral cortex is involved in generation of saccades to the contralateral side. After hemispheric stroke, the eyes usually deviate toward the lesioned side because of the unopposed action of the frontal eye field in the normal hemisphere. With time, this deficit resolves. Seizures generally have the opposite effect: the eyes deviate conjugately away from the irritative focus. Parietal lesions disrupt smooth pursuit of targets moving toward the side of the lesion. Bilateral parietal lesions produce Bálint’s syndrome, which is charac­ terized by impaired eye-hand coordination (optic ataxia), difficulty initiating voluntary eye movements (ocular apraxia), and visuospatial disorientation (simultanagnosia). Horizontal Gaze  Descending cortical inputs mediating horizon­ tal gaze ultimately converge at the level of the pons. Neurons in the paramedian pontine reticular formation are responsible for control­ ling conjugate gaze toward the same side. They project directly to the ipsilateral abducens nucleus. A lesion of either the paramedian pon­ tine reticular formation or the abducens nucleus causes an ipsilateral

conjugate gaze palsy. Lesions at either locus produce nearly identical clinical syndromes, with the following exception: vestibular stimula­ tion (oculocephalic maneuver or caloric irrigation) will succeed in driving the eyes conjugately to the side in a patient with a lesion of the paramedian pontine reticular formation but not in a patient with a lesion of the abducens nucleus.

INTERNUCLEAR OPHTHALMOPLEGIA  This results from damage to the medial longitudinal fasciculus ascending from the abducens nucleus in the pons to the oculomotor nucleus in the midbrain (hence, “inter­ nuclear”). Damage to fibers carrying the conjugate signal from abducens interneurons to the contralateral medial rectus motoneurons results in a failure of adduction on attempted lateral gaze. For example, a patient with a left internuclear ophthalmoplegia (INO) will have slowed or absent adducting movements of the left eye (Fig. 34-19). A patient with bilateral injury to the medial longitudinal fasciculus will have bilateral INO. Multiple sclerosis is the most common cause, although tumor, stroke, trauma, or any brainstem process may be responsible. One-anda-half syndrome is due to a lesion of the medial longitudinal fasciculus combined with a lesion of either the abducens nucleus or the paramedian pontine reticular formation on the same side. The patient’s only horizon­ tal eye movement is abduction of the eye on the other side. PART 2 Cardinal Manifestations and Presentation of Diseases Vertical Gaze  Midbrain lesions of the rostral interstitial nucleus of the medial longitudinal fasciculus and the interstitial nucleus of Cajal cause supranuclear paresis of upgaze, downgaze, or all vertical eye movements. Distal basilar artery ischemia is the most common etiol­ ogy. Skew deviation refers to a vertical misalignment of the eyes, usually constant in all positions of gaze. The finding has poor localizing value because skew deviation has been reported after lesions in widespread regions of the brainstem and cerebellum. PARINAUD’S SYNDROME  Also known as dorsal midbrain syndrome, this is a distinct supranuclear vertical gaze disorder caused by damage to the posterior commissure. It is a classic sign of hydrocephalus from aqueductal stenosis. Pineal region or midbrain tumors, cysticercosis, and stroke also cause Parinaud’s syndrome. Features include loss of upgaze (and sometimes downgaze), convergence-retraction nystagmus on attempted upgaze, downward ocular deviation (“setting sun” sign), lid retraction (Collier’s sign), skew deviation, pseudoabducens palsy, and light-near dissociation of the pupils. Nystagmus  This is a rhythmic oscillation of the eyes, occurring physiologically from vestibular and optokinetic stimulation or pathologi­ cally in a wide variety of diseases (Chap. 24). Abnormalities of the eyes or optic nerves, present at birth or acquired in childhood, can produce a complex, searching nystagmus with irregular pendular (sinusoidal) and jerk features. Examples are albinism, Leber’s congenital amaurosis, and bilateral cataract. This nystagmus is commonly referred to as congenital sensory nystagmus. This is a poor term because even in children with congenital lesions, the nystagmus does not appear until weeks after birth. Congenital motor nystagmus, which looks similar to congenital sensory nystagmus, develops in the absence of any abnormality of the sensory visual system. Visual acuity usually is also reduced, probably by the nys­ tagmus itself, but seldom below a level of 20/200. JERK NYSTAGMUS  This is characterized by a slow drift off the target, followed by a fast corrective saccade. By convention, the nystagmus is named after the quick phase. Jerk nystagmus can be downbeat, upbeat, horizontal (left or right), and torsional. The pattern of nystagmus may vary with gaze position. Some patients will be oblivious to their nystag­ mus. Others will complain of blurred vision or a subjective to-and-fro movement of the environment (oscillopsia) corresponding to the nys­ tagmus. Fine nystagmus may be difficult to see on gross examination of the eyes. Observation of nystagmoid movements of the optic disc on ophthalmoscopy is a sensitive way to detect subtle nystagmus. GAZE-EVOKED NYSTAGMUS  This is the most common form of jerk nystagmus. When the eyes are held eccentrically in the orbits, they have a natural tendency to drift back to primary position. The subject compensates by making a corrective saccade to maintain the deviated eye position. Many normal patients have mild gaze-evoked nystagmus.

A B C D FIGURE 34-19  Left internuclear ophthalmoplegia (INO). A. In primary position of gaze, the eyes appear normal. B. Horizontal gaze to the left is intact. C. On attempted horizontal gaze to the right, the left eye fails to adduct. In mildly affected patients, the eye may adduct partially or more slowly than normal. Nystagmus is usually present in the abducted eye. D. T2-weighted axial magnetic resonance image through the pons showing a demyelinating plaque in the left medial longitudinal fasciculus (arrow).

26 - 35 Disorders of Smell and Taste

35 Disorders of Smell and Taste

Exaggerated gaze-evoked nystagmus can be induced by drugs (seda­ tives, anticonvulsants, alcohol); muscle paresis; myasthenia gravis; demyelinating disease; and cerebellopontine angle, brainstem, and cerebellar lesions. VESTIBULAR NYSTAGMUS  Vestibular nystagmus results from dysfunc­ tion of the labyrinth (Ménière’s disease, benign paroxysmal positional vertigo), vestibular nerve, or vestibular nucleus in the brainstem. Peripheral vestibular nystagmus often occurs in discrete attacks, with symptoms of nausea and vertigo. There may be associated tinnitus and hearing loss. Sudden shifts in head position may provoke or exacerbate symptoms. DOWNBEAT NYSTAGMUS  Downbeat nystagmus results from lesions near the craniocervical junction (Chiari malformation, basilar invagi­ nation). It also has been reported in brainstem or cerebellar stroke, lith­ ium or anticonvulsant intoxication, alcoholism, and multiple sclerosis. Upbeat nystagmus is associated with damage to the pontine tegmentum from stroke, demyelination, or tumor. Opsoclonus  This rare, dramatic disorder of eye movements con­ sists of bursts of consecutive saccades (saccadomania). When the saccades are confined to the horizontal plane, the term ocular flutter is preferred. It can result from viral encephalitis, trauma, or a paraneo­ plastic effect of neuroblastoma, breast carcinoma, and other malignan­ cies. It has also been reported as a benign, transient phenomenon in otherwise healthy patients. ■ ■FURTHER READING Albert DM et al: Albert and Jakobiec’s Principles and Practice of Ophthalmology, 4th ed. New York, Springer Link, 2022. Apte RS: Age-related macular degeneration. N Engl J Med 385:540, 2021. Chen X et al: Shape perception via a high-channel-count neuroprosthesis in monkey visual cortex. Science 370:1191, 2020. Durand ML et al: Infectious keratitis. JAMA 326:1319, 2021. Heier JS et al: Pegcetacoplan for the treatment of geographic atrophy secondary to age-related macular degeneration (OAKS and DERBY): Two multicentre, randomised, double-masked, sham-controlled, phase 3 trials. Lancet 402:1434, 2023. Jhaveri CD: Aflibercept monotherapy or bevacizumab first for diabetic macular edema. N Engl J Med 387:692, 2022. Sahel JA: Partial recovery of visual function in a blind patient after optogenetic therapy. Nature Med 27:1223, 2021. Toth CA: Optical coherence tomography and eye care. N Engl J Med 389:1526, 2023. Yanoff M, Duker J: Ophthalmology, 6th ed. Singapore, Elsevier, 2023. Richard L. Doty, Steven M. Bromley

Disorders of Smell

and Taste All environmental chemicals necessary for life enter the body by the nose and mouth. The senses of smell (olfaction) and taste (gustation) monitor such chemicals, determine the flavor and palatability of foods and beverages, and warn of dangerous environmental conditions, including fire, air pollution, leaking natural gas, and bacteria-laden foodstuffs. These senses contribute significantly to quality of life and, when dysfunctional, can have untoward physical and psychological consequences. A longitudinal study of 1162 nondemented elderly persons found, even after controlling for confounders, that those with the lowest baseline olfactory test scores had a 45% mortality rate over

a 4-year period, compared to an 18% mortality rate for those with the highest olfactory test scores. A basic understanding of these senses in health and disease is critical for the physician because thousands of patients present to doctors’ offices each year with complaints of chemo­ sensory dysfunction. Among the more important recent developments in neurology is the discovery that decreased smell function is among the first signs of such neurodegenerative diseases as Parkinson’s disease (PD) and Alzheimer’s disease (AD), signifying their “presymptomatic” phase. ■ ■ANATOMY AND PHYSIOLOGY Disorders of Smell and Taste CHAPTER 35 Olfactory System  Odorous chemicals enter the front of nose during inhalation and active sniffing, as well as the back of the nose (nasopharynx) during deglutition. After reaching the highest recesses of the nasal cavity, they dissolve in the olfactory mucus and diffuse or are actively transported by specialized proteins to receptors located on the cilia of olfactory receptor cells. The cilia, dendrites, cell bodies, and proximal axonal segments of these bipolar cells are located within a unique neuroepithelium covering the cribriform plate, the superior nasal septum, superior turbinate, and sectors of the middle turbinate (Fig. 35-1). Nearly 400 types of G-protein-coupled odor receptors (GPCRs) are expressed on the cilia of the receptor cells, with only one type of GPCR being expressed on a given cell. Other receptors, includ­ ing trace amine-associated receptors and members of the non-GPCR membrane-spanning 4-domain family, subfamily A (MS4A) protein family, are also present on some receptor cells. Such a plethora of recep­ tor cell types does not exist in any other sensory system. Importantly, when damaged, the receptor cells can be replaced by stem cells near the basement membrane, although such replacement is often incomplete. After coalescing into bundles surrounded by glia-like ensheathing cells (termed fila), the receptor cell axons pass through the cribriform plate to the olfactory bulbs, where they synapse with dendrites of other cell types within the glomeruli (Fig. 35-2). These spherical structures, which make up a distinct layer of the olfactory bulb, are a site of con­ vergence of information, because many more fibers enter than leave them. Receptor cells that express the same type of receptor project to the same glomeruli, effectively making each glomerulus a functional unit. The major projection neurons of the olfactory system—the mitral and tufted cells—send primary dendrites into the glomeruli, connecting not only with the incoming receptor cell axons, but with dendrites of periglomerular cells. The activity of the mitral/tufted cells is modulated by the periglomerular cells, secondary dendrites from other mitral/tufted cells, and granule cells, the most numerous cells of the bulb. The latter cells, which are largely GABAergic, receive inputs from central brain structures and modulate the output of the mitral/ tufted cells. Interestingly, like the olfactory receptor cells, some cells within the bulb undergo replacement. Thus, neuroblasts formed within the anterior subventricular zone of the brain migrate along the rostral migratory stream, ultimately becoming granule and periglomerular cells. The axons of the mitral and tufted cells synapse within secondary olfactory structures, which largely compose the primary olfactory cortex (POC) (Fig. 35-3). The POC is defined as those cortical struc­ tures that receive direct projections from the olfactory bulb, most nota­ bly the piriform and entorhinal cortices. Although olfaction is unique in that its initial afferent projections bypass the thalamus, persons with damage to the thalamus can exhibit olfactory deficits, particularly ones of odor identification. Such deficits likely reflect the involvement of thalamic connections between the POC and the orbitofrontal cortex (OFC), where odor identification largely occurs. The close anatomic ties between the olfactory system and the amygdala, hippocampus, and hypothalamus help to explain the intimate associations between odor perception and cognitive functions such as memory, motivation, arousal, autonomic activity, digestion, and sex. Taste System  Tastants are sensed by specialized receptor cells present within taste buds—small grapefruit-like segmented structures located on the lateral margins and dorsum of the tongue, roof of the mouth, pharynx, larynx, and superior esophagus (Fig. 35-4). Lin­ gual taste buds are embedded in well-defined protuberances, termed

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 35-1  Anatomy of the nose, showing the distribution of olfactory receptors in the roof of the nasal cavity. (Copyright David Klemm, Faculty and Curriculum Support [FACS], Georgetown University Medical Center.) fungiform, foliate, and circumvallate papillae. After dissolving in a liquid, tastants enter the opening of the taste bud—the taste pore—and bind to receptors on microvilli, small extensions of receptor cells within each taste bud. Such binding changes the electrical potential across the taste cell, resulting in neurotransmitter release onto the first-order taste neurons. Although humans have ~7500 taste buds, not all harbor taste-sensitive cells; some contain only one class of receptor (e.g., cells responsive only to sugars), whereas others contain cells sensitive to more than one class. The number of taste receptor cells per taste bud ranges from zero to well over 100. A small family of three GPCRs, Olfactory bulb Granule cell Mitral/tufted cell Periglomerular cell Glomerulus Cribriform plate Olfactory neurons Olfactory receptor cells Supporting cell Olfactory cilia FIGURE 35-2  Schematic of the layers and wiring of the olfactory bulb. Each receptor type (red, green, blue) projects to a common glomerulus. The neural activity within each glomerulus is modulated by periglomerular cells. The activity of the primary projection cells, the mitral and tufted cells, is modulated by granule cells, periglomerular cells, and secondary dendrites from adjacent mitral and tufted cells. (Adapted from https://medicine.yale.edu/.)

namely T1R1, T1R2, and T1R3, mediate sweet and umami taste sensa­ tions. Bitter sensations, on the other hand, depend on T2R receptors, a family of ~30 GPCRs expressed on cells different from those that express the sweet and umami receptors. T2Rs sense a wide range of bitter substances but do not distinguish among them. Sour tastants are sensed by the PKD2L1 receptor, a member of the transient receptor potential protein (TRP) family. Perception of salty sensations, such as induced by sodium chloride, arises from the entry of Na+ ions into the cells via specialized membrane channels, such as the amiloride-sensitive Na+ channel. It is now well established that both bitter and sweet taste-related receptors are also present elsewhere in the body, most notably in the alimentary and respiratory tracts. This important discovery general­ izes the concept of taste-related chemoreception to areas of the body beyond the mouth and throat, with α-gustducin, the taste-specific G-protein α-subunit, expressed in so-called brush cells found specifi­ cally within the human trachea, lung, pancreas, and gallbladder. These brush cells are rich in nitric oxide (NO) synthase, known to defend against xenobiotic organisms, protect the mucosa from acid-induced Olfactory bulb Olfactory tract Medial olfactory stria Lateral olfactory stria Amygdala Pyriform area Entorhinal area Vagus nerve Spinal cord Cerebellar vermis Cerebellum FIGURE 35-3  Anatomy of the base of the brain showing the primary olfactory cortex.

FIGURE 35-4  Schematic of the taste bud and its opening (pore), as well as the location of buds on the three major types of papillae: fungiform (anterior), foliate (lateral), and circumvallate (posterior). TRC, taste receptor cell. lesions, and, in the case of the gastrointestinal tract, stimulate vagal and splanchnic afferent neurons. NO further acts on nearby cells, including enteroendocrine cells, absorptive or secretory epithelial cells, mucosal blood vessels, and cells of the immune system. Members of the T2R family of bitter receptors and the sweet receptors of the T1R family have been identified within the gastrointestinal tract and in entero­ endocrine cell lines. In some cases, these receptors are important for metabolism, with the T1R3 receptors and gustducin playing decisive roles in the sensing and transport of dietary sugars from the intestinal lumen into absorptive enterocytes via a sodium-dependent glucose transporter and in regulation of hormone release from gut enteroendo­ crine cells. In other cases, these receptors may be important for airway protection, with a number of T2R bitter receptors in the motile cilia of the human airway that respond to bitter compounds by increasing their beat frequency. One specific T2R38 taste receptor is expressed in human upper respiratory epithelia and responds to acyl-monoserine lactone quorum-sensing molecules secreted by Pseudomonas aerugi­ nosa and other gram-negative bacteria. Differences in T2R38 function­ ality, as related to TAS2R38 genotype, correlate with susceptibility to upper respiratory infections in humans. Taste information is sent to the brain via three cranial nerves (CNs): CN VII (the facial nerve, which involves the intermediate nerve with its branches, the greater petrosal and chorda tympani nerves), CN IX (the glossopharyngeal nerve), and CN X (the vagus nerve) (Fig. 35-5). CN VII innervates the anterior tongue and all of the soft palate, CN IX innervates the posterior tongue, and CN X innervates the laryngeal surface of the epiglottis, larynx, and proxi­ mal portion of the esophagus. The mandibular branch of CN V (V3) conveys somatosensory information (e.g., touch, burning, cooling, irritation) to the brain. Although not technically a gustatory nerve, CN V shares primary nerve routes with many of the gustatory nerve fibers and adds temperature, texture, pungency, and spiciness to the taste experience. The chorda tympani nerve is famous for taking a recurrent course through the facial canal in the petrosal portion of the temporal bone, passing through the middle ear, and then exit­ ing the skull via the petrotympanic fissure, where it joins the lingual nerve (a division of CN V) near the tongue. This nerve also carries parasympathetic fibers to the submandibular and sublingual glands, whereas the greater petrosal nerve supplies the palatine glands, thereby influencing saliva production.

Taste pore Taste bud Circumvallate Disorders of Smell and Taste CHAPTER 35 Taste bud TRC Foliate Taste bud Fungiform The axons of the projection cells, which synapse with taste buds, enter the rostral portion of the nucleus of the solitary tract (NTS) within the medulla of the brainstem (Fig. 35-5). From the NTS, neu­ rons then project to a division of the ventroposteromedial thalamic nucleus (VPM) via the medial lemniscus. From here, projections are made to the rostral part of the frontal operculum and adjoining insula, a brain region considered the primary taste cortex (PTC). Pro­ jections from the PTC then go to the secondary taste cortex, namely the caudolateral OFC. This brain region is involved in the conscious recognition of taste qualities. Moreover, because it contains cells that are activated by several sensory modalities, it is likely a center for establishing “flavor.” FIGURE 35-5  Schematic of the cranial nerves (CNs) that mediate taste function, including the chorda tympani nerve (CN VII), the glossopharyngeal nerve (CN IX), and the vagus nerve (CN X). (Copyright David Klemm, Faculty and Curriculum Support [FACS], Georgetown University Medical Center.)

■ ■DISORDERS OF OLFACTION The ability to smell is influenced, in everyday life, by such factors as age, gender, general health, nutrition, smoking, and reproductive state. Women typically outperform men on tests of olfactory function and retain normal smell function to a later age than do men.

Estimates of the prevalence of olfactory dysfunction in the general population vary; a cross-sectional analysis from the National Health and Nutrition Examination Survey (NHANES 2013–2014) found an overall prevalence of 13.5%. However, it is apparent that significant decrements in the ability to smell are present in >50% of the popula­ tion between 65 and 80 years of age and in 75% of those aged ≥80 years (Fig. 35-6). Such presbyosmia helps to explain why many elderly patients report that food has little flavor, a problem that can result in nutritional disturbances. This also helps to explain why a dispropor­ tionate number of elderly people die in accidental gas poisonings. A relatively complete listing of conditions and disorders that have been associated with olfactory dysfunction is presented in Table 35-1. PART 2 Cardinal Manifestations and Presentation of Diseases Aside from aging, the three most common identifiable causes of long-lasting or permanent smell loss seen in the clinic are, in order of frequency, severe upper respiratory infections, head trauma, and chronic rhinosinusitis. The physiologic basis for most head MALE NORMS: PERCENTILE VALUES Age of Examinee 5–9 10–14 15–19 20–24 25–29 30–34 35–39 40–44 45–49 50–54 55–59 60–64 65–69 70–74 75–79 80–84 ≥85

NORMOSMIA NORMOSMIA MILD MICROSMIA MILD MICROSMIA MODERATE MICROSMIA MODERATE MICROSMIA SEVERE MICROSMIA SEVERE MICROSMIA Test Score PROBABLE MALINGERING PROBABLE MALINGERING

N = FIGURE 35-6  Scores on the University of Pennsylvania Smell Identification Test (UPSIT) as a function of subject age and sex. Numbers by each data point indicate sample sizes. Women identify odorants better than men at all ages. (Reproduced with permission from RL Doty. Measurement of chemosensory function. WJOHNS 4:11-28, 2018.)

trauma–related losses is the shearing and subsequent scarring of the olfactory fila as they pass from the nasal cavity into the brain cavity. The cribriform plate does not have to be fractured or show pathology for smell loss to be present. Severity of trauma, as indexed by a poor Glasgow Coma Scale score on presentation and the length of posttrau­ matic amnesia, is associated with higher risk of olfactory impairment. Less than 10% of posttraumatic anosmic patients will recover age-related normal function over time. This increases to nearly 25% of those with less-than-total loss. Respiratory infections, such as those associated with the common cold, influenza, pneumonia, HIV, and COVID-19, can directly and permanently damage the olfactory epithelium, decreas­ ing receptor cell number, damaging cilia on remaining receptor cells, and inducing the replacement of sensory epithelium with respiratory epithelium. The smell loss associated with chronic rhinosinusitis is related to disease severity, with most loss occurring in cases where rhinosinusitis and polyposis are both present. Smell loss is among the first signs of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which is responsible for COVID-19. In most cases, this loss is independent of nasal inflammation. Many of those afflicted are unaware of their deficit until objectively tested. Failure to regain normal olfactory function occurs in up to 30% even a year after ANOSMIA ANOSMIA

TABLE 35-1  Disorders and Conditions Associated with Compromised Olfactory Function, as Measured by Olfactory Testing Endocrine and Metabolic Conditions Adrenal cortical insufficiency (Addison’s disease) Chromatin-negative gonadal dysgenesis (Turner’s syndrome) Cushing’s syndrome Diabetes Hypertension Hypothyroidism Idiopathic hypogonadotropic hypogonadism Kallmann’s syndrome Liver disease Renal disease/kidney failure Pregnancy Pseudohypoparathyroidism Wilson’s disease Nasosinus Disorders Adenoid hypertrophy Bacterial and viral upper respiratory infections Laryngopharyngeal reflux disease Rhinosinusitis/polyposis Neurologic Diseases/Disorders Alzheimer’s disease Amyotrophic lateral sclerosis (ALS) Bell’s palsy Degenerative ataxias Down’s syndrome Epilepsy Facial paralysis Fibromyalgia Frontotemporal lobe degeneration Guamanian ALS/Parkinson’s disease/dementia syndrome Head trauma Huntington’s disease Idiopathic inflammatory myopathies Korsakoff psychosis Lubag disease Migraine Multi-infarct dementia Narcolepsy with cataplexy Neoplasms, cranial/nasal Orthostatic tremor Parkinson’s disease Pick’s disease Rapid eye movement behavioral sleep disorder Stroke Immune-Related Diseases Acute disseminated encephalomyelitis Allergic rhinitis Asthma Autoimmune pancreatitis Behçet’s disease Churg-Strauss syndrome Cystic fibrosis Fibromyalgia Giant cell arteritis Hereditary angioedema Idiopathic inflammatory myopathies Inflammatory bowel diseases Lupus Mikulicz’s disease Multiple sclerosis Myasthenia gravis Neuromyelitis optica Pemphigus vulgaris Psoriasis vulgaris Rheumatoid arthritis Sjögren’s syndrome Systemic sclerosis (scleroderma) Wegener’s granulomatosis Psychiatric-Related Diseases/Disorders Anorexia nervosa Asperger’s syndrome Attention deficit/hyperactivity disorder Depression Obsessive compulsive disorder Panic disorder Posttraumatic stress disorder Psychopathy Schizophrenia Seasonal affective disorder 22q11 deletion syndrome Note: These disease/disorder classifications are not necessarily mutually exclusive. diagnosis, with 5–10% experiencing total loss. Although in rhinosi­ nusitis cases systemic glucocorticoid therapy can usually induce shortterm functional improvement, it does not, on average, return smell test scores to normal, implying that chronic permanent neural loss is present and/or that short-term administration of systemic glucocorticoids does not completely mitigate the inflammation. It is well established that microinflammation in an otherwise seemingly normal epithelium can influence smell function. A number of neurodegenerative diseases are accompanied by olfactory impairment, including PD, AD, Huntington’s disease, parkinsonism-

dementia complex of Guam, dementia with Lewy bodies (DLB), multiple system atrophy, corticobasal degeneration, frontotemporal dementia, and Down’s syndrome; smell loss can also occur in idio­ pathic rapid eye movement (REM) behavioral sleep disorder (iRBD), as well as in multiple sclerosis (MS) related to lesions within olfaction-related structures. Olfactory impairment in PD often predates the clinical diagnosis by a number of years. In staged cases, studies of the sequence of formation of abnormal α-synuclein aggregates and Lewy bodies

Viral, Bacterial, and Fungal Infections Candidiasis COVID-19 Hepatitis C Herpetic meningoencephalitis Human immunodeficiency virus Legionnaires’ disease Leprosy (Hansen’s disease) Lyme disease Poliomyelitis Rhinosinusitis Upper respiratory infections Disorders of Smell and Taste CHAPTER 35 Other Disorders or Factors Alcoholism Bardet-Biedl syndrome Chemical exposure Congenital Iatrogenesis, including chemotherapy and radiation Nutritional deficiencies Obesity Tobacco smoking Toxic chemical exposures Vitamin B12 deficiency suggest that the olfactory bulbs may be, along with the dorsomotor nucleus of the vagus, the first site of neural damage in PD. In postmor­ tem studies of patients with very mild “presymptomatic” signs of AD, poorer smell function has been associated with higher levels of AD-related pathology. Smell loss is more marked in patients with early clinical manifestations of DLB than in those with mild AD. Interestingly, smell loss is minimal or nonexistent in progressive supranuclear palsy and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism. The relative contributions of disease-specific pathology or differential damage to forebrain neuromodulator/neurotransmitter systems in explaining different degrees of olfactory dysfunction among the various neurodegenerative diseases are presently unknown. The smell loss seen in iRBD is of the same magnitude as that found in PD. This is of particular interest because patients with iRBD fre­ quently develop PD and hyposmia. REM behavior disorder is not only seen in its idiopathic form but can also be associated with narcolepsy (Chap. 33). A study of narcoleptic patients with and without REM behavior disorder demonstrated that narcolepsy, independent of REM

behavior disorder, was associated with impairments in olfactory func­ tion. Loss of hypothalamic neurons expressing orexin (also known as hypocretin) neuropeptides is believed to be responsible for narcolepsy and cataplexy. Orexin-containing neurons project throughout the entire olfactory system (from the olfactory epithelium to the olfac­ tory cortex), and damage to these projections may be one underlying mechanism for impaired olfactory performance in narcoleptic patients. Administration of intranasal orexin A (hypocretin-1) improved olfac­ tory function, supporting the notion that mild olfactory impairment is not only a primary feature of narcolepsy with cataplexy, but that orexin deficiency may be directly responsible for the loss of smell in this condition.

PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■DISORDERS OF TASTE The majority of patients who present with taste dysfunction exhibit olfactory, not taste, loss. This is because most flavors attributed to taste actually depend on retronasal stimulation of the olfactory receptors during deglutition. As noted earlier, taste buds only mediate basic tastes such as sweet, sour, bitter, salty, and umami. Significant impair­ ment of whole-mouth gustatory function is rare outside of generalized metabolic disturbances or systemic use of some medications, because taste bud regeneration occurs and peripheral damage alone would require the involvement of multiple CN pathways. Taste function can be influenced by age, diet, smoking behavior, use of medications, and other subject-related factors including (1) the release of foul-tasting materials from the oral cavity from oral medical conditions (e.g., gingivitis, purulent sialadenitis) or appliances; (2) transport problems of tastants to the taste buds (e.g., drying, infections, or inflammatory conditions of the orolingual mucosa), (3) damage to the taste buds themselves (e.g., local trauma, invasive carcinomas), (4) damage to the neural pathways innervating the taste buds (e.g., middle ear infec­ tions), (5) damage to central structures (e.g., multiple sclerosis, tumor, epilepsy, stroke), and (6) systemic disturbances of metabolism (e.g., diabetes, thyroid disease, medications). Unlike CN VII, CN IX is relatively protected along its path, although iatrogenic interventions such as tonsillectomy, bronchoscopy, laryn­ goscopy, endotracheal intubation, and radiation therapy can result in selective injury. CN VII damage commonly results from mastoidec­ tomy, tympanoplasty, and stapedectomy, in some cases inducing per­ sistent metallic sensations. Bell’s palsy (Chap. 452) is one of the most common causes of CN VII injury that results in taste disturbance. On rare occasions, migraine (Chap. 441) is associated with a gustatory prodrome or aura, and in some cases, tastants can trigger a migraine attack. Interestingly, dysgeusia occurs in some cases of burning mouth syndrome (also termed glossodynia or glossalgia), as does dry mouth and thirst. Burning mouth syndrome is likely associated with dysfunc­ tion of the trigeminal nerve (CN V). Some of the etiologies suggested for this poorly understood syndrome are amenable to treatment, including (1) nutritional deficiencies (e.g., iron, folic acid, B vitamins, zinc), (2) diabetes mellitus (possibly predisposing to oral candidiasis), (3) denture allergy, (4) mechanical irritation from dentures or oral devices, (5) repetitive movements of the mouth (e.g., tongue thrust­ ing, teeth grinding, jaw clenching), (6) tongue ischemia as a result of temporal arteritis, (7) periodontal disease, (8) reflux esophagitis, and (9) geographic tongue. Although both taste and smell can be adversely influenced by drugs, taste alterations are more common. Indeed, >250 medications have been reported to alter the ability to taste. Major offenders include antineoplastic agents, antirheumatic drugs, antibiotics, and blood pres­ sure medications. Terbinafine, a commonly used antifungal, has been linked to taste disturbance lasting up to 3 years. In a recent controlled trial, nearly two-thirds of individuals taking eszopiclone (Lunesta) for insomnia experienced a bitter dysgeusia that was stronger in women, systematically related to the time since drug administration, and posi­ tively correlated with both blood and saliva levels of the drug. Intra­ nasal use of nasal gels and sprays containing zinc, which are common over-the-counter prophylactics for upper respiratory viral infections, has been implicated in loss of smell function. Whether their efficacy in preventing such infections, which are the most common cause of

anosmia and hyposmia, outweighs their potential detriment to smell function requires study. Dysgeusia occurs commonly in the context of drugs used to treat or minimize symptoms of cancer, with a weighted prevalence from 56 to 76% depending on the type of cancer treatment. Attempts to prevent taste problems from such drugs using prophylac­ tic zinc sulfate or amifostine have proven to be minimally beneficial. Although antiepileptic medications are occasionally used to treat smell or taste disturbances, the use of topiramate has been reported to result in a reversible loss of an ability to detect and recognize tastes and odors during treatment. As with olfaction, a number of systemic disorders can affect taste. These include, but are not limited to, chronic renal failure, end-stage liver disease, vitamin and mineral deficiencies, diabetes mellitus, and hypothyroidism. In diabetes, there appears to be a progressive loss of taste beginning with glucose and then extending to other sweeteners, salty stimuli, and then all stimuli. Psychiatric conditions can be associ­ ated with chemosensory alterations (e.g., depression, schizophrenia, bulimia). A recent review of tactile, gustatory, and olfactory hallucina­ tions demonstrated that no one type of hallucinatory experience is pathognomonic to any given diagnosis. Pregnancy is a unique condition with regard to taste function. There appears to be an increase in dislike and intensity of bitter tastes during the first trimester that may help to ensure that pregnant women avoid poisons during a critical phase of fetal development. Similarly, a rela­ tive increase in the preference for salt and bitter in the second and third trimesters may support the ingestion of much-needed electrolytes to expand fluid volume and support a varied diet. ■ ■CLINICAL EVALUATION In most cases, a careful clinical history will establish the probable etiol­ ogy of a chemosensory problem, including questions about its nature, onset, duration, and pattern of fluctuations. Sudden loss suggests the possibility of head trauma, ischemia, infection, or a psychiatric condition. Gradual loss can reflect the development of a progressive obstructive lesion, although gradual loss can also follow head trauma. Intermittent loss suggests the likelihood of an inflammatory process. The patient should be asked about potential precipitating events, such as cold or flu infections, prior to symptom onset, because these often go underappreciated. Information regarding head trauma, smoking habits, drug and alcohol abuse (e.g., intranasal cocaine, chronic alco­ holism), exposures to pesticides and other toxic agents, and medical interventions is also informative. A determination of all the medica­ tions that the patient was taking before and at the time of symptom onset is important because many can cause chemosensory distur­ bances. Comorbid medical conditions associated with smell impair­ ment, such as renal failure, liver disease, hypothyroidism, diabetes, or dementia, should be assessed. Delayed puberty in association with anosmia (with or without midline craniofacial abnormalities, deafness, and renal anomalies) suggests the possibility of Kallmann’s syndrome. Recollection of epistaxis, discharge (clear, purulent, or bloody), nasal obstruction, allergies, and somatic symptoms, including headache or irritation, may have localizing value. Questions related to memory, par­ kinsonian symptoms, and seizure activity (e.g., automatisms, blackouts, auras, déjà vu) should be posed. Pending litigation and the possibility of malingering should be considered. Modern forced-choice olfactory tests can detect malingering from improbable responses. Neurologic and otorhinolaryngologic (ORL) examinations, along with appropriate brain and nasosinus imaging, aid in the evaluation of patients with olfactory or gustatory complaints. The neural evaluation should focus on CN function, with particular attention to possible skull base and intracranial lesions. Visual acuity, field, and optic disc exami­ nations aid in detection of intracranial mass lesions that produce raised intracranial pressure (papilledema) and optic atrophy. Foster Kennedy syndrome refers to raised intracranial pressure plus a compressive optic neuropathy; typical causes are olfactory groove meningiomas or other frontal lobe tumors. The ORL examination should thoroughly assess the intranasal architecture and mucosal surfaces. Polyps, masses, and adhesions of the turbinates to the septum may compromise the flow of air to the olfactory receptors, because less than a fifth of the inspired

air traverses the olfactory cleft in the unobstructed state. Blood tests may be helpful to identify such conditions as diabetes, infection, heavy metal exposure, nutritional deficiency (e.g., vitamin B6 or B12), allergy, and thyroid, liver, and kidney disease. As with other sensory disorders, quantitative sensory testing is advised. Self-reports of patients can be misleading, and some patients who complain of chemosensory dysfunction have normal function for their age and gender. Quantitative smell and taste testing provides objective information for worker’s compensation and other legal claims, as well as a way to accurately assess the effects of treatment interven­ tions. A number of standardized olfactory and taste tests are com­ mercially available. The most widely used olfactory test, the 40-item University of Pennsylvania Smell Identification Test (UPSIT), uses norms based on over 10,000 normal subjects. A determination is made of both absolute dysfunction (i.e., mild loss, moderate loss, severe loss, total loss, probable malingering) and relative dysfunction (percentile rank for age and gender). Although electrophysiologic testing is avail­ able at some smell and taste centers (e.g., odor event-related potentials), they require complex stimulus presentation and recording equipment and rarely provide additional diagnostic information. With the excep­ tion of electrogustometers, commercially available taste tests have only recently become available. Most use filter paper strips or similar materi­ als impregnated with tastants, so no stimulus preparation is required. ■ ■TREATMENT AND MANAGEMENT Given the various mechanisms by which olfactory and gustatory distur­ bance can occur, management of patients tends to be condition-specific. For example, patients with hypothyroidism, diabetes, or infections often benefit from specific treatments to correct the underlying disease process that is adversely influencing chemoreception. For most patients who present primarily with obstructive/transport loss affecting the nasal and paranasal regions (e.g., allergic rhinitis, polyposis, intranasal neoplasms, nasal deviations), medical and/or surgical intervention is often beneficial. Antifungal and antibiotic treatments may reverse taste problems secondary to candidiasis or other oral infections. Chlorhexi­ dine mouthwash mitigates some salty or bitter dysgeusias, conceivably as a result of its strong positive charge. Excessive dryness of the oral mucosa is a problem with many medications and conditions, and arti­ ficial saliva (e.g., Xerolube) or oral pilocarpine treatments may prove beneficial. Other methods to improve salivary flow include the use of mints, lozenges, or sugarless gum. Flavor enhancers may make food more palatable (e.g., monosodium glutamate), but caution is advised to avoid overusing ingredients containing sodium or sugar, particularly in circumstances when a patient also has underlying hypertension or diabetes. Medications that induce distortions of taste can often be dis­ continued and replaced with other types of medications or modes of therapy. As mentioned earlier, pharmacologic agents result in taste dis­ turbances much more frequently than smell disturbances. It is impor­ tant to note, however, that many drug-related effects are long lasting and not reversed by short-term drug discontinuance. A study of endoscopic sinus surgery in patients with chronic rhi­ nosinusitis and hyposmia revealed that patients with severe olfactory dysfunction prior to the surgery had a more dramatic and sustained improvement over time compared to patients with more mild olfactory dysfunction prior to intervention. In the case of intranasal and sinus-

related inflammatory conditions, such as seen with allergy, viruses, and traumas, the use of intranasal or systemic glucocorticoids may also be helpful. One common approach is to use a tapering course of oral pred­ nisone. Topical intranasal administration of glucocorticoids was found to be less effective in general than systemic administration; however, the effects of different nasal administration techniques were not analyzed. For example, intranasal glucocorticoids are more effective if adminis­ tered in the Moffett’s position (head in the inverted position such as over the edge of the bed with the bridge of the nose perpendicular to the floor). After head trauma, an initial trial of glucocorticoids may help to reduce local edema and the potential deleterious deposition of scar tissue around olfactory fila at the level of the cribriform plate. Treatments are limited for patients with chemosensory loss or pri­ mary injury to neural pathways. Nonetheless, spontaneous recovery

can occur. In a follow-up study of 542 patients presenting to our center with smell loss from a variety of causes, modest improvement occurred over an average time period of 4 years in about half of the participants. However, only 11% of the anosmic and 23% of the hyposmic patients regained normal age-related function. Interestingly, the amount of dys­ function at the time of presentation, not etiology, was the best predictor of prognosis. Other predictors were age and the duration of dysfunc­ tion prior to initial testing.

Several studies have reported that patients with hyposmia may benefit from repeated smelling of odors over the course of weeks or months, although it remains to be determined how much improve­ ment, if any, occurs over that known to occur spontaneously. The usual paradigm is to smell odors such as eucalyptol, citronella, eugenol, and phenyl ethyl alcohol before going to bed and immediately upon awak­ ening each day. The rationale for such an approach comes from animal studies demonstrating that prolonged exposure to odorants can induce increased neural activity within the olfactory bulb. There is also limited evidence that α-lipoic acid (400 mg/d), an essential cofactor for many enzyme complexes with possible antioxidant effects, may be beneficial in mitigating smell loss following viral infection of the upper respira­ tory tract. However, double-blind studies are needed to confirm this observation. α-Lipoic acid has also been suggested to be useful in some cases of hypogeusia and burning mouth syndrome. Disorders of Smell and Taste CHAPTER 35 The use of zinc and vitamin A in treating olfactory disturbances is controversial, and there does not appear to be much benefit beyond replenishing established deficiencies. However, zinc has been shown to improve taste function secondary to hepatic deficiencies, and retinoids (bioactive vitamin A derivatives) are known to play an essential role in the survival of olfactory neurons. One protocol in which zinc was infused with chemotherapy treatments suggested a possible protective effect against developing taste impairment. Diseases of the alimentary tract can not only influence chemoreceptive function but also occa­ sionally influence vitamin B12 absorption. This can result in a relative deficiency of vitamin B12, theoretically contributing to olfactory nerve disturbance. Vitamin B2 (riboflavin) and magnesium supplements are reported in the alternative literature to aid in the management of migraine that, in turn, may be associated with smell dysfunction. Because vitamin D deficiency is a cofactor of chemotherapy-induced mucocutaneous toxicity and dysgeusia, adding vitamin D3, 1000–2000 units per day, may benefit some patients with smell and taste complaints during or following chemotherapy. A number of medications have reportedly been used with success in ameliorating olfactory symptoms, although strong scientific evidence for efficacy is generally lacking. A report that theophylline improved smell function was uncontrolled and failed to account for the fact that some meaningful improvement occurs without treatment; indeed, the per­ centage of responders was about the same (~50%) as that noted by others to show spontaneous improvement over a similar time period. Anti­ epileptics and some antidepressants (e.g., amitriptyline) have been used to treat dysosmias and smell distortions, particularly following head trauma. Ironically, amitriptyline is also frequently on the list of medica­ tions that can ultimately distort smell and taste function, possibly from its anticholinergic effects. One study suggested that the centrally acting acetylcholinesterase inhibitor donepezil in AD resulted in improve­ ments on smell identification measures that correlated with overall clinician-based impressions of change in dementia severity scores. Alternative therapies, such as acupuncture, meditation, cognitive-

behavioral therapy, and yoga, can help patients manage uncomfortable experiences associated with chemosensory disturbance and oral pain syndromes and to cope with the psychosocial stressors surrounding the impairment. Additionally, modification of diet and eating habits is also important. By accentuating the other sensory experiences of a meal, such as food texture, aroma, temperature, and color, one can optimize the overall eating experience for a patient. In some cases, a flavor enhancer like monosodium glutamate (MSG) can be added to foods to increase palatability and encourage intake. Proper oral and nasal hygiene and routine dental care are extremely important ways for patients to protect themselves from disorders of the mouth and nose that can ultimately result in chemosensory

27 - 36 Disorders of Hearing

36 Disorders of Hearing

disturbance. Patients should be warned not to overcompensate for their taste loss by adding excessive amounts of sugar or salt. Smoking cessation and the discontinuance of oral tobacco use are essential in the management of any patient with smell and/or taste disturbance and should be repeatedly emphasized.

A major and often overlooked element of therapy comes from chemosensory testing itself. Confirmation or lack of conformation of loss is beneficial to patients who come to believe, in light of unsup­ portive family members and medical providers, that they may be “crazy.” In cases where the loss is minor, patients can be informed of the likelihood of a more positive prognosis. Importantly, quantitative testing places the patient’s problem into overall perspective. Thus, it is often therapeutic for an older person to know that, while their smell function is not what it used to be, it still falls above the average of their peer group. Without testing, many such patients are simply told that they are getting old and nothing can be done for them, leading in some cases to depression and decreased self-esteem. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■FURTHER READING Devanand DP et al: Olfactory identification deficits are associated with increased mortality in a multiethnic urban community. Ann Neurol 78:401, 2015. Doty RL: Olfactory dysfunction in COVID-19: Pathology and long-term implications for brain health. Trends Mol Med 28:781, 2022. Doty RL: Olfactory dysfunction in neurodegenerative diseases: Is there a common pathological substrate? Lancet Neurol 16:478, 2017. Doty RL et al: Systemic diseases and disorders. Handbook Clin Neurol 164:361, 2019. Doty RL et al: Taste function in early stage treated and untreated Parkinson’s disease. J Neurol 262:547, 2015. Doty RL et al: Treatments for smell and taste disorders: A critical review. Handbook Clin Neurol 164:455, 2019. Finlay JB et al: Persistent post-COVID-19 smell loss is associated with immune cell infiltration and altered gene expression in olfactory epithelium. Sci Transl Med 21:676, 2022. Fornazieri MA et al: Adherence and efficacy of olfactory training as a treatment for persistent olfactory loss. Am J Rhinol Allergy 34:238, 2020. Hawkes CH, Doty RL: Smell and Taste Disorders. Cambridge, Cambridge University Press, 2018. Liu G et al: Prevalence and risk factors of taste and smell impairment in a nationwide sample of the US population: A cross-sectional study. BMJ Open 6:e013246, 2016. London B et al: Predictors of prognosis in patients with olfactory disturbance. Ann Neurol 63:159, 2008. Moein ST et al: Smell dysfunction: A biomarker for COVID-19. Int Forum Allergy Rhinol 10:944, 2020. Perricone C et al: Smell and autoimmunity: A comprehensive review. Clin Rev Allergy Immunol 45:87, 2013. Anil K. Lalwani

Disorders of Hearing Hearing loss can present at any age and is one of the most common sensory disorders in humans. Nearly 10% of the adult population has some hearing loss, and one-third of individuals age >65 years have a hearing loss of sufficient magnitude to require a hearing aid. PHYSIOLOGY OF HEARING The function of the external and middle ear is to amplify sound to facilitate conversion of the mechanical energy of the sound wave into an electrical signal by the inner-ear hair cells, a process called

mechanotransduction (Fig. 36-1). Sound waves enter the external auditory canal and set the tympanic membrane (eardrum) in motion, which in turn moves the malleus, incus, and stapes of the middle ear. Movement of the footplate of the stapes causes pressure changes in the fluid-filled inner ear, eliciting a traveling wave in the basilar membrane of the cochlea. The tympanic membrane and the ossicular chain in the middle ear serve as an impedance-matching mechanism, improving the efficiency of energy transfer from air to the fluid-filled inner ear. In its absence, nearly 99.9% of the acoustical energy would be reflected and thus not heard. Instead, the eardrum and the ossicles boost the sound energy nearly 200-fold by the time it reaches the inner ear. Within the cochlea of the inner ear, there are two types of hair cells that aid in hearing: inner and outer. The inner and outer hair cells of the organ of Corti have different innervation patterns, but both are mechanoreceptors; they detect the mechanical energy of the acoustic signal and aid its conversion to an electrical signal that travels by the audi­ tory nerve. The afferent innervation relates principally to the inner hair cells while the efferent innervation relates principally to the outer hair cells. The outer hair cells outnumber the inner hair cells by nearly 6:1 (20,000 vs 3500). The motility of the outer hair cells alters the micromechanics of the inner hair cells, creating a cochlear amplifier, which explains the exquisite sensitivity and frequency selectivity of the cochlea. Stereocilia of the hair cells of the organ of Corti, which rests on the basilar membrane, are in contact with the tectorial membrane and are deformed by the traveling wave. The deformation stretches tiny filamentous connections (tip links) between stereocilia, leading to opening of ion channels, influx of potassium, and hair cell depolariza­ tion and subsequent neurotransmission. A point of maximal displace­ ment of the basilar membrane is determined by the frequency of the stimulating tone. High-frequency tones cause maximal displacement of the basilar membrane near the base of the cochlea, whereas for lowfrequency sounds, the point of maximal displacement is toward the apex of the cochlea. Beginning in the cochlea, the frequency specificity is maintained at each point of the central auditory pathway: dorsal and ventral cochlear nuclei, trapezoid body, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate body, and auditory cortex. At low frequencies, individual auditory nerve fibers can respond more or less synchronously with the stimulating tone. At higher frequen­ cies, phase-locking occurs so that neurons alternate in response to particular phases of the cycle of the sound wave. Intensity is encoded by the amount of neural activity in individual neurons, the number of neurons that are active, and the specific neurons that are activated. There is evidence that the right and left ears as well as the central nervous system may process speech asymmetrically. Generally, a sound is processed symmetrically from the peripheral to the central auditory system. However, a “right ear advantage” exists for dichotic listening tasks, in which subjects are asked to report on competing sounds pre­ sented to each ear. In most individuals, a perceptual right ear advantage for consonant-vowel syllables, stop consonants, and words also exists. Similarly, whereas central auditory processing for sounds is symmetric with minimal lateral specialization for the most part, speech process­ ing is lateralized. There is specialization of the left auditory cortex for speech recognition and production, and of the right hemisphere for emotional and tonal aspects of speech. Left hemisphere dominance for speech is found in 95–98% of right-handed persons and 70–80% of left-handed persons. ■ ■DISORDERS OF THE SENSE OF HEARING Hearing loss can result from disorders of the auricle, external auditory canal, middle ear, inner ear, or central auditory pathways. In general, lesions in the auricle, external auditory canal, or middle ear that impede the transmission of sound from the external environment to the inner ear cause conductive hearing loss, whereas lesions that impair mechanotransduction in the inner ear or transmission of the electrical signal along the eighth nerve to the brain cause sensorineural hearing loss (Table 36-1).

External acoustic meatus Middle ear Stapes Semicircular canals Incus Malleus Auricle or pinna Tympanic membrane External acoustic canal Eustachian tube Lobe External ear A
B FIGURE 36-1  Ear anatomy. A. Drawing of modified coronal section through external ear and temporal bone, with structures of the middle and inner ear demonstrated. B. High-resolution view of inner ear. Conductive Hearing Loss  The external ear, the external auditory canal, and the middle-ear apparatus are designed to collect and amplify sound and efficiently transfer the mechanical energy of the sound wave to the fluid-filled cochlea. Factors that obstruct the transmission of sound or dampen the acoustic energy result in conductive hearing loss. Conductive hearing loss can occur from obstruction of the external auditory canal by cerumen, debris, and foreign bodies; swelling of the lining of the canal; atresia or neoplasms of the canal; perforations of the tympanic membrane; disruption of the ossicular chain, as occurs with necrosis of the long process of the incus in trauma or infection; otosclerosis; or fluid, scarring, or neoplasms in the middle ear. Rarely, inner-ear malformations or pathologies that create a “third window” in the inner ear such as superior semicircular canal dehiscence, lateral semicircular canal dysplasia, incomplete partition of the inner ear, and large vestibular aqueduct, are also associated with conductive hearing loss. This pathologic third window is associated with loss of mechani­ cal energy associated with the sound wave leading to conductive hear­ ing loss (see below). Eustachian tube dysfunction is extremely common in adults and may predispose to acute otitis media (AOM) or serous otitis media (SOM). Balloon dilation has been shown to relieve acquired inflam­ matory obstruction of the Eustachian tube orifice and improve symp­ toms due to Eustachian tube dysfunction. Trauma, AOM, and chronic otitis media are the usual factors responsible for tympanic membrane perforation. While small perforations often heal spontaneously, larger defects usually require surgical intervention. Tympanoplasty is highly effective (>90%) in the repair of tympanic membrane perforations. Otoscopy is usually sufficient to diagnose AOM, SOM, chronic otitis media, cerumen impaction, tympanic membrane perforation, and Eustachian tube dysfunction; tympanometry and Eustachian tube function testing can be useful to confirm the clinical suspicion of these conditions. Cholesteatoma, a benign tumor composed of stratified squamous epithelium in the middle ear or mastoid, occurs frequently in adults, often in the setting of severe Eustachian tube dysfunction. This is a slowly growing lesion that destroys bone and normal ear tissue. Theories of pathogenesis include traumatic immigration and invasion of squamous epithelium through a retraction pocket of the tympanic membrane, implantation of squamous epithelia in the middle ear through a perforation or surgery, and metaplasia following chronic infection and irritation. A chronically draining ear that fails to respond to appropriate antibiotic therapy should raise suspicion of a choles­ teatoma. On examination, there is often a perforation of the tympanic membrane filled with cheesy white squamous debris. The presence of an aural polyp obscuring the tympanic membrane is highly suggestive of an underlying cholesteatoma. Conductive hearing loss secondary

Bony labyrinth (contains perilymph) Semicircular canals Anterior Membranous labyrinth (contains endolymph) Posterior Ampulla of semicircular canal Cochlea Inner ear Lateral Vestibulocochlear nerve Utricle Saccule Cochlea Disorders of Hearing CHAPTER 36 Oval window Vestibule Round window Cochlear duct to ossicular erosion is common. Bony destruction visualized on com­ puted tomography (CT) of the temporal bone is also highly suggestive of cholesteatoma. Surgery is required to remove this destructive pro­ cess and reconstruct the ossicles. Conductive hearing loss with a normal ear canal and intact tym­ panic membrane suggests either ossicular pathology or the presence of a “third window” in the inner ear (see below). Fixation of the stapes from otosclerosis is a common cause of low-frequency conductive hearing loss. It occurs equally in men and women and is inherited as an autosomal dominant trait with incomplete penetrance; in some cases, it may be a manifestation of osteogenesis imperfecta. Hearing impairment usually presents between the late teens and the forties. In women, the otosclerotic process is accelerated during pregnancy, and the hearing loss is often first noticeable at this time. A hearing aid or a simple outpatient surgical procedure (stapedectomy) can provide excellent auditory rehabilitation. Extension of otosclerosis beyond the stapes footplate to involve the cochlea (cochlear otosclerosis) can lead to mixed or sensorineural hearing loss. Fluoride therapy to prevent hearing loss from cochlear otosclerosis is of uncertain value. Disorders that lead to the formation of a pathologic “third window” in the inner ear can be associated with conductive hearing loss. There are normally two major openings, or windows, that connect the inner ear with the middle ear and serve as conduits for transmission of sound; these are, respectively, the oval and round windows. A third window is formed where the normally hard otic bone surrounding the inner ear is eroded; dissipation of the acoustic energy at the third window is responsible for the “inner-ear conductive hearing loss.” The superior semicircular canal dehiscence syndrome resulting from ero­ sion of the otic bone over the superior circular canal can present with conductive hearing loss that mimics otosclerosis. A common symptom is vertigo evoked by loud sounds (Tullio phenomenon), by Valsalva maneuvers that change middle-ear pressure, or by applying positive pressure on the tragus (the cartilage anterior to the external opening of the ear canal). Patients with this syndrome also complain of fullness of the ear, pulsatile tinnitus, and being able to hear the movement of their eyes and neck. A large jugular bulb or jugular bulb diverticulum can create a “third window” by eroding into the vestibular aqueduct or posterior semicircular canal; the symptoms are similar to those of the superior semicircular canal dehiscence syndrome. Other inner-ear malformations such as lateral semicircular canal dysplasia, large vestib­ ular aqueduct, or incomplete partition seen in stapes gusher syndrome can also be associated with inner-ear conductive hearing loss as a result of the third window. Low activation threshold on the vestibular-evoked myogenic potential test (VEMP test, see below) and inner-ear erosion on CT are diagnostic. Recalcitrant vertigo and dizziness may respond to surgical repair of the dehiscence.

TABLE 36-1  Common Causes of Conductive, Mixed, and Sensorineural Hearing Loss Conductive Hearing Loss Acute otitis media Cerumen impaction Cholesteatoma Eustachian tube dysfunction Inner ear dehiscence or “third window” Middle ear tumors (facial nerve tumors, glomus tympanicum, glomus jugulare) Ossicular discontinuity PART 2 Cardinal Manifestations and Presentation of Diseases Ossicular fixation Otosclerosis Serous otitis media Temporal bone trauma Tympanic membrane abnormalities Tympanic membrane perforation Mixed Hearing Loss Acute otitis media Cholesteatoma Inner ear dehiscence or “third window” Inner ear malformation Middle ear tumors (facial nerve tumors, glomus tympanicum, glomus jugulare) Otosclerosis Stapes gusher syndrome Temporal bone trauma Sensorineural Hearing Loss CNS infection (meningitis) CNS tumors Cerebellopontine angle tumors (vestibular schwannoma, meningioma) Endolymphatic hydrops (Ménière’s disease) Endolymphatic sac tumor Inner ear malformation Perilymphatic fistula Labyrinthitis Multiple sclerosis Noise-induced hearing loss Presbycusis Radiation therapy Sudden hearing loss Stroke Temporal bone or head trauma Sensorineural Hearing Loss  Sensorineural hearing loss results from either damage to the mechanotransduction apparatus of the cochlea or disruption of the electrical conduction pathway from the inner ear to the brain. Thus, injury to hair cells, supporting cells, audi­ tory neurons, or the central auditory pathway can cause sensorineural hearing loss. Damage to the hair cells of the organ of Corti may be caused by intense noise, viral infections, ototoxic drugs (e.g., salicy­ lates, quinine and its synthetic analogues, aminoglycoside antibiotics, loop diuretics such as furosemide and ethacrynic acid, and cancer chemotherapeutic agents such as cisplatin), fractures of the temporal bone, meningitis, cochlear otosclerosis (see above), Ménière’s disease, and aging. Congenital malformations of the inner ear may be the cause of hearing loss in some adults. Genetic predisposition alone or in con­ cert with environmental exposures may also be responsible (see below). Noise-Induced Hearing Loss  Exposure to loud noise, either a short burst or over a more prolonged period of time, can lead to noise-induced hearing loss. Acute exposure to noise can lead to either temporary or permanent threshold shifts, depending on the intensity and duration of

sound, due to hair cell injury and/or death. Typically, with permanent hearing loss, there is a “noise notch” with elevated hearing thresholds at 3000–4000 Hz. More recently, loud noise exposure has also been asso­ ciated with cochlear synaptopathy or “hidden hearing loss”—hidden, because routine audiometry shows the pure tone hearing to be normal. Patients usually complain of not being able to hear clearly and are more bothered by the presence of background noise. In contrast to hair cell loss, hidden hearing loss is thought to be due to loss of auditory synapses on hair cells following noise exposure. In an increasingly noisy world, avoiding acoustic trauma with earplugs or earmuffs is highly recom­ mended to prevent noise-induced or hidden hearing loss. Presbycusis (age-associated hearing loss) is the most common cause of sensorineural hearing loss in adults. It is estimated to affect over half of adults aged >75 years in the United States, a population that is expected to double in size over the next 40 years. In the early stages, it is characterized by symmetric, gentle to sharply sloping, high-frequency hearing loss (Fig. 36-2). With progression, the hearing loss involves all frequencies. More importantly, the hearing impairment is associated with significant loss in clarity. There is a loss of discrimination for phonemes, recruitment (abnormal growth of loudness), and particular difficulty in understanding speech in noisy environments such as at restaurants and social events. Poor hearing is also associated with an increased incidence of cognitive impairment, rate of cognitive decline, and falls. In the elderly, left untreated, hearing loss leads to dimin­ ished quality of life, and has been shown to increase overall morbidity and mortality through falls and accidents. Hearing aids are helpful in enhancing the signal-to-noise ratio by amplifying sounds that are close to the listener. Hearing aid use has been shown to reduce cogni­ tive decline and risk of falls. Although hearing aids are able to amplify sounds, they cannot restore the clarity of hearing. Thus, amplification with hearing aids may provide only limited rehabilitation once the word recognition score deteriorates below 50%. Cochlear implants are the treatment of choice when hearing aids prove inadequate, even when hearing loss is incomplete (see below). Ménière’s disease is characterized by episodic vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural fullness. An absence of vertigo is inconsistent with the diagnosis of Ménière’s disease, and the presence of fluctuating sensorineural hearing loss, tinnitus, and full­ ness without vertigo is more suggestive of cochlear hydrops. Tinnitus and/or deafness may be absent during the initial attacks of vertigo, but invariably appear as the disease progresses and increases in sever­ ity during acute attacks. The annual incidence of Ménière’s disease is 0.5–7.5 per 1000; onset is most frequently in the fifth decade of life but may also occur in young adults or the elderly. Histologically, there

Right 50 dB 64% Left 55 dB 70% SRT Disc.

dB HL

Frequency (Hz) FIGURE 36-2  Presbycusis or age-related hearing loss. The audiogram shows a moderate to severe downsloping sensorineural hearing loss typical of presbycusis. The loss of high-frequency hearing is associated with a decreased speech discrimination score; consequently, patients complain of lack of clarity of hearing, especially in a noisy background. HL, hearing threshold level; SRT, speech reception threshold.

is distention of the endolymphatic system (endolymphatic hydrops) leading to degeneration of vestibular and cochlear hair cells. This may result from endolymphatic sac dysfunction secondary to infection, trauma, autoimmune disease, inflammatory causes, or tumor; an idio­ pathic etiology constitutes the largest category and is most accurately referred to as Ménière’s disease. Endolymphatic sac tumors, often asso­ ciated with von Hippel Lindau disease, may clinically mimic Ménière’s disease. Although any pattern of hearing loss can be observed, typically, low-frequency, unilateral sensorineural hearing impairment is pres­ ent. An abnormal VEMP test (see below) may be helpful in detecting Ménière’s disease in a clinically unaffected contralateral ear. Magnetic resonance imaging (MRI) should be obtained to exclude retrocochlear pathology such as a cerebellopontine angle tumor, endolymphatic sac tumor, or demyelinating disorder. Therapy is directed toward the con­ trol of vertigo. A 2-g/d low-salt diet is the mainstay of treatment for control of rotatory vertigo. Diuretics, a short course of oral glucocor­ ticoids, intratympanic glucocorticoids, or intratympanic gentamicin may also be useful adjuncts in recalcitrant cases. Surgical therapy of vertigo is reserved for unresponsive cases and includes endolymphatic sac decompression, labyrinthectomy, and vestibular nerve section. Both labyrinthectomy and vestibular nerve section abolish rotatory vertigo in >90% of cases. Unfortunately, there is no effective therapy for hearing loss, tinnitus, or aural fullness from Ménière’s disease. Sensorineural hearing loss may also result from any neoplastic, vas­ cular, demyelinating, infectious, degenerative disease, or trauma affect­ ing the central auditory pathways. Characteristically, in hearing loss due to central nervous system pathology, a reduction in clarity of hearing and speech comprehension is much greater than the loss of the ability to hear pure tone. Auditory testing is consistent with an auditory neu­ ropathy; normal otoacoustic emissions (OAEs) and an abnormal audi­ tory brainstem response (ABR) are typical (see below). Hearing loss can accompany hereditary sensorimotor neuropathies and inherited disor­ ders of myelin. Tumors of the cerebellopontine angle such as vestibular schwannoma and meningioma (Chap. 95) usually present with asym­ metric sensorineural hearing loss with greater deterioration of speech understanding than pure tone hearing. Multiple sclerosis (Chap. 455) may present with acute unilateral or bilateral hearing loss; typically, pure tone testing remains relatively stable while speech understanding fluctu­ ates. Isolated labyrinthine infarction can present with acute hearing loss and vertigo due to a cerebrovascular accident involving the posterior circulation, usually the anterior inferior cerebellar artery; it may also be the heralding sign of impending catastrophic basilar artery infarction (Chap. 437). HIV (Chap. 208), which can produce both peripheral and central auditory system pathology, is another consideration in the evaluation of sensorineural hearing impairment. A finding of conductive and sensorineural hearing loss in combi­ nation is termed mixed hearing loss. Mixed hearing losses can result from pathology of both the middle and inner ear, as can occur in oto­ sclerosis involving the ossicles and the cochlea, head trauma, chronic otitis media, cholesteatoma, middle-ear tumors, and some inner-ear malformations. Trauma resulting in temporal bone fractures may be associated with conductive, sensorineural, or mixed hearing loss. If the fracture spares the inner ear, there may simply be conductive hearing loss due to rup­ ture of the tympanic membrane or disruption of the ossicular chain. These abnormalities can be surgically corrected. Profound hearing loss and severe vertigo are associated with temporal bone fractures involv­ ing the inner ear. A perilymphatic fistula associated with leakage of inner-ear fluid into the middle ear can occur and may require surgical repair. An associated facial nerve injury is not uncommon. Computed tomography (CT) is best suited to assess fracture of the traumatized temporal bone, evaluate the ear canal, and determine the integrity of the ossicular chain and involvement of the inner ear. Cerebrospinal fluid leaks that accompany temporal bone fractures are usually selflimited; the value of prophylactic antibiotics is uncertain. Central Auditory Processing Disorders (CAPD)  Follow­ ing the reception of sound by the inner ear hair cells, the generated electrical signal from mechanotransduction is carried by the central

auditory pathway—beginning with the auditory nerve to dorsal and ventral cochlear nuclei, trapezoid body, superior olivary complex, lateral lemniscus, inferior colliculus, medial geniculate body, and the auditory cortex—to refine, analyze, modify, organize, and interpret peripheral auditory input via central processing to facilitate speech comprehension, binaural processing, and interpret temporal cues. Loss of auditory nerve synapses due to loud noise exposure, tumors of the auditory/vestibular nerve, central nervous system (CNS) demyelinat­ ing disorders, diseases of the brainstem, cerebral stroke, and aging can all be associated with CAPDs. CAPDs can result in poor sound local­ ization, lateralization, and speech comprehension, and deterioration of auditory performance in background noise. Poor understanding of speech in background noise is a common complaint in the elderly; this may be due to peripheral hearing loss as well as deterioration of cen­ tral auditory processing. CAPD is best treated by enhancing the signal to noise ratio through amplifying sounds of interest while reducing/ minimizing background noise; other intervention may include audi­ tory training and strengthening compensatory strategies to minimize the impact of CAPD.

Disorders of Hearing CHAPTER 36 Tinnitus  Tinnitus is defined as the perception of a sound when there is no sound in the environment. It can have a buzzing, roaring, or ringing quality and may be pulsatile (synchronous with the heartbeat). Tinnitus is often associated with either a conductive or sensorineural hearing loss. The pathophysiology of tinnitus is not well understood. The cause of the tinnitus can usually be determined by finding the cause of the associated hearing loss. Tinnitus may be the first symptom of a serious condition such as a vestibular schwannoma. Pulsatile tin­ nitus requires evaluation of the vascular system of the head to exclude vascular tumors such as glomus jugulare tumors, aneurysms, dural arteriovenous fistulas, and stenotic arterial lesions; it may also occur with SOM, superior semicircular dehiscence, and inner-ear dehis­ cence. It is most commonly associated with some abnormality of the jugular bulb such as a large jugular bulb or jugular bulb diverticulum. In absence of demonstrated pathology on magnetic resonance angiog­ raphy (MRA)/magnetic resonance venography (MRV) or CT angiog­ raphy, pulsatile tinnitus is usually attributed to turbulent venous blood flow through the transverse sinus, sigmoid sinus, and the jugular bulb. ■ ■GENETIC CAUSES OF HEARING LOSS More than half of childhood hearing impairment is thought to be hereditary; hereditary hearing impairment (HHI) can also mani­ fest later in life. HHI may be classified as either nonsyndromic, when hearing loss is the only clinical abnormality, or syndromic, when hearing loss is associated with anomalies in other organ systems. Nearly two-thirds of HHIs are nonsyndromic. Between 70 and 80% of nonsyndromic HHI is inherited in an autosomal recessive manner and designated DFNB; another 15–20% is autosomal dominant (DFNA). Less than 5% is X-linked (DFNX) or maternally inherited via the mitochondria. More than 150 loci harboring genes for nonsyndromic HHI have been mapped, with recessive loci outnumbering dominant ones; numerous genes have now been identified (eTable 36-1: available at accessmedicine.com/harrisons). The hearing genes fall into the categories of structural proteins (MYH9, MYO7A, MYO15, TECTA, DIAPH1), transcription factors (POU3F4, POU4F3), ion channels (KCNQ4, SLC26A4), and gap junction proteins (GJB2, GJB3, GJB6). Several of these genes, including GJB2, TECTA, and TMC1, cause both autosomal dominant and recessive forms of nonsyndromic HHI. In general, the hearing loss associated with dominant genes has its onset in adolescence or adulthood, varies in severity, and progresses with age, whereas the hearing loss associated with recessive inheritance is congenital and profound. Connexin 26, a product of the GJB2 gene, is particularly important because it is responsible for nearly 20% of all cases of childhood deafness; half of genetic deafness in children is GJB2 related. Two frameshift mutations, 35delG and 167delT, account for

50% of the cases; however, screening for these two mutations alone is insufficient, and sequencing of the entire gene is required to fully cap­ ture GJB2-related recessive deafness. The 167delT mutation is highly

prevalent in Ashkenazi Jews; ~1 in 1765 individuals in this population is homozygous and affected. GJB2 hearing loss can also vary among the members of the same family, suggesting that other genes or factors influence the auditory phenotype. A single mutation in GJB2 in com­ bination with a single mutation in GJB6 (connexin 30) can also lead to hearing loss and is an example of digenic inheritance of hearing loss.

In addition to GJB2, several other nonsyndromic genes are associated with hearing loss that progresses with age. The contribution of genetics to presbycusis is also becoming better understood and likely reflects a combination of genetic susceptibility impacted by environmental expo­ sure to sound. Sensitivity to aminoglycoside ototoxicity can be mater­ nally transmitted through a mitochondrial mutation. Susceptibility to noise-induced hearing loss may also be genetically determined. PART 2 Cardinal Manifestations and Presentation of Diseases There are >400 syndromic forms of hearing loss. These include Usher’s syndrome (retinitis pigmentosa and hearing loss), Waardenburg’s syn­ drome (pigmentary abnormality and hearing loss), Pendred’s syndrome (thyroid organification defect and hearing loss), Alport’s syndrome (renal disease and hearing loss), Jervell and Lange-Nielsen syndrome (pro­ longed QT interval and hearing loss), neurofibromatosis type 2 (bilateral vestibular schwannoma), and mitochondrial disorders (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes [MELAS]; myo­ clonic epilepsy and ragged red fibers [MERRF]; and progressive exter­ nal ophthalmoplegia [PEO]) (eTable 36-2: available at accessmedicine. com/harrisons). APPROACH TO THE PATIENT Disorders of the Sense of Hearing The goal in the evaluation of a patient with auditory complaints is to determine (1) the nature of the hearing impairment (conductive vs sensorineural vs mixed), (2) the severity of the impairment (mild, moderate, severe, or profound), (3) the anatomy of the impairment (external ear, middle ear, inner ear, or central auditory pathway), and (4) the etiology. The presence of signs and symptoms associ­ ated with hearing loss should be ascertained (Table 36-2). The history should elicit characteristics of the hearing loss, including the duration of deafness, unilateral versus bilateral involvement, nature of onset (sudden vs insidious), and rate of progression (rapid vs slow). Symptoms of tinnitus, vertigo, imbalance, aural fullness, otorrhea, headache, facial nerve dysfunction, and head and neck paresthesias should be noted. Information regarding head trauma, exposure to ototoxins, occupational or recreational noise exposure, and family history of hearing impairment may also be important. A sudden onset of unilateral hearing loss, with or without tin­ nitus, may represent a viral infection of the inner ear, vestibular schwannoma, or a stroke. Patients with unilateral hearing loss (sensory or conductive) usually complain of reduced hearing, poor sound localization, and difficulty hearing clearly in the presence of background noise. Gradual progression of a hearing deficit is common with otosclerosis, noise-induced hearing loss, vestibular schwannoma, or Ménière’s disease. Small vestibular schwannomas typically present with asymmetric hearing impairment, tinnitus, and imbalance (rarely vertigo); cranial neuropathy, in particular of the trigeminal or facial nerve, may accompany larger tumors. TABLE 36-2  Signs and Symptoms Suggestive of Hearing Loss Saying “huh” a great deal Reduced clarity of hearing Difficulty understanding conversations in background noise Family complaining of hearing loss Tinnitus Turning the volume up on radio or television Sensitivity to noises Fullness in the ear Avoiding social settings

In addition to hearing loss, Ménière’s disease may be associated with episodic vertigo, tinnitus, and aural fullness. Sound-induced vertigo, autophony, and being able to hear one’s own neck or eye movement are highly suggestive of superior semicircular canal dehiscence. Hearing loss with otorrhea is most likely due to chronic otitis media or cholesteatoma. Examination should include the auricle, external ear canal, and tympanic membrane. In the elderly, the external ear canal is often dry and fragile; it is preferable to clean cerumen with wall-mounted suction or cerumen loops and to avoid irrigation. Irrigation should also be avoided when a tympanic membrane perforation is present or the integrity of the eardrum cannot be established. In examin­ ing the eardrum, the topography of the tympanic membrane is more important than the presence or absence of the light reflex. In addition to the pars tensa (the lower two-thirds of the tympanic membrane), the pars flaccida (upper one-third of the tympanic membrane) above the short process of the malleus should also be examined for retraction pockets that may be evidence of chronic Eustachian tube dysfunction or cholesteatoma. Insufflation of the ear canal is necessary to assess tympanic membrane mobility and compliance. Careful inspection of the nose, nasopharynx, and upper respiratory tract is important. Unilateral serous effusion or unexplained otalgia should prompt a fiberoptic examination of the nasopharynx and larynx to exclude neoplasms. Cranial nerves should be evaluated with special attention to facial and trigeminal nerves, which are commonly affected with tumors involving the cerebellopontine angle. The Rinne and Weber tuning fork tests, with a 512-Hz tuning fork, are used to screen for hearing loss, differentiate conductive from sensorineural hearing losses, and confirm the findings of audiologic evaluation. The Rinne test compares the ability to hear by air conduction with the ability to hear by bone conduction. The tines of a vibrating tuning fork are held near the opening of the external auditory canal, and then the stem is placed on the mastoid process; for direct contact, it may be placed on teeth or dentures. The patient is asked to indicate whether the tone is louder by air conduction or bone conduction. Normally, and in the presence of sensorineural hearing loss, a tone is heard louder by air conduction than by bone conduction; however, with conductive hearing loss of ≥30 dB (see “Audiologic Assessment,” below), the bone-conduction stimulus is perceived as louder than the air-conduction stimulus. For the Weber test, the stem of a vibrating tuning fork is placed on the head in the midline and the patient is asked whether the tone is heard in both ears or better in one ear than in the other. With a unilateral conductive hearing loss, the tone is perceived in the affected ear. With a unilateral sensorineural hearing loss, the tone is perceived in the unaffected ear. A 5-dB difference in hearing between the two ears is required for lateralization. ■ ■LABORATORY ASSESSMENT OF HEARING Audiologic Assessment  The minimum audiologic assessment for hearing loss should include the measurement of pure tone air-con­ duction and bone-conduction thresholds, speech reception threshold, word recognition score, tympanometry, acoustic reflexes, and acousticreflex decay. This test battery provides a screening evaluation of the entire auditory system and allows one to determine whether further differentiation of a sensory (cochlear) from a neural (retrocochlear) hearing loss is indicated. Pure tone audiometry assesses hearing acuity for pure tones. The test is administered by an audiologist and is performed in a sound-attenu­ ated chamber. The pure tone stimulus is delivered with an audiometer, an electronic device that allows the presentation of specific frequencies (generally between 250 and 8000 Hz) at specific intensities. Air- and bone-conduction thresholds are established for each ear. Air-conduction thresholds are determined by presenting the stimulus in air with the use of headphones. Bone-conduction thresholds are determined by placing the stem of a vibrating tuning fork or an oscillator of an audiometer in

contact with the head. In the presence of a hearing loss, broad-spectrum noise is presented to the nontest ear for masking purposes so that responses are based on perception from the ear under test. The responses are measured in decibels (dBs). An audiogram is a plot of intensity in dBs of hearing threshold versus frequency. A dB is equal to 20 times the logarithm of the ratio of the sound pressure required to achieve threshold in the patient to the sound pressure required to achieve threshold in a normal-hearing person. Therefore, a change of 6 dB represents doubling of sound pressure, and a change of 20 dB represents a tenfold change in sound pressure. Loudness, which depends on the frequency, intensity, and duration of a sound, doubles with approximately each 10-dB increase in sound pressure level. Pitch, on the other hand, does not directly correlate with frequency. The perception of pitch changes slowly in the low and high frequencies. In the middle tones, which are important for human speech, pitch varies more rapidly with changes in frequency. Pure tone audiometry establishes the presence and severity of hear­ ing impairment, unilateral versus bilateral involvement, and the type of hearing loss. Conductive hearing losses with a large mass component, as is often seen in middle-ear effusions, produce elevation of thresholds that predominate in the higher frequencies. Conductive hearing losses with a large stiffness component, as in fixation of the footplate of the stapes in early otosclerosis, produce threshold elevations in the lower frequencies. Often, the conductive hearing loss involves all frequencies, suggesting involvement of both stiffness and mass. In general, senso­ rineural hearing losses such as presbycusis affect higher frequencies more than lower frequencies (Fig. 36-3). An exception is Ménière’s disease, which is characteristically associated with low-frequency sen­ sorineural hearing loss (though any frequency can be affected). Noiseinduced hearing loss has an unusual pattern of hearing impairment in which the loss at 3000–4000 Hz is greater than at higher frequencies. Vestibular schwannomas characteristically affect the higher frequen­ cies, but any pattern of hearing loss can be observed. Speech recognition requires greater synchronous neural firing than is necessary for appreciation of pure tones. Speech audiometry tests the clarity with which one hears. The speech reception threshold (SRT) is defined as the intensity at which speech is recognized as a meaningful symbol and is obtained by presenting two-syllable words with an equal accent on each syllable. The intensity at which the patient can repeat 50% of the words correctly is the SRT. Once the SRT is determined, discrimination or word recognition ability is tested by presenting FIGURE 36-3  Stapedectomy. The fixation of stapes in otosclerosis can be addressed by placing a piston prosthesis from the incus to a small fenestration in the stapes footplate. This operation is successful in addressing the conductive hearing loss associated with otosclerosis. (Reproduced with permission from Julia Lerner.)

one-syllable words at 25–40 dB above the SRT. The words are phoneti­ cally balanced in that the phonemes (speech sounds) occur in the list of words at the same frequency that they occur in ordinary conversational English. An individual with normal hearing or conductive hearing loss can repeat 88–100% of the phonetically balanced words correctly. Patients with a sensorineural hearing loss have variable loss of dis­ crimination. As a general rule, neural lesions produce greater deficits in discrimination than do cochlear lesions. For example, in a patient with mild asymmetric sensorineural hearing loss, a clue to the diagno­ sis of vestibular schwannoma is the presence of greater than expected deterioration in discrimination ability. Deterioration in discrimination ability when words are presented at higher intensities above the SRT (“rollover phenonmena”) also suggests a lesion in the eighth nerve or central auditory pathways.

Disorders of Hearing CHAPTER 36 Tympanometry measures the impedance of the middle ear to sound and is useful in diagnosis of middle-ear effusions. A tympanogram is the graphic representation of change in impedance or compliance as the pressure in the ear canal is changed. Normally, the middle ear is most compliant at atmospheric pressure, and the compliance decreases as the pressure is increased or decreased (type A); this pattern is seen with normal hearing or in the presence of sensorineural hearing loss. Compliance that does not change with change in pressure suggests middle-ear effusion (type B). With a negative pressure in the middle ear, as with Eustachian tube obstruction, the point of maximal compli­ ance occurs with negative pressure in the ear canal (type C). A tympa­ nogram in which no point of maximal compliance can be obtained is most commonly seen with discontinuity of the ossicular chain (type Ad). A reduction in the maximal compliance peak can be seen in oto­ sclerosis (type As). During tympanometry, an intense tone elicits contraction of the stapedius muscle, also known as the acoustic reflex. The change in com­ pliance of the middle ear with contraction of the stapedius muscle can be detected. The presence or absence of the acoustic reflex is important in determining the etiology of hearing loss as well as in the anatomic localization of facial nerve paralysis. The acoustic reflex can help dif­ ferentiate between conductive hearing loss due to otosclerosis and that caused by an inner-ear “third window”: it is absent in otosclerosis and present in inner-ear conductive hearing loss. Normal or elevated acoustic reflex thresholds in an individual with sensorineural hearing impairment suggest a cochlear hearing loss. An absent acoustic reflex in the setting of sensorineural hearing loss is not helpful in localizing the site of lesion. Assessment of acoustic reflex decay helps differentiate sensory from neural hearing losses. In neural hearing loss, such as with vestibular schwannoma, the reflex adapts or decays with time. OAEs generated by outer hair cells only can be measured with microphones inserted into the external auditory canal. The emissions may be spontaneous or evoked with sound stimulation. The presence of OAEs indicates that the outer hair cells of the organ of Corti are intact and can be used to assess auditory thresholds and to distinguish sensory from neural hearing losses. Evoked Responses  Electrocochleography measures the earliest evoked potentials generated in the cochlea and the auditory nerve. Receptor potentials recorded include the cochlear microphonic, gener­ ated by the outer hair cells of the organ of Corti, and the summating potential, generated by the inner hair cells in response to sound. The whole nerve action potential representing the composite firing of the first-order neurons can also be recorded during electrocochleogra­ phy. Clinically, the test is useful in the diagnosis of Ménière’s disease, in which an elevation of the ratio of summating potential to action potential is seen. Brainstem auditory-evoked responses (BAERs), also known as ABRs, are useful in differentiating the site of sensorineural hearing loss. In response to sound, five distinct electrical potentials arising from differ­ ent stations along the peripheral and central auditory pathway (eighth nerve, cochlear nucleus, superior olivary complex, lateral lemniscus, and inferior colliculus) can be identified using computer averaging from scalp surface electrodes. BAERs are valuable in situations in which patients cannot or will not give reliable voluntary thresholds.

They are also used to assess the integrity of the auditory nerve and brainstem in various clinical situations, including diagnosis of retro­ cochlear pathology such as vestibular schwannoma, intraoperative monitoring of hearing, and determination of brain death.

The VEMP test investigates otolith and vestibular nerve function by presenting a high-level acoustic stimulus and evoking a short-latency electromyographic potential; cVEMP (or cervical VEMP) and oVEMP (or ocular VEMP) have been described. The cVEMP elicits a vestibulo­ collic reflex whose afferent limb arises from acoustically sensitive cells in the saccule, with signals conducted via the inferior vestibular nerve. cVEMP is a biphasic, short-latency response recorded from the toni­ cally contracted sternocleidomastoid muscle in response to loud audi­ tory clicks or tones. cVEMPs may be diminished or absent in patients with early and late Ménière’s disease, vestibular neuritis, benign paroxysmal positional vertigo, and vestibular schwannoma. On the other hand, the threshold for VEMPs may be lower in cases of superior canal dehiscence, other inner-ear dehiscence (“third window”), and perilymphatic fistula. The oVEMP, in contrast, is a response involving the utricle primarily and superior vestibular nerve. The oVEMP excit­ atory response is recorded from the extraocular muscle. The oVEMP is abnormal in superior vestibular neuritis. PART 2 Cardinal Manifestations and Presentation of Diseases Imaging Studies  The choice of radiologic tests is largely deter­ mined by whether the goal is to evaluate the bony anatomy of the exter­ nal, middle, and inner ear or to image the auditory nerve and brain. Axial and coronal CT of the temporal bone with fine 0.3-mm cuts is ideal for determining the caliber of the external auditory canal, integ­ rity of the ossicular chain, and presence of middle-ear or mastoid dis­ ease; it can also detect inner-ear malformations. CT is also ideal for the detection of bone erosion with chronic otitis media and cholesteatoma. Pöschl reformatting in the plane of the superior semicircular canal is required for the identification of dehiscence or absence of bone over the superior semicircular canal. MRI is superior to CT for imaging of retrocochlear pathology such as vestibular schwannoma, meningioma, other lesions of the cerebellopontine angle, demyelinating lesions of the brainstem, and brain tumors. Both CT and MRI are equally capable of identifying inner-ear malformations and assessing cochlear patency for preoperative evaluation of patients for cochlear implantation. TREATMENT Disorders of the Sense of Hearing In general, conductive hearing losses are amenable to surgical correction, whereas sensorineural hearing losses are usually man­ aged medically. Atresia of the ear canal can be surgically repaired, often with significant improvement in hearing. Alternatively, the conductive hearing loss associated with atresia can be addressed with a bone-anchored hearing aid (BAHA). Tympanic membrane perforations due to chronic otitis media or trauma can be repaired with an outpatient tympanoplasty. Likewise, conductive hearing loss associated with otosclerosis can be treated by stapedectomy, which is successful in >95% of cases (Fig. 36-3). Tympanostomy tubes allow the prompt return of normal hearing in individuals with middle-ear effusions. Hearing aids are effective and well tolerated in patients with conductive hearing losses. Patients with mild, moderate, and severe sensorineural hear­ ing losses are regularly rehabilitated with hearing aids of varying configuration and strength. Hearing aids have been improved to provide greater fidelity and have been miniaturized. The current generation of hearing aids is nearly invisible, thus reducing stigma associated with their use. In general, the more severe the hear­ ing impairment, the larger the hearing aid required for auditory rehabilitation. Digital hearing aids lend themselves to individual programming, and multiple and directional microphones at the ear level may be helpful in noisy surroundings. Because all hearing aids amplify noise as well as speech, the only absolute solution to the problem of noise is to place the microphone closer to the speaker than the noise source. This arrangement is not possible with a

self-contained, cosmetically acceptable device. A significant limita­ tion of rehabilitation with a hearing aid is that although it is able to enhance detection of sound with amplification, it cannot restore clarity of hearing that is lost with presbycusis. The cost of a single hearing aid is a significant obstacle for many hearing-impaired individuals, and usually bilateral amplification is recommended. To reduce cost and spur innovation, a new category of over-the-counter amplification devices that can be purchased similar to reading eyeglasses by simply walking into a store has been approved by the U.S. Food and Drug Administration. By reducing the cost of amplification devices to consumers, promoting innova­ tion, and increasing competition, this new class of devices is making hearing rehabilitation more accessible. Patients with unilateral deafness have difficulty with sound local­ ization and reduced clarity of hearing in background noise. They may benefit from a contralateral routing of signal (CROS) hearing aid in which a microphone is placed on the hearing-impaired side, and the sound is transmitted to the receiver placed on the con­ tralateral ear. The same result may be obtained with a BAHA, in which a hearing aid clamps to a screw integrated into the skull on the hearing-impaired side. Like the CROS hearing aid, the BAHA transfers the acoustic signal to the contralateral hearing ear, but it does so by vibrating the skull. Patients with profound deafness on one side and some hearing loss in the better ear are candidates for a BICROS hearing aid; it differs from the CROS hearing aid in that the patient wears a hearing aid, and not simply a receiver, in the better ear. Unfortunately, while CROS and BAHA devices provide benefit, they do not restore hearing in the deaf ear. Only cochlear implants can restore hearing (see below). Increasingly, cochlear implants are being used for the treatment of patients with singlesided deafness; in this setting, the cochlear implant restores hearing, reduces tinnitus, improves sound localization and performance in background noise, and reduces fatigue. In many situations, including lectures and the theater, hearingimpaired persons benefit from assistive devices that are based on the principle of having the speaker closer to the microphone than any source of noise. Assistive devices include infrared and fre­ quency-modulated (FM) transmission as well as an electromagnetic loop around the room for transmission to the individual’s hearing aid. Hearing aids with telecoils can also be used with properly equipped telephones in the same way. Bluetooth technology has revolutionized connectivity between hearing aids and other devices such as smart phones. In the event that the hearing aid provides inadequate reha­ bilitation, cochlear implants may be appropriate (Fig. 36-4). Cri­ teria for implantation include severe to profound hearing loss with open-set sentence cognition of ≤40% under best-aided conditions. Worldwide, >600,000 hearing-impaired individuals have received cochlear implants. Cochlear implants are neural prostheses that convert sound energy to electrical energy and can be used to stimulate the auditory division of the eighth nerve directly. In most cases of profound hearing impairment, the auditory hair cells are lost but the ganglionic cells of the auditory division of the eighth nerve are preserved. Cochlear implants consist of electrodes that are inserted into the cochlea through the round window, speech processors that extract acoustic elements of speech for conversion to electrical currents, and a means of transmitting the electrical energy through the skin. Patients with implants experience sound that helps with speech reading, allows open-set word recognition, and helps in modulating the person’s own voice. Usually, within the first 3–6 months after implantation, adult patients can under­ stand speech without visual cues. With the current generation of multichannel cochlear implants, nearly 75% of patients are able to converse on the telephone. Bilateral cochlear implantations are commonly performed, especially in children; these patients per­ form better in background noise, have better sound localization, and are less fatigued by the “work” compared to monaural hearing. Hybrid cochlear implants are indicated for the treatment of high-frequency hearing loss in patients who do not have profound

Headpiece microphone Magnetic headpiece Back microphone Implant Sound processor Front microphone Electrode array inside cochlea T-MicTM2 microphone FIGURE 36-4  A cochlear implant is composed of an external microphone and speech processor worn on the ear and a receiver implanted underneath the temporalis muscle. The internal receiver is attached to an electrode that is placed surgically in the cochlea. hearing loss and yet do not benefit from hearing aids. Patients with presbycusis typically have normal low-frequency hearing while suffering from high-frequency hearing loss associated with loss of clarity that cannot always be adequately rehabilitated with a hear­ ing aid. However, these patients are not candidates for conventional cochlear implants because they have too much residual hearing. The hybrid implant has been specifically designed for this patient population; it has a shorter electrode than a conventional cochlear implant and can be introduced into the cochlea atraumatically, thus preserving low-frequency hearing. Individuals with a hybrid implant use their own natural low-frequency “acoustic” hearing and rely on the implant for providing “electrical” high-frequency hearing. Patients who have received the hybrid implant perform better on speech discrimination tests in both quiet and noisy backgrounds. For individuals who were born without cochlea or have had both eighth nerves destroyed by trauma or bilateral vestibular schwanno­ mas (e.g., neurofibromatosis type 2), brainstem auditory implants placed near the cochlear nucleus may provide auditory rehabilita­ tion. Currently, brainstem implants provide sound awareness, but unfortunately, speech understanding remains elusive. Understanding of the genetic basis of hearing loss, the molecular signals for hair cell regeneration, and the pathways involved in envi­ ronmental and pharmaceutical ototoxicity has opened opportuni­ ties for molecular therapies. Molecular therapies, including gene therapy, stem cell therapy, RNA-based therapies, and CRISPR/Cas9 gene editing, hold promise for prevention and treatment of genetic and nongenetic causes of hearing loss. In one exciting recent devel­ opment, adeno-associated virus–mediated delivery of otoferlin pro­ tein restored hearing in congenitally deaf children. Thus, hearing loss may be treated with gene replacement, gene suppression, and genome editing technology, to protect, preserve, or regenerate deli­ cate inner ear structures.

Tinnitus often accompanies hearing loss. Similar to background noise, tinnitus can degrade speech comprehension in individuals with hearing impairment. Patients with tinnitus should be advised to minimize caffeine ingestion, avoid high dosages of nonsteroidal anti-inflammatory drugs (NSAIDs), and reduce stress. Therapy for tinnitus is usually directed toward minimizing the appreciation of tinnitus. Relief of the tinnitus may be obtained by masking it with background music or white noise. Hearing aids are also helpful in tinnitus suppression, as are tinnitus maskers, devices that present a sound to the affected ear that is more pleasant to listen to than the tinnitus. The use of a tinnitus masker is often followed by several hours of inhibition of the tinnitus. Antidepressants have also been shown to be beneficial in helping patients cope with tinnitus.

Disorders of Hearing CHAPTER 36 Hard-of-hearing individuals often benefit from a reduction in unnecessary noise in the environment (e.g., radio or television) to enhance the signal-to-noise ratio. Speech comprehension is aided by lip reading; therefore, the impaired listener should be seated so that the face of the speaker is well illuminated and easily seen. Although speech should be in a loud, clear voice, one should be aware that in sensorineural hearing losses in general and in hard-ofhearing elderly in particular, recruitment (abnormal perception of loud sounds) may be troublesome. Above all, optimal communica­ tion cannot take place without both parties giving it their full and undivided attention. Hearing nerve ■ ■PREVENTION Conductive hearing losses may be prevented by prompt antibiotic therapy of adequate duration for AOM and by ventilation of the middle ear with tympanostomy tubes in middle-ear effusions lasting ≥12 weeks. Loss of vestibular function and deafness due to aminoglycoside anti­ biotics can largely be prevented by careful monitoring of serum peak and trough levels. Some 10 million Americans have noise-induced hearing loss, and 20 million are exposed to hazardous noise in their employment. Noiseinduced hearing loss can be prevented by avoidance of exposure to loud noise or by regular use of earplugs or fluid-filled ear muffs to attenuate intense sound. Table 36-3 lists loudness levels for a variety of envi­ ronmental sounds. High-risk activities for noise-induced hearing loss include use of electrical equipment for wood- and metalworking, and target practice or hunting with small firearms. All internal-combustion and electric engines, including snow and leaf blowers, snowmobiles, outboard motors, and chainsaws, require protection of the user with hearing protectors. Virtually all noise-induced hearing loss is prevent­ able through education, which should begin before the teenage years. Programs for conservation of hearing in the workplace are required by the Occupational Safety and Health Administration (OSHA) whenever the exposure over an 8-h period averages 85 dB. OSHA mandates that TABLE 36-3  Decibel (Loudness) Level of Common

Environmental Noise SOURCE DECIBEL (dB) Weakest sound heard

Whisper

Normal conversation 55–65 City traffic inside car

OSHA Monitoring Requirement Begins

Jackhammer

Subway train at 200 ft

Power mower

Power saw

Painful Sound

Jet engine at 100 ft

12-gauge shotgun blast

Loudest sound that can occur

Abbreviation: OSHA, Occupational Safety and Health Administration.

29 - 38 Oral Manifestations of Disease

38 Oral Manifestations of Disease

Noninfectious causes of laryngitis include vocal trauma (e.g., due to yelling, screaming, or loud singing), inhalation injuries, allergies, gas­ troesophageal reflux disease (laryngopharyngeal reflux), asthma, and pollution. Immunosuppressed patients are at risk for infections with herpesvirus, HIV, and coxsackievirus. Smokers are at elevated risk for malignancy and other infections.

Laryngitis is characterized by a raspy, hoarse, or breathy voice, sometimes progressing to a complete loss of voice. Laryngitis can have associated dry cough and anterior throat pain; patients often feel a need to clear their throats. The physical examination in patients who may have laryngitis should focus on the head, neck, and lungs, but the diagnosis of laryngitis is generally based on history. If visualization of the vocal cords is necessary, indirect examination with a mirror or flexible laryngoscopy usually shows erythema and edema of the vocal cords and surrounding structures. PART 2 Cardinal Manifestations and Presentation of Diseases TREATMENT Laryngitis Laryngitis is generally self-limited, usually lasting 3–7 days, but may last up to 14 days. Vocal rest is crucial. Airway humidification and hydration should help. Patients likely to have laryngopharyngeal reflux should avoid gastroesophageal reflux–inducing foods and behaviors and should take antireflux medications. In randomized controlled trials, antibiotics were not effective in decreasing objec­ tive symptoms of laryngitis. Red flags for emergency evaluation and monitoring include short­ ness of breath, stridor, dysphagia, odynophagia, drooling, and pos­ turing that could indicate epiglottitis. Referral to an otolaryngologist should be considered for patients who rely on their voice for work, such as singers and teachers. A history of smoking or weight loss should raise suspicion of malignancy. Symptoms lasting >3 weeks should prompt referral to an otolaryngologist or speech specialist. ■ ■FURTHER READING Centor RM, Linder JA: Web exclusive. Annals on call—Fusobacterium pharyngitis debate. Ann Intern Med 171:OC1, 2019. Chua KP et al: Appropriateness of outpatient antibiotic prescribing among privately insured US patients: ICD-10-CM based cross sec­ tional study. BMJ 364:k5092, 2019. Lieberthal AS et al: Clinical practice guideline: The diagnosis and management of acute otitis media. Pediatrics 131:e964, 2013. Rowe TA, Linder JA: Novel approaches to decrease inappropriate ambulatory antibiotic use. Expert Rev Anti Infect Ther 17:511, 2019. Sanchez GV et al: Antibiotic stewardship in outpatient telemedicine: Adapting Centers for Disease Control and Prevention core elements to optimize antibiotic use. Telemed J E Health 30:951, 2024. Samuel C. Durso

Oral Manifestations

of Disease Internists are often asked to evaluate patients with disease of the oral soft tissues, teeth, and pharynx. Knowledge of the oral milieu and its unique structures is necessary to guide preventive services and rec­ ognize oral manifestations of local or systemic disease (Chap. A3). Furthermore, internists frequently collaborate with dentists in the care of patients who have a variety of medical conditions that affect oral

health or who undergo dental procedures that increase their risk of medical complications. ■ ■DISEASES OF THE TEETH AND PERIODONTAL STRUCTURES Tooth formation begins during the sixth week of embryonic life and continues through 17 years of age. Teeth start to develop in utero and continue to develop until after the tooth erupts. Normally, all 20 deciduous teeth have erupted by age 3 and have been shed by age 13. Permanent teeth, eventually totaling 32, begin to erupt by age 6 and have completely erupted by age 14, though third molars (“wisdom teeth”) may erupt later. The erupted tooth consists of the visible crown covered with enamel and the root submerged below the gum line and covered with bonelike cementum. Dentin, a material that is denser than bone and exquisitely sensitive to pain, forms the majority of the tooth substance, surround­ ing a core of myxomatous pulp containing the vascular and nerve supply. The tooth is held firmly in the alveolar socket by the peri­ odontium, supporting structures that consist of the gingivae, alveolar bone, cementum, and periodontal ligament. The periodontal ligament tenaciously binds the tooth’s cementum to the alveolar bone. Above this ligament is a collar of attached gingiva just below the crown. A few millimeters of unattached or free gingiva (1–3 mm) overlap the base of the crown, forming a shallow sulcus along the gum-tooth margin. Dental Caries, Pulpal and Periapical Disease, and Complica­ tions  Dental caries usually begin asymptomatically as a destructive infectious process of the enamel. Bacteria—principally Streptococ­ cus mutans—colonize the organic buffering biofilm (plaque) on the tooth surface. If not removed by brushing or by the natural cleansing and antibacterial action of saliva, bacterial acids can demineralize the enamel. Fissures and pits on the occlusal surfaces are the most frequent sites of early decay. Surfaces between the teeth, adjacent to tooth restorations and exposed roots, are also vulnerable, particularly as individuals age. Over time, dental caries extend to the underlying dentin, leading to cavitation of the enamel. Without management, the caries will penetrate to the tooth pulp, producing acute pulpitis. At this stage, when the pulp infection is limited, the tooth may become sensi­ tive to percussion and to hot or cold, and pain resolves immediately when the irritating stimulus is removed. Should the infection spread throughout the pulp, irreversible pulpitis occurs, leading to pulp necro­ sis. At this later stage, pain can be severe and has a sharp or throbbing visceral quality that may be worse when the patient lies down. Once pulp necrosis is complete, pain may be constant or intermittent, but cold sensitivity is lost. Treatment of caries involves removing the softened and infected hard tissue and restoration of the tooth structure with silver amalgam, glass ionomer, composite resin, or gold. Once irreversible pulpitis occurs, root canal therapy becomes necessary; removal of the contents of the pulp chamber and root canal is followed by thorough clean­ ing and filling with an inert material. Alternatively, the tooth may be extracted. Pulpal infection leads to periapical abscess formation, which can produce pain on chewing. If the infection is mild and chronic, a peri­ apical granuloma or eventually a periapical cyst forms, either of which produces radiolucency at the root apex. When unchecked, a periapical abscess can erode into the alveolar bone, producing osteomyelitis; penetrate and drain through the gingivae, producing a parulis (gum­ boil); or track along deep fascial planes, producing virulent cellulitis (Ludwig’s angina) involving the submandibular space and floor of the mouth (Chap. 182). Elderly patients, patients with diabetes mellitus, and patients taking glucocorticoids may experience little or no pain or fever as these complications develop. Periodontal Disease  Periodontal disease and dental caries are the primary causes of tooth loss. Like dental caries, chronic infection of the gingiva and anchoring structures of the tooth begins with formation of bacterial plaque. The process begins at the gum line. Plaque and calcu­ lus (calcified plaque) are preventable by appropriate daily oral hygiene, including periodic professional cleaning. Left undisturbed, chronic

inflammation can ensue and produce hyperemia of the free and attached gingivae (gingivitis), which then typically bleed with brush­ ing. If this issue is ignored, severe periodontitis can develop, leading to deepening of the physiologic sulcus and destruction of the periodontal ligament. Gingival pockets develop around the teeth. As the periodon­ tium (including the supporting bone) is destroyed, the teeth loosen. A role for chronic inflammation due to chronic periodontal disease in promoting coronary heart disease and stroke has been proposed. Epidemiologic studies have demonstrated a moderate but significant association between chronic periodontal inflammation and atherogen­ esis, though a causal role remains unproven. Acute and aggressive forms of periodontal disease are less common than the chronic forms described above. However, if the host is stressed or exposed to a new pathogen, rapidly progressive and destructive disease of the periodontal tissue can occur. A virulent example is acute necrotizing ulcerative gingivitis. The presentation includes sud­ den gingival inflammation, ulceration, bleeding, interdental gingival necrosis, and fetid halitosis. Localized juvenile periodontitis, which is seen in adolescents, is particularly destructive and appears to be asso­ ciated with impaired neutrophil chemotaxis. AIDS-related periodontitis resembles acute necrotizing ulcerative gingivitis in some patients and a more destructive form of adult chronic periodontitis in others. It may also produce a gangrene-like destructive process of the oral soft tissues and bone that resembles noma, an infectious condition seen in severely malnourished children in developing nations. Prevention of Tooth Decay and Periodontal Infection  Despite the reduced prevalences of dental caries and periodontal disease in the United States (due in large part to water fluoridation and improved dental care, respectively), both diseases constitute a major public health problem worldwide. The internist should promote preventive dental care and hygiene as part of health maintenance. Populations at high risk for dental caries and periodontal disease include those with hyposalivation and/or xerostomia, diabetics, alcoholics, tobacco users, persons with Down syndrome, and those with gingival hyperplasia. Furthermore, patients lacking access to dental care (e.g., due to low socioeconomic status) and patients with a reduced ability to provide self-care (e.g., individuals with disabilities, nursing home residents, and persons with dementia or upper-extremity disability) suffer dispropor­ tionately. It is important to provide counseling (to patients and/or their caregivers) regarding regular dental hygiene and professional cleaning, use of fluoride-containing toothpaste, professional fluoride treatments, and (for patients with limited dexterity) use of electric toothbrushes. Cost, fear of dental care, and differences in language and culture cre­ ate barriers that prevent some people from seeking preventive dental services. Developmental and Systemic Disease Affecting the Teeth and Periodontium  In addition to posing cosmetic issues, maloc­ clusion, the most common developmental oral problem, can interfere with mastication unless corrected through orthodontic and surgical techniques. Impacted third molars are common and can become infected or erupt into an insufficient space. Acquired prognathism due to acromegaly may also lead to malocclusion, as may deformity of the maxilla and mandible due to Paget’s disease of the bone. Delayed tooth eruption, a receding chin, and a protruding tongue are occasional features of cretinism and hypopituitarism. Congenital syphilis produces tapering, notched (Hutchinson’s) incisors and finely nodular (mulberry) molar crowns. Enamel hypoplasia results in crown defects ranging from pits to deep fissures of primary or permanent teeth. Intrauterine infection (syphilis, rubella), vitamin deficiency (A, C, or D), disorders of calcium metabolism (malabsorption, vitamin D–resistant rickets, hypoparathyroidism), prematurity, high fever, and rare inherited defects (amelogenesis imperfecta) are all causes. Tetracycline, given in sufficiently high doses during the first 8 years of life, may produce enamel hypoplasia and discoloration. Doxycycline does not cause permanent tooth staining in children despite warnings included for all tetracycline-class antibiotics. Worn enamel is seen with age, bruxism, or excessive acid exposure (e.g., chronic gastric reflux or bulimia).

Celiac disease is associated with nonspecific enamel defects in children but not in adults.

Total or partial tooth loss resulting from periodontitis is seen with cyclic neutropenia, Papillon-Lefévre syndrome, Chédiak-Higashi syn­ drome, and leukemia. Rapid focal tooth loosening is most often due to infection, but rarer causes include Langerhans cell histiocytosis, Ewing’s sarcoma, osteosarcoma, and Burkitt’s lymphoma. Early loss of primary teeth is a feature of hypophosphatasia, a rare congenital error of metabolism. Pregnancy may produce gingivitis and localized pyogenic granu­ lomas. Severe periodontal disease occurs in uncontrolled diabetes mellitus. Drug-induced gingival overgrowth may be caused by anti­ convulsants, calcium channel blockers, and immunosuppressants, although excellent daily oral care can prevent or reduce its occurrence. Idiopathic familial gingival fibromatosis and several syndrome-related disorders cause similar conditions. Discontinuation of the medication may reverse the drug-induced form, although surgery may be needed to control both of the latter entities. Linear gingival erythema is variably seen in patients with advanced HIV infection and probably represents immune deficiency and decreased neutrophil activity. Diffuse or focal gingival swelling may be a feature of early or late acute myelomono­ cytic leukemia as well as of other lymphoproliferative disorders. A rare but pathognomonic sign of granulomatosis with polyangiitis is a redpurplish, granular gingivitis (strawberry gums). Oral Manifestations of Disease CHAPTER 38 ■ ■DISEASES OF THE ORAL MUCOSA Infections  Most oral mucosal diseases involve microorganisms (Table 38-1). Pigmented Lesions  See Table 38-2. Dermatologic Diseases  See Tables 38-1, 38-2, and 38-3 and Chaps. 59–64. Diseases of the Tongue  See Table 38-4. HIV Disease and AIDS  See Tables 38-1, 38-2, 38-3, and 38-5; Chap. 208. Ulcers  Ulceration is the most common oral mucosal lesion. Although there are many causes, the host and the pattern of lesions, including the presence of organ system features, narrow the differential diagnosis (Table 38-1). Most acute ulcers are painful and self-limited. Recurrent aphthous ulcers and herpes simplex account for the majority. Persistent and deep aphthous ulcers can be idiopathic or can accompany HIV/ AIDS. Aphthous lesions are often the presenting symptom in Behçet’s syndrome (Chap. 376). Similar-appearing, though less painful, lesions may occur in reactive arthritis, and aphthous ulcers are occasionally present during phases of discoid or systemic lupus erythematosus (Chap. 372). Aphthous-like ulcers are seen in Crohn’s disease (Chap. 337), but, unlike the common aphthous variety, they may exhibit granuloma­ tous inflammation on histologic examination. Recurrent aphthae are more prevalent in patients with celiac disease and have been reported to remit with elimination of gluten. Of major concern are chronic, relatively painless ulcers and mixed red/white patches (erythroplakia and leukoplakia) of >2 weeks’ dura­ tion. Squamous cell carcinoma and premalignant dysplasia should be considered early and a diagnostic biopsy performed. This awareness and this procedure are critically important because early-stage malig­ nancy is vastly more treatable than late-stage disease. High-risk sites include the lower lip, floor of the mouth, ventral and lateral tongue, and soft palate–tonsillar pillar complex. Significant risk factors for oral cancer in Western countries include sun exposure (lower lip), tobacco and alcohol use, and human papillomavirus infection. In India and some other Asian countries, smokeless tobacco mixed with betel nut, slaked lime, and spices is a common cause of oral cancer. Rarer causes of chronic oral ulcer, such as tuberculosis, fungal infection, granuloma­ tosis with polyangiitis, and midline granuloma, may look identical to carcinoma. Making the correct diagnosis depends on recognizing other clinical features and performing a biopsy of the lesion. The syphilitic

TABLE 38-1  Vesicular, Bullous, or Ulcerative Lesions of the Oral Mucosa CONDITION USUAL LOCATION CLINICAL FEATURES COURSE Viral Diseases Primary acute herpetic gingivostomatitis (HSV type 1; rarely type 2) Lip and oral mucosa (buccal, gingival, lingual mucosa) Labial vesicles that rupture and crust, and intraoral vesicles that quickly ulcerate; extremely painful; acute gingivitis, fever, malaise, foul odor, and cervical lymphadenopathy; occurs primarily in infants, children, and young adults Recurrent herpes labialis Mucocutaneous junction of lip, perioral skin Eruption of groups of vesicles that may coalesce, then rupture and crust; painful to pressure or spicy foods Recurrent intraoral herpes simplex Palate and gingiva Small vesicles on keratinized epithelium that rupture and coalesce; painful PART 2 Cardinal Manifestations and Presentation of Diseases Chickenpox (VZV) Gingiva and oral mucosa Skin lesions may be accompanied by small vesicles on oral mucosa that rupture to form shallow ulcers; may coalesce to form large bullous lesions that ulcerate; mucosa may have generalized erythema Herpes zoster (VZV reactivation) Cheek, tongue, gingiva, or palate Unilateral vesicular eruptions and ulceration in linear pattern following sensory distribution of trigeminal nerve or one of its branches Infectious mononucleosis (Epstein-Barr virus) Oral mucosa Fatigue, sore throat, malaise, fever, and cervical lymphadenopathy; numerous small ulcers usually appear several days before lymphadenopathy; gingival bleeding and multiple petechiae at junction of hard and soft palates Herpangina (coxsackievirus A; also possibly coxsackievirus B and echovirus) Oral mucosa, pharynx, tongue Sudden onset of fever, sore throat, and oropharyngeal vesicles, usually in children <4 years old, during summer months; diffuse pharyngeal congestion and vesicles (1–2 mm), grayish-white surrounded by red areola; vesicles enlarge and ulcerate Hand-foot-and-mouth disease (most commonly coxsackievirus A16) Oral mucosa, pharynx, palms, and soles Fever, malaise, headache with oropharyngeal vesicles that become painful, shallow ulcers; highly infectious; usually affects children under age 10 Primary HIV infection Gingiva, palate, and pharynx Acute gingivitis and oropharyngeal ulceration, associated with febrile illness resembling mononucleosis and including lymphadenopathy Bacterial or Fungal Diseases Acute necrotizing ulcerative gingivitis (“trench mouth”) Gingiva Painful, bleeding gingiva characterized by necrosis and ulceration of gingival papillae and margins plus lymphadenopathy and foul breath Prenatal (congenital) syphilis Palate, jaws, tongue, and teeth Gummatous involvement of palate, jaws, and facial bones; Hutchinson’s incisors, mulberry molars, glossitis, mucous patches, and fissures at corner of mouth Primary syphilis (chancre) Lesion appearing where organism enters body; may occur on lips, tongue, or tonsillar area Small papule developing rapidly into a large, painless ulcer with indurated border; unilateral lymphadenopathy; chancre and lymph nodes containing spirochetes; serologic tests positive by third to fourth weeks Secondary syphilis Oral mucosa frequently involved with mucous patches, which occur primarily on palate and also at commissures of mouth Maculopapular lesions of oral mucosa, 5–10 mm in diameter with central ulceration covered by grayish membrane; eruptions occurring on various mucosal surfaces and skin, accompanied by fever, malaise, and sore throat Tertiary syphilis Palate and tongue Gummatous infiltration of palate or tongue followed by ulceration and fibrosis; atrophy of tongue papillae produces characteristic bald tongue and glossitis Gonorrhea Lesions may occur in mouth at site of inoculation or secondarily by hematogenous spread from a primary focus Most pharyngeal infection is asymptomatic; may produce burning or itching sensation; oropharynx and tonsils may be ulcerated and erythematous; saliva viscous and fetid Tuberculosis Tongue, tonsillar area, soft palate Painless, solitary, 1- to 5-cm, irregular ulcer covered with persistent exudate; ulcer has firm undermined border Cervicofacial actinomycosis Swellings in region of face, neck, and floor of mouth Infection may be associated with extraction, jaw fracture, or eruption of molar tooth; in acute form, resembles acute pyogenic abscess, but contains yellow “sulfur granules” (gram-positive mycelia and their hyphae)

Heals spontaneously in 10–14 days; unless secondarily infected, lesions lasting >3 weeks are not due to primary HSV infection Lasts ∼1 week, but condition may be prolonged if secondarily infected; if severe, topical or oral antiviral treatment may reduce healing time Heals spontaneously in ∼1 week; if severe, topical or oral antiviral treatment may reduce healing time Lesions heal spontaneously within 2 weeks Gradual healing without scarring unless secondarily infected; postherpetic neuralgia is common; oral acyclovir, famciclovir, or valacyclovir reduces healing time and postherpetic neuralgia Oral lesions disappear during convalescence; no treatment is given, though glucocorticoids are indicated if tonsillar swelling compromises the airway Incubation period of 2–9 days; fever for

1–4 days; recovery uneventful Incubation period 2–18 days; lesions heal spontaneously in 2–4 weeks Followed by HIV seroconversion, asymptomatic HIV infection, and usually ultimately by HIV disease Debridement and diluted (1:3) peroxide lavage provide relief within 24 h; antibiotics in acutely ill patients; relapse may occur Tooth deformities in permanent dentition irreversible Healing of chancre in 1–2 months, followed by secondary syphilis in 6–8 weeks Lesions may persist from several weeks to a year Gumma may destroy palate, causing complete perforation More difficult to eradicate than urogenital infection, though pharyngitis usually resolves with appropriate antimicrobial treatment Autoinoculation from pulmonary infection is usual; lesions resolve with appropriate antimicrobial therapy Typically, swelling is hard and grows painlessly; multiple abscesses with draining tracts develop; penicillin first choice; surgery usually necessary (Continued)

TABLE 38-1  Vesicular, Bullous, or Ulcerative Lesions of the Oral Mucosa CONDITION USUAL LOCATION CLINICAL FEATURES COURSE Bacterial or Fungal Diseases (Continued) Histoplasmosis Any area of the mouth, particularly tongue, gingiva, or palate Nodular, verrucous, or granulomatous lesions; ulcers are indurated and painful; usual source hematogenous or pulmonary, but may be primary Candidiasisa       Dermatologic Diseases Mucous membrane pemphigoid Typically produces marked gingival erythema and ulceration; other areas of oral cavity, esophagus, and vagina may be affected Painful, grayish-white collapsed vesicles or bullae of fullthickness epithelium with peripheral erythematous zone; gingival lesions desquamate, leaving ulcerated area EM minor and EM major (Stevens-Johnson syndrome) Primarily oral mucosa and skin of hands and feet Intraoral ruptured bullae surrounded by inflammatory area; lips may show hemorrhagic crusts; “iris” or “target” lesion on skin is pathognomonic; patient may have severe signs of toxicity Pemphigus vulgaris Oral mucosa and skin; sites of mechanical trauma (soft/hard palate, frenulum, lips, buccal mucosa) Usually (>70%) presents with oral lesions; fragile, ruptured bullae and ulcerated oral areas; mostly in older adults Lichen planus Oral mucosa and skin White striae in mouth; purplish nodules on skin at sites of friction; occasionally causes oral mucosal ulcers and erosive gingivitis Other Conditions Recurrent aphthous ulcers Usually on nonkeratinized oral mucosa (buccal and labial mucosa, floor of mouth, soft palate, lateral and ventral tongue) Single or clustered painful ulcers with surrounding erythematous border; lesions may be 1–2 mm in diameter in crops (herpetiform), 1–5 mm (minor), or 5–15 mm (major) Behçet’s syndrome Oral mucosa, eyes, genitalia, gut, and CNS Multiple aphthous ulcers in mouth; inflammatory ocular changes, ulcerative lesions on genitalia; inflammatory bowel disease and CNS disease Traumatic ulcers Anywhere on oral mucosa; dentures frequently responsible for ulcers in vestibule Localized, discrete ulcerated lesions with red border; produced by accidental biting of mucosa, penetration by foreign object, or chronic irritation by dentures Squamous cell carcinoma Any area of mouth, most commonly on lower lip, lateral borders of tongue, and floor of mouth Red, white, or red and white ulcer with elevated or indurated border; failure to heal; pain not prominent in early lesions Acute myeloid leukemia (usually monocytic) Gingiva Gingival swelling and superficial ulceration followed by hyperplasia of gingiva with extensive necrosis and hemorrhage; deep ulcers may occur elsewhere on mucosa, complicated by secondary infection Lymphoma Gingiva, tongue, palate, and tonsillar area Elevated, ulcerated area that may proliferate rapidly, giving appearance of traumatic inflammation Chemical or thermal burns Any area in mouth White slough due to contact with corrosive agents (e.g., aspirin, hot cheese) applied locally; removal of slough leaves raw, painful surface aSee Table 38-3. Abbreviations: CNS, central nervous system; EM, erythema multiforme; HSV, herpes simplex virus; VZV, varicella-zoster virus. chancre is typically painless and therefore easily missed. Regional lymphadenopathy is invariably present. Disorders of mucosal fragility often produce painful oral ulcers that fail to heal within 2 weeks. Mucous membrane pemphigoid and pemphigus vulgaris are the major acquired disorders. While their clinical features are often distinctive, a biopsy or immunohistochemi­ cal examination should be performed to diagnose these entities and to distinguish them from lichen planus and drug reactions. Hematologic and Nutritional Disease  Internists are more likely to encounter patients with acquired, rather than congenital, bleeding

(Continued) Systemic antifungal therapy necessary Protracted course with remissions and exacerbations; involvement of different sites develops slowly; glucocorticoids may temporarily reduce symptoms but do not control disease Oral Manifestations of Disease CHAPTER 38 Onset very rapid; usually idiopathic, but may be associated with trigger such as drug reaction; condition may last 3–6 weeks; mortality rate for untreated EM major is 5–15% With repeated occurrence of bullae, toxicity may lead to cachexia, infection, and death within 2 years; often controllable with oral glucocorticoids White striae alone usually asymptomatic; erosive lesions often difficult to treat, but may respond to glucocorticoids Lesions heal in 1–2 weeks but may recur monthly or several times a year; protective barrier with benzocaine and topical glucocorticoids relieve symptoms; systemic glucocorticoids may be needed in severe cases Oral lesions often first manifestation; persist several weeks and heal without scarring Lesions usually heal in 7–10 days when irritant is removed, unless secondarily infected Invades and destroys underlying tissues; frequently metastasizes to regional lymph nodes Usually responds to systemic treatment of leukemia; occasionally requires local irradiation Fatal if untreated; may indicate underlying HIV infection Lesion heals in several weeks if not secondarily infected disorders. Bleeding should stop 15 min after minor trauma and within an hour after tooth extraction if local pressure is applied. More pro­ longed bleeding, if not due to continued injury or rupture of a large vessel, should lead to investigation for a clotting abnormality. In addi­ tion to bleeding, petechiae and ecchymoses are prone to occur at the vibrating line between the soft and hard palates in patients with platelet dysfunction or thrombocytopenia. All forms of leukemia, but particularly acute myelomonocytic leuke­ mia, can produce gingival bleeding, ulcers, and gingival enlargement. Oral ulcers are a feature of agranulocytosis, and ulcers and mucositis are often severe complications of chemotherapy and radiation therapy

TABLE 38-2  Pigmented Lesions of the Oral Mucosa CONDITION USUAL LOCATION CLINICAL FEATURES COURSE Oral melanotic macule Any area of mouth Discrete or diffuse, localized, brown to black macule Remains indefinitely; no growth Diffuse melanin pigmentation Any area of mouth Diffuse pale to dark-brown pigmentation; may be physiologic (“racial”) or due to smoking Nevi Any area of mouth Discrete, localized, brown to black pigmentation Remains indefinitely Malignant melanoma Any area of mouth Can be flat and diffuse, painless, brown to black; or can be raised and nodular Addison’s disease Any area of mouth, but mostly buccal mucosa Blotches or spots of bluish-black to dark-brown pigmentation occurring early in disease, accompanied by diffuse pigmentation of skin; other symptoms of adrenal insufficiency PART 2 Cardinal Manifestations and Presentation of Diseases Peutz-Jeghers syndrome Any area of mouth Dark-brown spots on lips, buccal mucosa, with characteristic distribution of pigment around lips, nose, and eyes and on hands; concomitant intestinal polyposis Drug ingestion (neuroleptics, oral contraceptives, minocycline, zidovudine, quinine derivatives) Any area of mouth Brown, black, or gray areas of pigmentation Gradually disappears following cessation of drug intake Amalgam tattoo Gingiva and alveolar mucosa Small blue-black pigmented areas associated with embedded amalgam particles in soft tissues; may show up on radiographs as radiopaque particles in some cases Heavy metal pigmentation (bismuth, mercury, lead) Gingival margin Thin blue-black pigmented line along gingival margin; rarely seen except in children exposed to lead-based paint Black hairy tongue Dorsum of tongue Elongation of filiform papillae of tongue, which become stained by coffee, tea, tobacco, or pigmented bacteria Fordyce spots Buccal and labial mucosa Numerous small yellowish spots just beneath mucosal surface; no symptoms; due to hyperplasia of sebaceous glands Kaposi’s sarcoma Palate most common, but may occur at any other site Red or blue plaques of variable size and shape; often enlarge, become nodular, and may ulcerate Mucous retention cysts Buccal and labial mucosa Bluish, clear fluid–filled cyst due to extravasated mucus from injured minor salivary gland TABLE 38-3  White Lesions of Oral Mucosa CONDITION USUAL LOCATION CLINICAL FEATURES COURSE Lichen planus Buccal mucosa, tongue, gingiva, and lips; skin Striae, white plaques, red areas, ulcers in mouth; purplish papules on skin; may be asymptomatic, sore, or painful; lichenoid drug reactions may look similar White sponge nevus Oral mucosa, vagina, anal mucosa Painless white thickening of epithelium; adolescence/early adulthood onset; familial Smoker’s leukoplakia and smokeless tobacco lesions Any area of oral mucosa, sometimes related to location of habit White patch that may become firm, rough, or red-fissured and ulcerated; may become sore and painful but is usually painless Erythroplakia with or without white patches Floor of mouth commonly affected in men; tongue and buccal mucosa in women Velvety, reddish plaque; occasionally mixed with white patches or smooth red areas Candidiasis Any area in mouth Pseudomembranous type (“thrush”): creamy white curdlike patches that reveal a raw, bleeding surface when scraped; found in sick infants, debilitated elderly patients receiving high-dose glucocorticoids or broad-spectrum antibiotics, and patients with AIDS Erythematous type: flat, red, sometimes sore areas in same groups of patients Candidal leukoplakia: nonremovable white thickening of epithelium due to Candida Angular cheilitis: sore fissures at corner of mouth Responds to topical antifungal therapy Hairy leukoplakia Usually on lateral tongue, rarely elsewhere on oral mucosa White areas ranging from small and flat to extensive accentuation of vertical folds; found in HIV carriers (all risk groups for AIDS) Warts (human papillomavirus) Anywhere on skin and oral mucosa Single or multiple papillary lesions with thick, white, keratinized surfaces containing many pointed projections; cauliflower lesions covered with normal-colored mucosa or multiple pink or pale bumps (focal epithelial hyperplasia)

Remains indefinitely Expands and invades early; metastasis leads to death Condition controlled by adrenal steroid replacement Oral pigmented lesions remain indefinitely; gastrointestinal polyps may become malignant Remains indefinitely Indicative of systemic absorption; no significance for oral health Improves within 1–2 weeks with gentle brushing of tongue or (if due to bacterial overgrowth) discontinuation of antibiotic Benign; remains without apparent change Usually indicative of HIV infection or nonHodgkin’s lymphoma; rarely fatal, but may require treatment for comfort or cosmesis Benign; painless unless traumatized; may be removed surgically Protracted; responds to topical glucocorticoids Benign and permanent May or may not resolve with cessation of habit; 2% of patients develop squamous cell carcinoma; early biopsy essential High risk of squamous cell cancer; early biopsy essential Responds favorably to antifungal therapy and correction of predisposing causes where possible Course same as for pseudomembranous type Responds to prolonged antifungal therapy Due to Epstein-Barr virus; responds to high-dose acyclovir but recurs; rarely causes discomfort unless secondarily infected with Candida Lesions grow rapidly and spread; squamous cell carcinoma must be ruled out with biopsy; excision or laser therapy; may regress in HIV-infected patients receiving antiretroviral therapy

TABLE 38-4  Alterations of the Tongue TYPE OF CHANGE CLINICAL FEATURES Size or Morphology Macroglossia Enlarged tongue that may be part of a syndrome found in developmental conditions such as Down syndrome, Simpson-Golabi-Behmel syndrome, or Beckwith-Wiedemann syndrome; may be due to tumor (hemangioma or lymphangioma), metabolic disease (e.g., primary amyloidosis), or endocrine disturbance (e.g., acromegaly or cretinism); may occur when all teeth are removed Fissured (“scrotal”) tongue Dorsal surface and sides of tongue covered by painless shallow or deep fissures that may collect debris and become irritated Median rhomboid glossitis Congenital abnormality with ovoid, denuded area in median posterior portion of tongue; may be associated with candidiasis and may respond to antifungal treatment Color “Geographic” tongue (benign migratory glossitis) Asymptomatic inflammatory condition of tongue, with rapid loss and regrowth of filiform papillae leading to appearance of denuded red patches “wandering” across surface Hairy tongue Elongation of filiform papillae of medial dorsal surface area due to failure of keratin layer of papillae to desquamate normally; brownish-black coloration may be due to staining by tobacco, food, or chromogenic organisms “Strawberry” and “raspberry” tongue Appearance of tongue during scarlet fever due to hypertrophy of fungiform papillae as well as changes in filiform papillae “Bald” tongue Atrophy may be associated with xerostomia, pernicious anemia, iron-deficiency anemia, pellagra, or syphilis; may be accompanied by painful burning sensation; may be an expression of erythematous candidiasis and respond to antifungal treatment for hematologic and other malignancies. Plummer-Vinson syndrome (iron deficiency, angular stomatitis, glossitis, and dysphagia) raises the risk of oral squamous cell cancer and esophageal cancer at the postcricoidal tissue web. Atrophic papillae and a red, burning tongue may occur with pernicious anemia. Deficiencies in B-group vitamins produce many of these same symptoms, as well as oral ulceration and cheilosis. Consequences of scurvy include swollen, bleeding gums; ulcers; and loosening of the teeth. NONDENTAL CAUSES OF ORAL PAIN Most, but not all, oral pain emanates from inflamed or injured tooth pulp or periodontal tissues. Nonodontogenic causes are often over­ looked. In most instances, toothache is predictable and proportional to the stimulus applied, and an identifiable condition (e.g., caries, abscess) is found. Local anesthesia eliminates pain originating from dental or periodontal structures, but not referred pains. The most common nondental source of pain is myofascial pain referred from muscles of mastication, which become tender and ache with increased use. Many sufferers exhibit bruxism (grinding of the teeth) secondary to stress and anxiety. Temporomandibular joint disorder is closely related. Features include pain, limited mandibular movement, and temporomandibular joint sounds. The etiologies are complex; malocclusion does not play the primary role once attributed to it. Osteoarthritis is a common cause of masticatory pain. Anti-inflammatory medication, jaw rest, soft foods, and heat provide relief. The temporomandibular joint is involved in 50% of patients with rheumatoid arthritis and is usually a late feature of severe disease. Migrainous neuralgia may be localized to the mouth. Episodes of pain and remission without an identifiable cause and a lack of relief with local anesthesia are important clues. Trigeminal neuralgia (tic douloureux) can involve the entire branch or part of the mandibular

TABLE 38-5  Oral Lesions Associated with HIV Infection LESION MORPHOLOGY ETIOLOGIES Papules, nodules, plaques Candidiasis (hyperplastic and pseudomembranous)a Condyloma acuminatum (human papillomavirus infection) Squamous cell carcinoma (preinvasive and invasive) Non-Hodgkin’s lymphomaa Hairy leukoplakiaa Ulcers Recurrent aphthous ulcersa Oral Manifestations of Disease CHAPTER 38 Angular cheilitis Squamous cell carcinoma Acute necrotizing ulcerative gingivitisa Necrotizing ulcerative periodontitisa Necrotizing ulcerative stomatitis Non-Hodgkin’s lymphomaa Viral infection (herpes simplex, herpes zoster, cytomegalovirus infection) Infection caused by Mycobacterium tuberculosis or Mycobacterium avium-intracellulare Fungal infection (histoplasmosis, cryptococcosis, candidiasis, geotrichosis, aspergillosis) Bacterial infection (Escherichia coli, Enterobacter cloacae, Klebsiella pneumoniae, Pseudomonas aeruginosa) Drug reactions (single or multiple ulcers) Pigmented lesions Kaposi’s sarcomaa Bacillary angiomatosis (skin and visceral lesions more common than oral) Zidovudine pigmentation (skin, nails, and occasionally oral mucosa) Addison’s disease Miscellaneous Linear gingival erythemaa aStrongly associated with HIV infection. or maxillary branch of the fifth cranial nerve and can produce pain in one or a few teeth. Pain may occur spontaneously or may be trig­ gered by touching the lip or gingiva, brushing the teeth, or chewing. Glossopharyngeal neuralgia produces similar acute neuropathic symptoms in the distribution of the ninth cranial nerve. Swallowing, sneezing, coughing, or pressure on the tragus of the ear triggers pain that is felt in the base of the tongue, pharynx, and soft palate and may be referred to the temporomandibular joint. Neuritis involv­ ing the maxillary and mandibular divisions of the trigeminal nerve (e.g., maxillary sinusitis, neuroma, and leukemic infiltrate) is distin­ guished from ordinary toothache by the neuropathic quality of the pain. Occasionally, phantom pain follows tooth extraction. Pain and hyperalgesia behind the ear and on the side of the face in the day or so before facial weakness develops often constitute the earliest symp­ tom of Bell’s palsy. Likewise, similar symptoms may precede visible lesions of herpes zoster infecting the seventh nerve (Ramsy-Hunt syndrome) or trigeminal nerve. Postherpetic neuralgia may follow either condition. Coronary ischemia may produce pain exclusively in the face and jaw; as in typical angina pectoris, this pain is usually reproducible with increased myocardial demand. Aching in several upper molar or premolar teeth that is unrelieved by anesthetizing the teeth may point to maxillary sinusitis. Giant cell arteritis is notorious for producing headache, but it may also produce facial pain or sore throat without headache. Jaw and tongue claudication with chewing or talking is relatively common. Tongue infarction is rare. Patients with subacute thyroiditis often experience pain referred to the face or jaw before the tenderness of the thyroid gland and transient hyperthyroidism are appreciated. “Burning mouth syndrome” (glossodynia) occurs in the absence of an identifiable cause (e.g., vitamin B12 deficiency, iron deficiency, dia­ betes mellitus, low-grade Candida infection, food sensitivity, or subtle

xerostomia). The etiology may be neuropathic. Clonazepam, α-lipoic acid, and cognitive-behavioral therapy benefit some patients. Some cases associated with an angiotensin-converting enzyme inhibitor have remitted when the drug was discontinued.

■ ■DISEASES OF THE SALIVARY GLANDS Saliva is essential to oral health. Its absence leads to dental caries, periodontal disease, and difficulties in wearing dental prostheses, masticating, and speaking. Its major components, water and mucin, serve as a cleansing solvent and lubricating fluid. In addition, saliva contains antimicrobial factors (e.g., lysozyme, lactoperoxidase, secre­ tory IgA), epidermal growth factor, minerals, and buffering sys­ tems. The major salivary glands secrete intermittently in response to autonomic stimulation, which is high during a meal. Hundreds of minor glands in the lips and cheeks secrete mucus continuously throughout the day and night. Consequently, oral function becomes impaired when salivary function is reduced. The sensation of a dry mouth (xerostomia) is perceived when salivary flow is reduced by 50%. The most common etiology is medication, especially drugs with anticholinergic properties but also alpha and beta blockers, calcium channel blockers, and diuretics. Other causes include Sjögren’s syn­ drome, chronic parotitis, salivary duct obstruction, diabetes mellitus, HIV/AIDS, and radiation therapy that includes the salivary glands in the field. Management involves eliminating or limiting drying medications, preventive dental care, and supplementation with oral liquid or salivary substitutes. Sugarless mints or chewing gum may stimulate salivary secretion if dysfunction is mild. When sufficient exocrine tissue remains, pilocarpine or cevimeline can increase secre­ tions. Commercial saliva substitutes or gels relieve dryness. Fluoride supplementation is critical to prevent caries. PART 2 Cardinal Manifestations and Presentation of Diseases Sialolithiasis presents most often as painful swelling but in some instances as only swelling or only pain. Conservative therapy consists of local heat, massage, and hydration. Promotion of salivary secretion with mints or lemon drops may flush out small stones. Antibiotic treat­ ment is necessary when bacterial infection is suspected. In adults, acute bacterial parotitis is typically unilateral and most commonly affects postoperative, dehydrated, and debilitated patients. Staphylococcus aureus (including methicillin-resistant strains) and anaerobic bacteria are the most common pathogens. Chronic bacterial sialadenitis results from lowered salivary secretion and recurrent bacterial infection. When suspected bacterial infection is not responsive to therapy, the differential diagnosis should expand to include benign and malignant neoplasms, lymphoproliferative disorders, Sjögren’s syndrome, sar­ coidosis, tuberculosis, lymphadenitis, actinomycosis, and granuloma­ tosis with polyangiitis. Bilateral nontender parotid enlargement occurs with diabetes mellitus, cirrhosis, bulimia, HIV/AIDS, and drugs (e.g., iodide, propylthiouracil). Pleomorphic adenoma composes two-thirds of all salivary neo­ plasms. The parotid is the principal salivary gland affected, and the tumor presents as a firm, slow-growing mass. Although this tumor is benign, its recurrence is common if resection is incomplete. Malignant tumors such as mucoepidermoid carcinoma, adenoid cystic carcinoma, and adenocarcinoma tend to grow relatively fast, depending upon grade. They may ulcerate and invade nerves, producing numbness and facial paralysis. Surgical resection is the primary treatment. Radiation therapy (particularly neutron-beam therapy) is used when surgery is not feasible and after resection for certain histologic types with a high risk of recurrence. Malignant salivary gland tumors have a 5-year sur­ vival rate of 94% when the stage is local, 70% with regional spread, and 43% when distant. Dental Care for Medically Complex Patients  Routine dental care (e.g., uncomplicated extraction, scaling and cleaning, tooth resto­ ration, and root canal) is remarkably safe. The most common concerns regarding care of dental patients with medical disease are excessive bleeding for patients taking anticoagulants, infection of the heart valves and prosthetic devices from hematogenous seeding by the oral flora, and cardiovascular complications resulting from vasopressors used

with local anesthetics during dental treatment, although the risk of any of these complications is very low. Patients undergoing tooth extraction or alveolar and gingival surgery rarely experience uncontrolled bleeding when warfarin anticoagulation is maintained within the therapeutic range currently recommended for prevention of venous thrombosis, atrial fibrilla­ tion, or mechanical heart valve. Embolic complications and death, however, have been reported during subtherapeutic anticoagulation. Therapeutic anticoagulation should be confirmed before and contin­ ued through the procedure. Likewise, low-dose aspirin (e.g., 81–325 mg)

can safely be continued. For patients taking aspirin and another antiplatelet medication (e.g., clopidogrel), continuation of the second antiplatelet medication should be based on individual consideration of the risks of thrombosis and bleeding. Target-specific oral antico­ agulants (dabigatran, apixaban, rivaroxaban, and edoxaban) are in increasingly common use. Simple extractions of one to three teeth, periodontal surgery, abscess drainage, and implant positioning do not typically require interruption of therapy. More extensive surgery may necessitate delaying or holding a dose of the anticoagulant or more elaborate measures to manage the risk of thrombosis and bleeding. Patients at risk for bacterial endocarditis (Chap. 133) should main­ tain optimal oral hygiene, including flossing, and regular professional cleanings. Currently, guidelines recommend that prophylactic antibiot­ ics be restricted to patients at high risk for bacterial endocarditis who undergo dental and oral procedures involving significant manipulation of gingival or periapical tissue or penetration of the oral mucosa. If unexpected bleeding occurs, antibiotics given within 2 h after the pro­ cedure provide effective prophylaxis. Hematogenous bacterial seeding from oral infection can produce late prosthetic-joint infection and therefore requires removal of the infected tissue (e.g., drainage, extraction, root canal) and appropriate antibiotic therapy. However, evidence that late prosthetic-joint infec­ tion follows routine dental procedures is lacking. For this reason, anti­ biotic prophylaxis is generally not recommended before oral surgery or oral mucosal manipulation for patients who have undergone joint replacement surgery. Exceptions to this may be considered for patients who have experienced joint replacement complications. Concern often arises regarding the use of vasoconstrictors to treat patients with hypertension and heart disease. Vasoconstrictors enhance the depth and duration of local anesthesia, thus reducing the anesthetic dose and potential toxicity. If intravascular injection is avoided, 2% lidocaine with 1:100,000 epinephrine (limited to a total of 0.036 mg of epinephrine) can be used safely in patients with controlled hypertension and stable coronary heart disease, arrhythmia, or con­ gestive heart failure. Precautions should be taken with patients taking tricyclic antidepressants and nonselective beta blockers because these drugs may potentiate the effect of epinephrine. Elective dental treatments should be postponed for at least 1 month and preferably for 6 months after myocardial infarction, after which the risk of reinfarction is low provided the patient is medically stable (e.g., stable rhythm, stable angina, and no heart failure). Patients who have suffered a stroke should have elective dental care deferred for 9 months. In both situations, effective stress reduction requires good pain control, including the use of the minimal amount of vasoconstrictor necessary to provide good hemostasis and local anesthesia. Bisphosphonate therapy is associated with osteonecrosis of the jaw. However, the risk with oral bisphosphonate therapy is very low. Most patients affected have received high-dose aminobisphosphonate ther­ apy for multiple myeloma or metastatic breast cancer and have under­ gone tooth extraction or dental surgery. Intraoral lesions, of which two-thirds are painful, appear as exposed yellow-white hard bone involving the mandible or maxilla. Screening tests for determining risk of osteonecrosis are unreliable. Patients slated for aminobisphospho­ nate therapy should receive preventive dental care that reduces the risk of infection and the need for future dentoalveolar surgery. Halitosis  Halitosis typically emanates from the oral cavity or nasal passages. Bacterial decay of food and cellular debris account for the

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39 Dyspnea

malodor. Periodontal disease, caries, acute forms of gingivitis, poorly fitting dentures, oral abscess, and tongue coating are common causes. Treatment includes correcting poor hygiene, treating infection, and tongue brushing. Hyposalivation can produce and exacerbate halito­ sis. Pockets of decay in the tonsillar crypts, esophageal diverticulum, esophageal stasis (e.g., achalasia, stricture), sinusitis, and lung abscess account for some instances. A few systemic diseases produce distinc­ tive odors: renal failure and Helicobacter pylori gastritis (ammoniacal), hepatic (fishy), and ketoacidosis (fruity). If a patient presents because of concern about halitosis but no odor is detectable, then pseudohali­ tosis or halitophobia must be considered. Aging and Oral Health  While tooth loss and dental disease are not normal consequences of aging, a complex array of structural and functional changes that occur with age can affect oral health. Subtle changes in tooth structure (e.g., diminished pulp space and volume, sclerosis of dentinal tubules, and altered proportions of nerve and vascular pulp content) result in the elimination or diminution of pain sensitivity and a reduction in the reparative capacity of the teeth. In addition, age-associated fatty replacement of salivary acini may reduce physiologic reserve, thus increasing the risk of hyposaliva­ tion. In healthy older adults, there is minimal, if any, reduction in salivary flow. Poor oral hygiene often results when general health fails or when patients lose manual dexterity and upper-extremity flexibility. This situation is particularly common among frail older adults and nurs­ ing home residents, and regular oral cleaning and dental care reduce the incidence of pneumonia, oral disease, the mortality risk in this population. Other risks for dental decay include limited lifetime fluoride exposure. Without assiduous care, decay can become quite advanced yet remain asymptomatic. Consequently, much of a tooth— or the entire tooth—can be destroyed before the patient is aware of the process. Periodontal disease, a leading cause of tooth loss, is indicated by loss of alveolar bone height. More than 90% of the U.S. population has some degree of periodontal disease by age 50. Healthy adults who have not had significant alveolar bone loss by the sixth decade of life do not typically experience significant worsening with advancing age. Complete edentulousness in the United States is becoming less common in the elderly and is increasingly restricted to impoverished populations. When it is present, speech, mastication, and facial con­ tours are dramatically affected. Edentulousness may also exacerbate obstructive sleep apnea, particularly in asymptomatic individuals who wear dentures. Dentures can improve verbal articulation and restore diminished facial contours. Mastication can also be restored; however, patients expecting dentures to facilitate oral intake are often disappointed. Accommodation to dentures requires a period of adjustment. Pain can result from friction or traumatic lesions pro­ duced by loose dentures. Poor fit and poor oral hygiene may permit the development of candidiasis. This fungal infection may be either asymptomatic or painful and is suggested by erythematous smooth or granular tissue conforming to an area covered by the appliance. Individuals with dentures and no natural teeth need regular (annual) professional oral examinations. ■ ■FURTHER READING Chavez EM et al: Dental care for geriatric and special needs popula­ tions. Dent Clin N Am 62:245, 2018. Durso SC: Interaction with other health team members in caring for elderly patients. Dent Clin North Am 49:377, 2005. Kaplovitch E, Dounaevskaia V: Treatment in the dental practice of the patient receiving anticoagulant therapy. J Am Dent Assoc 150:602, 2019.

Section 5 Alterations in Circulatory and Respiratory Functions Rebecca M. Baron

Dyspnea Dyspnea CHAPTER 39 DYSPNEA ■ ■DEFINITION The American Thoracic Society consensus statement defines dyspnea as a “subjective experience of breathing discomfort that consists of qualitatively distinct sensations that vary in intensity. The experience derives from interactions among multiple physiological, psycho­ logical, social, and environmental factors and may induce secondary physiological and behavioral responses.” Dyspnea, a symptom, can be perceived only by the person experiencing it and, therefore, must be self-reported. In contrast, signs of increased work of breathing, such as tachypnea, accessory muscle use, and intercostal retraction, can be measured and reported by clinicians. ■ ■EPIDEMIOLOGY Dyspnea is common. It has been reported that up to one-half of inpa­ tients and one-quarter of ambulatory patients experience dyspnea, with a prevalence of 9–13% in the community that increases to as high as 37% for adults aged ≥70 years. Dyspnea is a frequent cause of emer­ gency room visits, accounting for as many as 3–4 million visits per year. Furthermore, it is increasingly appreciated that the degree of dyspnea may better predict outcomes in chronic obstructive pulmonary disease (COPD) than does the forced expiratory volume in 1 s (FEV1), and formal measures of dyspnea have been incorporated into the Global Initiative for Chronic Obstructive Lung Disease (GOLD) COPD sever­ ity assessment guidelines. Dyspnea may also predict outcomes in other chronic heart and lung diseases as well. Dyspnea can arise from a diverse array of pulmonary, cardiac, and neurologic underlying causes, and elucidation of particular symptoms may point toward a specific etiology and/or mechanism driving dyspnea (although additional diagnostic testing is often required, as will be further discussed below). There has been an increased focus on dyspnea given its increased inci­ dence in the setting of the SARS-CoV-2 pandemic, and post-COVID persistent symptoms in many patients (Chap. 205). ■ ■MECHANISMS UNDERLYING DYSPNEA The mechanisms underlying dyspnea are complex, as it can arise from different contributory respiratory sensations. Although a large body of research has increased our understanding of mechanisms underlying particular respiratory sensations such as “chest tightness” or “air hun­ ger,” it is likely that a given disease state might produce the sensation of dyspnea via more than one underlying mechanism. Dyspnea can arise from a variety of pathways, including generation of afferent signals from the respiratory system to the central nervous system (CNS), efferent signals from the CNS to the respiratory muscles, and particularly when there is a mismatch in the integrative signaling between these two path­ ways, termed efferent-reafferent mismatch (Fig. 39-1). Afferent signals trigger the CNS (brainstem and/or cortex) and include primarily: (1) peripheral chemoreceptors in the carotid body and aortic arch and central chemoreceptors in the medulla that are activated by hypoxemia, hypercapnia, or acidemia, and might produce a sense of “air hunger”; and (2) mechanoreceptors in the upper airways, lungs (including stretch receptors, irritant receptors, and J receptors), and chest wall (including muscle spindles as stretch receptors and tendon organs that monitor force generation) that are activated in the setting of an increased workload from a disease state producing an increase in airway resistance that may be associated with symptoms of chest tightness (e.g., asthma or COPD) or decreased lung or chest wall

Afferent signals Efferent signals Central chemoreceptors (in medulla) Air hunger Hypoxemia, hypercapnia, or acidemia Peripheral chemoreceptors (in carotid body and aortic arch) Air hunger PART 2 Cardinal Manifestations and Presentation of Diseases Mechanoreceptors (in upper airways, lungs, chest wall) Increase in airway resistance or decreased lung or chest wall compliance Chest tightness Metaboreceptors (in skeletal muscle) FIGURE 39-1  Potential signaling pathways underlying the sensation of dyspnea. Dyspnea is a complex sensation that can arise from a variety of physiologic stimuli (examples in pink boxes include hypoxemia, hypercapnia, acidemia, increase in airway resistance, and decrease in lung and/or chest wall compliance). Physiologic signals are mediated via relevant receptors (examples in yellow boxes include central chemoreceptors in the medulla; peripheral chemoreceptors in the carotid body and aortic arch; mechanoreceptors in upper airways, lungs, and chest wall; and metaboreceptors in skeletal muscle) that send afferent signals to the brainstem and sensory cortex. Efferent signals are sent from the brainstem and motor cortex to the respiratory muscles and sensory cortex. Potential symptoms associated with dyspnea that may be generated by these signals are indicated in italics. compliance (e.g., pulmonary fibrosis). Other afferent signals that trig­ ger dyspnea within the respiratory system can arise from pulmonary vascular receptor responses to changes in pulmonary artery pressure and skeletal muscle (termed metaboreceptors) that are believed to sense changes in the biochemical environment. Efferent signals are sent from the CNS (motor cortex and brainstem) to the respiratory muscles and are also transmitted by corollary dis­ charge to the sensory cortex; they are believed to underlie sensations of respiratory effort (or “work of breathing”) and perhaps contribute to sensations of “air hunger,” especially in response to an increased venti­ latory load in a disease state such as COPD. In addition, fear or anxiety may heighten the sense of dyspnea by exacerbating the underlying physiologic disturbance in response to an increased respiratory rate or disordered breathing pattern. ■ ■ASSESSING DYSPNEA While it is well appreciated that dyspnea is a difficult quality to mea­ sure reliably owing to multiple relevant possible domains that can be measured (e.g., sensory-perceptual experience, affective distress, and symptom impact or burden) and that there are no uniformly agreed upon tools for dyspnea assessment, consensus opinion holds that dyspnea should be formally assessed in a context most relevant and beneficial for patient management and, furthermore, that the specific domains being measured are adequately described. There are a number of emerging tools that have been developed for formal dyspnea assess­ ment. As an example, the GOLD criteria advocate use of a dyspnea assessment tool such as the Modified Medical Research Council Dys­ pnea Scale (Table 39-1) to assess symptom/impact burden in COPD. ■ ■DIFFERENTIAL DIAGNOSIS This chapter focuses largely on chronic dyspnea, which is defined as symptoms lasting longer than 1 month and can arise from a broad

Respiratory muscles Brainstem and sensory cortex Brainstem and motor cortex Work of breathing Sensory cortex array of different underlying conditions, most commonly attributable to pulmonary or cardiac conditions that account for as many as 85% of the underlying causes of dyspnea. However, as many as one-third of patients may have multifactorial reasons underlying dyspnea, with an increasing number of individuals suffering from dyspnea as part of a post-COVID syndrome (Chap. 205). Examples of a wide array of conditions that underlie dyspnea with possible mechanisms underlying the presenting symptoms are described in Table 39-2. Respiratory system causes include diseases of the airways (e.g., asthma and COPD), diseases of the parenchyma (more commonly, interstitial lung diseases are seen in the setting of chronic dyspnea, TABLE 39-1  An Example of a Clinical Method for Rating Dyspnea:

The Modified Medical Research Council Dyspnea Scalea GRADE OF DYSPNEA DESCRIPTION

Not troubled by breathlessness, except with strenuous exercise

Shortness of breath walking on level ground or with walking up a slight hill

Walks slower than people of similar age on level ground due to breathlessness, or has to stop to rest when walking at own pace on level ground

Stops to rest after walking 100 m or after walking a few minutes on level ground

Too breathless to leave the house, or breathless with activities of daily living (e.g., dressing/undressing) aThis scale has been integrated into the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines clinical classification scheme. Source: Reproduced with permission from DA Mahler, CK Wells: Evaluation of clinical methods for rating dyspnea. Chest 93:580, 1988.

TABLE 39-2  Differential Diagnosis of Disease Processes Underlying Dyspnea POSSIBLE PRESENTING DYSPNEA SYMPTOMS EXAMPLE OF DISEASE PROCESS SYSTEM TYPE OF PROCESS Pulmonary Airways disease Asthma, COPD, upper airway obstruction Chest tightness, tachypnea, increased WOB, air hunger, inability to get a deep breath   Parenchymal disease Interstitial lung diseasea Air hunger, inability to get a deep breath   Chest wall disease Kyphoscoliosis, neuromuscular (NM) weakness Increased WOB, inability to get a deep breath Pulmonary and cardiac Pulmonary vasculature Pulmonary hypertension Tachypnea Elevated right heart pressures, exertional hypoxemia Cardiac Left heart failure

---

Pericardial disease Coronary artery disease, cardiomyopathyc Chest tightness, air hunger

---

Constrictive pericarditis; cardiac tamponade Other Variable Anemia Deconditioning Psychological Metabolic disturbances Gastrointestinal (e.g., gastroesophageal reflux disease [GERD], aspiration pneumonitis) Post-COVID syndrome Exertional breathlessness Poor fitness Anxiety aDifferential diagnosis of interstitial lung disease includes idiopathic pulmonary fibrosis, collagen vascular disease, drug- or occupation-induced pneumonitis, lymphangitic spread of malignancy; processes that are more alveolar rather than interstitial in nature can also less commonly contribute to parenchymal lung disease underlying chronic dyspnea and include entities such as hypersensitivity pneumonitis, bronchiolitis obliterans organizing pneumonia, etc. bWould additionally consider these patients for CT angiography to evaluate for presence of thromboemboli and ventilation/perfusion scanning to evaluate for the presence of chronic thromboembolic disease. cDiastolic dysfunction in the setting of a stiff left ventricle is often seen and contributes significantly to insidious dyspnea that can be difficult to treat. dMay stimulate metaboreceptors if cardiac output is sufficiently reduced to result in a lactic acidosis. Abbreviations: BNP, brain natriuretic peptide; COPD, chronic obstructive pulmonary disease; COVID, coronavirus disease; CT, computed tomography; CXR, chest x-ray; ECG, electrocardiogram; ECHO, echocardiogram; GERD, gastroesophageal reflux disease; LHC, left heart catheterization; MIP/MEP, maximal inspiratory and maximal expiratory pressures (obtained in the pulmonary function testing laboratory); OVD, obstructive ventilatory defect; RVD, restrictive ventilatory defect; RHC, right heart catheterization; WOB, work of breathing. but alveolar filling processes, such as hypersensitivity pneumonitis or bronchiolitis obliterans organizing pneumonia [BOOP], can also present with similar symptoms), diseases affecting the chest wall (e.g., bony abnormalities such as kyphoscoliosis, or neuromuscular weak­ ness conditions such as amyotrophic lateral sclerosis), and diseases affecting the pulmonary vasculature (e.g., pulmonary hypertension that can arise from a variety of underlying causes, or chronic thrombo­ embolic disease). Diseases affecting the cardiovascular system that can present with dyspnea include processes affecting left heart function, such as coronary artery disease and cardiomyopathy, as well as disease processes affecting the pericardium, including constrictive pericarditis and cardiac tamponade. Other conditions underlying dyspnea that might not directly emanate from the pulmonary or cardiovascular systems include anemia (thereby potentially affecting oxygen-carrying capacity), deconditioning, and psychological processes such as anxiety. Distinguishing among the myriad of underlying processes that might present with dyspnea can be challenging. A graded approach that

POSSIBLE MECHANISMS UNDERLYING DYSPNEA POSSIBLE PHYSICAL FINDINGS INITIAL DIAGNOSTIC STUDIES (AND POSSIBLE FINDINGS) Wheezing, accessory muscle use, exertional hypoxemia (especially with COPD) Increased WOB, hypoxemia, hypercapnia, stimulation of pulmonary receptors Peak flow (reduced); spirometry (OVD); CXR (hyperinflation; loss of lung parenchyma in COPD), chest CT and airway examination for upper airway obstruction Dyspnea CHAPTER 39 Dry end-inspiratory crackles, clubbing, exertional hypoxemia Increased WOB, increased respiratory drive, hypoxemia, hypercapnia, stimulation of pulmonary receptors Spirometry and lung volumes (RVD); CXR and chest CT (interstitial lung disease) Decreased diaphragm excursion; atelectasis Increased WOB; stimulation of pulmonary receptors (if atelectasis is present) Spirometry and lung volumes (RVD); MIP and MEPs (reduced in NM weakness) Increased respiratory drive, hypoxemia, stimulation of vascular receptors Diffusion capacity (reduced); ECG; ECHO, RHC (to evaluate pulmonary artery pressures)b Elevated left heart pressures; wet crackles on lung examination; pulsus paradoxus (pericardial disease) Increased WOB and drive, hypoxemia, stimulation of vascular and pulmonary receptorsd Consider BNP testing, especially in the acute setting; ECG, ECHO, may need stress testing and/ or LHC Variable Metaboreceptors (anemia, poor fitness); chemoreceptors (anaerobic metabolism from poor fitness); some subjects may have increased sensitivity to hypercapnia Hematocrit for anemia; laboratory studies (e.g., metabolic panel, thyroid hormone testing for metabolic disturbances); consider upper gastrointestinal endoscopy and/or esophageal pH probe testing for GERD and concerns for aspiration; consider referral to post-COVID care center for persistent symptoms after COVID infection; exclude other causes begins with a history and physical examination, followed by selected laboratory testing that might then advance to additional diagnostics and potentially subspecialty referral, may help elucidate the underlying cause of dyspnea. However, a substantial proportion of patients may have persistent dyspnea despite treatment for an underlying process or may not have a specific underlying process identified that is driving the dyspnea. APPROACH TO THE PATIENT Dyspnea (See Fig. 39-2) OVERALL For patients with a known prior pulmonary, cardiac, or neuromus­ cular condition and worsening dyspnea, the initial focus of the evaluation will usually address determining whether the known

History and physical examination, plus: Walking oximetry Peak flow assessment Diagnosis obtained? Yes Treat No Further testing (“Phase 1”): Chest x-ray Spirometry ECG CBC, basic metabolic panel PART 2 Cardinal Manifestations and Presentation of Diseases Diagnosis obtained? Yes Treat No Further testing (“Phase 2”): Chest CT (consider angiography for thromboembolic disease) Lung volumes, DLCO, tests of neuromuscular function Echocardiogram, cardiac stress testing Diagnosis obtained? Yes Treat No Further testing (“Phase 3”): Consider cardiopulmonary exercise testing (and subspecialty referral) FIGURE 39-2  Possible algorithm for the evaluation of the patient with dyspnea. As described in the text, the approach should begin with a detailed history and physical examination, followed by progressive testing and ultimately more invasive testing and subspecialty referral as is indicated to determine the underlying cause of dyspnea. CBC, complete blood count; DLCO, diffusing capacity of the lungs for carbon monoxide; ECG, electrocardiogram. (Adapted from NG Karnani et al: Am Fam Physician 71:1529, 2005.) condition has progressed or whether a new process has devel­ oped that is causing dyspnea. For patients without a prior known potential cause of dyspnea, the initial evaluation will focus on determining an underlying etiology. Determining the underlying cause, if possible, is extremely important, as the treatment may vary dramatically based on the predisposing condition. An initial history and physical examination remain fundamental to the evaluation followed by initial diagnostic testing as indicated that might prompt subspecialty referral (e.g., pulmonary, cardiology, neurology, sleep, and/or specialized dyspnea clinic) if the cause of dyspnea remains elusive (Fig. 39-2). As many as two-thirds of patients will require diagnostic testing beyond the initial clinical presentation. HISTORY The patient should be asked to describe in their own words what the discomfort feels like as well as the effect of position, infections, and environmental stimuli on the dyspnea, as descriptors may be helpful in pointing toward an etiology. For example, symptoms of chest tightness might suggest the possibility of bronchoconstriction, and the sensation of inability to take a deep breath may correlate with dynamic hyperinflation from COPD. Orthopnea is a common indicator of congestive heart failure (CHF), mechanical impair­ ment of the diaphragm associated with obesity, or asthma triggered by esophageal reflux. Nocturnal dyspnea suggests CHF or asthma. Acute, intermittent episodes of dyspnea are more likely to reflect episodes of myocardial ischemia, bronchospasm, or pulmonary

embolism, whereas chronic persistent dyspnea is more typical of COPD, interstitial lung disease, and chronic thromboembolic dis­ ease. Information on risk factors for drug-induced or occupational lung disease and for coronary artery disease should be elicited. Left atrial myxoma or hepatopulmonary syndrome should be consid­ ered when the patient complains of platypnea—i.e., dyspnea in the upright position with relief in the supine position. PHYSICAL EXAMINATION Initial vital signs might be helpful in pointing toward an under­ lying etiology in the context of the remainder of the evalua­ tion. For example, the presence of fever might point toward an underlying infectious or inflammatory process; the presence of hypertension in the setting of a heart failure might point toward diastolic dysfunction; the presence of tachycardia might be associated with many different underlying processes including fever, cardiac dysfunction, and deconditioning; and the presence of resting hypoxemia suggests processes involving hypercapnia, ventilation-perfusion mismatch, shunt, or impairment in diffu­ sion capacity might be involved. An exertional oxygen saturation should also be obtained as described below. The physical exami­ nation should begin during the interview of the patient. Inability of the patient to speak in full sentences before stopping to get a deep breath suggests a condition that leads to stimulation of the controller or impairment of the ventilatory pump with reduced vital capacity. Evidence of increased work of breathing (supracla­ vicular retractions; use of accessory muscles of ventilation; and the tripod position, characterized by sitting with the hands braced on the knees) is indicative of increased airway resistance or stiffness of the lungs and the chest wall. When measuring the vital signs, the physician should accurately assess the respiratory rate and measure the pulsus paradoxus (Chap. 281); if the systolic pressure decreases by >10 mmHg on inspiration, the presence of COPD, acute asthma, or pericardial disease should be considered. Dur­ ing the general examination, signs of anemia (pale conjunctivae), cyanosis, and cirrhosis (spider angiomata, gynecomastia) should be sought. Examination of the chest should focus on symmetry of movement; percussion (dullness is indicative of pleural effusion; hyperresonance is a sign of pneumothorax and emphysema); and auscultation (wheezes, rhonchi, prolonged expiratory phase, and diminished breath sounds are clues to disorders of the airways; rales suggest interstitial edema or fibrosis). The cardiac examina­ tion should focus on signs of elevated right heart pressures (jugular venous distention, edema, accentuated pulmonic component to the second heart sound); left ventricular dysfunction (S3 and S4 gal­ lops); and valvular disease (murmurs). When examining the abdo­ men with the patient in the supine position, the physician should note whether there is paradoxical movement of the abdomen as well as the presence of increased respiratory distress in the supine position: inward motion during inspiration is a sign of diaphrag­ matic weakness, and rounding of the abdomen during exhalation is suggestive of pulmonary edema. Clubbing of the digits may be an indication of interstitial pulmonary fibrosis or bronchiectasis, and joint swelling or deformation as well as changes consistent with Raynaud’s disease may be indicative of a collagen-vascular process that can be associated with pulmonary disease. Patients should be asked to walk under observation with oxim­ etry in order to reproduce the symptoms. The patient should be examined during and at the end of exercise for new findings that were not present at rest (e.g., presence of wheezing) and for changes in oxygen saturation. CHEST IMAGING After the history elicitation and the physical examination, a chest radiograph should be obtained if the diagnosis remains elusive. The lung volumes should be assessed: hyperinflation is consistent with obstructive lung disease, whereas low lung volumes sug­ gest interstitial edema or fibrosis, diaphragmatic dysfunction, or

impaired chest wall motion. The pulmonary parenchyma should be examined for evidence of interstitial disease, infiltrates, and emphysema. Prominent pulmonary vasculature in the upper zones indicates pulmonary venous hypertension, while enlarged central pulmonary arteries may suggest pulmonary arterial hypertension. An enlarged cardiac silhouette can point toward dilated cardiomy­ opathy or valvular disease. Bilateral pleural effusions are typical of CHF and some forms of collagen-vascular disease. Unilateral effu­ sions raise the specter of carcinoma and pulmonary embolism but may also occur in heart failure or in the case of a parapneumonic effusion. CT of the chest is generally reserved for further evaluation of the lung parenchyma (e.g., interstitial lung disease) and possible pulmonary embolism (with CT angiography) if diagnostic uncer­ tainty remains. LABORATORY STUDIES Initial laboratory testing should include a hematocrit to exclude occult anemia as an underlying cause of reduced oxygen-carrying capacity contributing to dyspnea, and a basic metabolic panel may be helpful to exclude a significant underlying metabolic acido­ sis (and conversely, an elevated bicarbonate might point toward the possibility of carbon dioxide retention that might be seen in chronic respiratory failure—in such a setting, an arterial blood gas may provide useful additional information). Additional laboratory studies should include electrocardiography to seek evidence of ventricular hypertrophy and prior myocardial infarction, and spi­ rometry, which can be diagnostic of the presence of an obstructive ventilatory defect and suggest the possibility of a restrictive ventila­ tory defect (that then might prompt additional pulmonary function laboratory testing, including lung volumes, diffusion capacity, and possible tests of neuromuscular function). Echocardiography is indicated when systolic dysfunction, pulmonary hypertension, or valvular heart disease is suspected. Bronchoprovocation testing and/or home peak-flow monitoring may be useful in patients with intermittent symptoms suggestive of asthma who have a normal physical examination and spirometry; up to one-third of patients with the clinical diagnosis of asthma do not have reactive airways disease when formally tested. Measurement of brain natriuretic peptide levels in serum is increasingly used to assess for CHF in patients presenting with acute dyspnea but may be elevated in the presence of right ventricular strain as well. DISTINGUISHING CARDIOVASCULAR FROM RESPIRATORY SYSTEM DYSPNEA If a patient has evidence of both pulmonary and cardiac disease that is not responsive to treatment or it remains unclear what factors are primarily driving the dyspnea, a cardiopulmonary exercise test (CPET) can be conducted to determine which system is responsible for the exercise limitation. CPET includes incremental symptom-

limited exercise (cycling or treadmill) with measurements of ven­ tilation and pulmonary gas exchange and, in some cases, includes noninvasive and invasive measures of pulmonary vascular pressures and cardiac output. If, at peak exercise, the patient achieves pre­ dicted maximal ventilation, demonstrates an increase in dead space or hypoxemia, or develops bronchospasm, the respiratory system may be the cause of the problem. Alternatively, if the heart rate is

85% of the predicted maximum, if the anaerobic threshold occurs early, if the blood pressure becomes excessively high or decreases during exercise, if the O2 pulse (O2 consumption/heart rate, an indi­ cator of stroke volume) falls, or if there are ischemic changes on the electrocardiogram, an abnormality of the cardiovascular system is likely the explanation for the breathing discomfort. Additionally, a CPET may also help point toward a peripheral extraction deficit or metabolic/neuromuscular disease as potential underlying processes driving dyspnea.

TREATMENT Dyspnea The first goal is to correct the underlying condition(s) driving dyspnea and address potentially reversible causes with appropriate treatment for the particular condition. Multiple different inter­ ventions may be necessary, given that dyspnea often arises from multifactorial causes. If relief of dyspnea with treatment of the underlying condition(s) is not fully possible, an effort is made to lessen the intensity of the symptom and its effect on the patient’s quality of life. More recent work at the consensus conference level has sought to define an identifiable entity of persistent dyspnea in order to develop an approach to improving efforts to address symptom management for this condition. In 2017, an interna­ tional group of experts defined “chronic breathlessness syndrome” as “the experience of breathlessness that persists despite optimal treatment of the underlying pathophysiology and results in dis­ ability for the patient.” Despite an increased understanding of the mechanisms underlying dyspnea, there has been limited progress in treatment strategies for dyspnea. Supplemental O2 should be administered if the resting O2 saturation is ≤88% or if the patient’s saturation drops to these levels with activity or sleep. In particu­ lar, for patients with COPD, supplemental oxygen for those with hypoxemia has been shown to improve mortality, and pulmonary rehabilitation programs (including some home and communitybased exercise programs such as yoga and Tai Chi) have demon­ strated positive effects on dyspnea, exercise capacity, and rates of hospitalization. More recent studies have suggested that super­ vised exercise programs similarly improved outcomes in postCOVID conditions. Opioids have been shown in some studies to reduce symptoms of dyspnea, largely through reducing air hunger, thus likely suppressing respiratory drive and influencing cortical activity. However, a recent study did not support the benefit of two different doses of daily low-dose extended-release morphine in COPD, for which reason opioids should be considered for each patient individually based on the risk-benefit profile in regard to respiratory depression. Studies of anxiolytics for dyspnea have not demonstrated consistent benefit. Dyspnea CHAPTER 39 ■ ■FURTHER READING Benzo R et al: Promoting chronic obstructive pulmonary disease well­ ness through remote monitoring and health coaching: A clinical trial. Ann Am Thorac Soc 19:1808, 2022. Ekström M et al: Effect of regular, low-dose, extended-release mor­ phine on chronic breathlessness in chronic obstructive pulmonary disease. The BEAMS randomized clinical trial. JAMA 328:2022, 2022. Johnson M et al: Toward an expert consensus to delineate a clinical syndrome of chronic breathlessness: Chronic breathlessness syn­ drome. Eur Respir J 49:1602277, 2017. Müller A et al: Prevalence of dyspnea in general adult populations: A systematic review and meta-analysis. Respir Med 218:107379, 2023. O’Donnell DE et al: Unraveling the causes of unexplained dyspnea. Clin Chest Med 40:471, 2019. Parshall MB et al: An Official American Thoracic Society Statement: Update on the mechanisms, assessment, and management of dys­ pnea. Am J Respir Crit Care Med 185:435, 2012. Pouliopoulou DV et al: Rehabilitation interventions for physical capacity and quality of life in adults with post-COVID-19 condi­ tion. A systematic review and meta-analysis. JAMA Netw Open 6:e2333838, 2023. Ratarasarn K et al: Yoga and Tai Chi: A mind-body approach in managing respiratory symptoms in obstructive lung diseases. Curr Opin Pulm Med 26:186, 2020.

32 - 40 Cough

40 Cough

Bruce D. Levy

Cough Cough performs an essential protective function for human airways and lungs. Without an effective cough reflex, we are at risk for retained airway secretions and aspirated material predisposing to infection, atel­ ectasis, and respiratory compromise. At the other extreme, excessive coughing can be exhausting; can be complicated by emesis, syncope, muscular pain, or rib fractures; can aggravate low back pain, abdomi­ nal or inguinal hernias, and urinary incontinence; and can be a major impediment to social interactions. Cough is often a clue to the pres­ ence of respiratory disease. In many instances, cough is an expected and accepted manifestation of disease, as in acute respiratory tract infection; however, persistent cough in the absence of other respiratory symptoms commonly causes patients to seek medical attention. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■COUGH MECHANISM Both chemical (e.g., capsaicin) and mechanical (e.g., mucus, particu­ lates in air pollution) stimuli can initiate a cough. Cationic channels (e.g., transient receptor potential channels) and adenosine triphos­ phate–activated ion channels (P2X3) function as sensory neuronal receptors, with signals transmitted centrally via Aδ (mechanosensory) and C fibers (chemosensory). Afferent nerve endings richly innervate the pharynx, larynx, and airways to the level of the terminal bronchi­ oles and extend into the lung parenchyma. They are also located in the external auditory canal (the auricular branch of the vagus nerve, or Arnold’s nerve) and in the esophagus. Sensory signals travel via the vagus and superior laryngeal nerves to a region of the brainstem in the nucleus tractus solitarius. Integrated neural networks process this input into a conscious sensation referred to as the “urge to cough.” The efferent limb of the cough reflex involves a highly orchestrated series of involuntary muscular actions, with the potential for input from cortical pathways as well, making possible voluntary cough. The vocal cords adduct, leading to transient upper-airway occlusion. Expiratory muscles contract, generating positive intrathoracic pressures as high as 300 mmHg. With sudden release of the laryngeal contraction, rapid expiratory flows are generated, exceeding the normal “envelope” of maximal expiratory flow seen on the flow-volume curve (Fig. 40-1). Bronchial smooth-muscle contraction together with dynamic com­ pression of airways narrow airway lumens and maximize the velocity of exhalation. The kinetic energy available to dislodge mucus from the inside of airway walls is directly proportional to the square of the veloc­ ity of expiratory airflow. A deep breath preceding a cough optimizes the function of the expiratory muscles; a series of repetitive coughs at successively lower lung volumes sweeps the point of maximal expira­ tory velocity progressively further into the lung periphery.

Patient’s

Predicted

Flow (L/sec) Coughs

10 11 –2 –4 –6 –8 –10 Volume (L) FIGURE 40-1  Flow-volume curve shows spikes of high expiratory flow achieved with cough.

TABLE 40-1  Causes of Impaired Cough and Airway Clearance Respiratory muscle weakness Chest wall or abdominal pain Chest wall deformity (e.g., severe kyphoscoliosis) Impaired glottic closure or tracheostomy Central respiratory depression (e.g., anesthesia, sedation, or neurologic disease) Abnormal airway secretions Ciliary dysfunction Tracheobronchomalacia Bronchiectasis Tracheal or bronchial stenoses ■ ■IMPAIRED COUGH Weak or ineffective cough compromises the ability to clear lower respi­ ratory tract secretions, predisposing to more serious infections and their sequelae. Weakness or paralysis of the expiratory (abdominal and intercostal) muscles and pain in the chest wall or abdomen are among the most common causes of impaired cough (Table 40-1). Cough strength is generally assessed qualitatively; peak expiratory flow or maximal expiratory pressure at the mouth can be used as a surrogate marker for cough strength. A variety of assistive devices and tech­ niques have been developed to improve cough efficacy, running the gamut from simple (splinting of the abdominal muscles with a tightly held pillow to reduce postoperative pain while coughing) to complex (a mechanical cough-assist device supplied via face mask or tracheal tube that applies a cycle of positive pressure followed rapidly by nega­ tive pressure). Cough may fail to clear secretions completely despite a preserved ability to generate normal expiratory velocities; such failure may be due to abnormal airway secretions (e.g., abnormally viscous secretions of cystic fibrosis), ciliary dysfunction (e.g., primary ciliary dyskinesia), or structural abnormalities of the airways (e.g., tracheoma­ lacia with excessive expiratory collapse of the trachea during cough). ■ ■SYMPTOMATIC COUGH Cough may occur in the context of other respiratory symptoms that together point to a diagnosis; for example, cough accompanied by wheezing, shortness of breath, and chest tightness after exposure to a cat or other sources of allergens suggests asthma. At times, cough is the dominant or sole symptom of disease, and it may be of sufficient duration and severity that relief is sought. The duration of cough is a clue to its etiology, at least retrospectively. Acute cough (<3 weeks) is most commonly due to a respiratory tract infection, aspiration, or inhalation of noxious chemicals or smoke. Subacute cough (3–8 weeks in duration) is a common residuum of tracheobronchitis, as in pertus­ sis or “postviral tussive syndrome.” Chronic cough (>8 weeks) may be caused by a wide variety of cardiopulmonary diseases, including those of inflammatory, infectious, neoplastic, and cardiovascular etiologies. When initial assessment with chest examination and radiography is normal, cough-variant asthma, gastroesophageal reflux, rhinosinusitis with excessive nasopharyngeal drainage, and medications (angio­ tensin-converting enzyme [ACE] inhibitors) are the most common identifiable causes of chronic cough. In a long-time cigarette smoker, an early-morning, productive cough suggests chronic bronchitis. A dry, irritative cough that lingers for >2 months following one or more respiratory tract infections (“postbronchitic cough”) is a very com­ mon cause of chronic cough, especially in the winter months. Chronic cough in the absence of identifiable etiology has been recognized with increasing frequency, is thought to be due to exaggerated neurologic signaling via sensory cough-reflex pathways, and is referred to as “chronic cough hypersensitivity syndrome.” ■ ■ASSESSMENT OF CHRONIC COUGH Except for our ability to detect the sound of excess airway secretions, details as to the resonance of the cough, its time of occurrence during the day, and the pattern of coughing (e.g., occurring in paroxysms) infrequently provide useful etiologic clues. Regardless of cause, cough often worsens upon first lying down at night, with talking, or with the

hyperpnea of exercise; it frequently improves with sleep. An exception may involve the cough that occurs only with certain allergic exposures or exercise in cold air, as in asthma. Useful historical questions include what circumstances surrounded the onset of cough, what makes the cough better or worse, and whether the cough produces sputum. The physical examination seeks clues suggesting the presence of cardiopulmonary disease, including findings such as wheezing or crackles on chest examination. Examination of the auditory canals and tympanic membranes (for irritation of the latter resulting in stimula­ tion of Arnold’s nerve), the nasal passageways (for rhinitis or polyps), and the nails (for clubbing) may also provide etiologic clues. Because cough can be a manifestation of a systemic disease such as sarcoidosis or vasculitis, a thorough general examination is likewise important. In virtually all instances, evaluation of chronic cough merits a chest radiograph. The list of diseases that can cause persistent cough without other symptoms and without detectable abnormalities on physical examination is long. It includes serious illnesses such as sarcoidosis or Hodgkin’s disease in young adults, lung cancer in older patients, and (worldwide) pulmonary tuberculosis. An abnormal chest film prompts an evaluation aimed at explaining the radiographic abnormality. In a patient with chronic productive cough, examination of expectorated sputum is warranted, because determining the cause of mucus hyperse­ cretion is a crucial clue to etiology. Purulent-appearing sputum should be sent for routine bacterial culture and, in certain circumstances, mycobacterial culture as well. Cytologic examination of mucoid sputum may be useful to assess for malignancy and oropharyngeal aspiration and to distinguish neutrophilic from eosinophilic bronchi­ tis. Expectoration of blood—whether streaks of blood, blood mixed with airway secretions, or pure blood—deserves a special approach to assessment and management (Chap. 41). ■ ■CHRONIC COUGH WITH A NORMAL

CHEST RADIOGRAPH It is commonly held that (alone or in combination) the use of an ACE inhibitor; postnasal drainage; gastroesophageal reflux; and asthma account for >90% of cases of chronic cough with a normal or non­ contributory chest radiograph; however, clinical experience does not support this contention. Strict adherence to this concept discourages the search for alternative explanations by both clinicians and research­ ers. In recent years, the concept of a distinct “cough hypersensitivity syndrome” has emerged, emphasizing the putative role of sensitized sensory nerve endings and afferent neural pathways in causing chronic refractory cough, akin to chronic neuropathic pain. It presents with a dry or minimally productive cough and a tickle or sensitivity in the throat and is made worse with talking, laughing, or exertion. It is more common in women than men and can last for years. Specific diagnostic criteria are lacking; the diagnosis is suspected when alternative etiolo­ gies are excluded by diagnostic testing or failed therapeutic trials. It is uncertain whether persistent daily coughing elicits an inflammatory response and is thereby self-perpetuating. ACE inhibitor–induced cough occurs in 5–30% of patients taking these agents and is not dose-dependent. ACE metabolizes bradykinin and other tachykinins, such as substance P. The mechanism of ACE inhibitor–associated cough may involve sensitization of sensory nerve endings due to accumulation of bradykinin. Any patient with chronic unexplained cough who is taking an ACE inhibitor should have a trial period off the medication, regardless of the timing of the onset of cough relative to the initiation of ACE inhibitor therapy. In most instances, a safe alternative is available; angiotensin receptor blockers do not cause cough. Failure to observe a decrease in cough after 1 month off medication argues strongly against this etiology. Postnasal drainage of any etiology can cause cough as a response to stimulation of sensory receptors of the cough-reflex pathway in the hypopharynx or aspiration of draining secretions into the trachea. The term upper airway cough syndrome has been coined to encompass the concept that chronic inflammation in the nose and sinuses can cause cough even in the absence of physical drainage into the phar­ ynx. Historical clues suggesting this etiology include a sensation of postnasal drip, frequent throat clearing, and sneezing and rhinorrhea.

On speculum examination of the nose, excess mucoid or purulent secretions, inflamed and edematous nasal mucosa, and/or polyps may be seen; in addition, secretions or a cobblestoned appearance of the mucosa along the posterior pharyngeal wall may be noted. Unfortu­ nately, there is no means by which to quantitate postnasal drainage. In many instances, this diagnosis must rely on subjective information provided by the patient. Furthermore, this assessment must also be counterbalanced by the fact that many people who have chronic post­ nasal drainage do not experience cough.

Linking gastroesophageal reflux to chronic cough poses similar chal­ lenges. It is thought that reflux of gastric contents into the lower esopha­ gus may trigger cough via reflex pathways initiated in the esophageal mucosa. Reflux to the level of the pharynx (laryngopharyngeal reflux), with consequent aspiration of gastric contents, causes a chemical bron­ chitis and possibly pneumonitis that can elicit cough for days afterward, but it is an uncommon finding among persons with chronic cough. Retrosternal burning after meals or on recumbency, frequent eructa­ tion, hoarseness, and throat pain may be indicative of gastroesophageal reflux. Nevertheless, reflux may also elicit minimal or no symptoms. Glottic inflammation detected on laryngoscopy may be a manifesta­ tion of recurrent reflux to the level of the throat, but it is a nonspecific finding. Quantification of the frequency and level of reflux requires a somewhat invasive procedure to measure esophageal pH (either naso­ pharyngeal placement of a catheter with a pH probe into the esophagus for 24 h or endoscopic placement of a radiotransmitter capsule into the esophagus) and, with newer techniques, esophageal pressures (manom­ etry) and nonacid reflux. The precise interpretation of test results that permits an etiologic linking of reflux events and cough remains debated. Again, assigning the cause of cough to gastroesophageal reflux must be weighed against the observation that many people with symptomatic reflux do not experience chronic cough. Cough CHAPTER 40 Cough alone as a manifestation of asthma is common among children but not among adults. Cough due to asthma in the absence of wheezing, shortness of breath, and chest tightness is referred to as “cough-variant asthma.” A history suggestive of cough-variant asthma ties the onset of cough to an exposure that typically triggers asthma and the resolution of cough to discontinuation of the exposure. Objective testing can establish the diagnosis of asthma (airflow obstruction on spirometry that varies over time or reverses in response to a bronchodilator) or exclude it with certainty (a negative response to a bronchoprovocation challenge—e.g., with methacholine). In a patient capable of taking reliable measure­ ments, home expiratory peak flow monitoring can be a cost-effective method to support or discount a diagnosis of asthma. Eosinophilic bronchitis causes chronic cough with a normal chest radiograph. This uncommon condition is characterized by sputum eosinophilia in excess of 3% without airflow obstruction or bronchial hyperresponsiveness and is successfully treated with inhaled glucocor­ ticoids. Measurement of an elevated concentration of nitric oxide in exhaled breath has the potential to detect eosinophilic airway inflam­ mation (in asthma or eosinophilic bronchitis) and predict a favorable response to inhaled steroids in persons with chronic cough. Treatment of chronic cough in a patient with a normal chest radio­ graph is often empirical and is targeted at the most likely cause(s) of cough as determined by history, physical examination, and possibly pulmonary function testing. Therapy for postnasal drainage depends on the presumed etiology (infection, allergy, or vasomotor rhinitis) and may include systemic antihistamines; decongestants; antibiotics; nasal saline irrigation; and nasal pump sprays with glucocorticoids, antihistamines, or anticholinergics. Antacids, histamine type 2 (H2) receptor antagonists, and proton pump inhibitors are used to neutralize or decrease the production of gastric acid in gastroesophageal reflux disease; dietary changes, elevation of the head and torso during sleep, and medications to improve gastric emptying or impede the flow of refluxate (e.g., alginates) are additional therapeutic measures. Coughvariant asthma typically responds well to inhaled glucocorticoids and intermittent use of inhaled β2-agonist bronchodilators. Patients who fail to respond to treatment targeting the common causes of chronic cough or who have had these causes excluded by appropriate diagnostic testing should, in the opinion of the author,

33 - 41 Hemoptysis

41 Hemoptysis

undergo chest CT. Diseases causing cough that may be missed on chest x-ray include tumors, early interstitial lung disease, bronchiec­ tasis, and atypical mycobacterial pulmonary infection. On the other hand, patients with chronic cough who have normal findings on chest examination, lung function testing, oxygenation assessment, and chest CT can be reassured as to the absence of serious pulmonary pathology.

■ ■GLOBAL CONSIDERATIONS Regular exposure to air pollution can cause chronic cough and throat clearing, as well as lower respiratory tract disease. Smoke from cooking and heating fuels in poorly ventilated homes; toxic exposures in work settings lacking implementation of occupational safety standards; and ambient chemicals and particulates in highly polluted outdoor air are all forms of air pollution causing cough. Limited therapeutic options are available; treatment focuses on improving environmental air qual­ ity (e.g., use of a stove chimney in the home), removal from the expo­ sure, and use of an appropriate face mask. PART 2 Cardinal Manifestations and Presentation of Diseases In areas of the world where tuberculosis is endemic, chronic cough conjures the possibility of active pulmonary tuberculosis and mandates appropriate evaluation, including chest imaging and sputum analysis. ■ ■SYMPTOM-BASED TREATMENT OF COUGH Empiric treatment of chronic idiopathic cough with inhaled cortico­ steroids, inhaled anticholinergic bronchodilators, and macrolide anti­ biotics has been tried without consistent success. Currently available cough suppressants are only modestly effective. Most potent are nar­ cotic cough suppressants, such as codeine, hydrocodone, or morphine, which are thought to act in the “cough center” in the brainstem. The tendency of narcotic cough suppressants to cause drowsiness and con­ stipation and their potential for addictive dependence limit their appeal for long-term use. Dextromethorphan is an over-the-counter, centrally acting cough suppressant with fewer side effects and less efficacy than the narcotic cough suppressants. Dextromethorphan is thought to have a different site of action than narcotic cough suppressants and can be used in combination with them if necessary. Benzonatate is thought to inhibit neural activity of sensory nerves in the cough-reflex pathway. It is generally free of side effects; however, its effectiveness in suppressing cough is variable and unpredictable. Inhaled lidocaine, an inhibitor of voltage-gated sodium channels, provides transient cough suppres­ sion, but because of associated oropharyngeal anesthesia, it poses an increased risk of aspiration. Attempts to treat cough hypersensitivity syndrome have focused on inhibition of neural pathways. Small case series and randomized clinical trials have indicated benefit from off-label use of gabapentin, pregabalin, or amitriptyline. Recent studies suggest a role for behav­ ioral modification using specialized speech therapy techniques, but widespread application of this modality is currently not practical. Novel cough suppressants without the limitations of currently available agents are greatly needed. Approaches that are being explored include the development of neurokinin-1 receptor antagonists, transient recep­ tor protein vanilloid-1 (TRPV1) channel antagonists, P2X3 channel antagonists, and novel opioid and opioid-like receptor agonists. Acknowledgment Christopher H. Fanta contributed to this chapter in the 21st edition and some material from that chapter has been retained here. ■ ■FURTHER READING Brightling CE et al: Eosinophilic bronchitis as an important cause of chronic cough. Am J Respir Crit Care Med 160:406, 1999. Carroll TL (ed): Chronic Cough. San Diego, Plural Publishing, Inc., 2019. Gibson P et al: Treatment of unexplained chronic cough: CHEST guideline and expert panel report. Chest 149:27, 2016. Kahrilas PJ et al: Chronic cough due to gastroesophageal reflux in adults: CHEST Guideline and Expert Panel Report. Chest 150:1381, 2016. Mazzone SB et al: Chronic cough and cough hypersensitivity: From mech­ anistic insights to novel antitussives. Lancet Respir Med 10:1113, 2022. Morice AH et al: ERS guidelines on the diagnosis and treatment of chronic cough in adults and children. Eur Respir J 55:1901136, 2020. Smith JA, Woodcock A: Chronic cough. N Engl J Med 375:1544, 2016.

Erin M. DeBiasi, Carolyn D’Ambrosio

Hemoptysis Hemoptysis is the expectoration of blood originating from the lower respiratory tract. It can be confused initially with bleeding from the gastrointestinal tract (hematemesis) or nasal cavities (epistaxis). The amount of blood that is being expectorated (volume and frequency) is the most important information to gather as massive or life-threatening hemoptysis (variable definitions but commonly expectorating >150 mL in 24 h or a bleeding rate of ≥100 mL/h) requires emergent interven­ tion. This chapter focuses on non-life-threatening hemoptysis, which is more common. ANATOMY AND PHYSIOLOGY OF HEMOPTYSIS Hemoptysis originates in the lower respiratory tract, anywhere from the glottis to the alveolus. The bleeding most commonly arises from the bronchi or medium-sized airways, but a thorough evaluation of the entire respiratory tree is important. The blood supply to the lungs is from both the pulmonary and bronchial circulations. The pulmonary circulation is a low-pressure system that is essential for gas exchange at the alveoli; in contrast, the bronchial circulation originates from the aorta and, thus, is a higher-pressure system. The bronchial arteries supply the airways and can neovascularize tumors, dilated airways in bronchiectasis, and cavitary lesions. Most hemoptysis originates from the bronchial circulation, the higher-pressure system, which can make it difficult to control. ETIOLOGY Infection, malignancy, and vascular disease are some of the common causes of hemoptysis, but the differential is quite broad. In the United States, the most common causes remain viral bronchitis, bron­ chiectasis, or malignancy. In other parts of the world, infections such as tuberculosis are the most common causes. ■ ■INFECTIONS Although most small-volume hemoptysis cases are due to viral bron­ chitis, patients with chronic bronchitis are at risk for bacterial super­ infection. Streptococcus pneumoniae, Haemophilus influenzae, and Moraxella catarrhalis are the more common bacteria involved, and these infections can increase airway inflammation that leads to bleed­ ing. Similarly, patients with bronchiectasis, including those with cystic fibrosis, can have hemoptysis during exacerbations. Due to recurrent bacterial infection, bronchiectatic airways are dilated, inflamed, and highly vascular, supplied by the bronchial circulation. This can cause bronchiectasis to also be a significant cause of massive hemoptysis and subsequent death. Tuberculosis used to be the most common cause of hemop­ tysis worldwide, but in industrialized countries, bronchitis and bronchiectasis are more common. In patients with tuberculosis, development of cavitary disease is frequently the source of bleed­ ing, but rarer complications such as erosion of a pulmonary artery aneurysm into a preexisting cavity (i.e., Rasmussen’s aneurysm) can also be the source. Other infectious agents such as endemic fungi, Nocardia, and non­ tuberculous mycobacteria can present as cavitary lung disease com­ plicated by hemoptysis. In addition, Aspergillus species can develop into mycetomas within preexisting cavities, with neovascularization to these inflamed spaces leading to bleeding. Pulmonary abscesses and necrotizing pneumonia can cause bleeding by devitalizing lung paren­ chyma. Common responsible organisms include Staphylococcus aureus, Klebsiella pneumoniae, and oral anaerobes. Paragonimiasis can mimic tuberculosis and is another significant cause of hemoptysis seen globally; it is common in Southeast Asia and China, although cases have been reported in North America from raw

crayfish ingestion. It should be considered as a cause of hemoptysis in recent immigrants from endemic areas. ■ ■VASCULAR Hemoptysis from a vascular cause can be associated with cardiac disease, pulmonary embolism, arteriovenous malformation, or dif­ fuse alveolar hemorrhage (DAH). While the classic description of the sputum expectorated in pulmonary edema (from elevated left end-diastolic pressure) is “pink and frothy,” a spectrum of hemoptysis including frank blood can be seen. This observation is particularly true now with the more widespread use of anticoagulants and antiplatelet medications. Pulmonary embolism with parenchymal infarction can present with hemoptysis, but pulmonary emboli do not commonly cause hemop­ tysis. An ectatic vessel in an airway or a pulmonary arteriovenous malformation can be a source of bleeding. A rare vascular cause of hemoptysis is the rupture of an aortobronchial fistula; these fistulae arise in the setting of aortic pathology such as aneurysm or pseudoa­ neurysm and can cause small bleeding episodes that result in massive hemoptysis. DAH causes significant bleeding into the lung parenchyma but, interestingly, is not often associated with hemoptysis. DAH typically presents with diffuse ground-glass opacities on chest imaging. A range of insults cause DAH, including immune-mediated capillaritis from diseases such as systemic lupus erythematosus, toxicity from cocaine and other inhalants, and stem cell transplantation. The so-called

“pulmonary-renal” syndromes, including granulomatosis with polyan­ giitis and anti–glomerular basement membrane (anti-GBM) disease, may lead to both hemoptysis and hematuria (though one manifesta­ tion may be present without the other). A recently identified cause of hemoptysis and DAH is vaping-induced lung injury. ■ ■MALIGNANCY Bronchogenic carcinoma of any histology is a common cause of hemop­ tysis (both massive and nonmassive). Hemoptysis can indicate airway involvement of the tumor and can be a presenting symptom of carcinoid tumors, vascular lesions that frequently arise in the proximal airways. Small-cell and squamous cell carcinomas are fre­ quently central in nature and more likely to erode into major pulmonary vessels, resulting in massive hemoptysis. Pul­ monary metastases from distant tumors (e.g., melanoma, sarcoma, adenocarci­ nomas of the breast and colon) can also cause bleeding. Kaposi’s sarcoma, seen in advanced acquired immunodeficiency syndrome, is very vascular and can develop anywhere along the respiratory tract, from the bronchi to the oral cavity. Rule out other sources: -Oropharynx -Gastrointestinal tract Nonmassive No risk factors Risk factors ■ ■MECHANICAL AND OTHER CAUSES In addition to infection, vascular dis­ ease, and malignancy, other insults to the pulmonary system can cause hemoptysis. Pulmonary endometrio­ sis causes cyclical bleeding known as catamenial hemoptysis. Foreign body aspiration can lead to airway irritation and bleeding. Diagnostic and thera­ peutic procedures are also potential offenders: pulmonary vein stenosis can result from left atrial procedures, such as pulmonary vein isolation, and pul­ monary artery catheters can lead to rupture of the pulmonary artery if the distal balloon is kept inflated. Finally, in the setting of thrombocytopenia, Treat underlying disease (usually infection) Persistent bleeding FIGURE 41-1  Approach to the management of hemoptysis. CBC, complete blood count; CT, computed tomography; CXR, chest x-ray; UA, urinalysis.

coagulopathy, anticoagulation, or antiplatelet therapy, even minor insults can cause hemoptysis.

EVALUATION AND MANAGEMENT ■ ■HISTORY The initial history should be directed at assessing the pattern, severity, and quantity of hemoptysis. An approach to management of hemop­ tysis is outlined in Fig. 41-1. A patient’s description of the sputum (e.g., flecks of blood, pink-tinged, frank blood or clot) is helpful if you cannot examine it. Quantification is often challenging for patients, so using references like cups (one U.S. cup is 236 mL) can be helpful. Life-threatening hemoptysis is defined by the presence of significantly abnormal gas exchange, hemodynamic compromise, or threat for airway obstruction. Patients rarely die of exsanguination but, rather, are at risk of death due to asphyxiation from blood filling the airways and airspaces. This can occur with blood loss of >400 mL within 24 h or >150 mL at one time. Fortunately, life-threatening hemoptysis only accounts for 5–15% of cases of hemoptysis. Hemoptysis CHAPTER 41 Further history may help define the etiology of hemoptysis. Smok­ ing history and/or unintentional weight loss may point to possible malignancy. Preceding fevers, cough, and/or sputum production may suggest infection. A history of prior diagnosed chronic lung condi­ tions, especially cystic fibrosis or other chronic bronchiectatic diseases, is important to note. Screening for causes of pseudohemoptysis (i.e., other upper airway or gastrointestinal) is also helpful. ■ ■PHYSICAL EXAMINATION Patients should initially be assessed for signs of life-threatening hemop­ tysis including hypoxemia, tachycardia, and hemodynamic instability. Examination should include possible sites of extrapulmonary bleeding such as the nasal and oral cavities. Auscultation of the lungs may sug­ gest a laterality. Other relevant physical findings may suggest other etiologies of the hemoptysis and include clubbing, signs of a bleeding diathesis (e.g., skin or mucosal ecchymoses and petechiae), telangiec­ tasias, or skin rash. Patient with hemoptysis History and physical examination Quantify amount of bleeding Massive Protect airway CXR, CBC, UA, creatinine, coagulation studies Bleeding stops Bleeding continues Embolization or resection CT scan Bronchoscopy Treat underlying disease Persistent bleeding

34 - 42 Hypoxia and Cyanosis

42 Hypoxia and Cyanosis

■ ■DIAGNOSTIC STUDIES Laboratory studies for initial evaluation should include a complete blood count, coagulation studies, basic metabolic panel, and urinalysis (to evaluate for pulmonary-renal disease). The absence of anemia in lifethreatening hemoptysis is not uncommon, as asphyxiation can occur without large blood volume loss. Infectious workup (including bacterial sputum culture, acid-fast bacillus culture, and respiratory viral panel) and serologic workup (including antinuclear antibody, antineutrophilic cytoplasmic antibody, and anti-GBM) can be obtained if indicated.

Imaging of the chest is essential. While a chest radiograph is often first obtained, aside from large masses, it often does not localize the site and can be normal. In most patients without risk factors for malignancy or other abnormalities in the initial evaluation and with a normal chest radiograph, treating for bronchitis and ensuring close follow-up is a reasonable strategy, with further diagnostic workup. PART 2 Cardinal Manifestations and Presentation of Diseases In contrast, patients with risk factors for malignancy (i.e., age >40, especially those with risk factors for malignancy or significant hemop­ tysis) should have a chest computed tomography (CT). A chest CT identifies the site and cause of hemoptysis in the majority of patients. A CT angiogram can be considered to identify a source for possible embolization if needed. A diagnostic bronchoscopy can be a compli­ mentary study performed to evaluate for subtle mucosal lesions that are often missed on CT scans, perform interventions as per below, or localize the general location and laterality of bleeding. This is best performed during an acute episode of hemoptysis to increase the yield. ■ ■INTERVENTIONS When the amount of hemoptysis is life-threatening, there are three simultaneous goals: first, protect the nonbleeding lung; second, locate the site of bleeding; and third, control the bleeding. Protecting the airway and nonbleeding lung is paramount in the management of life-threatening hemoptysis because asphyxiation can happen quickly. If the side of bleeding is known, the patient should be positioned with the bleeding side down to use gravitational advantage to keep blood out of the nonbleeding lung. A strong cough reflex can often be highly effective at clearing clot from the airway, but intubation is sometimes necessary if the patient cannot protect their airway. Intubation with a large endotracheal tube (size 8.5) is preferred to allow for suctioning and interventions. If needed, this can be advanced into the mainstem airway of the nonbleeding lung for isolation. Double-lumen endotracheal tubes can also be used, but the lumen of each is often too small for suctioning and therapeutic interventions. Imaging obtained during initial evaluation can indicate the source of the bleeding. Flexible bronchoscopy during active bleeding is most useful. Even if a bleeding lesion is not identified, flexible bronchoscopy can help identify a side and lobe. Finally, proceeding directly to CT angiography is also a reasonable strategy given that it has both diag­ nostic and therapeutic capabilities. Controlling the bleeding during an episode of life-threatening hemoptysis can be accomplished in one of three ways: from the airway lumen, from the involved blood vessel, or by surgical resection of both airway and vessel involved. Any known bleeding diathesis should be corrected first. As above, bronchoscopic measures can often be diag­ nostic, but also therapeutic if the bleeding is from a central airway lesion. Initially, a flexible bronchoscope can be used to help stabilize a patient via suctioning clot and insertion of a balloon catheter or bron­ chial blocker to occlude the involved airway. Additionally, instillation of iced saline or epinephrine can help temporize bleeding. Tranexamic acid (TXA), an antifibrinolytic agent (500 mg/5 mL), can be instilled during bronchoscopy or administered via nebulizer. Rigid bronchos­ copy, done by an interventional pulmonologist or thoracic surgeon, allows therapeutic interventions of bleeding airway lesions such as argon plasma coagulation and cautery, which can be definitive. How­ ever, because most life-threatening cases of hemoptysis arise from the bronchial circulation, bronchial artery embolization is the procedure of choice for control of the bleeding. It is generally successful in the short term, with >80% success rate at controlling bleeding immediately, although bleeding can recur if the underlying disease (e.g., a myce­ toma) is not treated. Surgical resection has a high mortality rate (up to

15–40%) and should not be pursued unless initial measures have failed and bleeding is ongoing. Ideal candidates for surgery have localized disease but otherwise normal lung parenchyma. Acknowledgment Anna K. Brady and Patricia A. Kritek contributed to this chapter in the 20th edition and some material from that chapter has been retained here. ■ ■FURTHER READING Bellam BL et al: Efficacy of tranexamic acid in haemoptysis: A ran­ domized, controlled pilot study. Pulm Pharmacol Ther 40:80, 2016. Davidson K, Shojaee S: Managing massive hemoptysis. Chest 157:77, 2020. Flume PA et al: CF pulmonary guidelines. Pulmonary complications: Hemoptysis and pneumothorax. Am J Respir Crit Care Med 182:298, 2010. Layden JE et al: Pulmonary illness related to e-cigarette use in Illinois and Wisconsin-final report. N Engl J Med 382:903, 2020. Lim RK et al: Evaluating hemoptysis hospitalizations among patients with bronchiectasis in the United States: A population-based cohort study. BMC Pulm Med 21:392, 2021. Mondoni M et al: Observational, multicentre study on the epidemiology of haemoptysis. Eur Resp J 51:1701813, 2018. Mondoni M et al: Bronchoscopy to assess patients with hemoptysis: Which is the optimal timing? BMC Pulm Med 19:36, 2019. Joseph Loscalzo

Hypoxia and Cyanosis HYPOXIA The fundamental purpose of the cardiorespiratory system is to deliver O2 and nutrients to cells and to remove CO2 and other metabolic products from them. Proper maintenance of this function depends not only on intact cardiovascular and respiratory systems, but also on an adequate number of red blood cells and hemoglobin, and a supply of inspired gas containing adequate O2. ■ ■RESPONSES TO HYPOXIA Decreased O2 availability to cells typically results in an inhibition of oxidative phosphorylation and increased anaerobic glycolysis. This switch from aerobic to anaerobic metabolism, the Pasteur effect, reduces the yield of adenosine 5′-triphosphate (ATP) produced per mole of glucose. In severe hypoxia, when ATP production is inad­ equate to meet the energy requirements of ionic and osmotic equilib­ rium, cell membrane depolarization leads to uncontrolled Ca2+ influx and activation of Ca2+-dependent phospholipases and proteases. These events, in turn, cause cell swelling, activation of apoptotic pathways, and, ultimately, cell death. The adaptations to hypoxia are mediated, in part, by the upregu­ lation of genes encoding a variety of proteins, including glycolytic enzymes, such as phosphoglycerate kinase and phosphofructokinase, as well as the glucose transporters Glut-1 and Glut-2; and by growth factors, such as vascular endothelial growth factor (VEGF) and eryth­ ropoietin, which enhance erythrocyte production. The hypoxia-induced increase in expression of these and other key proteins is largely governed by the hypoxia-sensitive transcription factor, hypoxia-inducible factor-1 (HIF-1). During hypoxia, systemic arterioles dilate, at least in part, by opening of KATP channels in vascular smooth-muscle cells due to the hypoxiainduced reduction in ATP concentration. By contrast, in pulmonary

vascular smooth-muscle cells, inhibition of K+ channels causes depolar­ ization, which, in turn, activates voltage-gated Ca2+ channels, raising the cytosolic [Ca2+] and causing smooth-muscle cell contraction. Hypoxiainduced pulmonary arterial constriction shunts blood away from poorly ventilated portions toward better ventilated portions of the lung (i.e., improves ventilation-perfusion mismatch); however, it also increases pulmonary vascular resistance and right ventricular afterload. Effects on the Central Nervous System  Changes in the central nervous system (CNS) function, particularly the higher centers, are especially important consequences of hypoxia. Acute hypoxia causes impaired judgment, motor incoordination, and a clinical picture resembling acute alcohol intoxication. High-altitude illness is charac­ terized by headache secondary to cerebral vasodilation, gastrointestinal symptoms, dizziness, insomnia, fatigue, or somnolence. Pulmonary arterial and sometimes venous constriction causes capillary leakage and high-altitude pulmonary edema (HAPE) (Chap. 39), which inten­ sifies hypoxia, further promoting vasoconstriction. Rarely, high-altitude cerebral edema (HACE) develops, which is manifest by severe head­ ache and papilledema, and can cause coma. As hypoxia becomes more severe, the regulatory centers of the brainstem are affected, and death usually results from respiratory failure. Effects on the Cardiovascular System  Acute hypoxia stimu­ lates the chemoreceptor reflex arc to induce venoconstriction and systemic arterial vasodilation. These acute changes are accompanied by transiently increased myocardial contractility, which is followed by depressed myocardial contractility with prolonged hypoxia. ■ ■CAUSES OF HYPOXIA Respiratory Hypoxia  When hypoxia occurs from respiratory failure, Pao2 declines, and when respiratory failure is persistent, the hemoglobin-oxygen (Hb-O2) dissociation curve (see Fig. 103-2) is displaced to the right, with greater quantities of O2 released at any level of tissue Po2. Arterial hypoxemia, that is, a reduction of O2 saturation of arterial blood (Sao2), and consequent cyanosis are likely to be more marked when such depression of Pao2 results from pulmonary disease than when the depression occurs as the result of a decline in the frac­ tion of oxygen in inspired air (Fio2). In this latter situation, Paco2 falls secondary to anoxia-induced hyperventilation and the Hb-O2 dissocia­ tion curve is displaced to the left, limiting the decline in Sao2 at any level of Pao2. The most common cause of respiratory hypoxia is ventilation-perfusion mismatch resulting from perfusion of poorly ventilated alveoli. Respi­ ratory hypoxemia may also be caused by hypoventilation, in which case it is associated with an elevation of Paco2 (Chap. 296). These two forms of respiratory hypoxia are usually correctable by inspiring 100% O2 for several minutes. A third cause of respiratory hypoxia is shunting of blood across the lung from the pulmonary arterial to the venous bed (intrapulmonary right-to-left shunting) by perfusion of nonventilated portions of the lung, as in pulmonary atelectasis or through pulmonary arteriovenous connections. The low Pao2 in this situation is only par­ tially corrected by an Fio2 of 100%. Hypoxia Secondary to High Altitude  As one ascends rapidly to 3000 m (~10,000 ft), the reduction of the O2 content of inspired air (Fio2) leads to a decrease in alveolar Po2 to ∼60 mmHg, and a condition termed high-altitude illness develops (see above). At higher altitudes, arterial saturation declines rapidly and symptoms become more severe; and at 5000 m, unacclimated individuals usually cease to be able to function normally owing to the changes in CNS function described above. Hypoxia Secondary to Right-to-Left Extrapulmonary Shunting  From a physiologic viewpoint, this cause of hypoxia resembles intrapulmonary right-to-left shunting but is caused by con­ genital cardiac malformations, such as tetralogy of Fallot, transposition of the great arteries, atrial or ventricular septal defect, patent ductus arteriosus, and Eisenmenger’s syndrome (Chap. 280). As in pulmo­ nary right-to-left shunting, the Pao2 cannot be restored to normal with inspiration of 100% O2.

Anemic Hypoxia  A reduction in hemoglobin concentration of the blood is accompanied by a corresponding decline in the O2-carrying capacity of the blood. Although the Pao2 is normal in anemic hypoxia, the absolute quantity of O2 transported per unit volume of blood is diminished. As the anemic blood passes through the capillaries and the usual quantity of O2 is removed from it, the Po2 and saturation in the venous blood decline to a greater extent than normal.

Carbon Monoxide (CO) Intoxication  (See also Chap. 476) Hemoglobin that binds CO (carboxy-hemoglobin [COHb]) is unavail­ able for O2 transport. In addition, the presence of COHb shifts the Hb-O2 dissociation curve to the left (see Fig. 103-2) so that O2 is unloaded only at lower tensions, further contributing to tissue hypoxia. Hypoxia and Cyanosis CHAPTER 42 Circulatory Hypoxia  As in anemic hypoxia, the Pao2 is usually normal, but venous and tissue Po2 values are reduced as a conse­ quence of reduced tissue perfusion and greater tissue O2 extraction. This pathophysiology leads to an increased arterial-mixed venous O2 difference (a-v-O2 difference), or gradient. Generalized circulatory hypoxia occurs in heart failure (Chap. 264) and in most forms of shock (Chap. 314). Specific Organ Hypoxia  Localized circulatory hypoxia may occur as a result of decreased perfusion secondary to arterial obstruction, as in localized atherosclerosis in any vascular bed, or as a consequence of vasoconstriction, as observed in Raynaud’s phenomenon (Chap. 292). Localized hypoxia may also result from venous obstruction and the resultant expansion of interstitial fluid causing arteriolar compression and, thereby, reduction of arterial inflow. Edema, which increases the distance through which O2 must diffuse before it reaches cells, can also cause localized hypoxia. In an attempt to maintain adequate perfusion to more vital organs in patients with reduced cardiac output secondary to heart failure or hypovolemic shock, vasoconstriction may reduce perfusion in the limbs and skin, causing hypoxia of these regions. Increased O2 Requirements  If the O2 consumption of tissues is elevated without a corresponding increase in perfusion, tissue hypoxia ensues and the Po2 in venous blood declines. Ordinarily, the clinical picture of patients with hypoxia due to an elevated metabolic rate, as in fever or thyrotoxicosis, is quite different from that in other types of hypoxia: the skin is warm and flushed owing to increased cutaneous blood flow that dissipates the excessive heat produced, and cyanosis is usually absent. Exercise is a classic example of increased tissue O2 requirements. These increased demands are normally met by several mechanisms operating simultaneously: (1) an increase in the cardiac output and ventilation and, thus, O2 delivery to the tissues; (2) a preferential shift in blood flow to the exercising muscles by changing vascular resis­ tances in the circulatory beds of exercising tissues, directly and/or reflexly; (3) an increase in O2 extraction from the delivered blood and a widening of the arteriovenous O2 difference; and (4) a reduction in the pH of the tissues and capillary blood, shifting the Hb-O2 curve to the right (see Fig. 103-2) and thereby unloading more O2 from hemo­ globin. If the capacity of these mechanisms is exceeded, then hypoxia, especially of the exercising muscles, will result. Improper Oxygen Utilization  Cyanide (Chap. 470) and several other similarly acting poisons cause cellular hypoxia by impairing elec­ tron transport in mitochondria, thereby limiting oxidative phosphory­ lation and ATP production. The tissues are unable to use O2, and as a consequence, the venous blood tends to have a high O2 tension. This condition has been termed histotoxic hypoxia. ■ ■ADAPTATION TO HYPOXIA An important component of the respiratory response to hypoxia origi­ nates in special chemosensitive cells in the carotid and aortic bodies and in the respiratory center in the brainstem. The stimulation of these cells by hypoxia increases ventilation, with a loss of CO2, and can lead to respiratory alkalosis. When combined with the metabolic acidosis resulting from the production of lactic acid, the serum bicarbonate level declines (Chap. 58).

With the reduction of Pao2, cerebrovascular resistance decreases and cerebral blood flow increases in an attempt to maintain O2 delivery to the brain. However, when the reduction of Pao2 is accompanied by hyperventilation and a reduction of Paco2, cerebrovascular resistance rises, cerebral blood flow falls, and tissue hypoxia intensifies.

The diffuse, systemic vasodilation that occurs in generalized hypoxia increases the cardiac output. In patients with underlying heart disease, the requirements of peripheral tissues for an increase of cardiac output with hypoxia may precipitate congestive heart failure. In patients with ischemic heart disease, a reduced Pao2 may intensify myocardial isch­ emia and further impair left ventricular function. One of the important compensatory mechanisms for chronic hypoxia is an increase in the hemoglobin concentration and in the number of red blood cells in the circulating blood, that is, the devel­ opment of polycythemia induced by erythropoietin production (Chap. 108). In persons with chronic hypoxemia secondary to pro­ longed residence at a high altitude (>13,000 ft, 4200 m), a condition termed chronic mountain sickness develops. This disorder is character­ ized by a blunted respiratory drive, reduced ventilation, erythrocytosis, cyanosis, weakness, right ventricular enlargement secondary to pulmo­ nary hypertension, and even stupor. PART 2 Cardinal Manifestations and Presentation of Diseases CYANOSIS Cyanosis refers to a bluish color of the skin and mucous membranes resulting from an increased quantity of reduced hemoglobin (i.e., deoxygenated hemoglobin) or of hemoglobin derivatives (e.g., met­ hemoglobin or sulfhemoglobin) in the small blood vessels of those tissues. It is usually most marked in the lips, nail beds, ears, and malar eminences. Cyanosis, especially if developed recently, is more com­ monly detected by a family member than the patient. A cherry-colored flush, rather than cyanosis, is caused by COHb (Chap. 470). The degree of cyanosis is modified by the color of the cutaneous pigment and the thickness of the skin, as well as by the state of the cutaneous capillaries. The accurate clinical detection of the presence and degree of cyanosis is difficult, as proved by oximetric studies. In some instances, central cyanosis can be detected reliably when the Sao2 has fallen to 85%; in others, particularly in dark-skinned persons, it may not be detected until it has declined to 75%. In the latter case, examination of the mucous membranes in the oral cavity and the con­ junctivae rather than examination of the skin is more helpful in the detection of cyanosis. The increase in the quantity of reduced hemoglobin in the mucocu­ taneous vessels that produces cyanosis may be brought about either by an increase in the quantity of venous blood as a result of dilation of the venules (including precapillary venules) or by a reduction in the Sao2 in the capillary blood. In general, cyanosis becomes apparent when the concentration of reduced hemoglobin in capillary blood exceeds 40 g/L (4 g/dL). It is the absolute, rather than the relative, quantity of reduced hemo­ globin that is important in producing cyanosis. Thus, in a patient with severe anemia, the relative quantity of reduced hemoglobin in the venous blood may be very large when considered in relation to the total quantity of hemoglobin in the blood. However, since the concentra­ tion of the latter is markedly reduced, the absolute quantity of reduced hemoglobin may still be low, and therefore, patients with severe ane­ mia and even marked arterial desaturation may not display cyanosis. Conversely, the higher the total hemoglobin content, the greater is the tendency toward cyanosis; thus, patients with marked polycythemia tend to be cyanotic at higher levels of Sao2 than patients with normal hematocrit values. Likewise, local passive congestion, which causes an increase in the total quantity of reduced hemoglobin in the vessels in a given area, may cause cyanosis. Cyanosis is also observed when nonfunctional hemoglobin, such as methemoglobin (consequential or acquired) or sulfhemoglobin (Chap. 103), is present in blood. Cyanosis may be subdivided into central and peripheral types. In central cyanosis, the Sao2 is reduced or an abnormal hemoglobin deriv­ ative is present, and the mucous membranes and skin are both affected. Peripheral cyanosis is due to a slowing of blood flow and abnormally great extraction of O2 from normally saturated arterial blood; it results

from vasoconstriction and diminished peripheral blood flow, such as occurs in cold exposure, shock, congestive failure, and peripheral vas­ cular disease. Often in these conditions, the mucous membranes of the oral cavity, including the sublingual mucosa, may be spared. Clinical differentiation between central and peripheral cyanosis may not always be straightforward, and in conditions such as cardiogenic shock with pulmonary edema, there may be a mixture of both types. ■ ■DIFFERENTIAL DIAGNOSIS Central Cyanosis (Table 42-1)  Decreased Sao2 results from a marked reduction in the Pao2. This reduction may be brought about by a decline in the Fio2 without sufficient compensatory alveolar hyperventilation to maintain alveolar Po2. Cyanosis usually becomes manifest in an ascent to an altitude of 4000 m (13,000 ft). Seriously impaired pulmonary function, through perfusion of unven­ tilated or poorly ventilated areas of the lung or alveolar hypoventilation, is a common cause of central cyanosis (Chap. 296). This condition may occur acutely, as in extensive pneumonia or pulmonary edema, or chronically, with chronic pulmonary diseases (e.g., emphysema). In the latter situation, secondary polycythemia is generally present and club­ bing of the fingers (see below) may occur. Another cause of reduced Sao2 is shunting of systemic venous blood into the arterial circuit. Certain forms of congenital heart disease are associated with cyanosis on this basis (see above and Chap. 280). Pulmonary arteriovenous fistulae may be congenital or acquired, solitary or multiple, and microscopic or massive. The severity of cyano­ sis produced by these fistulae depends on their size and number. They occur with some frequency in hereditary hemorrhagic telangiectasia. Sao2 reduction and cyanosis may also occur in some patients with cirrhosis, presumably as a consequence of pulmonary arteriovenous fistulae or portal vein–pulmonary vein anastomoses. In patients with cardiac or pulmonary right-to-left shunts, the pres­ ence and severity of cyanosis depend on the size of the shunt relative to the systemic flow and on the Hb-O2 saturation of the venous blood. With increased extraction of O2 from the blood by the exercising muscles, the venous blood returning to the right side of the heart is more unsaturated than at rest, and shunting of this blood intensifies the cyanosis. Secondary polycythemia occurs frequently in patients in this setting and contributes to the cyanosis. TABLE 42-1  Causes of Cyanosis Central Cyanosis Decreased arterial oxygen saturation   Decreased atmospheric pressure—high altitude   Impaired pulmonary function     Alveolar hypoventilation     Inhomogeneity in pulmonary ventilation and perfusion (perfusion of hypoventilated alveoli)     Impaired oxygen diffusion   Anatomic shunts     Certain types of congenital heart disease     Pulmonary arteriovenous fistulas     Multiple small intrapulmonary shunts   Hemoglobin with low affinity for oxygen Hemoglobin abnormalities   Methemoglobinemia—hereditary, acquired   Sulfhemoglobinemia—acquired   Carboxyhemoglobinemia (not true cyanosis) Peripheral Cyanosis Reduced cardiac output Cold exposure Redistribution of blood flow from extremities Arterial obstruction Venous obstruction

35 - 43 Edema

43 Edema

Cyanosis can be caused by small quantities of circulating methe­ moglobin (Hb Fe3+) and by even smaller quantities of sulfhemoglobin (Chap. 103); both of these hemoglobin derivatives impair oxygen delivery to the tissues. Although they are uncommon causes of cya­ nosis, these abnormal hemoglobin species should be sought by spec­ troscopy when cyanosis is not readily explained by malfunction of the circulatory or respiratory systems. Generally, digital clubbing does not occur with these conditions. Peripheral Cyanosis  Probably the most common cause of periph­ eral cyanosis is the normal vasoconstriction resulting from exposure to cold air or water. When cardiac output is reduced, cutaneous vaso­ constriction occurs as a compensatory mechanism so that blood is diverted from the skin to more vital areas such as the CNS and heart, and cyanosis of the extremities may result even though the arterial blood is normally saturated. Arterial obstruction to an extremity, as with an embolus, or arte­ riolar constriction, as in cold-induced vasospasm (Raynaud’s phenom­ enon) (Chap. 292), generally results in pallor and coldness, and there may be associated cyanosis. Venous obstruction, as in thrombophlebi­ tis or deep venous thrombosis, dilates the subpapillary venous plexuses and thereby intensifies cyanosis. APPROACH TO THE PATIENT Cyanosis Certain features are important in arriving at the cause of cyanosis:

1. It is important to ascertain the time of onset of cyanosis. Cya­ nosis present since birth or infancy is usually due to congenital heart disease.
2. Central and peripheral cyanosis must be differentiated. Evidence of disorders of the respiratory or cardiovascular systems is help­ ful. Massage or gentle warming of a cyanotic extremity will increase peripheral blood flow and abolish peripheral, but not central, cyanosis.
3. The presence or absence of clubbing of the digits (see below) should be ascertained. The combination of cyanosis and club­ bing is frequent in patients with congenital heart disease and right-to-left shunting and is seen occasionally in patients with pulmonary disease, such as lung abscess or pulmonary arte­ riovenous fistulae. In contrast, peripheral cyanosis or acutely developing central cyanosis is not associated with clubbed digits.
4. Pao2 and Sao2 should be determined, and in patients with cya­ nosis in whom the mechanism is obscure, spectroscopic exami­ nation of the blood should be performed to look for abnormal types of hemoglobin (critical in the differential diagnosis of cyanosis). CLUBBING The selective bulbous enlargement of the distal segments of the fingers and toes due to proliferation of connective tissue, particularly on the dorsal surface, is termed clubbing; there is also increased sponginess of the soft tissue at the base of the clubbed nail. Clubbing may be heredi­ tary, idiopathic, or acquired and associated with a variety of disorders, including cyanotic congenital heart disease (see above), infective endo­ carditis, and a variety of pulmonary conditions (among them primary and metastatic lung cancer, bronchiectasis, asbestosis, sarcoidosis, lung abscess, cystic fibrosis, tuberculosis, and mesothelioma), as well as with some gastrointestinal diseases (including inflammatory bowel disease and hepatic cirrhosis). In some instances, it is occupational, for example, in jackhammer operators. Clubbing in patients with primary and metastatic lung cancer, mesothelioma, bronchiectasis, or hepatic cirrhosis may be associated with hypertrophic osteoarthropathy. In this condition, the subperios­ teal formation of new bone in the distal diaphyses of the long bones of the extremities causes pain and symmetric arthritis-like changes in the shoulders, knees, ankles, wrists, and elbows. The diagnosis of

hypertrophic osteoarthropathy may be confirmed by bone radiograph or magnetic resonance imaging (MRI). Although the mechanism of clubbing is unclear, it appears to be secondary to humoral substances that cause dilation of the vessels of the distal digits as well as growth factors released from platelet precursors in the digital circulation. In certain circumstances, clubbing is reversible, such as following lung transplantation for cystic fibrosis.

■ ■FURTHER READING Essouma M et al: Epidemiology of digital clubbing and hypertrophic osteoarthropathy: A systematic review and meta-analysis. J Clin Rheumatol 28:104, 2022. Gao H et al: Acquired methemoglobinemia: A systematic review of Edema CHAPTER 43 reported cases. Transfus Apher Sci 61:103299, 2022. MacIntyre NR: Tissue hypoxia: Implications for the respiratory clinician. Respir Care 59:1590, 2014. Joseph Loscalzo

Edema PLASMA AND INTERSTITIAL FLUID EXCHANGE Approximately two-thirds of total body water is intracellular and onethird is extracellular. One-fourth of the latter is in the plasma, and the remainder comprises the interstitial fluid. Edema represents an excess of interstitial fluid that has become evident clinically. There is constant interchange of fluid between the two compart­ ments of the extracellular fluid. The hydrostatic pressure within the capillaries and the colloid oncotic pressure in the interstitial fluid pro­ mote the movement of water and diffusible solutes from plasma to the interstitium. This movement is most prominent at the arterial origin of the capillary and falls progressively with the decline in intracapillary pressure and the rise in oncotic pressure toward the venular end. Fluid is returned from the interstitial space into the vascular system largely through the lymphatic system. These interchanges of fluids are nor­ mally balanced so that the volumes of the intravascular and interstitial compartments remain constant. However, a net movement of fluid from the intravascular to the interstitial spaces takes place and may be responsible for the development of edema under the following condi­ tions: (1) an increase in intracapillary hydrostatic pressure; (2) inad­ equate lymphatic drainage; (3) reductions in the oncotic pressure of plasma; (4) damage to or dysfunction of the capillary endothelial bar­ rier; and (5) increases in the oncotic pressure of the interstitial space. ■ ■REDUCTION OF EFFECTIVE ARTERIAL VOLUME In many forms of edema, the effective arterial blood volume, a param­ eter that represents the filling of the arterial tree and that effectively perfuses the tissues, is reduced. Underfilling of the arterial tree may be caused by a reduction of cardiac output and/or systemic vascular resistance, by the pooling of blood in the splanchnic veins (as in cir­ rhosis), and by hypoalbuminemia (Fig. 43-1A). As a consequence of this underfilling, a series of physiological responses designed to restore the effective arterial volume to normal are set into motion. A key ele­ ment of these responses is the renal retention of sodium and, therefore, water, thereby restoring effective arterial volume, but sometimes also leading to the development or intensification of edema. ■ ■RENAL FACTORS AND THE RENIN-ANGIOTENSINALDOSTERONE SYSTEM The diminished renal blood flow characteristic of states in which the effective arterial blood volume is reduced is translated by the renal

Low-output heart failure, Pericardial tamponade Constrictive pericarditis ↓Extracellular fluid volume ↓Cardiac output ↓Effective arterial volume Activation of ventricular and arterial receptors Nonosmotic vasopressin stimulation PART 2 Cardinal Manifestations and Presentation of Diseases SNS stimulation ↑Systemic and renal arterial vascular resistance Renal H2O retention Restoration of effective arterial volume A High-output cardiac failure Sepsis Cirrhosis Arteriovenous fistula Pregnancy Arterial vasodilators ↓Systemic vascular resistance ↓Effective arterial volume Activation of arterial baroreceptors SNS stimulation Nonosmotic AVP stimulation ↑Cardiac output ↑Systemic arterial, vascular, and renal resistance Renal H2O retention Maintenance of arterial circulatory integrity B FIGURE 43-1  Clinical conditions in which a decrease in cardiac output (A) and systemic vascular resistance (B) cause arterial underfilling with resulting neurohumoral activation and renal sodium and water retention. In addition to activating the neurohumoral axis, adrenergic stimulation causes renal vasoconstriction and enhances sodium and fluid transport by the proximal tubule epithelium. AVP, arginine vasopressin; RAAS, renin-angiotensin aldosterone system; SNS, sympathetic nervous system. (From Annals of Internal Medicine, RW Schrier: Body fluid volume regulation in health and disease: A unifying hypothesis. 113(2):155-159, 1990. Copyright © 1990, American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.) juxtaglomerular cells (specialized myoepithelial cells surrounding the afferent arteriole) into a signal for increased renin release. Renin is an enzyme with a molecular mass of about 40,000 Da that acts on its sub­ strate, angiotensinogen, an α2-globulin synthesized by the liver, to release angiotensin I, a decapeptide, which in turn is converted to angiotensin II (AII), an octapeptide. AII has generalized vasoconstrictor properties,

particularly on the renal efferent arteri­ oles. This action reduces the hydrostatic pressure in the peritubular capillaries, whereas the increased filtration frac­ tion raises the colloid osmotic pressure in these vessels, thereby enhancing salt and water reabsorption in the proximal tubule as well as in the ascending limb of the loop of Henle. ↓Oncotic pressure and/or ↑capillary permeability The renin-angiotensin-aldosterone system (RAAS) operates as both a hor­ monal and paracrine system. Its activa­ tion causes sodium and water retention and thereby contributes to edema for­ mation. Blockade of the conversion of angiotensin I to AII and blockade of the AII receptors enhance sodium and water excretion and reduce many forms of edema. AII that enters the systemic circulation stimulates the production of aldosterone by the zona glomeru­ losa of the adrenal cortex. Aldosterone in turn enhances sodium reabsorption (and potassium excretion) by the col­ lecting tubule, further favoring edema formation. Blockade of the action of aldosterone by spironolactone or eplerenone (aldosterone antagonists) or by amiloride (a blocker of epithelial sodium channels) often induces a mod­ erate diuresis in edematous states. Activation of RAAS Renal Na+ retention ■ ■ARGININE VASOPRESSIN (See also Chap. 393) The secretion of arginine vasopressin (AVP) by the posterior pituitary gland occurs in response to increased intracellular osmolar concentration; by stimulat­ ing V2 receptors, AVP increases the reabsorption of free water in the dis­ tal tubules and collecting ducts of the kidney, thereby increasing total body water. Circulating AVP is elevated in many patients with heart failure sec­ ondary to a nonosmotic stimulus asso­ ciated with decreased effective arterial volume and reduced compliance of the left atrium. Such patients fail to show the normal reduction of AVP with a reduction of osmolality, contributing to edema formation and hyponatremia. Activation of RAAS Renal Na+ retention ■ ■ENDOTHELIN-1 This potent peptide vasoconstrictor is released by endothelial cells. Its con­ centration in the plasma is elevated in patients with severe heart failure and contributes to renal vasoconstriction, sodium retention, and edema. ■ ■NATRIURETIC PEPTIDES Atrial distention causes release into the circulation of atrial natriuretic peptide (ANP), a 3000-Da polypeptide. A high-molecular-weight precursor of ANP is stored in secretory granules within atrial myocytes. A closely related natriuretic peptide (pre-prohormone brain natriuretic peptide [BNP]) is stored primarily in ventricular myocytes and is released when ventricular diastolic pressure rises. Released ANP and BNP (which is derived from its precursor) bind to the natriuretic receptor-A, which

causes (1) excretion of sodium and water by augmenting glomerular filtration, inhibiting sodium reabsorption in the proximal tubule, and inhibiting release of renin and aldosterone; and (2) dilation of arteri­ oles and venules by antagonizing the vasoconstrictor actions of AII, AVP, and sympathetic stimulation. Thus, elevated levels of natriuretic peptides have the capacity to oppose sodium retention in hypervolemic and edematous states. Although circulating levels of ANP and BNP are elevated in heart failure and in cirrhosis with ascites, these natriuretic peptides are not sufficiently potent to prevent edema formation. Indeed, in edema­ tous states, resistance to the actions of natriuretic peptides may be increased, further reducing their effectiveness. Further discussion of the control of sodium and water balance is found in Chap. S1. ■ ■CLINICAL CAUSES OF EDEMA A weight gain of several kilograms usually precedes overt manifes­ tations of generalized edema. Anasarca refers to gross, generalized edema. Ascites (Chap. 53) and hydrothorax refer to accumulation of excess fluid in the peritoneal and pleural cavities, respectively, and are considered special forms of edema. Edema is recognized by the persistence of an indentation of the skin after pressure, known as “pitting” edema. In its more subtle form, edema may be detected by noting that after the stethoscope is removed from the chest wall, the rim of the bell leaves an indentation on the skin of the chest for a few minutes. Edema may be present when the ring on a finger fits more snugly than in the past or when a patient complains of difficulty putting on shoes, particularly in the evening when dependent edema is greatest. Edema may also be recognized by puffiness of the face (most prominent upon awakening), which is most readily appar­ ent in the periorbital areas owing to relative tissue laxity. ■ ■GENERALIZED EDEMA The differences among the major causes of generalized edema are shown in Table 43-1. Cardiac, renal, hepatic, or nutritional disorders are responsible for a large majority of patients with generalized edema. Consequently, the differential diagnosis of generalized edema should be directed toward identifying or excluding these several conditions. Heart Failure  (See also Chap. 264) In heart failure, the impaired systolic emptying of the ventricle(s) and/or the impairment of ven­ tricular relaxation promotes an accumulation of blood in the venous circulation at the expense of the effective arterial volume. In addition, TABLE 43-1  Principal Causes of Generalized Edema: History, Physical Examination, and Laboratory Findings ORGAN SYSTEM HISTORY PHYSICAL EXAMINATION LABORATORY FINDINGS Cardiac Dyspnea with exertion prominent—often associated with orthopnea—or paroxysmal nocturnal dyspnea Elevated jugular venous pressure, ventricular (S3) gallop; occasionally with displaced or dyskinetic apical impulse; peripheral cyanosis, cool extremities, low pulse pressure when severe Hepatic Dyspnea uncommon, except if associated with significant degree of ascites; most often a history of ethanol abuse Frequently associated with ascites; jugular venous pressure normal or low; blood pressure lower than in renal or cardiac disease; one or more additional signs of chronic liver disease (jaundice, palmar erythema, Dupuytren’s contracture, spider angiomata, male gynecomastia; asterixis and other signs of encephalopathy) may be present Renal (CRF) Usually chronic: may be associated with uremic signs and symptoms, including decreased appetite, altered (metallic or fishy) taste, altered sleep pattern, difficulty concentrating, restless legs, or myoclonus; dyspnea can be present, but generally less prominent than in heart failure Elevated blood pressure; hypertensive retinopathy; uremic fetor; pericardial friction rub in advanced cases with uremia Renal (NS) Childhood diabetes mellitus; plasma cell dyscrasias Periorbital edema; hypertension Proteinuria (≥3.5 g/d); hypoalbuminemia; hypercholesterolemia; microscopic hematuria Abbreviations: CRF, chronic renal failure; NS, nephrotic syndrome. Source: Reproduced with permission from GM Chertow, E Braunwald, L Goldman (eds). Approach to the patient with edema, in Primary Cardiology, 2nd ed. Philadelphia, Saunders, 2003.

activation of the sympathetic nervous system and the RAAS (see above) acts in concert to cause renal vasoconstriction and reduction of glomerular filtration and salt and water retention. Sodium and water retention continue, and the increment in blood volume accumulates in the venous circulation, raising venous and intracapillary pressure and resulting in edema (Fig. 43-1).

The presence of overt cardiac disease, as manifested by cardiac enlargement and/or ventricular hypertrophy, together with clinical evi­ dence of cardiac failure, such as dyspnea, basilar rales, venous disten­ tion, and hepatomegaly, usually indicates that edema results from heart failure. Noninvasive tests such as electrocardiography, echocardiogra­ phy, and measurements of BNP (or N-terminal proBNP [NT-proBNP]) are helpful in establishing the diagnosis of heart disease. The edema of heart failure typically occurs in the dependent portions of the body. Edema CHAPTER 43 Edema of Renal Disease  (See also Chap. 326) The edema that occurs during the acute phase of glomerulonephritis is characteristi­ cally associated with hematuria, proteinuria, and hypertension. In most instances, the edema results from primary retention of sodium and water by the kidney owing to renal dysfunction. This state differs from most forms of heart failure in that it is characterized by a normal (or sometimes even increased) cardiac output. Patients with chronic renal failure may also develop edema due to primary renal retention of sodium and water. Nephrotic Syndrome and Other Hypoalbuminemic States  The primary alteration in the nephrotic syndrome is a dimin­ ished colloid oncotic pressure due to losses of large quantities (≥3.5 g/d) of protein into the urine and hypoalbuminemia (<3.0 g/dL). As a result of the reduced colloid osmotic pressure, the sodium and water that are retained cannot be confined within the vascular compartment, and total and effective arterial blood volumes decline. This process initi­ ates the edema-forming sequence of events described above, including activation of the RAAS. The nephrotic syndrome may occur during the course of a variety of kidney diseases, including glomerulonephritis, diabetic glomerulosclerosis, and hypersensitivity reactions. The edema is diffuse, symmetric, and most prominent in the dependent areas; periorbital edema is most prominent in the morning. Hepatic Cirrhosis  (See also Chap. 355) This condition is char­ acterized, in part, by hepatic venous outflow obstruction, which in turn expands the splanchnic blood volume, and hepatic lymph formation. Intrahepatic hypertension acts as a stimulus for renal sodium retention Elevated urea nitrogen-to-creatinine ratio common; serum sodium often decreased; elevated natriuretic peptides If severe, reductions in serum albumin, cholesterol, other hepatic proteins (transferrin, fibrinogen); liver enzymes elevated, depending on the cause and acuity of liver injury; tendency toward hypokalemia, respiratory alkalosis; macrocytosis from folate deficiency Elevation of serum creatinine and cystatin C; albuminuria; hyperkalemia, metabolic acidosis, hyperphosphatemia, hypocalcemia, anemia (usually normocytic)

and causes a reduction of effective arterial blood volume. These altera­ tions are frequently complicated by hypoalbuminemia secondary to reduced hepatic synthesis, as well as peripheral arterial vasodilation. These effects reduce the effective arterial blood volume, leading to activation of the sodium- and water-retaining mechanisms described above (Fig. 43-1B). The concentration of circulating aldosterone often is elevated by the failure of the liver to metabolize this hormone. Ini­ tially, the excess interstitial fluid is localized preferentially proximal (upstream) to the congested portal venous system, causing ascites (Chap. 53). In later stages, particularly when there is severe hypoal­ buminemia, peripheral edema may develop. A sizable accumulation of ascitic fluid may increase intraabdominal pressure and impede venous return from the lower extremities, thereby contributing to the accumu­ lation of the edema.

PART 2 Cardinal Manifestations and Presentation of Diseases Drug-Induced Edema  A large number of widely used drugs can cause edema (Table 43-2). Mechanisms include renal vasoconstriction (nonsteroidal anti-inflammatory drugs and cyclosporine), arteriolar dilation (vasodilators), augmented renal sodium reabsorption (steroid hormones), and capillary damage. Edema of Nutritional Origin  A diet grossly deficient in calo­ ries and particularly in protein over a prolonged period may produce hypoproteinemia and edema. The latter may be intensified by the development of beriberi heart disease, which also is of nutritional origin, in which multiple peripheral arteriovenous fistulae result in reduced effective systemic perfusion and effective arterial blood vol­ ume, thereby enhancing edema formation (Chap. 344) (Fig. 43-1B). Edema develops or becomes intensified when famished subjects are first provided with an adequate diet. The ingestion of more food may increase the quantity of sodium ingested, which is then retained along with water. So-called refeeding edema also may be linked to increased release of insulin, which directly increases tubular sodium reabsorp­ tion. In addition to hypoalbuminemia, hypokalemia and caloric defi­ cits may be involved in the edema of starvation. ■ ■LOCALIZED EDEMA In thrombophlebitis, varicose veins, and primary venous valve failure, the hydrostatic pressure in the capillary bed upstream (proximal) of TABLE 43-2  Drugs Associated with Edema Formation Nonsteroidal anti-inflammatory drugs Antihypertensive agents   Direct arterial/arteriolar vasodilators   Hydralazine   Clonidine   Methyldopa   Guanethidine   Minoxidil   Calcium channel antagonists α-Adrenergic antagonists Thiazolidinediones Steroid hormones   Glucocorticoids   Anabolic steroids   Estrogens   Progestins Cyclosporine Growth hormone Immunotherapies   Interleukin 2   OKT3 monoclonal antibody Source: Reproduced with permission from GM Chertow, in E Braunwald, L Goldman (eds): Approach to the patient with edema, in Primary Cardiology, 2nd ed. Philadelphia, Saunders, 2003.

the obstruction increases so that an abnormal quantity of fluid is trans­ ferred from the vascular to the interstitial space, which may give rise to localized edema. The latter may also occur in lymphatic obstruction caused by chronic lymphangitis, resection of regional lymph nodes, filariasis, and genetic (frequently called primary) lymphedema. The latter is particularly intractable because restriction of lymphatic flow results in both an increase in intracapillary pressure and increased protein concentration in the interstitial fluid, which act in concert to aggravate fluid retention. Other Causes of Edema  These causes include hypothyroidism (myxedema) due to tissue deposition of hyaluronic acid; hyper­ thyroidism (pretibial myxedema secondary to Graves’ disease), in which edema is typically nonpitting; hypercortisolism; pregnancy; and administration of estrogens and vasodilators, particularly calcium channel blockers. ■ ■DISTRIBUTION OF EDEMA The distribution of edema is an important guide to its cause. Edema associated with heart failure tends to be more extensive in the legs and to be accentuated in the evening, a feature also determined largely by posture. When patients with heart failure are confined to bed, edema may be most prominent in the presacral region. Edema resulting from hypoproteinemia, as occurs in the nephrotic syndrome, characteristically is generalized, but it is especially evi­ dent in the very soft tissues of the eyelids and face and tends to be most pronounced in the morning owing to the recumbent posture assumed during the night. Less common causes of facial edema include trichinosis, allergic reactions, and myxedema. Edema limited to one leg or to one or both arms is usually the result of venous and/ or lymphatic obstruction. Unilateral paralysis reduces lymphatic and venous drainage on the affected side and may also be responsible for unilateral edema. In patients with obstruction of the superior vena cava, edema is confined to the face, neck, and upper extremities in which the venous pressure is elevated compared with that in the lower extremities. APPROACH TO THE PATIENT Edema An important first question is whether the edema is localized or generalized. If it is localized, the local phenomena that may be responsible should be identified. If the edema is generalized, one should determine if there is serious hypoalbuminemia, e.g., serum albumin <3.0 g/dL. If so, the history, physical examination, uri­ nalysis, and other laboratory data will help evaluate the question of cirrhosis, severe malnutrition, or the nephrotic syndrome as the underlying disorder. If hypoalbuminemia is not present, one should determine if there is evidence of heart failure severe enough to promote generalized edema. Finally, it should be ascertained as to whether or not the patient has an adequate urine output or if there is significant oliguria or anuria. These abnormalities are discussed in Chaps. 55, 321, and 322. ■ ■FURTHER READING Clark AL, Cleland JG: Causes and treatment of oedema in patients with heart failure. Nature Rev Cardiol 10:156, 2013. Frison S et al: Omitting edema measurement: How much acute malnutrition are we missing? Am J Clin Nutr 102:1176, 2015. Koirala A et al: Etiology and management of edema: A review. Adv Kidney Dis Health 30:110, 2023. Levick JR, Michel CC: Microvascular fluid exchange and the revised Starling principle. Cardiovascular Res 87:198, 2010. Telinius N, Hjortdal VE: Role of the lymphatic vasculature in cardiovascular medicine. Heart 105:1777, 2019.

37 - 45 Palpitations

45 Palpitations

Joseph Loscalzo

Palpitations Palpitations are extremely common among patients who present to their internists and can best be defined as a “thumping,” “pounding,” or “fluttering” sensation in the chest. This sensation can be either inter­ mittent or sustained and either regular or irregular. Most patients inter­ pret palpitations as an unusual awareness of the heartbeat and become especially concerned when they sense that they have had “skipped” or “missing” heartbeats. Palpitations are often noted when the patient is quietly resting, during which time other stimuli are minimal. Palpita­ tions that are positional generally reflect a structural process within (e.g., atrial myxoma) or adjacent to (e.g., mediastinal mass) the heart. Palpitations are brought about by cardiac (43%), psychiatric (31%), miscellaneous (10%), and unknown (16%) causes, according to one large series. Among the cardiovascular causes are premature atrial and ventricular contractions, supraventricular and ventricular arrhythmias, mitral valve prolapse (with or without associated arrhythmias), aortic insufficiency, atrial myxoma, myocarditis, and pulmonary embolism. Intermittent palpitations are commonly caused by premature atrial or ventricular contractions: the post-extrasystolic beat is sensed by the patient owing to the increase in ventricular end-diastolic dimension following the pause in the cardiac cycle and the increased strength of contraction (post-extrasystolic potentiation) of that beat. Regular, sustained palpitations can be caused by regular supraventricular and ventricular tachycardias. Irregular, sustained palpitations can be caused by atrial fibrillation. It is important to note that most arrhythmias are not associated with palpitations. In those that are, it is often useful either to ask the patient to “tap out” the rhythm of the palpitations or to take their pulse during palpitations. In general, hyperdynamic cardio­ vascular states caused by catecholaminergic stimulation from exercise, stress, or pheochromocytoma can lead to palpitations. Palpitations are common among athletes, especially older endurance athletes. In addi­ tion, the enlarged ventricle of aortic regurgitation and accompanying hyperdynamic precordium frequently lead to the sensation of palpita­ tions. Other factors that enhance the strength of myocardial contrac­ tion, including tobacco, caffeine, aminophylline, atropine, thyroxine, cocaine, amphetamines, and cannabis, can cause palpitations. Psychiatric causes of palpitations include panic attacks or dis­ orders, anxiety states, and somatization, alone or in combination. Patients with psychiatric causes for palpitations more commonly report a longer duration of the sensation (>15 min) and other accom­ panying symptoms than do patients with other causes. Among the miscellaneous causes of palpitations are thyrotoxicosis, drugs (see above) and ethanol, spontaneous skeletal muscle contractions of the chest wall, pheochromocytoma, systemic mastocytosis, and postCOVID syndrome. APPROACH TO THE PATIENT Palpitations The principal goal in assessing patients with palpitations is to deter­ mine whether the symptom is caused by a life-threatening arrhyth­ mia. Patients with preexisting coronary artery disease (CAD) or risk factors for CAD are at greatest risk for ventricular arrhythmias (Chap. 253) as a cause for palpitations. In addition, the associa­ tion of palpitations with other symptoms suggesting hemodynamic compromise, including syncope or lightheadedness, supports this diagnosis. Palpitations caused by sustained tachyarrhythmias in patients with CAD can be accompanied by angina pectoris or dyspnea, and, in patients with ventricular dysfunction (systolic or diastolic), aortic stenosis, hypertrophic cardiomyopathy, or mitral stenosis (with or without CAD), can be accompanied by dyspnea from increased left atrial and pulmonary venous pressure.

Key features of the physical examination that will help confirm or refute the presence of an arrhythmia as a cause for palpita­ tions (as well as its adverse hemodynamic consequences) include measurement of the vital signs, assessment of the jugular venous pressure and pulse, and auscultation of the chest and precordium. A resting electrocardiogram can be used to document the arrhyth­ mia. If exertion is known to induce the arrhythmia and accom­ panying palpitations, exercise electrocardiography can be used to make the diagnosis. If the arrhythmia is sufficiently infrequent, other methods must be used, including continuous electrocar­ diographic (Holter) monitoring; telephonic monitoring, through which the patient can transmit an electrocardiographic tracing during a sensed episode; loop recordings (external or implantable), which can capture the electrocardiographic event for later review; and mobile (self-monitoring) cardiac outpatient telemetry. Data suggest that Holter monitoring is of limited clinical utility, while the implantable loop recorder and mobile cardiac outpatient telemetry are safe and possibly more cost-effective in the assessment of patients with (infrequent) recurrent, unexplained palpitations. The use of a diary or an electronic marker to indicate the timing of palpitations sensed by the patient is essential for appropriate interpretation of these studies. Exercise Intolerance CHAPTER 46 Most patients with palpitations do not have serious arrhythmias or underlying structural heart disease. If sufficiently troubling to the patient, occasional benign atrial or ventricular premature con­ tractions can often be managed with beta-blocker therapy. Palpita­ tions incited by alcohol, tobacco, or illicit drugs need to be managed by abstention, while those caused by pharmacologic agents should be addressed by considering alternative therapies when appropri­ ate or possible. Psychiatric causes of palpitations may benefit from cognitive therapy or pharmacotherapy. The physician should note that palpitations are at the very least bothersome and, on occasion, frightening to the patient. Once serious causes for the symptom have been excluded, the patient should be reassured that the palpi­ tations will not adversely affect overall prognosis. ■ ■FURTHER READING Crossland S, Berkin L: Problem based review: The patient with palpitations. Acute Med 11:169, 2012. Jamshed N et al: Emergency management of palpitations in the elderly: Epidemiology, diagnostic approaches, and therapeutic options. Clin Geriatr Med 29:205, 2013. Martson HR et al: Mobile self-monitoring ECG devices to diagnose arrhythmias that coincide with palpitations: A scoping review. Healthcare (Basel) 7:E96, 2019. Sakh R et al: Insertable cardiac monitors: current indications and devices. Expert Rev Med Devices 16:45, 2019. Weinstock C et al: Evidence-based approach to palpitations. Med Clin North Am 105:93, 2021. Joseph Loscalzo, William M. Oldham

Exercise Intolerance Exercise intolerance is defined as the inability to perform physical activity at a level expected for a person of a given age, sex, body mass, and muscle mass. Reduced exercise tolerance is a common symptom of many chronic diseases, including ischemic heart disease, valvular heart disease, heart failure, chronic obstructive pulmonary disease, inter­ stitial lung disease, cystic fibrosis, pulmonary hypertension, stroke, neuromuscular disorders, and postinfection syndromes, and it reduces

38 - 46 Exercise Intolerance

46 Exercise Intolerance

Joseph Loscalzo

Palpitations Palpitations are extremely common among patients who present to their internists and can best be defined as a “thumping,” “pounding,” or “fluttering” sensation in the chest. This sensation can be either inter­ mittent or sustained and either regular or irregular. Most patients inter­ pret palpitations as an unusual awareness of the heartbeat and become especially concerned when they sense that they have had “skipped” or “missing” heartbeats. Palpitations are often noted when the patient is quietly resting, during which time other stimuli are minimal. Palpita­ tions that are positional generally reflect a structural process within (e.g., atrial myxoma) or adjacent to (e.g., mediastinal mass) the heart. Palpitations are brought about by cardiac (43%), psychiatric (31%), miscellaneous (10%), and unknown (16%) causes, according to one large series. Among the cardiovascular causes are premature atrial and ventricular contractions, supraventricular and ventricular arrhythmias, mitral valve prolapse (with or without associated arrhythmias), aortic insufficiency, atrial myxoma, myocarditis, and pulmonary embolism. Intermittent palpitations are commonly caused by premature atrial or ventricular contractions: the post-extrasystolic beat is sensed by the patient owing to the increase in ventricular end-diastolic dimension following the pause in the cardiac cycle and the increased strength of contraction (post-extrasystolic potentiation) of that beat. Regular, sustained palpitations can be caused by regular supraventricular and ventricular tachycardias. Irregular, sustained palpitations can be caused by atrial fibrillation. It is important to note that most arrhythmias are not associated with palpitations. In those that are, it is often useful either to ask the patient to “tap out” the rhythm of the palpitations or to take their pulse during palpitations. In general, hyperdynamic cardio­ vascular states caused by catecholaminergic stimulation from exercise, stress, or pheochromocytoma can lead to palpitations. Palpitations are common among athletes, especially older endurance athletes. In addi­ tion, the enlarged ventricle of aortic regurgitation and accompanying hyperdynamic precordium frequently lead to the sensation of palpita­ tions. Other factors that enhance the strength of myocardial contrac­ tion, including tobacco, caffeine, aminophylline, atropine, thyroxine, cocaine, amphetamines, and cannabis, can cause palpitations. Psychiatric causes of palpitations include panic attacks or dis­ orders, anxiety states, and somatization, alone or in combination. Patients with psychiatric causes for palpitations more commonly report a longer duration of the sensation (>15 min) and other accom­ panying symptoms than do patients with other causes. Among the miscellaneous causes of palpitations are thyrotoxicosis, drugs (see above) and ethanol, spontaneous skeletal muscle contractions of the chest wall, pheochromocytoma, systemic mastocytosis, and postCOVID syndrome. APPROACH TO THE PATIENT Palpitations The principal goal in assessing patients with palpitations is to deter­ mine whether the symptom is caused by a life-threatening arrhyth­ mia. Patients with preexisting coronary artery disease (CAD) or risk factors for CAD are at greatest risk for ventricular arrhythmias (Chap. 253) as a cause for palpitations. In addition, the associa­ tion of palpitations with other symptoms suggesting hemodynamic compromise, including syncope or lightheadedness, supports this diagnosis. Palpitations caused by sustained tachyarrhythmias in patients with CAD can be accompanied by angina pectoris or dyspnea, and, in patients with ventricular dysfunction (systolic or diastolic), aortic stenosis, hypertrophic cardiomyopathy, or mitral stenosis (with or without CAD), can be accompanied by dyspnea from increased left atrial and pulmonary venous pressure.

Key features of the physical examination that will help confirm or refute the presence of an arrhythmia as a cause for palpita­ tions (as well as its adverse hemodynamic consequences) include measurement of the vital signs, assessment of the jugular venous pressure and pulse, and auscultation of the chest and precordium. A resting electrocardiogram can be used to document the arrhyth­ mia. If exertion is known to induce the arrhythmia and accom­ panying palpitations, exercise electrocardiography can be used to make the diagnosis. If the arrhythmia is sufficiently infrequent, other methods must be used, including continuous electrocar­ diographic (Holter) monitoring; telephonic monitoring, through which the patient can transmit an electrocardiographic tracing during a sensed episode; loop recordings (external or implantable), which can capture the electrocardiographic event for later review; and mobile (self-monitoring) cardiac outpatient telemetry. Data suggest that Holter monitoring is of limited clinical utility, while the implantable loop recorder and mobile cardiac outpatient telemetry are safe and possibly more cost-effective in the assessment of patients with (infrequent) recurrent, unexplained palpitations. The use of a diary or an electronic marker to indicate the timing of palpitations sensed by the patient is essential for appropriate interpretation of these studies. Exercise Intolerance CHAPTER 46 Most patients with palpitations do not have serious arrhythmias or underlying structural heart disease. If sufficiently troubling to the patient, occasional benign atrial or ventricular premature con­ tractions can often be managed with beta-blocker therapy. Palpita­ tions incited by alcohol, tobacco, or illicit drugs need to be managed by abstention, while those caused by pharmacologic agents should be addressed by considering alternative therapies when appropri­ ate or possible. Psychiatric causes of palpitations may benefit from cognitive therapy or pharmacotherapy. The physician should note that palpitations are at the very least bothersome and, on occasion, frightening to the patient. Once serious causes for the symptom have been excluded, the patient should be reassured that the palpi­ tations will not adversely affect overall prognosis. ■ ■FURTHER READING Crossland S, Berkin L: Problem based review: The patient with palpitations. Acute Med 11:169, 2012. Jamshed N et al: Emergency management of palpitations in the elderly: Epidemiology, diagnostic approaches, and therapeutic options. Clin Geriatr Med 29:205, 2013. Martson HR et al: Mobile self-monitoring ECG devices to diagnose arrhythmias that coincide with palpitations: A scoping review. Healthcare (Basel) 7:E96, 2019. Sakh R et al: Insertable cardiac monitors: current indications and devices. Expert Rev Med Devices 16:45, 2019. Weinstock C et al: Evidence-based approach to palpitations. Med Clin North Am 105:93, 2021. Joseph Loscalzo, William M. Oldham

Exercise Intolerance Exercise intolerance is defined as the inability to perform physical activity at a level expected for a person of a given age, sex, body mass, and muscle mass. Reduced exercise tolerance is a common symptom of many chronic diseases, including ischemic heart disease, valvular heart disease, heart failure, chronic obstructive pulmonary disease, inter­ stitial lung disease, cystic fibrosis, pulmonary hypertension, stroke, neuromuscular disorders, and postinfection syndromes, and it reduces

quality of life. While not all patients with these disorders necessarily manifest exercise intolerance, those who do often have an increased rate of disease progression, as well as mortality.

PATHOBIOLOGY The pathobiology of exercise intolerance depends on the specific underlying cause but can be physiologically defined by measuring exercise capacity in terms of the rate of oxygen consumption (V⋅O2) at peak exercise (V⋅O2max). Any factor that impairs O2 delivery or utilization can reduce V⋅O2max and cause exercise intolerance. In natural sequence, reduced inspired O2 concentration, reduced alveolar ventilation, impaired lung diffusion from alveolus to capillary, reduced hemoglobin concentration or transport (loading or release) of O2, decreased cardiac output, impaired diffusion of O2 into (skeletal) muscle, and impaired mitochondrial respiration can each lead to decreased exercise capacity and exercise intolerance (Fig. 46-1). In the absence of clear evidence for a singular cause among these specific pathophysiologic abnormalities (such as decreased cardiac output in a patient with heart failure with reduced ejection fraction) or in the set­ ting of multiple causes, cardiopulmonary exercise testing (CPET) can serve as an important diagnostic test. CPET typically involves measure­ ment of breath-by-breath O2 consumption and CO2 production and continuously recording the electrocardiogram during stationary cycle ergometry. In more advanced types of CPET, intracardiac (right-heart) pressures are also measured during exercise, as are arterial blood gases and lactate before, during, and after exercise, providing additional diagnostic information to identify the underlying physiologic etiology of exercise limitation. PART 2 Cardinal Manifestations and Presentation of Diseases SIGNS AND SYMPTOMS The signs and symptoms of exercise intolerance can vary depending on its severity and etiology. For example, patients with heart failure with reduced ejection fraction following an acute myocardial infarction may be unable to walk up a flight of stairs yet feel comfortable at rest, or patients with severe pulmonary arterial hypertension may be short of breath with minimal exertion. In some cases, patients who are quite intolerant of exercise may note unusual breathlessness or dyspnea at rest accompanied by tachypnea, (sinus) tachycardia, muscle fatigue, weakness, or frank myalgias. SPECIFIC DISORDERS Exercise intolerance in patients with heart failure with preserved ejec­ tion fraction (HFpEF) is a well-recognized feature of the syndrome. The great majority of patients with HFpEF manifest multiple causes, including (in decreasing order of frequency) impaired skeletal muscle diffusion of O2, reduced cardiac output (with exercise), decreased alveolar ventilation, reduced lung diffusing capacity, and anemia. Internal work, a body mass index–related measure of the cost of initiating movement, is higher in patients with HFpEF compared with controls and is associated with rapid increases in cardiac filling pressures (and the pulmonary capillary wedge pressure) early in exercise. Other associated mechanisms for these abnormalities include increased large artery stiffness, chronotropic incompe­ tence, and microvascular dysfunction (both endothelium-dependent and endotheliumindependent) (Fig. 46-2). Accompanying comorbid conditions may also contribute to these multifactorial drivers of exercise intol­ erance in HFpEF, including inflammation, adipokine signaling, and insulin resistance in obese diabetics. Ascertaining the set of causes in any individual patient serves as the basis for a precision medicine approach to the treatment of this common symptom in HFpEF, as is the case for other diseases associated with exercise intolerance. Decreased alveolar ventilation Reduced lung diffusing capacity Lung Skeletal Muscle FIGURE 46-2  Determinants of exercise intolerance in heart failure with preserved ejection fraction (HFpEF).

Inspired oxygen Alveolar ventilation Lung diffusing capacity Hemoglobin transport Cardiac output Microvascular perfusion Muscle diffusion Mitochondrial respiration FIGURE 46-1  Oxygen delivery and utilization pathway. A variety of (post)viral syndromes are also associated with exer­ cise intolerance, including Epstein-Barr virus infection and postCOVID-19 (long COVID) syndrome. Patients with long COVID often have symptoms that are similar to those of patients with myalgic encephalomyelitis; however, the latter more typically include postex­ ertional malaise. In patients following recovery from acute COVID, the inability to return to normal activity levels often heralds the devel­ opment of long COVID. In patients with long COVID, a significant number noted exertional dyspnea, fatigue, and anxiety for up to 3 months after the acute infection, with fatigue remaining as the most common symptom thereafter. Orthostatic intolerance and positional tachycardia are common and reflect autonomic dysfunction. Among the mecha­ nisms for long COVID–associated fatigue and exercise intolerance are oxidative stress, altered energy metabolism, and dysbiosis of the gut microbiome. Cardiac deconditioning is also believed to play a role in the exercise intolerance of long COVID. Thus, focused exercise pre­ scriptions guided by patient-specific pathophysiology have been shown to relieve symptoms in many individuals. Heart Increased filling pressures Chronotropic incompetence Increased large artery stiffness Decreased cardiac output Anemia Microvascular dysfunction Impaired skeletal muscle diffusion

40 - 47 Dysphagia

47 Dysphagia

■ ■FURTHER READING Bunsawat K et al: Exercise intolerance in heart failure with preserved ejection fraction: Causes, consequences and the journey toward a cure. Exp Physiol 109:502, 2023. Edwards JA et al: Characteristics and treatment of exercise intolerance in patients with long COVID. J Cardiopulm Rehabil Prev 43:400, 2023. Houstis NE et al: Exercise intolerance in heart failure with preserved ejection fraction. Circulation 137:148, 2018. McCoy J et al: Pathophysiology of exercise intolerance in chronic dis­ eases: The role of diminished cardiac performance in mitochondrial and heart failure patients. Open Heart 4:000632, 2017. Ramirez MF et al: Obesity-related biomarkers are associated with exercise intolerance in HFpEF. Circ Heart Fail 16:010618, 2023. Shah RV et al: Metabolic cost of exercise initiation in patients with heart failure with preserved ejection fraction vs community dwelling adults. JAMA Cardiol 6:653, 2021. Section 6 Alterations in Gastrointestinal Function Ikuo Hirano*, Peter J. Kahrilas

Dysphagia Dysphagia—difficulty with swallowing—refers to problems with the transit of food or liquid from the mouth to the hypopharynx or through the esophagus. Severe dysphagia can compromise nutrition, cause aspiration, and reduce quality of life. Additional terminology pertaining to swallowing dysfunction is as follows. Aphagia (inability to swallow) typically denotes complete esophageal obstruction, most commonly encountered in the acute setting of a food bolus or foreign body impaction. Odynophagia refers to painful swallowing, typically resulting from mucosal ulceration within the oropharynx or esopha­ gus. It commonly is accompanied by dysphagia, but the converse is not true. Globus pharyngeus is a foreign body sensation localized in the neck that does not interfere with swallowing and sometimes is relieved by swallowing. Transfer dysphagia frequently results in nasal regurgita­ tion or pulmonary aspiration during swallowing and is characteristic of oropharyngeal dysphagia. Phagophobia (fear of swallowing) and refusal to swallow may be psychogenic or related to anticipatory anxiety about food bolus obstruction, odynophagia, or aspiration. ■ ■PHYSIOLOGY OF SWALLOWING Swallowing begins with a voluntary (oral) phase that includes prepara­ tion during which food is masticated and mixed with saliva. This is followed by a transfer phase during which the bolus is pushed into the pharynx by the tongue. Bolus entry into the hypopharynx initiates the pharyngeal swallow response, which is centrally mediated and involves a complex series of actions, the net result of which is to propel food through the pharynx into the esophagus while preventing its entry into the airway. To accomplish this, the larynx is elevated and pulled forward, actions that also facilitate upper esophageal sphincter (UES) opening. Tongue pulsion then propels the bolus through the UES, fol­ lowed by a peristaltic contraction that clears residue from the pharynx and through the esophagus. The lower esophageal sphincter (LES) relaxes as the food enters the esophagus and remains relaxed until the peristaltic contraction has delivered the bolus into the stomach. Peri­ staltic contractions elicited in response to a swallow are called primary peristalsis and involve sequenced inhibition followed by contraction of the musculature along the entire length of the esophagus. The ■ ■PATHOPHYSIOLOGY OF DYSPHAGIA Dysphagia can be subclassified both by location and by the circum­ stances in which it occurs. With respect to location, distinct consid­ erations apply to oral, pharyngeal, or esophageal dysphagia. Normal transport of an ingested bolus depends on the consistency and size of the bolus, the caliber of the lumen, the integrity of peristaltic contrac­ tion, and deglutitive inhibition of both the UES and the LES. Dyspha­ gia caused by an oversized bolus or a narrow lumen is called structural dysphagia, whereas dysphagia due to abnormalities of peristalsis or impaired sphincter relaxation after swallowing is called propulsive or motor dysphagia. More than one mechanism may be operative in a patient with dysphagia. Scleroderma commonly presents with absent peristalsis as well as a weakened LES that predisposes patients to peptic stricture formation. Likewise, radiation therapy for head and neck can­ cer may compound the functional deficits in the oropharyngeal swal­ low attributable to the tumor and cause cervical esophageal stenosis. It is worth noting that in addition to bolus transit, symptom reporting of dysphagia is dependent upon intact sensory innervation and cen­ tral nervous system perception. Chronicity of motor dysfunction in *Deceased.

inhibition that precedes the peristaltic contraction is called degluti­ tive inhibition. Local distention of the esophagus anywhere along its length, as may occur with gastroesophageal reflux, activates secondary peristalsis that begins at the point of distention and proceeds distally. Tertiary esophageal contractions are nonperistaltic, disordered esopha­ geal contractions that may be observed to occur spontaneously during fluoroscopic observation.

The musculature of the oral cavity, pharynx, UES, and cervical esophagus is striated and directly innervated by lower motor neurons carried in cranial nerves (Fig. 47-1). Oral cavity muscles are innervated by the fifth (trigeminal) and seventh (facial) cranial nerves; the tongue, by the twelfth (hypoglossal) cranial nerve. Pharyngeal muscles are innervated by the ninth (glossopharyngeal) and tenth (vagus) cranial nerves. Dysphagia CHAPTER 47 Physiologically, the UES consists of the cricopharyngeus muscle, the adjacent inferior pharyngeal constrictor, and the proximal portion of the cervical esophagus. UES innervation is derived from the vagus nerve, whereas the innervation to the musculature acting on the UES to facilitate its opening during swallowing comes from the fifth, sev­ enth, and twelfth cranial nerves. The UES remains closed at rest owing to both its inherent elastic properties and neurogenically mediated contraction of the cricopharyngeus muscle. UES opening during swal­ lowing involves both cessation of vagal excitation to the cricopharyn­ geus and simultaneous contraction of the suprahyoid and geniohyoid muscles that pull open the UES in conjunction with the upward and forward displacement of the larynx. The neuromuscular apparatus for peristalsis is distinct in proximal and distal parts of the esophagus. The cervical esophagus, like the pharyngeal musculature, consists of striated muscle and is directly innervated by lower motor neurons of the vagus nerve. Peristalsis in the proximal esophagus is governed by the sequential activation of the vagal motor neurons in the nucleus ambiguus. In contrast, the distal esophagus and LES are composed of smooth muscle and are controlled by excitatory and inhibitory neurons within the esophageal myenteric plexus. Medullary preganglionic neurons from the dorsal motor nucleus of the vagus trigger peristalsis via these ganglionic neu­ rons during primary peristalsis. Neurotransmitters of the excitatory ganglionic neurons are acetylcholine and substance P; those of the inhibitory neurons are vasoactive intestinal peptide and nitric oxide. Peristalsis results from the patterned activation of inhibitory followed by excitatory ganglionic neurons, with progressive dominance of the inhibitory neurons distally. Similarly, LES relaxation occurs with the onset of deglutitive inhibition and persists until the peristaltic sequence is complete. At rest, the LES is contracted because of excitatory gan­ glionic stimulation and its intrinsic myogenic tone, a property that distinguishes it from the adjacent esophagus. The function of the LES is supplemented by the surrounding muscle of the right diaphragmatic crus, which acts as an external sphincter during inspiration, cough, or abdominal straining.

Sagittal view of the pharynx Musculature of the pharynx Hard palate Soft palate Oral pharynx Oral cavity Valeculae PART 2 Cardinal Manifestations and Presentation of Diseases Epiglottis Tongue Laryngeal pharynx (hypopharynx) Mylohyoid ms Hyoid bone Hyoid bone Esophagus Thyrohyoid membrane Vocal cord Transverse arytenoid ms. Cricothyroid membrane Cricoid cartilage FIGURE 47-1  Sagittal and diagrammatic views of the musculature involved in enacting oropharyngeal swallowing. Note the dominance of the tongue in the sagittal view and the intimate relationship between the entrance to the larynx (airway) and the esophagus. In the resting configuration illustrated, the esophageal inlet is closed. This is transiently reconfigured such that the esophageal inlet is open and the laryngeal inlet closed during swallowing. (Adapted from PJ Kahrilas, in DW Gelfand and JE Richter [eds]: Dysphagia: Diagnosis and Treatment. New York, Igaku-Shoin Medical Publishers, 1989, pp. 11–28.) combination with defects in peripheral sensory perception may reduce patient-reported dysphagia in patients with achalasia. Oral and Pharyngeal (Oropharyngeal) Dysphagia  Oral-phase dysphagia is associated with poor bolus formation and control so that food has prolonged retention within the oral cavity and may seep out of the mouth. Drooling and difficulty in initiating swallowing are charac­ teristic signs. Poor bolus control also may lead to premature spillage of food into the hypopharynx with resultant aspiration into the trachea, evident as swallow-induced cough or regurgitation into the nasal cavity. Pharyngeal-phase dysphagia is associated with retention of food in the pharynx due to poor tongue or pharyngeal propulsion or obstruction at the UES. Signs and symptoms of concomitant hoarseness or cranial nerve dysfunction may be associated with oropharyngeal dysphagia that is associated with neurologic disorders. Oropharyngeal dysphagia may be due to neurologic, muscular, structural, iatrogenic, infectious, and metabolic causes. Iatrogenic, neurologic, and structural pathologies are most common. Iatrogenic causes include surgery and radiation, often in the setting of head and neck cancer. Neurogenic dysphagia resulting from cerebrovascular accidents, Parkinson’s disease, and amyotrophic lateral sclerosis is a major source of morbidity related to aspiration and malnutrition. Medullary nuclei directly innervate the oropharynx. Lateralization of pharyngeal dysphagia implies either a structural pharyngeal lesion or a neurologic process that selectively targets the ipsilateral brainstem nuclei or cranial nerve. Advances in functional brain imaging have elucidated an important role of the cerebral cortex in swallow func­ tion and dysphagia. Asymmetry in the cortical representation of the pharynx provides an explanation for the dysphagia that occurs as a consequence of unilateral cortical cerebrovascular accidents. Oropharyngeal structural lesions causing dysphagia include Zenk­ er’s diverticulum, cricopharyngeal bar, and neoplasia. Zenker’s diver­ ticulum typically is encountered in elderly patients. In addition to dysphagia, patients may present with regurgitation of particulate food debris, aspiration, and halitosis. The pathogenesis is related to stenosis of the cricopharyngeus that causes diminished opening of the UES and results in increased hypopharyngeal pressure during swallowing with development of a pulsion diverticulum immediately above the cricopharyngeus in a region of potential weakness known as Killian’s dehiscence. A cricopharyngeal bar, appearing as a prominent

Lateral pterygoid plate Superior constrictor Stylohyoid process Digastric (post. belly) Stylohyoid ligament Buccinator Stylopharyngeus
Mylohyoid Glossopharyngeus
Styloglossus Digastric (ant. belly) Middle constrictor Hyoglossus Thyrohyoid membrane Inferior constrictor Thyroid cartilage Cricopharyngeus Cricothyroid membrane Esophagus Cricoid cartilage indentation behind the lower third of the cricoid cartilage, is related to Zenker’s diverticulum in that it involves limited distensibility of the cricopharyngeus and can lead to the formation of a Zenker’s diver­ ticulum. However, a cricopharyngeal bar is a common radiographic finding, and most patients with transient cricopharyngeal bars are asymptomatic, making it important to rule out alternative etiologies of dysphagia before treatment. Furthermore, cricopharyngeal bars may be secondary to other neuromuscular disorders that impair opening of the UES. Since the pharyngeal phase of swallowing occurs in less than a second, rapid-sequence fluoroscopy is necessary to evaluate functional abnormalities. Adequate fluoroscopic examination requires that the patient be conscious and cooperative. The study incorporates record­ ings of swallow sequences during ingestion of food and liquids of vary­ ing consistencies. The pharynx is examined to detect bolus retention, regurgitation into the nose, or aspiration into the trachea. Timing and integrity of pharyngeal contraction and opening of the UES with a swallow are analyzed to assess both aspiration risk and the potential for swallow therapy. Structural abnormalities of the oropharynx, espe­ cially those that may require biopsies, also should be assessed by direct laryngoscopic examination. Esophageal Dysphagia  The adult esophagus measures 18–26 cm in length and is anatomically divided into the cervical esophagus, extend­ ing from the pharyngoesophageal junction to the suprasternal notch, and the thoracic esophagus, which continues to the diaphragmatic hiatus. When distended, the esophageal lumen has internal dimensions of about 2 cm in the anteroposterior plane and 3 cm in the lateral plane. Solid food dysphagia becomes common when the lumen is narrowed to <13 mm, but also can occur with larger diameters in the setting of poorly masticated food or motor dysfunction. Circumferential lesions are more likely to cause dysphagia than are lesions that involve only a partial circumference of the esophageal wall. The most common struc­ tural causes of dysphagia are Schatzki’s rings, eosinophilic esophagitis, and peptic strictures. Dysphagia also occurs in the setting of gastro­ esophageal reflux disease without a stricture, perhaps on the basis of altered esophageal sensation, reduced esophageal mural distensibility, or motor dysfunction. Propulsive disorders leading to esophageal dysphagia result from abnormalities of peristalsis and/or deglutitive inhibition, potentially

affecting the cervical or thoracic esophagus. Since striated muscle pathol­ ogy usually involves both the oropharynx and the cervical esophagus, the clinical manifestations usually are dominated by oropharyngeal dysphagia. Diseases affecting smooth muscle involve both the thoracic esophagus and the LES. A dominant manifestation of this, absent peristal­ sis, refers to either the complete absence of swallow-induced contraction (absent contractility) or the presence of nonperistaltic, disordered con­ tractions. Absent peristalsis and failure of deglutitive LES relaxation are the defining features of achalasia. In distal esophageal spasm (DES), LES function is normal, with the disordered motility restricted to the esopha­ geal body. Absent contractility combined with severe weakness of the LES is a pattern commonly found in patients with scleroderma. APPROACH TO THE PATIENT Dysphagia Figure 47-2 shows an algorithm for the approach to a patient with dysphagia. HISTORY The patient history is extremely valuable in making a presumptive diagnosis or at least substantially limiting the differential diagnoses in most patients. Key elements of the history are the localization of dysphagia, the circumstances in which dysphagia is experienced, other symptoms associated with dysphagia, and progression. Dys­ phagia that localizes to the suprasternal notch may indicate either an oropharyngeal or an esophageal etiology as distal dysphagia is referred proximally about 30% of the time. Dysphagia that local­ izes to the chest is esophageal in origin. Nasal regurgitation and tracheobronchial aspiration manifest by coughing with swallow­ ing are hallmarks of oropharyngeal dysphagia. Severe cough with swallowing may also be a sign of a tracheoesophageal fistula. The presence of hoarseness may be another important diagnostic clue. When hoarseness precedes dysphagia, the primary lesion is usually laryngeal; hoarseness that occurs after the development of dyspha­ gia may result from compromise of the recurrent laryngeal nerve by a malignancy. The type of food causing dysphagia is an important Dysphagia localized to neck, nasal regurgitation, aspiration, associated ENT symptoms Oropharyngeal dysphagia Esophageal dysphagia Propulsive Propulsive Structural Structural Myogenic Neurogenic • Cerebral vascular accident • Parkinson’s • Amyotropic lateral sclerosis • Brainstem tumor • Guillain-Barré • Huntington’s chorea • Post-polio syndrome • Multiple sclerosis • Cerebral palsy • Zenker’s diverticulum • Neoplasm • Cervical web • Cricopharyngeal bar • Osteophytes • Congenital abnormalities • Post head and neck surgery • Chemotherapy mucositis • Radiation • Corrosive injury • Infection • Myasthenia gravis • Polymyositis • Mixed connective tissue disorders • Oculopharyngeal muscular dystrophy • Paraneoplastic syndrome • Myotonic dystrophy • Sarcoidosis FIGURE 47-2  Approach to the patient with dysphagia. Etiologies in bold print are the most common. ENT, ear, nose, and throat; GERD, gastroesophageal reflux disease.

consideration. Intermittent dysphagia that occurs only with solid food implies structural dysphagia, whereas constant dysphagia with both liquids and solids strongly suggests an esophageal motor abnormality. Two caveats to this pattern are that despite having a motor abnormality, patients with scleroderma generally develop mild dysphagia for solids only and that patients with oropharyn­ geal dysphagia often have greater difficulty managing liquids than solids. Dysphagia that is progressive over the course of weeks to months raises concern for neoplasia. Episodic dysphagia to sol­ ids that is unchanged or slowly progressive over years indicates a benign disease process such as a Schatzki ring or eosinophilic esophagitis. Food impaction with a prolonged inability to pass an ingested bolus even with ingestion of liquid is typical of structural dysphagia. Chest pain may accompany dysphagia whether it is related to motor disorders, structural disorders, or reflux disease. A prolonged history of heartburn preceding the onset of dysphagia is suggestive of peptic stricture and, infrequently, esophageal adeno­ carcinoma. A history of prolonged nasogastric intubation, esopha­ geal or head and neck surgery, ingestion of caustic agents or pills, previous radiation or chemotherapy, or associated mucocutaneous diseases may help isolate the cause of dysphagia. With accompany­ ing odynophagia, which usually is indicative of ulceration, infec­ tious or pill-induced esophagitis should be suspected. In patients with AIDS or other immunocompromised states, esophagitis due to opportunistic infections such as Candida, herpes simplex virus, or cytomegalovirus and to tumors such as Kaposi’s sarcoma and lym­ phoma should be considered. A history of atopy increases concerns for eosinophilic esophagitis, which is most prevalent in Caucasian male patients between the ages of 20 and 40 years. Medication use should identify agents associated with pill esophagitis and narcot­ ics that are associated with opioid-induced esophageal dysmotility. Dysphagia CHAPTER 47 PHYSICAL EXAMINATION Physical examination is important in the evaluation of oral and pha­ ryngeal dysphagia because dysphagia is usually only one of many manifestations of a more global disease process. Signs of bulbar or pseudobulbar palsy, including dysarthria, dysphonia, ptosis, and Dysphagia Dysphagia localized to chest or neck, food impaction Solid and liquid dysphagia Solid dysphagia Odynophagia Intermittent • Schatzki ring • Esophageal web • Pill esophagitis • Infectious esophagitis • Caustic injury • Chemotherapy mucositis • Sclerotherapy • Crohn’s disease • Behcet’s syndrome • Bullous pemphygoid • Lichen planus Progressive • Neoplasm • GERD with weak peristalsis • Achalasia (primary and secondary) • Diffuse esophageal spasm • Scleroderma Variable • Peptic stricture • Eosinophilic esophagitis • Hiatal hernia • Extrinsic compression • Surgical stenosis • Radiation esophagitis • Ringed esophagus • Congenital esophageal stenosis

41 - 48 Nausea, Vomiting, and Indigestion

48 Nausea, Vomiting, and Indigestion

tongue atrophy, in addition to evidence of generalized neuromuscular disease, should be elicited. The neck should be examined for thyro­ megaly or lymphadenopathy. A careful inspection of the mouth and pharynx should disclose inflammatory or infectious lesions. Missing dentition can interfere with mastication and exacerbate an exist­ ing cause of dysphagia. Physical examination is less helpful in the evaluation of esophageal dysphagia as the most relevant pathology is restricted to the esophagus. The notable exception is skin disease. Changes in the skin and oral mucosa may suggest a diagnosis of sclero­ derma or mucocutaneous diseases such as pemphigoid, lichen planus, and epidermolysis bullosa, all of which can involve the esophagus. PART 2 Cardinal Manifestations and Presentation of Diseases DIAGNOSTIC PROCEDURES Although most instances of dysphagia are attributable to benign disease processes, dysphagia is also a cardinal symptom of several malignancies, making it an important symptom to evaluate. Cancer may result in dysphagia, most commonly as the result of intralumi­ nal obstruction (esophageal or proximal gastric cancer, metastatic deposits) and less commonly due to extrinsic compression (lym­ phoma, lung cancer) or paraneoplastic syndromes. Even when not attributable to malignancy, dysphagia is usually a manifestation of an identifiable and treatable disease entity, making its evaluation beneficial to the patient and gratifying to the practitioner. The spe­ cific diagnostic algorithm to pursue is guided by the details of the history (Fig. 47-2). If oral or pharyngeal dysphagia is suspected, a fluoroscopic swallow study, usually done by a swallow therapist, is the procedure of choice. Otolaryngoscopic and neurologic evalu­ ation also can be important, depending on the circumstances. For suspected esophageal dysphagia, upper endoscopy is the single most useful test. Endoscopy allows better visualization of mucosal lesions than does barium radiography and also allows for procure­ ment of mucosal biopsies. Endoscopic or histologic abnormalities are evident in the leading causes of esophageal dysphagia: Schatzki’s ring, gastroesophageal reflux disease, and eosinophilic esophagi­ tis. Furthermore, therapeutic intervention with esophageal dilation can be done as part of the procedure if it is deemed necessary. The emergence of eosinophilic esophagitis as a leading cause of dyspha­ gia in both children and adults has led to the recommendation that esophageal mucosal biopsies be obtained routinely in the evalua­ tion of unexplained dysphagia even if characteristic, endoscopically identified esophageal mucosal features are absent. For cases of sus­ pected esophageal motility disorders, endoscopy is still the appro­ priate initial evaluation as neoplastic and inflammatory conditions can secondarily produce patterns of either achalasia or esophageal spasm. Esophageal manometry is done if dysphagia is not adequately explained by endoscopy or to confirm the diagnosis of a suspected esophageal motor disorder. Barium radiography can provide useful adjunctive information in cases of subtle or complex esophageal strictures, prior esophageal surgery, esophageal diverticula, or para­ esophageal herniation. Use of a barium tablet in conjunction with fluoroscopy can identify strictures and esophageal motility disor­ ders that may be overlooked with liquid barium. In specific cases, computed tomography (CT) examination, esophageal manometry with solid meal challenge, and endoscopic ultrasonography may be useful. Impedance planimetry using the functional lumen imaging probe (FLIP) device is increasingly used in the evaluation of dys­ phagia, particularly for disorders of the esophagogastric junction (esophagogastric junction outflow obstruction and achalasia) (see Chap. 334). Advantages of this technology include patient tolerance, as the procedure is done at the time of upper endoscopy with seda­ tion, and, more importantly, the information regarding the dynamic opening characteristics of the esophagogastric junction in response to distension that complements esophageal manometry. TREATMENT Treatment of dysphagia depends on both the locus and the specific etiology. Oropharyngeal dysphagia most commonly results from functional deficits caused by neurologic disorders. In such circum­ stances, the treatment focuses on utilizing postures or maneuvers

devised to reduce pharyngeal residue and enhance airway protec­ tion learned under the direction of a swallow therapist. Aspiration risk may be reduced by altering the consistency of ingested food and liquid. Dysphagia resulting from a cerebrovascular accident usually, but not always, spontaneously improves within the first few weeks after the event. More severe and persistent cases may require consideration of gastrostomy and enteral feeding. Patients with myasthenia gravis (Chap. 459) and polymyositis (Chap. 377) may respond to medical treatment of the primary neuromuscular disease. Surgical intervention with cricopharyngeal myotomy is usually not helpful, with the exception of specific disorders such as symptomatic cricopharyngeal bar, Zenker’s diverticulum, and oculopharyngeal muscular dystrophy. Chronic neurologic disor­ ders such as Parkinson’s disease and amyotrophic lateral sclerosis may manifest with severe oropharyngeal dysphagia. Feeding by a nasogastric tube or an endoscopically placed gastrostomy tube may be considered for nutritional support; however, these maneuvers do not provide protection against aspiration of salivary secretions or refluxed gastric contents. Treatment of esophageal dysphagia is covered in detail in Chap. 334. The majority of causes of structural, esophageal dysphagia are effectively managed by means of esophageal dila­ tion using bougie or balloon dilators. Cancer and achalasia are often managed surgically, although endoscopic techniques are available for both palliation and primary therapy, respectively. Infectious etiologies respond to antimicrobial medications or treatment of the underlying immunosuppressive state. Finally, eosinophilic esophagitis is an important and increasingly recog­ nized cause of dysphagia that is amenable to treatment by elimi­ nation of dietary allergens, proton pump inhibition, swallowed, topically acting glucocorticoids, and biologic therapies targeting cytokines involved in type 2 inflammation. While diet and medi­ cal therapies are effective at reducing dysphagia, esophageal dila­ tion is used adjunctively for persistent strictures. ■ ■FURTHER READING Hirano I: Esophagus: Anatomy and structural anomalies, in Yamada Atlas of Gastroenterology, 7th ed. New York, Wiley-Blackwell Publishing Co., 2022, pp 42–59. Kim JP, Kahrilas PJ: How I approach dysphagia. Curr Gastroenterol Rep 21:49, 2019. Pandolfino JE, Kahrilas PJ: Esophageal neuromuscular function and motility disorders, in Sleisenger and Fordtran’s Gastrointestinal and Liver Disease, 11th ed, Feldman M, Friedman LS, Brandt LJ (eds). Philadelphia, Elsevier, 2020, pp 638–660. Shaker R et al (eds): Principles of Deglutition: A Multidisciplinary Text for Swallowing and Its Disorders. New York, Springer, 2016. Yadlapati R et al: The Chicago Classification of esophageal motility disorders, v4.0. Neurogastroenterol Motil 33:e14058, 2021. William L. Hasler

Nausea, Vomiting, and Indigestion Nausea is the feeling of a need to vomit. Vomiting (emesis) is the oral expulsion of gastrointestinal contents resulting from gut and thoracoabdominal wall contractions. Vomiting is contrasted with regurgitation, the effortless passage of gastric contents into the mouth. Rumination is the repeated regurgitation of food residue. In contrast to

emesis, these phenomena exhibit volitional control. Indigestion broadly encompasses complaints including nausea, vomiting, heartburn, regur­ gitation, and dyspepsia (defined as symptoms that are thought to origi­ nate in the gastroduodenal region). Some individuals with dyspepsia experience postprandial fullness, early satiety (inability to complete a meal due to premature fullness), bloating, belching, and anorexia. Oth­ ers report predominant epigastric pain or burning. NAUSEA AND VOMITING ■ ■MECHANISMS Vomiting is coordinated by the brainstem and is effected by responses in the gut, pharynx, and somatic musculature. Mechanisms underlying nausea likely involve the cerebral cortex, as nausea requires cognitive and emotional input and is associated with autonomic responses (dia­ phoresis, pallor, altered heart rate). Functional brain imaging studies support this idea showing activation of cerebral regions including the insula, anterior cingulate cortex, and amygdala during nausea. Coordination of Vomiting  Brainstem nuclei—including the nucleus tractus solitarius; dorsal vagal and phrenic nuclei; medullary nuclei regulating respiration; and nuclei that control pharyngeal, facial, and tongue movements—coordinate vomiting involving neurokinin NK1, serotonin 5-HT3, endocannabinoid, and vasopressin pathways. Somatic and visceral muscles respond stereotypically during emesis. Inspiratory thoracic and abdominal wall muscles contract, increasing intrathoracic and intraabdominal pressures to help gastric evacuation. During vomiting, propulsive gastroduodenal motor activity is replaced by orally propagating retrograde contractions that facilitate expulsion of gut contents. Activators of Emesis  Emetic stimuli act at several sites. Emesis evoked by unpleasant thoughts or smells originates in the brain. Motion sickness and inner ear disorders act on labyrinthine pathways. Gastric irritants and cytotoxic agents like cisplatin stimulate vagal afferent nerves. Nongastric afferents are activated by bowel obstruction and mesenteric ischemia. The area postrema, in the medulla, responds to bloodborne stimuli (emetogenic drugs, bacterial toxins, uremia, ketoacidosis) and is termed the chemoreceptor trigger zone. Neurotransmitters mediating vomiting are selective for different sites. Labyrinthine disorders stimulate vestibular muscarinic M1 and histaminergic H1 receptors. Vagal afferent stimuli activate 5-HT3 recep­ tors. The area postrema is served by 5-HT3, M1, H1, and dopamine D2 pathways. Central nervous system (CNS) NK1 receptors mediate both nausea and vomiting. Cannabinoid CB1 pathways participate in the cerebral cortex and brainstem. These receptor-mediated pathways are targets for many agents that treat nausea and vomiting. ■ ■DIFFERENTIAL DIAGNOSIS Nausea and vomiting are caused by conditions within and outside the gut, medications, and circulating toxins (Table 48-1). In an epidemio­ logic study, nausea alone at least weekly was reported by 1.9% while nausea plus vomiting was noted by 1.1% of the population. Intraperitoneal Disorders  Obstruction and inflammation of hollow and solid viscera may elicit vomiting. Ulcers and malignancy cause gastric obstruction, while adhesions, masses, volvulus, intus­ susception, or inflammatory diseases like Crohn’s disease cause small intestinal and colonic obstruction. The superior mesenteric artery syndrome, occurring after weight loss or prolonged immobilization, results when the duodenum is compressed by the overlying superior mesenteric artery. Median arcuate ligament syndrome, with celiac artery compression, is a rare cause of vomiting. Enteric infectious causes of vomiting include viruses (norovirus, rotavirus), bacteria (Staphylococcus aureus, Bacillus cereus), and opportunistic organisms like cytomegalovirus or herpes simplex in immunocompromised individuals. Abdominal irradiation impairs intestinal motility and induces strictures. Biliary colic causes nausea by acting on afferent nerves. Vomiting with pancreatitis, cholecystitis, and appendicitis results from visceral irritation and ileus.

TABLE 48-1  Causes of Nausea and Vomiting MEDICATIONS/ METABOLIC DISORDERS INTRAPERITONEAL EXTRAPERITONEAL Obstructing disorders   Pyloric obstruction   Small-bowel Cardiopulmonary disease   Cardiomyopathy   Myocardial infarction Labyrinthine disease   Motion sickness   Labyrinthitis   Malignancy Intracerebral disorders   Malignancy   Hemorrhage   Abscess   Hydrocephalus Psychiatric illness   Anorexia and bulimia Drugs   Cancer chemotherapy   Opioids   Analgesics   Glucagon-like obstruction   Colonic obstruction   Superior mesenteric peptide-1 (GLP-1) receptor agonists   Oral hypoglycemics   Parkinson’s disease/ artery syndrome Enteric infections   Viral   Bacterial Inflammatory diseases   Cholecystitis   Pancreatitis   Appendicitis   Hepatitis Altered sensorimotor function   Gastroparesis   Intestinal Nausea, Vomiting, and Indigestion CHAPTER 48 restless legs therapies   Antidepressants   Smoking cessation agents   Antibiotics   Cardiac antiarrhythmics/ antihypertensives   Oral contraceptives Endocrine/metabolic disease   Pregnancy   Uremia   Ketoacidosis   Thyroid and nervosa   Depression Postoperative vomiting pseudoobstruction   Gastroesophageal reflux   Chronic nausea vomiting syndrome (CNVS)   Gastroparesis-like parathyroid disease   Adrenal insufficiency Toxins   Liver failure   Ethanol symptoms (GPLS)   Cyclic vomiting syndrome (CVS)   Cannabinoid hyperemesis syndrome (CHS)   Rumination syndrome Mesenteric insufficiency   Celiac artery stenosis   Median arcuate ligament syndrome Biliary colic Abdominal irradiation Gut motor and sensory dysfunction often causes nausea and vomit­ ing. Gastroparesis presents most often with nausea and is documented by demonstrating delayed gastric emptying. Idiopathic gastroparesis occurring in the absence of systemic illness is the most prevalent etiol­ ogy and follows a viral illness in ∼15−20% of cases. Gastroparesis also occurs after vagotomy or with neoplasm, mesenteric vascular insuf­ ficiency, or organic diseases like diabetes, connective tissue diseases including scleroderma, Parkinson’s disease, and amyloidosis. Rapid gastric emptying is associated with nausea and vomiting in some conditions. Intestinal pseudoobstruction is characterized by disrupted intestinal motility with retention of food residue and secretions; bac­ terial overgrowth; nutrient malabsorption; and symptoms of nausea, vomiting, bloating, pain, and altered defecation. Intestinal pseudoob­ struction may be idiopathic, inherited, related to a mitochondrial dis­ order, result from systemic disease like scleroderma or an infiltrative process like amyloidosis, or occur as a paraneoplastic consequence of malignancy. Patients with gastroesophageal reflux disease (GERD), irritable bowel syndrome (IBS), or chronic constipation often report nausea and vomiting. Other gastroduodenal disorders of gut-brain interaction (DGBIs) without organic abnormalities have been characterized. Chronic nausea vomiting syndrome is defined as bothersome nausea and/ or one or more vomiting episodes at least weekly. A syndrome termed gastroparesis-like symptoms (GPLS) presents with symptoms

indistinguishable from gastroparesis but with normal gastric empty­ ing. Cyclic vomiting syndrome (CVS) presents with discrete episodes of relentless vomiting, has a prevalence of 1.4%, and is associated with migraines, autonomic dysfunction, and menstrual cycling. Some cases exhibit rapid gastric emptying. A related condition, cannabinoid hyper­ emesis syndrome (CHS), presents with cyclical vomiting in individuals with long-standing (>1 year) use of large quantities of cannabis at least 4 days weekly and resolves with its discontinuation for ≥6 months. Rumination syndrome is often misdiagnosed as refractory vomiting.

Extraperitoneal Disorders  Myocardial infarction and congestive heart failure may cause nausea and vomiting. Postoperative emesis occurs after 25% of surgeries. Increased intracranial pressure from tumors, bleeding, abscess, or blockage of cerebrospinal fluid outflow produces vomiting with or without nausea. Patients with anorexia nervosa, bulimia nervosa, anxiety, and depression often report nausea associated with delayed gastric emptying. PART 2 Cardinal Manifestations and Presentation of Diseases Medications and Metabolic Disorders  Many medications cause nausea and vomiting including opioids, nonsteroidal anti-

inflammatory drugs (NSAIDs), glucagon-like peptide-1 receptor ago­ nists, oral hypoglycemics, antiparkinsonian drugs, agents for restless legs, antidepressants (especially selective serotonin norepinephrine reuptake inhibitors), smoking cessation drugs, antibiotics, cardiac antiarrhythmics, antihypertensives, and contraceptives. Cancer che­ motherapy causes acute (within hours of administration), delayed (after ≥1 day), or anticipatory vomiting. Acute emesis from highly emetogenic agents is mediated by 5-HT3 pathways while delayed emesis is dependent on NK1 mechanisms. Anticipatory nausea responds better to anxiolytic therapy than antiemetics. Metabolic disorders elicit nausea and vomiting. Nausea affects 70% of women in the first trimester of pregnancy. Hyperemesis gravidarum is a severe form of nausea of pregnancy that produces dehydration and electrolyte disturbances and may result from excessive amounts of a blood protein—growth differentiation factor 15. Uremia, ketoacidosis, adrenal insufficiency, and parathyroid and thyroid disease are other etiologies. Circulating toxins evoke emesis via effects on the area postrema. Endogenous toxins are generated in fulminant liver failure, whereas exogenous enterotoxins may be produced by enteric bacterial infection. Ethanol intoxication is a common toxic etiology of nausea and vomiting. APPROACH TO THE PATIENT Nausea and Vomiting HISTORY AND PHYSICAL EXAMINATION The history helps define the etiology of nausea and vomiting. Drugs, toxins, and infections often cause acute symptoms, whereas established illnesses evoke chronic complaints. Gastroparesis and pyloric obstruction elicit vomiting within an hour of eating. Emesis from intestinal blockage occurs later. Vomiting occurring minutes after eating characterizes rumination syndrome. With severe gastric emptying delays, vomitus may contain food residue ingested days before. Intense episodic emesis with intervening intervals with much less severe symptoms suggests CVS or CHS. Hematemesis raises suspicion of ulcer, malignancy, or Mallory-Weiss tear. Fecu­ lent emesis is noted with distal intestinal or colonic obstruction. Bilious vomiting excludes gastric obstruction. Emesis of undigested food is consistent with a Zenker’s diverticulum or achalasia. Vomit­ ing can relieve abdominal pain from a bowel obstruction but has no effect in pancreatitis or cholecystitis. Weight loss raises concern about malignancy or ischemia. Taking prolonged hot baths or showers is associated with CHS and CVS but is less common with CNVS or gastroparesis. Intracranial sources are considered if there are headaches or visual changes. Vertigo or tinnitus indicates laby­ rinthine disease. The physical examination complements the history. Orthostatic hypotension and reduced skin turgor indicate fluid loss. Pulmonary

abnormalities raise concern for aspiration of vomitus. Bowel sounds are absent with ileus. High-pitched rushes suggest bowel obstruc­ tion. A succussion splash is found with gastroparesis or pyloric obstruction. Involuntary guarding raises suspicion of inflamma­ tion. Fecal blood suggests ulcer, ischemia, or tumor. Neurologic disease presents with papilledema or focal neural abnormalities. Neoplasm is suggested by palpable masses or adenopathy. DIAGNOSTIC TESTING For intractable symptoms or an elusive diagnosis, screening testing directs care. Electrolyte replacement is indicated for hypokalemia or metabolic alkalosis. Iron-deficiency anemia mandates exclusion of mucosal causes. Abnormal pancreatic or liver biochemistries are found with pancreaticobiliary disease. Endocrinologic, rheu­ matologic, or paraneoplastic etiologies are suggested by hormone or serologic abnormalities. Small-bowel obstruction is indicated by intestinal air-fluid levels and reduced colonic air on abdominal radiography, while ileus is characterized by diffusely dilated airfilled bowel loops. Anatomic studies are performed if initial testing is nondiagnos­ tic. Upper endoscopy detects ulcers, malignancy, and food retention in gastroparesis. Computed tomography (CT) can diagnose partial bowel obstruction. CT and magnetic resonance imaging (MRI) enterography provide detailed definition of bowel wall thickening or inflammation as seen with Crohn’s disease. Ultrasound is helpful for biliary etiologies. Mesenteric angiography, CT, or MRI is useful for suspected ischemia. Brain CT or MRI delineates intracranial disease. Gastrointestinal motility testing can detect underlying motor disorders. Gastroparesis commonly is diagnosed by gastric scintig­ raphy, which measures emptying of a radiolabeled meal. A nonra­ dioactive 13C-labeled gastric emptying breath test is an alternative to scintigraphy. Intestinal pseudoobstruction is suggested by luminal dilation on imaging or abnormal transit on intestinal scintigraphy or contrast radiography. Small-intestinal manometry confirms a diagnosis of pseudoobstruction and discriminates between neuro­ pathic or myopathic disease. Nausea as a manifestation of atypical GERD can be diagnosed by esophageal pH monitoring. Combined esophageal pH/impedance testing with high-resolution manometry facilitates diagnosis of rumination syndrome. Impedance planim­ etry detects reduced pyloric distensibility and diameter in some cases of gastroparesis. TREATMENT Nausea and Vomiting GENERAL PRINCIPLES Therapy of vomiting is tailored to correct remediable abnormalities if possible. Patients with severe dehydration should be hospitalized if oral replenishment is unsustainable. Once oral intake is tolerated, low-fat liquid nutrients are initially restarted. Low-residue, smallparticle diets have shown durable efficacy in gastroparesis. Glyce­ mic control should be optimized in diabetic gastroparesis patients. If feasible, medications deemed to contribute to a patient’s nausea should be discontinued or their doses reduced. ANTIEMETIC MEDICATIONS Most antiemetic agents act on CNS sites and have been evaluated for specific indications (Table 48-2). Antihistamines like dimenhy­ drinate and meclizine and anticholinergics like scopolamine act on vestibular pathways to treat motion sickness and labyrinthine dis­ orders. D2 antagonists treat emesis evoked by area postrema stimuli including medications, toxins, and metabolic disturbances. 5-HT3 antagonists like ondansetron prevent postoperative vomiting, radiation–induced symptoms, and cancer chemotherapy–induced emesis. NK1 antagonists such as aprepitant and cannabinoids like dronabinol are approved for chemotherapy-induced vomiting.

TABLE 48-2  Treatment of Nausea and Vomiting TREATMENT MECHANISM EXAMPLES CLINICAL INDICATIONS Antiemetic agents Antihistaminergic Dimenhydrinate, meclizine Motion sickness, inner ear disease Anticholinergic Scopolamine Motion sickness, inner ear disease Antidopaminergic Prochlorperazine, thiethylperazine, haloperidol 5-HT3 antagonist Ondansetron, granisetron Chemotherapy- and radiation-induced emesis, postoperative emesis, opioid-induced nausea and vomiting Cannabinoids Tetrahydrocannabinol, cannabidiol Chemotherapy-induced emesis, gastroparesis Tricyclic antidepressant Amitriptyline, nortriptyline Chronic nausea vomiting syndrome, cyclic vomiting syndrome,? gastroparesis Other antidepressant/atypical antipsychotic Mirtazapine, olanzapine Functional dyspepsia, chemotherapy-induced emesis,? gastroparesis Neuropathic modulator Gabapentin Chemotherapy-induced emesis Neurokinin (NK1) receptor antagonists Aprepitant, fosaprepitant, netupitant, rolapitant Prokinetic agents 5-HT4 agonist and antidopaminergic Metoclopramide Gastroparesis Motilin agonist Erythromycin Gastroparesis,? intestinal pseudoobstruction Peripheral antidopaminergic Domperidone Gastroparesis Pure 5-HT4 agonist Prucalopride Idiopathic gastroparesis Somatostatin analogue Octreotide Intestinal pseudoobstruction Acetylcholinesterase inhibitor Pyridostigmine ?Small-intestinal dysmotility/pseudoobstruction Special settings Benzodiazepines Lorazepam Anticipatory nausea and vomiting with chemotherapy, cyclic vomiting syndrome 5-HT1A agonist Buspirone, tandospirone Functional dyspepsia Glucocorticoids Methylprednisolone, dexamethasone Chemotherapy-induced emesis Anticonvulsants Topiramate, zonisamide, levetiracetam Cyclic vomiting syndrome Antimigraine agents Sumatriptan Cyclic vomiting syndrome Topical analgesic Capsaicin cream Cannabinoid hyperemesis syndrome Note:? , indication is uncertain. Although these drug classes have divergent mechanisms of action, they are broadly employed in a range of settings for their antinausea and antiemetic actions. Aprepitant can reduce symptoms in CVS and gastroparesis. The cannabinoid agent cannabidiol was benefi­ cial in a controlled trial in gastroparesis. Tricyclic antidepressants can reduce symptoms in CVS and func­ tional causes of vomiting but did not show benefits in a controlled trial in gastroparesis. Other neuromodulators with antiemetic action in some settings include the antidepressant mirtazapine, the atypical antipsychotic olanzapine, and the pain-modulating agent gabapentin. GASTROINTESTINAL MOTOR STIMULANTS Drugs that stimulate gastric emptying are used for gastroparesis (Table 48-2). Metoclopramide, a 5-HT4 agonist and D2 antagonist, is effective in gastroparesis. Erythromycin increases gastroduode­ nal motility by action on receptors for motilin, a transmitter that regulates fasting motility. Erythromycin may be useful for shortterm use, but its long-term benefits are limited by development of tolerance. Domperidone, a D2 antagonist not available in the United States, exhibits prokinetic and antiemetic effects but does not penetrate most brain regions. Prucalopride, a 5-HT4 agonist, accelerates gastric emptying and improves symptoms in idiopathic gastroparesis. Refractory motility disorders pose challenges. Intestinal pseu­ doobstruction may respond to the somatostatin analogue octreo­ tide, which induces propagative small-intestinal contractions. Acetylcholinesterase inhibitors like pyridostigmine benefit some patients with small-bowel dysmotility. Pyloric botulinum toxin injections reduced gastroparesis symptoms in uncontrolled stud­ ies, but small controlled trials observed benefits no greater than sham treatments. Surgical pyloroplasty and gastric peroral endo­ scopic myotomy (G-POEM) of the pylorus improved symptoms

Medication-, toxin-, or metabolic-induced emesis, chemotherapy-induced emesis,? cannabinoid hyperemesis syndrome Nausea, Vomiting, and Indigestion CHAPTER 48 Chemotherapy-induced emesis in case series and one sham-controlled trial. Enteral feedings through a jejunostomy reduce hospitalizations and improve over­ all health in some patients with refractory gastroparesis. The utilities of surgical gastric bypass and sleeve gastrectomy for gas­ troparesis are unproven. Implanted gastric electrical stimulators may reduce symptoms and health care expenditures in medicationrefractory gastroparesis. A controlled trial confirmed greater improvements in vomiting during gastric electrical stimulation versus sham treatment. SAFETY CONSIDERATIONS Safety concerns have been raised about selected antiemetics and prokinetics. Dopamine antagonists that cross the blood-brain bar­ rier cause anxiety, mood disturbances, movement disorders, and hyperprolactinemic effects (galactorrhea, sexual dysfunction). Metoclopramide causes irreversible movement disorders like tar­ dive dyskinesia, particularly in older patients. This risk should be explained and documented in the medical record. Domperidone rarely causes dystonias but can induce hyperprolactinemic side effects by penetrating pituitary regions with a porous blood-brain barrier. Domperidone, erythromycin, tricyclic antidepressants, and 5-HT3 antagonists increase risks of cardiac arrhythmias and sudden cardiac death in those with QTc interval prolongation on electro­ cardiography (ECG). Surveillance ECG testing is advocated for some agents. OTHER CLINICAL SETTINGS Combining a 5-HT3 antagonist, an NK1 antagonist, and a glu­ cocorticoid can control acute and delayed vomiting after highly emetogenic cancer chemotherapy (Chaps. 74 and 78). Antici­ patory nausea and vomiting is managed with benzodiazepines like lorazepam or behavioral therapy. Other therapies that benefit chemotherapy-induced emesis include cannabinoids,

olanzapine, metoclopramide, gabapentin, and alternative thera­ pies like ginger.

Clinicians should exercise caution in managing nausea of preg­ nancy. Studies of teratogenic effects of antiemetic agents provide conflicting results. Antihistamines like meclizine and doxylamine, antidopaminergics like prochlorperazine, and antiserotonergics like ondansetron demonstrate limited efficacy. Some obstetricians rec­ ommend alternative therapies including pyridoxine, acupressure, or ginger. Managing CVS and CHS is challenging. Prophylaxis with tri­ cyclic agents or anticonvulsants (topiramate, zonisamide, leve­ tiracetam) reduces the severity and frequency of CVS attacks in uncontrolled reports. Combining intravenous 5-HT3 or NK1 antagonists with the sedating effects of lorazepam is a mainstay for aborting acute flares in the emergency department. Studies report benefits with aprepitant and injectable or intranasal forms of the 5-HT1 agonist sumatriptan to manage acute CVS episodes. These treatments are less effective for CHS, but intravenous or intramus­ cular haloperidol, topical capsaicin cream, or benzodiazepines may reduce acute CHS attacks. PART 2 Cardinal Manifestations and Presentation of Diseases INDIGESTION ■ ■MECHANISMS Several mechanisms contribute to indigestion, including acid reflux, altered gut motility or sensation, inflammation, microbial processes, and other factors. Gastroesophageal Reflux  Gastroesophageal reflux results from many defects. Reduced lower esophageal sphincter (LES) tone causes reflux in scleroderma and pregnancy and may also be a factor in some patients without systemic illness. Other cases exhibit frequent transient LES relaxations (TLESRs). Reductions in esophageal body motility or saliva production prolong esophageal acid clearance. Increased intra­ gastric pressure promotes gastroesophageal reflux with obesity. Large hiatal hernias can increase symptomatic acid reflux. Gastric Motor Dysfunction  Disturbed gastric motility may con­ tribute to gastroesophageal reflux in up to one-third of cases. Delayed gastric emptying is also found in ∼30% of functional dyspeptics, while rapid gastric emptying affects 5%. Impairment of gastric fundus relaxation after eating (i.e., accommodation) may underlie selected dyspeptic symptoms like bloating, nausea, and early satiety in ∼40% of patients and may predispose to TLESRs and acid reflux. Visceral Afferent Hypersensitivity  Disturbed gastric sensation is another pathogenic factor in functional dyspepsia. Approximately 30% of dyspeptic patients note discomfort with gastric or duodenal distention to lower pressures than in healthy controls. Other individuals with dys­ pepsia exhibit hypersensitivity to chemical stimulation of the stomach and duodenum with capsaicin or with duodenal acid or lipid perfusion. Some patients with heartburn without increased reflux of acidic or non­ acidic fluid exhibit heightened perception of normal esophageal acidity and are conferred a diagnosis of esophageal hypersensitivity. Immune Activation  Increases in duodenal epithelial permeability in functional dyspepsia may relate to increases in eosinophils and mast cells adjacent to submucosal neurons, most prominently in the 20% of patients who report symptom onset after a viral illness. Increased activation of these cells may contribute to gastric emptying delays and altered sensory function in functional dyspepsia and may elicit early satiety and epigastric pain. Populations of selected duodenal bacteria are altered in functional dyspepsia and correlate with symptom sever­ ity, suggesting a role for microbiome alterations. Food antigens, gluten, and fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs) increase duodenal inflammation. Other Factors  Helicobacter pylori has a proven etiologic role in peptic ulcer disease but is a minor factor in functional dyspep­ sia pathogenesis. Anxiety, depression, and stress play contributing roles in some functional dyspepsia cases. Other studies observe

hypothalamic-pituitary-adrenal axis dysregulation. Parasympathetic and sympathetic autonomic nervous system abnormalities also have been found. Functional MRI and positron emission tomography stud­ ies show increased activation of several brain regions, emphasizing CNS contributions. Bile salt composition is abnormal in functional dyspepsia and relates to dyspeptic symptoms and gastric emptying. Analgesics cause dyspepsia, whereas nitrates, calcium channel block­ ers, theophylline, and progesterone promote gastroesophageal reflux. Ethanol, tobacco, and caffeine induce LES relaxation and reflux. Genetic factors can predispose to development of reflux and dyspepsia. ■ ■DIFFERENTIAL DIAGNOSIS Gastroesophageal Reflux Disease  Heartburn or regurgitation is reported weekly by 18–28% of the population, highlighting GERD prevalence. Symptoms of heartburn and regurgitation confer 70% sen­ sitivity and specificity for a diagnosis of GERD. Other causes of these symptoms include esophageal hypersensitivity, hypervigilance, and regurgitation of nonacidic fluid. Functional Dyspepsia  Functional dyspepsia is the cause of symp­ toms in 70–80% of dyspeptic patients and has a population prevalence of 7.2%. The disorder is defined as bothersome postprandial fullness, early satiety, or epigastric pain or burning with symptom onset ≥6 months before diagnosis in the absence of organic cause. Functional dyspepsia is subdivided into postprandial distress syndrome (PDS) (prevalence 6.1%), characterized by meal-induced fullness and early satiety, and epigastric pain syndrome (EPS) (prevalence 2.4%), with epigastric pain or burning that may or may not be meal-related. The overlap of PDS and EPS has a prevalence of 1.3%. Functional dyspepsia is associated with other DGBIs including IBS and nongastrointestinal disorders like fibromyalgia, chronic fatigue, and anxiety. Ulcer Disease  Most GERD patients do not exhibit esophageal injury, but 5% develop esophageal ulcers. Symptoms cannot distinguish nonerosive from erosive or ulcerative esophagitis. A minority of cases of dyspepsia stem from gastric or duodenal ulcers. The most common causes of ulcers are H. pylori infection and NSAID use. Other rare causes of gastroduodenal ulcers include Crohn’s disease (Chap. 337) and Zollinger-Ellison syndrome (Chap. 335), resulting from gastrin overproduction by an endocrine tumor. Malignancy  Dyspeptic patients may seek care because of fear of cancer, but few cases result from malignancy. Esophageal adenocar­ cinoma usually complicates prolonged acid reflux. Eight to 20% of GERD patients exhibit esophageal intestinal metaplasia, termed Bar­ rett’s metaplasia, which predisposes to esophageal adenocarcinoma (Chap. 85). Esophageal squamous cell carcinoma occurs most often with long-standing tobacco or ethanol intake. Other risks include prior caustic ingestion, achalasia, and the hereditary disorder tylosis. Gastric malignancies include adenocarcinoma, which is prevalent in certain Asian societies, and lymphoma. Other Causes  Opportunistic fungal or viral esophageal infections may produce heartburn but more often cause odynophagia. Other causes of esophageal inflammation include eosinophilic esophagitis and pill esophagitis. Biliary colic can cause unexplained chronic upper abdominal pain, but most patients report discrete acute episodes of right upper quadrant or epigastric pain rather than chronic burning or fullness. Twenty percent of gastroparesis patients note predominance of pain rather than nausea and vomiting. Intestinal lactase deficiency may cause gas, bloating, and discomfort, more commonly in blacks and Asians. Intolerance of other carbohydrates (e.g., fructose, sorbitol) produces similar symptoms. Small-intestinal bacterial overgrowth may cause dyspepsia, as well as bowel dysfunction, distention, and malab­ sorption. Celiac disease, nonceliac gluten sensitivity, pancreatic disease (chronic pancreatitis, malignancy), hepatocellular carcinoma, Ménétrier’s disease, infiltrative diseases (sarcoidosis, mastocytosis, eosinophilic gastroenteritis), mesenteric ischemia, thyroid and parathyroid disease, and abdominal wall strain cause dyspepsia. Extraperitoneal etiologies of indigestion include congestive heart failure and tuberculosis.

APPROACH TO THE PATIENT Indigestion HISTORY AND PHYSICAL EXAMINATION Managing indigestion requires a thorough interview. GERD classi­ cally produces heartburn, a substernal warmth that moves toward the neck. Heartburn often is exacerbated by meals and may awaken the patient. Associated symptoms include regurgitation of acid or nonacidic fluid and water brash, the reflex release of salty saliva into the mouth. Atypical symptoms include pharyngitis, asthma, cough, bronchitis, hoarseness, and chest pain. Some patients with acid reflux on esophageal pH testing note abdominal pain instead of heartburn. Dyspeptic patients report symptoms referable to the upper abdomen that may be meal-related or independent of food ingestion. The history in functional dyspepsia may also report symptoms of GERD or IBS. The physical exam with GERD and functional dyspepsia usually is normal. In atypical GERD, pharyngeal erythema and wheezing may be noted. Recurrent regurgitation may cause poor dentition. Dyspeptics may exhibit epigastric tenderness or distention. Discriminating functional from structural causes of indigestion mandates excluding certain historic and exam features. Odyno­ phagia suggests esophageal infection. Dysphagia is concerning for esophageal blockage. Other alarm features include unexplained weight loss, recurrent vomiting, dysphagia, occult or gross bleeding, nocturnal symptoms, jaundice, palpable mass or adenopathy, fever, and a family history of gastrointestinal neoplasm. Patients with an abdominal wall source of upper abdominal pain may exhibit a posi­ tive Carnett’s sign of increased tenderness with tensing of abdomi­ nal muscles upon lifting the head from the exam table. DIAGNOSTIC TESTING Because indigestion is prevalent and most cases result from GERD or functional dyspepsia, it is generally recommended to perform no more than limited and directed diagnostic testing in most individuals. After excluding alarm factors (Table 48-3), patients with typical GERD do not need further evaluation and are treated empirically for 4–8 weeks with single or double dosing of a proton pump inhibi­ tor (PPI) acid suppressant. Upper endoscopy is indicated for cases with persistent symptoms, atypical presentations, or alarm factors. For heartburn >5 years in duration, especially in patients >50 years old, endoscopy is advocated to screen for Barrett’s metaplasia. Endoscopy is not needed in low-risk patients who respond to acid suppressants. Up to one-third of patients with presumed GERD do not respond to PPI therapy. Ambulatory esophageal pH measure­ ment for 48–96 hours off acid-suppressing medications using a wireless capsule endoscopically attached to the esophageal wall is considered for drug-refractory symptoms. Combined esophageal pH and impedance testing using a transnasal catheter while on PPI therapy can define if a patient with persistent or atypical symp­ toms has esophageal hypersensitivity or regurgitation of nonacidic or incompletely controlled acid fluid. High-resolution esophageal manometry is ordered when fundoplication is considered for treat­ ment of GERD. Poor esophageal body peristalsis raises concern about postoperative dysphagia and directs the choice of surgical technique. TABLE 48-3  Alarm Symptoms in Gastroesophageal Reflux Disease Odynophagia or dysphagia Unexplained weight loss Recurrent vomiting Occult or gross gastrointestinal bleeding Jaundice Palpable mass or adenopathy Family history of gastroesophageal malignancy

In the absence of alarm features and for patients <60 years old, assessment of H. pylori status by fecal antigen or urea breath testing should be performed as initial diagnostic testing for uninvestigated dyspepsia. Those who are H. pylori positive are given therapy to eradicate the infection. Confirmation of H. pylori eradication should be conducted 4–6 weeks after completing therapy. Empiric PPI therapy is reserved for those who are negative for infection or who fail to respond to H. pylori treatment. Upper endoscopy is advocated to exclude malignancy for patients with unexplained dyspepsia who are >60 years old, who report alarm symptoms, or who fail to respond to these therapies. Nausea, Vomiting, and Indigestion CHAPTER 48 Further testing is indicated in some settings. For associated bleeding, a blood count can exclude anemia. Thyroid chemistries or calcium levels screen for metabolic etiologies. Serologies may sug­ gest celiac disease. Pancreatic and liver chemistries are obtained for suspected pancreaticobiliary causes, which are further investigated with ultrasound, CT, or MRI. Gastric emptying testing is considered to exclude gastroparesis in patients who report symptoms resem­ bling PDS when therapy fails. Breath testing after carbohydrate ingestion detects lactase deficiency, intolerance to other carbohy­ drates, or small-intestinal bacterial overgrowth. TREATMENT Indigestion LIFESTYLE, DIET, AND NONMEDICATION RECOMMENDATIONS Patients with mild indigestion are reassured that careful evaluation revealed no serious disease and are offered no other interven­ tion. If possible, drugs that cause GERD or dyspepsia should be stopped. GERD patients should limit ethanol, caffeine, chocolate, and tobacco use and can ingest smaller low-fat meals with no snacks before bedtime, avoid tight clothing, and elevate the head of the bed. Functional dyspepsia patients are advised to reduce intake of fat, spicy foods, caffeine, and alcohol. Dietary lactose restric­ tion is appropriate for lactase deficiency, while gluten exclusion is indicated for celiac disease. Small studies suggest benefits of low FODMAP, six-food elimination, and gluten-free diets. These find­ ings warrant confirmation in larger functional dyspepsia cohorts. ACID-SUPPRESSING OR -NEUTRALIZING MEDICATIONS Drugs that reduce or neutralize gastric acid are commonly pre­ scribed for GERD. Histamine H2 antagonists like cimetidine and famotidine are useful in mild to moderate GERD. For severe symp­ toms or for erosive or ulcerative esophagitis, PPIs like omeprazole, lansoprazole, rabeprazole, pantoprazole, esomeprazole, or dexlan­ soprazole are needed. These drugs inhibit gastric H+, K+-ATPase and are more potent than H2 antagonists. Heartburn responds better to PPI therapy than regurgitation or atypical GERD symp­ toms. Some individuals respond to doubling of the PPI dose or adding an H2 antagonist. Complications of long-term PPI ther­ apy include diarrhea (Clostridioides difficile infection, microscopic colitis), small-intestinal bacterial overgrowth, nutrient deficiency (vitamin B12, iron, calcium), hypomagnesemia, bone demineral­ ization, interstitial nephritis, and impaired medication absorp­ tion (clopidogrel). Many patients started on a PPI can be stepped down to an H2 antagonist or switched to on-demand use. Nor­ mal acid exposure on 96-hour esophageal pH testing predicts successful PPI withdrawal. Vonoprazan is a new potassium-

competitive acid blocker, more potent than PPI medications, that was recently approved for erosive esophagitis. Acid suppressants are also effective for both the PDS and EPS subtypes of functional dyspepsia as initial therapy in H. pylori–negative patients or for persisting symptoms after H. pylori eradication. A meta-analysis of 18 controlled trials calculated a risk ratio of 0.88, with a 95% confidence interval of 0.82–0.94, favoring PPI therapy over placebo in functional dyspepsia. A 4- to 8-week PPI trial is

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49 Diarrhea and Constipation

advocated and should be discontinued if no benefit is observed. H2 antagonists also improve symptoms in functional dyspepsia, but a guideline advocated PPIs over H2 antagonists as first-line therapy.

Antacids are useful for short-term control of mild GERD but have less benefit in severe cases unless given at high doses that cause side effects (diarrhea and constipation with magnesium- and aluminum-containing agents, respectively). Alginic acid combined with antacids forms a floating barrier to reflux in patients with postprandial or nocturnal symptoms. Sucralfate, a salt of aluminum hydroxide and sucrose octasulfate that buffers acid and binds pep­ sin and bile salts, shows efficacy in GERD similar to H2 antagonists. HELICOBACTER PYLORI ERADICATION The benefits of H. pylori eradication in functional dyspepsia are limited but are statistically significant with a 9% risk reduction compared to placebo. A systematic review of 25 controlled trials calculated a pooled risk ratio of 1.24, with a 95% confidence interval of 1.12–1.37, favoring H. pylori eradication over placebo. Most drug combinations (Chaps. 168 and 335) include 7–14 days of a PPI plus two or three antibiotics with or without bismuth products. H. pylori infection is associated with reduced prevalence of GERD. However, H. pylori eradication does not worsen GERD symptoms. PART 2 Cardinal Manifestations and Presentation of Diseases AGENTS THAT MODIFY GASTROINTESTINAL MOTOR ACTIVITY The γ-aminobutyric acid B (GABA-B) agonist baclofen reduces esophageal exposure to refluxed gastric contents by reducing TLESRs by 40% and can be used in patients with refractory regurgitation of acid or nonacid fluid. Several studies promote the efficacy of agents that stimulate gastric emptying in functional dys­ pepsia with 33% relative risk reductions, but publication bias and small sample sizes raise questions about the true benefits of these agents. The PDS subtype may respond preferentially to such proki­ netic drugs. Although the 5-HT4 agonist prucalopride can reduce symptoms in idiopathic gastroparesis, no similar studies have been conducted in functional dyspepsia. The 5-HT1A agonists buspirone and tandospirone may improve symptoms in functional dyspep­ sia and gastroparesis by enhancing meal-induced gastric accom­ modation. Acotiamide stimulates gastric emptying and augments accommodation by enhancing acetylcholine release via muscarinic receptor antagonism and acetylcholinesterase inhibition. This agent is approved for functional dyspepsia in Japan and India. CENTRALLY ACTING NEUROMODULATORS Some patients with refractory functional heartburn respond to tricyclic antidepressants. Their mechanism of action may involve blunting of visceral pain processing in the brain. In one con­ trolled trial in functional dyspepsia, the tricyclic drug amitriptyline produced symptom reductions, whereas the selective serotonin reuptake inhibitor (SSRI) escitalopram had no benefit in a threeway comparison with placebo. A second study reported greater improvement with a different tricyclic agent imipramine versus placebo. In a controlled trial of a different antidepressant, mirtazap­ ine produced superior symptom reductions in functional dyspepsia compared to placebo. In contrast, a meta-analysis of 13 trials of SSRIs and serotonin-norepinephrine reuptake inhibitors observed no benefits in this disorder. OTHER OPTIONS Gas and bloating may be difficult to control in patients with indi­ gestion. Simethicone, activated charcoal, α-galactosidase, and other over-the-counter herbal products provide benefits in some cases. One trial suggested possible benefits of the nonabsorbable anti­ biotic rifaximin in functional dyspepsia, while another reported improvement with the probiotic Lactobacillus gasseri. Herbal rem­ edies like STW 5 (a mixture of nine herbal agents) and formula­ tions of caraway oil and menthol show efficacy in some dyspeptic patients in controlled studies. Acupuncture has shown benefits in sham-controlled trials. Psychological treatments (e.g., behavioral therapy, psychotherapy, hypnotherapy, diaphragmatic breathing,

mindfulness) may be offered for refractory heartburn due to esoph­ ageal hypersensitivity or functional dyspepsia; a meta-analysis of four trials reported benefits in patients with persistent dyspepsia. Antireflux surgery (fundoplication) to enhance the barrier func­ tion of the LES may be offered to GERD patients who are young and require lifelong therapy, have typical heartburn, are responsive to PPIs, and show acid reflux on pH monitoring. Surgery also is effective for some cases with prominent regurgitation. Factors associated with poor response to fundoplication include atypical reflux symptoms, no pathologic acid reflux on pH testing, esopha­ geal body motor disturbances on manometry, and delayed gastric emptying. Dysphagia, gas-bloat syndrome, and gastroparesis are long-term complications of fundoplication; ∼60% develop recurrent GERD symptoms over time. Magnetic sphincter augmentation may be appropriate for GERD treatment, while endoscopic transoral incisionless fundoplication can be considered for some patients. ■ ■FURTHER READING Camilleri M et al: ACG Clinical Guideline: gastroparesis. Am J Gastroenterol 117:1197, 2022. Frazier R et al: Diagnosis and management of cyclic vomiting syndrome: A critical review. Am J Gastroenterol 118:1157, 2023. Hungin AP et al: Management advice for patients with reflux-like symptoms: An evidence-based consensus. Eur J Gastroenterol Hepatol 36:13, 2024. Moshiree B, Talley NJ: Functional dyspepsia: A critical appraisal of the European consensus from a global perspective. Neurogastroenterol Motil 33:e14216, 2021. Sperber AD et al: Worldwide prevalence and burden of functional gastrointestinal disorders, results of Rome Foundation Global Study. Gastroenterology 160:99, 2021. Michael Camilleri, Joseph A. Murray

Diarrhea and

Constipation Diarrhea and constipation are exceedingly common and, together, exact an enormous toll in terms of mortality, morbidity, social inconvenience, loss of work productivity, and consumption of medi­ cal resources. Worldwide, >1 billion individuals suffer one or more episodes of acute diarrhea each year. Among the 100 million persons affected annually by acute diarrhea in the United States, nearly half must restrict activities, 10% consult physicians, ~250,000 require hospitalization, and ~5000 die (primarily the elderly). Updated 2021 annual disease burden data from the United States show 4.05 million annual clinic or emergency department visits for constipation or diar­ rhea or irritable bowel syndrome (IBS), and annual median economic burden to society for functional intestinal disorders of $145 million. Acute infectious diarrhea is the second leading cause of death in children, and the World Health Organization reports around 525,000 children under age 5 years die each year from acute diarrhea. Recurrent, acute diarrhea in children in tropical countries results in environmental enteropathy with long-term impacts on physical (stunted growth) and intellectual development. Constipation, by contrast, is rarely associated with mortality and is exceedingly common in developed countries, leading to frequent self-medication and, in a third of those, to medical consultation. Annual disease burden data for 2016 show about 5 million clinic or emergency department (ED) visits for constipation or hemorrhoids,

and over 190,000 ED visits for a primary diagnosis of hemorrhoids in 2018. Population statistics on chronic diarrhea and constipation have been the subject of global studies, and in U.S. population surveys, the prevalence rates were 5.0% (95% confidence interval [CI], 4.1%–6.0%) for chronic diarrhea and 8.8% (95% CI, 7.5%–10.0%) for chronic constipation, with women affected 1.5 times as often as men. Diarrhea and constipation are among the most common patient complaints presenting in primary care and account for nearly 50% of referrals to gastroenterologists. Although diarrhea and constipation may present as mere nuisance symptoms at one extreme, they can be severe or life threatening at the other. Even mild symptoms may signal a serious underlying gastro­ intestinal (GI) lesion, such as colorectal cancer, or systemic disorder, such as thyroid disease. Given the heterogeneous causes and potential severity of these common complaints, it is imperative for clinicians to appreciate the pathophysiology, etiologic classification, diagnostic strategies, and principles of management of diarrhea and constipation so that rational and cost-effective care can be delivered. NORMAL PHYSIOLOGY While the primary function of the small intestine is the digestion and assimilation of nutrients from food, the small intestine and colon together perform important functions that regulate the secretion and absorption of water and electrolytes, the storage and subsequent transport of intraluminal contents aborally, and the salvage of some nutrients that are not absorbed in the small intestine after bacterial metabolism of carbohydrate allows salvage of short-chain fatty acids. The main motor functions are summarized in Table 49-1. Alterations in fluid and electrolyte handling contribute significantly to diarrhea. Alterations in motor and sensory functions of the colon result in highly prevalent syndromes such as IBS, chronic diarrhea, and chronic constipation. ■ ■NEURAL CONTROL The small intestine and colon have intrinsic and extrinsic innervation. The intrinsic innervation, also called the enteric nervous system, com­ prises myenteric, submucosal, and mucosal neuronal layers. The func­ tion of these layers is modulated by interneurons through the actions of neurotransmitter amines or peptides, including acetylcholine, vasoactive intestinal peptide (VIP), opioids, norepinephrine, serotonin, adenosine triphosphate (ATP), and nitric oxide (NO). The myenteric plexus regulates smooth-muscle function through intermediary pace­ maker-like cells called the interstitial cells of Cajal, and the submucosal plexus affects secretion, absorption, and mucosal blood flow. The enteric nervous system receives input from the extrinsic nerves, but it is capable of independent control of these functions and peristalsis. The extrinsic innervations of the small intestine and colon are part of the autonomic nervous system and also modulate motor and secretory functions. The parasympathetic nerves convey visceral sensory path­ ways from and excitatory pathways to the small intestine and colon. Parasympathetic fibers via the vagus nerve reach the small intestine TABLE 49-1  Normal Gastrointestinal Motility: Functions at Different Anatomic Levels Stomach and Small Bowel Synchronized MMC in fasting Accommodation, trituration, mixing, transit   Stomach ~3 h   Small bowel ~3 h Ileal reservoir empties boluses Colon: Irregular Mixing, Fermentation, Absorption, Transit Cecum, ascending, transverse: reservoirs Descending: conduit Sigmoid/rectum: volitional reservoir Abbreviation: MMC, migrating motor complex.

and proximal colon along the branches of the superior mesenteric artery. The distal colon is supplied by sacral parasympathetic nerves (S2–4) via the pelvic plexus; these fibers course through the wall of the colon as ascending intracolonic fibers as far as the proximal colon. The chief excitatory neurotransmitters controlling motor function are ace­ tylcholine and the tachykinins, such as substance P. The sympathetic nerves reach the small intestine and colon along their arterial vessels. Sympathetic input to the gut is generally excitatory to sphincters and inhibitory to nonsphincteric muscle. Visceral afferents convey sensa­ tion from the gut to the central nervous system (CNS). Some afferent fibers synapse in the prevertebral ganglia and reflexly modulate intes­ tinal motility, blood flow, and secretion.

Diarrhea and Constipation CHAPTER 49 ■ ■INTESTINAL FLUID ABSORPTION

AND SECRETION On an average day, 9 L of fluid enter the GI tract, ~1 L of residual fluid reaches the colon, and the stool excretion of fluid constitutes about 0.2 L/d. The colon has a large capacitance and functional reserve and may recover up to four times the usual recovered volume of 0.8 L/d, provided the rate of flow permits reabsorption to occur. Thus, the colon can partially compensate for excess fluid delivery to the colon that may result from intestinal absorptive or secretory disorders. In the small intestine and colon, sodium absorption is predomi­ nantly electrogenic (i.e., it can be measured as an ionic current across the membrane because there is not an equivalent loss of a cation from the cell), and uptake takes place at the apical membrane; it is compensated for by the export functions of the basolateral sodium pump. Several active transport proteins are at the apical membrane, especially in the small intestine, whereby sodium ion entry is coupled to monosaccharides (e.g., glucose through the transporter SGLT1 or fructose through GLUT-5). Glucose then exits the basal membrane through a specific transport protein, GLUT-2, creating a glucose concentration and osmotic gradient between the lumen and the intercellular space, drawing water and electrolytes passively from the lumen. Several channels mediate the secretion of chloride ions in diarrheal diseases or in response to medications administered for the treatment of constipation. The diverse ion channels (chloride channels and cystic fibrosis transmembrane regulator), transporters (SGLT1, GLUT-2), and receptors (e.g., guanylate cyclase C receptor) are summarized in Fig. 49-1. A variety of neural and nonneural mediators regulate colonic fluid and electrolyte balance, including cholinergic, adrenergic, and seroto­ nergic mediators. Angiotensin and aldosterone also influence colonic absorption, reflecting the common embryologic development of the distal colonic epithelium and the renal tubules. ■ ■SMALL-INTESTINAL MOTILITY During the fasting period, the motility of the small intestine is characterized by a cyclical event called the migrating motor com­ plex (MMC), which serves to clear nondigestible residue from the small intestine (the intestinal “housekeeper”). This organized, propagated series of contractions lasts, on average, 4 min, occurs every 60–90 min, and usually involves the entire small intestine. After food ingestion, the small intestine produces irregular, mixing contractions of relatively low amplitude, except in the distal ileum where more powerful contractions occur intermittently and empty the ileum by bolus transfers. ■ ■ILEOCOLONIC STORAGE AND SALVAGE The distal ileum acts as a reservoir, emptying intermittently by bolus movements. This action allows time for salvage of fluids, electrolytes, and nutrients. Segmentation by haustra compartmentalizes the colon and facilitates mixing, retention of residue, and formation of solid stools. There is increased appreciation of the intimate interaction between the colonic function and the luminal ecology. The resident microorganisms, predominantly anaerobic bacteria, in the colon are necessary for the digestion of unabsorbed carbohydrates that reach the colon even in health, thereby providing a vital source of nutrients to the mucosa. Normal intestinal flora also keeps pathogens at bay by

GC-C agonists, linaclotide, plecanatide GC-C receptor CaCC CFTR NHE3 inhibitor, tenapanor, lubiprostone Apical ClClClSGLTs SAACTs NHE3 HCO3H+ CIC-2 Na+ Na+ Na+ PART 2 Cardinal Manifestations and Presentation of Diseases Glucose Amino acids CIC-2 channel inhibitor, lubiprostone cAMP/cGMP [Ca2+]i Jejunum Distal colon Glucose Cl2 ClCIC-2 Na+ K+ 2 K+ GLUT2 Glucose K+ channel Na+-K+ ATPase K+ K+ channel 3 Na+ K+ NKCC1 Basal FIGURE 49-1  Important ion transport mechanisms in the jejunum and colon, and the site of action of medications used as secretagogues in the treatment of chronic constipation. CFTR, cystic fibrosis transmembrane regulator; ClC2, type 2 chloride channel, DRA, downregulated in adenoma (also called SLC26A3); ENaC, epithelial sodium channel; GC-C, guanylate cyclase C; Na+-K+ ATPase, sodium-potassium adenosine triphosphatase; NHE3, sodium-hydrogen exchanger; NKCC1, Na-K-Cl cotransporter; SAACT, sodium amino acid co-transporters; SGLT, sodium glucose transporters. a variety of mechanisms including a crucial role in the development and maintenance of a potent but well-regulated immune response capacity to pathogens and tolerance to normal ingesta. In health, the ascending and transverse regions of colon function as reservoirs (average transit time, 15 h), and the descending colon acts as a con­ duit (average transit time, 3 h). The colon is efficient at conserving sodium and water, a function that is particularly important in sodium-depleted patients in whom the small intestine alone is unable to maintain sodium balance. Diarrhea or constipation may result from alteration in the reservoir function of the proximal colon or the propulsive function of the left colon. Constipation may also result from disturbances of the rectal or sigmoid reservoir, typically as a result of dysfunction of the pelvic floor, the anal sphincters, and the coordination of defecation. ■ ■COLONIC MOTILITY AND TONE The small-intestinal MMC only rarely continues into the colon. However, short duration or phasic antegrade and retrograde contractions mix colonic contents, and high-amplitude (>75 mmHg) propagated contractions (HAPCs) are sometimes associated with mass movements through the colon and normally occur approxi­ mately five times per day, usually on awakening in the morning and postprandially. Increased frequency of HAPCs may result in diarrhea or urgency. Pubis Coccyx Puborectalis External anal sphincter Internal anal sphincter A B Colonic tone refers to the back­ ground contractility upon which phasic contractile activity is superimposed. It is an important cofactor in the colon’s capacitance (volume accommodation) and sensation. FIGURE 49-2  Sagittal view of the anorectum (A) at rest and (B) during straining to defecate. Continence is maintained by normal rectal sensation and tonic contraction of the internal anal sphincter and the puborectalis muscle, which wraps around the anorectum, maintaining an anorectal angle between 80° and 110°. During defecation, the pelvic floor muscles (including the puborectalis) relax, allowing the anorectal angle to straighten by at least 15°, and the perineum descends by 1–3.5 cm. The external anal sphincter also relaxes and reduces pressure on the anal canal. (From The New England Journal of Medicine, A Lembo, M Camilleri; Chronic constipation, 349:1360, Copyright © 2003, Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

Lumen Apical DRA ENaC Cl2 K+ 3 Na+ Na+-K+ ATPase Basal Blood ■ ■COLONIC MOTILITY AFTER MEAL INGESTION After meal ingestion, colonic phasic and tonic contractility increase for a period of ~2 h. The initial phase (~10 min) is mediated by the vagus nerve in response to mechanical distention of the stomach. The sub­ sequent response of the colon requires caloric stimulation (e.g., intake of at least 500 kcal) and is mediated, at least in part, by hormones (e.g., motilin and cholecystokinin). ■ ■DEFECATION Tonic contraction of the puborectalis muscle, which forms a sling around the rectoanal junction, is important to maintain continence; during defecation, sacral parasympathetic nerves relax this mus­ cle, facilitating the straightening of the rectoanal angle (Fig. 49-2). At rest During straining Anorectal angle Anorectal angle Descent of the pelvic floor

Distention of the rectum results in transient relaxation of the inter­ nal anal sphincter via intrinsic and reflex sympathetic innervation. As sigmoid and rectum contract, and straining (Valsalva maneuver) increases intraabdominal pressure and pressure within the rectum, the rectosigmoid angle opens by >15°. Voluntary relaxation of the external anal sphincter (striated muscle innervated by the pudendal nerve) in response to the sensation produced by distention permits the evacua­ tion of feces. Defecation can also be delayed voluntarily by contraction of the external anal sphincter. DIARRHEA ■ ■DEFINITION Diarrhea is loosely defined as passage of abnormally liquid or unformed stools at an increased frequency. For adults on a typical Western diet, stool weight >200 g/d can generally be considered diarrheal. Diarrhea may be further defined as acute if <2 weeks, persistent if 2–4 weeks, and chronic if >4 weeks in duration. Two common conditions, usually associated with the passage of stool totaling <200 g/d, must be distinguished from diarrhea, because diagnostic and therapeutic algorithms differ. Pseudodiarrhea, or the frequent passage of small volumes of stool, is often associated with rectal urgency, tenesmus, or a feeling of incomplete evacuation and accompanies IBS or proctitis. Fecal incontinence is the involuntary discharge of rectal contents and is most often caused by neuromuscu­ lar disorders or structural anorectal problems. Diarrhea and urgency, especially if severe, may aggravate or cause incontinence. Pseudodi­ arrhea and fecal incontinence occur at prevalence rates comparable to or higher than that of chronic diarrhea and should always be considered in patients complaining of “diarrhea.” Overflow diarrhea may occur in nursing home patients due to fecal impaction that is readily detectable by rectal examination. A careful history and physi­ cal examination generally allow these conditions to be discriminated from true diarrhea. ■ ■ACUTE DIARRHEA More than 90% of cases of acute diarrhea are caused by infectious agents; these cases are often accompanied by vomiting, fever, and abdominal pain. The remaining 10% or so are caused by medica­ tions, toxic ingestions, ischemia, food indiscretions, and other conditions. Infectious Agents  Domestically, infections predominate, whereas bacterial infections may be more important in travel-acquired disease. Most infectious diarrheas are acquired by fecal-oral transmission or, more commonly, via ingestion of food or water contaminated with pathogens from human or animal feces. In the immunocompetent person, the resident fecal microflora, containing >500 taxonomically distinct species, are rarely the source of diarrhea and may actually play a role in suppressing the growth of ingested pathogens. Disturbances of flora by antibiotics can lead to diarrhea by reducing the digestive function or by allowing the overgrowth of pathogens, such as Clos­ tridioides difficile (Chap. 139). Acute infection or injury occurs when the ingested agent overwhelms or bypasses the host’s mucosal immune and nonimmune (gastric acid, digestive enzymes, mucus secretion, peristalsis, and suppressive resident flora) defenses. Established clinical associations with specific enteropathogens may offer diagnostic clues. Diarrhea occasionally is an early symptom of infection such as SARSCoV-2 and Legionella. In the United States, five high-risk groups are recognized:

1. Travelers. Up to 40% of U.S. tourists to endemic regions of Latin America, Africa, and Asia develop so-called traveler’s diarrhea, most commonly due to enterotoxigenic or enteroaggregative Escherichia coli as well as to Campylobacter, Shigella, Aeromonas, norovirus, Coronavirus, and Salmonella. Other causative organisms in traveler’s diarrhea among campers, backpackers, and swimmers are Giardia and Cyclospora. Cruise ships may be affected by outbreaks of gastro­ enteritis caused by agents such as norovirus.

2. Consumers of certain foods. Diarrhea closely following food con­

sumption at a picnic, banquet, or restaurant may suggest infection with Salmonella, Campylobacter, or Shigella from chicken; entero­ hemorrhagic E. coli (O157:H7) from undercooked hamburger; Bacillus cereus from fried rice or other reheated food; Staphylococ­ cus aureus or Salmonella from mayonnaise or creams; Salmonella from eggs; Listeria from fresh or frozen uncooked foods, mush­ rooms, or dairy products; and Vibrio species, Salmonella, or acute hepatitis A from seafood, especially if raw. State departments of public health and the National Outbreak Reporting System issue communications regarding domestic and foreign food-related ill­ nesses, often identified by rapid DNA typing (PulseNet), that cause epidemics in the United States (e.g., the Listeria epidemic of 2020 from imported enoki mushrooms). Diverse foods including meat, seafood, and fresh produce and drinking water may be contami­ nated with C. difficile and the same ribotypes that actually cause the human disease. However, it has not been conclusively dem­ onstrated that food or water actually causes community-acquired C. difficile infection other than a waterborne outbreak in Finland associated with contamination of a public tap water distribution system. 3. Immunodeficient persons. Individuals at risk for diarrhea include Diarrhea and Constipation CHAPTER 49 those with either primary immunodeficiency (e.g., IgA deficiency, common variable hypogammaglobulinemia, chronic granuloma­ tous disease) or secondary immunodeficiency states (e.g., AIDS, senescence, pharmacologic suppression). Common enteric patho­ gens often cause a more severe and protracted diarrheal illness. In persons with AIDS, opportunistic infections, such as by Myco­ bacterium species, certain viruses (cytomegalovirus, adenovirus, and herpes simplex), and protozoa (Cryptosporidium, Isospora belli, microsporidia, and Blastocystis hominis) may also play a role (Chap. 208). In patients with AIDS, agents transmitted venereally per rectum or by extension from vaginal infection (e.g., Neisseria gonorrhoeae, Treponema pallidum, Chlamydia) may contribute to proctocolitis. Persons with hemochromatosis are especially prone to invasive, even fatal, enteric infections with Vibrio species and Yersinia infections and should avoid raw fish and exposing open wounds to seawater. 4. Daycare attendees and their family members. Infections with Shigella, Giardia, Cryptosporidium, rotavirus, and other agents are very common. 5. Institutionalized persons. Infectious diarrhea is one of the most fre­ quent nosocomial infections in hospitals and long-term care facili­ ties; the causes are a variety of microorganisms but most commonly C. difficile. C. difficile can affect those with no history of antibiotic use and is often community acquired. The pathophysiology underlying acute diarrhea by infectious agents results in specific clinical features that may be helpful in diagnosis (Table 49-2). Profuse, watery diarrhea secondary to smallbowel hypersecretion occurs with ingestion of preformed bacterial toxins, enterotoxin-producing bacteria, and enteroadherent patho­ gens. Abrupt onset of diarrhea associated with marked vomiting and minimal or no fever within a few hours after ingestion suggests a toxin etiology; vomiting is usually less, abdominal cramping or bloat­ ing is greater, and fever is higher with enteroadherent pathogens. Cytotoxin-producing and invasive microorganisms all cause high fever and abdominal pain. Invasive bacteria and Entamoeba histo­ lytica often cause bloody diarrhea (referred to as dysentery). Yersinia invades the terminal ileal and proximal colon mucosa and may cause especially severe abdominal pain with tenderness mimicking acute appendicitis. Finally, infectious diarrhea may be associated with systemic mani­ festations. Reactive arthritis or the combination of arthritis, urethritis, and conjunctivitis (Reiter’s syndrome) may accompany or follow infec­ tions by Salmonella, Campylobacter, Shigella, and Yersinia. Yersiniosis may also lead to an autoimmune-type thyroiditis, pericarditis, and glomerulonephritis. Both enterohemorrhagic E. coli (O157:H7) and Shigella can lead to the hemolytic-uremic syndrome with an attendant

TABLE 49-2  Association Between Pathobiology of Causative Agents and Clinical Features in Acute Infectious Diarrhea INCUBATION PERIOD VOMITING PATHOBIOLOGY/AGENTS Toxin producers   Preformed toxin     Bacillus cereus, Staphylococcus aureus, 1–8 h 8–24 h 3–4+ 1–2+ 0–1+ 3–4+, watery Clostridium perfringens Enterotoxin   Vibrio cholerae, enterotoxigenic Escherichia coli, 8–72 h 2–4+ 1–2+ 0–1+ 3–4+, watery Klebsiella pneumoniae, Aeromonas species PART 2 Cardinal Manifestations and Presentation of Diseases Enteroadherent   Enteropathogenic and enteroadherent E. coli, 1–8 d 0–1+ 1–3+ 0–2+ 1–2+, watery, mushy Giardia organisms, cryptosporidiosis, helminths Cytotoxin producers   Clostridioides difficile 1–3 d 0–1+ 3–4+ 1–2+ 1–3+, usually watery, occasionally bloody   Hemorrhagic E. coli 12–72 h 0–1+ 3–4+ 1–2+ 1–3+, initially watery, quickly bloody Invasive organisms   Minimal inflammation   Rotavirus and norovirus 1–3 d 1–3+ 2–3+ 3–4+ 1–3+, watery Variable inflammation   Salmonella, Campylobacter, and Aeromonas 12 h–11 d 0–3+ 2–4+ 3–4+ 1–4+, watery or bloody species, Vibrio parahaemolyticus, Yersinia Severe inflammation   Shigella species, enteroinvasive E. coli, Entamoeba 12 h–8 d 0–1+ 3–4+ 3–4+ 1–2+, bloody histolytica Source: Adapted from DW Powell, in T Yamada (ed): Textbook of Gastroenterology and Hepatology, 4th ed. Philadelphia, Lippincott Williams & Wilkins, 2003. high mortality rate. The syndrome of postinfectious IBS has now been recognized as a complication of infectious diarrhea, particularly Campylobacter jejuni infection. Similarly, acute gastroenteritis may precede the diagnosis of celiac disease or Crohn’s disease, but the risk of developing these diseases is low, and there is no indication to screen for these diseases (e.g., by serology or endoscopy) during the episode of acute gastroenteritis. Acute diarrhea can also be a major symptom of several systemic infections including viral hepatitis, listeriosis, legionel­ losis, and toxic shock syndrome. Other Causes  Side effects from medications are probably the most common noninfectious causes of acute diarrhea, and etiology may be suggested by a temporal association between use and symptom onset. Although innumerable medications may produce diarrhea, some of the more frequently incriminated include antibiotics, cardiac antidys­ rhythmics, antihypertensives, nonsteroidal anti-inflammatory drugs (NSAIDs), certain antidepressants, weight loss agents, chemotherapeu­ tic agents, bronchodilators, antacids, and laxatives. Occlusive or nonocclusive ischemic colitis typically occurs in persons aged >50 years; often presents as acute lower abdominal pain preceding watery, then bloody diarrhea; and generally results in acute inflamma­ tory changes in the sigmoid or left colon while sparing the rectum. Acute diarrhea may accompany colonic diverticulitis and graft-versushost disease. Acute diarrhea, often associated with systemic compromise, can follow ingestion of toxins including organophosphate insecticides, amanita and other mushrooms, arsenic, and preformed toxins in seafood such as ciguatera (from algae that the fish eat) and scom­ broid (an excess of histamine due to inadequate refrigeration). Acute allergic reaction to food ingestion, including galactose alpha-1,3-ga­ lactose (alpha gal) contained in meat, can have a similar presentation including systemic collapse, which should not be mistaken for simple dehydration secondary to diarrhea. Conditions causing chronic diar­ rhea can also be confused with acute diarrhea early in their course. This confusion may occur with inflammatory bowel disease (IBD) and some of the other inflammatory chronic diarrheas that may have an abrupt rather than insidious onset and exhibit features that mimic infection.

ABDOMINAL PAIN FEVER DIARRHEA APPROACH TO THE PATIENT Acute Diarrhea The decision to evaluate acute diarrhea depends on its severity and duration and on various host factors (Fig. 49-3). Most episodes of acute diarrhea are mild and self-limited and do not justify the cost and potential morbidity rate of diagnostic or pharmacologic inter­ ventions. Indications for evaluation (stool microbiological studies) include profuse diarrhea with dehydration, overtly bloody stools, fever ≥38.5°C (≥101°F), duration >48 h without improvement, recent antibiotic use, new community outbreaks, associated severe abdominal pain in patients aged >50 years, and elderly (≥70 years) or immunocompromised patients. In some cases of moderately severe febrile diarrhea associated with fecal leukocytes (or increased fecal levels of the leukocyte proteins, such as calprotectin) or with overt blood, a diagnostic evaluation might be avoided in favor of an empirical antibiotic trial (see below). The cornerstone of diagnosis in those suspected of severe acute infectious diarrhea acquired domestically is microbiologic analysis of the stool. Workup for a microbiologic cause now starts with culture-

independent methods. These methods, relying on the identification of unique DNA sequences, are more rapid, sensitive, specific, and cost-effective. The less sensitive culture-based methods for bacte­ ria, direct inspection for ova and parasites, and immunoassays for certain bacterial toxins (C. difficile), viral antigens (rotavirus), and protozoal antigens (Giardia, E. histolytica) are now primarily used when multiplexed tests are not available or for outbreak detection that still relies on isolate cultures and should be done when an outbreak is suspected or in domestically acquired severe diarrhea. Alternatively, the aforementioned clinical and epidemiologic asso­ ciations may assist in focusing the evaluation. If a particular patho­ gen or set of possible pathogens is so implicated, either the whole panel of routine studies may not be necessary or, in some instances, special cultures may be appropriate, as for enterohemorrhagic and other types of E. coli, Vibrio species, and Yersinia. There is no indi­ cation for serologic or endoscopic evaluation to exclude underlying intestinal diseases in the context of acute diarrhea.

Acute Diarrhea History and physical exam Likely noninfectious Evaluate and treat accordingly Likely infectious Moderate (activities altered) Mild (unrestricted) Severe (incapacitated) Institute fluid and electrolyte replacement Fever ≥38.5°C, bloody stools, fecal WBCs, immunocompromised or elderly host Observe Stool microbiology studies Yes† No Resolves Persists* Antidiarrheal agents Pathogen found Resolves Persists* Yes† No Select specific treatment Empirical treatment + further evaluation FIGURE 49-3  Algorithm for the management of acute diarrhea. Consider empirical treatment before evaluation with (*) metronidazole and with (†) quinolone. WBCs, white blood cells. Persistent diarrhea is commonly due to Giardia (Chap. 230), but additional causative organisms that should be considered include C. difficile (especially if antibiotics had been administered), E. histolytica, Cryptosporidium, Campylobacter, and others. If stool studies are unrevealing and if the diarrhea continues to become chronic (>30 days), flexible sigmoidoscopy with biopsies and upper endoscopy with duodenal aspirates and biopsies may be indicated to exclude celiac or Crohn’s disease, but these should not be per­ formed during or early after acute enteritis because of risk of falsepositive results. Brainerd diarrhea is an increasingly recognized entity characterized by an abrupt-onset diarrhea that persists for at least 4 weeks, but may last 1–3 years, and is thought to be of infec­ tious origin. It may be associated with subtle inflammation of the distal small intestine or proximal colon. Structural examination by sigmoidoscopy, colonoscopy, or abdominal computed tomography (CT) scanning (or other imag­ ing approaches) should only be used for patients with uncharacter­ ized persistent diarrhea when other symptoms suggest IBD or as an initial approach in patients with suspected noninfectious acute diarrhea such as might be caused by ischemic colitis, diverticuli­ tis, or partial bowel obstruction. However, acute diarrhea may be associated with finding of air-fluid levels on abdominal radiograph, necessitating CT imaging to exclude organic obstruction. TREATMENT Acute Diarrhea Fluid and electrolyte replacement are of central importance to all forms of acute diarrhea. Fluid replacement alone may suffice for mild cases. Oral sugar-electrolyte solutions (iso-osmolar sport drinks or designed formulations) should be instituted promptly

with severe diarrhea to limit dehydration or in elderly or vulnerable patients, which is the major cause of death. Profoundly dehydrated patients, especially infants and the elderly, require IV rehydration.

In moderately severe nonfebrile and nonbloody diarrhea, antimotil­ ity and antisecretory agents such as loperamide can be useful adjuncts to control symptoms. Such agents should be avoided with febrile dys­ entery, which may be prolonged by them, and should be used with cau­ tion with drugs that increase levels due to cardiac arrhythmia (due to effect on cardiac transmembrane ion channels). Bismuth subsalicylate may reduce symptoms of vomiting and diarrhea but should not be used to treat immunocompromised patients or those with renal impairment because of the risk of bismuth encephalopathy. Diarrhea and Constipation CHAPTER 49 Judicious use of antibiotics is appropriate in selected instances of acute diarrhea, especially in traveler’s diarrhea, and may reduce its severity and duration (Fig. 49-3). Many physicians treat moder­ ately to severely ill patients with febrile diarrheal illness empirically without diagnostic evaluation using a macrolide such as azithromy­ cin (single dose of 500 mg) or a quinolone such as ciprofloxacin (500 mg bid for 3–5 d). Empirical treatment can also be considered for suspected giardiasis with metronidazole (250 mg qid for 7 d). Selection of antibiotics and dosage regimens are otherwise dictated by specific pathogens, geographic patterns of resistance, and condi­ tions found (Chaps. 138, 166, and 170–176). Because of resistance to first-line treatments, newer agents such as nitazoxanide (500 mg bid for 3 d) may be required for Giardia and Cryptosporidium infec­ tions. Antibiotic coverage is indicated, whether or not a causative organism is discovered, in patients who are immunocompromised, have mechanical heart valves or recent vascular grafts, or are elderly. Bismuth subsalicylate may reduce the frequency of traveler’s diar­ rhea. Antibiotic prophylaxis is only indicated for certain patients traveling to high-risk countries in whom the likelihood or seri­ ousness of acquired diarrhea would be especially high, including those with immunocompromise, IBD, hemochromatosis, or gastric achlorhydria. Use of ciprofloxacin, azithromycin, or rifaximin may reduce bacterial diarrhea by 90% in such travelers. Rifaximin is not suitable for invasive disease but rather as treatment for uncomplicated traveler’s diarrhea. There is little role for endoscopic evaluation in most circumstances except in immunocompromised patients. Finally, physicians should be vigilant to identify if an out­ break of diarrheal illness and to alert the public health authorities promptly in order to reduce further spread. ■ ■CHRONIC DIARRHEA Diarrhea lasting >4 weeks warrants evaluation to exclude serious underlying pathology. In contrast to acute diarrhea, most of the causes of chronic diarrhea are noninfectious. The classification of chronic diarrhea by pathophysiologic mechanism facilitates a rational approach to management, although many diseases cause diarrhea by more than one mechanism (Table 49-3). Secretory Causes  Secretory diarrheas are due to derangements in fluid and electrolyte transport across the enterocolonic mucosa. They are characterized by watery, large-volume fecal outputs that are typi­ cally painless and persist with fasting. Because there is no malabsorbed solute, stool osmolality shows no fecal osmotic gap. MEDICATIONS  Side effects from regular ingestion of drugs and toxins are the most common secretory causes of chronic diarrhea. Hundreds of prescription and over-the-counter medications (see earlier section, “Acute Diarrhea, Other Causes”) may produce diarrhea. Surreptitious or habitual use of stimulant laxatives (e.g., senna, cascara, bisacodyl, ricinoleic acid [castor oil]) must also be considered. Chronic ethanol consumption may cause a secretory-type diarrhea due to enterocyte injury with impaired sodium and water absorption, rapid transit, and other alterations. Inadvertent ingestion of certain environmental toxins (e.g., arsenic) may lead to chronic rather than acute diarrhea. Certain bacterial infections may occasionally persist and be associated with a secretory-type diarrhea. The oral angiotensin receptor blockers, including olmesartan, are associated with diarrhea due to sprue-like

TABLE 49-3  Major Causes of Chronic Diarrhea According to Predominant Pathophysiologic Mechanism Secretory Causes   Exogenous stimulant laxatives   Chronic ethanol ingestion   Other drugs and toxins   Endogenous laxatives (dihydroxy bile acids)   Idiopathic secretory diarrhea or bile acid diarrhea   Certain bacterial infections   Bowel resection, disease, or fistula (↓ absorption) PART 2 Cardinal Manifestations and Presentation of Diseases   Partial bowel obstruction or fecal impaction   Hormone-producing tumors (carcinoid, VIPoma, medullary cancer of thyroid, mastocytosis, gastrinoma, colorectal villous adenoma)   Addison’s disease   Congenital electrolyte absorption defects Osmotic Causes   Osmotic laxatives (Mg2+, PO4 −3, SO4 −2)   Lactase and other disaccharide deficiencies   Nonabsorbable carbohydrates (fructose, sorbitol, lactulose, polyethylene glycol)   Wheat and FODMAP intolerance Steatorrheal Causes   Intraluminal maldigestion (pancreatic exocrine insufficiency, bacterial overgrowth, bariatric surgery, liver disease)   Mucosal malabsorption (celiac disease, Whipple’s disease, infections, abetalipoproteinemia, ischemia, drug-induced enteropathy)   Postmucosal obstruction (1° or 2° lymphatic obstruction), amyloidosis Inflammatory Causes   Idiopathic inflammatory bowel disease (Crohn’s, chronic ulcerative colitis)   Lymphocytic and collagenous colitis   Immune-related mucosal disease (1° or 2° immunodeficiencies, food allergy, eosinophilic gastroenteritis, C1-esterase inhibitor deficiency, graft-versushost disease)   Infections (invasive bacteria, viruses, and parasites, Brainerd diarrhea)   Radiation injury   Gastrointestinal malignancies Dysmotile Causes   Irritable bowel syndrome (including postinfectious IBS)   Visceral neuromyopathies   Hyperthyroidism   Drugs (prokinetic agents) and poisons   Postvagotomy Factitial Causes   Munchausen   Eating disorders Iatrogenic Causes   Cholecystectomy   Ileal resection   Bariatric surgery   Vagotomy, fundoplication Abbreviations: FODMAP, fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; IBS, irritable bowel syndrome. enteropathy, and more rarely, angiotensin-converting enzyme inhibi­ tors are associated with intestinal angioedema. Diarrhea is also a rela­ tively infrequent adverse effect of treatment with glucagon-like peptide 1 receptor agonists (e.g., semaglutide), although the mechanism in humans has not been elucidated. BOWEL RESECTION OR BYPASS, MUCOSAL DISEASE, OR ENTEROCOLIC FISTULA  These conditions may result in a secretory-type diarrhea

because of inadequate surface for reabsorption of secreted fluids and electrolytes. Unlike other secretory diarrheas, this subset of conditions tends to worsen with eating. With disease (e.g., Crohn’s ileitis) or resec­ tion of <100 cm of terminal ileum, dihydroxy bile acids may escape absorption and stimulate colonic secretion (cholerheic diarrhea). This mechanism may contribute to so-called idiopathic secretory diarrhea or bile acid diarrhea (BAD), in which bile acids are functionally mal­ absorbed from a normal-appearing terminal ileum. This may account for an average of 40% of unexplained chronic diarrhea and about 1% of the general population (same as celiac disease). Reduced negative feedback regulation of bile acid synthesis in hepatocytes by fibroblast growth factor 19 (FGF-19) produced by ileal enterocytes results in a degree of bile-acid synthesis that exceeds the normal capacity for ileal reabsorption, producing BAD. BAD is characterized by severe diar­ rhea, urgency, and impaired quality of life in part due to the need to be close to toilet facilities. It can be positively diagnosed by elevated fasting serum 7αC4 or fecal primary or total bile acids. Partial bowel obstruction, ostomy stricture, or fecal impaction may paradoxically lead to increased fecal output due to fluid hypersecretion. HORMONES  Although uncommon, secretory diarrhea may be medi­ ated by hormones. Metastatic gastrointestinal carcinoid tumors or, rarely, primary bronchial carcinoids may produce watery diarrhea alone or as part of the carcinoid syndrome that comprises episodic flushing, wheezing, dyspnea, and right-sided valvular heart disease. Diarrhea is due to the release into the circulation of potent intestinal secretagogues including serotonin, histamine, prostaglandins, and various kinins. Pellagra-like skin lesions may rarely occur as the result of serotonin overproduction with niacin depletion. Gastrinoma typically presents with refractory peptic ulcers, but diarrhea occurs in up to one-third of cases and may be the only clinical manifestation in 10%. Diarrhea most often results from fat maldigestion owing to pancreatic enzyme inactivation by low intraduodenal pH secondary to gastric acid hyper­ secretion. The watery diarrhea, hypokalemia, achlorhydria syndrome, also called pancreatic cholera, is due to secretion of VIP and a host of other peptide hormones by a non-β cell pancreatic adenoma, referred to as a VIPoma. The secretory diarrhea is often massive, with stool volumes >3 L/d; daily volumes as high as 20 L have been reported. Life-threatening dehydration; neuromuscular dysfunction from asso­ ciated hypokalemia, hypomagnesemia, or hypercalcemia; flushing; and hyperglycemia may accompany a VIPoma. Medullary carcinoma of the thyroid may present with watery diarrhea caused by calcitonin, other secretory peptides, or prostaglandins. Prominent diarrhea is often associated with metastatic disease and poor prognosis. Systemic mastocytosis, which may be associated with the skin lesion urticaria pigmentosa, may cause diarrhea that is either secretory and mediated by histamine or inflammatory due to intestinal infiltration by mast cells. Large colorectal villous adenomas may rarely be associated with a secretory diarrhea that may cause hypokalemia; these effects may be mediated by prostaglandins and can be inhibited by NSAIDs. CONGENITAL DEFECTS IN ION ABSORPTION  Rarely, defects in specific carriers associated with ion absorption cause watery diarrhea from birth. These disorders include defective Cl−/HCO3 − exchange (congeni­ tal chloridorrhea) with alkalosis (which results from a mutated DRA [down-regulated in adenoma] gene) and defective Na+/H+ exchange (congenital sodium diarrhea), which results from a mutation in the NHE3 (sodium-hydrogen exchanger) gene and results in acidosis. Some hormone deficiencies may be associated with watery diarrhea, such as occurs with adrenocortical insufficiency (Addison’s disease). Osmotic Causes  Osmotic diarrhea occurs when ingested, poorly absorbable, osmotically active solutes draw enough fluid into the lumen to exceed the reabsorptive capacity of the colon. Fecal water output increases in proportion to such a solute load. Osmotic diarrhea characteristically ceases with fasting or with discontinuation of the causative agent. OSMOTIC LAXATIVES  Ingestion of magnesium-containing antacids, health supplements, or laxatives may induce osmotic diarrhea typi­ fied by a stool osmotic gap (>50 mosmol/L), which is calculated by

serum osmolarity (typically 290 mosmol/kg) − (2 × [fecal sodium + potassium concentration]). Measurement of fecal osmolarity may be erroneous because carbohydrates are metabolized by colonic bacteria, causing an increase in osmolarity. CARBOHYDRATE MALABSORPTION  Carbohydrate malabsorption due to acquired or congenital defects in brush-border disaccharidases and other enzymes leads to osmotic diarrhea with a low fecal pH. One of the most common causes of chronic diarrhea in adults is lactase defi­ ciency, which affects three-fourths of nonwhites worldwide and 5–30% of persons in the United States; the total lactose load at any one time influences the symptoms experienced. Most patients learn to avoid milk products without requiring treatment with enzyme supplements. Sugars such as sorbitol, lactulose, or fructose ingested with medica­ tions, gum, or high fructose–containing beverages or candies may be incompletely absorbed, and diarrhea ensues. FODMAP AND WHEAT INTOLERANCE  Chronic diarrhea, bloating, and abdominal pain are recognized as symptoms of nonceliac wheat intolerance (which is associated with impaired intestinal or colonic barrier function) and intolerance of fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs). The latter’s effects represent the interaction between the GI microbiome and the nutrients. Steatorrheal Causes  Fat malabsorption may lead to greasy, foulsmelling, difficult-to-flush diarrhea often associated with weight loss and nutritional deficiencies due to concomitant malabsorption of amino acids and vitamins. Increased fecal output is caused by the osmotic effects of fatty acids, especially after bacterial hydroxylation, and, to a lesser extent, by the neutral fat. Whereas the normal fecal fat is <7 g/d on a 100 g/d fat diet, rapid-transit diarrhea may result in fecal fat up to 14 g/d of fat; daily fecal fat averages 15–25 g with small-intestinal dis­ eases and is often >32 g with pancreatic exocrine insufficiency. Intralu­ minal maldigestion, mucosal malabsorption, or lymphatic obstruction may produce steatorrhea. INTRALUMINAL MALDIGESTION  This condition most commonly results from pancreatic exocrine insufficiency, which occurs when

90% of pancreatic secretory function is lost. Chronic pancreatitis, usu­ ally a sequel of ethanol abuse, most frequently causes pancreatic insuf­ ficiency. Other causes include medications, cystic fibrosis, pancreatic duct obstruction, and, rarely, somatostatinoma. Bacterial overgrowth in the small intestine may deconjugate bile acids and alter micelle forma­ tion, impairing fat digestion; it occurs with stasis from a blind-loop, multiple small-bowel diverticula, or dysmotility with intestinal dilata­ tion. Finally, cirrhosis or biliary obstruction may lead to mild steator­ rhea due to deficient intraluminal bile acid concentration. MUCOSAL MALABSORPTION  Mucosal malabsorption occurs from a variety of enteropathies, most commonly celiac disease. This glutensensitive enteropathy affects all ages and is characterized by villous atrophy and crypt hyperplasia in the proximal small bowel and can present with steatorrhea with multiple nutritional deficiencies of vary­ ing severity. Celiac disease, which is more frequent than previously thought, affects ~1% of the population, frequently presents without steatorrhea, can mimic IBS, and has many other GI and extraintestinal manifestations. Tropical sprue may produce a similar histologic and clinical syndrome but occurs in residents of or travelers to tropical climates; abrupt onset and response to antibiotics suggest an infectious etiology. Whipple’s disease, due to the bacillus Tropheryma whipplei and macrophage infiltration of the small-bowel mucosa, is a far less com­ mon cause of steatorrhea that typically occurs in young or middle-aged men; it is frequently associated with arthralgias, fever, lymphadenopa­ thy, and extreme fatigue, and it may affect the CNS and endocardium. A similar clinical and histologic picture results from Mycobacterium avium-intracellulare infection in patients with AIDS. Abetalipoprotein­ emia is a rare defect of chylomicron formation and fat malabsorption in children. It is associated with acanthocytic erythrocytes, ataxia, and retinitis pigmentosa. Several other conditions may cause muco­ sal malabsorption including infections, especially with protozoa such as

Giardia, numerous medications (e.g., olmesartan, mycophenolate mofetil,

colchicine, cholestyramine, neomycin), idiopathic enteropathies, lym­ phoproliferative disorders, amyloidosis, and chronic ischemia.

POSTMUCOSAL LYMPHATIC OBSTRUCTION  This may result from rare congenital intestinal lymphangiectasia or from acquired lymphatic obstruction secondary to trauma, tumor, cardiac disease, or infection, and leads to the unique fat malabsorption with enteric losses of protein (often causing edema) and lymphocytopenia. Carbohydrate and amino acid absorption are preserved. Inflammatory Causes  Inflammatory diarrheas are generally accompanied by pain, fever, bleeding, or other manifestations of inflammation. The mechanism of diarrhea may not only be exudation but, depending on lesion site, may include fat malabsorption, disrupted fluid/electrolyte absorption, and hypersecretion or hypermotility from release of cytokines and other inflammatory mediators. Stool analysis reveals leukocytes or leukocyte-derived proteins such as calprotectin. With severe inflammation, exudative protein loss can lead to anasarca (generalized edema). Any middle-aged or older person with chronic inflammatory-type diarrhea, especially with blood, should be carefully evaluated (e.g., with colonoscopy) to exclude a colorectal tumor. Diarrhea and Constipation CHAPTER 49 IDIOPATHIC INFLAMMATORY BOWEL DISEASE  Crohn’s disease and chronic ulcerative colitis are among the most common organic causes of chronic diarrhea in adults and range in severity from mild to ful­ minant and life-threatening. They may be associated with uveitis, polyarthralgias, oral ulceration, cholestatic liver disease (primary sclerosing cholangitis), and skin lesions (erythema nodosum, pyo­ derma gangrenosum). Microscopic colitis, including both lymphocytic and collagenous colitis, may cause chronic watery diarrhea, especially in middle-aged women and those on NSAIDs, statins, proton pump inhibitors (PPIs), and selective serotonin reuptake inhibitors (SSRIs); biopsy of an otherwise normal-appearing colon is required for his­ tologic diagnosis. It may coexist with symptoms suggesting IBS or with celiac sprue or drug-induced enteropathy. It may be associated with BAD. It typically responds well to anti-inflammatory drugs (e.g., bismuth), the opioid agonist loperamide, or budesonide or bile acid sequestrants. PRIMARY OR SECONDARY FORMS OF IMMUNODEFICIENCY  Immuno­ deficiency may lead to prolonged infectious diarrhea. With selective IgA deficiency or common variable hypogammaglobulinemia, diarrhea is particularly prevalent and often the result of giardiasis, bacterial overgrowth, or sprue or Strongyloides stercoralis acquired in the tropics or subtropics. EOSINOPHILIC GASTROENTERITIS  Eosinophil infiltration of the mucosa, muscularis, or serosa at any level of the GI tract may cause diarrhea, pain, vomiting, or ascites. Affected patients often have an atopic history, Charcot-Leyden crystals due to extruded eosinophil contents may be seen on microscopic inspection of stool, and periph­ eral eosinophilia is present in 50–75% of patients. While hypersensitiv­ ity to certain foods occurs in adults, true food allergy causing chronic diarrhea is rare. OTHER CAUSES  Chronic inflammatory diarrhea may be caused by radiation enterocolitis, chronic graft-versus-host disease, autoimmune or idiopathic enteropathies, Behçet’s syndrome, and Cronkhite-Canada syndrome, among others. Dysmotility Causes  Rapid transit may accompany many diar­ rheas as a secondary or contributing phenomenon, but primary dys­ motility is an unusual etiology of true diarrhea. Stool features often suggest a secretory diarrhea, but mild steatorrhea of up to 14 g of fat per day can be produced by maldigestion from rapid transit alone. Hyperthyroidism, carcinoid syndrome, and certain drugs (e.g., prosta­ glandins, prokinetic agents, cholinesterase inhibitors) may produce hypermotility with resultant diarrhea. Primary visceral neuromyopa­ thies or idiopathic acquired intestinal pseudoobstruction may lead to stasis with secondary bacterial overgrowth causing diarrhea. Diabetic diarrhea, often accompanied by peripheral and generalized autonomic neuropathies, may occur in part because of intestinal dysmotility.

The exceedingly common IBS (10% point prevalence, 1–2% per year incidence) is characterized by disturbed intestinal and colonic motor and sensory responses to various stimuli. Symptoms of increased stool frequency typically cease at night, alternate with periods of constipa­ tion, are accompanied by abdominal pain relieved with defecation, and rarely result in weight loss.

Factitial Causes  Factitial diarrhea accounts for up to 15% of unex­ plained diarrheas referred to tertiary care centers. Either as a form of Munchausen syndrome (deception or self-injury for secondary gain) or eating disorders, some patients covertly self-administer laxatives alone or in combination with other medications (e.g., diuretics) or sur­ reptitiously add water or urine to stool sent for analysis. Such patients are typically women, often with histories of psychiatric illness and disproportionately involved in careers in health care. Hypotension and hypokalemia are common co-presenting features. The evaluation of PART 2 Cardinal Manifestations and Presentation of Diseases Chronic diarrhea Blood p.r. Fatty diarrhea Pain aggravated before BM, relieved with BM, sense incomplete evacuation Colonoscopy

• biopsy Small bowel: imaging, biopsy, aspirate Suspect IBS Consider functional diarrhea Limited screen for organic disease: hematology, chemistry, CRP, ESR, Fe, folate, B12, TTG-igA, C4, stool for excess fat, calprotectin Low Hb, Alb; abnormal MCV, MCH; excess fat in stool Low serum K+ Screening tests all normal Stool vol, osm, pH; laxative screen; hormonal screen Small bowel: x-ray, biopsy, aspirate; stool 48h fat Colonoscopy
• biopsy 48h stool bile acid Stool fat 14–20 g/day: search for small bowel cause Stool fat

20 g/day: pancreatic function Normal and stool fat <14 g/day FIGURE 49-4  Algorithm for management of chronic diarrhea. Patients undergo an initial evaluation based on different symptom presentations, leading to selection of patients for imaging, biopsy analysis, and limited screens for organic diseases. Alb, albumin; BA, bile acid; BM, bowel movement; C4, 7 α-hydroxy-4-cholesten-3-one; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; Hb, hemoglobin; Hx, history; IBS, irritable bowel syndrome; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; osm, osmolality; p.r., per rectum; Rx, treatment; TTG, tissue transglutaminase. (Reproduced with permission from M Camilleri, JH Sellin, KE Barrett: Pathophysiology, evaluation, and management of chronic watery diarrhea. Gastroenterology 152:515, 2017.)

such patients may be difficult: contamination of the stool with water or urine is suggested by very low or high stool osmolarity, respectively. Such patients often deny this possibility when confronted, but they do benefit from psychiatric counseling when they acknowledge their behavior. APPROACH TO THE PATIENT Chronic Diarrhea The laboratory tools available to evaluate the very common problem of chronic diarrhea are extensive, and many are costly and invasive. As such, the diagnostic evaluation must be rationally directed by a careful history, including medications, and physical examination (Fig. 49-4). When this strategy is unrevealing, simple triage tests are often warranted to direct the choice of more complex investigations Exclude iatrogenic problem: medication, surgery No blood, features of malabsorption Dietary exclusion, e.g., lactose, sorbitol Opioid Rx

• follow-up Persistent chronic diarrhea Full gut transit Titrate Rx to speed of transit BA sequestrant

TABLE 49-4  Physical Examination in Patients with Chronic Diarrhea

1. Are there general features to suggest malabsorption or inflammatory bowel disease (IBD) such as anemia, arthritis, dermatitis herpetiformis, edema, or clubbing?
2. Are there features to suggest underlying autonomic neuropathy or collagenvascular disease in the pupils, orthostasis, skin, hands, or joints?
3. Is there an abdominal mass or tenderness?
4. Are there any abnormalities of rectal mucosa, rectal defects, or altered anal sphincter functions?
5. Are there any mucocutaneous manifestations of systemic disease such as dermatitis herpetiformis (celiac disease), erythema nodosum (ulcerative colitis), flushing (carcinoid), or oral ulcers for IBD or celiac disease? (Fig. 49-4). The history, physical examination (Table 49-4), and routine blood studies should attempt to characterize the mecha­ nism of diarrhea, identify diagnostically helpful associations, and assess the patient’s fluid/electrolyte and nutritional status. Patients should be questioned about the onset, duration, pattern, aggravat­ ing (especially diet) and relieving factors, and stool characteristics of their diarrhea (such as relationship to food ingestion, presence of nocturnal episodes, undigested food or fat in the stool, and consis­ tency based on Bristol Stool Form Scale). The presence or absence of fecal incontinence, fever, weight loss, pain, certain exposures (travel, medications, contacts with diarrhea), and common extraintesti­ nal manifestations (skin changes, arthralgias, oral aphthous ulcers) should be noted. A family history of IBD or celiac disease may indicate those possibilities. Physical findings may offer clues such as a skin rash, thyroid mass, wheezing, heart murmurs, edema, hepa­ tomegaly, abdominal masses, lymphadenopathy, mucocutaneous abnormalities, perianal fistulas, or anal sphincter laxity. Peripheral blood leukocytosis, elevated sedimentation rate, or C-reactive pro­ tein suggests inflammation; anemia reflects blood loss or nutritional deficiencies; or eosinophilia may occur with parasitoses, neoplasia, collagen-vascular disease, allergy, or eosinophilic gastroenteritis. Blood chemistries may demonstrate electrolyte, hepatic, or other metabolic disturbances. Measuring IgA tissue transglutaminase antibodies while eating gluten may help detect celiac disease. Bile acid diarrhea is confirmed by a scintigraphic radiolabeled bile acid retention test; where unavailable, a screening blood test (serum 7αC4 or FGF-19), measurement of fecal bile acids, or a therapeutic trial with a bile acid sequestrant (e.g., cholestyramine, colestipol or colesevelam) is indicated. A therapeutic trial is often appropriate, definitive, and highly cost-effective when a specific diagnosis is suggested on the initial physician encounter. For example, chronic watery diarrhea, which ceases with fasting in an otherwise healthy young adult, may justify a trial of a lactose-restricted diet; bloating and diarrhea persisting since a mountain backpacking trip may warrant a trial of metro­ nidazole for likely giardiasis; and postprandial diarrhea persisting following resection of terminal ileum might be due to bile acid malabsorption and be treated with cholestyramine, colestipol, or colesevelam before further evaluation. Persistent symptoms require additional investigation. Certain diagnoses may be suggested on the initial encounter (e.g., idiopathic IBD); however, additional focused evaluations may be nec­ essary to confirm the diagnosis and characterize the severity or extent of disease so that treatment can be best guided. Patients suspected of having IBS should be initially evaluated with flexible sigmoidoscopy with colorectal biopsies to exclude IBD, or particularly microscopic colitis, which is clinically indistinguishable from IBS with diarrhea or functional diarrhea. Patients with normal findings might be reas­ sured and, as indicated, treated empirically with antispasmodics, antidiarrheals, or antidepressants (e.g., tricyclic agents). Any patient who presents with chronic diarrhea and hematochezia should be evaluated with stool microbiologic studies and colonoscopy. In an estimated two-thirds of cases, the cause for chronic diar­ rhea remains unclear after the initial encounter, and further testing

is required. Quantitative stool collection and analyses can yield important objective data that may establish a diagnosis or charac­ terize the type of diarrhea as a triage for focused additional studies (Fig. 49-4). If stool weight is >200 g/d, additional stool analyses should be performed that might include electrolyte concentration, pH, occult blood testing, leukocyte inspection (or leukocyte protein assay), fat and bile acid quantitation, and laxative screens. For secretory diarrheas (watery, with normal osmotic gap), possible medication-related side effects or surreptitious laxative use should be reconsidered. Stool microbiologic studies should be done with a multiplex panel initially or, if negative and diarrhea is persistent, fecal bacterial cultures (including media for Aeromonas and Plesiomonas), inspection for ova and parasites, and Giardia antigen assay (the most sensitive test for giardiasis). Small-bowel bacterial overgrowth can be excluded by intestinal aspirates with quantitative cultures or with glucose or lactulose breath tests involv­ ing measurement of breath hydrogen, methane, or other metabolite with an early peak in breath excretion. Note, interpretation of these breath tests may be confounded by disturbances of intestinal transit, e.g., if the gas peak is beyond 60 min. Upper endoscopy and colo­ noscopy with biopsies and small-bowel x-rays (formerly barium, but increasingly CT with enterography or magnetic resonance with enteroclysis) are helpful to rule out structural or occult inflamma­ tory disease. When suggested by history or other findings, screens for peptide hormones should be pursued (e.g., serum gastrin, VIP, calcitonin, thyroid hormone/thyroid-stimulating hormone, urinary 5-hydroxyindolacetic acid, histamine). Diarrhea and Constipation CHAPTER 49 Further evaluation of osmotic diarrhea should include tests for lactose and fructose intolerance and magnesium ingestion; intoler­ ance of fructose is usually the result of ingestion of high fructose corn sweetener in which the fructose is ingested in the absence of sufficient glucose, which normally enhances fructose uptake. Low fecal pH suggests carbohydrate malabsorption; lactose malabsorp­ tion can be confirmed by lactose breath testing or by a therapeutic trial with lactose exclusion and observation of the effect of lactose challenge (e.g., a liter of milk). Lactase determination on smallbowel biopsy is not generally available. If fecal magnesium or laxa­ tive levels are elevated, inadvertent or surreptitious ingestion should be considered and psychiatric help should be sought. For those with proven fatty diarrhea, endoscopy with smallbowel biopsy (including aspiration for quantitative cultures, if available) should be performed; if this procedure is unrevealing, a small-bowel radiograph is often an appropriate next step. If smallbowel studies are negative or if pancreatic disease is suspected, pancreatic exocrine insufficiency (PEI) should be excluded if pos­ sible with direct tests, such as the secretin-cholecystokinin stimu­ lation test or a variation that could be performed endoscopically. In general, indirect tests for PEI such as assay of fecal elastase or chymotrypsin activity or a bentiromide test may be performed, but they have low sensitivity and specificity. Chronic inflammatory-type diarrheas should be suspected by the presence of blood or leukocytes in the stool. Such findings warrant stool pathogen testing; colonoscopy with biopsies; and, if indicated, small-bowel imaging studies. TREATMENT Chronic Diarrhea Treatment of chronic diarrhea depends on the specific etiology and may be curative, suppressive, or empirical. If the cause can be eradi­ cated, treatment is curative as with resection of a colorectal cancer, antibiotic administration for Whipple’s disease or tropical sprue, or discontinuation of a drug. For many chronic conditions, diarrhea can be controlled by suppression of the underlying mechanism. Examples include restriction of dietary lactose for lactase deficiency or gluten for celiac sprue, use of anti-inflammatory agents for idio­ pathic IBDs, bile acid sequestrants for bile acid malabsorption, PPIs

for the gastric acid hypersecretion of gastrinomas, somatostatin analogues such as octreotide for malignant carcinoid syndrome, prostaglandin inhibitors such as indomethacin for medullary car­ cinoma of the thyroid, and pancreatic enzyme replacement for pancreatic insufficiency. When the specific cause or mechanism of chronic diarrhea evades diagnosis, empirical therapy may be ben­ eficial. Mild opiates, such as diphenoxylate or loperamide, are often helpful in mild or moderate watery diarrhea. For those with more severe diarrhea, codeine or tincture of opium may be beneficial. Such antimotility agents should be avoided with severe IBD because toxic megacolon may be precipitated. Clonidine, an α2-adrenergic agonist, may allow control of diabetic diarrhea, although the medi­ cation may be poorly tolerated because it causes postural hypoten­ sion; an alternative to oral administration is a clonidine skin patch. The 5-HT3 receptor antagonists (e.g., alosetron, ondansetron) may relieve diarrhea and urgency in patients with IBS diarrhea. Other medications approved for the treatment of diarrhea associated with IBS are the nonabsorbed antibiotic, rifaximin, and the mixed μ-opioid receptor (OR) and κ-OR agonist and δ-OR antagonist, eluxadoline. The latter may induce sphincter of Oddi spasm and subsequent acute pancreatitis, usually in patients with prior chole­ cystectomy. Crofelemer, an antisecretory agent, has been used for AIDS-associated diarrhea. For all patients with chronic diarrhea, fluid and electrolyte repletion is an important component of man­ agement (see “Acute Diarrhea,” earlier). Replacement of fat-soluble vitamins may also be necessary in patients with chronic steatorrhea.

PART 2 Cardinal Manifestations and Presentation of Diseases CONSTIPATION ■ ■DEFINITION Constipation is a common complaint in clinical practice and usually refers to persistent, difficult, infrequent, or seemingly incomplete defecation. Because of the wide range of normal bowel habits, consti­ pation is difficult to define precisely. Most persons have at least three bowel movements per week; however, low stool frequency alone is not the sole criterion for the diagnosis of constipation. Many constipated patients have a normal frequency of defecation but complain of exces­ sive straining, hard stools, lower abdominal fullness, or a sense of incomplete evacuation. The individual patient’s symptoms must be analyzed in detail to ascertain what is meant by “constipation” or “dif­ ficulty” with defecation. Stool form and consistency (which can be assessed using the Bristol Stool Form Scale) are well correlated with the time elapsed from the pre­ ceding defecation. Hard, pellety stools occur with slow transit, whereas loose, watery stools are associated with rapid transit. Both small pellety or very large stools are more difficult to expel than normal stools. The perception of hard stools or excessive straining is more difficult to assess objectively, and the need for enemas or digital disimpaction is a clinically useful way to corroborate the patient’s perceptions of dif­ ficult defecation. Psychosocial or cultural factors may also be important. A person whose parents attached great importance to daily defecation will become greatly concerned when they miss a daily bowel movement; some children withhold stool to gain attention or because of fear of pain from anal irritation; and some adults habitually ignore or delay the call to have a bowel movement. ■ ■CAUSES Pathophysiologically, chronic constipation generally results from sed­ entary lifestyle, habitually ignoring the call to stool, inadequate fiber or fluid intake, or disordered colonic transit or anorectal function. These result from neurogastroenterologic disturbance, certain drugs, advanc­ ing age, or in association with a large number of systemic diseases that affect the GI tract (Table 49-5). Constipation of recent onset may be a symptom of significant organic disease such as colorectal cancer, anorectal irritation, or stricture. In idiopathic constipation, a subset of patients exhibits delayed emptying of the ascending and transverse colon with prolongation of transit (often in the proximal colon) and a reduced frequency of propulsive HAPCs. Outlet obstruction to

TABLE 49-5  Causes of Constipation in Adults TYPES OF CONSTIPATION AND CAUSES EXAMPLES Recent Onset Colonic obstruction Neoplasm; stricture: ischemic, diverticular, inflammatory Anal sphincter spasm Anal fissure, painful hemorrhoids Medications Chronic Irritable bowel syndrome Constipation-predominant, alternating Medications Ca2+ blockers, antidepressants Colonic pseudoobstruction Slow-transit constipation, megacolon (rare Hirschsprung’s, Chagas’ diseases) Disorders of rectal evacuation Pelvic floor dysfunction; anismus; descending perineum syndrome; rectal mucosal prolapse; rectocele Endocrinopathies Hypothyroidism, hypercalcemia, pregnancy Psychiatric disorders Depression, eating disorders, drugs Neurologic disease Parkinsonism, multiple sclerosis, spinal cord injury Generalized muscle disease Progressive systemic sclerosis defecation (also called evacuation disorders or dyssynergic defecation) accounts for at least a quarter of cases presenting with constipation in tertiary care and may cause delayed colonic transit, which is usu­ ally corrected by biofeedback retraining of the disordered defecation. Constipation of any cause may be exacerbated by hospitalization or chronic illnesses that lead to physical or mental impairment and result in inactivity or physical immobility. APPROACH TO THE PATIENT Constipation A careful history should explore the patient’s symptoms and con­ firm whether they are indeed constipated based on frequency (e.g., fewer than three bowel movements per week), consistency (lumpy/ hard), excessive straining, prolonged defecation time, or need to support the perineum or digitate the anorectum to facilitate stool evacuation. These latter items identified in the history suggest the presence of a rectal evacuation disorder. In the vast majority of cases (probably >90%), there is no underlying cause (e.g., cancer, depression, or hypothyroidism), and constipation responds to ample hydration, exercise, and supplementation of dietary fiber (15–25 g/d). A good diet and medication history and attention to psychosocial issues are key. Physical examination and, particularly, rectal examination are mandatory and should exclude fecal impac­ tion and most of the important diseases that present with con­ stipation and possibly indicate features suggesting an evacuation disorder (e.g., high anal sphincter tone, failure of perineal descent, or paradoxical puborectalis contraction or puborectalis tenderness during straining to simulate stool evacuation). The presence of weight loss, rectal bleeding, or anemia with constipation mandates either flexible sigmoidoscopy plus barium enema or colonoscopy alone, to exclude structural diseases such as colorectal cancer (CRC) or strictures; however, screening should start earlier in patients with a known or suspected predispos­ ing hereditary CRC syndrome and/or a family history of CRC. Colonoscopy alone is most cost-effective in this setting because it provides an opportunity to biopsy mucosal lesions, perform pol­ ypectomy, or dilate strictures. Barium enema has advantages over colonoscopy in the patient with isolated constipation because it is less costly and identifies colonic dilation and all significant mucosal lesions or strictures that are likely to present with constipation. Mel­ anosis coli, or pigmentation of the colon mucosa, indicates the use of anthraquinone laxatives such as cascara or senna. An unexpected

Chronic Constipation Clinical and basic laboratory tests Bloods, chest, and abd x-ray Exclude mechanical obstruction, e.g., colonoscopy Normal Colonic transit Consider functional bowel disease Abnormal Slow colonic transit Known disorder No known underlying disorder Anorectal manometry and balloon expulsion Normal Rectoanal angle measurement, defecation proctography? Rx Appropriate Rx: Rehabilitation program, surgery, or other FIGURE 49-5  Algorithm for the management of constipation. abd, abdominal; Rx, treatment. disorder such as megacolon or cathartic colon may also be detected by colonic radiographs. Measurement of serum calcium, potassium, and thyroid-stimulating hormone levels will identify rare patients with metabolic disorders. Patients with more troublesome constipation may not respond to fiber alone and may be helped by a bowel-training regimen, which involves taking an osmotic laxative (e.g., polyethylene glycol magnesium salts, lactulose, sorbitol) and evacuating with enema or suppository (e.g., glycerin or bisacodyl) as needed. After break­ fast, a distraction-free 15–20 min on the toilet without straining is encouraged. The use of squat position may help. Excessive straining may lead to development of hemorrhoids and, if there is weakness of the pelvic floor or injury to the pudendal nerve, may result in obstructed defecation from descending perineum syndrome several years later. Those few who do not benefit from the simple measures delineated above or require long-term treatment or fail to respond to potent laxatives should undergo further investigation (Fig. 49-5). Novel agents that induce secretion (e.g., lubiprostone, a chloride channel activator, or linaclotide or plecanatide, both guanylate cyclase C agonists that activate chloride secretion, or tenapanor, an NHE3 inhibitor) are also available. ■ ■INVESTIGATION OF SEVERE CONSTIPATION A small minority (probably <5%) of patients have severe or “intrac­ table” constipation; at least 25% (of patients seen in gastroenterology clinics) have evacuation disorders. These are the patients most likely to require evaluation by gastroenterologists or in referral centers. Further observation of the patient may occasionally reveal a previously unrec­ ognized cause, such as an evacuation disorder, laxative abuse, malin­ gering, or psychological disorder. In these patients, evaluations of the physiologic function of the colon and pelvic floor and of psychological status aid in the rational choice of treatment. Even among these highly selected patients with severe constipation, a cause can be identified in only about one-third of tertiary referral patients, with the others being diagnosed with normal transit constipation. Since evacuation disorders also retard colonic transit through the left colon or the entire colon, anorectal and pelvic floor testing should precede transit measurements

if there is clinical suspicion of an evacuation disorder. If an evacuation disorder is identified on testing, colonic transit may be unnecessary.

Measurement of Colonic Transit  Radiopaque marker transit tests are easy, repeatable, generally safe, inexpensive, reliable, and highly applicable in evaluating constipated patients in clinical practice. Several validated methods are very simple. For example, radiopaque markers are ingested; an abdominal flat film taken 5 days later should indicate passage of 80% of the markers out of the colon without the use of laxatives or enemas. This test does not provide useful information about the transit profile of the stomach and small bowel. An alternative approach involves ingestion of 24 radiopaque markers on 3 successive days and an abdominal radiograph on the fourth day. The number of markers counted in the radiograph is an estimate of the colonic transit in hours. The collection of gas in the rectum between the level of the ischial spines and the lower border of the sacroiliac joints may suggest the presence of a rectal evacuation disorder as the cause of constipation. Diarrhea and Constipation CHAPTER 49 Radioscintigraphy has been used to noninvasively characterize nor­ mal, accelerated, or delayed colonic function over 24–72 h with low radiation exposure. These approaches simultaneously assess gastric, small bowel (which may be important in ~20% of patients with delayed colonic transit because they reflect a more generalized GI motility dis­ order), and colonic transit. The disadvantages are the greater cost and the need for specific materials prepared in a nuclear medicine labora­ tory. Newer approaches consisting of extracorporeal detector plate, ingestible electromagnetic capsules, and analysis software are becom­ ing available and may obviate need for approaches involving radiation. Anorectal and Pelvic Floor Tests  Pelvic floor dysfunction is suggested by the inability to completely evacuate the rectum, a feeling of persistent rectal fullness, rectal pain, the need to extract stool from the rectum digitally, application of pressure on the posterior wall of the vagina (suggestive of anterior rectocele), support of the perineum during straining, and excessive straining. These significant symptoms contrast with simple sense of incomplete rectal evacuation, which is common in IBS. Formal psychological evaluation may identify eating disorders including ARFID (avoidant/restrictive food intake disorder), “control issues,” depression, or posttraumatic stress disorders that may respond to cognitive or other intervention and may be important in restoring quality of life to patients who might present with chronic constipation. A simple clinical test in the office to document a nonrelaxing puborectalis muscle is to have the patient strain to expel the index finger during a digital rectal examination. Motion of the puborectalis posteriorly with descent during straining indicates proper coordina­ tion of the pelvic floor muscles. Motion anteriorly with paradoxical puborectalis contraction or limited perineal descent (<1.5 cm) during simulated evacuation indicates pelvic floor dysfunction. Measurement of perineal descent is relatively easy to gauge clinically by placing the patient in the left decubitus position and watching the perineum to detect inadequate descent (<1.5 cm, a sign of pelvic floor dysfunction) or perineal ballooning during straining relative to bony landmarks (>4 cm, suggesting excessive perineal descent). A useful overall test of evacuation is the balloon expulsion test. A balloon-tipped urinary catheter is placed and inflated with 50 mL of water. Normally, a patient can expel it while seated on a toilet or in the left lateral decubitus position. In the lateral position, the weight needed to facilitate expulsion of the balloon is determined; normally, expulsion occurs unaided within 1 min. Anorectal manometry, when used in the evaluation of patients with severe constipation, may find an excessively high resting (>80 mmHg) or squeeze anal sphincter tone, suggesting anismus (anal sphincter spasm). The rectoanal pressure difference along with a balloon expul­ sion time >60 s is consistently identified as the most useful indicators of evacuation disorders. This test also identifies rare syndromes, such as Hirschsprung’s disease, by absence of the rectoanal inhibitory reflex (RAIR). However, the RAIR may be absent in patients with enlarged rectum due to prolonged retention of stool.

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50 Unintentional Weight Loss

Defecography (a dynamic barium enema including lateral views obtained during barium expulsion or a magnetic resonance defeco­ gram) measures changes in rectoanal angle, degree of pelvic floor relax­ ation and perineal descent, as well as anatomic defects of the rectum such as internal mucosal prolapse, intussusception, and enteroceles or rectoceles. Surgically remediable conditions are identified in only a few patients with severe, whole-thickness intussusception or extremely large rectocele that fills preferentially during attempts at defecation instead of expulsion through the anus. Magnetic resonance defecogra­ phy provides more information about the structure of the pelvic floor, distal colorectum, and anal sphincters and some information about the function during defecatory effort; however, it is performed in supine rather than seated position.

PART 2 Cardinal Manifestations and Presentation of Diseases Neurologic testing (electromyography) is rarely performed in the evaluation of patients with constipation. The absence of neurologic signs in the lower extremities suggests that any documented dener­ vation of the puborectalis results from pelvic (e.g., obstetric) injury or from stretching of the pudendal nerve by chronic, long-standing straining. Constipation is common among patients with spinal cord injuries, neurologic diseases such as Parkinson’s disease, multiple scle­ rosis, and diabetic neuropathy. Spinal-evoked responses during electrical rectal stimulation or stimulation of external anal sphincter contraction by applying mag­ netic stimulation over the lumbosacral cord identify patients with limited sacral neuropathies with sufficient residual nerve conduction to attempt biofeedback training. In summary, a balloon expulsion test is an important component of anorectal manometry as screening tests for anorectal dysfunction. An anatomic evaluation of the rectum or anal sphincters is rarely required when evaluating patients in whom obstructed defecation is suspected. Indications for anatomic evaluation are symptoms of rectal mucosal prolapse, pressure of the posterior wall of the vagina to facilitate defeca­ tion (suggestive of anterior rectocele), or prior pelvic surgery that may be complicated by enterocele. TREATMENT Constipation After the cause of constipation is characterized, a treatment decision can be made. Slow-transit constipation requires aggressive medical or surgical treatment; conversely, anismus or pelvic floor dysfunc­ tion usually responds to biofeedback management (Fig. 49-5). The remaining ~60% of patients with constipation have normal colonic transit and can be treated symptomatically. Patients with spinal cord injuries or other neurologic disorders require a dedicated bowel regimen that often includes rectal stimulation, enema therapy, and carefully timed laxative therapy. Patients with constipation are treated with bulk (fiber, psyllium), osmotic (milk of magnesia, lactulose, polyethylene glycol), secre­ tory (linaclotide, lubiprostone, plecanatide, tenapanor), and proki­ netic or stimulant laxatives (including diphenyl methanes such as bisacodyl and sodium picosulfate, senna alkaloids, and the 5-HT4 agonist prucalopride). If a 3- to 6-month trial of medical therapies fails, unassociated with obstructed defecation, the patient should be considered for laparoscopic colectomy with ileorectostomy; however, this should not be undertaken for pain or in the presence of continued evidence of an evacuation disorder or a generalized GI dysmotility. Referral to a specialized center for further tests of colonic motor function is warranted. The decision to resort to sur­ gery is facilitated by the presence of megacolon and megarectum or documented sigmoid or cecal volvulus. The complications after surgery include small-bowel obstruction (11%) and fecal soiling, particularly at night during the first postoperative year. Frequency of defecation is 3–8 per day during the first year, dropping to 1–3 per day from the second year after surgery. Patients who have a combined (evacuation and transit/motility) disorder should first pursue pelvic floor retraining (biofeedback and muscle relaxation), psychological counseling, and dietetic advice. If

symptoms are intractable despite biofeedback and optimized medical therapy, colectomy and ileorectostomy could be considered as long as the evacuation disorder is resolved and optimized medical therapy is unsuccessful. In patients with pelvic floor dysfunction alone, bio­ feedback training for 3 months has a 70–80% success rate, measured by the acquisition of comfortable stool habits. Attempts to manage pelvic floor dysfunction with operations (internal anal sphincter or puborectalis muscle division) or injections with botulinum toxin have achieved only mediocre success and have been largely abandoned. Persistence of the evacuation disorder despite physical therapy with biofeedback may require regular enemas or consideration of a loop- or end-ileostomy to relieve the intractable constipation. ■ ■FURTHER READING Assi R et al: Sexually transmitted infections of the anus and rectum. World J Gastroenterol 20:15262, 2014. Blackett JW et al: Comparison of anorectal manometry, rectal bal­ loon expulsion test, and defecography for diagnosing defecatory disorders. Gastroenterology 163:1582, 2022. Boeckxstaens G et al: Fundamentals of neurogastroenterology: Physiology/motility—sensation. Gastroenterology 150:1292, 2016. BouSaba J et al: Impact of bile acid diarrhea in patients with diarrhea-

predominant irritable bowel syndrome on symptoms and quality of life. Clin Gastro Hepatol 20:2083, 2022. Camilleri M et al: Chronic constipation. Nat Rev Dis Primers 3:17095, 2017. Camilleri M et al: Pathophysiology, evaluation, and management of chronic watery diarrhea. Gastroenterology 152:515, 2017. Issaka RB et al: AGA clinical practice update on risk stratification for colorectal cancer screening and post-polypectomy surveillance: Expert review. Gastroenterology 165:1280, 2023. Peery AF et al: Burden and cost of gastrointestinal, liver, and pan­ creatic diseases in the United States: Update 2021. Gastroenterology 162:621, 2022. Palsson OS et al: Prevalence and associated factors of disorders of gutbrain interaction in the United States: Comparison of two nationwide internet surveys. Neurogastro Motil 35:e14564, 2023. Riddle MS et al: ACG Clinical Guideline: Diagnosis, treatment, and prevention of acute diarrheal infections in adults. Am J Gastroenterol 111:602, 2016. Rubio-Tapia A et al: American College of Gastroenterology guidelines update: Diagnosis and management of celiac disease. Am J Gastroen­ terol 118:59, 2023. Sanchez DA et al: Characterization of infectious and non-infectious gastrointestinal disease in common variable immunodeficiency: Analysis of 114 patient cohort. Front Immunol 14:1209570, 2023. Smalley W et al: AGA Clinical Practice Guidelines on the laboratory evaluation of functional diarrhea and diarrhea-predominant irritable bowel syndrome in adults (IBS-D). Gastroenterology 157:851, 2019. J. Larry Jameson

Unintentional Weight

Loss Involuntary or unintentional weight loss (UWL) is frequently insidious and can have important implications, often serving as a harbinger of serious underlying disease. Clinically important weight loss is defined as the loss of >5% of body weight over a period of 6–12 months. UWL is not uncommon in individuals aged ≥65 years. It can be challeng­ ing to recognize in patients with preexisting obesity or inadequate

documentation of previous weights. There is no identifiable cause in up to one-quarter of patients despite extensive investigation. People with no known cause of weight loss generally have a better prognosis than do those with known causes, particularly when the source is neoplastic. Weight loss in older persons is associated with a variety of deleterious effects, including falls and fractures, pressure ulcers, impaired immune function, and decreased functional status. Not surprisingly, significant weight loss is associated with increased mortality within 1–2 years. ■ ■PHYSIOLOGY OF WEIGHT REGULATION

WITH AGING (See also Chaps. 413 and 488) Among healthy aging people, total body weight peaks in the sixth decade of life and generally remains stable until the ninth decade, after which it gradually falls. In contrast, lean body mass (fat-free mass) begins to decline at a rate of 0.3 kg per year in the third decade, and the rate of decline increases further beginning at age 60 in men and age 65 in women. These changes in lean body mass largely reflect the age-dependent decline in growth hormone secretion and, consequently, circulating levels of insulinlike growth factor type I (IGF-I) that occur with normal aging. Loss of sex steroids, at menopause in women and more gradually in men, also contributes to these changes in body composition. In the healthy elderly, an increase in fat tissue balances the loss in lean body mass until very old age, when loss of both fat and skeletal muscle occurs. Age-dependent changes also occur at the cellular level. Telomeres shorten, and body cell mass—the fat-free portion of cells—declines steadily with aging. Between ages 20 and 80, mean energy intake is reduced by up to 1200 kcal/d in men and 800 kcal/d in women. Decreased hunger is a reflection of reduced physical activity and loss of lean body mass, pro­ ducing lower demand for calories and food intake. Several important age-associated physiologic changes also predispose elderly persons to weight loss, such as declining chemosensory function (smell and taste), reduced efficiency of chewing, slowed gastric emptying, and alterations in the neuroendocrine axis, including changes in levels of leptin, cho­ lecystokinin, neuropeptide Y, and other hormones and peptides. These changes are associated with early satiety and a decline in both appetite and the hedonistic appreciation of food. Collectively, they contribute to the “anorexia of aging.” As noted below, these physiologic changes with aging may be accompanied by social isolation, poverty, and immobility, further contributing to undernutrition. ■ ■CAUSES OF UNINTENTIONAL WEIGHT LOSS Most causes of UWL belong to one of four categories: (1) malignant neoplasms, (2) chronic inflammatory or infectious diseases, (3) meta­ bolic disorders (e.g., hyperthyroidism and diabetes), or (4) psychiatric disorders (Table 50-1). Not infrequently, more than one of these causes can be responsible for UWL. Depending upon patient populations, UWL is caused by malignant disease in a quarter of patients and by organic disease in one-third, with the remainder due to psychiatric disease, medications, or uncertain causes. Risk factors for undiagnosed cancer include a history of smoking, particularly for men, localizing symptoms, and abnormal laboratory tests. The most common malignant causes of UWL are gastrointestinal, hepatobiliary, hematologic, lung, breast, genitourinary, ovarian, and prostate. Half of all patients with cancer lose some body weight; onethird lose more than 5% of their original body weight, and up to 20% of all cancer deaths are caused directly by cachexia (through immobility and/or cardiac/respiratory failure). The greatest incidence of weight loss is seen among patients with solid tumors. Malignancy that reveals itself through significant weight loss usually has a very poor prognosis. In addition to malignancies, gastrointestinal diseases are among the most prominent causes of UWL. Peptic ulcer disease, inflamma­ tory bowel disease, dysmotility syndromes, chronic pancreatitis, celiac disease, constipation, and atrophic gastritis are some of the more common entities. Oral and dental problems are easily overlooked and may manifest with halitosis, poor oral hygiene, xerostomia, inability to chew, reduced masticatory force, nonocclusion, temporomandibular joint syndrome, edentulousness, and pain due to caries or abscesses.

TABLE 50-1  Causes of Involuntary Weight Loss Cancer   Upper gastrointestinal   Lung   Colon   Hepatobiliary   Hematologic   Breast   Genitourinary   Ovarian   Prostate Gastrointestinal disorders   Difficulty swallowing   Malabsorption   Peptic ulcer   Inflammatory bowel disease   Pancreatitis   Obstruction/constipation   Pernicious anemia Endocrine and metabolic   Hyperthyroidism   Diabetes mellitus   Pheochromocytoma   Adrenal insufficiency Cardiac disorders   Chronic ischemia   Chronic congestive heart failure Respiratory disorders   Emphysema   Chronic obstructive pulmonary Medications   Sedatives   Antibiotics   Nonsteroidal anti-inflammatory drugs   Serotonin reuptake inhibitors   Metformin   Levodopa   Angiotensin-converting enzyme Unintentional Weight Loss CHAPTER 50 inhibitors   Other drugs Disorders of the mouth and teeth   Dental caries   Dysgeusia Age-related factors   Physiologic changes   Visual impairment   Decreased taste and smell   Functional disabilities Neurologic   Stroke   Parkinson’s disease   Neuromuscular disorders   Dementia Social   Isolation   Poverty Psychiatric and behavioral   Depression   Anxiety   Paranoia   Bereavement   Alcoholism   Eating disorders   Increased activity or exercise Idiopathic disease Renal insufficiency Rheumatologic disease Infections   HIV   Tuberculosis   Parasitic infection   Subacute bacterial endocarditis Tuberculosis, fungal diseases, parasites, subacute bacterial endocar­ ditis, and HIV are well-documented causes of UWL. Cardiovascular and pulmonary diseases cause UWL through increased metabolic demand and decreased appetite and caloric intake. Repeated surgeries may lead to weight loss because of reduced caloric intake and increased metabolic demands resulting from a systemic inflammatory response. Uremia produces nausea, anorexia, and vomiting. Connective tissue diseases may increase metabolic demand and disrupt nutritional bal­ ance. As the incidence of diabetes mellitus increases with aging, the associated glucosuria can contribute to weight loss. Hyperthyroidism in the elderly may have less prominent sympathomimetic features and may present as “apathetic hyperthyroidism” or T3 toxicosis (Chap. 394). Neurologic injuries such as stroke, quadriplegia, and multiple scle­ rosis may lead to visceral and autonomic dysfunction that can impair caloric intake. Dysphagia from these neurologic insults is a common mechanism. Functional disability that compromises activities of daily living (ADLs) is a common cause of undernutrition in the elderly. Visual impairment from ophthalmic or central nervous system disor­ ders such as a tremor can limit the ability of people to prepare and eat meals. UWL may be one of the earliest manifestations of Alzheimer’s dementia. Isolation and depression are significant causes of UWL that may manifest as an inability to care for oneself, including nutritional needs. A cytokine-mediated inflammatory metabolic cascade can be both a cause of and a manifestation of depression. Bereavement can be a cause

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51 Gastrointestinal Bleeding

of UWL and is often more pronounced in men. More intense forms of mental illness such as paranoid disorders may lead to delusions about food and cause weight loss. Alcoholism can be a significant source of weight loss and malnutrition.

Elderly persons living in poverty may have to choose whether to purchase food or use the money for other expenses, including medica­ tions. Screening questions can probe whether patients have run out of food or whether they routinely purchase less than they need. Institu­ tionalization is an independent risk factor, as up to 30–50% of nursing home patients have inadequate food intake. Medications can cause anorexia, nausea, vomiting, gastrointestinal distress, diarrhea, dry mouth, and changes in taste. This is particularly an issue in the elderly, many of whom take five or more medications. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■ASSESSMENT The four major manifestations of UWL are (1) anorexia (loss of appetite), (2) sarcopenia (loss of muscle mass), (3) cachexia (a syndrome that combines weight loss, loss of muscle and adipose tissue, anorexia, and weakness), and (4) dehydration. The current obesity epidemic adds complexity, as excess adipose tissue can mask the development of sarcopenia and delay awareness of the development of cachexia. If it is not possible to measure weight directly, a change in clothing size, cor­ roboration of weight loss by a relative or friend, and a numeric estimate of weight loss provided by the patient are suggestive of true weight loss. Initial assessment includes a comprehensive history and physical, a complete blood count, tests of liver enzyme levels, C-reactive protein, erythrocyte sedimentation rate, renal function studies, thyroid function tests, chest radiography, and an abdominal ultrasound (Table 50-2). Age-, sex-, and risk factor–specific cancer screening tests, such as fecal occult blood, colonoscopy, or mammography, should be performed (Chap. 75). Patients at risk should have HIV testing. All elderly patients with weight loss should undergo screen­ ing for dementia and depression by using instruments such as the Mini-Mental State Examination and the Geriatric Depression Scale, respectively (Chap. 489). The Mini Nutritional Assessment (www. mna-elderly.com) and the Nutrition Screening Initiative (http://www. ncbi.nlm.nih.gov/pmc/articles/PMC1694757/) are also available for the TABLE 50-2  Assessment and Testing for Involuntary Weight Loss Indications Laboratory 5% weight loss in 6 mo Complete blood count   Comprehensive electrolyte and metabolic panel, including liver and renal function tests Body mass index <21 Thyroid function tests 25% of food left uneaten after 7 d Erythrocyte sedimentation rate Change in fit of clothing C-reactive protein Change in appetite, smell, or taste Ferritin Abdominal pain, nausea, vomiting, diarrhea, constipation, dysphagia HIV testing, if indicated Assessment Radiology Complete physical examination, including dental evaluation Chest x-ray Abdominal ultrasound Medication review   Recommended cancer screening   Mini-Mental State Examinationa   Mini-Nutritional Assessmenta   Nutrition Screening Initiativea   Simplified Nutritional Assessment Questionnairea   Observation of eatinga   Activities of daily livinga   Instrumental activities of daily livinga   aMay be more specific to assess weight loss in the elderly.

nutritional assessment of elderly patients. Almost all patients with a malignancy and >90% of those with other organic diseases have at least one laboratory abnormality. In patients presenting with substan­ tial UWL, major organic and malignant diseases are unlikely when a baseline evaluation is completely normal. Careful follow-up rather than additional undirected testing is advised because the prognosis of weight loss of undetermined cause is generally favorable. TREATMENT Unintentional Weight Loss The first priority in managing weight loss is to identify and treat the underlying causes. Treatment of underlying metabolic, social, psychiatric, dental, infectious, or other systemic disorders may be sufficient to restore weight and functional status gradually. Medications that cause nausea or anorexia should be withdrawn or changed, if possible. For those with unexplained UWL, oral nutri­ tional supplements such as high-energy drinks sometimes reverse weight loss. Advising patients to choose appealing foods and to consume supplements between meals rather than with a meal may help minimize appetite suppression and facilitate increased over­ all intake. Orexigenic, anabolic, and anticytokine agents are not generally recommended. In selected patients, the antidepressant mirtazapine significantly increases body weight, body fat mass, and leptin concentration. However, side effects, including dizziness, fatigue, and somnolence, occur in about 10% of patients. Patients with wasting conditions who can comply with an appropriate exer­ cise program gain muscle protein mass, strength, and endurance and may be more capable of performing ADLs. ■ ■FURTHER READING Gaddey HL, Holder KK: Unintentional weight loss in older adults. Am Fam Physician 104:34, 2021. McMinn J et al: Investigation and management of unintentional weight loss in older adults. BMJ 342:d1732, 2011. Nicholson BD et al: Prioritising primary care patients with unexpected weight loss for cancer investigation. BMJ 370:m2651, 2020. Perera LAM et al: Approach to patients with unintentional weight loss. Med Clin North Am 105:175, 2021. Wong CJ: Involuntary weight loss. Med Clin North Am 98:625, 2014. Loren Laine

Gastrointestinal

Bleeding Gastrointestinal bleeding (GIB) presents as either overt or occult bleeding. Overt GIB is manifested by hematemesis, vomitus of red blood or “coffee-grounds” material; melena, black, tarry stool; and/or hematochezia, passage of red or maroon blood from the rectum. In the absence of overt bleeding, occult GIB may present with symptoms of blood loss or anemia such as lightheadedness, syncope, angina, or dyspnea; with iron-deficiency anemia; or a positive fecal occult blood test on colorectal cancer screening. GIB is also categorized by the site of bleeding as upper, from the esophagus, stomach, or duodenum; lower, from the colon; small intestinal; or obscure GIB if the source is unclear. GIB is the most common gastrointestinal condition leading to hos­ pitalization in the United States, accounting for ~530,000 admissions annually and a case fatality of ~2%. Patients generally die from decom­ pensation of other underlying illnesses rather than exsanguination.

■ ■SOURCES OF GASTROINTESTINAL BLEEDING Upper Gastrointestinal Sources of Bleeding  •  PEPTIC ULCERS  Peptic ulcers are the most common cause of upper GIB (UGIB), accounting for ~50% of UGIB hospitalizations. Features of an ulcer at endoscopy provide important prognostic information that guides subsequent management decisions (Fig. 51-1). Approximately 20% of patients with bleeding ulcers have the highest-risk findings of active bleeding or a nonbleeding visible vessel; one-third of such patients have further bleeding that requires urgent surgery if they are treated conservatively. These patients benefit from endoscopic therapy such as bipolar electrocoagulation, heater probe, injection therapy (e.g., absolute alcohol, 1:10,000 epinephrine), clips, and/or topical hemostatic powder with reductions in bleeding, hospital stay, mortality, and costs. In contrast, patients with clean-based ulcers have rates of serious rebleeding approaching zero. If stable with no other reason for hospitalization, such patients may be discharged home after endoscopy. Randomized controlled trials document that high-dose, proton pump inhibitor (PPI), given to reduce intragastric acid and thereby enhance clot stability, decreases further bleeding and mortality in patients with high-risk ulcers (active bleeding, nonbleeding visible ves­ sel, adherent clot) when given after endoscopic therapy. Meta-analysis of randomized trials indicates that outcomes are comparable with highdose PPIs given as a constant infusion or intermittently. Patients with lower-risk findings (flat pigmented spot, clean base) do not require endoscopic therapy and receive standard doses of oral PPI. Approximately 10–50% of patients with bleeding ulcers rebleed within the next year if no preventive strategies are employed. Pre­ vention of recurrent bleeding focuses on the three main factors in ulcer pathogenesis, Helicobacter pylori, nonsteroidal anti-inflammatory drugs (NSAIDs), and acid. Eradication of H. pylori in patients with bleeding ulcers decreases rebleeding rates to <5%. If a bleeding ulcer develops in a patient taking NSAIDs, the NSAIDs should be discon­ tinued. If NSAIDs must be given, a cyclooxygenase-2 selective NSAID plus a PPI is recommended, based on results of a randomized trial. Patients with established cardiovascular disease who develop bleeding Endoscopic Diagnosis Ulcer Erosions Flat pigmented spot Active bleeding or visible vessel Endoscopic Features Adherent clot May consider endoscopic therapy No endoscopic therapy Endoscopic Therapy Endoscopic therapy Medical Therapy High-dose PPI therapya High-dose PPI therapya Once-daily PPI therapy Once-daily PPI therapy Clear liquids for ~2 days Clear liquids for ~2 days Clear liquids for ~1 day Regular diet Dietc Hospital Stayd Hospitalize 3 days Hospitalize ~1–2 days Discharge after endoscopy Hospitalize 3 days FIGURE 51-1  Suggested algorithm for patients with acute upper gastrointestinal bleeding (hematemesis, melena) based on endoscopic findings. aIntravenous bolus (80 mg) followed by infusion (8 mg/h) or by intermittent oral or intravenous doses (e.g., 40 mg 2–4 times per day) for 3 days. bIntravenous 50 μg bolus followed by 50 μg/h infusion for 2–5 days. cDiet after endoscopy, assuming no nausea or vomiting. dDuration after endoscopy assuming patient stable without further bleeding or concurrent medical conditions requiring hospitalization. PPI, proton pump inhibitor.

ulcers while taking low-dose aspirin for secondary prevention should not discontinue aspirin and, if aspirin is held, should restart aspi­ rin once hemostasis is confirmed. A randomized trial showed that immediate reinstitution of aspirin was associated with a lower 8-week mortality compared to not restarting aspirin (1% vs 13%; hazard ratio, 0.2; 95% CI, 0.1–0.6). In contrast, aspirin should be discontinued in patients taking aspirin for primary prevention of cardiovascular events who develop UGIB. Patients with bleeding ulcers unrelated to H. pylori or NSAIDs should remain on PPI therapy indefinitely given a 42% inci­ dence of rebleeding at 7 years without protective therapy. Peptic ulcers are discussed in Chap. 335.

Gastrointestinal Bleeding CHAPTER 51 MALLORY-WEISS TEARS  Mallory-Weiss tears account for ~2–10% of UGIB hospitalizations. The classic history is vomiting, retching, or coughing preceding hematemesis. Bleeding from these tears, which are usually on the gastric side of the gastroesophageal junction, stops spontaneously in ~80–90% of patients and recurs in only 0–10%. Endoscopic therapy is indicated for actively bleeding Mallory-Weiss tears. Mallory-Weiss tears are discussed in Chap. 334. ESOPHAGEAL VARICES  The proportion of UGIB hospitalizations due to varices varies widely from ~2–40%, depending on the popula­ tion. Patients with variceal hemorrhage have poorer outcomes than patients with other sources of UGIB. Esophageal varices are treated with endoscopic ligation and an IV vasoactive medication (octreotide, somatostatin, vapreotide, terlipressin) for 2–5 days. Combination of endoscopic and medical therapy is superior to either therapy alone in decreasing rebleeding. Over the long term, treatment with nonselective beta blockers plus endoscopic ligation is recommended because the combination is more effective than either alone in reduction of recur­ rent esophageal variceal bleeding. Transjugular intrahepatic portosys­ temic shunt (TIPS) is recommended in patients who have persistent or recurrent bleeding despite endoscopic and medical therapy. TIPS also is suggested for acute variceal bleeding in patients with advanced liver disease (Child-Pugh class B with score 8–9 and active bleeding at endoscopy, Child-Pugh class C with score 10–13), because randomized trials show significant decreases in rebleeding and mortality compared with standard endoscopic and medical therapy. Esophageal Varices Mallory-Weiss Tear Clean base Active bleeding No active bleeding No endoscopic therapy No endoscopic therapy No endoscopic therapy Endoscopic ligation Endoscopic therapy Antiemetic if ongoing nausea Antiemetic if ongoing nausea Vasoactive drug (e.g., octreotideb) + antibiotic (e.g., ceftriaxone) Once-daily PPI therapy Clear liquids for ~2 days Clear liquids for ~1 day Regular diet Regular diet Hospitalize ~3–5 days Hospitalize ~1–2 days Discharge after endoscopy Discharge after endoscopy

Portal hypertension is also responsible for bleeding from gastric varices, varices in the small and large intestine, and portal hypertensive gastropathy and enterocolopathy. Bleeding gastric varices are treated with endoscopic injection of tissue adhesive (e.g., n-butyl cyanoacry­ late), TIPS, or retrograde transvenous obliteration.

EROSIVE DISEASE  Erosions are endoscopically visualized breaks that are confined to the mucosa and do not cause major bleeding because arteries and veins are not present in the mucosa. Erosions in the esophagus, stomach, or duodenum commonly cause mild UGIB, with erosive esophagitis (primarily due to gastroesophageal reflux disease), gastritis, and duodenitis accounting for up to perhaps ~30% of UGIB hospitalizations. The most important cause of gastric and duodenal erosions is NSAID use: up to ~50% of patients who chronically ingest NSAIDs may have gastric erosions. Other potential causes of gastric erosions include alcohol intake, H. pylori infection, and stress-related mucosal injury. PART 2 Cardinal Manifestations and Presentation of Diseases Stress-related gastric mucosal injury occurs only in extremely ill patients, such as those with serious trauma, major surgery, burns cov­ ering more than one-third of the body surface area, major intracranial disease, or severe medical illness. Severe bleeding should not develop unless ulceration occurs. The mortality rate in these patients is high because of their serious underlying illnesses. The incidence of bleeding from stress-related gastric mucosal injury has decreased dramatically in recent years, most likely due to better care of critically ill patients. Meta-analysis of randomized trials indicates prophylaxis with PPIs reduces clinically important GIB more than no prophylaxis or H2-receptor antagonists without impacting mortality or risk of infection (e.g., pneumonia, Clostridioides difficile). A guideline suggested PPI prophylaxis in critically ill patients at high risk (≥4%) of bleeding, defined as mechanical ventilation without enteral nutrition, portal hypertension, cirrhosis, platelets <50 × 109/L, international nor­ malized ratio >1.5, or two of the following: mechanical ventilation with enteral nutrition, acute kidney injury, sepsis, or shock. OTHER CAUSES  Less common causes of UGIB include neoplasms, vascular ectasias (including hereditary hemorrhagic telangiectasias and gastric antral vascular ectasia), Dieulafoy’s lesion (in which an aberrant vessel in the mucosa bleeds from a pinpoint mucosal defect), prolapse gastropathy (prolapse of proximal stomach into esophagus with retch­ ing), aortoenteric fistulas, and hemobilia or hemosuccus pancreaticus (bleeding from the bile duct or pancreatic duct). Small-Intestinal Sources of Bleeding  Patients without a source of GIB identified on upper endoscopy and colonoscopy were previ­ ously labeled as having obscure GIB. With the advent of improved diagnostic modalities, ~75% of GIB previously labeled obscure is now estimated to originate in the small intestine beyond the extent of a standard upper endoscopic exam. Small-intestinal GIB may account for ~5% of GIB cases. The most common causes in adults include vascular ectasias, neoplasm (e.g., gastrointestinal stromal tumor, car­ cinoid, adenocarcinoma, lymphoma, metastases), and NSAID-induced erosions and ulcers. Meckel’s diverticulum is the most common cause of significant small-intestinal GIB in children, decreasing in frequency as a cause of bleeding with age. Other less common causes of smallintestinal GIB include Crohn’s disease, infection, ischemia, vasculitis, small-bowel varices, diverticula, intussusception, Dieulafoy’s lesions, aortoenteric fistulas, and duplication cysts. Small-intestinal vascular ectasias are treated initially with endo­ scopic therapy, based on observational studies suggesting short-term efficacy. However, rebleeding is common, with pooled rebleeding rates of ~45% over a mean follow-up of ~2 years in systematic reviews, lead­ ing guidelines to suggest medical therapy if further bleeding occurs after endoscopic therapy. The best available evidence supports use of thalidomide, with a multicenter double-blind randomized trial show­ ing marked reductions in bleeding episodes, transfusions, and hospi­ talizations. Monthly intramuscular injection of octreotide long-acting release also is suggested based on observational studies and a small open-label randomized trial. Other isolated lesions, such as tumors, generally require surgical resection.

Colonic Sources of Bleeding  Hemorrhoids are probably the most common cause of lower GIB (LGIB); anal fissures also cause minor bleeding and pain. If these local anal processes, which rarely require hospitalization, are excluded, the most common cause of LGIB in adults is diverticulosis. Other causes include vascular ectasias (especially in the proximal colon of patients >70 years), neoplasms (primarily adenocarcinoma), colitis (ischemic, infectious, Crohn’s or ulcerative colitis, NSAID-induced colitis or ulcers), postpolypectomy bleeding, and radiation proctopathy. Rarer causes include solitary rec­ tal ulcer syndrome, varices (most commonly rectal), lymphoid nodular hyperplasia, vasculitis, trauma, and aortocolic fistulas. In children and adolescents, the most common colonic causes of significant GIB are inflammatory bowel disease and juvenile polyps. Diverticular bleeding is abrupt in onset, usually painless, sometimes massive, and often from the right colon; chronic or occult bleeding is not characteristic. Case series from the United States and Europe suggest colonic diverticula stop bleeding spontaneously in ≥90% of patients, with rebleeding on long-term follow-up as low as ~15% over 4–5 years. Rebleeding is substantially higher in reports from Asia. Case series suggest endoscopic therapy may decrease recurrent bleeding in the uncommon case when colonoscopy identifies the specific bleeding diverticulum. When diverticular bleeding is found at angiography, transcatheter arterial embolization by superselective technique pre­ vents further bleeding in most patients. Segmental surgical resection is recommended for refractory diverticular bleeding. Bleeding from colonic vascular ectasias may be overt or occult; it tends to be chronic and only occasionally hemodynamically signifi­ cant. Endoscopic hemostatic therapy may be used in the treatment of vascular ectasias, as well as discrete bleeding ulcers and postpolyp­ ectomy bleeding. Transcatheter arterial embolization also may be attempted for persistent bleeding from vascular ectasias and other lesions, although rebleeding is higher in nondiverticular LGIB at ~45%. Surgical therapy is generally required for major persistent or recur­ rent bleeding from colonic sources that cannot be treated medically, endoscopically, or angiographically. Patients with Heyde’s syndrome (bleeding vascular ectasias and aortic stenosis) appear to benefit from aortic valve replacement. APPROACH TO THE PATIENT Gastrointestinal Bleeding INITIAL ASSESSMENT Measurement of the heart rate and blood pressure is the best way to initially assess a patient with GIB. Clinically significant bleeding leads to postural changes in heart rate or blood pressure, tachycar­ dia, and, finally, recumbent hypotension. In contrast, hemoglobin does not fall immediately with acute GIB, due to proportionate reductions in plasma and red cell volumes (“people bleed whole blood”). Thus, hemoglobin may be normal or only minimally decreased at initial presentation of a severe bleeding episode. As extravascular fluid enters the vascular space to restore volume, the hemoglobin falls, but this process may take up to 72 h. Transfusion is recommended when the hemoglobin drops below 7 g/dL, based on a large randomized trial showing this restrictive transfusion strategy decreases rebleeding and death in acute UGIB compared with a transfusion threshold of 9 g/dL. Patients with slow, chronic GIB may have very low hemoglobin values despite normal blood pressure and heart rate. With the development of iron-deficiency anemia, the mean corpuscular volume is low and red-blood-cell distribution width is increased. DIFFERENTIATION OF UGIB FROM LGIB Hematemesis indicates an UGIB source. Melena indicates blood has been present in the gastrointestinal (GI) tract for ≥14 h and as long as 3–5 days. The more proximal the bleeding site, the more likely melena will occur. Hematochezia usually represents a lower GI source of bleeding, although an upper GI lesion may bleed so briskly that blood transits the bowel before melena develops. When

hematochezia is the presenting symptom of UGIB, it is associated with hemodynamic instability and dropping hemoglobin. Bleeding lesions of the small bowel may present as melena or hematochezia. Other clues to UGIB include hyperactive bowel sounds and elevated blood urea nitrogen (due to volume depletion and blood proteins absorbed in the small intestine). A nonbloody nasogastric aspirate may be seen in ~15% of patients with UGIB who present with clinically serious hemato­ chezia. A bile-stained appearance does not exclude UGIB because reports of bile in the aspirate are incorrect in ~50% of cases. Testing of aspirates that are not grossly bloody for occult blood is not useful. EVALUATION AND MANAGEMENT OF UGIB (FIG. 51-1) Initial Risk Assessment  Baseline characteristics predictive of rebleed­ ing and death include hemodynamic compromise (tachycardia or hypotension), increasing age, and comorbidities. Risk assessment tools may be used to identify patients with very low risk. Discharge from the emergency room with outpatient management is suggested for patients with a Glasgow-Blatchford score (possible range 0–23, Table 51-1) of 0–1 because only ~1% of patients who require transfusion, require hemostatic intervention, or die have a score of 0–1. Pre-Endoscopic Medications  PPI infusion may be considered at presentation; it modestly decreases need for endoscopic therapy due to a reduction in high-risk ulcer stigmata (e.g., active bleeding) but does not improve clinical outcomes such as further bleeding or death. The promotility agent erythromycin, 250 mg intravenously ~30–90 min before endoscopy, is suggested to improve visualization at endoscopy, thereby reducing the need for repeat endoscopy and hospital stay. Cirrhotic patients presenting with UGIB should be given an antibiotic (e.g., ceftriaxone) and IV vasoactive medication (e.g., octreotide) upon presentation. Antibiotics decrease bacterial infections, rebleeding, and mortality, and vasoactive medications improve control of bleeding in the 12 h after presentation. Endoscopy  Upper endoscopy should be performed within 24 h in most patients hospitalized with UGIB whether they have clinical No Hemodynamic Instability Hemodynamic Instability Colonoscopya Site identified, bleeding persists Site not identified Site identified, bleeding stops Angiography Bleeding persists Surgery FIGURE 51-2  Suggested algorithm for patients with acute lower gastrointestinal (GI) bleeding (hematochezia). aFor patients <35 years old with minor bleeding (e.g., blood on toilet paper), normal blood pressure and heart rate, normal hemoglobin and iron panel, and no family history of colorectal cancer, some would suggest flexible sigmoidoscopy is adequate.

TABLE 51-1  Glasgow-Blatchford Score RISK FACTORS AT ADMISSION SCORE Blood urea nitrogen (mg/dL)   18.2 to <22.4

  22.4 to <28.0

  28.0 to <70.0

  ≥70.0

Hemoglobin (g/dL)   12.0 to <13.0 (men); 10.0 to <12.0 (women)

Gastrointestinal Bleeding CHAPTER 51   10.0 to <12.0 (men)

  <10.0

Systolic blood pressure (mmHg)   100–109

  90–99

  <90

Heart rate (beats per minute)   ≥100

Melena

Syncope

Hepatic disease

Cardiac failure

features predicting low or high risk of further bleeding and death. Even in high-risk patients, more urgent endoscopy (performed within 6–12 h of gastroenterology consultation) does not improve clinical outcomes, and some observational studies suggest increased mortality with endoscopy within 6–12 h in high-risk patients. Early endoscopy in low-risk patients (e.g., hemodynamically stable without severe comorbidities) identifies low-risk findings (e.g., clean-based ulcers, erosions, nonbleeding Mallory-Weiss tears) that allow discharge in ≥40% of patients, thereby reducing hospital stay Upper endoscopy No upper GI source Able to prep Too unstable to prep No Extravasation CT angiography Able to prep Extravasation Angiography Bleeding persists Instability persists Workup for small intestinal/obscure bleeding site Surgery (with intraoperative endoscopy if site has not been identified)

45 - 52 Jaundice

52 Jaundice

and costs. Patients with high-risk endoscopic findings (e.g., varices, ulcers with active bleeding or a visible vessel) benefit from hemo­ static therapy at endoscopy. EVALUATION AND MANAGEMENT OF LGIB (FIG. 51-2) Patients with hematochezia and hemodynamic instability should have upper endoscopy to rule out an upper GI source before evalua­ tion of the lower GI tract. Colonoscopy after an oral lavage solution is the procedure of choice in most patients admitted with LGIB. If ongoing hemody­ namically significant hematochezia precludes bowel preparation and colonoscopy, computed tomography (CT) angiography is sug­ gested. If extravasation is seen, angiography is performed, allowing treatment with transcatheter arterial embolization. If no extravasa­ tion is seen, colonoscopy is subsequently performed. PART 2 Cardinal Manifestations and Presentation of Diseases EVALUATION AND MANAGEMENT OF SMALL-INTESTINAL OR OBSCURE GIB In patients with severe bleeding suspected to be from the small intestine, CT angiography or angiography is the initial test. For others, video capsule endoscopy is generally the next diagnostic test suggested, although repeat upper and lower endoscopy may be considered because second-look procedures in some observational studies identify a source in up to ~25% of cases (a push enteros­ copy, usually performed with a pediatric colonoscope to inspect the entire duodenum and proximal jejunum, may be substituted for a repeat standard upper endoscopy). Systematic reviews report a diagnostic yield with capsule endoscopy of ~55%. Limitations of capsule endoscopy include the inability to fully visualize the small intestinal mucosa, sample tissue, or apply therapy. If capsule endoscopy is positive, management is dictated by the finding. If capsule endoscopy is negative, clinically stable patients may be observed and treated with iron if iron deficiency is present. In those with further bleeding (e.g., need for transfusions), additional testing is performed. A second capsule endoscopy may be considered because some observational studies report it identifies a source in up to 50% or more of cases. CT enterography also may follow a negative capsule endoscopy, given its higher sensitivity for small-intestinal masses (CT enterography also may be used initially instead of video capsule in patients with concern for small bowel narrowing [e.g., stricture, prior surgery or radiation, Crohn’s disease]). “Deep” enteroscopy (double-balloon, single-balloon, or spiral enteroscopy) is commonly the next test after capsule endoscopy for clinically important GIB documented or suspected to be from the small intestine because it allows the endoscopist to examine, obtain specimens from, and provide therapy to much or all of the small intestine. Other imaging techniques sometimes used in evaluation of obscure GIB include CT angiography, angiography, 99mTc-labeled red-blood-cell scintigraphy, and 99mTc-pertechnetate scintigraphy for Meckel’s diverticulum (especially in young patients). If all tests are unrevealing, intraoperative endoscopy is indicated in patients with severe recurrent or persistent bleeding requiring repeated transfusions. POSITIVE FECAL OCCULT BLOOD TEST Fecal occult blood testing is recommended only for colorectal can­ cer screening, beginning at age 45 years in average-risk adults. A positive test necessitates colonoscopy. If evaluation of the colon is negative, further workup is not recommended unless iron-deficiency anemia or GI symptoms are present. ■ ■FURTHER READING Chen H et al: Thalidomide for recurrent bleeding due to small-intestinal angiodysplasia. N Engl J Med 389:1649, 2023. Kaplan DE et al: AASLD practice guidance on risk stratification and management of portal hypertension and varices in cirrhosis. Hepatology 79:1180, 2024. Karuppasamy K et al: ACR Appropriateness criteria® radiologic man­ agement of lower gastrointestinal tract bleeding: 2021 update. J Am Coll Radiol 18:S139, 2021.

Laine L et al: ACG clinical guideline: Upper gastrointestinal and ulcer bleeding. Am J Gastroenterol 116:899, 2021. Lau JYW et al: Timing of endoscopy for acute upper gastrointestinal bleeding. N Engl J Med 382:1299, 2020. Pennazio M et al: Small-bowel capsule endoscopy and device-assisted enteroscopy for diagnosis and treatment of small-bowel disorders: European Society of Gastrointestinal Endoscopy (ESGE) guideline— update 2022. Endoscopy 55:58, 2023. Sengupta N et al: Management of patients with acute lower gastro­ intestinal bleeding: An updated ACG guideline. Am J Gastroenterol 118:208, 2023. Villaneuva C et al: Transfusion strategies for acute upper gastrointes­ tinal bleeding. N Engl J Med 368:11, 2013. Ye Z et al: Gastrointestinal bleeding prophylaxis for critically ill patients: A clinical practice guideline. BMJ 368:16722, 2020. Savio John, Daniel S. Pratt

Jaundice Jaundice is a yellowish discoloration of body tissues resulting from the deposition of bilirubin. Tissue deposition of bilirubin occurs only in the presence of serum hyperbilirubinemia and is a sign of either liver dis­ ease or, less often, a hemolytic disorder or disorder of bilirubin metabo­ lism. The degree of serum bilirubin elevation can be estimated by physical examination. Slight increases in serum bilirubin level are best detected by examining the sclerae for icterus. Sclerae have a particular affinity for bilirubin due to their high elastin content, and the presence of scleral icterus indicates a serum bilirubin level of at least 51 μmol/L (3 mg/dL). The ability to detect scleral icterus is made more difficult if the examining room has fluorescent lighting. If the examiner suspects scleral icterus, a second site to examine is underneath the tongue. As serum bilirubin levels rise, the skin will eventually become yellow in light-skinned patients and even green if the process is long-standing; the green color is produced by oxidation of bilirubin to biliverdin. The differential diagnosis for yellowing of the skin is limited. In addition to jaundice, it includes carotenoderma; the use of drugs including quinacrine, sunitinib, and sorafenib; and excessive exposure to phenols. Carotenoderma, a yellow coloring of the skin, is associ­ ated with diabetes, hypothyroidism, and anorexia nervosa, but most commonly, it is caused by the ingestion of an excessive amount of vegetables and fruits such as carrots, leafy vegetables, squash, peaches, and oranges that contain carotene. In jaundice, the yellow coloration of the skin is uniformly distributed over the body, whereas in caroteno­ derma, the pigment is concentrated on the palms, soles, forehead, and nasolabial folds. Carotenoderma can be distinguished from jaundice by the sparing of the sclerae. Quinacrine causes a yellow discoloration of the skin in 4–37% of patients treated with it. It has also been reported with the use of the tyrosine kinase inhibitors sunitinib and sorafenib. Another sensitive indicator of increased serum bilirubin is dark­ ening of the urine, which is due to the renal excretion of conjugated bilirubin. Patients often describe their urine as tea- or cola-colored. Bilirubinuria indicates an elevation of the direct serum bilirubin frac­ tion and, therefore, the presence of liver or biliary disease. Serum bilirubin levels increase when an imbalance exists between bilirubin production and clearance. A logical evaluation of the patient who is jaundiced requires an understanding of bilirubin production and metabolism. ■ ■PRODUCTION AND METABOLISM OF BILIRUBIN (See Chap. 349) Bilirubin, a tetrapyrrole pigment, is a breakdown product of heme (ferroprotoporphyrin IX). About 80–85% of the

4 mg/kg body weight of bilirubin produced each day is derived from the breakdown of hemoglobin in senescent red blood cells. The remainder comes from prematurely destroyed erythroid cells in bone marrow and from the turnover of hemoproteins such as myoglobin and cytochromes found in tissues throughout the body. The formation of bilirubin occurs in reticuloendothelial cells, primarily in the spleen and liver. The first reaction, catalyzed by the microsomal enzyme heme oxygenase, oxidatively cleaves the α bridge of the porphyrin group and opens the heme ring. The end products of this reaction are biliverdin, carbon monoxide, and iron. The sec­ ond reaction, catalyzed by the cytosolic enzyme biliverdin reductase, reduces the central methylene bridge of biliverdin and converts it to bilirubin. Bilirubin formed in the reticuloendothelial cells is virtually insoluble in water due to tight internal hydrogen bonding between the water-soluble moieties of bilirubin—that is, the bonding of the propionic acid carboxyl groups of one dipyrrolic half of the molecule with the imino and lactam groups of the opposite half. This configura­ tion blocks solvent access to the polar residues of bilirubin and places the hydrophobic residues on the outside. To be transported in blood, bilirubin must be solubilized. Solubilization is accomplished by the reversible, noncovalent binding of bilirubin to albumin. Unconjugated bilirubin bound to albumin is transported to the liver. There, the bilirubin—but not the albumin—is taken up by hepatocytes via a pro­ cess that at least partly involves carrier-mediated membrane transport. Remarkably, a full understanding of this process remains elusive as no specific bilirubin transporter has yet been identified (Chap. 349, Fig. 349-1). After entering the hepatocyte, unconjugated bilirubin is bound in the cytosol to several proteins including proteins in the glutathione-S-

transferase superfamily. These proteins serve both to reduce efflux of bilirubin back into the serum and to present the bilirubin for conjuga­ tion. In the endoplasmic reticulum, bilirubin is made aqueous soluble by conjugation to glucuronic acid, a process that disrupts the hydro­ phobic internal hydrogen bonds and yields bilirubin monoglucuronide and diglucuronide. The conjugation of glucuronic acid to bilirubin is catalyzed by bilirubin uridine diphosphate-glucuronosyl transferase (UDPGT). The now-hydrophilic bilirubin conjugates diffuse from the endoplasmic reticulum to the canalicular membrane, where bilirubin monoglucuronide and diglucuronide are actively transported into canalicular bile by an energy-dependent mechanism involving the mul­ tidrug resistance–associated protein 2 (MRP2). A portion of bilirubin glucuronides is transported into the sinusoids and portal circulation by MRP3 and is subjected to reuptake into the hepatocyte by the sinu­ soidal organic anion transport protein 1B1 (OATP1B1) and OATP1B3. The conjugated bilirubin excreted into bile drains into the duodenum and passes unchanged through the proximal small bowel. Conjugated bilirubin is not reabsorbed by the intestinal mucosa due to its hydro­ philicity and increased molecular size. When the conjugated bilirubin reaches the distal ileum and colon, it is hydrolyzed to unconjugated bilirubin by bacterial β-glucuronidases. The unconjugated bilirubin is reduced by normal gut bacteria to form a group of colorless tetrapyr­ roles called urobilinogens and other products, the nature and relative amounts of which depend on the bacterial flora. About 80–90% of these products are excreted in feces, either unchanged or oxidized to orange derivatives called urobilins. The remaining 10–20% of the urobilinogens undergo enterohepatic cycling. A small fraction (usually <3 mg/dL) escapes hepatic uptake, filters across the renal glomerulus, and is excreted in urine. Increased urinary excretion of urobilinogen can be due to increased bilirubin production, increased hepatic reab­ sorption of urobilinogen from the colon, or decreased hepatic clear­ ance of urobilinogen. ■ ■MEASUREMENT OF SERUM BILIRUBIN The terms direct and indirect bilirubin—that is, conjugated and unconjugated bilirubin, respectively—are based on the original van den Bergh reaction. This assay, or a variation of it, is still used in most clinical chemistry laboratories to determine the serum bilirubin level. In this assay, bilirubin is exposed to diazotized sulfanilic acid and splits into two relatively stable dipyrrylmethene azopigments that absorb

maximally at 540 nm, allowing photometric analysis. The direct frac­ tion is that which reacts with diazotized sulfanilic acid in the absence of an accelerator substance such as alcohol. The direct fraction provides an approximation of the conjugated bilirubin level in serum. The total serum bilirubin is the amount that reacts after the addition of alcohol to allow the release of unconjugated bilirubin from albumin binding sites. The indirect fraction is the difference between the total and the direct bilirubin levels and provides an estimate of the unconjugated bilirubin in serum. Unconjugated bilirubin also reacts with diazo reagents, albeit slowly, even when the accelerator is absent. Thus, the calculated indirect bilirubin may underestimate the true amount of unconjugated bilirubin in circulation.

Jaundice CHAPTER 52 With the van den Bergh method, the normal serum bilirubin con­ centration usually is between 17 and 26 μmol/L (1 and 1.5 mg/dL). Total serum bilirubin concentrations are between 3.4 and 15.4 μmol/L (0.2 and 0.9 mg/dL) in 95% of a normal population. Unconjugated hyperbilirubinemia is present when the direct fraction is <15% of the total serum bilirubin. The presence of even limited amounts of true conjugated bilirubin in serum suggests significant hepatobiliary pathology. As conjugated hyperbilirubinemia is always associated with bilirubinuria (except in the presence of delta bilirubin in prolonged cholestasis when jaundice is overt), detection of bilirubin in urine via dipstick test is extremely helpful to confirm the presence of conjugated hyperbilirubinemia in a patient with a mildly elevated direct fraction. Other techniques, although less convenient to perform, have added considerably to our understanding of bilirubin metabolism. First, studies using these methods demonstrate that, in normal persons or those with Gilbert’s syndrome, almost 100% of the serum bilirubin is unconjugated; <3% is monoconjugated bilirubin. Second, in jaundiced patients with hepatobiliary disease, the total serum bilirubin concen­ tration measured by these more accurate methods is lower than the values found with diazo methods. This finding suggests that there are diazo-positive compounds distinct from bilirubin in the serum of patients with hepatobiliary disease. Third, these studies indicate that, in jaundiced patients with hepatobiliary disease, monoglucuronides of bilirubin predominate over diglucuronides. Fourth, part of the directreacting bilirubin fraction includes conjugated bilirubin that is cova­ lently linked to albumin. This albumin-linked fraction of conjugated bilirubin (delta fraction, delta bilirubin, or biliprotein) represents an important fraction of total serum bilirubin in patients with cholestasis and hepatobiliary disorders. The delta bilirubin is formed in serum when hepatic excretion of bilirubin glucuronides is impaired and the glucuronides accumulate in serum. By virtue of its tight binding to albumin, the clearance rate of delta bilirubin from serum approximates the longer half-life of albumin (18–20 days) rather than the short halflife of bilirubin (about 4 h). The prolonged half-life of albumin-bound conjugated bilirubin accounts for two previously unexplained enigmas in jaundiced patients with liver disease: (1) that some patients with conjugated hyperbiliru­ binemia do not exhibit bilirubinuria during the recovery phase of their disease because the delta bilirubin, although conjugated, is covalently bound to albumin and therefore not filtered by the renal glomeruli, and (2) that the elevated serum bilirubin level declines more slowly than expected in some patients who otherwise appear to be recovering satisfactorily. Late in the recovery phase of hepatobiliary disorders, all the conjugated bilirubin may be in the albumin-linked form. ■ ■MEASUREMENT OF URINE BILIRUBIN Unconjugated bilirubin is always bound to albumin in the serum, is not filtered by the kidney, and is not found in the urine. Conjugated bilirubin is filtered at the glomerulus, and the majority is reabsorbed by the proximal tubules; a small fraction is excreted in the urine. Any bilirubin found in the urine is conjugated bilirubin. The presence of bilirubinuria on urine dipstick test (Ictotest) indicates an elevation of the conjugated bilirubin fraction that cannot be excreted from the liver and implies the presence of hepatobiliary disease. A false-negative result is possible in patients with prolonged cholestasis due to the predomi­ nance of delta bilirubin, which is covalently bound to albumin and therefore not filtered by the renal glomeruli.

APPROACH TO THE PATIENT Jaundice The goal of this chapter is not to provide an encyclopedic review of every condition that causes jaundice. Rather, the chapter is intended to offer a framework that helps a physician to evaluate the patient with jaundice in a logical way (Fig. 52-1). The initial step is to perform appropriate blood tests in order to determine whether the patient has an isolated elevation of serum bilirubin. If so, is the bilirubin elevation due to an increased unconjugated or conjugated fraction? If the hyperbilirubinemia is accompanied by other liver test abnormalities, is the disorder hepatocellular or cholestatic? If cholestatic, is the cause intra- or extrahepatic? These questions can all be answered with a thought­ ful history, physical examination, and interpretation of appropriate laboratory and radiologic tests and procedures. PART 2 Cardinal Manifestations and Presentation of Diseases The bilirubin present in serum represents a balance between input from the production of bilirubin and hepatic/biliary removal of the pigment. Hyperbilirubinemia may result from (1) overproduction of bilirubin; (2) impaired uptake, conjugation, or excretion of bilirubin; or (3) regurgitation of unconjugated or conjugated bilirubin from damaged hepatocytes or bile ducts. History (focus on medication/drug exposure) Physical examination Lab tests: Bilirubin with fractionation, ALT, AST, alkaline phosphatase, prothrombin time, and albumin Isolated elevation of the bilirubin Direct hyperbilirubinemia (direct >15%) See Table 52-1 Inherited disorders Dubin-Johnson syndrome Rotor syndrome Indirect hyperbilirubinemia (direct <15%) See Table 52-1 Drugs Rifampicin Probenecid Results negative Additional virologic testing CMV DNA, EBV capsid antigen Hepatitis D antibody (if indicated) Hepatitis E IgM (if indicated)
Inherited disorders Gilbert’s syndrome Crigler-Najjar syndromes Hemolytic disorders Ineffective erythropoiesis Results negative Results negative FIGURE 52-1  Evaluation of the patient with jaundice. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; ANA, antinuclear antibody; AST, aspartate aminotransferase; CMV, cytomegalovirus; EBV, Epstein-Barr virus; ERCP, endoscopic retrograde cholangiopancreatography; LKM, liver-kidney microsomal antibody; MRCP, magnetic resonance cholangiopancreatography; SMA, smooth-muscle antibody; SPEP, serum protein electrophoresis.

An increase in unconjugated bilirubin in serum results from overproduction, impaired uptake, or conjugation of bilirubin. An increase in conjugated bilirubin is due to decreased excretion into the bile ductules or backward leakage of the pigment. The initial steps in evaluating the patient with jaundice are to determine (1) whether the hyperbilirubinemia is predominantly conjugated or unconjugated in nature and (2) whether other biochemical liver tests are abnormal. The thoughtful interpretation of limited data permits a rational evaluation of the patient (Fig. 52-1). The fol­ lowing discussion will focus solely on the evaluation of the adult patient with jaundice. ISOLATED ELEVATION OF SERUM BILIRUBIN Unconjugated Hyperbilirubinemia  The differential diagnosis of isolated unconjugated hyperbilirubinemia is limited (Table 52-1). The critical determination is whether the patient is suffering from a hemolytic process resulting in an overproduction of biliru­ bin (hemolytic disorders and ineffective erythropoiesis) or from impaired hepatic uptake/conjugation of bilirubin (drug effect or genetic disorders). Hemolytic disorders that cause excessive heme production may be either inherited or acquired. Inherited disorders include Bilirubin and other liver tests elevated Hepatocellular pattern: ALT/AST elevated out of proportion to alkaline phosphatase See Table 52-2 Cholestatic pattern: Alkaline phosphatase out of proportion ALT/AST See Table 52-3 Ultrasound

1. Viral serologies Hepatitis A IgM Hepatitis B surface antigen and core antibody (IgM) Hepatitis C RNA
2. Toxicology screen Acetaminophen level
3. Ceruloplasmin (if patient <40 years of age)
4. ANA, SMA, SPEP Dilated ducts Extrahepatic cholestasis CT/MRCP/ERCP Ducts not dilated Intrahepatic cholestasis Serologic testing AMA Hepatitis serologies Hepatitis A, CMV, EBV Review drugs (see Table 52-3) AMA positive Liver biopsy MRCP/Liver biopsy Liver biopsy

TABLE 52-1  Causes of Isolated Hyperbilirubinemia I. Indirect hyperbilirubinemia A. Hemolytic disorders B. Ineffective erythropoiesis C. Increased bilirubin production

1. Massive blood transfusion
2. Resorption of hematoma D. Drugs
3. Rifampin
4. Probenecid
5. Atazanavir
6. Antibiotics—cephalosporins and penicillins E. Inherited conditions
7. Crigler-Najjar types I and II
8. Gilbert’s syndrome II. Direct hyperbilirubinemia (inherited conditions) A. Dubin-Johnson syndrome B. Rotor syndrome spherocytosis, sickle cell anemia, thalassemia, and deficiency of red cell enzymes such as pyruvate kinase and glucose-6-phosphate dehydrogenase. In these conditions, the serum bilirubin level rarely exceeds 86 μmol/L (5 mg/dL). Higher levels may occur when there is coexistent renal or hepatocellular dysfunction or in acute hemo­ lysis, such as a sickle cell crisis. In evaluating jaundice in patients with chronic hemolysis, it is important to remember the high inci­ dence of pigmented (calcium bilirubinate) gallstones found in these patients, which increases the likelihood of choledocholithiasis as an alternative explanation for hyperbilirubinemia. Acquired hemolytic disorders include microangiopathic hemo­ lytic anemia (e.g., hemolytic-uremic syndrome), paroxysmal nocturnal hemoglobinuria, spur cell anemia, immune hemolysis, and parasitic infections (e.g., malaria and babesiosis). Ineffective erythropoiesis occurs in cobalamin, folate, and iron deficiencies. Resorption of hematomas and massive blood transfusions both can result in increased hemoglobin release and overproduction of bilirubin. In the absence of hemolysis, the physician should consider a problem with the hepatic uptake or conjugation of bilirubin. Cer­ tain drugs, including rifampin and probenecid, may cause uncon­ jugated hyperbilirubinemia by diminishing hepatic uptake of bilirubin. Impaired bilirubin conjugation occurs in three genetic conditions: Crigler-Najjar syndrome types I and II and Gilbert’s syndrome. Crigler-Najjar type I is an exceptionally rare condition found in neonates and characterized by severe jaundice (bilirubin

342 μmol/L [>20 mg/dL]) and neurologic impairment due to kernicterus, frequently leading to death in infancy or childhood. These patients have a complete absence of bilirubin UDPGT activ­ ity; are totally unable to conjugate bilirubin; and hence cannot excrete it. Crigler-Najjar type II is somewhat more common than type I. Patients live into adulthood with serum bilirubin levels of 103–428 μmol/L (6–25 mg/dL). In these patients, mutations in the bilirubin UDPGT gene cause the reduction—typically ≤10%—of the enzyme’s activity. Bilirubin UDPGT activity can be induced by the administration of phenobarbital, which can reduce serum bilirubin levels in these patients. Despite marked jaundice, these patients usually survive into adulthood, although they may be susceptible to kernicterus under the stress of concurrent illness or surgery. Gilbert’s syndrome is also marked by the impaired conjugation of bilirubin due to reduced bilirubin UDPGT activity (typically 10–35% of normal). Patients with Gilbert’s syndrome have mild unconjugated hyperbilirubinemia, with serum levels almost always <103 μmol/L (6 mg/dL). The serum levels may fluctuate, and

jaundice is often identified only during periods of stress, concur­ rent illness, alcohol use, or fasting. Unlike both Crigler-Najjar syndromes, Gilbert’s syndrome is very common. The reported inci­ dence is 3–7% of the population, with males predominating over females by a ratio of 1.5–7:1. The mildly elevated indirect serum hyperbilirubinemia seen in Gilbert’s syndrome is generally of no clinical consequence and may actually have protective effects. Conjugated Hyperbilirubinemia  Elevated conjugated hyperbiliru­ binemia is found in two rare inherited conditions: Dubin-Johnson syndrome and Rotor syndrome (Table 52-1). Patients with either condition present with asymptomatic jaundice. The defect in Dubin-Johnson syndrome is the presence of mutations in the gene for MRP2. These patients have altered excretion of bilirubin into the bile ducts. Rotor syndrome is caused by a deficiency of the major hepatic drug reuptake transporters OATP1B1 and OATP1B3. Differentiating between these syndromes is possible but is clinically unnecessary due to their benign nature. Jaundice CHAPTER 52 ELEVATION OF SERUM BILIRUBIN WITH OTHER

LIVER TEST ABNORMALITIES The remainder of this chapter will focus on the evaluation of patients with conjugated hyperbilirubinemia in the setting of other liver test abnormalities. This group of patients can be divided into those with a primary hepatocellular process and those with intra- or extrahepatic cholestasis. This distinction, which is based on the history and physical examination as well as the pattern of liver test abnormalities, guides the clinician’s evaluation (Fig. 52-1). History  A complete medical history is perhaps the single most important part of the evaluation of the patient with unexplained jaundice. Important considerations include the use of or exposure to any chemical or medication, whether physician-prescribed, overthe-counter, complementary, or alternative medicines (e.g., herbal and vitamin preparations) or other drugs such as anabolic steroids. The patient should be carefully questioned about possible paren­ teral exposures, including transfusions, intravenous and intranasal drug use, tattooing, and sexual activity. Other important points include recent travel history; exposure to people with jaundice; exposure to possibly contaminated foods; occupational exposure to hepatotoxins; alcohol consumption; the duration of jaundice; and the presence of any accompanying signs and symptoms, such as arthralgias, myalgias, rash, anorexia, weight loss, abdominal pain, fever, pruritus, and changes in the urine and stool. While none of the latter manifestations is specific for any one condition, any of them can suggest a diagnosis. A history of arthralgias and myalgias predating jaundice suggests hepatitis, either viral or drug related. Jaundice associated with the sudden onset of severe right-upperquadrant pain and shaking chills suggests choledocholithiasis and ascending cholangitis. Physical Examination  The general assessment should include evaluation of the patient’s nutritional status. Temporal and proximal muscle wasting suggests long-standing disease such as pancreatic cancer or cirrhosis. Stigmata of chronic liver disease, including spider nevi, palmar erythema, gynecomastia, caput medusae, Dupuytren’s contractures, parotid gland enlargement, and testicular atrophy, are commonly seen in advanced alcohol-related cirrhosis and occasionally in other types of cirrhosis. An enlarged left supra­ clavicular node (Virchow’s node) or a periumbilical nodule (Sister Mary Joseph’s nodule) suggests an abdominal malignancy. Jugular venous distention, a sign of right-sided heart failure, and/or a pulsa­ tile liver suggest hepatic congestion. Right pleural effusion even in the absence of clinically apparent ascites may be seen in advanced cirrhosis. The abdominal examination should focus on the size and con­ sistency of the liver, on whether the spleen is palpable and hence enlarged, and on whether ascites is present. Patients with cirrhosis may have an enlarged left lobe of the liver, which is felt below the xiphoid, and an enlarged spleen. A grossly enlarged nodular liver

or an obvious abdominal mass suggests malignancy. An enlarged tender liver could signify viral or alcoholic hepatitis; an infiltrative process such as amyloidosis; or, less often, an acutely congested liver secondary to right-sided heart failure. Severe right-upper-quadrant tenderness with respiratory arrest on inspiration (Murphy’s sign) suggests cholecystitis. Ascites in the presence of jaundice suggests either cirrhosis or malignancy with peritoneal spread. Laboratory Tests  A battery of tests are helpful in the initial evaluation of a patient with unexplained jaundice. These include total and direct serum bilirubin measurement; determination of serum aminotransferase, alkaline phosphatase, and albumin con­ centrations; and prothrombin time tests. Enzyme tests (alanine aminotransferase [ALT], aspartate aminotransferase [AST], and alkaline phosphatase [ALP]) are helpful in differentiating between a hepatocellular process and a cholestatic process (Table 348-1; Fig. 52-1)—a critical step in determining what additional workup is indicated. Patients with a hepatocellular process generally have a rise in the aminotransferases that is disproportionate to that in ALP, whereas patients with a cholestatic process have a rise in ALP that is disproportionate to that of the aminotransferases. The serum bilirubin can be prominently elevated in both hepatocellular and cholestatic conditions and therefore is not necessarily helpful in differentiating between the two. PART 2 Cardinal Manifestations and Presentation of Diseases In addition to enzyme tests, all jaundiced patients should have additional blood tests—specifically, an albumin level and a pro­ thrombin time—to assess liver function. A low albumin level suggests a chronic process such as cirrhosis or cancer. A normal albumin level is suggestive of a more acute process such as viral hepatitis or choledocholithiasis. An elevated prothrombin time indicates either vitamin K deficiency due to prolonged jaundice and malabsorption of vitamin K or significant hepatocellular dysfunc­ tion. The failure of the prothrombin time to correct with parenteral administration of vitamin K indicates severe hepatocellular injury. The results of the bilirubin, enzyme, albumin, and prothrombin time tests will usually indicate whether a jaundiced patient has a hepatocellular or a cholestatic disease and offer some indication of the duration and severity of the disease. The causes and evaluations of hepatocellular and cholestatic diseases are quite different. Hepatocellular Conditions  Hepatocellular diseases that can cause jaundice include viral hepatitis, drug or environmental tox­ icity, alcohol, and end-stage cirrhosis from any cause (Table 52-2). Wilson’s disease occurs primarily in young adults and usually between the ages of 3 and 55. Autoimmune hepatitis is typically seen in young to middle-aged women but may affect men and TABLE 52-2  Hepatocellular Conditions That May Produce Jaundice Viral hepatitis   Hepatitis A, B, C, D, and E   Epstein-Barr virus   Cytomegalovirus   Herpes simplex virus Alcoholic hepatitis Chronic liver disease and cirrhosis Drug toxicity   Predictable, dose-dependent (e.g., acetaminophen)   Unpredictable, idiosyncratic (e.g., isoniazid) Environmental toxins   Vinyl chloride   Jamaica bush tea—pyrrolizidine alkaloids   Kava kava   Wild mushrooms—Amanita phalloides, A. verna Wilson’s disease Autoimmune hepatitis

women of any age. Alcoholic hepatitis can be differentiated from viral and toxin-related hepatitis by the pattern of the aminotrans­ ferases: patients with alcoholic hepatitis typically have an AST-toALT ratio of at least 2:1, and the AST level rarely exceeds 300 U/L. Patients with acute viral hepatitis and toxin-related injury severe enough to produce jaundice typically have aminotransferase levels

500 U/L, with the ALT greater than or equal to the AST. While ALT and AST values <8 times normal may be seen in either hepa­ tocellular or cholestatic liver disease, values 25 times normal or higher are seen primarily in acute hepatocellular diseases. Patients with jaundice from cirrhosis can have normal or only slightly elevated aminotransferase levels. When the clinician determines that a patient has a hepatocellular disease, appropriate testing for acute viral hepatitis includes a hepa­ titis A IgM antibody assay, a hepatitis B surface antigen and core IgM antibody assay, a hepatitis C viral RNA test, and, depending on the circumstances, a hepatitis E IgM antibody assay. The hepatitis C

antibody can take up to 6 weeks to become detectable, making it an unreliable test if acute hepatitis C is suspected. Studies for hepatitis D, Epstein-Barr virus (EBV), and cytomegalovirus (CMV) may also be indicated. Ceruloplasmin is the initial screening test for Wilson’s disease. Testing for autoimmune hepatitis usually includes antinuclear antibody and anti–smooth muscle antibody assays and measurement of specific immunoglobulins. Drug-induced hepatocellular injury can be classified as either predictable or unpredictable. Predictable drug reactions are dosedependent and affect all patients who ingest a toxic dose of the drug in question. The classic example is acetaminophen hepatotoxicity. Unpredictable or idiosyncratic drug reactions are not dose-dependent and occur in a minority of patients. A great number of drugs can cause idiosyncratic hepatic injury. Environmental toxins are also an important cause of hepatocellular injury. Examples include industrial chemicals such as vinyl chloride, herbal preparations containing pyrrolizidine alkaloids (Jamaica bush tea) or kava, and the mushrooms Amanita phalloides and A. verna, which contain highly hepatotoxic amatoxins. Cholestatic Conditions  When the pattern of the liver tests sug­ gests a cholestatic disorder, the first step is to determine whether it is intra- or extrahepatic cholestasis (Fig. 52-1). Distinguishing intrahepatic from extrahepatic cholestasis may be difficult. His­ tory, physical examination, and laboratory tests often are not helpful. The next appropriate test is an ultrasound. The ultra­ sound is inexpensive, does not expose the patient to ionizing radiation, and can detect dilation of the intra- and extrahepatic biliary tree with a high degree of sensitivity and specificity. The absence of biliary dilation suggests intrahepatic cholestasis, while its presence indicates extrahepatic cholestasis. False-negative results occur in patients with partial obstruction of the common bile duct or in patients with cirrhosis or primary sclerosing chol­ angitis (PSC), in which scarring prevents the intrahepatic ducts from dilating. Although ultrasonography may indicate extrahepatic cholesta­ sis, it rarely identifies the site or cause of obstruction. The distal common bile duct is a particularly difficult area to visualize by ultrasound because of overlying bowel gas. Appropriate next tests include computed tomography (CT), magnetic resonance cholan­ giopancreatography (MRCP), endoscopic retrograde cholangiopan­ creatography (ERCP), percutaneous transhepatic cholangiography (PTC), and endoscopic ultrasound (EUS). CT and MRCP are better than ultrasonography for assessing the head of the pancreas and for identifying choledocholithiasis in the distal common bile duct, particularly when the ducts are not dilated. ERCP is the “gold standard” for identifying choledocholithiasis. Beyond its diagnostic capabilities, ERCP allows therapeutic interventions, including the removal of common bile duct stones and the placement of stents. PTC can provide the same information as ERCP and also allows for intervention in patients in whom ERCP is unsuccessful due to

proximal biliary obstruction or altered gastrointestinal anatomy. MRCP has replaced ERCP as the initial diagnostic test in most cases. EUS displays sensitivity and specificity comparable to that of MRCP in the detection of bile duct obstruction and allows biopsy of suspected malignant lesions. In patients with apparent intrahepatic cholestasis, the diagnosis is often made by serologic testing in combination with a liver biopsy. The list of possible causes of intrahepatic cholestasis is long and varied (Table 52-3). A number of conditions that typically cause a hepatocellular pattern of injury can also present as a cholestatic variant. Both hepatitis B and C viruses can cause cholestatic hepa­ titis (fibrosing cholestatic hepatitis). This disease variant has been TABLE 52-3  Cholestatic Conditions That May Produce Jaundice I. Intrahepatic A. Viral hepatitis

1. Fibrosing cholestatic hepatitis—hepatitis B and C
2. Hepatitis A, Epstein-Barr virus infection, cytomegalovirus infection B. Alcoholic hepatitis C. Drug toxicity
3. Pure cholestasis—anabolic and contraceptive steroids
4. Cholestatic hepatitis—chlorpromazine, erythromycin estolate
5. Chronic cholestasis—chlorpromazine and prochlorperazine D. Primary biliary cholangitis E. Sclerosing cholangitis, primary and secondary F. Vanishing bile duct syndrome
6. Chronic rejection of liver transplants
7. Sarcoidosis
8. Drugs G. Congestive hepatopathy and ischemic hepatitis H. Inherited conditions
9. Progressive familial intrahepatic cholestasis
10. Benign recurrent intrahepatic cholestasis I. Cholestasis of pregnancy J. Total parenteral nutrition K. Nonhepatobiliary sepsis L. Benign postoperative cholestasis M. Paraneoplastic syndrome N. Veno-occlusive disease O. Graft-versus-host disease P. Infiltrative disease
11. Tuberculosis
12. Lymphoma
13. Amyloidosis Q. Infections
14. Malaria
15. Leptospirosis II. Extrahepatic A. Malignant
16. Cholangiocarcinoma
17. Pancreatic cancer
18. Gallbladder cancer
19. Ampullary cancer
20. Malignant involvement of the porta hepatis lymph nodes B. Benign
21. Choledocholithiasis
22. Postoperative biliary strictures
23. Primary sclerosing cholangitis
24. Chronic pancreatitis
25. AIDS cholangiopathy
26. Mirizzi’s syndrome
27. Parasitic disease (ascariasis)

reported in patients who have undergone solid organ transplanta­ tion. The availability of direct-acting antiviral drugs has reduced the incidence of this condition. Hepatitis A and E, alcoholic hepatitis, and EBV or CMV infections may also present as cholestatic liver disease. Drugs may cause intrahepatic cholestasis that is usually revers­ ible after discontinuation of the offending agent, although it may take many months for cholestasis to resolve. Drugs most commonly associated with cholestasis are the anabolic and con­ traceptive steroids. Cholestatic hepatitis has been reported with chlorpromazine, imipramine, tolbutamide, sulindac, cimetidine, and erythromycin estolate. It also occurs in patients taking trim­ ethoprim; sulfamethoxazole; and penicillin-based antibiotics such as ampicillin, dicloxacillin, and clavulanic acid. Rarely, cholestasis may be chronic and associated with progressive fibrosis despite early discontinuation of the offending drug. Chronic cholestasis has been associated with chlorpromazine and prochlorperazine. Jaundice CHAPTER 52 Primary biliary cholangitis is an autoimmune disease predomi­ nantly affecting women and characterized by progressive destruc­ tion of interlobular bile ducts. The diagnosis is made by the detection of antimitochondrial antibody, which is found in 95% of patients. PSC is characterized by the destruction and fibrosis of larger bile ducts. The diagnosis of PSC is made with cholangiogra­ phy (MRCP), which demonstrates the pathognomonic segmental strictures. Approximately 75% of patients with PSC also have inflammatory bowel disease. The vanishing bile duct syndrome and adult bile ductopenia are rare conditions in which a decreased number of bile ducts are seen in liver biopsy specimens. This histologic picture is also seen in patients who develop chronic rejection after liver transplantation and in those who develop graft-versus-host disease after bone mar­ row transplantation. Vanishing bile duct syndrome also occurs in rare cases of sarcoidosis, in patients taking certain drugs (including chlorpromazine), and idiopathically. There are also familial forms of intrahepatic cholestasis. The familial intrahepatic cholestatic syndromes include progressive familial intrahepatic cholestasis (PFIC) types 1–3 and benign recur­ rent intrahepatic cholestasis (BRIC) types 1 and 2. BRIC is charac­ terized by episodic attacks of pruritus, cholestasis, and jaundice beginning at any age, which can be debilitating but do not lead to chronic liver disease. Serum bile acids are elevated during episodes, but serum γ-glutamyltransferase (γ-GT) activity is normal. PFIC disorders begin at childhood and are progressive in nature. All three types of PFIC are associated with progressive cholestasis, elevated levels of serum bile acids, and similar phenotypes but different genetic mutations. Only type 3 PFIC is associated with high levels of γ-GT. Cholestasis of pregnancy occurs in the second and third tri­ mesters and resolves after delivery. Its cause remains unknown, but the condition is probably inherited, and cholestasis can be triggered by estrogen administration. Other causes of intrahepatic cholestasis include total parenteral nutrition (TPN); nonhepatobiliary sepsis; benign postoperative cholestasis; and a paraneoplastic syndrome associated with a number of different malignancies, including Hodgkin’s disease, medullary thyroid cancer, renal cell cancer, renal sarcoma, T-cell lymphoma, prostate cancer, and several gastrointestinal malig­ nancies. In patients developing cholestasis in the intensive care unit, the major considerations should be sepsis, ischemic hepatitis (“shock liver”), and TPN-related jaundice. Jaundice occurring after bone marrow transplantation is most likely due to veno-occlusive disease (also called sinusoidal obstruction syndrome) or graftversus-host disease. In addition to hemolysis, sickle cell disease may cause intrahepatic and extrahepatic cholestasis. Jaundice is a late finding in heart failure caused by hepatic congestion and hepatocellular hypoxia. Ischemic hepatitis is a distinct entity of acute hypoperfusion characterized by an acute and dramatic elevation in the serum aminotransferases followed by a gradual peak in serum bilirubin.

46 - 53 Abdominal Swelling and Ascites

53 Abdominal Swelling and Ascites

Jaundice with associated liver dysfunction can be seen in severe cases of Plasmodium falciparum malaria. The jaundice in these cases is due to a combination of indirect hyperbilirubinemia from hemolysis and both cholestatic and hepatocellular jaundice. Weil’s disease, a severe presentation of leptospirosis, is marked by jaundice with renal failure, fever, headache, and muscle pain. Causes of extrahepatic cholestasis can be split into malignant and benign (Table 52-3). Malignant causes include pancreatic, gallbladder, and ampullary cancers as well as cholangiocarci­ noma. This last malignancy is most commonly associated with PSC and is exceptionally difficult to diagnose because its appear­ ance is often identical to that of PSC. Pancreatic and gallblad­ der tumors as well as cholangiocarcinoma are rarely resectable at the time of diagnosis and have poor prognoses. Ampullary carcinoma has the highest surgical cure rate of all the tumors that present as painless jaundice. Hilar lymphadenopathy due to metastases from other cancers may cause obstruction of the extrahepatic biliary tree. PART 2 Cardinal Manifestations and Presentation of Diseases Choledocholithiasis is the most common cause of extrahe­ patic cholestasis. The clinical presentation can range from mild right-upper-quadrant discomfort with only minimal elevations of enzyme test values to ascending cholangitis with jaundice, sepsis, and circulatory collapse. PSC may occur with clinically important strictures limited to the extrahepatic biliary tree. IgG4-associated cholangitis is marked by stricturing of the biliary tree. It is criti­ cal that the clinician differentiate this condition from PSC as it is responsive to glucocorticoid therapy. In rare instances, chronic pancreatitis causes strictures of the distal common bile duct, where it passes through the head of the pancreas. AIDS cholan­ giopathy is a condition that is usually due to infection of the bile duct epithelium with CMV or cryptosporidia and has a cholangio­ graphic appearance similar to that of PSC. The affected patients usually present with greatly elevated serum alkaline phosphatase levels (mean, 800 IU/L), but the bilirubin level is often near nor­ mal. These patients do not typically present with jaundice. Its inci­ dence has dropped dramatically since the introduction of potent antiretrovirals in the 1990s. ■ ■GLOBAL CONSIDERATIONS While extrahepatic biliary obstruction and drugs are common causes of new-onset jaundice in developed countries, infections remain the leading cause in developing countries. Liver involvement and jaundice are observed with numerous infections, particularly malaria, babesio­ sis, severe leptospirosis, infections due to Mycobacterium tuberculosis and the Mycobacterium avium complex, typhoid fever, infection with hepatitis viruses A–E, EBV, CMV, viral hemorrhagic fevers including Ebola virus, late phases of yellow fever, dengue fever, schistosomiasis, fascioliasis, clonorchiasis, opisthorchiasis, ascariasis, echinococcosis, hepatosplenic candidiasis, disseminated histoplasmosis, cryptococ­ cosis, coccidioidomycosis, ehrlichiosis, chronic Q fever, yersiniosis, brucellosis, syphilis, and leprosy. Bacterial infections that do not nec­ essarily involve the liver and bile ducts may also lead to jaundice, as in cholestasis of sepsis. The presence of fever or abdominal pain sug­ gests concurrent infection, sepsis, or complications from gallstones. The development of encephalopathy and coagulopathy in a jaundiced patient with no preexisting liver disease signifies acute liver failure, which warrants urgent liver transplant evaluation. ■ ■FURTHER READING Erlinger S et al: Inherited disorders of bilirubin transport and conju­ gation: New insights into molecular mechanisms and consequences. Gastroenterology 146:1625, 2014. Wolkoff AW et al: Bilirubin metabolism and jaundice, in Schiff’s Diseases of the Liver, 11th ed, Schiff ER et al (eds). Oxford, UK, John Wiley & Sons, Ltd, 2012, pp 120–150.

Lawrence S. Friedman

Abdominal Swelling

and Ascites ABDOMINAL SWELLING Abdominal swelling is a manifestation of numerous diseases. Patients may complain of bloating or abdominal fullness and may note increas­ ing abdominal girth on the basis of increased clothing or belt size. Abdominal discomfort is often reported, but pain is less frequent. When abdominal pain does accompany swelling, it is frequently the result of an intraabdominal infection, peritonitis, or pancreatitis. Patients with abdominal distention from ascites (fluid in the abdomen) may report the new onset of an inguinal or umbilical hernia. Dyspnea may result from pressure against the diaphragm and the inability to expand the lungs fully. ■ ■CAUSES The causes of abdominal swelling can be remembered conveniently as the six Fs: flatus, fat, fluid, fetus, feces, or a “fatal growth” (often a neoplasm). Flatus  Abdominal swelling may be the result of increased intes­ tinal gas. The normal small intestine contains ~200 mL of gas made up of nitrogen, oxygen, carbon dioxide, hydrogen, and methane. Nitrogen and oxygen are consumed (swallowed), whereas carbon dioxide, hydrogen, and methane are produced intraluminally by bacte­ rial fermentation. Increased intestinal gas can occur in a number of conditions. Aerophagia, the swallowing of air, can result in increased amounts of oxygen and nitrogen in the small intestine and lead to abdominal swelling. Aerophagia typically results from gulping food; chewing gum; smoking; or as a response to anxiety, which can lead to repetitive belching. Celiac disease, or gluten-sensitive enteropathy, and gastroparesis may be associated with bloating and distention. In some cases, increased intestinal gas is the consequence of bacterial metabo­ lism of excess fermentable substances such as lactose, fructose, and other fermentable oligosaccharides, disaccharides, monosaccharides, and polyols (FODMAPs), which can lead to production of hydrogen, carbon dioxide, or methane, as occurs also in small intestinal bacterial overgrowth or intestinal methanogen overgrowth. In some persons, particularly those with irritable bowel syndrome and bloating, the subjective sense of abdominal pressure is attributable to impaired intestinal transit of gas (rather than increased gas volume) or to vis­ ceral hypersensitivity. Abdominal distention—an objective increase in girth—may result from a lack of coordination between diaphragmatic contraction and anterior abdominal wall relaxation (“abdomino­ phrenic dyssynergia”), a response in some cases to intraluminal bowel stimuli; dietary alterations, manipulation of the intestinal microbiota, or biofeedback may be effective therapy. Occasionally, increased lum­ bar lordosis accounts for apparent abdominal distention. Fat  Weight gain with an increase in abdominal fat can result in an increase in abdominal girth and can be perceived as abdominal swell­ ing. Abdominal fat may be caused by an imbalance between caloric intake and energy expenditure associated with a poor diet and seden­ tary lifestyle; it also can be a manifestation of certain diseases, such as Cushing’s syndrome. Excess abdominal fat has been associated with an increased risk of insulin resistance and cardiovascular disease. Fluid  The accumulation of fluid within the abdominal cavity (asci­ tes) often results in abdominal distention and is discussed in detail below. Grade 1 ascites is detectable only by ultrasonography; grade 2 ascites is detectable by physical examination; and grade 3 ascites results in marked abdominal distention. Fetus  Pregnancy results in increased abdominal girth. Typically, an increase in abdominal size is first noted at 12–14 weeks of gestation,

when the uterus moves from the pelvis into the abdomen. Abdominal distention may be seen before this point as a result of fluid retention and relaxation of the abdominal muscles. Feces  In the setting of severe constipation or intestinal obstruction, increased stool in the colon leads to increased abdominal girth. These conditions are often accompanied by abdominal discomfort or pain, nausea, and vomiting and can be diagnosed by imaging studies. Fatal Growth  An abdominal mass can result in abdominal swelling. Neoplasms (including ovarian cancer in women), abscesses, or cysts can grow to sizes that lead to increased abdominal girth. Enlargement of the intraabdominal organs, specifically the liver (hepatomegaly) or spleen (splenomegaly), or an abdominal aortic aneurysm can result in abdominal distention. Bladder distention also may result in abdominal swelling. APPROACH TO THE PATIENT Abdominal Swelling HISTORY Determining the etiology of abdominal swelling begins with history-taking and a physical examination. Patients should be questioned regarding the onset and timing of bloating and disten­ tion, the relationship to food or bowel movements, prior surgery, dietary habits, and medications, as well as symptoms suggestive of malignancy, including weight loss, night sweats, and anorexia. Inability to pass stool or flatus together with nausea or vomiting suggests bowel obstruction, severe constipation, or an ileus (lack of peristalsis). Increased eructation and flatus may point toward aero­ phagia or increased intestinal production of gas. Patients should be questioned about risk factors for or symptoms of chronic liver disease, including excessive alcohol use and jaundice, which sug­ gest ascites. Patients should also be asked about symptoms of other medical conditions, including heart failure and tuberculosis, which may cause ascites. PHYSICAL EXAMINATION Physical examination should include an assessment for signs of sys­ temic disease. The presence of lymphadenopathy, especially supra­ clavicular lymphadenopathy (Virchow’s node), suggests metastatic abdominal malignancy. Care should be taken during the cardiac examination to evaluate for elevation of jugular venous pressure (JVP); Kussmaul’s sign (elevation of the JVP during inspiration); a pericardial knock, which may be seen in constrictive pericarditis and heart failure; or a murmur of tricuspid regurgitation. Spider angiomas, palmar erythema, dilated superficial veins around the umbilicus (caput medusae), and gynecomastia suggest liver disease. The abdominal examination should begin with inspection for the presence of uneven distention or an obvious mass. Auscultation should follow. The absence of bowel sounds or the presence of highpitched localized bowel sounds points toward an intestinal obstruc­ tion or ileus. An umbilical venous hum may suggest the presence of portal hypertension, and a harsh bruit over the liver is heard rarely in patients with hepatocellular carcinoma or alcohol-associated hepatitis. Abdominal swelling caused by intestinal gas can be differentiated from swelling caused by fluid or a solid mass by percussion; an abdomen filled with gas is tympanic, whereas an abdomen contain­ ing a mass or fluid is dull to percussion. The absence of abdominal dullness, however, does not exclude ascites, because a minimum of 1500 mL of ascitic fluid is required for detection on physical exami­ nation. The abdomen should be palpated to assess for tenderness, a mass, enlargement of the spleen or liver, or presence of a nodular liver suggesting cirrhosis or tumor. Light palpation of the liver may detect pulsations suggesting retrograde vascular flow from the heart in patients with right-sided heart failure, particularly tricuspid regurgitation. A rectal examination may help identify an evacuation disorder in patients with constipation.

Abdominal Swelling and Ascites CHAPTER 53 FIGURE 53-1  CT of a patient with a cirrhotic, nodular liver (white arrow), splenomegaly (yellow arrow), and ascites (arrowheads). ■ ■IMAGING AND LABORATORY EVALUATION Abdominal x-rays can be used to detect dilated loops of bowel suggest­ ing intestinal obstruction or ileus. Motility studies may be considered in patients with severe constipation. Abdominal ultrasonography can detect as little as 100 mL of ascitic fluid, hepatosplenomegaly, a nodular liver, or a mass. Ultrasonography is often inadequate to detect retro­ peritoneal lymphadenopathy or a pancreatic lesion because of overly­ ing bowel gas. If malignancy or pancreatic disease is suspected, CT can be performed. CT may also detect changes associated with advanced cirrhosis and portal hypertension (Fig. 53-1). Laboratory evaluation should include liver biochemical testing, serum albumin level measurement, and prothrombin time determina­ tion (international normalized ratio) to assess hepatic function as well as a complete blood count to evaluate for the presence of cytopenias that may result from portal hypertension or of leukocytosis, anemia, and thrombocytosis that may result from systemic infection. Serum amylase and lipase levels should be checked to evaluate the patient for acute pancreatitis. Urinary protein quantitation is indicated when nephrotic syndrome, which may cause ascites, is suspected. Hydrogen and methane absorbed from the intestine are not metabolized by the host and are excreted in expired air, and detection of increased amounts of these gases in expired breath is the basis for tests used to diagnose carbohydrate (e.g., lactose) malabsorption and small intes­ tinal bacterial overgrowth, although the reliability of the test results for the diagnosis of small intestinal bacterial overgrowth has been questioned. In selected cases, the hepatic venous pressure gradient (pressure across the liver between the portal and hepatic veins) can be measured via cannulation of the hepatic vein to confirm that ascites is caused by cirrhosis. In some cases, noninvasive tests for liver fibrosis, including liver stiffness measurement by elastography, or a liver biopsy may be necessary to confirm cirrhosis (Chap. 355). ASCITES ■ ■PATHOGENESIS IN THE PRESENCE OF CIRRHOSIS Ascites in patients with cirrhosis is the result of portal hypertension and renal salt and water retention. Similar mechanisms contribute to ascites formation in heart failure. Portal hypertension signifies eleva­ tion of the pressure within the portal vein. According to Ohm’s law,

pressure is the product of resistance and flow. Increased hepatic resis­ tance occurs by several mechanisms. First, the development of hepatic fibrosis, which defines cirrhosis, disrupts the normal architecture of the hepatic sinusoids and impedes normal blood flow through the liver. Second, activation of hepatic stellate cells, which mediate fibrogenesis, leads to smooth-muscle contraction and fibrosis. Finally, cirrhosis is associated with a decrease in endothelial nitric oxide synthetase (eNOS) production, which results in decreased nitric oxide production and increased intrahepatic vasoconstriction.

The development of cirrhosis is also associated with increased systemic circulating levels of nitric oxide (in contrast to the decrease seen intrahepatically), as well as increased levels of vascular endothe­ lial growth factor and tumor necrosis factor, that result in splanchnic arterial vasodilation. Vasodilation of the splanchnic circulation results in pooling of blood and a decrease in the effective circulating volume, which is perceived by the kidneys as hypovolemia. Compensatory vasoconstriction via release of antidiuretic hormone ensues; the con­ sequences are free water retention and activation of the sympathetic nervous system and the renin-angiotensin-aldosterone system, which lead in turn to renal sodium and water retention. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■PATHOGENESIS IN THE ABSENCE OF CIRRHOSIS Ascites in the absence of cirrhosis generally results from peritoneal carcinomatosis, peritoneal infection, pancreatic disease, or marked hypoalbuminemia. Peritoneal carcinomatosis can result from primary peritoneal malignancies such as mesothelioma or sarcoma, abdominal malignancies such as gastric or colonic adenocarcinoma, or metastatic disease from breast or lung carcinoma or melanoma (Fig. 53-2). The tumor cells lining the peritoneum produce a protein-rich fluid that contributes to the development of ascites. Fluid from the extracellular space is drawn into the peritoneum, further contributing to the devel­ opment of ascites. Tuberculous peritonitis causes ascites via a similar mechanism; tubercles deposited on the peritoneum exude a protein­ aceous fluid. Pancreatic ascites results from leakage of pancreatic enzymes into the peritoneum. Marked hypoalbuminemia may result from nephrotic syndrome, protein-losing enteropathy, or malnutrition. ■ ■CAUSES Cirrhosis accounts for 84% of cases of ascites. Cardiac ascites, perito­ neal carcinomatosis, and “mixed” ascites resulting from cirrhosis and a second disease account for 10–15% of cases. Less common causes of ascites include massive hepatic metastasis, infection (tuberculo­ sis, Chlamydia infection), pancreatitis, and renal disease (nephrotic FIGURE 53-2  CT of a patient with peritoneal carcinomatosis (white arrow) and ascites (yellow arrow).

syndrome). Rare causes of ascites include hypothyroidism and familial Mediterranean fever. ■ ■EVALUATION Once the presence of ascites has been confirmed, the etiology of the ascites is best determined by paracentesis, a bedside procedure in which a needle or small catheter is passed transcutaneously to extract ascitic fluid from the peritoneum. The lower quadrants are the most frequent sites for paracentesis. The left lower quadrant is preferred because of the greater depth of ascites and the thinner abdominal wall. Paracen­ tesis is a safe procedure even in patients with coagulopathy; complica­ tions, including abdominal wall hematomas, hypotension, hepatorenal syndrome, and infection, are infrequent. Once ascitic fluid has been extracted, its gross appearance should be examined. Turbid fluid can result from the presence of infection or tumor cells. White, milky fluid indicates a triglyceride level >200 mg/ dL (and often >1000 mg/dL), which is the hallmark of chylous ascites. Chylous ascites results from lymphatic disruption that may occur with trauma, cirrhosis, tumor, tuberculosis, or certain congenital abnor­ malities. Dark brown fluid can reflect a high bilirubin concentration and indicates biliary tract perforation. Black fluid may indicate the presence of pancreatic necrosis or metastatic melanoma. The ascitic fluid should be sent for measurement of albumin and total protein levels, cell and differential counts, and, if infection is sus­ pected, Gram’s stain and culture, with inoculation into blood culture bottles at the patient’s bedside to maximize the yield. A serum albumin level should be measured simultaneously to permit calculation of the serum-ascites albumin gradient (SAAG). The SAAG is useful for distinguishing ascites caused by portal hypertension from nonportal hypertensive ascites (Fig. 53-3). The SAAG reflects the pressure within the hepatic sinusoids and correlates with the hepatic venous pressure gradient. The SAAG is calculated by subtracting the ascitic albumin concentration from the serum albumin level and does not change with diuresis. A SAAG ≥1.1 g/dL reflects the presence of portal hypertension and indicates that the ascites is due to increased pressure in the hepatic sinusoids. According to Starling’s law, a high SAAG reflects the oncotic pressure that counterbalances the portal pressure. Possible causes include cirrhosis, cardiac ascites, hepatic vein thrombosis (Budd-Chiari syndrome), sinusoidal obstruc­ tion syndrome (veno-occlusive disease), or massive liver metastases. A SAAG <1.1 g/dL indicates that the ascites is not related to portal hypertension, as in tuberculous peritonitis, peritoneal carcinomatosis, pancreatic ascites, or nephrotic syndrome. For high-SAAG (≥1.1) ascites, the ascitic protein level can provide further clues to the etiology (Fig. 53-3). An ascitic protein level of ≥2.5 g/dL indicates that the hepatic sinusoids are normal and are allowing passage of protein into the ascites, as occurs in cardiac ascites, early Budd-Chiari syndrome, or sinusoidal obstruction syndrome. An ascitic protein level <2.5 g/dL indicates that the hepatic sinusoids have been damaged and scarred and no longer allow passage of protein, as occurs with cirrhosis, late Budd-Chiari syndrome, or massive liver metastases. Pro-brain-type natriuretic peptide (BNP) is a natriuretic hormone released by the heart as a result of increased volume and ventricular wall stretch. High levels of BNP in serum occur in heart failure and may be useful in identifying heart failure as the cause of high-SAAG ascites. Further tests are indicated only in specific clinical circumstances. When secondary peritonitis resulting from a perforated hollow viscus is suspected, ascitic glucose and lactate dehydrogenase (LDH) levels can be measured. In contrast to “spontaneous” bacterial peritonitis, which may complicate cirrhotic ascites (see “Complications,” below), secondary peritonitis is suggested by an ascitic glucose level <50 mg/ dL, an ascitic LDH level higher than the serum LDH level, and the detection of multiple pathogens on ascitic fluid culture. When pancre­ atic ascites is suspected, the ascitic amylase level should be measured and is typically >1000 mg/dL. Cytology can be useful in the diagnosis of peritoneal carcinomatosis. At least 50 mL of fluid should be obtained and sent for immediate processing. Tuberculous peritonitis is typi­ cally associated with ascitic fluid lymphocytosis but can be difficult to

≥1.1 g/dL Ascitic protein <2.5 g/dL Heart failure/constrictive pericarditis Cirrhosis Late Budd-Chiari syndrome Early Budd-Chiari syndrome Massive liver metastases IVC obstruction Sinusoidal obstruction syndrome FIGURE 53-3  Algorithm for the diagnosis of ascites according to the serum-ascites albumin gradient (SAAG). IVC, inferior vena cava. diagnose by paracentesis. A smear for acid-fast bacilli has a diagnostic sensitivity of only 0–3%; a culture increases the sensitivity to 35–50%. In patients without cirrhosis, an elevated ascitic adenosine deaminase level has a sensitivity of >90% for tuberculous ascites when a cut-off value of 30–45 U/L is used. When the cause of ascites remains uncer­ tain, laparotomy or laparoscopy with peritoneal biopsies for histology and culture remains the gold standard. TREATMENT Ascites The initial treatment for cirrhotic ascites is moderate restriction of sodium intake to 2 g/d. When sodium restriction alone is inad­ equate to control ascites, oral diuretics—typically the combination of spironolactone and furosemide—are used to increase urinary sodium excretion. Spironolactone is an aldosterone antagonist that inhibits sodium resorption in the distal convoluted tubule of the kidney. Use of spironolactone may be limited by hypona­ tremia, hyperkalemia, and painful gynecomastia. If the gyneco­ mastia is distressing, amiloride (5–40 mg/d) may be substituted for spironolactone. Furosemide is a loop diuretic that is generally combined with spironolactone in a ratio of 40:100; maximal daily doses of spironolactone and furosemide are generally 400 mg and 160 mg, respectively. Fluid intake may be restricted in patients with hyponatremia (serum sodium <125 mEq/L). Nonsteroidal anti-inflammatory drugs, angiotensin-converting enzyme inhibi­ tors, and angiotensin receptor blockers should be avoided in patients with cirrhosis and ascites. Refractory cirrhotic ascites is defined by the persistence of asci­ tes despite sodium restriction and maximum diuretic use (diuretic resistant) or the development of side effects of diuretics that preclude the use of maximum doses (diuretic intractable). Phar­ macologic therapy for refractory ascites includes the addition of midodrine, an α1-adrenergic agonist, or clonidine, an α2-adrenergic agonist, to diuretic therapy. These agents act as vasoconstrictors, counteracting splanchnic vasodilation. Midodrine alone or in com­ bination with clonidine improves systemic hemodynamics and control of ascites over that obtained with diuretics alone. Although β-adrenergic blocking agents (beta blockers) are often prescribed to prevent variceal hemorrhage in patients with cirrhosis, the use of beta blockers in patients with refractory ascites may be associated with decreased survival rates. When medical therapy alone is insufficient, refractory cirrhotic ascites can be managed by repeated large-volume (>5 L) paracente­ sis (LVP) or a transjugular intrahepatic peritoneal shunt (TIPS)—a radiologically placed portosystemic shunt that decompresses the hepatic sinusoids. Intravenous (IV) infusion of albumin accom­ panying LVP decreases the risk of “postparacentesis circulatory dysfunction” and death. Patients undergoing LVP should receive IV

SAAG <1.1 g/dL Ascitic protein ≥2.5 g/dL Biliary leak Abdominal Swelling and Ascites CHAPTER 53 Nephrotic syndrome Pancreatitis Peritoneal carcinomatosis Tuberculosis albumin infusions of 6–8 g/L of ascitic fluid removed. TIPS place­ ment is superior to LVP in reducing the reaccumulation of ascites but is associated with an increased frequency of hepatic encepha­ lopathy, with no difference in mortality rates. The Alfapump sys­ tem, which consists of an automated pump and tunneled peritoneal catheter that transports ascites from the peritoneal cavity to the urinary bladder, has shown promise in the management of refrac­ tory ascites but is associated with a high frequency of technical difficulties and renal dysfunction. Malignant ascites does not respond to sodium restriction or diuretics. Patients must undergo serial LVPs, transcutaneous drain­ age catheter placement, or, rarely, creation of a peritoneovenous shunt (a shunt from the abdominal cavity to the vena cava) or place­ ment of the Alfapump system, if available. Ascites caused by tuberculous peritonitis is treated with standard antituberculosis therapy. Noncirrhotic ascites of other causes is treated by correction of the precipitating condition. ■ ■COMPLICATIONS Spontaneous bacterial peritonitis (SBP; Chap. 137) is a common and potentially lethal complication of cirrhotic ascites. Occasionally, SBP also complicates ascites caused by nephrotic syndrome, heart failure, acute hepatitis, and acute liver failure but is rare in malignant asci­ tes. Patients with SBP generally note an increase in abdominal girth; however, abdominal tenderness is found in only 40% of patients, and rebound tenderness is uncommon. Patients may present with fever, nausea, vomiting, or the new onset or an exacerbation of preexisting hepatic encephalopathy. In hospitalized patients with ascites, paracentesis within 12 hours of admission reduces mortality because of early detection of SBP. SBP is defined by a polymorphonuclear neutrophil (PMN) count of ≥250/ μL in the ascitic fluid. Cultures of ascitic fluid should be performed in blood culture bottles and typically reveal one bacterial pathogen. The presence of multiple pathogens in the setting of an elevated ascitic PMN count suggests secondary peritonitis from a ruptured viscus or abscess (Chap. 137). The presence of multiple pathogens without an elevated PMN count suggests bowel perforation from the paracentesis needle. SBP is generally the result of enteric bacteria that have translo­ cated across an edematous bowel wall. The most common pathogens are gram-negative rods, including Escherichia coli and Klebsiella, as well as streptococci and enterococci. Treatment of SBP has traditionally been with a third-generation cephalosporin such as IV cefotaxime, 2 g every 12 hours, and is gen­ erally effective against gram-negative and gram-positive aerobes. A 5-day course of treatment is sufficient if the patient improves clini­ cally. Repeat paracentesis is recommended after 48 hours of antibiotic therapy to confirm that the ascitic PMN count has decreased by at least 25% from baseline. Increasingly, SBP, particularly if nosocomial or health care–acquired, is caused by multidrug-resistant bacteria, and

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55 Azotemia and Urinary Abnormalities

diagnosis of exclusion is based largely on history and physical examina­ tion and its treatment is based on a minimally invasive algorithm, with the focus on the patient’s clinical phenotype and the initial implemen­ tation of conservative therapeutic measures, IC/BPS can be well man­ aged even in resource-poor settings. As with many poorly understood and difficult-to-treat conditions, the greatest barrier to its diagnosis and treatment may perhaps be its recognition. ■ ■FURTHER READING Clemens JQ et al: Urologic chronic pelvic pain syndrome: Insights from the MAPP Research Network. Nat Rev Urol 16:187, 2019. Clemens JQ et al: AUA guideline for the diagnosis and treatment of interstitial cystitis/bladder pain syndrome. J Urol 208:34, 2022. Cox A et al: CUA guideline: Diagnosis and treatment of interstitial cystitis/bladder pain syndrome. Can Urol Assoc J 10:E136, 2016. Moldwin RM et al: Interstitial cystitis/bladder pain syndrome and related disorders, in Campbell-Walsh-Wein Urology, 12th ed. AW Partin et al (eds). Philadelphia, Elsevier, 2021. Nickel JC et al: MV140 sublingual vaccine reduces recurrent urinary tract infection in women. Results from the first North American clinical experience study. Can Urol Assoc J 18:25, 2024. David B. Mount

Azotemia and Urinary Abnormalities Normal kidney functions occur through numerous cellular processes to maintain body homeostasis. Disturbances in any of these functions can lead to abnormalities that may be detrimental to survival. Clini­ cal manifestations of these disorders depend on the pathophysiology of renal injury and often are identified as a complex of symptoms, abnormal physical findings, and laboratory changes that constitute specific syndromes. These renal syndromes (Table 55-1) may arise from systemic illness or as primary renal disease. Nephrologic syn­ dromes usually consist of several elements that reflect the underlying pathologic processes, typically including one or more of the following: (1) reduction in glomerular filtration rate (GFR), (2) abnormalities of urine sediment (red blood cells [RBCs], white blood cells [WBCs], casts, and crystals), (3) abnormal urinary excretion of serum proteins (proteinuria), (4) disturbances in urine volume (oliguria, anuria, poly­ uria), (5) presence of hypertension and/or expanded total body fluid volume (edema), (6) electrolyte abnormalities, and (7) in some syn­ dromes, fever/pain. The specific combination of these findings should permit identification of one of the major nephrologic syndromes (Table 55-1) and allow differential diagnoses to be narrowed so that the appropriate diagnostic and therapeutic course can be determined. All these syndromes and their associated diseases are discussed in more detail in subsequent chapters. This chapter focuses on several aspects of renal abnormalities that are critically important for distinguishing among those processes: (1) reduction in GFR, (2) alterations of the urinary sediment and/or protein excretion, and (3) abnormalities of urinary volume. AZOTEMIA ■ ■ASSESSMENT OF GFR Monitoring the GFR is important in both hospital and outpatient set­ tings, and several different methodologies are available. GFR is the pri­ mary metric for kidney “function,” and its direct measurement involves administration of a radioactive isotope (such as inulin or iothalamate)

that is filtered at the glomerulus into the urinary space but is neither reabsorbed nor secreted throughout the tubule. GFR—i.e., the clear­ ance of inulin or iothalamate in milliliters per minute—is calculated from the rate of appearance of the isotope in the urine over several hours. In most clinical circumstances, direct GFR measurement is not feasible, and the plasma creatinine level is used as a surrogate to esti­ mate GFR. Plasma creatinine (PCr) is the most widely used marker for GFR, which is related directly to urine creatinine (UCr) excretion and inversely to PCr. On the basis of this relationship (with some important caveats, as discussed below), GFR will fall in roughly inverse propor­ tion to the rise in PCr. Failure to account for GFR reductions in drug dosing can lead to significant morbidity and death from drug toxicities (e.g., digoxin, imipenem). In the outpatient setting, PCr serves as an estimate for GFR (although much less accurate; see below). In patients with chronic progressive renal disease, there is an approximately linear relationship between 1/PCr (y axis) and time (x axis). The slope of that line will remain constant for an individual; when values deviate, an investigation for a superimposed acute process (e.g., volume depletion, drug reaction) should be initiated. Signs and symptoms of uremia, the clinical symptom complex associated with renal failure, develop at significantly different levels of PCr, depending on the patient (size, age, and sex), underlying renal disease, existence of concurrent diseases, and true GFR. Generally, patients do not develop symptomatic uremia until renal insufficiency is severe (GFR <15 mL/min).

Azotemia and Urinary Abnormalities CHAPTER 55 A significantly reduced GFR (either acute or chronic) is usually reflected in a rise in PCr, leading to retention of nitrogenous waste products (defined as azotemia) such as urea. Azotemia may result from reduced renal perfusion, intrinsic renal disease, or postrenal processes (ureteral obstruction; see below and Fig. 55-1). Precise determination of GFR is problematic, as both commonly measured indices (urea and creatinine) have characteristics that affect their accuracy as markers of clearance. Urea clearance may underestimate GFR significantly because of urea reabsorption by the tubule. In contrast, creatinine is derived from muscle metabolism of creatine, and its generation varies little from day to day. Creatinine clearance (CrCl), an approximation of GFR, is measured from plasma and urinary creatinine excretion rates for a defined period (usually 24 h) and is expressed in milliliters per minute: CrCl = (Uvol × UCr)/(PCr × Tmin). The “adequacy” or “completeness” of the urinary collection is estimated by the urinary volume and creatinine content; creatinine is produced from muscle and excreted at a relatively con­ stant rate. For a 20- to 50-year-old man, creatinine excretion should be 18.5–25.0 mg/kg body weight; for a woman of the same age, it should be 16.5–22.4 mg/kg body weight. For example, an 80-kg man should excrete between ~1500 and 2000 mg of creatinine in an “adequate” col­ lection. Creatinine is useful for estimating GFR because it is a small, freely filtered solute that is not reabsorbed by the tubules. PCr levels can increase acutely from dietary ingestion of cooked meat, however, and creatinine can be secreted into the proximal tubule through an organic cation pathway (especially in advanced progressive chronic kidney disease [CKD]), leading to overestimation of GFR. When a timed col­ lection for CrCl is not available, decisions about drug dosing must be based on PCr alone. Two formulas are used widely to estimate kidney function from PCr: (1) Cockcroft-Gault and (2) four-variable MDRD (Modification of Diet in Renal Disease). Cockcroft-Gault: CrCl(mL/min) (140 age) Lean Body Weight (kg) Serum Creatinine (mg/dL)

( 0.85 if female)

− × × × MDRD: eGFR (mL/min per 1.73 m2) = 186.3 × PCr (e−1.154) × age (e−0.203) × (0.742 if female) × (1.21 if black). Numerous websites are available to assist with these calcula­ tions (www.kidney.org/professionals/kdoqi/gfr_calculator.cfm). A newer Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) esti­ mated GFR (eGFR), which was developed by pooling several cohorts

TABLE 55-1  Initial Clinical and Laboratory Database for Defining Major Syndromes in Nephrology SYNDROME IMPORTANT CLUES TO DIAGNOSIS COMMON FINDINGS Acute or rapidly progressive renal failure Anuria Hypertension, hematuria 321, 326, 328, 331 Oliguria Proteinuria, pyuria   Documented recent decline in GFR Casts, edema   Acute nephritis Hematuria, RBC casts Proteinuria

Azotemia, reduced GFR, oliguria Pyuria   Edema, hypertension Circulatory congestion   PART 2 Cardinal Manifestations and Presentation of Diseases Chronic renal failure Azotemia for >3 months Proteinuria, casts

Symptoms or signs of uremia, (late manifestation), casts Symptoms or signs of renal osteodystrophy Polyuria, nocturia   Kidneys reduced in size bilaterally Edema, hypertension   Broad casts in urinary sediment Hyperkalemia, metabolic acidosis   Nephrotic syndrome Proteinuria, with >3.5 g/24 h per 1.73 m2 Casts

Hypoalbuminemia Lipiduria   Edema Hypercoagulable state   Hyperlipidemia     Asymptomatic urinary abnormalities Hematuria  

Proteinuria (below nephrotic range)     Sterile pyuria, casts     Urinary tract infection/pyelonephritis Bacteriuria, with >105 cfu/mL Hematuria

Other infectious agent documented in urine Mild azotemia and reduced GFR   Pyuria, leukocyte casts Mild proteinuria   Frequency, urgency Fever   Bladder tenderness, flank tenderness     Renal tubular defects Electrolyte disorders Hematuria 327, 328 Polyuria, nocturia “Tubular” proteinuria (<1 g/24 h)   Renal calcification Enuresis   Large kidneys Electrolyte and/or acid-base abnormalities   Renal transport defects Other electrolyte issues, e.g., hypomagnesemia   Hypertension Systolic/diastolic hypertension Proteinuria 288, 329   Casts     Azotemia   Nephrolithiasis Previous history of stone passage or removal Hematuria

Previous history of stone seen by x-ray Pyuria   Renal colic Frequency, urgency   Urinary tract obstruction Azotemia, oliguria, anuria Hematuria

Polyuria, nocturia, urinary retention Pyuria   Slowing of urinary stream Enuresis, dysuria   Large prostate, large kidneys     Flank tenderness, full bladder after voiding     Abbreviations: cfu, colony-forming units; GFR; glomerular filtration rate; RBC, red blood cell. with and without kidney disease who had data on directly measured GFR, appears to be more accurate: CKD-EPI: eGFR = 141 × min (PCr/k, 1)a × max (PCr/k, 1)−1.209 × 0.993Age × 1.018 [if female] × 1.159 [if black], where PCr is plasma creatinine, k is 0.7 for females and 0.9 for males, a is –0.329 for females and –0.411 for males, min indicates the minimum of PCr/k or 1, and max indicates the maximum of PCr/k or 1 (https://www. mdcalc.com/ckd-epi-equations-glomerular-filtration-rate-gfr). There are limitations to all creatinine-based estimates of GFR. Each equation, along with 24-h urine collection for measurement of creati­ nine clearance, is based on the assumption that the patient is in steady state, without daily increases or decreases in PCr as a result of rapidly changing GFR. The MDRD equation is better correlated with true GFR when the GFR is <60 mL/min per 1.73 m2. The gradual loss of muscle

CHAP(S). DISCUSSING DISEASE-CAUSING SYNDROME Hypocalcemia, hyperphosphatemia, hyperparathyroidism   from chronic illness, chronic use of glucocorticoids, or malnutrition can mask significant changes in GFR with small or imperceptible changes in PCr. The coefficient of 1.159 in the CKD-EPI equation to adjust for self-reported black race reflects that measured GFR was 16% higher in blacks than nonblacks with similar age, sex, and creatinine in the data set used to develop the equation. Race is a social rather than a biological construct, for which reason the use of the “race modifier” in calculating eGFR using CKD-EPI and other equations has come under scrutiny. In particular, given the implications of utilizing selfreported race to modify clinical laboratory results, many medical centers have recently stopped reporting eGFRs that have been calcu­ lated using a race modifier. This change is projected to have positive consequences, in particular, improved access to waitlisting for renal transplantation in black patients at an earlier stage of CKD. Potential

AZOTEMIA Urinalysis and renal ultrasound Hydronephrosis Renal size parenchyma Urinalysis Urologic evaluation Relieve obstruction Normal size kidneys Intact parenchyma Bacteria Pyelonephritis Small kidneys, thin cortex, bland sediment, isosthenuria <3.5 g protein/24 h Acute Renal Failure Normal urinalysis with oliguria Chronic Renal Failure Symptomatic treatment delay progression If end-stage, prepare for dialysis Urine electrolytes Muddy brown casts, amorphous sediment

• protein FeNa <1% U osmolality >500 mosmol FeNa >1% U osmolality <350 mosmol Renal biopsy Prerenal Azotemia Volume contraction, cardiac failure, vasodilatation, drugs, sepsis, renal vasoconstriction, impaired autoregulation Acute Tubular Necrosis Glomerulonephritis or vasculitis Immune complex, anti-GBM disease FIGURE 55-1  Approach to the patient with azotemia. FeNa, fractional excretion of sodium; GBM, glomerular basement membrane; RBC, red blood cell; U, urine; WBC, white blood cell. negative consequences include “overdiagnosis” of CKD, inadequate or inaccurate dosing of drugs that are eliminated through the kidney (e.g., metformin), reduced access to imaging modalities for black patients with CKD with a lower reported eGFR, and reductions in living kidney donation among blacks. These and the other limitations in creatinine-based eGFR have led to the development of alternative methods for estimat­ ing GFR. Cystatin C, a member of the cystatin superfamily of cysteine prote­ ase inhibitors, is produced at a relatively constant rate from all nucle­ ated cells. Serum cystatin C has been proposed to be a more sensitive marker of early GFR decline than is PCr, with lesser effects of muscle mass on circulating levels; however, cystatin C levels are influenced by the patient’s sex and the presence of diabetes mellitus, smoking, and inflammation. To the extent that cystatin C–based calculation of eGFR is less affected by self-reported race and muscle mass, it is an increas­ ingly important adjunct to creatinine-based eGFR. Recently, eGFR equations that include both creatinine and cystatin C have been shown to be more accurate than the single-measurement equations. Clinical judgement and clinical assessment also play an important role in inter­ preting eGFR values. For example, a bodybuilder may have an elevated creatinine level due to increased muscle mass, with an underestimate

Azotemia and Urinary Abnormalities CHAPTER 55 WBC, casts eosinophils Interstitial nephritis Abnormal urinalysis Red blood cells Renal artery or vein occlusion RBC casts Proteinuria Angiogram of GFR based on a creatinine-based eGFR; in that case, the cystatin C eGFR may be more accurate. APPROACH TO THE PATIENT Azotemia Once GFR reduction has been established, the physician must decide if it represents acute or chronic renal injury. The clinical circumstances, history, and laboratory data often make this an easy distinction. However, the laboratory abnormalities characteristic of chronic renal failure, including anemia, hypocalcemia, and hyper­ phosphatemia, are also often present in patients presenting with acute renal failure. Radiographic evidence of renal osteodystrophy (Chap. 322) can be seen only in chronic renal failure but is a very late finding, typically in patients with end-stage renal disease (ESRD) maintained on dialysis. The urinalysis and renal ultrasound can facilitate distinguishing acute from chronic renal failure. An approach to the evaluation of azotemic patients is shown in Fig. 55-1. Patients with advanced chronic renal insufficiency often have some protein­ uria, nonconcentrated urine (isosthenuria; isosmotic with plasma),

and small kidneys on ultrasound, characterized by increased echo­ genicity and cortical thinning. Treatment should be directed toward slowing the progression of renal disease and providing symptomatic relief for edema, acidosis, anemia, and hyperphosphatemia, as discussed in Chap. 322. Acute renal failure (Chap. 321) can result from processes that affect blood flow and glomerular perfusion (prerenal azotemia), intrinsic renal diseases (affecting small vessels, glomeruli, or tubules), or postrenal processes (obstruction of urine flow in ureters, bladder, or urethra) (Chap. 331). PRERENAL FAILURE Decreased renal perfusion accounts for 40–80% of cases of acute renal failure and, if appropriately treated, is readily reversible. The etiologies of prerenal azotemia include any cause of decreased circulating blood volume (gastrointestinal hemorrhage, burns, diarrhea, diuretics), volume sequestration (pancreatitis, peritonitis, rhabdomyolysis), or decreased effective arterial volume (cardio­ genic shock, sepsis). Renal and glomerular perfusion also can be affected by reductions in cardiac output from peripheral vasodi­ lation (sepsis, drugs) or profound renal vasoconstriction (severe heart failure, hepatorenal syndrome, agents such as nonsteroidal anti-inflammatory drugs [NSAIDs]). True or “effective” arterial hypovolemia leads to a fall in mean arterial pressure, which in turn triggers a series of neural and humoral responses, including activa­ tion of the sympathetic nervous and renin-angiotensin-aldosterone systems and vasopressin (AVP) release. GFR is maintained by pros­ taglandin-mediated dilatation of afferent arterioles and angiotensin II–mediated constriction of efferent arterioles. Once the mean arte­ rial pressure falls below 80 mmHg, GFR declines steeply. PART 2 Cardinal Manifestations and Presentation of Diseases Blockade of prostaglandin production by NSAIDs can result in severe vasoconstriction and acute renal failure. Blocking angioten­ sin action with angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) decreases efferent arteriolar tone and in turn decreases glomerular capillary perfusion pres­ sure. Patients taking NSAIDs and/or ACE inhibitors/ARBs are most susceptible to hemodynamically mediated acute renal failure when blood volume or arterial perfusion pressure is reduced for any reason; under these circumstances, preservation of GFR is dependent on afferent vasodilation due to prostaglandins and effer­ ent vasoconstriction due to angiotensin II. Patients with bilateral renal artery stenosis (or stenosis in a solitary kidney) can also be dependent on efferent arteriolar vasoconstriction for maintenance of glomerular filtration pressure and are particularly susceptible to a precipitous decline in GFR when given ACE inhibitors or ARBs. Prolonged renal hypoperfusion may lead to acute tubular necro­ sis (ATN), an intrinsic renal disease that is discussed below. The urinalysis and urinary electrolyte measurements can be useful in distinguishing prerenal azotemia from ATN (Table 55-2). The TABLE 55-2  Laboratory Findings in Acute Renal Failure OLIGURIC ACUTE RENAL FAILURE INDEX PRERENAL AZOTEMIA BUN/PCr ratio

20:1 10–15:1 Urine sodium UNa, meq/L <20 40 Urine osmolality, mosmol/L H2O 500 <350 Fractional excretion of sodiuma <1% 2% Urine/plasma creatinine UCr/PCr 40 <20 Urinalysis (casts) None or hyaline/granular Muddy brown = × × × FE U P

P U a Na Na Cr Na cr Abbreviations: BUN, blood urea nitrogen; PCr, plasma creatinine concentration; PNa, plasma sodium concentration; UCr, urine creatinine concentration; UNa, urine sodium concentration.

urine Na and osmolality of patients with prerenal azotemia can be predicted from the stimulatory actions of norepinephrine, angio­ tensin II, AVP, aldosterone, and low tubule fluid flow rate. In pre­ renal conditions, the tubules are intact, leading to a concentrated urine (>500 mosmol), avid Na retention (urine Na concentration, <20 mmol/L; fractional excretion of Na [FENa], <1%), and UCr/PCr

40 (Table 55-2). The FENa is typically >1% in ATN but may be <1% in patients with milder, nonoliguric ATN (e.g., from rhabdomyolysis) and in patients with underlying “prerenal” disorders, such as con­ gestive heart failure (CHF) or cirrhosis or hepatorenal syndrome. The prerenal urine sediment is usually normal or has hyaline and granular casts, whereas the sediment of ATN usually is filled with cellular debris, tubular epithelial casts, and dark (muddy brown) granular casts. Microscopic examination of a urine sediment is a key test in AKI, since the presence of dark granular casts and/or tubular epithelial cells in the urine is highly predictive of ATN. The measurement of urinary biomarkers associated with tubular injury is a promising technique to detect subclinical ATN and/or help further diagnose the exact cause of acute renal failure. POSTRENAL AZOTEMIA Urinary tract obstruction accounts for <5% of cases of acute renal failure but is usually reversible and must be ruled out early in the evaluation (Fig. 55-1). Since a single kidney is capable of adequate clearance, complete obstructive acute renal failure requires obstruc­ tion at the urethra or bladder outlet, bilateral ureteral obstruction, or unilateral obstruction in a patient with a single functioning kidney. Obstruction is usually diagnosed by the presence of ure­ teral and renal pelvic dilation on renal ultrasound. However, early in the course of obstruction or if the ureters are unable to dilate (e.g., encasement by pelvic or periureteral tumors or by retroperito­ neal fibrosis), the ultrasound examination may be negative. Other imaging, such as a furosemide renogram (MAG3 nuclear medicine study), may be required to better define the presence or absence of obstructive uropathy. The specific urologic conditions that cause obstruction are discussed in Chap. 331. INTRINSIC RENAL DISEASE When prerenal and postrenal azotemia have been excluded as etiologies of renal failure, an intrinsic parenchymal renal disease is present. Intrinsic renal disease can arise from processes involving large renal vessels, intrarenal microvasculature and glomeruli, or the tubulointerstitium. Ischemic and toxic ATN account for ~90% of cases of acute intrinsic renal failure. As outlined in Fig. 55-1, the clinical setting and urinalysis are helpful in separating the possible etiologies. Prerenal azotemia and ATN are part of a spectrum of renal hypoperfusion; evidence of structural tubule injury is pres­ ent in ATN, whereas prompt reversibility occurs with prerenal azotemia upon restoration of adequate renal perfusion. Thus, ATN often can be distinguished from prerenal azotemia by urinalysis and urine electrolyte composition (Table 55-2 and Fig. 55-1). Ischemic ATN is observed most frequently in patients who have undergone major surgery, trauma, severe hypovolemia, overwhelming sepsis, or extensive burns. Nephrotoxic ATN complicates the administra­ tion of many common medications, usually by inducing a combi­ nation of intrarenal vasoconstriction, direct tubule toxicity, and/ or tubular obstruction. The kidney is vulnerable to toxic injury by virtue of its rich blood supply (25% of cardiac output) and its ability to concentrate and metabolize toxins. A diligent search for hypo­ tension and nephrotoxins usually uncovers the specific etiology of ATN. Discontinuation of nephrotoxins and stabilization of blood pressure often suffice without the need for dialysis, with ongoing regeneration of tubular cells. An extensive list of potential drugs and toxins implicated in ATN is found in Chap. 321. Processes involving the tubules and interstitium can lead to acute kidney injury (AKI), a subtype of acute renal failure. These processes include drug-induced interstitial nephritis (especially by antibiotics, NSAIDs, and proton pump inhibitors), severe infections

(both bacterial and viral), systemic diseases (e.g., systemic lupus erythematosus), and systemic disorders (e.g., sarcoidosis, Sjögren’s syndrome, lymphoma, or leukemia). A list of drugs associated with allergic interstitial nephritis is found in Chap. 328. Urinalysis usu­ ally shows mild to moderate proteinuria, hematuria, and pyuria (~75% of cases) and occasionally WBC casts. The finding of RBC casts in interstitial nephritis has been reported but should prompt a search for glomerular diseases (Fig. 55-1). Renal biopsy will be needed to distinguish among these possibilities. The classic sediment finding in allergic interstitial nephritis is a predominance (>10%) of urinary eosinophils with Wright’s or Hansel’s stain; how­ ever, urinary eosinophils can be increased in several other causes of AKI, such that measurement of urine eosinophils has no diagnostic utility in renal disease. This test is no longer recommended in the workup of AKI. Occlusion of large renal vessels, including arteries and veins, is an uncommon cause of acute renal failure. A significant reduc­ tion in GFR by this mechanism suggests bilateral processes or, in a patient with a single functioning kidney, a unilateral process. In patients with preexisting renal artery stenosis, a substantial renal collateral circulation can develop over time and sustain renal perfusion—typically not enough to sustain glomerular filtration, but enough to maintain tissue viability—in the event of total renal artery occlusion. Renal arteries can be occluded with atheroemboli, thromboemboli, in situ thrombosis, aortic dissection, or vasculitis. Atheroembolic renal failure can occur spontaneously but most often is associated with recent aortic instrumentation. The emboli are cholesterol-rich and lodge in medium and small renal arteries, with a consequent eosinophil-rich inflammatory reaction. Patients with atheroembolic acute renal failure often have a normal urinaly­ sis, but the urine may contain eosinophils and casts. The diagnosis can be confirmed by renal biopsy, but this procedure is often unnec­ essary when other stigmata of atheroemboli are present (livedo reticularis, distal peripheral infarcts, eosinophilia). Renal artery thrombosis may lead to mild proteinuria and hematuria, whereas renal vein thrombosis typically occurs in the context of heavy pro­ teinuria and hematuria. These vascular complications often require angiography for confirmation and are discussed in Chap. 329. Diseases of the glomeruli (glomerulonephritis and vasculitis) and the renal microvasculature (hemolytic-uremic syndromes, thrombotic thrombocytopenic purpura, and malignant hyperten­ sion) usually present with various combinations of glomerular injury: proteinuria, hematuria, reduced GFR, and alterations of sodium excretion that lead to hypertension, edema, and circulatory congestion (acute nephritic syndrome). These findings may occur as primary renal diseases or as renal manifestations of systemic dis­ eases. The clinical setting and other laboratory data help distinguish primary renal diseases from systemic diseases. The finding of RBC casts in the urine is an indication for early renal biopsy (Fig. 55-1), as the pathologic pattern has important implications for diagnosis, prognosis, and treatment. Hematuria without RBC casts can also be an indication of glomerular disease, since RBC casts are highly specific but very insensitive for glomerulonephritis. The specificity of urine microscopy can be enhanced by examining urine with a phase contrast microscope capable of detecting dysmorphic red cells (“acanthocytes”) that are associated with glomerular disease. This evaluation is summarized in Fig. 55-2. A detailed discussion of glomerulonephritis and diseases of the microvasculature is found in Chap. 328. OLIGURIA AND ANURIA Oliguria refers to a 24-h urine output <400 mL, and anuria is the complete absence of urine formation (<100 mL). Anuria can be caused by complete bilateral urinary tract obstruction; a vascular catastrophe (dissection or arterial occlusion); renal vein throm­ bosis; acute cast nephropathy in myeloma; renal cortical necrosis; severe ATN; severe rapidly progressive glomerulonephritis; com­ bined therapy with NSAIDs, ACE inhibitors, and/or ARBs; and

HEMATURIA Proteinuria (>500 mg/24 h), Dysmorphic RBCs or RBC casts Pyuria, WBC casts Urine culture Urine eosinophils Serologic and hematologic evaluation: blood cultures, anti-GBM antibody, ANCA, complement levels, cryoglobulins, hepatitis B and C serologies, VDRL, HIV, ASLO Azotemia and Urinary Abnormalities CHAPTER 55 Hemoglobin electrophoresis Urine cytology UA of family members 24 h urinary calcium/uric acid IVP +/– Renal ultrasound As indicated: retrograde pyelography or arteriogram, or cyst aspiration Renal biopsy Cystoscopy Urogenital biopsy and evaluation Renal CT scan Renal biopsy of mass/lesion Follow periodic urinalysis FIGURE 55-2  Approach to the patient with hematuria. ANCA, antineutrophil cytoplasmic antibody; ASLO, antistreptolysin O; CT, computed tomography; GBM, glomerular basement membrane; IVP, intravenous pyelography; RBC, red blood cell; UA, urinalysis; VDRL, Venereal Disease Research Laboratory; WBC, white blood cell. hypovolemic, cardiogenic, or septic shock. Oliguria is never nor­ mal, since at least 400 mL of maximally concentrated urine must be produced to excrete the obligate daily osmolar load. Nonoliguria refers to urine output >400 mL/d in patients with acute or chronic azotemia. With nonoliguric ATN, disturbances of potassium and hydrogen balance are less severe than in oliguric patients, and recovery to normal renal function is usually more rapid. ABNORMALITIES OF THE URINE ■ ■PROTEINURIA The evaluation of proteinuria is shown schematically in Fig. 55-3 and typically is initiated after detection of proteinuria by dipstick examina­ tion. The dipstick measurement detects only albumin and gives falsepositive results at pH >7.0 or when the urine is very concentrated or contaminated with blood. Because the dipstick relies on urinary albu­ min concentration, a very dilute urine may obscure significant protein­ uria on dipstick examination. Quantification of urinary albumin on a spot urine sample (ideally from a first morning void) by measurement of an albumin-to-creatinine ratio (ACR) is helpful in approximating a 24-h albumin excretion rate (AER), where ACR (mg/g) ≈ AER (mg/24 h). Furthermore, proteinuria that is not predominantly due to albumin will be missed by dipstick screening. This information is particularly important for the detection of Bence-Jones proteins in the urine of patients with multiple myeloma. Tests to measure total urine protein concentration accurately rely on precipitation with sulfosalicylic or trichloroacetic acid (Fig. 55-3). As with albuminuria, the ratio of

PROTEINURIA ON URINE DIPSTICK Quantify by 24-h urinary excretion of protein and albumin or first morning spot albumin-to-creatinine ratio *Severely increased albuminuria 300–3500 mg/d or 300–3500 mg/g *Moderately increased albuminuria 30–300 mg/d or 30–300 mg/g PART 2 Cardinal Manifestations and Presentation of Diseases RBCs or RBC casts on urinalysis In addition to disorders listed under *moderately increased albuminuria consider Myeloma-associated kidney disease (check UPEP) Intermittent proteinuria Postural proteinuria Congestive heart failure Fever Exercise Consider Early diabetes Essential hypertension Early stages of glomerulonephritis (especially with RBCs, RBC casts) *Moderately and severely increased albuminuria were previously termed “microalbuminuria” and “macroalbuminuria,” respectively. FIGURE 55-3  Approach to the patient with proteinuria. Investigation of proteinuria is often initiated by a positive dipstick on routine urinalysis. Conventional dipsticks detect predominantly albumin and provide a semiquantitative assessment (trace, 1+, 2+, or 3+), which is influenced by urinary concentration as reflected by urine specific gravity (minimum, <1.005; maximum, 1.030). However, more exact determination of proteinuria should employ a spot morning protein/creatinine ratio (mg/g) or a 24-h urine collection (mg/24 h). FSGS, focal segmental glomerulosclerosis; RBC, red blood cell; UPEP, urine protein electrophoresis. protein to creatinine in a random “spot” urine can also provide a rough estimate of protein excretion; for example, a protein/creatinine ratio of 3.0 correlates to ~3.0 g of proteinuria per day. Formal assessment of urinary protein excretion requires a 24-h urine protein collection (see “Assessment of GFR,” above). The magnitude of proteinuria and its composition in the urine depend on the mechanism of renal injury that leads to protein losses. Both charge and size selectivity normally prevent virtually all plasma albumin, globulins, and other high-molecular-weight proteins from crossing the glomerular wall; however, if this barrier is disrupted, plasma proteins may leak into the urine (glomerular proteinuria; Fig. 55-3). Smaller proteins (<20 kDa) are freely filtered but are read­ ily reabsorbed by the proximal tubule. Typically, healthy individuals excrete <150 mg/d of total protein and <30 mg/d of albumin. However, even at albuminuria levels <30 mg/d, risk for progression to overt nephropathy or subsequent cardiovascular disease is increased. The remainder of the protein in the urine is secreted by the tubules (TammHorsfall, IgA, and urokinase) or represents small amounts of filtered β2microglobulin, apoproteins, enzymes, and peptide hormones. Another mechanism of proteinuria entails excessive production of an abnormal protein that exceeds the capacity of the tubule for reabsorption. This situation most commonly occurs with plasma cell dyscrasias, such as multiple myeloma, amyloidosis, and lymphomas, that are associated with monoclonal production of immunoglobulin light chains. Other causes include lysozyme-associated nephropathy, a rare cause of kidney injury in patients with chronic myelomonocytic leukemia (CMML); overproduction of lysozyme results in excessive reabsorption of the enzyme by the proximal tubule, resulting in a severe tubulopathy with intracytoplasmic, membrane-bound vacuoles containing homogenous or granular electron dense material on electron microscopy. The normal glomerular endothelial cell forms a barrier composed of pores of ~100 nm that retain blood cells but offer little impediment to passage of most proteins. The glomerular basement membrane traps most large proteins (>100 kDa), and the foot processes of epithelial cells (podocytes) cover the urinary side of the glomerular basement

membrane and produce a series of nar­ row channels (slit diaphragms) to allow molecular passage of small solutes and water but not proteins. Some glomeru­ lar diseases, such as minimal change disease, cause fusion of glomerular epi­ thelial cell foot processes, resulting in predominantly “selective” (Fig. 55-3) loss of albumin. Other glomerular diseases can present with disruption of the base­ ment membrane and slit diaphragms (e.g., by immune complex deposition), resulting in losses of albumin and other plasma proteins. The fusion of foot pro­ cesses causes increased pressure across the capillary basement membrane, resulting in areas with larger pore sizes (and more severe “nonselective” protein­ uria) (Fig. 55-3). Nephrotic range

3500 mg/d or 3500 mg/g Go to Fig. 55-2 Nephrotic syndrome Diabetes Amyloidosis Minimal change disease FSGS Membranous glomerulopathy IgA nephropathy When the total daily urinary excretion of protein is >3.5 g, hypoalbuminemia, hyperlipidemia, and edema (nephrotic syndrome; Fig. 55-3) are often present as well. However, total daily urinary pro­ tein excretion >3.5 g can occur without the other features of the nephrotic syn­ drome in a variety of other renal diseases, including diabetes (Fig. 55-3). Plasma cell dyscrasias (multiple myeloma) can be associated with large amounts of excreted light chains in the urine, which may not be detected by dipstick. The light chains are filtered by the glomerulus and over­ whelm the reabsorptive capacity of the proximal tubule. Renal failure from these disorders occurs through a variety of mechanisms, including but not limited to proximal tubule injury, tubule obstruction (cast nephropathy), amyloid deposition, and light chain deposition (Chap. 328). The specific renal lesion is dictated by the sequence and structural characteristics of the monoclonal light chain; however, not all excreted light chains are nephrotoxic. Hypoalbuminemia in nephrotic syndrome occurs through excessive urinary losses and increased proximal tubule catabolism of filtered albumin. Edema results from renal sodium retention and reduced plasma oncotic pressure, which favors fluid movement from capillaries to interstitium. To compensate for the perceived decrease in effective intravascular volume, activation of the renin-angiotensin system, stim­ ulation of AVP, and activation of the sympathetic nervous system take place, promoting continued renal salt and water reabsorption and pro­ gressive edema. Filtered proteases, normally retained by the glomerular filtration barrier, can also directly activate sodium reabsorption by the epithelial Na channels in principal cells (ENaC) in nephrotic syndrome. Despite these changes, hypertension is uncommon in primary kidney diseases resulting in the nephrotic syndrome (Fig. 55-3 and Chap. 326). The urinary loss of regulatory proteins and changes in hepatic synthe­ sis contribute to the other manifestations of the nephrotic syndrome. A hypercoagulable state may arise from urinary losses of antithrombin III, reduced serum levels of proteins S and C, hyperfibrinogenemia, and enhanced platelet aggregation. Hypercholesterolemia may be severe and results from increased hepatic lipoprotein synthesis. Loss of immunoglobulins contributes to an increased risk of infection. Many diseases (some listed in Fig. 55-3) and drugs can cause the nephrotic syndrome; a complete list is found in Chap. 326. ■ ■HEMATURIA, PYURIA, AND CASTS Isolated hematuria without proteinuria, other cells, or casts is often indicative of bleeding from the urinary tract. Hematuria is defined as two to five RBCs per high-power field (HPF) and can be detected by dipstick. A false-positive dipstick for hematuria (where no RBCs are seen on urine microscopy) may occur when myoglobinuria is present,

often in the setting of rhabdomyolysis. Common causes of isolated hematuria include stones, neoplasms, tuberculosis, trauma, and pros­ tatitis. Gross hematuria with blood clots usually is not an intrinsic renal process; rather, it suggests a postrenal source in the urinary collecting system. Evaluation of patients presenting with microscopic hematuria is outlined in Fig. 55-2. A single urinalysis with hematuria is common and can result from menstruation, viral illness, allergy, exercise, or mild trauma. Persistent or significant hematuria (>3 RBCs/HPF on three urinalyses, a single urinalysis with >100 RBCs, or gross hematu­ ria) is associated with significant renal or urologic lesions in 9.1% of cases. The level of suspicion for urogenital neoplasms in patients with isolated painless hematuria and nondysmorphic RBCs increases with age. Neoplasms are rare in the pediatric population, and isolated hema­ turia is more likely to be “idiopathic” or associated with a congenital anomaly. Hematuria with pyuria and bacteriuria is typical of infection and should be treated with antibiotics after appropriate cultures. Acute cystitis or urethritis in women can cause gross hematuria. Hypercalci­ uria and hyperuricosuria are also risk factors for unexplained isolated hematuria in both children and adults. In some of these patients (50–60%), reducing calcium and uric acid excretion through dietary interventions can eliminate the microscopic hematuria. Isolated microscopic hematuria can be a manifestation of glo­ merular diseases. The RBCs of glomerular origin are often dysmor­ phic when examined by phase-contrast microscopy. Irregular shapes of RBCs may also result from pH and osmolarity changes produced along the distal nephron. Observer variability in detecting dysmorphic RBCs is common. The most common etiologies of isolated glomerular hematuria are IgA nephropathy, hereditary nephritis, and thin base­ ment membrane disease. IgA nephropathy and hereditary nephritis can lead to episodic gross hematuria. A family history of renal failure is often present in hereditary nephritis, and patients with thin base­ ment membrane disease often have family members with microscopic hematuria. A renal biopsy is needed for the definitive diagnosis of these disorders, which are discussed in more detail in Chap. 326. Hematuria with dysmorphic RBCs, RBC casts, and protein excretion >500 mg/d is virtually diagnostic of glomerulonephritis. RBC casts form as RBCs that enter the tubule fluid and become trapped in a cylindrical mold of gelled Tamm-Horsfall protein. Even in the absence of azotemia, these patients should undergo serologic evaluation and renal biopsy as outlined in Fig. 55-2. Isolated pyuria is unusual since inflammatory reactions in the kidney or collecting system also are associated with hematuria. The presence of bacteria suggests infection, and WBC casts with bacteria are indicative of pyelonephritis; “sterile pyuria” with negative urinary bacterial cultures can be seen in urogenital tuberculosis. WBCs and/or WBC casts also may be seen in acute glomerulonephritis as well as in tubulointerstitial processes such as interstitial nephritis and transplant rejection. Casts can be seen in chronic renal diseases. Degenerated cellular casts called waxy casts or broad casts (arising in the dilated tubules that have undergone compensatory hypertrophy in response to reduced renal mass) may be seen in the urine. ABNORMALITIES OF URINE VOLUME ■ ■POLYURIA By history, it is often difficult for patients to distinguish urinary fre­ quency (often of small volumes) from true polyuria (>3 L/d), and a quantification of volume by 24-h urine collection may be needed (Fig. 55-4). Polyuria results from two potential mechanisms: (1) excre­ tion of nonabsorbable solutes (such as glucose) or (2) excretion of water (usually from a defect in AVP production or renal responsiveness). To distinguish a solute diuresis from a water diuresis and to determine whether the diuresis is appropriate for the clinical circumstances, urine osmolality is measured. The average person excretes between 600 and 800 mosmol of solutes per day, primarily as urea and electrolytes. If the urine output is >3 L/d and the urine is dilute (<250 mosmol/L), total osmolar excretion is normal and a water diuresis is present. This circumstance could arise from polydipsia, inadequate secretion of AVP

POLYURIA (>3 L/24 h) Urine osmolality <250 mosmol

300 mosmol Solute diuresis Glucose, mannitol, radiocontrast, urea (from high protein feeding), medullary cystic diseases, resolving ATN, or obstruction, diuretics Azotemia and Urinary Abnormalities CHAPTER 55 Water deprivation test or ADH level History, low serum sodium Diabetes insipidus (DI) Central DI (vasopressin-sensitive) Posthypophysectomy, trauma, supra- or intrasellar tumor/cyst histiocystosis or granuloma, encroachment by aneurysm, Sheehan’s syndrome, infection, Guillain-Barré, fat embolus, empty sella Primary polydipsia Psychogenic Hypothalamic disease Drugs (thioridazine, chlorpromazine, anticholinergic agents) Nephrogenic DI (vasopressin-insensitive) Acquired tubular diseases: pyelonephritis, analgesic nephropathy, multiple myeloma, amyloidosis, obstruction, sarcoidosis, hypercalcemia, hypokalemia, Sjögren’s syndrome, sickle cell anemia Drugs or toxins: lithium, demeclocycline, methoxyflurane, ethanol, diphenylhydantoin, propoxyphene, amphotericin Congenital: hereditary, polycystic or medullary cystic disease FIGURE 55-4  Approach to the patient with polyuria. ADH, antidiuretic hormone; ATN, acute tubular necrosis. (central diabetes insipidus), or failure of renal tubules to respond to AVP (nephrogenic diabetes insipidus). If the urine volume is >3 L/d and urine osmolality is >300 mosmol/L, a solute diuresis is clearly present and a search for the responsible solute(s) is mandatory. Excessive filtration of a poorly reabsorbed solute such as glucose or mannitol can depress reabsorption of NaCl and water in the proximal tubule and lead to enhanced excretion in the urine. Poorly controlled diabetes mellitus with glucosuria is the most common cause of a sol­ ute diuresis, leading to volume depletion and serum hypertonicity. Since the urine sodium concentration is less than that of blood, more water than sodium is lost, causing hypernatremia and hypertonicity. Common iatrogenic solute diuresis occurs in association with man­ nitol administration, radiocontrast media, and high-protein feedings (enteral or parenteral), leading to increased urea production and excretion. Less commonly, excessive sodium loss may result from cystic renal diseases or Bartter’s syndrome or may develop during a tubulointerstitial process (such as resolving ATN). In these so-called salt-wasting disorders, the tubule damage results in direct impairment of sodium reabsorption and indirectly reduces the responsiveness of the tubule to aldosterone. Usually, the sodium losses are mild, and the obligatory urine output is <2 L/d; resolving ATN and postobstructive diuresis are exceptions and may be associated with significant natri­ uresis and polyuria. Formation of large volumes of dilute urine is usually due to poly­ dipsic states or diabetes insipidus. Primary polydipsia can result from habit, psychiatric disorders, neurologic lesions, or medications. During

50 - 56 Fluid and Electrolyte Disturbances

56 Fluid and Electrolyte Disturbances

deliberate polydipsia, extracellular fluid volume is normal or expanded and plasma AVP levels are reduced because serum osmolality tends to be near the lower limits of normal. Urine osmolality is also maximally dilute at 50 mosmol/L.

Central diabetes insipidus may be idiopathic in origin or secondary to a variety of conditions, including hypophysectomy, trauma, neoplas­ tic, inflammatory, vascular, or infectious hypothalamic diseases. Idio­ pathic central diabetes insipidus is associated with selective destruction of the AVP-secreting neurons in the supraoptic and paraventricular nuclei and can either be inherited as an autosomal dominant trait or occur spontaneously. Nephrogenic diabetes insipidus can occur in a variety of clinical situations, as summarized in Fig. 55-4. PART 2 Cardinal Manifestations and Presentation of Diseases A plasma AVP level is recommended as the best method for distin­ guishing between central and nephrogenic diabetes insipidus. Assays for circulating copeptin, a peptide that is cleaved from pre-pro-AVP during axonal transport in the posterior pituitary, are also now avail­ able in many centers. A water deprivation test plus exogenous desmo­ pressin (DDAVP) may distinguish primary polydipsia from central and nephrogenic diabetes insipidus. Measurement of hypertonic saline–stimulated plasma copeptin, if available, can substitute for water deprivation testing. For a detailed discussion, see Chap. 393. Acknowledgment Julie Lin and Brad Denker contributed to this chapter in the 19th edition and some material from that chapter has been retained here. ■ ■FURTHER READING Emmett M et al: Approach to the patient with kidney disease, in Brenner and Rector’s The Kidney, 10th ed, K Skorecki et al (eds). Philadelphia, W.B. Saunders & Company, 2016, pp. 754–779. Eneanya ND et al: Reconsidering the consequences of using race to estimate kidney function. JAMA 322:113, 2019. Köhler H et al: Acanthocyturia—a characteristic marker for glomerular bleeding. Kidney Int 40:115, 1991. Inker LA et al: New creatinine- and cystatin C-based equations to estimate GFR without race. N Engl J Med 385:1737, 2021. Perazella MA: The urine sediment as a biomarker of kidney disease. Am J Kidney Dis 66:748, 2015. Weisord SD et al: Prevention and management of acute kidney injury in Brenner and Rector’s The Kidney, 11th ed, ASL Yu et al (eds). Philadelphia, W.B. Saunders & Company, 2020, pp. 940–977. David B. Mount

Fluid and Electrolyte Disturbances SODIUM AND WATER ■ ■COMPOSITION OF BODY FLUIDS Water is the most abundant constituent in the body, comprising ~50% of body weight in women and 60% in men. Total-body water is distrib­ uted in two major compartments: 55–75% is intracellular (intracellular fluid [ICF]), and 25–45% is extracellular (extracellular fluid [ECF]). The ECF is further subdivided into intravascular (plasma water) and extravascular (interstitial) spaces in a ratio of 1:3. Fluid movement between the intravascular and interstitial spaces occurs across the cap­ illary wall and is determined by Starling forces, i.e., capillary hydraulic pressure and colloid osmotic pressure. The transcapillary hydraulic pressure gradient exceeds the corresponding oncotic pressure gradient,

thereby favoring the movement of plasma ultrafiltrate into the extra­ vascular space. The return of fluid into the intravascular compartment occurs via lymphatic flow. The solute or particle concentration of a fluid is known as its osmo­ lality, expressed as milliosmoles per kilogram of water (mOsm/kg). Water easily diffuses across most cell membranes to achieve osmotic equilibrium (ECF osmolality = ICF osmolality). Notably, the extracel­ lular and intracellular solute compositions differ considerably owing to the activity of various transporters, channels, and ATP-driven mem­ brane pumps. The major ECF particles are Na+ and its accompanying anions Cl– and HCO3 –, whereas K+ and organic phosphate esters (ATP, creatine phosphate, and phospholipids) are the predominant ICF osmoles. Solutes that are restricted to the ECF or the ICF determine the “tonicity” or effective osmolality of that compartment. Certain solutes, particularly urea, do not contribute to water shifts across most membranes and are thus known as ineffective osmoles. Water Balance  Vasopressin secretion, water ingestion, and renal water transport collaborate to maintain human body fluid osmolality between 280 and 295 mOsm/kg. Vasopressin (AVP) is synthesized in magnocellular neurons within the hypothalamus; the distal axons of these neurons project to the posterior pituitary or neurohypophy­ sis, from which AVP is released into the circulation. A network of central “osmoreceptor” neurons, which includes the AVP-expressing magnocellular neurons themselves, sense circulating osmolality via nonselective, stretch-activated cation channels. These osmoreceptor neurons are activated or inhibited by modest increases and decreases in circulating osmolality, respectively; activation leads to AVP release and thirst. AVP secretion is stimulated as systemic osmolality increases above a threshold level of ~285 mOsm/kg, above which there is a linear relation­ ship between osmolality and circulating AVP (Fig. 56-1). Thirst and thus water ingestion are also activated at ~285 mOsm/kg, beyond which there is an equivalent linear increase in the perceived intensity of thirst as a function of circulating osmolality. Changes in blood volume and blood pressure are also direct stimuli for AVP release and thirst, albeit with a less sensitive response profile. Of perhaps greater clinical relevance to the pathophysiology of water homeostasis, ECF volume strongly modulates the relationship between circulating osmolality and AVP release, such that hypovolemia reduces the osmotic threshold and increases the slope of the response curve to osmolality; hypervolemia has an opposite effect, increasing the osmotic threshold and reducing the slope of the response curve (Fig. 56-1). Notably, AVP has a half-life in the circulation of only 10–20 min; thus, changes in ECF volume and/or circulating osmolality can rapidly affect water homeostasis. In addition to volume status, a number of other “nonosmotic” stimuli have potent activating effects on

Hypovolemic Euvolemic Plasma AVP (pg/mL)

Hypervolemic

Plasma osmolality (mOsm/kg) FIGURE 56-1  Circulating levels of vasopressin (AVP) in response to changes in osmolality. Plasma AVP becomes detectable in euvolemic, healthy individuals at a threshold of ~285 mOsm/kg, above which there is a linear relationship between osmolality and circulating AVP. The AVP response to osmolality is modulated strongly by volume status. The osmotic threshold is thus slightly lower in hypovolemia, with a steeper response curve; hypervolemia reduces the sensitivity of circulating AVP levels to osmolality.

osmosensitive neurons and AVP release, including nausea, intracerebral angiotensin II, serotonin, and multiple drugs. The excretion or retention of electrolyte-free water by the kidney is modulated by circulating AVP. AVP acts on renal, V2-type receptors in the thick ascending limb of Henle and principal cells of the collecting duct (CD), increasing intracellular levels of cyclic AMP and activating protein kinase A (PKA)–dependent phosphorylation of multiple trans­ port proteins. The AVP- and PKA-dependent activation of Na+-Cl– and K+ transport by the thick ascending limb of the loop of Henle (TALH) is a key participant in the countercurrent mechanism (Fig. 56-2). The countercurrent mechanism ultimately increases the interstitial osmo­ lality in the inner medulla of the kidney, driving water absorption across the renal CD. However, water, salt, and solute transport by both proximal and distal nephron segments participates in the renal con­ centrating mechanism (Fig. 56-2). Water transport across apical and basolateral aquaporin-1 water channels in the descending thin limb of the loop of Henle is thus involved, as is passive absorption of Na+-Cl– by the thin ascending limb, via apical and basolateral CLC-K1 chloride channels and paracellular Na+ transport. Renal urea transport in turn plays important roles in the generation of the medullary osmotic gradi­ ent and the ability to excrete solute-free water under conditions of both high and low protein intake (Fig. 56-2). AVP-induced, PKA-dependent phosphorylation of the aquaporin-2 water channel in principal cells stimulates the insertion of active water channels into the lumen of the CD, resulting in transepithelial water absorption down the medullary osmotic gradient (Fig. 56-3). Under “antidiuretic” conditions, with increased circulating AVP, the kidney reabsorbs water filtered by the glomerulus, equilibrating the osmolality across the CD epithelium to excrete a hypertonic, “concentrated” urine (osmolality of up to 1200 mOsm/kg). In the absence of circulating AVP, insertion of aquaporin-2 channels and water absorption across the CD is essentially abolished, resulting in secretion of a hypotonic, dilute urine (osmolality as low as 30–50 mOsm/kg). Abnormalities in this “final com­ mon pathway” are involved in most disorders of water homeostasis, e.g., a reduced or absent insertion of active aquaporin-2 water channels into the membrane of principal cells in diabetes insipidus (DI). Maintenance of Arterial Circulatory Integrity  Sodium is actively pumped out of cells by the Na+/K+-ATPase membrane pump. In consequence, 85–90% of body Na+ is extracellular, and the ECF NCC Cl– Na+ NaCI Cortex K+ AQP1 ROMK Na+ Outer Medulla H2O K+ 2Cl– NKCC2 AQP1 Descending Vasa Recta: AQP1, UT-B H2O UT-A2 Inner Medulla CIC-K1 CI– Na+ AQP1 H2O Urea Urea UT-A1 and UT-A3 NaCI FIGURE 56-2  The renal concentrating mechanism. Water, salt, and solute transport by both proximal and distal nephron segments participates in the renal concentrating mechanism (see text for details). Diagram showing the location of the major transport proteins involved; a loop of Henle is depicted on the left, collecting duct on the right. AQP, aquaporin; CLC-K1, chloride channel; NKCC2, Na-K-2Cl cotransporter; ROMK, renal outer medullary K+ channel; UT, urea transporter. (Reproduced with permission from JM Sands: Molecular approaches to urea transporters. J Am Soc Nephro 13(11):2795, 2002.)

Medullary Interstitium (Vasa Recta or Blood Side) Collecting duct principal cell Tubule Lumen (Urine) AQP2 AQP3/ AQP4 PKA pAQP2 H2O Fluid and Electrolyte Disturbances CHAPTER 56 cAMP V2R AC Vasopressin, also called antidiuretic hormone (ADH) FIGURE 56-3  Vasopressin and the regulation of water permeability in the renal collecting duct. Vasopressin binds to the type 2 vasopressin receptor (V2R) on the basolateral membrane of principal cells, activates adenylyl cyclase (AC), increases intracellular cyclic adenosine monophosphatase (cAMP), and stimulates protein kinase A (PKA) activity. Cytoplasmic vesicles carrying aquaporin-2 (AQP) water channel proteins are inserted into the luminal membrane in response to vasopressin, thereby increasing the water permeability of this membrane. When vasopressin stimulation ends, water channels are retrieved by an endocytic process and water permeability returns to its low basal rate. The AQP3 and AQP4 water channels are expressed on the basolateral membrane and complete the transcellular pathway for water reabsorption. pAQP2, phosphorylated aquaporin-2. (From Annals of Internal Medicine JM Sands, DG Bichet: Nephrogenic diabetes insipidus. 144:186, 2006. Copyright © 2006 American College of Physicians. All Rights Reserved. Reprinted with the permission of American College of Physicians, Inc.) volume (ECFV) is a function of total-body Na+ content. Arterial perfusion and circulatory integrity are, in turn, determined by renal Na+ retention or excretion, in addition to the modulation of systemic arterial resistance. Within the kidney, Na+ is filtered by the glomeruli and then sequentially reabsorbed by the renal tubules. The Na+ cation is typically reabsorbed with the chloride anion (Cl–), and thus, chloride homeostasis also affects the ECFV. On a quantitative level, at a glo­ merular filtration rate (GFR) of 180 L/d and serum Na+ of ~140 mM, the kidney filters some 25,200 mmol/d of Na+. This is equivalent to ~1.5 kg of salt, which would occupy roughly 10 times the extracellular space; 99.6% of filtered Na+-Cl– must be reabsorbed to excrete 100 mM per day. Minute changes in renal Na+-Cl– excretion will thus have significant effects on the ECFV, leading to edema syn­ dromes or hypovolemia. AQP2,3 H2O Urea Cortex Approximately two-thirds of filtered Na+-Cl– is reab­ sorbed by the renal proximal tubule, via both paracellular and transcellular mechanisms. The TALH subsequently reabsorbs another 25–30% of filtered Na+-Cl– via the apical, furosemide-sensitive Na+-K+-2Cl– cotransporter. The adjacent aldosterone-sensitive distal nephron, com­ prising the distal convoluted tubule (DCT), connecting tubule (CNT), and CD, accomplishes the “fine-tuning” of renal Na+-Cl– excretion. The thiazide-sensitive api­ cal Na+-Cl– cotransporter (NCC) reabsorbs 5–10% of filtered Na+-Cl– in the DCT. Principal cells in the CNT and CD reabsorb Na+ via electrogenic, amiloride-sensitive epithelial Na+ channels (ENaC); Cl– ions are primarily reabsorbed by adjacent intercalated cells, via apical Cl– exchange (Cl–-OH– and Cl–-HCO3 AQP2,3 H2O Urea AQP2–4 H2O Urea AQP2–4 H2O – exchange, mediated by the SLC26A4 anion exchanger) (Fig. 56-4). Renal tubular reabsorption of filtered Na+-Cl– is regu­ lated by multiple circulating and paracrine hormones, in addition to the activity of renal nerves. Angiotensin II activates proximal Na+-Cl– reabsorption, as do adrener­ gic receptors under the influence of renal sympathetic

H+ ATP H+-ATPase HCO3 – Cl– SLC26A4 CLC-KB Cl– Cl– B-IC PART 2 Cardinal Manifestations and Presentation of Diseases Na+ ATP 3Na+ ENaC Na+ (–) 2K+ BK ROMK K+ K+ AQP-3,4 AQP-2 H2O H2O PC Interstitium Lumen FIGURE 56-4  Sodium, water, and potassium transport in principal cells (PC) and adjacent `-intercalated cells (B-IC). The absorption of Na+ via the amiloridesensitive epithelial sodium channel (ENaC) generates a lumen-negative potential difference, which drives K+ excretion through the apical secretory K+ channel ROMK (renal outer medullary K+ channel) and/or the flow-dependent BK channel. Transepithelial Cl– transport occurs in adjacent β-intercalated cells, via apical Cl–- HCO3 – and Cl–-OH– exchange (SLC26A4 anion exchanger, also known as pendrin) basolateral CLC chloride channels. Water is absorbed down the osmotic gradient by principal cells, through the apical aquaporin-2 (AQP-2) and basolateral aquaporin-3 and aquaporin-4 (Fig. 56-3). innervation; locally generated dopamine, in contrast, has a natriuretic effect. Aldosterone primarily activates Na+-Cl– reabsorption within the aldosterone-sensitive distal nephron. In particular, aldosterone activates the ENaC channel in principal cells, inducing Na+ absorption and promoting K+ excretion (Fig. 56-4). Circulatory integrity is critical for the perfusion and function of vital organs. “Underfilling” of the arterial circulation is sensed by ventricular and vascular pressure receptors, resulting in a neurohumoral activa­ tion (increased sympathetic tone, activation of the renin-angiotensin-

aldosterone axis, and increased circulating AVP) that synergistically increases renal Na+-Cl– reabsorption, vascular resistance, and renal water reabsorption. This occurs in the context of decreased cardiac output, as occurs in hypovolemic states, low-output cardiac failure, decreased oncotic pressure, and/or increased capillary permeability. Alternatively, excessive arterial vasodilation results in relative arte­ rial underfilling, leading to neurohumoral activation in the defense of tissue perfusion. These physiologic responses play important roles in many of the disorders discussed in this chapter. In particular, it is important to appreciate that AVP functions in the defense of circu­ latory integrity, inducing vasoconstriction, increasing sympathetic nervous system tone, increasing renal retention of both water and Na+-Cl–, and modulating the arterial baroreceptor reflex. Most of these responses involve activation of systemic V1A AVP receptors, but concomitant activation of V2 receptors in the kidney can result in renal water retention and hyponatremia. ■ ■HYPOVOLEMIA Etiology  True volume depletion, or hypovolemia, generally refers to a state of combined salt and water loss, leading to contraction of the ECFV. The loss of salt and water may be renal or nonrenal in origin.

RENAL CAUSES  Excessive urinary Na+-Cl– and water loss is a feature of several conditions. A high filtered load of endogenous solutes, such as glucose and urea, can impair tubular reabsorption of Na+-Cl– and water, leading to an osmotic diuresis. Exogenous mannitol, often used to decrease intracerebral pressure, is filtered by glomeruli but not reab­ sorbed by the proximal tubule, thus causing an osmotic diuresis. Phar­ macologic diuretics selectively impair Na+-Cl– reabsorption at specific sites along the nephron, leading to increased urinary Na+-Cl– excre­ tion. Other drugs can induce natriuresis as a side effect. For example, acetazolamide can inhibit proximal tubular Na+-Cl– absorption via its inhibition of carbonic anhydrase; other drugs, such as the antibiot­ ics trimethoprim (TMP) and pentamidine, inhibit distal tubular Na+ reabsorption through the amiloride-sensitive ENaC channel, leading to urinary Na+-Cl– loss. Hereditary defects in renal transport proteins are also associated with reduced reabsorption of filtered Na+-Cl– and/or water. Alternatively, mineralocorticoid deficiency, mineralocorticoid resistance, or inhibition of the mineralocorticoid receptor (MLR) can reduce Na+-Cl– reabsorption by the aldosterone-sensitive distal neph­ ron. Finally, tubulointerstitial injury, as occurs in interstitial nephritis, acute tubular injury, or obstructive uropathy, can reduce distal tubular Na+-Cl– and/or water absorption. Excessive excretion of free water, i.e., water without electrolytes, can also lead to hypovolemia. However, the effect on ECFV is usually less marked, given that two-thirds of the water volume is lost from the ICF. Excessive renal water excretion occurs in the setting of decreased circulating AVP or renal resistance to AVP (central and nephrogenic DI, respectively). EXTRARENAL CAUSES  Nonrenal causes of hypovolemia include fluid loss from the gastrointestinal tract, skin, and respiratory system. Accumulations of fluid within specific tissue compartments, typically the interstitium, peritoneum, or gastrointestinal tract, can also cause hypovolemia. Approximately 9 L of fluid enter the gastrointestinal tract daily, 2 L by ingestion and 7 L by secretion; almost 98% of this volume is absorbed, such that daily fecal fluid loss is only 100–200 mL. Impaired gastrointestinal reabsorption or enhanced secretion of fluid can cause hypovolemia. Because gastric secretions have a low pH (high H+ con­ centration), whereas biliary, pancreatic, and intestinal secretions are alkaline (high HCO3 – concentration), vomiting and diarrhea are often accompanied by metabolic alkalosis and acidosis, respectively. Evaporation of water from the skin and respiratory tract (so-called “insensible losses”) constitutes the major route for loss of solute-free water, which is typically 500–650 mL/d in healthy adults. This evapora­ tive loss can increase during febrile illness or prolonged heat exposure. Hyperventilation can also increase insensible losses via the respiratory tract, particularly in ventilated patients; the humidity of inspired air is another determining factor. In addition, increased exertion and/or ambient temperature will increase insensible losses via sweat, which is hypotonic to plasma. Profuse sweating without adequate repletion of water and Na+-Cl– can thus lead to both hypovolemia and hypertonicity. Alternatively, replacement of these insensible losses with a surfeit of free water, without adequate replacement of electrolytes, may lead to hypovolemic hyponatremia. Excessive fluid accumulation in interstitial and/or peritoneal spaces can also cause intravascular hypovolemia. Increases in vascular per­ meability and/or a reduction in oncotic pressure (hypoalbuminemia) alter Starling forces, resulting in excessive “third spacing” of the ECFV. This occurs in sepsis syndrome, burns, pancreatitis, nutritional hypo­ albuminemia, and peritonitis. Alternatively, distributive hypovolemia can occur due to accumulation of fluid within specific compartments, for example, within the bowel lumen in gastrointestinal obstruction or ileus. Hypovolemia can also occur after extracorporeal hemorrhage or after significant hemorrhage into an expandable space, for example, the retroperitoneum. Diagnostic Evaluation  A careful history will usually determine the etiologic cause of hypovolemia. Symptoms of hypovolemia are non­ specific and include fatigue, weakness, thirst, and postural dizziness; more severe symptoms and signs include oliguria, cyanosis, abdominal

and chest pain, and confusion or obtundation. Associated electrolyte disorders may cause additional symptoms, for example, muscle weak­ ness in patients with hypokalemia. On examination, diminished skin turgor and dry oral mucous membranes are less than ideal markers of a decreased ECFV in adult patients; more reliable signs of hypovo­ lemia include a decreased jugular venous pressure (JVP), orthostatic tachycardia (an increase of >15–20 beats/min upon standing), and orthostatic hypotension (a >10–20 mmHg drop in blood pressure on standing). More severe fluid loss leads to hypovolemic shock, with hypotension, tachycardia, peripheral vasoconstriction, and peripheral hypoperfusion; these patients may exhibit peripheral cyanosis, cold extremities, oliguria, and altered mental status. Routine chemistries may reveal an increase in blood urea nitrogen (BUN) and creatinine, reflective of a decrease in GFR. Creatinine is the more dependable measure of GFR, because BUN levels may be influ­ enced by an increase in tubular reabsorption (“prerenal azotemia”), an increase in urea generation in catabolic states, hyperalimentation, or gastrointestinal bleeding, and/or a decreased urea generation in decreased protein intake. In hypovolemic shock, liver function tests and cardiac biomarkers may show evidence of hepatic and cardiac ischemia, respectively. Routine chemistries and/or blood gases may reveal evidence of acid-base disorders. For example, bicarbonate loss due to diarrheal illness is a very common cause of metabolic acidosis; alternatively, patients with severe hypovolemic shock may develop lac­ tic acidosis with an elevated anion gap. The neurohumoral response to hypovolemia stimulates an increase in renal tubular Na+ and water reabsorption. Therefore, the urine Na+ concentration is typically <20 mM in nonrenal causes of hypovole­ mia, with a urine osmolality of >450 mOsm/kg. The reduction in both GFR and distal tubular Na+ delivery may cause a defect in renal potassium excretion, with an increase in plasma K+ concentration. Of note, patients with hypovolemia and a hypochloremic alkalosis due to vomiting, diarrhea, or diuretics will typically have a urine Na+ concen­ tration >20 mM and urine pH of >7.0, due to the increase in filtered HCO3 –; the urine Cl– concentration in this setting is a more accurate indicator of volume status, with a level <25 mM suggestive of hypovo­ lemia. The urine Na+ concentration is often >20 mM in patients with renal causes of hypovolemia, such as acute tubular necrosis; similarly, patients with DI will have an inappropriately dilute urine. TREATMENT Hypovolemia The therapeutic goals in hypovolemia are to restore normovole­ mia and replace ongoing fluid losses. Mild hypovolemia can usu­ ally be treated with oral hydration and resumption of a normal maintenance diet. More severe hypovolemia requires intravenous hydration, tailoring the choice of solution to the underlying patho­ physiology. Isotonic, “normal” saline (0.9% NaCl, 154 mM Na+) is the most appropriate resuscitation fluid for normonatremic or hyponatremic patients with severe hypovolemia; colloid solutions such as intravenous albumin are not demonstrably superior for this purpose. Hypernatremic patients should receive a hypotonic solution, 5% dextrose if there has only been water loss (as in DI), or hypotonic saline (1/2 or 1/4 normal saline) if there has been water and Na+-Cl– loss; changes in free water administration should be made if necessary, based on frequent measuring of serum chemis­ tries. Patients with bicarbonate loss and metabolic acidosis, as occur frequently in diarrhea, should receive intravenous bicarbonate, either an isotonic solution (150 meq of Na+-HCO3 – in 5% dextrose) or a more hypotonic bicarbonate solution in dextrose or dilute saline. Patients with severe hemorrhage or anemia should receive red cell transfusions, without increasing the hematocrit beyond 35%. SODIUM DISORDERS Disorders of serum Na+ concentration are caused by abnormalities in water homeostasis, leading to changes in the relative ratio of Na+ to body water. Water intake and circulating AVP constitute the two key

effectors in the defense of serum osmolality; defects in one or both of these two defense mechanisms cause most cases of hyponatremia and hypernatremia. In contrast, abnormalities in sodium homeostasis per se lead to a deficit or surplus of whole-body Na+-Cl– content, a key determinant of the ECFV and circulatory integrity. Notably, volume status also modulates the release of AVP by the posterior pituitary, such that hypovolemia is associated with higher circulating levels of the hormone at each level of serum osmolality. Similarly, in “hypervol­ emic” causes of arterial underfilling, e.g., heart failure and cirrhosis, the associated neurohumoral activation encompasses an increase in circu­ lating AVP, leading to water retention and hyponatremia. Therefore, a key concept in sodium disorders is that the absolute plasma Na+ con­ centration tells one nothing about the volume status of a given patient, which furthermore must be taken into account in the diagnostic and therapeutic approach.

Fluid and Electrolyte Disturbances CHAPTER 56 ■ ■HYPONATREMIA Hyponatremia, which is defined as a plasma Na+ concentration <135 mM, is a very common disorder, occurring in up to 22% of hospitalized patients. This disorder is almost always the result of an increase in circulating AVP and/or increased renal sensitivity to AVP, combined with an intake of free water; a notable exception is hyponatremia due to low solute intake (see below). The underlying pathophysiology for the exaggerated or “inappropriate” AVP response differs in patients with hyponatremia as a function of their ECFV. Hyponatremia is thus subdivided diagnostically into three groups, depending on clinical his­ tory and volume status, i.e., “hypovolemic,” “euvolemic,” and “hyper­ volemic” (Fig. 56-5). Hypovolemic Hyponatremia  Hypovolemia causes a marked neu­ rohumoral activation, increasing circulating levels of AVP. The increase in circulating AVP helps preserve blood pressure via vascular and baroreceptor V1A receptors and increases water reabsorption via renal V2 receptors; activation of V2 receptors can lead to hyponatremia in the setting of increased free water intake. Nonrenal causes of hypovolemic hyponatremia include gastrointestinal loss (e.g., vomiting, diarrhea, tube drainage) and insensible loss (sweating, burns) of Na+-Cl– and water, in the absence of adequate oral replacement; urine Na+ concentration is typically <20 mM. Notably, these patients may be clinically classified as euvolemic, with only the reduced urinary Na+ concentration to indicate the cause of their hyponatremia. Indeed, a urine Na+ concentra­ tion <20 mM, in the absence of a cause of hypervolemic hyponatremia, predicts a rapid increase in plasma Na+ concentration in response to intravenous normal saline; saline therapy thus induces a water diuresis in this setting, as circulating AVP levels plummet. The renal causes of hypovolemic hyponatremia share an inappro­ priate loss of Na+-Cl– in the urine, leading to volume depletion and an increase in circulating AVP; urine Na+ concentration is typically >20 mM (Fig. 56-5). A deficiency in circulating aldosterone and/or its renal effects can lead to hyponatremia in primary adrenal insufficiency and other causes of hypoaldosteronism; hyperkalemia and hyponatremia in a hypotensive and/or hypovolemic patient with high urine Na+ concentration (much greater than 20 mM) should strongly suggest this diagnosis. Salt-losing nephropathies may lead to hyponatremia when sodium intake is reduced, due to impaired renal tubular function; typical causes include reflux nephropathy, interstitial nephropathies, postobstructive uropathy, medullary cystic disease, and the recovery phase of acute tubular necrosis. Thiazide diuretics cause hyponatre­ mia via a number of mechanisms, including polydipsia and diuretic-

induced volume depletion; presentations can mimic the syndrome of inappropriate antidiuresis (SIAD). Notably, thiazides do not inhibit the renal concentrating mechanism, such that circulating AVP retains a full effect on renal water retention. In contrast, loop diuretics, which are less frequently associated with hyponatremia, inhibit Na+-Cl– and K+ absorption by the TALH, blunting the countercurrent mechanism and reducing the ability to concentrate the urine. Increased excretion of an osmotically active nonreabsorbable or poorly reabsorbable sol­ ute can also lead to volume depletion and hyponatremia; important causes include glycosuria, ketonuria (e.g., in starvation or in diabetic

Assessment of volume status Hypovolemia • Total body water ↓ • Total body sodium ↓↓ Euvolemia (no edema) • Total body water ↑ • Total body sodium ←→ UNa >20 UNa <20 UNa >20 UNa >20 UNa <20 PART 2 Cardinal Manifestations and Presentation of Diseases Renal losses Diuretic excess Mineral corticoid deficiency Salt-losing deficiency Bicarbonaturia with renal tubal acidosis and metabolic alkalosis Ketonuria Osmotic diuresis Cerebral salt wasting syndrome Glucocorticoid deficiency Hypothyroidism Stress Drugs Syndrome of inappropriate antidiuretic hormone secretion Extrarenal losses Vomiting Diarrhea Third spacing of fluids Burns Pancreatitis Trauma FIGURE 56-5  The diagnostic approach to hyponatremia. (Reproduced with permission from S Kumar, T Berl: Diseases of water metabolism, in RW Schrier [ed], Atlas of Diseases of the Kidney, Philadelphia, Current Medicine, Inc, 1999.) or alcoholic ketoacidosis), and bicarbonaturia (e.g., in renal tubular acidosis or metabolic alkalosis, where the associated bicarbonaturia leads to loss of Na+). Finally, the syndrome of “cerebral salt wasting” is a rare cause of hypovolemic hyponatremia, encompassing hyponatremia with clinical hypovolemia and inappropriate natriuresis in association with intracranial disease; associated disorders include subarachnoid hemorrhage, traumatic brain injury, craniotomy, encephalitis, and meningitis. Distinction from the more common syndrome SIAD is critical because cerebral salt wasting will typically respond to aggres­ sive Na+-Cl– repletion. Hypervolemic Hyponatremia  Patients with hypervolemic hypo­ natremia develop an increase in total-body Na+-Cl– that is accompa­ nied by a proportionately greater increase in total-body water, leading to a reduced plasma Na+ concentration. As in hypovolemic hyponatre­ mia, the causative disorders can be separated by the effect on urine Na+ concentration, with acute or chronic renal failure uniquely associated with an increase in urine Na+ concentration (Fig. 56-5). The patho­ physiology of hyponatremia in the sodium-avid edematous disorders (congestive heart failure [CHF], cirrhosis, and nephrotic syndrome) is similar to that in hypovolemic hyponatremia, except that arterial fill­ ing and circulatory integrity is decreased due to the specific etiologic factors (e.g., cardiac dysfunction in CHF, peripheral vasodilation in cirrhosis). Urine Na+ concentration is typically very low, i.e., <10 mM, even after hydration with normal saline; this Na+-avid state may be obscured by diuretic therapy. The degree of hyponatremia provides an indirect index of the associated neurohumoral activation and is an important prognostic indicator in hypervolemic hyponatremia. Euvolemic Hyponatremia  Euvolemic hyponatremia can occur in moderate to severe hypothyroidism, with correction after achiev­ ing a euthyroid state. Severe hyponatremia can also be a consequence of secondary adrenal insufficiency due to pituitary disease; whereas the deficit in circulating aldosterone in primary adrenal insufficiency causes hypovolemic hyponatremia, the predominant glucocorticoid deficiency in secondary adrenal failure is associated with euvolemic hyponatremia. Glucocorticoids exert a negative feedback on AVP release by the posterior pituitary such that hydrocortisone replacement in these patients can rapidly normalize the AVP response to osmolality, reducing circulating AVP. SIAD is the most frequent cause of euvolemic hyponatremia (Table 56-1). The generation of hyponatremia in SIAD requires an

Hypervolemia • Total body water ↑↑ • Total body sodium ↑ Nephrotic syndrome Cirrhosis Cardiac failure Acute or chronic renal failure intake of free water, with persistent intake at serum osmolalities that are lower than the usual threshold for thirst; as one would expect, the osmotic threshold and osmotic response curves for the sensation of thirst are shifted downward in patients with SIAD. Four distinct patterns of AVP secretion have been recognized in patients with SIAD, independent for the most part of the underlying cause. Unregulated, erratic AVP secretion is seen in about a third of patients, with no obvious correlation between serum osmolality and circulating AVP levels. Other patients fail to suppress AVP secretion at lower serum osmolalities, with a nor­ mal response curve to hyperosmolar conditions; others have a “reset osmostat,” with a lower threshold osmolality and a left-shifted osmotic response curve. Finally, the fourth subset of patients have essentially no detectable circulating AVP, suggesting either a gain in function in renal water reabsorption or a circulating antidiuretic substance that is distinct from AVP. Gain-in-function mutations of a single specific residue in the V2 AVP receptor have been described in some of these patients, lead­ ing to constitutive activation of the receptor in the absence of AVP and “nephrogenic” SIAD. Strictly speaking, patients with SIAD are not euvolemic but are sub­ clinically volume-expanded, due to AVP-induced water and Na+-Cl– retention; “AVP escape” mechanisms invoked by sustained increases in AVP serve to limit distal renal tubular transport, preserving a modestly hypervolemic steady state. Serum uric acid is often low (<4 mg/dL) in patients with SIAD, consistent with suppressed proximal tubular transport in the setting of increased distal tubular Na+-Cl– and water transport; in contrast, patients with hypovolemic hyponatremia will often be hyperuricemic due to a shared activation of proximal tubular Na+-Cl– and urate transport. Common causes of SIAD include pulmonary disease (e.g., pneumo­ nia, tuberculosis, pleural effusion) and central nervous system (CNS) diseases (e.g., tumor, subarachnoid hemorrhage, meningitis). SIAD also occurs with malignancies, most commonly with small-cell lung carcinoma (75% of malignancy-associated SIAD); ~10% of patients with this tumor will have a plasma Na+ concentration of <130 mM at presentation. SIAD is also a frequent complication of certain drugs, most commonly the selective serotonin reuptake inhibitors (SSRIs). Other drugs can potentiate the renal effect of AVP, without exerting direct effects on circulating AVP levels (Table 56-1). Low Solute Intake and Hyponatremia  Hyponatremia can occasionally occur in patients with a very low intake of dietary solutes. Classically, this occurs in alcoholics whose sole nutrient is beer, hence

TABLE 56-1  Causes of the Syndrome of Inappropriate Antidiuresis (SIAD) MALIGNANT DISEASES PULMONARY DISORDERS DISORDERS OF THE CENTRAL NERVOUS SYSTEM DRUGS OTHER CAUSES Carcinoma Lung   Small cell   Mesothelioma Oropharynx Gastrointestinal tract   Stomach   Duodenum   Pancreas Genitourinary tract   Ureter   Bladder   Prostate   Endometrium Endocrine thymoma Lymphomas Sarcomas   Ewing’s sarcoma Infections Bacterial pneumonia Viral pneumonia Pulmonary abscess Tuberculosis Aspergillosis Asthma Cystic fibrosis Respiratory failure associated with positive-pressure breathing Infection Encephalitis Meningitis Brain abscess Rocky Mountain spotted fever AIDS Bleeding and masses   Subdural hematoma   Subarachnoid hemorrhage   Cerebrovascular accident   Brain tumors   Head trauma   Hydrocephalus   Cavernous sinus thrombosis Other   Multiple sclerosis   Guillain-Barré syndrome   Shy-Drager syndrome   Delirium tremens   Acute intermittent porphyria Abbreviations: AVP, vasopressin; MDMA; 3,4-methylenedioxymethamphetamine; SSRI, selective serotonin reuptake inhibitor. Source: From DH Ellison, T Berl: The syndrome of inappropriate antidiuresis. N Engl J Med 356:2064, 2007. Copyright © 2007 Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. the diagnostic label of beer potomania; beer is very low in protein and salt content, containing only 1–2 mM of Na+. The syndrome has also been described in nonalcoholic patients with highly restricted solute intake due to nutrient-restricted diets, e.g., extreme vegetarian diets. Patients with hyponatremia due to low solute intake typically present with a very low urine osmolality (<100–200 mOsm/kg) with a urine Na+ concentration that is <10–20 mM. The fundamental abnormality is the inadequate dietary intake of solutes; the reduced urinary solute excretion limits water excretion such that hyponatremia ensues after relatively modest polydipsia. AVP levels have not been reported in patients with beer potomania but are expected to be suppressed or rapidly suppressible with saline hydration; this fits with the overly rapid correction in plasma Na+ concentration that can be seen with saline hydration. Resumption of a normal diet and/or saline hydration will also correct the causative deficit in urinary solute excretion, such that patients with beer potomania typically correct their plasma Na+ concentration promptly after admission to the hospital. Clinical Features of Hyponatremia  Hyponatremia induces gen­ eralized cellular swelling, a consequence of water movement down the osmotic gradient from the hypotonic ECF to the ICF. The symptoms of hyponatremia are primarily neurologic, reflecting the development of cerebral edema within a rigid skull. The initial CNS response to acute hyponatremia is an increase in interstitial pressure, leading to shunting of ECF and solutes from the interstitial space into the cerebrospinal fluid and then on into the systemic circulation. This is accompanied by an efflux of the major intracellular ions, Na+, K+, and Cl–, from brain cells. Acute hyponatremic encephalopathy ensues when these volume regulatory mechanisms are overwhelmed by a rapid decrease in tonic­ ity, resulting in acute cerebral edema. Early symptoms can include nausea, headache, and vomiting. However, severe complications can rapidly evolve, including seizure activity, brainstem herniation, coma, and death. A key complication of acute hyponatremia is normocapneic or hypercapneic respiratory failure; the associated hypoxia may amplify the neurologic injury. Normocapneic respiratory failure in this setting is typically due to noncardiogenic, “neurogenic” pulmonary edema, with a normal pulmonary capillary wedge pressure. Acute symptomatic hyponatremia is a medical emergency, occur­ ring in a number of specific settings (Table 56-2). Women, particularly

Drugs that stimulate release of AVP or enhance its action Chlorpropamide SSRIs Tricyclic antidepressants Clofibrate Carbamazepine Vincristine Nicotine Narcotics Antipsychotic drugs Ifosfamide Cyclophosphamide Nonsteroidal anti-inflammatory drugs MDMA (“Ecstasy”, “Molly”) AVP analogues Desmopressin Oxytocin Vasopressin Hereditary (gain-of-function mutations in the vasopressin V2 receptor) Idiopathic Transient Endurance exercise General anesthesia Nausea Pain Stress Fluid and Electrolyte Disturbances CHAPTER 56 before menopause, are much more likely than men to develop encepha­ lopathy and severe neurologic sequelae. Acute hyponatremia often has an iatrogenic component, e.g., when hypotonic intravenous fluids are given to postoperative patients with an increase in circulating AVP. Exercise-associated hyponatremia, an important clinical issue at mara­ thons and other endurance events, has similarly been linked to both a “nonosmotic” increase in circulating AVP and excessive free water intake. The recreational drugs Molly and Ecstasy, which share an active ingredient (MDMA, 3,4-methylenedioxymethamphetamine), cause a rapid and potent induction of both thirst and AVP, leading to severe acute hyponatremia. Persistent, chronic hyponatremia results in an efflux of organic osmolytes (creatine, betaine, glutamate, myoinositol, and taurine) from brain cells; this response reduces intracellular osmolality and the osmotic gradient favoring water entry. This reduction in intracel­ lular osmolytes is largely complete within 48 h, the time period that clinically defines chronic hyponatremia; this temporal definition has considerable relevance for the treatment of hyponatremia (see below). The cellular response to chronic hyponatremia does not fully protect patients from symptoms, which can include vomiting, nausea, confu­ sion, and seizures, usually at plasma Na+ concentration <125 mM. Even patients who are judged “asymptomatic” can manifest subtle gait and cognitive defects that reverse with correction of hyponatremia; TABLE 56-2  Causes of Acute Hyponatremia Iatrogenic   Postoperative: premenopausal women   Hypotonic fluids with cause of ↑ vasopressin   Glycine irrigation: TURP, uterine surgery   Colonoscopy preparation Recent institution of thiazides Polydipsia MDMA (“Ecstasy,” “Molly”) ingestion Exercise induced Multifactorial, e.g., thiazide and polydipsia Abbreviations: MDMA, 3,4-methylenedioxymethamphetamine; TURP, transurethral resection of the prostate.

notably, chronic “asymptomatic” hyponatremia increases the risk of falls. Chronic hyponatremia also increases the risk of bony fractures owing to the associated neurologic dysfunction and to a hyponatremiaassociated reduction in bone density. Therefore, every attempt should be made to safely correct the plasma Na+ concentration in patients with chronic hyponatremia, even in the absence of overt symptoms (see the section on treatment of hyponatremia below).

The management of chronic hyponatremia is complicated sig­ nificantly by the asymmetry of the cellular response to correction of plasma Na+ concentration. Specifically, the reaccumulation of organic osmolytes by brain cells is attenuated and delayed as osmolality increases after correction of hyponatremia, sometimes resulting in degenerative loss of oligodendrocytes and an osmotic demyelination syndrome (ODS). Overly rapid correction of hyponatremia (>8–10 mM in 24 h or 18 mM in 48 h) causes hypertonic stress in astrocytes within brain regions prone to ODS, leading to generalized protein ubiquitination and endoplasmic reticulum stress due to activation of the unfolded protein response; this is accompanied by apoptotic and autophagic cell death. Rapid correction of hyponatremia also causes a disruption in integrity of the blood-brain barrier, allowing the entry of immune mediators that may contribute to demyelination. The lesions of ODS classically affect the pons, a neuroanatomic structure wherein the delay in the reaccumulation of osmotic osmolytes is particularly pronounced; clinically, patients with central pontine myelinolysis can present 1 or more days after overcorrection of hyponatremia with para­ paresis or quadriparesis, dysphagia, dysarthria, diplopia, a “locked-in syndrome,” and/or loss of consciousness. Other regions of the brain can also be involved in ODS, most commonly in association with lesions of the pons but occasionally in isolation; in order of frequency, the lesions of extrapontine myelinolysis can occur in the cerebellum, lateral geniculate body, thalamus, putamen, and cerebral cortex or sub­ cortex. Clinical presentation of ODS can, therefore, vary as a function of the extent and localization of extrapontine myelinolysis, with the reported development of ataxia, mutism, parkinsonism, dystonia, and catatonia. Relowering of plasma Na+ concentration after overly rapid correction can prevent or attenuate ODS (see the section on treatment of hyponatremia below). However, even appropriately slow correction can be associated with ODS, particularly in patients with additional risk factors; these include alcoholism, malnutrition, hypokalemia, and liver transplantation. PART 2 Cardinal Manifestations and Presentation of Diseases Diagnostic Approach to Hyponatremia  Clinical assessment of hyponatremic patients should focus on the underlying cause; a detailed drug history is particularly crucial (Table 56-1). A careful clinical assessment of volume status is obligatory for the classical diagnostic approach to hyponatremia (Fig. 56-5). Hyponatremia is frequently multifactorial, particularly when severe; clinical evaluation should consider all the possible causes for excessive circulating AVP, including volume status, drugs, and the presence of nausea and/or pain. Radio­ logic imaging may also be appropriate to assess whether patients have a pulmonary or CNS cause for hyponatremia. A screening chest x-ray may fail to detect a small-cell carcinoma of the lung; computed tomog­ raphy (CT) scanning of the thorax should be considered in patients at high risk for this tumor (e.g., patients with a smoking history). Laboratory investigation should include a measurement of serum osmolality to exclude pseudohyponatremia, which is defined as the coexistence of hyponatremia with a normal or increased plasma tonic­ ity. Most clinical laboratories measure plasma Na+ concentration by testing diluted samples with automated ion-sensitive electrodes, cor­ recting for this dilution by assuming that plasma is 93% water. This correction factor can be inaccurate in patients with pseudohyponatre­ mia due to extreme hyperlipidemia and/or hyperproteinemia, in whom serum lipid or protein makes up a greater percentage of plasma volume. The measured osmolality should also be converted to the effective osmolality (tonicity) by subtracting the measured concentration of urea (divided by 2.8, if in mg/dL); patients with hyponatremia have an effective osmolality of <275 mOsm/kg. Elevated BUN and creatinine in routine chemistries can also indi­ cate renal dysfunction as a potential cause of hyponatremia, whereas

hyperkalemia may suggest adrenal insufficiency or hypoaldosteronism. Serum glucose should also be measured; plasma Na+ concentration falls by ~1.6–2.4 mM for every 100-mg/dL increase in glucose, due to glucose-induced water efflux from cells; this “true” hyponatremia resolves after correction of hyperglycemia. Measurement of serum uric acid should also be performed; whereas patients with SIAD-type physiology will typically be hypouricemic (serum uric acid <4 mg/dL), volume-depleted patients will often be hyperuricemic. In the appropri­ ate clinical setting, thyroid, adrenal, and pituitary function should also be tested; hypothyroidism and secondary adrenal failure due to pitu­ itary insufficiency are important causes of euvolemic hyponatremia, whereas primary adrenal failure causes hypovolemic hyponatremia. A cosyntropin stimulation test is necessary to assess for primary adrenal insufficiency. Urine electrolytes and osmolality are crucial tests in the initial evaluation of hyponatremia. A urine Na+ concentration <20–30 mM is consistent with hypovolemic hyponatremia, in the clinical absence of a hypervolemic, Na+-avid syndrome such as CHF (Fig. 56-5). In contrast, patients with SIAD will typically excrete urine with an Na+ concentration that is >30 mM. However, there can be substantial overlap in urine Na+ concentration values in patients with SIAD and hypovolemic hyponatremia, particularly in the elderly; the ultimate “gold standard” for the diagnosis of hypovolemic hyponatremia is the demonstration that plasma Na+ concentration corrects after hydration with normal saline. Patients with thiazide-associated hyponatremia may also present with higher than expected urine Na+ concentration and other findings suggestive of SIAD; one should defer making a diagnosis of SIAD in these patients until 1–2 weeks after discontinu­ ing the thiazide. A urine osmolality <100 mOsm/kg is suggestive of polydipsia; urine osmolality >400 mOsm/kg indicates that AVP excess is playing a more dominant role, whereas intermediate values are more consistent with multifactorial pathophysiology (e.g., AVP excess with a significant component of polydipsia). Patients with hyponatremia due to decreased solute intake (beer potomania) typically have urine Na+ concentration <20 mM and urine osmolality in the range of <100 to the low 200s. Finally, the measurement of urine K+ concentration is required to calculate the urine-to-plasma electrolyte ratio, which is useful to predict the response to fluid restriction (see the section on treatment of hyponatremia below). TREATMENT Hyponatremia Three major considerations guide the therapy of hyponatremia. First, the presence and/or severity of symptoms determine the urgency and goals of therapy. Patients with acute hyponatremia (Table 56-2) present with symptoms that can range from headache, nausea, and/or vomiting, to seizures, obtundation, and central her­ niation; patients with chronic hyponatremia, present for >48 h, are less likely to have severe symptoms. Second, patients with chronic hyponatremia are at risk for ODS if plasma Na+ concentration is corrected by >8–10 mM within the first 24 h and/or by >18 mM within the first 48 h. Third, the response to interventions such as hypertonic saline, isotonic saline, or AVP antagonists can be highly unpredictable, such that frequent monitoring of plasma Na+ con­ centration during corrective therapy is imperative. Once the urgency in correcting the plasma Na+ concentration has been established and appropriate therapy instituted, the focus should be on treatment or withdrawal of the underlying cause. Patients with euvolemic hyponatremia due to SIAD, hypothy­ roidism, or secondary adrenal failure will respond to successful treatment of the underlying cause, with an increase in plasma Na+ concentration. However, not all causes of SIAD are immediately reversible, necessitating pharmacologic therapy to increase the plasma Na+ concentration (see below). Hypovolemic hyponatre­ mia will respond to intravenous hydration with isotonic normal saline, with a rapid reduction in circulating AVP and a brisk water diuresis; it may be necessary to reduce the rate of correction if

the history suggests that hyponatremia has been chronic, i.e., present for >48 h (see below). Hypervolemic hyponatremia due to CHF will often respond to improved therapy of the underlying cardiomyopathy, e.g., following the institution or intensification of angiotensin-converting enzyme (ACE) inhibition. Finally, patients with hyponatremia due to beer potomania and low solute intake will respond very rapidly to intravenous saline and the resumption of a normal diet. Notably, patients with beer potomania have a very high risk of developing ODS, due to the associated hypokale­ mia, alcoholism, malnutrition, and high risk of overcorrecting the plasma Na+ concentration. Water deprivation has long been a cornerstone of the therapy of chronic hyponatremia. However, patients who are excreting mini­ mal electrolyte-free water will require aggressive fluid restriction; this can be very difficult for patients with SIAD to tolerate, given that their thirst is also inappropriately stimulated. The urine-toplasma electrolyte ratio (urinary [Na+] + [K+]/plasma [Na+]) can be exploited as a quick indicator of electrolyte-free water excretion (Table 56-3); patients with a ratio of >1 should be more aggressively restricted (<500 mL/d) if possible, those with a ratio of ~1 should be restricted to 500–700 mL/d, and those with a ratio <1 should be restricted to <1 L/d. In hypokalemic patients, potassium replace­ ment will serve to increase plasma Na+ concentration, given that the plasma Na+ concentration is a function of both exchangeable Na+ and exchangeable K+ divided by total-body water; a corollary is that aggressive repletion of K+ has the potential to overcorrect the plasma Na+ concentration even in the absence of hypertonic saline. Plasma Na+ concentration will also tend to respond to an increase in dietary solute intake, which increases the ability to excrete free water; this can be accomplished with oral salt tablets and with newly available, palatable preparations of oral urea. Patients in whom therapy with fluid restriction, potassium replacement, and/or increased solute intake fails may merit phar­ macologic therapy to increase their plasma Na+ concentration. Some patients with SIAD initially respond to combined therapy with oral furosemide, 20 mg twice a day (higher doses may be necessary in renal insufficiency), and oral salt tablets; furosemide serves to inhibit the renal countercurrent mechanism and blunt urinary concentrating ability, whereas the salt tablets counter­ act diuretic-associated natriuresis. The risk of hypokalemia and/ or renal dysfunction limits enthusiasm for this approach, which requires careful titration of diuretic and salt tablets. Demeclocycline is a potent inhibitor of principal cells and can be used in patients whose Na levels do not increase in response to furosemide and salt tablets. However, this agent can be associated with a reduction in TABLE 56-3  Management of Hypernatremia Water Deficit 1.  Estimate total-body water (TBW): 50% of body weight in women and 60% in men 2.  Calculate free-water deficit: [(Na+ – 140)/140] × TBW 3.  Administer deficit over 48–72 h, without decrease in plasma Na+ concentration by >10 mM/24 h Ongoing Water Losses 4.  Calculate free-water clearance, CeH2O:

× − +     C H O V 1 U U P e

Na k Na where V is urinary volume, UNa is urinary [Na+], UK is urinary [K+], and PNa is plasma [Na+] Insensible Losses 5.  ~10 mL/kg per day: less if ventilated, more if febrile Total 6.  Add components to determine water deficit and ongoing water loss; correct the water deficit over 48–72 h and replace daily water loss. Avoid correction of plasma [Na+] by >10 mM/d.

GFR, due to excessive natriuresis and/or direct renal toxicity; it should be avoided in cirrhotic patients in particular, who are at higher risk of nephrotoxicity due to drug accumulation. If avail­ able, palatable preparations of oral urea can also be used to manage SIAD, with comparable efficacy to AVP antagonists (vaptans); the increase in solute excretion with oral urea ingestion increases free water excretion, thus reducing the plasma Na+.

AVP antagonists (vaptans) are highly effective in SIAD and in hypervolemic hyponatremia due to heart failure or cirrhosis, reli­ ably increasing plasma Na+ concentration due to their “aquaretic” effects (augmentation of free water clearance). Most of these agents specifically antagonize the V2 AVP receptor; tolvaptan is currently the only oral V2 antagonist to be approved by the U.S. Food and Drug Administration. Conivaptan, the only available intravenous vaptan, is a mixed V1A/V2 antagonist, with a modest risk of hypoten­ sion due to V1A receptor inhibition. Therapy with vaptans must be initiated in a hospital setting, with a liberalization of fluid restric­ tion (>2 L/d) and close monitoring of plasma Na+ concentration. Although approved for the management of all but hypovolemic hyponatremia and acute hyponatremia, the clinical indications are limited. Oral tolvaptan is perhaps most appropriate for the man­ agement of significant and persistent SIAD (e.g., in small-cell lung carcinoma) that has not responded to water restriction and/or oral furosemide and salt tablets. Abnormalities in liver function tests have been reported with chronic tolvaptan therapy; hence, the use of this agent should be restricted to <1–2 months. Fluid and Electrolyte Disturbances CHAPTER 56 Treatment of acute symptomatic hyponatremia should include hypertonic 3% saline (513 mM) to acutely increase plasma Na+ concentration by 1–2 mM/h to a total of 4–6 mM; this modest increase is typically sufficient to alleviate severe acute symptoms, after which corrective guidelines for chronic hyponatremia are appropriate (see below). A bolus of 100 mL of hypertonic saline is more effective than an infusion, rapidly improving both serum sodium and mental status. For ongoing infusions, a number of equations have been developed to estimate the required rate of hypertonic saline, which has an Na+-Cl– concentration of 513 mM.

The traditional approach is to calculate an Na+ deficit, where the Na+ deficit = 0.6 × body weight × (target plasma Na+ concentration –

starting plasma Na+ concentration), followed by a calculation of the required rate. Regardless of the method used to determine the rate of administration, the increase in plasma Na+ concentration can be highly unpredictable during treatment with hypertonic saline, due to rapid changes in the underlying physiology; plasma Na+ concentration should be monitored every 2–4 h during treatment, with appropriate changes in therapy based on the observed rate of change. The administration of supplemental oxygen and ventila­ tory support is also critical in acute hyponatremia, in the event that patients develop acute pulmonary edema or hypercapneic respiratory failure. Intravenous loop diuretics will help treat acute pulmonary edema and will also increase free water excretion, by interfering with the renal countercurrent multiplication system. AVP antagonists do not have an approved role in the management of acute hyponatremia. The rate of correction should be comparatively slow in chronic hyponatremia (<6–8 mM in the first 24 h and <6 mM each subse­ quent 24 h) so as to avoid ODS; lower target rates are appropriate in patients at particular risk for ODS, such as alcoholics or hypokale­ mic patients. Overcorrection of the plasma Na+ concentration can occur when AVP levels rapidly normalize, for example, following the treatment of patients with chronic hypovolemic hyponatremia with intravenous saline or following glucocorticoid replacement of patients with hypopituitarism and secondary adrenal failure. Approximately 10% of patients treated with vaptans will overcorrect; the risk is increased if water intake is not liberalized. In the event that the plasma Na+ concentration overcorrects following therapy, hyponatremia should be reinduced or stabilized by the administra­ tion of the AVP agonist desmopressin acetate (DDAVP) and/or the administration of free water, typically intravenous D5W; the goal is to prevent or reverse the development of ODS. Alternatively,

the treatment of patients with marked hyponatremia can be initi­ ated with the twice-daily administration of DDAVP to maintain constant AVP bioactivity, combined with the administration of hypertonic saline to slowly correct the serum sodium in a more controlled fashion, thus reducing upfront the risk of overcorrection.

■ ■HYPERNATREMIA Etiology  Hypernatremia is defined as an increase in the plasma Na+ concentration to >145 mM. Considerably less common than hyponatremia, hypernatremia is nonetheless associated with mortality rates of as high as 40–60%, mostly due to the severity of the associated underlying disease processes. Hypernatremia is usually the result of a combined water and electrolyte deficit, with losses of H2O in excess of Na+. Less frequently, the ingestion or iatrogenic administration of excess Na+ can be causative, for example, after IV administration of excessive hypertonic Na+-Cl– or Na+-HCO3 PART 2 Cardinal Manifestations and Presentation of Diseases – (Fig. 56-6). Elderly individuals with reduced thirst and/or diminished access to fluids are at the highest risk of developing hypernatremia. Patients with hypernatremia may rarely have a central defect in hypothalamic osmoreceptor function, with a mixture of both decreased thirst and reduced AVP secretion. Causes of this adipsic DI include primary or metastatic tumor, occlusion or ligation of the anterior communicating artery, trauma, hydrocephalus, and inflammation such as sarcoidosis. Hypernatremia can develop following the loss of water via both renal and nonrenal routes. Insensible losses of water may increase in the setting of fever, exercise, heat exposure, severe burns, or mechani­ cal ventilation. Diarrhea is, in turn, the most common gastrointestinal cause of hypernatremia. Notably, osmotic diarrhea and viral gastro­ enteritides typically generate stools with Na+ and K+ <100 mM, thus leading to water loss and hypernatremia; in contrast, secretory diarrhea typically results in isotonic stool and thus hypovolemia with or without hypovolemic hyponatremia. Common causes of renal water loss include osmotic diuresis secondary to hyperglycemia, excess urea, postobstructive diuresis, or mannitol; these disorders share an increase in urinary solute excretion and urinary osmolality (see “Diagnostic Approach,” below). Hypernatremia due to a water diuresis occurs in central or nephrogenic DI (NDI). NDI is characterized by renal resistance to AVP, which can be par­ tial or complete (see “Diagnostic Approach,” below). Genetic causes ECF Volume Increased Not increased Administration of hypertonic NaCl or NaHCO3 Minimum volume of maximally concentrated urine Yes No Insensible water loss Gastrointestinal water loss Remote renal water loss Urine osmole excretion rate

750 mOsm/d

No Yes Renal response to desmopressin Diuretic Osmotic diureses Urine osmolality unchanged Urine osmolality increased Nephrogenic diabetes insipidus Central diabetes insipidus FIGURE 56-6  The diagnostic approach to hypernatremia. ECF, extracellular fluid.

include loss-of-function mutations in the X-linked V2 receptor; muta­ tions in the AVP-responsive aquaporin-2 water channel can cause autosomal recessive and autosomal dominant NDI, whereas recessive deficiency of the aquaporin-1 water channel causes a more modest concentrating defect (Fig. 56-2). Hypercalcemia can also cause poly­ uria and NDI; calcium signals directly through the calcium-sensing receptor to downregulate Na+, K+, and Cl– transport by the TALH and water transport in principal cells, thus reducing renal concentrating ability in hypercalcemia. Another common acquired cause of NDI is hypokalemia, which inhibits the renal response to AVP and downregu­ lates aquaporin-2 expression. Several drugs can cause acquired NDI, in particular, lithium, ifosfamide, and several antiviral agents. Lithium causes NDI by multiple mechanisms, including direct inhibition of renal glycogen synthase kinase-3 (GSK3), a kinase thought to be the pharmacologic target of lithium in bipolar disease; GSK3 is required for the response of principal cells to AVP. The entry of lithium through the amiloride-sensitive Na+ channel ENaC (Fig. 56-4) is required for the effect of the drug on principal cells, such that combined therapy within lithium and amiloride can mitigate lithium-associated NDI. However, lithium causes chronic tubulointerstitial scarring and chronic kidney disease after prolonged therapy, such that patients may have a persistent NDI long after stopping the drug, with a reduced therapeutic benefit from amiloride. Finally, gestational DI is a rare complication of late-term pregnancy wherein increased activity of a circulating placental protease with “vasopressinase” activity leads to reduced circulating AVP and poly­ uria, often accompanied by hypernatremia. DDAVP is an effective therapy for this syndrome, given its resistance to the vasopressinase enzyme. Clinical Features  Hypernatremia increases osmolality of the ECF, generating an osmotic gradient between the ECF and ICF, an efflux of intracellular water, and cellular shrinkage. As in hyponatremia, the symptoms of hypernatremia are predominantly neurologic. Altered mental status is the most frequent manifestation, ranging from mild confusion and lethargy to deep coma. The sudden shrinkage of brain cells in acute hypernatremia may lead to parenchymal or subarachnoid hemorrhages and/or subdural hematomas; however, these vascular complications are primarily encountered in pediatric and neonatal patients. Rarely, osmotic demyelination may occur in acute hyper­ natremia. Osmotic damage to muscle membranes can also lead to hypernatremic rhabdomyolysis. Brain cells accommodate to a chronic increase in ECF osmolality (>48 h) by activating membrane trans­ porters that mediate influx and intracellular accumulation of organic osmolytes (creatine, betaine, glutamate, myoinositol, and taurine); this results in an increase in ICF water and normalization of brain paren­ chymal volume. In consequence, patients with chronic hypernatremia are less likely to develop severe neurologic compromise. However, the cellular response to chronic hypernatremia predisposes pediatric patients with hypernatremia, particularly infants, to the development of cerebral edema and seizures during overly rapid hydration (overcor­ rection of plasma Na+ concentration by >10 mM/d). Diagnostic Approach  The history should focus on the presence or absence of thirst, polyuria, and/or an extrarenal source for water loss, such as diarrhea. The physical examination should include a detailed neurologic exam and an assessment of the ECFV; patients with a particularly large water deficit and/or a combined deficit in electro­ lytes and water may be hypovolemic, with reduced JVP and orthostasis. Accurate documentation of daily fluid intake and daily urine output is also critical for the diagnosis and management of hypernatremia. Laboratory investigation should include a measurement of serum and urine osmolality, in addition to urine electrolytes. The appropriate response to hypernatremia and a serum osmolality >295 mOsm/kg is an increase in circulating AVP and the excretion of low volumes (<500 mL/d) of maximally concentrated urine, i.e., urine with osmolality

800 mOsm/kg; should this be the case, then an extrarenal source of water loss is primarily responsible for the generation of hypernatremia. Many patients with hypernatremia are polyuric; should an osmotic diuresis be responsible, with excessive excretion of Na+-Cl–, glucose,

and/or urea, then daily solute excretion will be >750–1000 mOsm/d (>15 mOsm/kg body water per day) (Fig. 56-6). More commonly, patients with hypernatremia and polyuria will have a predominant water diuresis, with excessive excretion of hypotonic, dilute urine. Adequate differentiation between nephrogenic and central causes of DI requires the measurement of the response in urinary osmolality to DDAVP, combined with measurement of circulating AVP in the setting of hypertonicity. If measurement of serum copeptin is avail­ able, an “indirect water deprivation” test can be performed in patients with hypotonic polyuria without hypernatremia; if an infusion of hypertonic saline increases the level of circulating copeptin, a peptide co-secreted with AVP, then the patient suffers from polydipsia rather than central DI. By definition, patients with baseline hypernatremia are hypertonic, with an adequate stimulus for AVP by the posterior pituitary. Therefore, in contrast to polyuric patients with a normal or reduced baseline plasma Na+ concentration and osmolality, a water deprivation test (Chap. 55) is unnecessary in hypernatremia; indeed, water deprivation is absolutely contraindicated in this setting, given the risk for worsening the hypernatremia. Hypernatremic patients with NDI will have high serum levels of AVP and copeptin. Their low urine osmolality will also fail to respond to DDAVP, increasing by <50% or <150 mOsm/kg from baseline; patients with central DI will respond to DDAVP, with a reduced circulating AVP and copeptin. Patients may exhibit a partial response to DDAVP, with a >50% rise in urine osmolality that nonetheless fails to reach 800 mOsm/kg; the level of circulating AVP will help differentiate the underlying cause, i.e., NDI versus central DI. In pregnant patients, AVP assays should be drawn in tubes containing the protease inhibitor 1,10-phenanthroline to prevent in vitro degradation of AVP by placental vasopressinase. For patients with hypernatremia due to renal loss of water, it is criti­ cal to quantify ongoing daily losses using the calculated electrolyte-free water clearance, in addition to calculation of the baseline water deficit (the relevant formulas are discussed in Table 56-3). This requires daily measurement of urine electrolytes, combined with accurate measure­ ment of daily urine volume. TREATMENT Hypernatremia The underlying cause of hypernatremia should be withdrawn or corrected, be it drugs, hyperglycemia, hypercalcemia, hypokalemia, or diarrhea. The approach to the correction of hypernatremia is outlined in Table 56-3. It is imperative to correct hypernatremia slowly to avoid cerebral edema, typically replacing the calculated free water deficit over 48 h. Ideally, the plasma Na+ concentration should be corrected by no more than 10 mM/d, which may take longer than 48 h in patients with severe hypernatremia (>160 mM). In critically ill adults, however, recent evidence does not indicate that rapid correction of hypernatremia is associated with a higher risk for mortality, seizure, alteration of consciousness, and/or cere­ bral edema. Given that restricting the rate of correction to <10 mM/d has no physiologic sequelae, it seems prudent to restrict correction in adults to this rate; however, should that rate be exceeded, hyper­ natremia does not need to be reinduced. Water should ideally be administered by mouth or by nasogas­ tric tube, as the most direct way to provide free water, i.e., water without electrolytes. Alternatively, patients can receive free water in dextrose-containing IV solutions, such as 5% dextrose (D5W); blood glucose should be monitored in case hyperglycemia occurs. Depending on the history, blood pressure, or clinical volume status, it may be appropriate to initially treat with hypotonic saline solu­ tions (1/4 or 1/2 normal saline); normal saline is usually inappro­ priate in the absence of very severe hypernatremia, where normal saline is proportionally more hypotonic relative to plasma, or frank hypotension. Calculation of urinary electrolyte-free water clearance (Table 56-3) is required to estimate daily, ongoing loss of free water in patients with NDI or central DI, which should be replenished daily.

Additional therapy may be feasible in specific cases. Patients with central DI should respond to the administration of intrave­ nous, intranasal, or oral DDAVP. Patients with NDI due to lithium may reduce their polyuria with amiloride (2.5–10 mg/d), which decreases entry of lithium into principal cells by inhibiting ENaC (see above); in practice, however, most patients with lithium-

associated DI are able to compensate for their polyuria by simply increasing their daily water intake. Thiazides may reduce polyuria due to NDI, ostensibly by inducing hypovolemia and increasing proximal tubular water reabsorption. Occasionally, nonsteroidal anti-inflammatory drugs (NSAIDs) have been used to treat polyuria associated with NDI, reducing the negative effect of intrarenal pros­ taglandins on urinary concentrating mechanisms; however, this assumes the risks of NSAID-associated gastric and/or renal toxicity. Furthermore, it must be emphasized that thiazides, amiloride, and NSAIDs are only appropriate for chronic management of polyuria from NDI and have no role in the acute management of associated hypernatremia, where the focus is on replacing free water deficits and ongoing free water loss.

Fluid and Electrolyte Disturbances CHAPTER 56 POTASSIUM DISORDERS Homeostatic mechanisms maintain plasma K+ concentration between 3.5 and 5.0 mM, despite marked variation in dietary K+ intake. In a healthy individual at steady state, the entire daily intake of potassium is excreted, ~90% in the urine and 10% in the stool; thus, the kidney plays a dominant role in potassium homeostasis. However, >98% of total-body potassium is intracellular, chiefly in muscle; buffering of extracellular K+ by this large intracellular pool plays a crucial role in the regulation of plasma K+ concentration. Changes in the exchange and distribution of intra- and extracellular K+ can thus lead to marked hypo- or hyperkalemia. A corollary is that massive necrosis and the attendant release of tissue K+ can cause severe hyperkalemia, particu­ larly in the setting of acute kidney injury and reduced excretion of K+. Changes in whole-body K+ content are primarily mediated by the kidney, which reabsorbs filtered K+ in hypokalemic, K+-deficient states and secretes K+ in hyperkalemic, K+-replete states. Although K+ is trans­ ported along the entire nephron, it is the principal cells of the connect­ ing segment (CNT) and cortical CD that play a dominant role in renal K+ secretion, whereas alpha-intercalated cells of the outer medullary CD function in renal tubular reabsorption of filtered K+ in K+-deficient states. In principal cells, apical Na+ entry via the amiloride-sensitive ENaC generates a lumen-negative potential difference, which drives passive K+ exit through apical K+ channels (Fig. 56-4). Two major K+ channels mediate distal tubular K+ secretion: the secretory K+ chan­ nel ROMK (renal outer medullary K+ channel; also known as Kir1.1 or KcnJ1) and the flow-sensitive “big potassium” (BK) or maxi-K K+ channel. ROMK is thought to mediate the bulk of constitutive K+ secre­ tion, whereas increases in distal flow rate and/or genetic absence of ROMK activate K+ secretion via the BK channel. An appreciation of the relationship between ENaC-dependent Na+ entry and distal K+ secretion (Fig. 56-4) is required for the bedside interpretation of potassium disorders. For example, decreased distal delivery of Na+, as occurs in hypovolemic, prerenal states, tends to blunt the ability to excrete K+, leading to hyperkalemia; on the other hand, an increase in distal delivery of Na+ and distal flow rate, as occurs after treatment with thiazide and loop diuretics, can enhance K+ secretion and lead to hypokalemia. Hyperkalemia is also a predict­ able consequence of drugs that directly inhibit ENaC, due to the role of this Na+ channel in generating a lumen-negative potential difference. Aldosterone in turn has a major influence on potassium excretion, increasing the activity of ENaC channels and thus amplifying the driv­ ing force for K+ secretion across the luminal membrane of principal cells. Abnormalities in the renin-angiotensin-aldosterone system can thus cause both hypokalemia and hyperkalemia. Notably, however, potassium excess and potassium restriction have opposing, aldosterone-

independent effects on the density and activity of apical K+ channels in the distal nephron, i.e., factors other than aldosterone modulate the renal capacity to secrete K+. In addition, potassium restriction and

hypokalemia activate aldosterone-independent distal reabsorption of filtered K+, activating apical H+/K+-ATPase activity in intercalated cells within the outer medullary CD. Reflective perhaps of this physiology, changes in plasma K+ concentration are not universal in disorders asso­ ciated with changes in aldosterone activity.

■ ■HYPOKALEMIA Hypokalemia, defined as a plasma K+ concentration of <3.5 mM, occurs in up to 20% of hospitalized patients. Hypokalemia is associated with a tenfold increase in in-hospital mortality, due to adverse effects on cardiac rhythm, blood pressure, and cardiovascular morbidity. Mechanistically, hypokalemia can be caused by redistribution of K+ between tissues and the ECF or by renal and nonrenal loss of K+ (Table 56-4). Systemic hypomagnesemia can also cause treatment-resistant hypokalemia, due PART 2 Cardinal Manifestations and Presentation of Diseases TABLE 56-4  Causes of Hypokalemia I. Decreased intake A. Starvation B. Clay ingestion II. Redistribution into cells A. Acid-base

1. Metabolic alkalosis B. Hormonal
2. Insulin
3. Increased β2-adrenergic sympathetic activity: post–myocardial infarction, head injury
4. β2-Adrenergic agonists—bronchodilators, tocolytics
5. α-Adrenergic antagonists
6. Thyrotoxic periodic paralysis
7. Downstream stimulation of Na+/K+-ATPase: theophylline, caffeine C. Anabolic state
8. Vitamin B12 or folic acid administration (red blood cell production)
9. Granulocyte-macrophage colony-stimulating factor (white blood cell production)
10. Total parenteral nutrition D. Other
11. Pseudohypokalemia
12. Hypothermia
13. Familial hypokalemic periodic paralysis
14. Barium toxicity: systemic inhibition of “leak” K+ channels III. Increased loss A. Nonrenal
15. Gastrointestinal loss (diarrhea)
16. Integumentary loss (sweat) B. Renal
17. Increased distal flow and distal Na+ delivery: diuretics, osmotic diuresis, salt-wasting nephropathies
18. Increased secretion of potassium a. Mineralocorticoid excess: primary hyperaldosteronism (aldosteroneproducing adenomas, primary or unilateral adrenal hyperplasia, idiopathic hyperaldosteronism due to bilateral adrenal hyperplasia, and adrenal carcinoma), genetic hyperaldosteronism (familial hyperaldosteronism types I/II/III, congenital adrenal hyperplasias), secondary hyperaldosteronism (malignant hypertension, reninsecreting tumors, renal artery stenosis, hypovolemia), Cushing’s syndrome, Bartter’s syndrome, Gitelman’s syndrome b. Apparent mineralocorticoid excess: genetic deficiency of 11β-dehydrogenase-2 (syndrome of apparent mineralocorticoid excess), inhibition of 11β-dehydrogenase-2 (glycyrrhetinic/ glycyrrhizinic acid and/or carbenoxolone; itraconazole and posaconazole; licorice, food products, drugs), Liddle’s syndrome (genetic activation of epithelial Na+ channels) c. Distal delivery of nonreabsorbed anions: vomiting, nasogastric suction, proximal renal tubular acidosis, diabetic ketoacidosis, gluesniffing (toluene abuse), penicillin derivatives (penicillin, nafcillin, dicloxacillin, ticarcillin, oxacillin, and carbenicillin)
19. Magnesium deficiency

to a combination of reduced cellular uptake of K+ and exaggerated renal secretion. Spurious hypokalemia or “pseudohypokalemia” can occasion­ ally result from in vitro cellular uptake of K+ after venipuncture, for example, due to profound leukocytosis in acute leukemia. Redistribution and Hypokalemia  Insulin, β2-adrenergic activ­ ity, thyroid hormone, and alkalosis promote Na+/K+-ATPase-mediated cellular uptake of K+, leading to hypokalemia. Inhibition of the passive efflux of K+ can also cause hypokalemia, albeit rarely; this typically occurs in the setting of systemic inhibition of K+ channels by toxic barium ions. Exogenous insulin can cause iatrogenic hypokalemia, par­ ticularly during the management of K+-deficient states such as diabetic ketoacidosis. Alternatively, the stimulation of endogenous insulin can provoke hypokalemia, hypomagnesemia, and/or hypophosphatemia in malnourished patients given a carbohydrate load. Alterations in the activity of the endogenous sympathetic nervous system can cause hypokalemia in several settings, including alcohol withdrawal, hyper­ thyroidism, acute myocardial infarction, and severe head injury. β2 agonists, including both bronchodilators and tocolytics (ritodrine), are powerful activators of cellular K+ uptake; “hidden” sympathomimet­ ics, such as pseudoephedrine and ephedrine in cough syrup or dieting agents, may also cause unexpected hypokalemia. Finally, xanthine-

dependent activation of cAMP-dependent signaling, downstream of the β2 receptor, can lead to hypokalemia, usually in the setting of over­ dose (theophylline) or marked overingestion (dietary caffeine). Redistributive hypokalemia can also occur in the setting of hyper­ thyroidism, with periodic attacks of hypokalemic paralysis (thyrotoxic periodic paralysis [TPP]). Similar episodes of hypokalemic weakness in the absence of thyroid abnormalities occur in familial hypokalemic periodic paralysis, usually caused by missense mutations of voltage sensor domains within the α1 subunit of L-type calcium channels or the skeletal Na+ channel; these mutations generate an abnormal gat­ ing pore current activated by hyperpolarization. TPP develops more frequently in patients of Asian or Latin American origin; this shared predisposition has been linked to genetic variation in Kir2.6, a musclespecific, thyroid hormone–responsive K+ channel. Genome-wide asso­ ciation studies have also implicated variation in the KCNJ2 gene, which encodes a related muscle K+ channel, Kir 2.1, in predisposition to TPP. Patients with TPP typically present with weakness of the extremities and limb girdles, with paralytic episodes that occur most frequently between 1 and 6 a.m. Signs and symptoms of hyperthyroidism are not invariably present. Hypokalemia is usually profound and almost invariably accompanied by hypophosphatemia and hypomagnesemia. The hypokalemia in TPP is also attributed to both direct and indirect activation of the Na+/K+-ATPase, resulting in increased uptake of K+ by muscle and other tissues. Increases in β-adrenergic activity play an important role in that high-dose propranolol (3 mg/kg) rapidly reverses the associated hypokalemia, hypophosphatemia, and paraly­ sis. Outward-directed inward-rectifying K+ current, mediated by KIR channels (primarily Kir2.1 and Kir2.2 tetramers), is also reduced in skeletal muscles of patients with TPP, providing an additional mecha­ nism for hypokalemia. Together with increased Na+/K+-ATPase activity and increased circulating insulin, this reduced KIR current may trigger a “feedforward” cycle of hypokalemia leading to inactivation of muscle Na+ channels, paradoxical depolarization, and paralysis. Nonrenal Loss of Potassium  The loss of K+ in sweat is typically low, except under extremes of physical exertion. Direct gastric losses of K+ due to vomiting or nasogastric suctioning are also minimal; however, the ensuing hypochloremic alkalosis results in persistent kaliuresis due to secondary hyperaldosteronism and bicarbonaturia, i.e., a renal loss of K+. Diarrhea is a globally important cause of hypokalemia, given the worldwide prevalence of infectious diarrheal disease. Noninfectious gastrointestinal processes such as celiac disease, ileostomy, villous adeno­ mas, inflammatory bowel disease, colonic pseudo-obstruction (Ogilvie’s syndrome), VIPomas, and chronic laxative abuse can also cause signifi­ cant hypokalemia; an exaggerated intestinal secretion of potassium by upregulated colonic BK channels has been directly implicated in the pathogenesis of hypokalemia in some of these disorders.

Renal Loss of Potassium  Drugs can increase renal K+ excretion by a variety of different mechanisms. Diuretics are a particularly com­ mon cause, due to associated increases in distal tubular Na+ delivery and distal tubular flow rate, in addition to secondary hyperaldosteron­ ism. Thiazides have a greater effect on plasma K+ concentration than loop diuretics, despite their lesser natriuretic effect. The diuretic effect of thiazides is largely due to inhibition of the Na+-Cl– cotransporter NCC in DCT cells. This leads to a direct increase in the delivery of luminal Na+ to the principal cells immediately downstream in the CNT and cortical CD, which augments Na+ entry via ENaC, increases the lumen-negative potential difference, and amplifies K+ secretion. The higher propensity of thiazides to cause hypokalemia may also be secondary to thiazide-associated hypocalciuria, versus the hypercal­ ciuria seen with loop diuretics; the increases in downstream luminal calcium in response to loop diuretics inhibit ENaC in principal cells, thus reducing the lumen-negative potential difference and attenuating distal K+ excretion. High doses of penicillin-related antibiotics (nafcil­ lin, dicloxacillin, ticarcillin, oxacillin, and carbenicillin) can increase obligatory K+ excretion by acting as nonreabsorbable anions in the distal nephron. Finally, several renal tubular toxins cause renal K+ and magnesium wasting, leading to hypokalemia and hypomagnesemia; these drugs include aminoglycosides, amphotericin, foscarnet, cispla­ tin, and ifosfamide (see also “Magnesium Deficiency and Hypokale­ mia,” below). Aldosterone activates the ENaC channel in principal cells via mul­ tiple synergistic mechanisms, thus increasing the driving force for K+ excretion. In consequence, increases in aldosterone bioactivity and/ or gains in function of aldosterone-dependent signaling pathways are associated with hypokalemia. Increases in circulating aldoste­ rone (hyperaldosteronism) may be primary or secondary. Increased levels of circulating renin in secondary forms of hyperaldosteronism lead to increased angiotensin II and thus aldosterone; renal artery stenosis is perhaps the most frequent cause (Table 56-4). Primary hyperaldosteronism may be genetic or acquired. Hypertension and hypokalemia, due to increases in circulating 11-deoxycorticosterone, occur in patients with congenital adrenal hyperplasia caused by defects in either steroid 11β-hydroxylase or steroid 17α-hydroxylase; deficient 11β-hydroxylase results in associated virilization and other signs of androgen excess, whereas reduced sex steroids in 17α-hydroxylase deficiency lead to hypogonadism. The major forms of isolated primary genetic hyperaldosteronism are familial hyperaldosteronism type I (FH-I, also known as glucocorticoid-

remediable hyperaldosteronism [GRA]) and familial hyperaldosteron­ ism types II and III (FH-II and FH-III), in which aldosterone produc­ tion is not repressible by exogenous glucocorticoids. FH-I is caused by a chimeric gene duplication between the homologous 11β-hydroxylase (CYP11B1) and aldosterone synthase (CYP11B2) genes, fusing the adrenocorticotropic hormone (ACTH)–responsive 11β-hydroxylase promoter to the coding region of aldosterone synthase; this chimeric gene is under the control of ACTH and thus repressible by glucocorti­ coids. FH-III is caused by mutations in the KCNJ5 gene, which encodes the G protein–activated inward rectifier K+ channel 4 (GIRK4); these mutations lead to the acquisition of sodium permeability in the mutant GIRK4 channels, causing an exaggerated membrane depolarization in adrenal glomerulosa cells and the activation of voltage-gated calcium channels. The resulting calcium influx is sufficient to produce aldoste­ rone secretion and cell proliferation, leading to adrenal adenomas and hyperaldosteronism. Acquired causes of primary hyperaldosteronism include aldosterone-

producing adenomas (APAs), primary or unilateral adrenal hyper­ plasia (PAH), idiopathic hyperaldosteronism (IHA) due to bilateral adrenal hyperplasia, and adrenal carcinoma; APA and IHA account for close to 60% and 40%, respectively, of diagnosed hyperaldosteronism. Acquired somatic mutations in KCNJ5 or less frequently in the ATP1A1 (an Na+/K+ ATPase α subunit) and ATP2B3 (a Ca2+ ATPase) genes can be detected in APAs; as in FH-III (see above), the exaggerated depo­ larization of adrenal glomerulosa cells caused by these mutations is implicated in the excessive adrenal proliferation and the exaggerated release of aldosterone.

Random testing of plasma renin activity (PRA) and aldosterone is a helpful screening tool in hypokalemic and/or hypertensive patients, with an aldosterone:PRA ratio of >50 suggestive of primary hyperaldo­ steronism. Hypokalemia and multiple antihypertensive drugs may alter the aldosterone:PRA ratio by suppressing aldosterone or increasing PRA, leading to a ratio of <50 in patients who do in fact have primary hyperaldosteronism; therefore, the clinical context should always be considered when interpreting these results. Additionally, drugs that modulate the renin-angiotensin-aldosterone axis should be stopped during workup of hyperaldosteronism; the only antihypertensives that do not interfere with the workup of hyperaldosteronism are verapamil, alpha blockers, hydralazine, and low-dose amiloride.

Fluid and Electrolyte Disturbances CHAPTER 56 The glucocorticoid cortisol has equal affinity for the MLR to that of aldosterone, with resultant “mineralocorticoid-like” activity. However, cells in the aldosterone-sensitive distal nephron are protected from this “illicit” activation by the enzyme 11β-hydroxysteroid dehydrogenase-2 (11βHSD-2), which converts cortisol to cortisone; cortisone has mini­ mal affinity for the MLR. Recessive loss-of-function mutations in the 11βHSD-2 gene are thus associated with cortisol-dependent activation of the MLR and the syndrome of apparent mineralocorticoid excess (SAME), encompassing hypertension, hypokalemia, hypercalciuria, and metabolic alkalosis, with suppressed PRA and suppressed aldo­ sterone. A similar syndrome is caused by biochemical inhibition of 11βHSD-2 by glycyrrhetinic/glycyrrhizinic acid and/or carbenoxolone. Glycyrrhizinic acid is a natural sweetener found in licorice root, typi­ cally encountered in licorice and its many guises or as a flavoring agent in tobacco and food products. More recently, the antifungals itracon­ azole and posaconazole have been shown to inhibit 11βHSD-2, leading to hypertension and hypokalemia. Finally, hypokalemia may also occur with systemic increases in glu­ cocorticoids. In Cushing’s syndrome caused by increases in pituitary ACTH (Chap. 398), the incidence of hypokalemia is only 10%, whereas it is 60–100% in patients with ectopic secretion of ACTH, despite a similar incidence of hypertension. Indirect evidence suggests that the activity of renal 11βHSD-2 is reduced in patients with ectopic ACTH compared with Cushing’s syndrome, resulting in SAME. Finally, defects in multiple renal tubular transport pathways are associated with hypokalemia. For example, loss-of-function muta­ tions in subunits of the acidifying H+-ATPase in alpha-intercalated cells cause hypokalemic distal renal tubular acidosis, as do many acquired disorders of the distal nephron. Liddle’s syndrome is caused by autosomal dominant gain-in-function mutations of ENaC subunits. Disease-associated mutations either activate the channel directly or abrogate aldosterone-inhibited retrieval of ENaC subunits from the plasma membrane; the end result is increased expression of activated ENaC channels at the plasma membrane of principal cells. Patients with Liddle’s syndrome classically manifest severe hyperten­ sion with hypokalemia, unresponsive to spironolactone yet sensitive to amiloride. Hypertension and hypokalemia are, however, variable aspects of the Liddle’s phenotype; more consistent features include a blunted aldosterone response to ACTH and reduced urinary aldoste­ rone excretion. Loss of the transport functions of the TALH and DCT nephron seg­ ments causes hereditary hypokalemic alkalosis and Bartter’s syndrome (BS) and Gitelman’s syndrome (GS), respectively. Patients with classic BS typically suffer from polyuria and polydipsia, due to the reduction in renal concentrating ability. They may have an increase in urinary cal­ cium excretion, and 20% are hypomagnesemic. Other features include marked activation of the renin-angiotensin-aldosterone axis. Patients with antenatal BS suffer from a severe systemic disorder characterized by marked electrolyte wasting, polyhydramnios, and hypercalciuria with nephrocalcinosis; renal prostaglandin synthesis and excretion are significantly increased, accounting for much of the systemic symptoms. There are five disease genes for BS, all of them functioning in some aspect of regulated Na+, K+, and Cl– transport by the TALH. In contrast, GS is genetically homogeneous, caused almost exclusively by loss-offunction mutations in the thiazide-sensitive Na+-Cl– cotransporter of the DCT. Patients with GS are uniformly hypomagnesemic and exhibit marked hypocalciuria, rather than the hypercalciuria typically seen in

BS; urinary calcium excretion is thus a critical diagnostic test in GS. GS is a milder phenotype than BS; however, patients with GS may suffer from chondrocalcinosis, an abnormal deposition of calcium pyrophos­ phate dihydrate (CPPD) in joint cartilage (Chap. 327).

Magnesium Deficiency and Hypokalemia  Magnesium deple­ tion has inhibitory effects on muscle Na+/K+-ATPase activity, reducing influx into muscle cells and causing a secondary kaliuresis. In addition, magnesium depletion causes exaggerated K+ secretion by the distal nephron; this effect is attributed to a reduction in the magnesium-

dependent, intracellular block of K+ efflux through the secretory K+ channel of principal cells (ROMK; Fig. 56-4). In consequence, hypomagnesemic patients are clinically refractory to K+ replacement in the absence of Mg2+ repletion. Notably, magnesium deficiency is also a common concomitant of hypokalemia because many disorders of the distal nephron may cause both potassium and magnesium wast­ ing (Chap. 327). PART 2 Cardinal Manifestations and Presentation of Diseases Clinical Features  Hypokalemia has prominent effects on cardiac, skeletal, and intestinal muscle cells. In particular, hypokalemia is a major risk factor for both ventricular and atrial arrhythmias. Hypo­ kalemia predisposes to digoxin toxicity by a number of mechanisms, including reduced competition between K+ and digoxin for shared binding sites on cardiac Na+/K+-ATPase subunits. Electrocardiographic changes in hypokalemia include broad flat T waves, ST depression, and QT prolongation; these are most marked when serum K+ is <2.7 mmol/L. Hypokalemia can thus be an important precipitant of arrhythmia in patients with additional genetic or acquired causes of QT prolongation. Hypokalemia also results in hyperpolarization of skeletal muscle, thus impairing the capacity to depolarize and contract; weak­ ness and even paralysis may ensue. It also causes a skeletal myopathy and predisposes to rhabdomyolysis. Finally, the paralytic effects of hypokalemia on intestinal smooth muscle may cause intestinal ileus. The functional effects of hypokalemia on the kidney can include Na+-Cl– and HCO3 – retention, polyuria, phosphaturia, hypocitraturia, and an activation of renal ammoniagenesis. Bicarbonate retention and other acid-base effects of hypokalemia can contribute to the generation of metabolic alkalosis. Hypokalemic polyuria is due to a combination of central polydipsia and an AVP-resistant renal concentrating defect. Structural changes in the kidney due to hypokalemia include a rela­ tively specific vacuolizing injury to proximal tubular cells, interstitial nephritis, and renal cysts. Hypokalemia also predisposes to acute kidney injury and can lead to end-stage renal disease (ESRD) in patients with long-standing hypokalemia due to eating disorders and/ or laxative abuse. Hypokalemia and/or reduced dietary K+ are implicated in the patho­ physiology and progression of hypertension, heart failure, vascular disease, and stroke. For example, short-term K+ restriction in healthy humans and patients with essential hypertension induces Na+-Cl– retention and hypertension. Correction of hypokalemia is particularly important in hypertensive patients treated with diuretics, in whom blood pressure improves with potassium supplementation and the establishment of normokalemia. Diagnostic Approach  The cause of hypokalemia is usually evi­ dent from history, physical examination, and/or basic laboratory tests. The history should focus on medications (e.g., laxatives, diuretics, antibiotics), diet and dietary habits (e.g., licorice), and/or symptoms that suggest a particular cause (e.g., periodic weakness, diarrhea). The physical examination should pay particular attention to blood pressure, volume status, and signs suggestive of specific hypokalemic disorders, e.g., hyperthyroidism and Cushing’s syndrome. Initial laboratory eval­ uation should include electrolytes, BUN, creatinine, serum osmolality, Mg2+, Ca2+, a complete blood count, and urinary pH, osmolality, creati­ nine, and electrolytes (Fig. 56-7). The presence of a non–anion gap aci­ dosis suggests a distal, hypokalemic renal tubular acidosis or diarrhea; calculation of the urinary anion gap can help differentiate these two diagnoses. Renal K+ excretion can be assessed with a 24-h urine col­ lection; a 24-h K+ excretion of <15 mmol is indicative of an extrarenal cause of hypokalemia (Fig. 56-7). If only a random, spot urine sample

is available, serum and urine osmolality can be used to calculate the transtubular K+ gradient (TTKG), which should be <3 in the presence of hypokalemia (see also “Hyperkalemia”). Alternatively, a urinary K+-to-creatinine ratio of >13 mmol/g creatinine (>1.5 mmol/mmol creatinine) is compatible with excessive renal K+ excretion. Urine Cl– is usually decreased in patients with hypokalemia from a nonreabsorb­ able anion, such as antibiotics or HCO3 –. The most common causes of chronic hypokalemic alkalosis are surreptitious vomiting, diuretic abuse, and GS; these can be distinguished by the pattern of urinary electrolytes. Hypokalemic patients with vomiting due to bulimia will thus typically have a urinary Cl– <10 mmol/L; urine Na+, K+, and Cl– are persistently elevated in GS, due to loss of function in the thiazidesensitive Na+-Cl– cotransporter, but less elevated in diuretic abuse and with greater variability. Urine diuretic screens for loop diuretics and thiazides may be necessary to further exclude diuretic abuse. Other tests, such as urinary Ca2+, thyroid function tests, and/or PRA and aldosterone levels, may also be appropriate in specific cases. A plasma aldosterone:PRA ratio of >50, due to suppression of circulat­ ing renin and an elevation of circulating aldosterone, is suggestive of hyperaldosteronism. Patients with hyperaldosteronism or apparent mineralocorticoid excess may require further testing, for example, adrenal vein sampling (Chap. 398) or the clinically available testing for specific genetic causes (e.g., FH-I, SAME, Liddle’s syndrome). Patients with primary aldosteronism should thus be tested for the chimeric FH-I/GRA gene (see above) if they are younger than 20 years of age or have a family history of primary aldosteronism or stroke at a young age (<40 years). Preliminary differentiation of Liddle’s syndrome due to mutant ENaC channels from SAME due to mutant 11βHSD-2 (see above), both of which cause hypokalemia and hypertension with aldosterone suppression, can be made on a clinical basis and then confirmed by genetic analysis; patients with Liddle’s syndrome should respond to amiloride (ENaC inhibition) but not spironolactone, whereas patients with SAME will respond to spironolactone. TREATMENT Hypokalemia The goals of therapy in hypokalemia are to prevent life-threatening and/or serious chronic consequences, to replace the associated K+ deficit, and to correct the underlying cause and/or mitigate future hypokalemia. The urgency of therapy depends on the severity of hypokalemia, associated clinical factors (e.g., cardiac disease, digoxin therapy), and the rate of decline in serum K+. Patients with a prolonged QT interval and/or other risk factors for arrhythmia should be monitored by continuous cardiac telemetry during reple­ tion. Urgent but cautious K+ replacement should be considered in patients with severe redistributive hypokalemia (plasma K+ concen­ tration <2.5 mM) and/or when serious complications ensue; how­ ever, this approach has a risk of rebound hyperkalemia following acute resolution of the underlying cause. When excessive activity of the sympathetic nervous system is thought to play a dominant role in redistributive hypokalemia, as in TPP, theophylline overdose, and acute head injury, high-dose propranolol (3 mg/kg) should be considered; this nonspecific β-adrenergic blocker will correct hypo­ kalemia without the risk of rebound hyperkalemia. Oral replacement with K+-Cl– is the mainstay of therapy in hypokalemia. Potassium phosphate, oral or IV, may be appropriate in patients with combined hypokalemia and hypophosphatemia. Potassium bicarbonate or potassium citrate should be considered in patients with concomitant metabolic acidosis. Notably, hypomag­ nesemic patients are refractory to K+ replacement alone, such that concomitant Mg2+ deficiency should always be corrected with oral or intravenous repletion. The deficit of K+ and the rate of correc­ tion should be estimated as accurately as possible; renal function, medications, and comorbid conditions such as diabetes should also be considered, so as to gauge the risk of overcorrection. In the absence of abnormal K+ redistribution, the total deficit correlates with serum K+, such that serum K+ drops by ~0.27 mM for every

Yes Hypokalemia (Serum K+<3.5 mmol/L) Emergency? Pseudohypokalemia? Move to therapy No No Yes Treat accordingly Clear evidence of low intake Treat accordingly and re-evaluate History, physical examination & basic laboratory tests No No <15 mmol/day OR <15 mmol/g Cr

15 mmol/g Cr OR >15 mmol/day Extrarenal loss/remote renal loss Acid-base status Metabolic acidosis -GI K+ loss Normal -Profuse sweating Metabolic alkalosis -Remote diuretic use -Remote vomiting or stomach drainage -Profuse sweating Low OR normal Non-reabsorbable anions other than HCO3 – Acid-base status Variable Aldosterone -Hippurate -Penicillins Metabolic alkalosis Metabolic acidosis -Proximal RTA -Distal RTA -DKA -Amphotericin B -Acetazolamide Urine Cl– (mmol/L) 20 Urine Ca/Cr (molar ratio) 0.20 <0.15 -Thiazide diuretic -Gitelman’s syndrome -Loop diuretic -Bartter’s syndrome FIGURE 56-7  The diagnostic approach to hypokalemia. See text for details. AME, apparent mineralocorticoid excess; BP, blood pressure; CCD, cortical collecting duct; DKA, diabetic ketoacidosis; FH-I, familial hyperaldosteronism type I; FHPP, familial hypokalemic periodic paralysis; GI, gastrointestinal; GRA, glucocorticoid remediable aldosteronism; HTN, hypertension; PA, primary aldosteronism; RAS, renal artery stenosis; RST, renin-secreting tumor; RTA, renal tubular acidosis; SAME, syndrome of apparent mineralocorticoid excess; TTKG, transtubular potassium gradient. (Reproduced with permission from DB Mount, K Zandi-Nejad: Disorders of potassium balance, in BM Brenner [ed], Brenner and Rector’s The Kidney, 8th ed, Philadelphia, W.B. Saunders & Company, 2008.) 100-mmol reduction in total-body stores; loss of 400–800 mmol of total-body K+ results in a reduction in serum K+ by ~2.0 mM. Notably, given the delay in redistributing potassium into intracel­ lular compartments, this deficit must be replaced gradually over 24–48 h, with frequent monitoring of plasma K+ concentration to avoid transient overrepletion and transient hyperkalemia. The use of intravenous administration should be limited to patients unable to use the enteral route or in the setting of severe complications (e.g., paralysis, arrhythmia). Intravenous K+-Cl– should always be administered in saline solutions, rather than dextrose, because the dextrose-induced increase in insulin can acutely exacerbate hypokalemia. The peripheral intravenous dose is usually 20–40 mmol of K+-Cl– per liter; higher concentra­ tions can cause localized pain from chemical phlebitis, irritation,

Yes No further workup Yes Clear evidence of transcellular shift -Insulin excess -β2-adrenergic agonists -FHPP -Hyperthyroidism -Barium intoxication -Theophylline -Chloroquine Urine K+ Fluid and Electrolyte Disturbances CHAPTER 56 Renal loss TTKG

4 <2 ↑ Distal K+ secretion ↑ Tubular flow -Osmotic diuresis BP and/or Volume High Low High Cortisol Renin <10 -Vomiting -Chloride diarrhea High Low High Normal -Liddle’s syndrome -Licorice -SAME -RAS -RST -Malignant HTN -PA -FH-I -Cushing’s syndrome and sclerosis. If hypokalemia is severe (<2.5 mmol/L) and/or critically symptomatic, intravenous K+-Cl– can be administered through a central vein with cardiac monitoring in an intensive care setting, at rates of 10–20 mmol/h; higher rates should be reserved for acutely life-threatening complications. The absolute amount of administered K+ should be restricted (e.g., 20 mmol in 100 mL of saline solution) to prevent inadvertent infusion of a large dose. Strategies to minimize K+ losses should also be considered. These measures may include minimizing the dose of non-K+-sparing diuretics, restricting Na+ intake, and using clinically appropriate combinations of non-K+-sparing and K+-sparing medications (e.g., loop diuretics with ACE inhibitors).

■ ■HYPERKALEMIA Hyperkalemia is defined as a plasma potassium level of 5.5 mM, occurring in up to 10% of hospitalized patients; severe hyperka­ lemia (>6.0 mM) occurs in ~1%, with a significantly increased risk of mortality. Although redistribution and reduced tissue uptake can acutely cause hyperkalemia, a decrease in renal K+ excretion is the most frequent underlying cause (Table 56-5). Excessive intake of K+ is a rare

TABLE 56-5  Causes of Hyperkalemia I. Pseudohyperkalemia A. Cellular efflux; thrombocytosis, erythrocytosis, leukocytosis, in vitro PART 2 Cardinal Manifestations and Presentation of Diseases hemolysis B. Hereditary defects in red cell membrane transport II. Intra- to extracellular shift A. Acidosis B. Hyperosmolality; radiocontrast, hypertonic dextrose, mannitol C. β2-Adrenergic antagonists (noncardioselective agents) D. Digoxin and related glycosides (yellow oleander, foxglove, bufadienolide) E. Hyperkalemic periodic paralysis F. Lysine, arginine, and ε-aminocaproic acid (structurally similar, positively charged) G. Succinylcholine; thermal trauma, neuromuscular injury, disuse atrophy, mucositis, or prolonged immobilization H. Rapid tumor lysis III. Inadequate excretion A. Inhibition of the renin-angiotensin-aldosterone axis; ↑ risk of hyperkalemia when used in combination

1. Angiotensin-converting enzyme (ACE) inhibitors
2. Renin inhibitors; aliskiren (in combination with ACE inhibitors or angiotensin receptor blockers [ARBs])
3. ARBs
4. Blockade of the mineralocorticoid receptor: spironolactone, eplerenone, drospirenone
5. Blockade of the epithelial sodium channel (ENaC): amiloride, triamterene, trimethoprim, pentamidine, nafamostat B. Decreased distal delivery
6. Congestive heart failure
7. Volume depletion C. Hyporeninemic hypoaldosteronism
8. Tubulointerstitial diseases: systemic lupus erythematosus (SLE), sickle cell anemia, obstructive uropathy
9. Diabetes, diabetic nephropathy
10. Drugs: nonsteroidal anti-inflammatory drugs (NSAIDs), cyclooxygenase 2 (COX2) inhibitors, β blockers, cyclosporine, tacrolimus
11. Chronic kidney disease, advanced age
12. Pseudohypoaldosteronism type II: defects in WNK1 or WNK4 kinases, Kelch-like 3 (KLHL3), or Cullin 3 (CUL3) D. Renal resistance to mineralocorticoid
13. Tubulointerstitial diseases: SLE, amyloidosis, sickle cell anemia, obstructive uropathy, post–acute tubular necrosis
14. Hereditary: pseudohypoaldosteronism type I; defects in the mineralocorticoid receptor or the epithelial sodium channel (ENaC) E. Advanced renal insufficiency
15. Chronic kidney disease
16. End-stage renal disease
17. Acute oliguric kidney injury F. Primary adrenal insufficiency
18. Autoimmune: Addison’s disease, polyglandular endocrinopathy
19. Infectious: HIV, cytomegalovirus, tuberculosis, disseminated fungal infection
20. Infiltrative: amyloidosis, malignancy, metastatic cancer
21. Drug-associated: heparin, low-molecular-weight heparin
22. Hereditary: adrenal hypoplasia congenita, congenital lipoid adrenal hyperplasia, aldosterone synthase deficiency
23. Adrenal hemorrhage or infarction, including in antiphospholipid syndrome

cause, given the adaptive capacity to increase renal secretion; however, dietary intake can have a major effect in susceptible patients, e.g., diabetics with hyporeninemic hypoaldosteronism and chronic kidney disease. Drugs that impact on the renin-angiotensin-aldosterone axis are also a major cause of hyperkalemia. Pseudohyperkalemia  Hyperkalemia should be distinguished from factitious hyperkalemia or “pseudohyperkalemia,” an artifactual increase in serum K+ due to the release of K+ during or after venipunc­ ture. Pseudohyperkalemia can occur in the setting of excessive muscle activity during venipuncture (e.g., fist clenching), a marked increase in cellular elements (thrombocytosis, leukocytosis, and/or erythrocy­ tosis) with in vitro efflux of K+, and acute anxiety during venipuncture with respiratory alkalosis and redistributive hyperkalemia. Cooling of blood following venipuncture is another cause, due to reduced cellular uptake; the converse is the increased uptake of K+ by cells at high ambi­ ent temperatures, leading to normal values for hyperkalemic patients and/or to spurious hypokalemia in normokalemic patients. Finally, there are multiple genetic subtypes of hereditary pseudohyperkalemia, caused by increases in the passive K+ permeability of erythrocytes. For example, causative mutations have been described in the red cell anion exchanger (AE1, encoded by the SLC4A1 gene), leading to reduced red cell anion transport, hemolytic anemia, the acquisition of a novel AE1mediated K+ leak, and pseudohyperkalemia. Redistribution and Hyperkalemia  Several different mecha­ nisms can induce an efflux of intracellular K+ and hyperkalemia. Acidemia is associated with cellular uptake of H+ and an associated efflux of K+; it is thought that this effective K+-H+ exchange serves to help maintain extracellular pH. Notably, this effect of acidosis is limited to non–anion gap causes of metabolic acidosis and, to a lesser extent, respiratory causes of acidosis; hyperkalemia due to an acidosis-

induced shift of potassium from the cells into the ECF does not occur in the anion gap acidoses lactic acidosis and ketoacidosis. Hyperkale­ mia due to hypertonic mannitol, hypertonic saline, and intravenous immune globulin is generally attributed to a “solvent drag” effect, as water moves out of cells along the osmotic gradient. Diabetics are also prone to osmotic hyperkalemia in response to intravenous hypertonic glucose, when given without adequate insulin. Cationic amino acids, specifically lysine, arginine, and the structurally related drug epsilon-

aminocaproic acid, cause efflux of K+ and hyperkalemia, through an effective cation-K+ exchange of unknown identity and mechanism. Digoxin inhibits Na+/K+-ATPase and impairs the uptake of K+ by skel­ etal muscle, such that digoxin overdose predictably results in hyperka­ lemia. Structurally related glycosides are found in specific plants (e.g., yellow oleander, foxglove) and in the cane toad, Bufo marinus (bufa­ dienolide); ingestion of these substances and extracts thereof can also cause hyperkalemia. Finally, fluoride ions also inhibit Na+/K+-ATPase, such that fluoride poisoning is typically associated with hyperkalemia. Succinylcholine depolarizes muscle cells, causing an efflux of K+ through acetylcholine receptors (AChRs). The use of this agent is contraindicated in patients who have sustained thermal trauma, neu­ romuscular injury, disuse atrophy, mucositis, or prolonged immobili­ zation. These disorders share a marked increase and redistribution of AChRs at the plasma membrane of muscle cells; depolarization of these upregulated AChRs by succinylcholine leads to an exaggerated efflux of K+ through the receptor-associated cation channels, resulting in acute hyperkalemia. Hyperkalemia Caused by Excess Intake or Tissue Necrosis 

Increased intake of even small amounts of K+ may provoke severe hyperkalemia in patients with predisposing factors; hence, an assess­ ment of dietary intake is crucial. Foods rich in potassium include tomatoes, bananas, and citrus fruits; occult sources of K+, particu­ larly K+-containing salt substitutes, may also contribute significantly. Iatrogenic causes include simple overreplacement with K+-Cl– or the administration of a potassium-containing medication (e.g., K+-

penicillin) to a susceptible patient. Red cell transfusion is a well-described cause of hyperkalemia, typically in the setting of massive transfusions. Finally, severe tissue necrosis, as in acute tumor lysis syndrome and

rhabdomyolysis, will predictably cause hyperkalemia from the release of intracellular K+. Hypoaldosteronism and Hyperkalemia  Aldosterone release from the adrenal gland may be reduced by hyporeninemic hypoal­ dosteronism, medications, primary hypoaldosteronism, or isolated deficiency of ACTH (secondary hypoaldosteronism). Primary hypoal­ dosteronism may be genetic or acquired (Chap. 398) but is commonly caused by autoimmunity, either in Addison’s disease or in the context of a polyglandular endocrinopathy. HIV is a particularly important infectious cause of adrenal insufficiency. The adrenal involvement in HIV disease is usually subclinical; however, adrenal insufficiency may be precipitated by stress, drugs such as ketoconazole that inhibit steroidogenesis, or the acute withdrawal of steroid agents such as megestrol. Among medications associated with hyperkalemia, heparin preparations can cause selective inhibition of aldosterone synthesis by zona glomerulosa cells, leading to hyperreninemic hypoaldosteronism. Hyporeninemic hypoaldosteronism is a very common predispos­ ing factor in several overlapping subsets of hyperkalemic patients: diabetics, the elderly, and patients with renal insufficiency. Classically, patients should have suppressed PRA and aldosterone; ~50% have an associated acidosis, with a reduced renal excretion of NH4 +, a posi­ tive urinary anion gap, and urine pH <5.5. Most patients are volume expanded, with secondary increases in circulating atrial natriuretic peptide (ANP) that inhibit both renal renin release and adrenal aldo­ sterone release. Renal Disease and Hyperkalemia  Chronic kidney disease and end-stage kidney disease are very common causes of hyperkalemia, due to the associated deficit or absence of functioning nephrons. Hyperkalemia is more common in oliguric acute kidney injury; distal tubular flow rate and Na+ delivery are less limiting factors in nono­ liguric patients. Hyperkalemia out of proportion to GFR can also be seen in the context of tubulointerstitial disease that affects the distal nephron, such as amyloidosis, sickle cell anemia, interstitial nephritis, and obstructive uropathy. Hereditary renal causes of hyperkalemia have overlapping clinical features with hypoaldosteronism, hence the diagnostic label pseudo­ hypoaldosteronism (PHA). PHA type I (PHA-I) has both an autosomal recessive and an autosomal dominant form. The autosomal dominant form is due to loss-of-function mutations in the MLR; the recessive form is caused by various combinations of mutations in the three subunits of ENaC, resulting in impaired Na+ channel activity in prin­ cipal cells and other tissues. Patients with recessive PHA-I suffer from lifelong salt wasting, hypotension, and hyperkalemia, whereas the phenotype of autosomal dominant PHA-I due to MLR dysfunction improves in adulthood. PHA type II (PHA-II; also known as hereditary hypertension with hyperkalemia) is in every respect the mirror image of GS caused by loss of function in NCC, the thiazide-sensitive Na+- Cl– cotransporter (see above); the clinical phenotype includes hyper­ tension, hyperkalemia, hyperchloremic metabolic acidosis, suppressed PRA and aldosterone, hypercalciuria, and reduced bone density. PHA-II thus behaves like a gain of function in NCC, and treatment with thiazides results in resolution of the entire clinical phenotype. However, the NCC gene is not directly involved in PHA-II, which is caused by mutations in the WNK1 and WNK4 serine-threonine kinases or the upstream Kelch-like 3 (KLHL3) and Cullin 3 (CUL3) proteins, two components of an E3 ubiquitin ligase complex that regu­ lates these kinases; these proteins collectively regulate NCC activity, with PHA-II-associated activation of the transporter. Medication-Associated Hyperkalemia  Most medications asso­ ciated with hyperkalemia cause inhibition of some component of the renin-angiotensin-aldosterone axis. ACE inhibitors, angiotensin receptor blockers, renin inhibitors, and MLRs are predictable and common causes of hyperkalemia, particularly when prescribed in combination. The oral contraceptive agent Yasmin-28 contains the progestin drospirenone, which inhibits the MLR and can cause hyper­ kalemia in susceptible patients. Cyclosporine, tacrolimus, NSAIDs, and cyclooxygenase 2 (COX2) inhibitors cause hyperkalemia by multiple

mechanisms, but share the ability to cause hyporeninemic hypoal­ dosteronism. Notably, most drugs that affect the renin-angiotensin-

aldosterone axis also block the local adrenal response to hyperkale­ mia, thus attenuating the direct stimulation of aldosterone release by increased plasma K+ concentration.

Inhibition of apical ENaC activity in the distal nephron by amiloride and other K+-sparing diuretics results in hyperkalemia, often with a voltage-dependent hyperchloremic acidosis and/or hypovolemic hyponatremia. Amiloride is structurally similar to the antibiotics TMP and pentamidine, which also block ENaC; risk factors for TMP-

associated hyperkalemia include the administered dose, renal insufficiency, and hyporeninemic hypoaldosteronism. Indirect inhibition of ENaC at the plasma membrane is also a cause of drug-associated hyperkalemia; nafa­ mostat, a protease inhibitor used in some countries for anticoagulation and for the management of pancreatitis, inhibits aldosterone-induced renal proteases that activate ENaC by proteolytic cleavage. Fluid and Electrolyte Disturbances CHAPTER 56 Clinical Features  Hyperkalemia is a medical emergency due to its effects on the heart. Cardiac arrhythmias associated with hyper­ kalemia include sinus bradycardia, sinus arrest, slow idioventricular rhythms, ventricular tachycardia, ventricular fibrillation, and asystole. Mild increases in extracellular K+ affect the repolarization phase of the cardiac action potential, resulting in changes in T-wave morphol­ ogy; further increase in plasma K+ concentration depresses intracar­ diac conduction, with progressive prolongation of the PR and QRS intervals. Severe hyperkalemia results in loss of the P wave and a progressive widening of the QRS complex; development of a sine-wave sinoventricular rhythm suggests impending ventricular fibrillation or asystole. Hyperkalemia can also cause a type I Brugada pattern in the electrocardiogram (ECG), with a pseudo–right bundle branch block and persistent coved ST-segment elevation in at least two precordial leads. This hyperkalemic Brugada’s sign occurs in critically ill patients with severe hyperkalemia and can be differentiated from genetic Brugada’s syndrome by an absence of P waves, marked QRS widen­ ing, and an abnormal QRS axis. Classically, the ECG manifestations in hyperkalemia progress from tall peaked T waves (5.5–6.5 mM), to a loss of P waves (6.5–7.5 mM), to a widened QRS complex (7.0–8.0 mM), and, ultimately, a to a sine wave pattern (>8.0 mM). However, these changes are notoriously insensitive, particularly in patients with chronic kidney disease or ESRD. Hyperkalemia from a variety of causes can also present with ascending paralysis, denoted secondary hyperkalemic paralysis to dif­ ferentiate it from familial hyperkalemic periodic paralysis (HYPP). The presentation may include diaphragmatic paralysis and respiratory failure. Patients with familial HYPP develop myopathic weakness dur­ ing hyperkalemia induced by increased K+ intake or rest after heavy exercise. Depolarization of skeletal muscle by hyperkalemia unmasks an inactivation defect in skeletal Na+ channel; autosomal dominant mutations in the SCN4A gene encoding this channel are the predomi­ nant cause. Within the kidney, hyperkalemia has negative effects on the ability to excrete an acid load, such that hyperkalemia per se can contribute to metabolic acidosis. This defect appears to be due in part to competition between K+ and NH4

• for reabsorption by the TALH and subsequent countercurrent multiplication, ultimately reducing the medullary gradient for NH3/NH4 excretion by the distal nephron. Regardless of the underlying mechanism, restoration of normokalemia can, in many instances, correct hyperkalemic metabolic acidosis. Diagnostic Approach  The first priority in the management of hyperkalemia is to assess the need for emergency treatment, followed by a comprehensive workup to determine the cause (Fig. 56-8). His­ tory and physical examination should focus on medications, diet and dietary supplements, risk factors for kidney failure, reduction in urine output, blood pressure, and volume status. Initial laboratory tests should include electrolytes, BUN, creatinine, serum osmolality, Mg2+ and Ca2+, a complete blood count, and urinary pH, osmolality, creati­ nine, and electrolytes. A urine Na+ concentration of <20 mM indicates that distal Na+ delivery is a limiting factor in K+ excretion; volume

No further action K+ ≥6.0 or ECG changes Emergency therapy Yes Hyperkalemia (Serum K+ ≥5.5 mmol/L) No No Yes Treat accordingly and re-evaluate History, physical examination & basic laboratory tests Evidence of increased potassium load No No PART 2 Cardinal Manifestations and Presentation of Diseases Decreased urinary K+ excretion (<40 mmol/day) Urine Na+ Decreased distal Na+ delivery Urine electrolytes <25 mmol/L

8 <5 Reduced tubular flow Reduced distal K+ secretion (GFR >20 ml/min) Advanced kidney failure (GFR ≤20 ml/min) Reduced ECV TTKG <8 (Tubular resistance) TTKG ≥8 Other causes -Tubulointerstitial diseases -Urinary tract obstruction -PHA type I -PHA type II -Sickle cell disease -Renal transplant -SLE High Low Drugs -Amiloride -Spironolactone -Triamterene -Trimethoprim -Pentamidine -Eplerenone -Drospirenone -Calcineurin inhibitors FIGURE 56-8  The diagnostic approach to hyperkalemia. See text for details. ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; CCD, cortical collecting duct; ECG, electrocardiogram; ECV, effective circulatory volume; GFR, glomerular filtration rate; GN, glomerulonephritis; HIV, human immunodeficiency virus; LMW heparin, low-molecular-weight heparin; NSAIDs, nonsteroidal anti-inflammatory drugs; PHA, pseudohypoaldosteronism; SLE, systemic lupus erythematosus; TTKG, transtubular potassium gradient. (Reproduced with permission from DB Mount, K Zandi-Nejad: Disorders of potassium balance, in BM Brenner [ed], Brenner and Rector’s The Kidney, 8th ed, Philadelphia, W.B. Saunders & Company, 2008.) repletion with 0.9% saline or treatment with furosemide may be effec­ tive in reducing plasma K+ concentration. Serum and urine osmolality are required for calculation of the transtubular K+ gradient (TTKG) (Fig. 56-8). The expected values of the TTKG are largely based on his­ torical data, and are <3 in the presence of hypokalemia and >7–8 in the presence of hyperkalemia. Notably, some authors have opined that the TTKG does not consider the effects of distal tubular urea reabsorption on potassium excretion, concluding that the TTKG is, thus, an unreli­ able test in the assessment of hyperkalemia. These criticisms are theo­ retical and not supported by animal experiments; the TTKG remains a helpful bedside test of urinary potassium excretion in hyperkalemia.

= × × + TTKG [K ] Osm [K ] Osm urine serum serum urine

Yes Pseudohyperkalemia? Yes Evidence of transcellular shift Treat accordingly and re-evaluate -Hypertonicity (e.g., mannitol) -Hyperglycemia -Succinylcholine -ε-aminocaproic acid -Digoxin -β-blockers -Metabolic acidosis (non-organic) -Arginine or lysine infusion -Hyperkalemic periodic paralysis -↓Insulin -Exercise TTKG 9α-Fludrocortisone Low aldosterone Renin -Diabetes mellitus -Acute GN -Tubulointerstitial diseases -PHA type II -NSAIDs -β-Blockers -Primary adrenal insufficiency -Isolated aldosterone deficiency -Heparin/LMW heparin -ACE-I/ARB -Ketoconazole TREATMENT Hyperkalemia ECG manifestations of hyperkalemia should be considered a medi­ cal emergency and treated urgently. However, patients with sig­ nificant hyperkalemia (plasma K+ concentration ≥6.5 mM) in the absence of ECG changes should also be aggressively managed, given the limitations of ECG changes as a predictor of cardiac toxicity. Urgent management of hyperkalemia includes admission to the hospital, continuous cardiac monitoring, and immediate treatment. The treatment of hyperkalemia is divided into three stages:

1. Immediate antagonism of the cardiac effects of hyperkalemia. Intravenous calcium serves to protect the heart, whereas other

measures are taken to correct hyperkalemia. Calcium raises the action potential threshold and reduces excitability, without changing the resting membrane potential. By restoring the difference between resting and threshold potentials, calcium reverses the depolarization blockade due to hyperkalemia. The recommended dose is 10 mL of 10% calcium gluconate (3–4 mL of calcium chloride), infused intravenously over 2–3 min with cardiac monitoring. The effect of the infusion starts in 1–3 min and lasts 30–60 min; the dose should be repeated if there is no change in ECG findings or if they recur after initial improve­ ment. Hypercalcemia potentiates the cardiac toxicity of digoxin; hence, intravenous calcium should be used with extreme caution in patients taking this medication; if judged necessary, 10 mL of 10% calcium gluconate can be added to 100 mL of 5% dextrose in water and infused over 20–30 min to avoid acute hypercalcemia. 2. Rapid reduction in plasma K+ concentration by redistribution into cells. Insulin lowers plasma K+ concentration by shifting K+ into cells. The recommended dose is 10 units of intravenous regular insulin followed immediately by 50 mL of 50% dextrose (D50W, 25 g of glucose total); the effect begins in 10–20 min, peaks at 30–60 min, and lasts for 4–6 h. Bolus D50W without insulin is never appropriate, given the risk of acutely worsening hyperka­ lemia due to the osmotic effect of hypertonic glucose. Hypogly­ cemia is common with insulin plus glucose; hence, this should be followed by an infusion of 10% dextrose at 50–75 mL/h, with close monitoring of plasma glucose concentration. In hyperka­ lemic patients with glucose concentrations of ≥200–250 mg/dL, insulin should be administered without glucose, again with close monitoring of glucose concentrations.     β2-Agonists, most commonly albuterol, are effective but unde­ rused agents for the acute management of hyperkalemia. Alb­ uterol and insulin with glucose have an additive effect on plasma K+ concentration; however, ~20% of patients with ESRD are resistant to the effect of β2-agonists; hence, these drugs should not be used without insulin. The recommended dose for inhaled albuterol is 10–20 mg of nebulized albuterol in 4 mL of normal saline, inhaled over 10 min; the effect starts at about 30 min, reaches its peak at about 90 min, and lasts for 2–6 h. Hyperglyce­ mia is a side effect, along with tachycardia. β2-Agonists should be used with caution in hyperkalemic patients with known cardiac disease.     Intravenous bicarbonate has no role in the acute treatment of hyperkalemia but may slowly attenuate hyperkalemia with sustained administration over several hours. It should not be given repeatedly as a hypertonic intravenous bolus of undiluted ampules, given the risk of associated hypernatremia and hyper­ tonicity, but should instead be infused in an isotonic or hypo­ tonic fluid (e.g., 150 milliequivalents of sodium bicarbonate in 1 L of D5W). In patients with metabolic acidosis, a delayed drop in plasma K+ concentration can be seen after 4–6 h of isotonic bicarbonate infusion. 3. Removal of potassium. This is typically accomplished using cation exchange resins, diuretics, and/or dialysis. The cation exchange resin sodium polystyrene sulfonate (SPS) exchanges Na+ for K+ in the gastrointestinal tract and increases the fecal excretion of K+. The recommended dose of SPS is 15–30 g of powder, almost always given in a premade suspension with 33% sorbitol. The effect of SPS on plasma K+ concentration is slow; the full effect may take up to 24 h and usually requires repeated doses every 4–6 h. Intestinal necrosis, typically of the colon or ileum, is a rare but usually fatal complication of SPS. Intestinal necrosis is more common in patients with reduced intestinal motility (e.g., in the postoperative state or after treatment with opioids). The coadministration of SPS with sorbitol appears to increase the risk of intestinal necrosis; however, this complication can also occur with SPS alone, and in animal models, SPS is the causative agent. The low but real risk of intestinal necrosis with SPS, which can sometimes be the only available or appropriate therapy for the removal of potassium, must be weighed against the delayed

onset of efficacy. Whenever possible, alternative therapies for the acute management of hyperkalemia (i.e., alternative potassium binders, aggressive redistributive therapy, isotonic bicarbonate infusion, diuretics, and/or hemodialysis) should be used instead of SPS.     Two other intestinal potassium binders are available for the

management of hyperkalemia. These agents lack the intestinal toxicity of SPS and are preferred over SPS for the management of hyperkalemia. Patiromer is a nonabsorbed polymer provided as a powder for suspension, which binds K+ in exchange for Ca2+. In healthy adults, patiromer causes a decrease in urinary potas­ sium, magnesium, and sodium excretion, suggesting the binding of the polymer to these cations in the intestine; notably, a major side effect of the medication is hypomagnesemia. Sodium zir­ conium cyclosilicate is an inorganic, nonabsorbable crystalline compound that exchanges both Na+ and H+ ions in exchange for K+ and NH4 Fluid and Electrolyte Disturbances CHAPTER 56

• in the intestine. These agents have revolutionized the management of both chronic and acute hyperkalemia. In particular, the availability of safe, well-tolerated potassium bind­ ers allows for greater intensity of renin-angiotensin-aldosterone system inhibition in both renal and cardiac disease.     Therapy with intravenous saline may be beneficial in hypovo­ lemic patients with oliguria and decreased distal delivery of Na+, with the associated reductions in renal K+ excretion. Loop and thiazide diuretics can be used to reduce plasma K+ concentration in volume-replete or hypervolemic patients with sufficient renal function for a diuretic response; this may need to be combined with intravenous saline or isotonic bicarbonate to achieve or maintain euvolemia.     Hemodialysis is the most effective and reliable method to reduce plasma K+ concentration; peritoneal dialysis is consider­ ably less effective. Patients with acute kidney injury require tem­ porary, urgent venous access for hemodialysis, with the attendant risks; in contrast, patients with ESRD or advanced chronic kid­ ney disease may have a preexisting venous access. The amount of K+ removed during hemodialysis depends on the relative distribution of K+ between ICF and ECF (potentially affected by prior therapy for hyperkalemia), the type and surface area of the dialyzer used, dialysate and blood flow rates, dialysate flow rate, dialysis duration, and the plasma-to-dialysate K+ gradient. ■ ■FURTHER READING Choi M et al: K+ channel mutations in adrenal aldosterone-producing adenomas and hereditary hypertension. Science 331:768, 2011. Clase KM et al: Potassium homeostasis and management of dyskale­ mia in kidney diseases: conclusions from a Kidney Disease: Improv­ ing Global Outcomes (KDIGO) Controversies Conference. Kidney Int 97:42, 2020. Fenske W et al: A copeptin-based approach in the diagnosis of diabe­ tes insipidus. N Engl J Med 379:428, 2018. Gankam-Kengne F et al: Osmotic stress–induced defective glial proteostasis contributes to brain demyelination after hyponatremia treatment. J Am Soc Nephrol 28:1802, 2017. Mount DB: Disorders of potassium balance, in Brenner and Rector’s The Kidney, 11th ed, ASL Yu et al: (eds). Philadelphia, W.B. Saunders & Company, 2020, pp. 537–579. Packham DK et al: Sodium zirconium cyclosilicate in hyperkalemia. N Engl J Med 372:222, 2015. Perianayagam A et al: DDAVP is effective in preventing and reversing inadvertent overcorrection of hyponatremia. Clin J Am Soc Nephrol 3:331, 2008. Rondon-Berrios H, Sterns RH: Hypertonic saline for hyponatremia: Meeting goals and avoiding harm. Am J Kidney Dis 79:890, 2022. Soupart A et al: Efficacy and tolerance of urea compared with vap­ tans for long-term treatment of patients with SIADH. Clin J Am Soc Nephrol 7:742, 2012. Turcu AF et al: Primary aldosteronism: A multidimensional syn­ drome. Nat Rev Endocrinol 18:665, 2022.

51 - 57 Hypercalcemia and Hypocalcemia

57 Hypercalcemia and Hypocalcemia

Dwight A. Towler

Hypercalcemia and Hypocalcemia Calcium is the most abundant mineral in the human body, fulfilling numerous physiological functions. These functions include provid­ ing fundamental structure and strength of the skeleton [as the solid hydroxyapatite salt Ca10(PO4)6(OH)2]; cellular signaling and hormone secretion; cardiac pacemaker rhythmicity and contractility; skeletal muscle contractility; immune function; and neural signaling, among others. Given these and other vital biological functions, intracellular and extracellular calcium concentrations are tightly regulated on tim­ escales of milliseconds (intracellular) to minutes–hours (extracellular), with the former very dynamic and the latter very stable as necessary for health. PART 2 Cardinal Manifestations and Presentation of Diseases Serum calcium concentrations are maintained within an exquisitely narrow range through feedback mechanisms that involve parathyroid hormone (PTH) and the vitamin D metabolites 1,25-dihydroxyvitamin D [1,25(OH)2D] and 25-hydroxyvitamin D [25(OH)D]. PTH increases osteocyte production of RANKL, a potent stimulus for osteoclastmediated bone resorption that mobilizes skeletal calcium. These feed­ back mechanisms integrate signals between the parathyroid glands, kidney, intestine, and bone to control circulating extracellular calcium (Fig. 57-1; Chap. 421). Disorders of serum calcium concentration are very common, arising from primary or secondary perturbations in the calciotropic functions. Disease manifestations reflect not only the impact of acute calcium changes on organ function, but also the impact of chronic Parathyroid glands

PTH

ECF Ca2+

Kidney

Bone 1,25 (OH)2D Intestine FIGURE 57-1  Homeostatic feedback mechanisms maintain extracellular calcium concentrations within a narrow physiologic range, typically 8.5–10.5 mg/dL (2.1–2.6 mM) (reference values vary slightly by lab). A decrease in extracellular (ECF) calcium (Ca2+) triggers an increase in parathyroid hormone (PTH) secretion (1) via the calcium sensor receptor (CaSR) on parathyroid chief cells. PTH, in turn, increases resorption of calcium from bone (2, left) and distal renal tubule reabsorption of filtered urinary calcium (2, right), and also stimulates renal proximal tubule 1,25(OH)2D production (3). Circulating 1,25(OH)2D acts on the small intestine to increase dietary calcium absorption (4). Collectively, these homeostatic mechanisms defend against life-threatening hypocalcemia and serve to restore serum calcium levels to normal.

compensatory responses that come with clinical consequences (e.g., osteoporosis, nephrocalcinosis). This chapter provides a brief sum­ mary of the approach to patients with altered serum calcium levels. See Chap. 422 for a detailed discussion of this topic. HYPERCALCEMIA ■ ■ETIOLOGY The causes of hypercalcemia can be understood based on derange­ ments in the normal feedback mechanisms that regulate serum calcium (Table 57-1). Primary hyperparathyroidism and malignancy are the two most common causes of hypercalcemia, although other diseases must be considered (Table 57-2). Excess PTH production, which is not appropriately suppressed by increased serum calcium concentra­ tions, occurs in primary hyperparathyroidism (pHPT). pHPT is almost always due to a nonmalignant neoplastic disorder of the parathyroid glands (a parathyroid adenoma or parathyroid hyperplasia) that is associated with increased parathyroid cell mass and impaired feedback TABLE 57-1  Causes of Hypercalcemia Excessive PTH production   Primary hyperparathyroidism     Sporadic or familial (e.g., MEN) parathyroid adenoma or hyperplasia     Rarely parathyroid carcinoma   Tertiary hyperparathyroidism (long-term stimulation of PTH secretion in renal insufficiency)   Ectopic PTH secretion (very rare)   FHH (mutations reducing CaSR signaling)   Nongenetic alterations in CaSR function (lithium therapy, rare CaSR inhibitory autoantibodies) Hypercalcemia of malignancy   Overproduction of PTHrP (many solid tumors)   Lytic skeletal metastases (breast, myeloma) Excessive 1,25(OH)2D production (by constitutive macrophage CYP27B1 activity)   Granulomatous diseases (many causes: sarcoidosis, tuberculosis, leprosy, fungal infections, foreign body reaction)   Lymphomas (B cell, cutaneous T cell/Sezary syndrome) Vitamin D intoxication   Ingestion of excessive vitamin D: 25(OH)D   Ingestion of excessive 1,25(OH)2D (calcitriol) or 1-alpha-hydroxylated vitamin D analogues   Reduced vitamin D catabolism due to CYP24A1 deficiency Primary increase in bone resorption   Hyperthyroidism   Paget’s disease of bone   Immobilization   Ketogenic diet (in treatment of children with refractory epilepsy, uncommon) Excessive calcium intake   Milk-alkali syndrome   Total parenteral nutrition Other causes   Endocrine disorders (adrenal insufficiency, pheochromocytoma, acromegaly, VIPoma)   Medications (thiazides, vitamin A, lithium, foscarnet, teriparatide, aromatase inhibitors)   Discontinuation of denosumab with rebound resorption   Recovery phase of rhabdomyolysis with renal failure   Williams-Beuren syndrome   Excessive mammary PTHrP production with pregnancy or lactation (rare)   Pseudohypercalcemia (e.g., calcium-binding IgM in Waldenström’s macroglobulinemia) Abbreviations: CaSR, calcium sensor receptor; FHH, familial hypocalciuric hypercalcemia; MEN, multiple endocrine neoplasia; PTH, parathyroid hormone; PTHrP, PTH-related peptide.

TABLE 57-2  Causes of Hypocalcemia Low Parathyroid Hormone Levels (Hypoparathyroidism) Parathyroid agenesis   Isolated (genetic: autosomal recessive GCM2 loss of function; X-linked mutations)   Syndromic (e.g., DiGeorge’s, HDR, Kearns-Sayre) Parathyroid destruction   Surgical   Autoimmune (genetic, e.g., APS-1; or acquired, including immune checkpoint inhibitors)   Radiation   Iron or copper overload (hemochromatosis, transfusion-dependent thalassemia, Wilson’s disease)   Infiltration by metastases or systemic diseases (sarcoid, IgG4-related disease, Riedel’s struma) Reduced bioactive PTH secretion   Hypomagnesemia (genetic, drug-induced, anti–claudin-16 antibodies)   Severe hypermagnesemia (e.g., obstetric magnesium infusions)   Autosomal dominant hypocalcemia (CaSR activating mutations)   Autoimmune (CaSR activating antibodies; immune checkpoint inhibitor therapy)   Familial isolated hypoparathyroidism (rare PTH gene mutations) High Parathyroid Hormone Levels (Secondary Hyperparathyroidism) Vitamin D deficiency or impaired 1,25(OH)2D production/action   Nutritional vitamin D deficiency (poor intake or absorption)   Renal insufficiency [phosphate retention, impaired 1,25(OH)2D production]   Excessive intravenous phosphate infusion   Vitamin D resistance, including receptor defects Intrinsic small intestine disorders with chronic calcium malabsorption   Roux-en-Y bariatric surgery, other causes of short bowel syndrome   Celiac disease, Crohn’s disease (often with concomitant vitamin D deficiency) Parathyroid hormone resistance   Pseudohypoparathyroidism (GNAS mutations or imprinting defects)   Congenital PTH receptor mutation syndromes   PTH receptor blocking autoantibodies Drugs   Alcohol (both acute and chronic ingestion)   Calcium chelators (including citrate from massive blood transfusion or FFP)   Inhibitors of bone resorption (bisphosphonates, denosumab, plicamycin)   Increased vitamin D catabolism (phenytoin, phenobarbital)   Phosphate-containing enemas (excessive or with renal disease) Miscellaneous causes   Acute pancreatitis   Acute rhabdomyolysis   Hungry bone syndrome after parathyroidectomy   Osteoblastic metastases with marked stimulation of bone formation (prostate cancer)   Respiratory or metabolic alkalosis (increased calcium binding to albumin)   Refeeding syndrome and its management Pseudohypocalcemia (e.g., low serum albumin with malnutrition, nephrotic syndrome, cirrhosis; gadoversetamide MRI contrast) Abbreviations: APS-1, autoimmune polyglandular syndrome type 1; CaSR, calcium sensing receptor; FFP, fresh frozen plasma; HDR, hypoparathyroidism, sensorineural deafness, and renal disease; MEN, multiple endocrine neoplasia; MRI, magnetic resonance imaging; PTH, parathyroid hormone. inhibition by calcium. When investigated, genetic causes can be identi­ fied in approximately 30% of pHPT cases even in nonfamilial sporadic pHPT, primarily affecting cyclin D1 or menin expression. Moreover, reduced calcium-sensing receptor (CaSR) expression due to CASR chromatin inhibitory H3K27me3 and H3K9me3 hypermethylation is observed in about 50% of sporadic parathyroid adenomas. Reduced

CASR protein expression increases both adenoma growth and the basal point for PTH secretion. Inappropriate PTH secretion for the ambient level of serum calcium also occurs in familial hypocalciuric hypercalce­ mia (FHH). FHH is an autosomal dominant syndrome most commonly involving inactivating mutations in the CASR gene (FHH type 1), with rare families having mutations in other genes encoding proteins neces­ sary for normal CaSR signal transduction. All FHH mutations impair extracellular calcium sensing in both the parathyroid gland and the kidneys, leading to concomitant inappropriate PTH secretion and decreased urinary calcium excretion. In hypercalcemic disorders with normal parathyroid function, PTH levels are suppressed by high serum calcium levels that activate the CaSR to inhibit parathyroid gland PTH production (Fig. 57-1). This is frequently encountered in patients with advanced malignancy. Many solid tumors produce PTH-related pep­ tide (PTHrP). Once processed and secreted, PTHrP shares homology with the first 13 amino acids of PTH and binds the PTH receptor, thus mimicking effects of PTH on bone and kidney to cause hypercalcemia. The hypercalcemia associated with lymphoma or with granulomatous disease (e.g., sarcoidosis, tuberculosis, foreign body reaction) is caused by extrarenal conversion of 25(OH)D to the more potent pro-calcific hormone 1,25(OH)2D by macrophage CYP27B1 activity. The latter is a feature of local innate immune regulation by vitamin D that oper­ ates independent of the normal negative feedback loops outlined in Figure 57-1. In granulomatous disorders, this chronic 1,25(OH)2D production enhances intestinal calcium absorption, resulting in hyper­ calcemia and suppressed PTH. Reduced 1,25(OH)2D catabolism due to genetic deficiency in the inactivating 24-hydroxylase CYP24A1 can also cause hypercalcemia. Unlike the direct actions of 1,25(OH)2D intoxication, mechanisms of acute vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol) intoxication relate to acute cellular bioavail­ ability of the 25(OH)D prohormone that is normally stored bound to plasma vitamin D binding protein (DBP). Excessive vitamin D ingestion rapidly displaces this large pool of 25(OH)D normally sequestered by plasma DBP. Although the potency of 25(OH)D for the cellular vitamin D receptor is 500-fold less than 1,25(OH)2D, acute displacement of 25(OH)D from DBP by excessive exogenous vitamin D exposes tissues to 25(OH)D concentrations sufficient to directly activate the receptor in small intestine, increase transcellular calcium absorption, and drive hypercalcemia. While 1,25(OH)2D is normally metabolized within a day or two, the longer half-lives of vitamin D and 25(OH)D can prolong hypercalcemia from vitamin D intoxication for several weeks. Disorders that directly increase calcium mobilization from bone, such as thyrotoxicosis, Paget’s disease of bone, or osteolytic metastases, also lead to hypercalcemia with suppressed PTH secretion, as does exogenous calcium overload. The latter is most commonly observed in excessive oral ingestion (e.g., milk-alkali syndrome) or during total parenteral nutrition with excessive calcium supplementation. Ketogenic diets used to mitigate refractory seizures in children also increase bone resorption and can cause hypercalcemia. Hypercalcemia associated with prolonged immobilization arises from reduced mechanical loading of bone that increases osteocyte RANKL production and osteoclast-mediated bone resorption. In this setting, particularly with older patients, a previously unrecognized contributor to bone resorption (e.g., pHPT, Paget’s disease, or myeloma) may be present and should be considered. Immune checkpoint inhibitors have been rarely associated with either hypercalcemia or hypocalcemia, dependent upon whether the autoimmune immunoglobulin response elicited inhibits or activates the CaSR, respectively.

Hypercalcemia and Hypocalcemia CHAPTER 57 ■ ■CLINICAL MANIFESTATIONS Mild hypercalcemia (10.5–11.9 mg/dL) is largely asymptomatic and usually recognized only on routine calcium measurements. Some patients may complain of vague neuropsychiatric symptoms, includ­ ing trouble concentrating, personality changes, or depression. Other common presenting symptoms may include fatigue, proximal muscle weakness, constipation, hyporeflexia, or nephrolithiasis, and bone mineral density may be reduced. Moderate (≥12–14 mg/dL) to severe (≥14 mg/dL) hypercalcemia may result in progressive lethargy, stupor, or coma, as well as prominent gastrointestinal symptoms (nausea,

vomiting, anorexia, peptic ulcer, or pancreatitis) and acute renal failure. Hypercalcemia decreases renal concentrating ability in part by down­ regulating renal collecting duct aquaporin 2, which causes polyuria and volume depletion with frequent prerenal failure. With long-standing hyperparathyroidism, patients may present with bone pain or patho­ logic fractures and hypertension. Finally, hypercalcemia can result in significant electrocardiographic changes, including bradycardia, atrio­ ventricular block, QRS widening, and short QTc interval.

■ ■DIAGNOSTIC APPROACH The first step in the diagnostic evaluation of hypercalcemia or hypo­ calcemia is to ensure that the reported alteration in serum calcium is not due to an abnormal albumin concentration or a similar confounder (pseudohypercalcemia or pseudohypocalcemia; Tables 57-1 and 57-2). About 50% of total serum calcium is ionized, with the remainder bound principally to albumin. Although direct measurements of ion­ ized calcium are possible, these are easily influenced by collection methods that alter calcium binding to albumin (e.g., prolonged tourni­ quet application during phlebotomy). Thus, it is generally preferable to measure total serum calcium and albumin to “correct” the serum calcium. When serum albumin concentrations are reduced, a corrected calcium concentration is calculated by adding 0.8 mg/dL to the total calcium level for every decrement in serum albumin of 1.0 g/dL below the albu­ min reference value of 4.0 g/dL. Conversely, when albumin concentra­ tions are increased, calcium is corrected by subtracting 0.8 mg/dL from the total serum calcium for every increase in serum albumin of 1.0 g/dL above 4.0 g/dL. PART 2 Cardinal Manifestations and Presentation of Diseases A detailed history provides important clues regarding the etiology of hypercalcemia (Table 57-1). Chronic hypercalcemia (many months to several years), often fluctuating between high normal to just above the limits of normal, is most commonly caused by pHPT or by FHH, and occasionally by multiple myeloma. Because of the phosphaturic actions of PTH, the hypercalcemia of pHPT is often accompanied by low serum phosphate or frank hypophosphatemia. Most malignancy-

associated hypercalcemia presents with a more acute course. The history should include review of medications (e.g., thiazides, recent initiation of an aromatase inhibitor), over-the-counter supplements or special diets, personal or family history of nephrolithiasis or other endocrine/ metabolic disorders, any previous neck surgery, prior or current malig­ nancy diagnosis, and systemic symptoms suggestive of sarcoidosis, lymphoma, or hyperthyroidism that may be causative or contributory. Once true hypercalcemia is established, the second most important laboratory test in the diagnostic evaluation is a PTH level using a twosite assay for the intact hormone. Serum creatinine should be measured to assess renal function; hypercalcemia can impair renal function, and reduced clearance of inactive PTH fragments may still be detected in some third-generation two-site PTH assays. However, if the PTH level is increased (or “inappropriately normal”) in the setting of elevated calcium and low/low-normal phosphorus, the diagnosis is almost always pHPT, particularly if the 24-hour urinary fractional excretion of calcium is elevated (>0.02; described below). Genetic analysis is important if early-onset or dominant hereditary pHPT is present with (1) other endocrinopathy suggesting multiple endocrine neopla­ sia or (2) a lytic-sclerotic tumor of the jaw. In the latter, the inactivat­ ing mutations in the tumor suppressor gene CDC73 that cause this syndromic pHPT profoundly increase the lifetime risk for parathyroid carcinoma (~30%). Because individuals with FHH may also present with mildly elevated PTH levels and hypercalcemia, FHH should be considered and excluded because parathyroid surgery is ineffective in this condition. Due to impaired CaSR function in parathyroids and kidney, a calcium/creatinine clearance ratio (calculated as urine cal­ cium/serum calcium divided by urine creatinine/serum creatinine) of <0.01 is suggestive of FHH, particularly when there is a family history of mild, asymptomatic hypercalcemia or recurrent unsuccessful surger­ ies for “presumed” pHPT. Sequencing of the genes that control CaSR signaling (CASR, GNA11, AP2S1) is now commonly performed for the definitive diagnosis of FHH, particularly if urine calcium studies are inconclusive. Prolonged lithium therapy increases the CaSR set point for negative feedback by calcium and can cause hyperparathyroidism

due to parathyroid hyperplasia or adenoma. Ectopic PTH secretion is extremely rare but has been reported in carcinomas with PTH gene rearrangements; unlike pHPT or parathyroid carcinoma, ectopic PTH secretion does not fluctuate in response to therapeutic correction of hypercalcemia since it is not controlled by a CaSR-sensitive tissue. A suppressed PTH level in the face of hypercalcemia indicates that the hypercalcemia is independent of parathyroid gland function; while many other causes must be excluded (Table 57-1), this is most often due to an underlying malignancy. Although a tumor that causes hyper­ calcemia is generally overt, a PTHrP level may be needed to establish the diagnosis of hypercalcemia of malignancy. Multiple myeloma must be evaluated in this setting as well, including measurement of serum free light chains since ~3% of myeloma may be undetected by serum or urine protein electrophoresis with immunofixation. Measurement of serum 25(OH)D is useful for evaluation of both hypercalcemia and hypocalcemia. Hypercalcemia is one of the few settings where a serum 1,25(OH)2D measurement is useful. In hypercalcemia caused by granulomatous disorders or lymphomas, serum 1,25(OH)2D levels are either frankly increased or inappropriately normal, in the setting of a low serum PTH. With vitamin D– or 1,25(OH)2D-mediated hypercalcemia, serum phosphate is frequently elevated or high normal due to increased gastrointestinal absorption and reduced renal excre­ tion. In the vast majority of cases, clinical evaluation in combination with laboratory testing should provide a diagnosis. The very useful mnemonic “VITAMINS TRAP” captures much of the differential for the various disorders listed in Table 57-1: vitamin D, vitamin A intoxication; immobilization; thyrotoxicosis, thiazides, 24-hydroxylase deficiency; Addison’s disease, acromegaly, acquired autoimmune; milk-alkali syndrome; inflammation (chronic); neoplasia including multiple myeloma; sarcoidosis; tuberculosis or another granulomatous disease; rhabdomyolysis recovery phase, rebound from denosumab discontinuation; AIDS; PTH (hyperparathyroidism), Paget’s disease, parenteral sources, pheochromocytoma, pregnancy-associated PTHrP, and pseudohypercalcemia. TREATMENT Hypercalcemia Mild, asymptomatic hypercalcemia does not require immediate therapy beyond assiduous maintenance of adequate oral hydration with close diagnostic follow-up; management is dictated by the underlying cause. By contrast, significant, symptomatic hypercal­ cemia requires acute intervention to restore normocalcemia inde­ pendent of the etiology, in addition to treatment of the underlying cause. Initial therapy of significant hypercalcemia begins with volume expansion because hypercalcemia invariably leads to dehy­ dration, as noted above; 4–6 L of intravenous saline may be required over the first 24 h, keeping in mind that underlying comorbidities (e.g., congestive heart failure) will impact the clinical euvolemic set­ point. Saline infusion improves renal perfusion, urine output, and thus natriuresis, which thereby increases calciuresis. Although loop diuretics can be transiently used to further augment sodium and thus calcium excretion by the distal tubule, loop diuretics should not be initiated until the volume status has been restored to nor­ mal. Following intravenous hydration, which helps to most rapidly address hypercalcemia, the mainstays of therapy are intravenous aminobisphosphonates. Aminobisphosphonates are potent inhibi­ tors of osteoclast-mediated bone resorption, the major contributor to severe hypercalcemia in most malignancies and hyperparathy­ roidism. Zoledronic acid (4 mg intravenously over ~30 min) and pamidronate (60–90 mg intravenously over 2–4 h) are commonly used for the treatment of hypercalcemia of malignancy and para­ thyroid crisis in adults and are occasionally deployed at lower doses in life-threatening hypercalcemia in children. The onset of intravenous aminobisphosphonate action is within 1–2 days, with normalization of serum calcium levels occurring in 60–90% of patients. To achieve a more rapid albeit transient reduction in bone resorption, calcitonin is routinely implemented as well (4–8 IU/kg

given intramuscularly or subcutaneously every 6 h) during the first 48 hours following admission in conjunction with hydration and aminobisphosphonate infusion. Denosumab (dosed 120 mg subcutaneously on days 1, 8, 15, and 29, then monthly thereafter), an antibody to RANKL, is a potent inhibitor of bone resorption and has been shown to be effective in treating hypercalcemia of malignancy refractory to aminobisphosphonates. Lower doses of denosumab (e.g., 0.3 mg/kg) can be used to treat hypercalcemia patients in the setting of advanced kidney disease, since intrave­ nous aminobisphosphonates are contraindicated with glomerular filtration rate <35 mL/min/1.73 m2 and denosumab is cleared by the reticuloendothelial system. In some instances, dialysis may be required to control severe hypercalcemia, particularly in the set­ tings of anuric acute renal failure or congestive heart failure. When diagnosed, parathyroid carcinoma, a rare cause of hypercalcemia of malignancy driven by PTH, is treated with the CaSR agonist cina­ calcet, starting with 30 mg orally twice daily and titrated to normal­ ize serum calcium. Of note, cinacalcet is also used to treat patients with pHPT who are not candidates for parathyroid gland surgery. In patients with vitamin D– or 1,25(OH)2D-mediated hypercal­ cemia, glucocorticoids represent foundational pharmacotherapy, as they directly reduce calcium absorption from the small intestine and decrease 1,25(OH)2D production. Intravenous hydrocortisone (200–400 mg daily) for 3–5 days or oral prednisone (40–60 mg daily) for 7–10 days is used most often, with prolonged taper as guided by serum calcium. However, for severe vitamin D–induced intoxication requiring hospitalization, intravenous hydration and aminobisphosphonates are frequently necessary to rapidly restore normocalcemia. Other drugs, such as ketoconazole, chloroquine, and hydroxychloroquine, decrease 1,25(OH)2D production but are used infrequently due to side effects. However, for individuals with genetic CYP24A1 deficiency, inhibiting 1,25(OH)2D synthesis with ketoconazole or fluconazole can help control hypercalcemia and mitigate the toxicity of chronic glucocorticoid administration. For hypercalcemia of thyroid storm, the aggressive management of the underlying thyrotoxicosis, which also includes intravenous glucocorticoid administration in addition to thionamides, usually restores normocalcemia. HYPOCALCEMIA ■ ■ETIOLOGY The causes of hypocalcemia can be differentiated according to whether serum PTH levels are low (hypoparathyroidism) or high (second­ ary hyperparathyroidism). Although there are many potential causes of hypocalcemia, impaired PTH production and severely impaired intestinal calcium absorption with or without profound vitamin D deficiency are the most common etiologies (Table 57-2) (Chap. 422). Because PTH is the main minute-by-minute defense against hypocal­ cemia, disorders associated with deficient PTH production may be associated with profound, debilitating, and life-threatening hypocal­ cemia. In adults, hypoparathyroidism most commonly results from inadvertent damage to all four parathyroid glands during thyroid or parathyroid gland surgery. Hypoparathyroidism is a cardinal feature of autoimmune endocrinopathies (Chap. 400), responsible for about a quarter of hypoparathyroidism. Even late-onset adult idiopathic hypoparathyroidism—unrelated to neck surgery or autoimmune poly­ glandular syndrome type 1 (APS-1)—frequently exhibits autoimmu­ nity that targets CaSR and other parathyroid antigens. In patients with APS-1, anti-interferon and anti-NALP5 antibodies are frequently pres­ ent. Hypoparathyroidism may be associated with infiltrative diseases such sarcoidosis or IgG4-related disease, iron overload (hemochroma­ tosis, transfusion-dependent thalassemia), copper overload (Wilson’s syndrome), genetic disorders (e.g., DiGeorge’s syndrome), or parathy­ roid involution following neck irradiation. During the COVID-19 pan­ demic, via unknown mechanisms, transient hypoparathyroidism and even spontaneous resolution of pHPT were reported. Rare, congenital hypoparathyroidism has been well documented due to inactivating

mutations in GCM2, GATA3, or even the PTH gene itself. Conversely, activating mutations in the CaSR, or in the GNA11 protein that mediates CaSR signaling (autosomal dominant hypocalcemia), also cause congenital hypoparathyroidism. More commonly, impaired PTH secretion may be secondary to magnesium deficiency (via intracellular actions). Hypomagnesemia with hypocalcemia can arise from druginduced renal loss including chronic alcohol abuse, oncotherapeutics (cisplatin, anti–epidermal growth factor [EGF] antibodies), proton pump inhibitors, or rare autoimmunity that causes tubulointerstitial nephritis with claudin-16 inhibition. Because extracellular magnesium can bind the CaSR with an affinity about one-third that of calcium, severe hypermagnesemia arising from obstetric magnesium infusions for preeclampsia or preterm labor can also suppress PTH release; this rarely causes symptomatic hypoparathyroidism that must be managed until the magnesium infusion is discontinued.

Hypercalcemia and Hypocalcemia CHAPTER 57 Vitamin D deficiency, impaired 1,25(OH)2D production due to chronic renal insufficiency, or vitamin D resistance also cause hypo­ calcemia. However, the degree of hypocalcemia in these disorders is most often not as severe as that seen with hypoparathyroidism; this is because the parathyroids are capable of mounting a compensatory increase in PTH secretion that buffers the extent of hypocalcemia to the detriment of bone. By increasing calcium binding to albumin, both respiratory alkalosis (e.g., hyperventilation) and metabolic alkalosis (e.g., intractable vomiting) can also cause hypocalcemia. When tetany arises with alkalosis, another cause of impaired calcium homeostasis is frequently present. Hypocalcemia may also occur in conditions associ­ ated with severe tissue injury such as burns, rhabdomyolysis, tumor lysis, or pancreatitis. The cause of hypocalcemia in these settings may include a combination of hyperphosphatemia, tissue deposition of calcium, and impaired PTH secretion. ■ ■CLINICAL MANIFESTATIONS Patients with hypocalcemia may be asymptomatic if the decreases in serum calcium are relatively mild and chronic, or they may present with life-threatening complications. Moderate to severe hypocalcemia is associated with paresthesias, usually of the fingers, toes, and circum­ oral regions, and is caused by increased neuromuscular irritability. On physical examination, a Chvostek’s sign (twitching of the ipsilateral perioral levator and zygomaticus muscles in response to gentle tapping of the facial nerve, just anterior to the ear or between the corner of the mouth and zygomatic arch) may be elicited, although it is also present in ~10% of normal individuals. As a more definitive sign of neuromus­ cular irritability and impending tetany, carpal spasm may be induced by inflation of an upper arm blood pressure cuff to 20 mmHg above the patient’s systolic blood pressure for 3 min (Trousseau’s sign; ipsilateral thumb apposition with wrist flexion). With profound vitamin D insuf­ ficiency or hypomagnesemia, proximal myopathy is frequently evident with difficulty rising from a chair while sitting with arms crossed over the chest. Severe hypocalcemia can induce seizures, carpopedal spasm, bronchospasm, laryngospasm, and prolongation of the QTc interval with risk of ventricular tachyarrhythmia (cardiac Torsade) and sudden death. ■ ■DIAGNOSTIC APPROACH In addition to measuring serum calcium, it is important to determine albumin, phosphorus, and magnesium levels. As for the evaluation of hypercalcemia, determining the PTH level is central to the evaluation of hypocalcemia. A suppressed (or “inappropriately low”) PTH level in the setting of hypocalcemia establishes impaired PTH secretion (hypoparathyroidism) as the cause of the hypocalcemia. The history will often elicit the underlying cause (e.g., prior neck surgery with parathyroid gland destruction). By contrast, an elevated PTH level (secondary hyperparathyroidism, a compensatory change in response to low calcium) should direct attention to the vitamin D axis or pri­ mary disease of the small intestine (e.g., short bowel syndrome due to Roux-en-Y bariatric surgery) as the cause of hypocalcemia. These latter patients are at great risk for hypocalcemia with even modest hypopara­ thyroidism following neck surgery and can be very difficult to manage. Nutritional vitamin D deficiency is best assessed by obtaining serum

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58 Acidosis and Alkalosis

25(OH)D levels, which reflect vitamin D stores. Urinary calcium levels in 24-hour collections are low with both vitamin D deficiency and pri­ mary intestinal disease-causing severe calcium malabsorption. In the setting of nonnutritional rickets, with suspected vitamin D resistance, serum 1,25(OH)2D levels are informative.

TREATMENT Hypocalcemia The approach to treatment depends on the severity of the hypocal­ cemia, the rapidity with which it develops, and the accompanying complications (e.g., tetany, seizures, QTc prolongation). Acute, symptomatic hypocalcemia is initially managed with calcium glu­ conate, a 10-mL ampule of 10% wt/vol (90 mg or 2.2 mmol) diluted in 50 mL of 5% dextrose or 0.9% sodium chloride and given intravenously over 5–10 min with telemetry. After one or two additional ampules are given at 10-60 minute intervals as needed to initially resolve symptoms, while transitioning to oral medication symptomatic hypocalcemia often requires a period of continuous intravenous calcium infusion (often starting at 1 mg/min elemental calcium for adults) that is titrated to symptoms, ECG, and blood calcium levels targeting the lower limit of normal. Telemetry with serial exams and blood calcium levels every 4–6 hours should be closely monitored. Accompanying hypomagnesemia, if present, should be treated with appropriate magnesium supplementa­ tion, with initiation of chronic-phase treatment once tetany has resolved, the patient is stable and able to safely take oral medication, and the QTc has normalized. PART 2 Cardinal Manifestations and Presentation of Diseases Chronic hypocalcemia due to hypoparathyroidism is treated with oral calcium supplements (1000–3000 mg/d elemental cal­ cium in divided doses), with careful titration of oral calcitriol [1,25(OH)2D, 0.25–1 μg/d] to achieve albumin-corrected low-normal serum calcium levels. Because calcium resorption in the distal con­ voluted tubule (about 10% of the filtered load) is dependent upon PTH, normalization of calcium to above the low-normal range in the absence of PTH replacement increases hypercalciuria with risk of nephrolithiasis and nephrocalcinosis. Urine 24-hour calcium targets are under 250 mg (women) to 300 mg (men). Adequate vitamin D3 nutrition (1000–2000 IU daily for most adults) must still be maintained and monitored every 6–12 months, measuring serum 25(OH)D levels. PTH (1-84) (Natpara), approved by the Food and Drug Admin­ istration for treatment of hypoparathyroidism, has now been discontinued by the manufacturer. PTH (1-34), also known as teriparatide, is approved for osteoporosis, but has been success­ fully used off-label (20 μg subcutaneously twice daily) for treating refractory hypoparathyroidism. Dosing may need to be decreased in patients with chronic renal insufficiency to avoid hypercalcemia. Palopegteriparatide, a pegylated prodrug form of teriparatide with pharmacokinetics that enable daily subcutaneous dosing for PTH replacement, is now under consideration for regulatory approval. Routine daily vitamin D (~1000 IU D3) and calcium (~1000 mg elemental calcium) nutrition suffices, and hypercalciuria should be absent, with PTH replacement strategies. Hypocalcemia from vitamin D deficiency is best treated using vitamin D supplementa­ tion, with the dose depending on the severity of the deficit and the underlying cause. Thus, nutritional vitamin D deficiency generally responds to moderate doses of oral vitamin D (e.g., ergocalciferol at 50,000 IU, 2–3 times per week for several months), whereas vita­ min D deficiency due to severe enteric malabsorption may require much higher doses (e.g., ergocalciferol carefully titrated up to 100,000 IU/d), as is often the case following Roux-en-Y bariatric surgery. In the setting of intestinal disease, calcium supplementation as calcium citrate is preferred because it is better absorbed, and this formulation increases urinary citrate to mitigate the risk of nephro­ lithiasis in this setting due to increased dietary oxalate absorption. Serum calcium, phosphate, and PTH should be monitored initially every 4 weeks when treating the hypocalcemia of severe vitamin

D insufficiency or gastrointestinal calcium malabsorption, with the goal of normalizing serum biochemistries and 24-hour urine calcium levels to low normal. ■ ■GLOBAL CONSIDERATIONS In countries with limited access to health care or screening laboratory testing of serum calcium levels, pHPT often presents in its advanced form with severe skeletal complications (osteitis fibrosa cystica), in contrast to the incidental finding of asymptomatic hypercalcemia com­ mon in developed countries. Climate change increases the negative impacts of hypercalcemia on risks for nephrolithiasis and heat-related ill­ ness with dehydration in those with previously asymptomatic disease. In addition, vitamin D deficiency is paradoxically common in some countries despite extensive sunlight (e.g., India) due to poor dietary vitamin D intake and avoidance of sun exposure. Acknowledgment The author gratefully acknowledges the contributions of Dr. Sundeep Khosla to this chapter in previous editions of Harrison’s. ■ ■FURTHER READING El-Hajj Fuleihan G: Treatment of hypercalcemia of malignancy in adults: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab 108:507, 2023. Hannan FM et al: The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases. Nat Rev Endocrinol 15:33, 2018. Kahn AA et al: Evaluation and management of hypoparathyroidism. Summary statement and guidelines from the Second International Workshop. J Bone Miner Res 37:2568, 2022. Minisola S et al: Epidemiology, pathophysiology, and genetics of primary hyperparathyroidism. J Bone Miner Res 37:2315, 2022. Motlaghzadeh Y et al: Rare causes of hypercalcemia: 2021 update. J Clin Endocrinol Metab 106:3113, 2021. Walker MD, Shane E: Hypercalcemia. A review. JAMA 328:1624, 2022. Thomas D. DuBose, Jr.

Acidosis and Alkalosis NORMAL ACID-BASE HOMEOSTASIS Systemic arterial pH is maintained between 7.35 and 7.45 by extracel­ lular and intracellular chemical buffering together with respiratory and renal regulatory mechanisms. The control of arterial CO2 tension (Paco2) by the central nervous system (CNS) and respiratory system and the control of plasma bicarbonate by the kidney stabilize the arte­ rial pH by excretion or retention of acid or alkali. The metabolic and respiratory components that regulate systemic pH are described by the Henderson-Hasselbalch equation and solved for pH when the solubil­ ity of CO2 is considered (dissolved CO2 in mmol/L = 0.03 × Paco2 in mmHg), at a pK′ of 6.1: − K pH p log [HCO ] PCO

= ′+ α CO

Under most circumstances, CO2 production and excretion are matched, and the usual steady-state Paco2 is maintained at ~40 mmHg. Underexcretion of CO2 produces hypercapnia, and overexcretion causes hypocapnia. Nevertheless, production and excretion are again

matched at a new steady-state Paco2. Therefore, the Paco2 is regulated primarily by neural respiratory factors and is not subject to regulation by the rate of CO2 production. Hypercapnia is usually the result of hypoventilation rather than of increased CO2 production. Increases or decreases in Paco2 represent derangements of neural respiratory control or are due to compensatory changes in response to a primary alteration in the plasma [HCO3 −]. DIAGNOSIS OF GENERAL TYPES OF DISTURBANCES The most common clinical disturbances are simple acid-base disor­ ders; i.e., metabolic acidosis or alkalosis or respiratory acidosis or alka­ losis occurring individually. Recognition of simple acid-base disorders requires appreciation of the limits of physiologic compensation for a primary disturbance. ■ ■SIMPLE ACID-BASE DISORDERS Primary respiratory disturbances (primary changes in Paco2) invoke compensatory metabolic responses (secondary changes in [HCO3 −]), and primary metabolic disturbances elicit predictable compensa­ tory respiratory responses (secondary changes in Paco2). Physiologic compensation can be predicted from the relationships displayed in Table 58-1. In general, with one exception, compensatory responses return the pH toward, but not to, the normal value. Chronic respira­ tory alkalosis when prolonged is an exception to this rule and may return the pH to a normal value. Metabolic acidosis due to an increase in endogenous acid production (e.g., ketoacidosis or lactic acid aci­ dosis) lowers extracellular fluid [HCO3 −] and decreases extracellular pH. This change stimulates the medullary chemoreceptors to increase ventilation and to return the ratio of [HCO3 −] to Paco2, and, thus, pH, toward, but not typically to, the normal value. The degree of respiratory compensation expected in a metabolic acidosis can be predicted from the relationship: Paco2 = (1.5 × [HCO3 −]) + 8 ± 2 (Winter’s equation). For example, applying this equation, a patient with metabolic acidosis and [HCO3 −] of 12 mmol/L would be expected to have a Paco2 of approximately 26 mmHg. Therefore, if values for Paco2 were <24 or TABLE 58-1  Prediction of Compensatory Responses to Simple

Acid-Base Disturbances and Pattern of Changes RANGE OF VALUES – Paco2 Metabolic acidosis DISORDER PREDICTION OF COMPENSATION PH HCO3 Paco2 = (1.5 × HCO3 –) + 8 ± 2 or Paco2 will ↓ 1.25 mmHg per mmol/L ↓ in [HCO3 Low Low Low –] or Paco2 = [HCO3 –] + 15 Metabolic alkalosis High High High Paco2 will ↑ 0.75 mmHg per mmol/L ↑ in [HCO3 –] or Paco2 will ↑ 6 mmHg per 10 mmol/L ↑ in [HCO3 –] or Paco2 = [HCO3 –] + 15 Respiratory alkalosis   High Low Low   Acute [HCO3       –] will ↓ 0.2 mmol/L per mmHg ↓ in Paco2   Chronic [HCO3       –] will ↓ 0.4 mmol/L per mmHg ↓ in Paco2 Respiratory acidosis   Low High High   Acute [HCO3       –] will ↑ 0.1 mmol/L per mmHg ↑ in Paco2   Chronic [HCO3       –] will ↑ 0.4 mmol/L per mmHg ↑ in Paco2

Arterial blood [H+] (nmol/L) 100 90 80 70 60

100 90 80

Metabolic alkalosis Chronic respiratory acidosis Arterial plasma [HCO3] (mmol/L) –

Acidosis and Alkalosis CHAPTER 58

Acute respiratory acidosis

Normal

Acute respiratory alkalosis

Chronic respiratory alkalosis

Metabolic acidosis

PCO2(mmHg)

7.0 7.1 7.2 7.3 7.4 7.5 7.6 7.7 7.8 Arterial blood, pH FIGURE 58-1  Acid-base nomogram. Shown are the 90% confidence limits (range of values) of the normal respiratory and metabolic compensations for primary acidbase disturbances. (Reproduced with permission from LL Hamm and TD DuBose Jr, in Alan S.L. Yu, et al (eds): Brenner and Rector’s The Kidney, 11th ed. Philadelphia, Elsevier, 2020.)

28 mmHg, values that exceed the boundaries for compensation for a simple disorder, a mixed disturbance should be recognized (metabolic acidosis plus respiratory alkalosis or metabolic acidosis plus respiratory acidosis, respectively). Compensatory responses for primary meta­ bolic disorders move the Paco2 in the same direction as the change in [HCO3 −], while compensation for primary respiratory disorders moves the [HCO3 −] in the same direction as the primary change in Paco2 (Table 58-1). Therefore, changes in Paco2 and [HCO3 −] in opposite directions (i.e., Paco2 or [HCO3 −] is increased, but the accompanying value is decreased) indicate a mixed acid-base disturbance. Another way to judge the appropriateness of the response in [HCO3 −] or Paco2 is to use an acid-base nomogram (Fig. 58-1). While the shaded areas of the nomogram show the 95% confidence limits for physiologic com­ pensation in simple disturbances, finding acid-base values within the shaded area does not necessarily rule out a mixed disturbance. Impo­ sition of one disorder over another may result in values lying within the area of a third. Thus, the nomogram, while convenient, is not a substitute for the equations in Table 58-1. ■ ■MIXED ACID-BASE DISORDERS Acid-base disorders in this category are defined as independently coex­ isting disorders, not merely compensatory responses. These types of disturbances are often seen in critically ill patients and can lead to dan­ gerous extremes of pH (Table 58-2). The diagnosis of mixed acid-base disorders requires consideration of the anion gap (AG). To be accurate, the AG requires the presence of, or correction to, a normal serum albumin of 4.5 g/dL (see below, “Evaluate the Anion Gap”). If a patient with diabetic ketoacidosis (metabolic acidosis) and a high AG has an independent and concomitant respiratory disorder (e.g., pneumonia), the latter may lead to a superimposed respiratory acidosis or alkalosis and the Paco2 will deviate from the predicted value for the response to a pure high-AG metabolic acidosis (Table 58-2). Patients with underlying chronic obstructive pulmonary disease may not respond to metabolic acidosis with an appropriate ventilatory response owing to insufficient respiratory reserve (Table 58-2). The combined presence of respiratory acidosis and metabolic acidosis can lead to severe acidemia. In contrast, when metabolic acidosis and metabolic alkalosis coexist in the same patient, the pH may be in the normal range. In this

TABLE 58-2  Clinical Examples of Mixed Acid-Base Disorders Mixed Metabolic and Respiratory Metabolic acidosis—respiratory alkalosis   Key: High-AG metabolic acidosis; prevailing Paco2 below predicted value (Table 58-1)   Example: Na+, 140; K+, 4.0; Cl−, 106; HCO3 −, 14; AG, 20; Paco2, 24; pH, 7.39 (etiology: lactic acidosis, sepsis in ICU) Metabolic acidosis—respiratory acidosis   Key: High-AG metabolic acidosis; prevailing Paco2 above predicted value (Table 58-1)   Example: Na+, 140; K+, 4.0; Cl−, 102; HCO3 −, 18; AG, 20; Paco2, 42; pH, 7.25 (etiology: severe pneumonia or pulmonary edema) PART 2 Cardinal Manifestations and Presentation of Diseases Metabolic alkalosis—respiratory alkalosis   Key: Paco2 does not increase as predicted; pH higher than expected   Example: Na+, 140; K+, 4.0; Cl−, 91; HCO3 −, 33; AG, 16; Paco2, 38; pH, 7.56

(end-stage liver disease with ascites in patient receiving diuretics) Metabolic alkalosis—respiratory acidosis   Key: Paco2 higher than predicted; pH normal although both Paco2 and HCO3 − abnormal   Example: Na+, 140; K+, 3.5; Cl−, 88; HCO3 −, 42; AG, 10; Paco2, 67; pH, 7.42

(COPD in patient receiving diuretics) Mixed Metabolic Disorders Metabolic acidosis—metabolic alkalosis   Key: Only detectable if in patient with high-AG acidosis; ΔAG (10) >> ΔHCO3 (0)   Example: Na+, 140; K+, 3.0; Cl−, 95; HCO3 −, 25; AG, 20; Paco2, 40; pH, 7.42 (uremia with vomiting) Metabolic acidosis—metabolic acidosis   Key: Mixed high-AG—normal-AG acidosis; ΔHCO3 – accounted for by combined change in ΔAG and ΔCl−   Example: Na+, 135; K+, 3.0; Cl−, 110; HCO3 −, 10; AG, 15; Paco2, 25; pH, 7.20 (diarrhea and lactic acidosis, toluene toxicity, treatment of diabetic ketoacidosis) Abbreviations: AG, anion gap; COPD, chronic obstructive pulmonary disease;

ICU, intensive care unit. circumstance, it is the recognition of an elevated AG (see below) that denotes the existence of an accompanying metabolic acidosis. Assum­ ing a normal value for the AG of 10 mmol/L, incongruity in the ΔAG (existing AG minus normal AG) and the ΔHCO3 − (normal value of

25 mmol/L minus abnormal HCO3 − in the patient) indicates the pres­ ence of a mixed high-gap acidosis—metabolic alkalosis (see example below). A diabetic patient with ketoacidosis may have acute or chronic kidney failure resulting in a combination of metabolic acidoses from accumulation of both ketoacids and uremic acids. Patients who have ingested an overdose of drug combinations such as sedatives and salicylates may have mixed disturbances as a result of the acid-base response to the individual drugs (metabolic acidosis mixed with respi­ ratory acidosis or respiratory alkalosis, respectively). Triple acid-base disturbances are more complex. For example, patients with metabolic acidosis due to alcoholic ketoacidosis may develop metabolic alkalosis due to vomiting and superimposed respiratory alkalosis due to the hyperventilation of hepatic dysfunction or alcohol withdrawal. APPROACH TO THE PATIENT Acid-Base Disorders The accurate diagnosis of acid-base disorders requires adherence to a stepwise approach (Table 58-3). Blood for plasma electrolytes and arterial blood gases should be drawn simultaneously, prior to therapy. An increase in [HCO3 −] occurs with either metabolic alkalosis or respiratory acidosis. Conversely, a decrease in [HCO3 −] occurs with either metabolic acidosis or respiratory alkalosis. In the determination of arterial blood gases by the clinical laboratory, both pH and Paco2 are measured, and the [HCO3 −] is calculated from

TABLE 58-3  Steps in Accurate Diagnosis of Acid-Base Disorders

1. Obtain arterial blood gas (ABG) and venous electrolytes simultaneously.
2. Calculated [HCO3 −] on ABG and measured value on electrolyte panel should be approximately same; if not, suspect lab error or sampling error.
3. Assess anion gap (AG); correct to albumin concentration of 4.5 g/dL if hypoalbuminemia; high AG present if AG >10 mEq/L.
4. Known causes of high-AG acidosis (Table 58-4; ketoacidosis, lactic acid acidosis, advanced kidney disease, or toxic alcohol ingestion).
5. Known causes of nongap acidosis (Table 58-5; bicarbonate loss from gastrointestinal tract, renal tubular acidosis).
6. Estimate predicted compensatory response (Table 58-1).
7. Compare delta values (ΔAG and ΔHCO3 −).
8. Compare change in [Cl−] with change in [Na+]s on the electrolyte panel. the Henderson-Hasselbalch equation. This calculated value should be compared with the measured [HCO3 −] (or total CO2) on the electrolyte panel. These two values should agree within ±2 mmol/L. If the values do not agree, the blood samples may not have been drawn simultaneously, or a laboratory error may be present. After verifying the blood acid-base values, the precise acid-base disorder can then be classified. EVALUATE THE ANION GAP Evaluations of acid-base disorders should begin with appreciation of the patient’s AG. The AG is calculated, either by the clinical labo­ ratory or the clinician, as follows: AG = Na+ – (Cl− + HCO3 −). The value for plasma [K+] is typically omitted from the calculation of the AG in the United States. The “normal” value for the AG reported by clinical laboratories has declined with improved methodology for measuring plasma electrolytes and ranges from 6−12 mmol/L, with an average of approximately 10 mmol/L. The unmeasured anions normally present in plasma include anionic proteins (e.g., albumin), phosphate, sulfate, and organic anions. When acid anions, such as acetoacetate and lactate, accumulate in extracellular fluid, the AG increases, causing a high-AG acidosis. An increase in the AG is most often due to an increase in unmeasured anions but, less com­ monly, may be due to a decrease in unmeasured cations (calcium, magnesium, potassium). In addition, the AG may increase with an increase in anionic albumin (e.g., severe dehydration). A decrease in the AG can be due to (1) an increase in unmeasured cations; (2) the addition to the blood of abnormal cations, such as lithium (lithium intoxication) or cationic immunoglobulins (plasma cell dyscrasias); (3) a reduction in the plasma anion albumin concen­ tration (nephrotic syndrome, liver disease, or malabsorption); or (4) hyperviscosity and severe hyperlipidemia, which can lead to an underestimation of sodium and chloride concentrations. Since a normal AG of the normal AG of approximately 10 mmol/L assumes that the serum albumin is normal if hypoalbuminemia is present, the value for the calculated AG must be corrected. For each g/dL of serum albumin below the normal value (4.5 g/dL), 2.5 mmol/L should be added to the reported (uncorrected) AG. Therefore, in a patient with a serum albumin of 2.5 g/dL (2 g/dL below the normal value) and an uncorrected AG of 15, the corrected AG is calculated by adding 5 mmol/L (2.5 × 2 = 5); thus, adding this value to the calculated AG (5 + 15), a corrected AG of 20 mmol/L is appreciated. Since clinical laboratories do not correct the AG for coexisting hypoalbuminemia and typically report the uncorrected value, the attention of the clinician to the prevailing serum albumin concentration is necessary. The clinical disorders that may cause a high-AG acidosis are displayed in Table 58-4. A high AG is usually due to accumulation of non–chloride-con­ taining acids that contain inorganic (phosphate, sulfate), organic (ketoacids, lactate, uremic organic anions), exogenous (salicylate or ingested toxins with organic acid production), or unidentified anions. The high AG is meaningful even if the [HCO3 −] or pH is normal. Simultaneous metabolic acidosis of the high-AG variety

plus either chronic respiratory acidosis or metabolic alkalosis rep­ resents a situation in which [HCO3 −] may be normal or even high (Table 58-3). In cases of high-AG metabolic acidosis, it is valu­ able to compare the decline in [HCO3 −] from the normal value (ΔHCO3 −: 25 – patient’s [HCO3 −]) with the increase in the AG (ΔAG: patient’s AG – 10). Similarly, normal values for [HCO3 −], Paco2, and pH do not ensure the absence of an acid-base disturbance. For example, an alcoholic who has been vomiting prior to admission may develop a metabolic alkalosis with a pH of 7.55, Paco2 of 47 mmHg, [HCO3 −] of 40 mmol/L, [Na+] of 135, [Cl−] of 80, and [K+] of 2.8. If such a patient were then to develop a superimposed alcoholic ketoacidosis with a β-hydroxybutyrate concentration of 15 mmol/L, the arterial pH would fall to 7.40, the [HCO3 −] to 25 mmol/L, and the Paco2 to 40 mmHg. Although these values are normal, the AG is signifi­ cantly elevated at 30 mmol/L, documenting that a mixed metabolic alkalosis and metabolic acidosis coexist. A mixture of high-gap acidosis and metabolic alkalosis is recognized easily by comparing the differences (Δ values) in the normal to prevailing patient values. In this example, the ΔHCO3 − is 0 (25 − 25 mmol/L), but the ΔAG is 20 (30 – 10 mmol/L). Therefore, 20 mmol/L is unaccounted for in the Δ/Δ value (ΔAG to ΔHCO3 −). METABOLIC ACIDOSIS Metabolic acidosis can occur because of an increase in endogenous acid production (such as lactate and ketoacids), loss of bicarbonate (as in diarrhea), or accumulation of endogenous acids because of inappro­ priately low excretion of net acid by the kidney (as in chronic kidney disease). Metabolic acidosis has profound effects on the respiratory, cardiac, and nervous systems. The fall in blood pH is accompanied by a characteristic increase in ventilation. Intrinsic cardiac contractility may be depressed, but inotropic function can be normal because of catecholamine release. Both peripheral arterial vasodilation and central venoconstriction may be present; accordingly, the decrease in central and pulmonary vascular compliance predisposes to pulmonary edema with even minimal volume overload. CNS function is depressed, with headache, lethargy, stupor, and, in some cases, coma. Glucose intoler­ ance may also occur. There are two major categories of clinical metabolic acidosis: highAG and non-AG acidosis (Tables 58-3 and 58-4). The presence of metabolic acidosis, a normal AG, and hyperchloremia denotes the presence of a non-AG metabolic acidosis. TREATMENT Metabolic Acidosis Treatment of metabolic acidosis with alkali should be reserved for severe acidemia except when the patient has no “potential HCO3 −” in plasma. The potential [HCO3 −] can be estimated from the increment (Δ) in the AG (ΔAG = patient’s AG – 10), only if the acid anion that has accumulated in plasma is metaboliz­ able (i.e., β-hydroxybutyrate, acetoacetate, and lactate). Conversely, nonmetabolizable anions that may accumulate in advanced-stage chronic kidney disease or after toxin ingestion are not metaboliz­ able and do not represent “potential” HCO3 −. In patients with acute

kidney failure or acute-on-chronic kidney failure, improvement in TABLE 58-4  Causes of High-Anion Gap Metabolic Acidosis Lactic acidosis Toxins Ketoacidosis   Ethylene glycol   Diabetic   Methanol   Alcoholic   Salicylates   Starvation   Propylene glycol     Pyroglutamic acid (5-oxoproline)   Kidney failure (acute and chronic)

kidney function after volume resuscitation may improve the serum [HCO3

−], but this is a slow and unpredictable process. Conse­ quently, patients with a non-AG acidosis (hyperchloremic acidosis) or an AG acidosis attributable to a nonmetabolizable anion due to advanced kidney failure (“uremic” acidosis) should receive alkali therapy, either PO (NaHCO3 tablets or Shohl’s solution) or IV (NaHCO3), in an amount necessary to slowly increase the plasma [HCO3 −] to a target value of 22 mmol/L. Importantly, overcorrec­ tion should be avoided. Bicarbonate therapy in diabetic ketoacidosis (DKA) is reserved for adult patients with severe acidemia (pH <7.00) and/or evidence of shock. In such circumstances, bicarbonate may be administered IV, as a slow infusion of 50 meq of NaHCO3 diluted in 300 mL of a saline solution, over 30–45 min, during the initial 1–2 h of therapy. Bolus administration should be avoided. Administration of NaHCO3 requires careful monitoring of plasma electrolytes dur­ ing the course of therapy because of the risk for hypokalemia as urine output is reestablished. A reasonable initial goal in DKA is to increase the [HCO3 Acidosis and Alkalosis CHAPTER 58 −] to a target of 10–12 mmol/L and the pH to approximately 7.20, but definitely not to increase these values to normal. ■ ■HIGH-ANION GAP ACIDOSES APPROACH TO THE PATIENT High-Anion Gap Acidoses There are four principal causes of a high-AG acidosis: (1) lactic acidosis, (2) ketoacidosis, (3) ingested toxins, and (4) acute and chronic kidney failure (Table 58-4). Initial screening to differenti­ ate the high-AG acidoses should include (1) a careful history of whether drug or toxin ingestion is present and measurement of arterial blood gas to detect coexistent respiratory alkalosis (e.g., salicylate intoxication); (2) a history of diabetes mellitus (DKA); (3) evidence of alcohol abuse or increased levels of β-hydroxybutyrate (alcoholic ketoacidosis); (4) a history of progressive chronic kidney disease (CKD) and an increase in the patient’s baseline blood urea nitrogen (BUN) and creatinine values (uremic acidosis); (5) inspec­ tion of the urine for oxalate crystals (ethylene glycol ingestion); and (6) recognition of the numerous clinical settings in which lactate levels may be increased (hypotension, shock, cardiac failure, leuke­ mia, cancer, and drug or toxin ingestion). Lactic Acidosis  An increase in plasma l-lactate may be secondary to poor tissue perfusion (“type A” lactic acidosis)—circulatory insuf­ ficiency (shock, cardiac failure), severe anemia, mitochondrial enzyme defects, and inhibitors (carbon monoxide, cyanide)—or to aerobic dis­ orders (“type B” lactic acidosis)—malignancies, nucleoside analogue reverse transcriptase inhibitors in HIV, diabetes mellitus, kidney or hepatic failure, thiamine deficiency, severe infections (cholera, malaria), seizures, or drugs/toxins (biguanides, ethanol, and the toxic alcohols: ethylene glycol, methanol, or propylene glycol). Unrecog­ nized bowel ischemia or infarction in a patient with severe atheroscle­ rosis or cardiac decompensation receiving vasopressors is a relatively common cause of lactic acidosis in elderly patients. Pyroglutamic acidemia may occur in critically ill patients receiving acetaminophen, because of depletion of glutathione and accumulation of 5-oxyprolene. d-Lactic acid acidosis, which may be associated with jejunoileal bypass, short bowel syndrome, or intestinal obstruction, is due to formation of d-lactate by gut bacteria. APPROACH TO THE PATIENT l-Lactic Acid Acidosis The overarching goal of treatment in lactic acidosis is to correct the underlying condition that disrupts lactate metabolism; e.g., tissue perfusion should be restored when inadequate, but vasoconstrictors

should be avoided, if possible, or used cautiously, because they may worsen tissue perfusion. Alkali therapy is generally advocated for acute, severe acidemia (pH <7.00) to improve cardiovascular function. However, NaHCO3 therapy may paradoxically depress cardiac performance and exacerbate acidosis by enhancing lactate production (HCO3 − stimulates phosphofructokinase). While the use of alkali in moderate lactic acidosis is controversial, it is gener­ ally agreed that attempts to return the pH or [HCO3 −] to normal by administration of exogenous NaHCO3 are deleterious. A reasonable approach with severe acidemia is to infuse sufficient NaHCO3 to raise arterial pH to no more than 7.2 or the [HCO3 –] to no more than 12 mmol/L. PART 2 Cardinal Manifestations and Presentation of Diseases NaHCO3 therapy can cause fluid overload, hypercapnia, and hypertension because the amount required can be massive when accumulation of lactic acid is relentless. Fluid administration is poorly tolerated, especially in the oliguric patient, when central venoconstriction coexists. If the underlying cause of the lactic acidosis can be remedied, blood lactate will be converted to HCO3 − and may result in an overshoot alkalosis if exogenous NaHCO3 has been administered excessively. Ketoacidosis  •  DIABETIC KETOACIDOSIS (DKA)  This condition is caused by increased fatty acid metabolism and the accumulation of ketoacids (acetoacetate and β-hydroxybutyrate). DKA usually occurs in insulin-dependent diabetes mellitus in association with cessation of insulin administration or an intercurrent illness such as an infection, gastroenteritis, pancreatitis, or myocardial infarction, which increases insulin requirements temporarily and acutely. DKA is characterized by hyperglycemia, ketonemia, and a high-AG acidosis. Nevertheless, the plasma glucose may be normal or only slightly elevated in the set­ ting of starvation ketoacidosis or in diabetics receiving an agent that inhibits the proximal tubule sodium-glucose co-transporter 2 (SGLT2 inhibitors) (euglycemic DKA [eDKA]). These agents cause glycosuria, an osmotic diuresis, volume depletion, and decreased plasma glucose. Although the accumulation of ketoacids in plasma accounts for the increment in the AG in both classical DKA and eDKA, the plasma glucose is elevated in classical DKA but is typically in the normal range in eDKA. Measurement of urine ketones (by the dipstick nitroprus­ side reaction) does not detect β-hydroxybutyrate accurately and may underestimate the degree of ketosis (see below). Excretion of ketoacids obligates the excretion of cations, such as Na+ and K+, contributing to volume depletion and Cl– retention. In some circumstances, a mixed non-AG–high-AG acidosis may occur simultaneously and is recog­ nized when the ΔHCO3 – exceeds the ΔAG. It should be noted that bicarbonate therapy is rarely necessary in DKA in adults, except with extreme acidemia (pH <7.00) or if the patient is in shock. If adminis­ tered, NaHCO3 should be given in only limited amounts because of the risk for cerebral edema. Patients with DKA are typically volume depleted and require fluid resuscitation with isotonic saline. Volume overexpansion with isotonic saline should be avoided, however, because aggressive saline administration may cause overt volume over­ load and/or hyperchloremic acidosis during or following treatment of DKA. Regular insulin should be administered IV as an initial bolus of 0.1 U/kg followed by an infusion of 0.1 U/kg/h until the AG returns to normal; see Chap. 417 for more detail. ALCOHOLIC KETOACIDOSIS (AKA)  AKA is usually associated with chronic alcoholism, binge drinking, vomiting, abdominal pain, poor nutrition, and volume depletion. The glucose concentration is variable, and acidosis may be severe because of elevated ketones, predominantly β-hydroxybutyrate. The presence of a high-AG acidosis, in the absence of hyperglycemia, in a patient with chronic alcoholism suggests the diagnosis of AKA. Mixed acid-base disorders are common in AKA. Hypoperfusion may enhance lactic acid production (mixed high-AG acidosis), chronic respiratory alkalosis may accompany liver disease (mixed high-AG acidosis and respiratory alkalosis), and metabolic alkalosis can result from vomiting (mixed high-AG acidosis and metabolic alkalosis: ΔAG exceeds ΔHCO3 −). As the circulation is restored by administration of IV fluids, the preferential accumulation

of β-hydroxybutyrate is then shifted to acetoacetate. This explains the common clinical observation of an increasingly positive nitroprusside reaction (ketones) as the circulation is restored. The nitroprusside reaction can detect acetoacetic acid but not β-hydroxybutyrate, so that the degree of ketosis and ketonuria can not only change with therapy but can also be underestimated initially. Therefore, the plasma β-hydroxybutyrate level should be measured specifically. Patients with AKA usually present with relatively normal kidney function, as opposed to DKA, where kidney function is often compromised because of volume depletion (osmotic diuresis) or diabetic nephropathy. The AKA patient with normal kidney function may excrete relatively large quantities of ketoacids and retain Cl– and, therefore, may have a mixed high-AG–non-AG metabolic acidosis (ΔHCO3 − exceeds ΔAG). TREATMENT Alcoholic Ketoacidosis Extracellular fluid deficits almost always accompany AKA and should be repaired by IV administration, initially, of saline and glucose (5% dextrose in 0.9% NaCl). Hypophosphatemia, hypoka­ lemia, and hypomagnesemia may coexist and should be monitored carefully and corrected when indicated. Hypophosphatemia typically emerges 12–24 h after admission and may be severe. Hypophosphate­ mia is exacerbated by glucose infusion, and, if severe, may induce marked muscle weakness, hemolysis, rhabdomyolysis, or respira­ tory arrest. Upper gastrointestinal hemorrhage, pancreatitis, and pneumonia may accompany this disorder. Drug- and Toxin-Induced Acidosis  •  SALICYLATES  (See also Chap. 469) Salicylate intoxication in adults usually causes respiratory alkalosis or a mixture of high-AG metabolic acidosis and respiratory alkalosis. Only a portion of the AG is due to salicylates. Lactic acid production is also often increased. TREATMENT Salicylate-Induced Acidosis Vigorous gastric lavage with isotonic saline (not NaHCO3) should be initiated immediately. All patients should receive at least one round of activated charcoal per nasogastric tube (1 g/kg up to 50 g). To facilitate excretion of salicylate in the acidotic patient, IV NaHCO3 is administered in amounts adequate to alkalinize the urine (urine pH >7.5) and to maintain urine output. Raising urine pH from 6.5 to 7.5 increases salicylate clearance fivefold. Patients with coex­ isting respiratory alkalosis may also receive NaHCO3, but if given, it should be administered cautiously to avoid excessive alkalemia. Acetazolamide may be administered with coexisting alkalemia, when an alkaline diuresis cannot be achieved, or to ameliorate volume overload associated with NaHCO3 administration. Caution is needed because acetazolamide may cause systemic metabolic acidosis if the excreted HCO3 − is not replaced, a circumstance that can markedly reduce salicylate clearance. Hypokalemia should be anticipated with vigorous bicarbonate therapy and should be treated promptly and aggressively. Glucose-containing fluids should be administered because of the danger of hypoglycemia. Exces­ sive insensible fluid losses may cause severe volume depletion and hypernatremia. If acute kidney injury prevents rapid clearance of salicylate, hemodialysis should be performed against a standard bicarbonate dialysate ([HCO3 –] = 30–35 meq/L). ALCOHOLS  Under most physiologic conditions, sodium, urea, and glucose generate the osmotic pressure of blood. Plasma osmolality is calculated according to the following expression: Posm = 2Na+ + Glu + BUN (all in mmol/L), or using conventional laboratory values in which glucose and BUN are expressed in mg/dL: Posm = 2Na+ + Glu/18 + BUN/2.8. The calculated and determined osmolality should agree within 10–15 mmol/kg H2O. When the measured osmolality exceeds the calculated osmolality by >10–15 mmol/kg H2O, one of two

circumstances prevails. Either the serum sodium is spuriously low, as with hyperlipidemia or hyperproteinemia (pseudohyponatremia), or osmolytes other than sodium salts, glucose, or urea have accumulated in plasma. Examples of such osmolytes include mannitol, radiocontrast media, ethanol, isopropyl alcohol, ethylene glycol, propylene glycol, methanol, and acetone. In this situation, the difference between the calculated osmolality and the measured osmolality (osmolar gap) is proportional to the concentration of the unmeasured solute. With an appropriate clinical history and index of suspicion, identification of a serum osmolar gap is helpful in identifying the presence of toxic alcohol-associated AG acidosis. Three alcohols may cause fatal intoxi­ cations: ethylene glycol, methanol, and isopropyl alcohol. All cause an elevated osmolar gap, but only the first two cause a high-AG acidosis. Isopropyl alcohol ingestion does not typically elevate the AG unless extreme overdose causes hypotension and lactic acid acidosis. ETHYLENE GLYCOL  (See also Chap. 469) Ethylene glycol (EG) (com­ monly used in antifreeze, but also in brake fluid and windshield washer fluid deicers) is metabolized by alcohol dehydrogenase. Ingestion of EG leads to metabolic acidosis and severe damage to the CNS, heart, lungs, and kidneys. The combination of both a high AG and osmolar gap is highly suspicious for EG or methanol intoxication. The osmolar gap is determined by comparing the calculated and measured serum osmolality (Measured Sosm – Calculated Sosm). The serum osmolality is calculated as follows: Osmolality = 2 [Na+] + [BUN]/2.8 + [Glucose]/18 The serum osmolality is measured in the clinical laboratory most accurately by freezing point depression. The combination of a high AG and high osmolar gap in a patient suspected of EG ingestion should be taken as evidence of EG toxicity prior to measurement of EG levels, especially when the history is suspicious or highly suggestive of EG ingestion. Most importantly, in the face of an elevated osmolar gap and anion gap, treatment should not be delayed while awaiting return of ethylene glycol or methanol levels from the laboratory. The osmolar gap is typically elevated earlier than the AG, and as the osmolar gap declines, the AG usually increases. The increased AG and osmolar gap in EG intoxication are attributable to accumulation of EG and its metabolites, glycolate, oxalate, and other organic acids. Lactic acid pro­ duction (l-lactate) increases secondary to inhibition of the tricarbox­ ylic acid cycle and an altered intracellular redox state, thus contributing to the high AG. Acute tubule injury is caused initially by glycolate and later is amplified by tubule obstruction from oxalate crystals. TREATMENT Ethylene Glycol Intoxication Therapy requires prompt institution of IV isotonic fluids, thiamine and pyridoxine supplements, fomepizole, and usually, hemodialy­ sis. Ethanol is of historic interest and is no longer recommended as initial therapy unless fomepizole is not available. Both fomepizole and ethanol compete with EG for metabolism by alcohol dehydro­ genase. Fomepizole (4-methylpyrazole; 15 mg/kg IV over 30 min as a loading dose, then 10 mg/kg for four doses every 12 h) is the agent of choice and offers the advantage of a predictable decline in EG levels without excessive obtundation, as commonly seen during ethyl alcohol infusion. Fomepizole should be continued until blood pH is normal or the osmolar gap is <10 mOsm/kg H2O. Hemodi­ alysis is indicated when the arterial pH is <7.3, a high-AG acidosis is present, the osmolar gap exceeds 20 mOsm/kg H2O, or there is evidence of end organ damage such as CNS manifestations and kidney failure. METHANOL  (See also Chap. 469) The ingestion of methanol (wood alcohol) causes metabolic acidosis, and its metabolites formaldehyde and formic acid cause severe optic nerve and CNS damage. Lactic acid, ketoacids, and other unidentified organic acids contribute to the aci­ dosis. Due to its low molecular mass (32 Da), an osmolar gap is present and may precede the elevation of the AG.

TREATMENT Methanol Intoxication Treatment of methanol intoxication is similar to that for EG intoxi­ cation, including general supportive measures, fomepizole, and hemodialysis. PROPYLENE GLYCOL  Propylene glycol is the vehicle used in the IV preparation of diazepam, lorazepam, phenobarbital, nitroglycerine, etomidate, enoximone, and phenytoin. Propylene glycol is generally safe for limited use in these IV preparations, but toxicity has been reported in the setting of the intensive care unit in patients receiving frequent or continuous administration, because propylene glycol may accumulate in plasma. This form of high-gap acidosis should be con­ sidered in patients with unexplained high-gap acidosis, hyperosmolal­ ity, and clinical deterioration, especially in the setting of treatment for alcohol withdrawal. Propylene glycol, like EG and methanol, is metabolized by alcohol dehydrogenase. With intoxication by propylene glycol, the first response is to stop the offending infusion. Additionally, fomepizole may be administered in severely acidotic patients. Acidosis and Alkalosis CHAPTER 58 ISOPROPYL ALCOHOL  Ingested isopropanol is absorbed rapidly and may be fatal when as little as 150 mL of rubbing alcohol, solvent, or deicer is consumed. A plasma level >400 mg/dL is life-threatening. Isopropyl alcohol is metabolized by alcohol dehydrogenase to acetone. The characteristic features differ significantly from EG and methanol intoxication in that the parent compound (isopropyl alcohol), not its metabolites, causes toxicity, and a high-AG acidosis is not present because acetone is rapidly excreted. Both isopropyl alcohol and acetone increase the osmolar gap, and hypoglycemia is common. Alternative diagnoses should be considered if the patient does not improve sig­ nificantly within a few hours. Patients with hemodynamic instability and/or plasma levels above 400 mg/dL should be considered for acute hemodialysis. TREATMENT Isopropyl Alcohol Toxicity Isopropanol alcohol toxicity is treated by supportive therapy, IV flu­ ids, pressors, ventilatory support if needed, and acute hemodialysis for prolonged coma, hemodynamic instability, or levels >400 mg/dL. PYROGLUTAMIC ACID  Acetaminophen-induced high-AG metabolic acidosis is being recognized more frequently and is observed in patients with acetaminophen overdose and in malnourished or critically ill patients receiving acetaminophen in standard dosage. 5-Oxoproline accumulation after acetaminophen should be suspected in the set­ ting of an unexplained high-AG acidosis in the absence of an elevated osmolar gap in patients receiving acetaminophen. The first step in treatment is to immediately discontinue acetaminophen. Additionally, sodium bicarbonate should be given IV. Although N-acetylcysteine has been suggested, it has not been demonstrated unequivocally that it hastens the metabolism of 5-oxoproline by increasing intracellular glutathione concentrations in this setting, as assumed. Chronic Kidney Disease  (See also Chap. 322) The hyperchlo­ remic acidosis of moderate CKD (stage 3B) is eventually converted to the high-AG acidosis of advanced renal failure (stages 4 and 5 CKD). Poor filtration and reabsorption of organic anions contribute to the pathogenesis. As renal disease progresses, the number of functioning nephrons eventually becomes insufficient to keep pace with net acid production. Uremic acidosis in advanced CKD is characterized by a reduced rate of NH4

• production and excretion. Alkaline salts from bone buffer the acid retained in CKD. Despite significant retention of acid (up to 20 mmol/d), the serum [HCO3 −] does not typically decrease further, indicating participation of buffers outside the extra­ cellular compartment. Therefore, a recognized trade-off in untreated chronic metabolic acidosis of CKD stages 3 and 4 is significant loss of bone mass due to reduction in bone calcium carbonate. Chronic

acidosis also contributes significantly to muscle wasting and disability in advancing CKD. Evidence has been advanced recently that the high anion gap acidosis of chronic kidney disease contributes significantly per se to the progressive loss of kidney function.

TREATMENT Metabolic Acidosis of Chronic Kidney Disease Because chronic metabolic acidosis in advanced CKD is clearly associated with muscle catabolism, bone disease, and more rapid progression of CKD, both the “uremic acidosis” of end-stage renal disease and the non-AG metabolic acidosis of stages 3 and 4 CKD require oral alkali replacement to increase and maintain the [HCO3 PART 2 Cardinal Manifestations and Presentation of Diseases −] to a value >22–24 mmol/L. This can be accomplished with relatively modest amounts of alkali (1.0–1.5 mmol/kg body weight per day) and has been shown to slow the progression of CKD. Either NaHCO3 tablets (650-mg tablets contain 7.8 meq) or oral sodium citrate (Shohl’s solution) is effective. The addition of fruits and vegetables (citrate) to the diet increases the plasma [HCO3 –] and slows progression of CKD safely and is well tolerated. Hyperka­ lemia is not a common complication of increasing the dietary intake of fruits and vegetables. ■ ■NON–ANION GAP METABOLIC ACIDOSES Alkali can be lost from the gastrointestinal tract as a result of diarrhea or from the kidneys due to renal tubular abnormalities (e.g., renal tubular acidosis [RTA]). In these disorders (Table 58-5), reciprocal changes in [Cl−] and [HCO3 −] maintain a normal AG. In non-AG acidosis the increase in [Cl−] above the normal value approximates the decrease in [HCO3 −]. The absence of such a relationship (disparity in the D values) suggests a mixed disturbance. Stool contains a higher concentration of HCO3 − and decomposed HCO3 − than plasma so that metabolic acidosis develops in diarrhea. Instead of an acid urine pH (as anticipated with systemic acidosis), urine pH is usually >6 because metabolic acidosis and hypokalemia increase renal synthesis and excretion of NH4 +, thus providing a uri­ nary buffer that increases urine pH. Metabolic acidosis due to gastro­ intestinal losses with a high urine pH can be differentiated from RTA because urinary NH4

• excretion is typically low in RTA and high with diarrhea. Urinary NH4
• levels are not routinely measured by clinical laboratories, but can be estimated by calculating the urine anion gap (UAG): UAG = [Na+ + K+]u – [Cl−]u. When [Cl−]u > [Na+ + K+]u, the UAG is negative by definition. This suggests that the urine ammonium level is appropriately increased, supporting an extrarenal cause of the acidosis. Conversely, when the UAG is positive, the urine ammonium level is predictably low, suggesting a renal tubular origin of the acidosis. Recent studies have shown a poor correlation between the UAG and the measured urine ammonium, thus calling the estimation of urine ammonium by calculation of the UAG into question. Therefore, clini­ cal laboratories should be encouraged to measure urine ammonium by adaptation of automated plasma ammonium assays, using the enzy­ matic method. This is easily accomplished if the urine sample is diluted 1:200 in normal saline. Proximal RTA (type 2 RTA) (Chap. 327) is often due to generalized proximal tubular dysfunction manifested by glycosuria, generalized aminoaciduria, and phosphaturia (Fanconi syndrome). When the plasma [HCO3 −] is low, the urine pH is acid (pH <5.5) but exceeds 5.5 with exogenous alkali therapy. The fractional excretion of [HCO3 −] may exceed 10–15% when the serum HCO3 − is >20 mmol/L. Because of the defect in HCO3 − reabsorption by the proximal tubule, therapy with NaHCO3 will enhance delivery of HCO3 – to the distal nephron and enhance renal potassium secretion, thereby causing hypokalemia. For this reason, potassium supplementation is often added to alkali therapy and may be accomplished by administration of potassium citrate–citric acid solution (Polycitra K or Cytra-K), as discussed below. Distal RTA (type 1 RTA) may be seen as an acquired or inher­ ited disorder. The features of classical distal RTA (type 1 RTA) include hypokalemia, a non-AG metabolic acidosis, low urinary NH4

TABLE 58-5  Causes of Non–Anion Gap Acidosis I. Gastrointestinal bicarbonate loss A. Diarrhea B. External pancreatic or small-bowel drainage/fistula C. Diversion of ureter: ureterosigmoidostomy, jejunal loop, ileal loop D. Drugs

1. Calcium chloride (acidifying agent)
2. Magnesium sulfate (diarrhea)
3. Cholestyramine (bile acid diarrhea) II. Renal acidosis A. Hypokalemia
4. Proximal RTA (type 2 RTA) Drug-induced: acetazolamide, topiramate Inherited: (a) autosomal recessive missense mutation of SLCA4 (encodes for basolateral NBCe1) (accompanied by ocular abnormalities); (b) autosomal dominant mutation of NHE3 (apical Na+/H+ exchanger) (rare; associated with short stature)
5. Distal (classic) RTA (type 1 RTA) Drug-induced: amphotericin B, ifosfamide Inherited: defect of ATP6V1B1 (encodes for basolateral HCO3 –/Cl– exchanger of distal tubule and collecting duct) B. Hyperkalemia
6. Generalized distal nephron dysfunction (type 4 RTA) a. Selective aldosterone deficiency b. Mineralocorticoid resistance (PHA I, autosomal dominant) c. Voltage defect (PHA I, autosomal recessive, and PHA II) d. Hyporeninemic hypoaldosteronism e. Tubulointerstitial disease C. Normokalemia
7. Chronic progressive kidney disease III. Drug-induced hyperkalemia (with CKD) A. Potassium-sparing diuretics (amiloride, triamterene, spironolactone, eplerenone) B. Trimethoprim C. Pentamidine D. ACE-Is and ARBs E. Nonsteroidal anti-inflammatory drugs F. Calcineurin inhibitors G. Heparin in critically ill patients IV. Other A. Acid loads (ammonium chloride, IV hyperalimentation [uncommon]) B. Loss of potential bicarbonate: ketosis with ketone excretion C. Expansion acidosis (rapid saline administration) D. Hippurate E. Cation exchange resins Abbreviations: ACE-I, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CKD, chronic kidney disease; PHA, pseudohypoaldosteronism; RTA, renal tubular acidosis. excretion (positive UAG, low urine [NH4 +]), and an inappropriately high urine pH (pH >5.5) for the prevailing metabolic acidosis. Most patients have hypocitraturia and hypercalciuria. Therefore, nephroli­ thiasis, nephrocalcinosis, and bone disease are common. In contrast, in generalized distal RTA (type 4 RTA), hyperkalemia is disproportion­ ate to the accompanying reduction in glomerular filtration rate (GFR) because of coexisting impairment of potassium and acid secretion. Urinary ammonium excretion is invariably depressed, and kidney function may be compromised secondary to diabetic nephropathy, obstructive uropathy, or chronic tubulointerstitial disease. Hyporeninemic hypoaldosteronism typically presents as a non-AG metabolic acidosis in older adults with diabetes mellitus or tubuloin­ terstitial disease and stage 3 or 4 CKD. These patients typically have hyperkalemia ([K+] 5.2–6.0 mmol/L), hypertension, and congestive heart failure. Both the metabolic acidosis and the hyperkalemia are out of proportion to the reduction in GFR. Nonsteroidal anti-inflammatory

drugs, trimethoprim, pentamidine, angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor blockers (ARBs) may also increase the risk for hyperkalemia and a non-AG metabolic acidosis in patients with CKD, especially from diabetic nephropathy (Table 58-5). TREATMENT Non–Anion Gap Metabolic Acidoses For non-AG acidosis due to gastrointestinal losses of bicarbon­ ate, NaHCO3 may be administered intravenously or orally, as indicated by the severity of both the acidosis and the accompany­ ing volume depletion. Proximal RTA is the most challenging of the RTAs to treat if the goal is to restore the serum [HCO3 –] to normal (as recommended to support normal growth in children with isolated bicarbonate wasting), because administration of oral alkali increases urinary excretion of bicarbonate and potassium. In patients with proximal RTA (type 2), potassium administration is typically necessary. An oral solution of sodium and potassium citrate (citric acid 334 mg, sodium citrate 500 mg, and potas­ sium citrate 550 mg per 5 mL) may be prescribed for this purpose (Virtrate or Cytra-3). In classical distal RTA (type 1), hypokalemia should be corrected initially. When accomplished, alkali therapy with either sodium citrate (Shohl’s solution) or NaHCO3 tablets (650-mg tablets contain 7.8 meq) should be initiated to correct and maintain the serum [HCO3 –] in the range of 24–26 meq/L. Type 1 RTA patients typically respond to chronic alkali therapy readily. The long-term benefits of adequate alkali therapy in distal (type 1) RTA include a decrease in the frequency of nephrolithia­ sis, improvement in bone density, resumption of normal growth patterns in children, and preservation of kidney function in both adults and children. For type 4 RTA, it is necessary to correct the metabolic acidosis, using the same approach as for classical distal RTA (type 1 RTA), and also to correct the plasma [K+]. Hyper­ kalemia directly reduces ammoniagenesis and net acid excretion. Therefore, restoration of normokalemia increases urinary net acid excretion and consequently can greatly improve the metabolic aci­ dosis. Historically, hyperkalemia was treated by chronic administra­ tion of oral sodium polystyrene sulfonate (15 g of power prepared as an oral solution, without sorbitol, once daily 2–3 times per week). However, this preparation is often unpalatable and patient compli­ ance is low. The nonabsorbed, calcium-potassium cation exchange polymer, patiromer, may be considered for type 4 RTA patients with hyperkalemia because it is more palatable and more effective but has very few side effects. Patiromer is administered as 8.4-g packets of powder for suspension PO twice daily with dose adjustment at weekly intervals, based on the plasma [K+], not to exceed 25.2 g/d. Additionally, the diet should be low in potassium-containing foods or supplements (e.g., salt substitute). Potassium-retaining medica­ tions should be discontinued. Finally, patients with documented isolated hypoaldosteronism should receive fludrocortisone, but the dose varies with the cause of the hormone deficiency. This agent should be administered very cautiously and in combination with furosemide in patients with edema and hypertension because of potential aggravation of these conditions. METABOLIC ALKALOSIS Metabolic alkalosis is established by an elevated arterial pH, an increase in the serum [HCO3 −], and an increase in Paco2 as a result of compensatory alveolar hypoventilation (Table 58-1). It is often accom­ panied by hypochloremia and hypokalemia. The elevation in arterial pH establishes the diagnosis because pH is decreased in respiratory acidosis, even though both have an elevated Paco2. Metabolic alkalosis may present as a mixed acid-base disorder in association with either respiratory acidosis, respiratory alkalosis, or metabolic acidosis. ■ ■ETIOLOGY AND PATHOGENESIS Metabolic alkalosis occurs as a result of net gain of [HCO3 −] or loss of nonvolatile acid (usually HCl by vomiting) from the extracellular fluid.

When vomiting causes loss of HCl from the stomach, HCO3 − secretion cannot be initiated in the small bowel, so that HCO3

− is retained in the extracellular fluid. Thus, vomiting or nasogastric suction is an example of the generation stage of metabolic alkalosis, in which the loss of acid typically causes alkalosis. Upon cessation of vomiting, the maintenance stage ensues because secondary factors prevent the kidneys from excreting HCO3 − appropriately. Maintenance of metabolic alkalosis, therefore, represents a failure of the kidneys to eliminate excess HCO3 − from the extracellular compart­ ment. The kidneys will retain, rather than excrete, the excess alkali and maintain the alkalosis if (1) volume deficiency, chloride deficiency, and K+ deficiency exist in combination with a reduced GFR (associated with a low urine [Cl–]) or (2) hypokalemia exists because of autono­ mous hyperaldosteronism (normal urine [Cl–]). In the first example, saline-responsive metabolic alkalosis is corrected by extracellular fluid volume (ECFV) restoration (IV administration of NaCl and KCl), whereas, in the latter, it may be necessary to repair the alkalosis by pharmacologic or surgical intervention, not with saline administration (saline-unresponsive metabolic alkalosis). Acidosis and Alkalosis CHAPTER 58 ■ ■DIFFERENTIAL DIAGNOSIS To establish the cause of metabolic alkalosis (Table 58-6), it is nec­ essary to assess the status of the patient’s ECFV. It is important to measure the recumbent and upright blood pressure and pulse (to determine if orthostasis is present) and to obtain a serum [K+] and a urine [Cl–]. When hyperreninemia or isolated hyperaldosteronism is suspected, renin and aldosterone should be measured. For example, the presence of chronic hypertension and chronic hypokalemia in an alkalotic patient suggests either mineralocorticoid excess or that the hypertensive patient is receiving diuretics. Low plasma renin activity and values for urine [Cl−] >20 meq/L in a patient not receiving diuretics suggest primary mineralocorticoid excess. The combination of hypo­ kalemia and alkalosis in a normotensive, nonedematous patient may be due to Bartter’s or Gitelman’s syndrome, magnesium deficiency, vomit­ ing, exogenous alkali, or diuretic ingestion. Measurement of urine elec­ trolytes (especially the urine [Cl−]) is recommended, and occasionally, screening of the urine for diuretics may be necessary if surreptitious diuretic abuse is suspected. If the urine is alkaline, with an elevated [Na+]u and [K+]u but low [Cl−]u, the diagnosis of either vomiting (overt or surreptitious) or alkali ingestion should be considered. If the urine is relatively acid with low concentrations of Na+, K+, and Cl−, the most likely possibilities are prior vomiting, the posthypercapnic state, or prior diuretic ingestion. If the urine sodium, potassium, and chloride concentrations are not depressed, magnesium deficiency, Bartter’s or Gitelman’s syndrome, or current diuretic ingestion should be consid­ ered. Bartter’s syndrome is distinguished from Gitelman’s syndrome by the presence of hypocalciuria in the latter disorder. Alkali Administration  Chronic administration of alkali to indi­ viduals with normal renal function rarely causes alkalosis. However, in patients with coexistent hemodynamic disturbances associated with effective ECFV depletion (e.g., congestive heart failure), alkalosis can develop because of diminished capacity to excrete HCO3 − or enhanced reabsorption of HCO3 −. Such patients include those who receive NaHCO3 (PO or IV), citrate loads IV (transfusions of whole blood or therapeutic apheresis), or antacids plus cation-exchange resins (alu­ minum hydroxide and sodium polystyrene sulfonate [uncommon]). Nursing home patients receiving enteral tube feedings have a higher incidence of metabolic alkalosis than nursing home patients receiving regular diets. ■ ■METABOLIC ALKALOSIS ASSOCIATED WITH ECFV CONTRACTION, K+ DEPLETION, AND SECONDARY HYPERRENINEMIC HYPERALDOSTERONISM Gastrointestinal Origin  Gastrointestinal loss of H+ from vomit­ ing or gastric aspiration causes simultaneous addition of HCO3 − into the extracellular fluid. During active vomiting, the filtered load of bicarbonate reaching the kidneys is acutely increased and will exceed the reabsorptive capacity of the proximal tubule for HCO3 − absorption.

TABLE 58-6  Causes of Metabolic Alkalosis I. Exogenous HCO3 – loads A. Acute alkali administration B. Milk-alkali syndrome II. Effective ECFV depletion, normal or low BP (with orthostasis), K+ deficiency, and secondary hyperreninemic hyperaldosteronism A. Gastrointestinal origin

1. Vomiting
2. Gastric aspiration
3. Congenital chloridorrhea
4. Gastrocystoplasty
5. Villous adenoma B. Renal origin PART 2 Cardinal Manifestations and Presentation of Diseases
6. Diuretic use (thiazides and loop diuretics)
7. Posthypercapnic state
8. Hypercalcemia/hypoparathyroidism
9. Recovery from lactic acidosis or ketoacidosis
10. Nonreabsorbable anion administration (e.g., IV penicillin, carbenicillin)
11. Mg2+ deficiency
12. K+ depletion
13. Bartter’s syndrome (loss-of-function mutations of transporters and ion channels in TALH)
14. Gitelman’s syndrome (loss-of-function mutation of Na+-Cl– cotransporter in DCT and collecting duct) III. ECFV expansion, hypertension, K+ deficiency, and mineralocorticoid excess A. High renin
15. Renal artery stenosis
16. Accelerated hypertension
17. Renin-secreting tumor
18. Estrogen therapy B. Low renin
19. Primary aldosteronism a. Adenoma b. Hyperplasia c. Carcinoma
20. Adrenal enzyme defects a. 11β-Hydroxylase deficiency b. 17α-Hydroxylase deficiency
21. Cushing’s syndrome or disease
22. Other a. Licorice b. Carbenoxolone c. Chewer’s tobacco IV. Gain-of-function mutation of sodium channel in DCT (ENaC) with ECFV expansion, hypertension, K+ deficiency, and hyporeninemic-hypoaldosteronism A. Liddle’s syndrome Abbreviations: DCT, distal convoluted tubule; ECFV, extracellular fluid volume; TALH, thick ascending limb of Henle’s loop. Subsequently, enhanced delivery of HCO3 – to the distal nephron, where the capacity for HCO3 – reabsorption is lower, will result in excretion of alkaline urine that stimulates potassium secretion. When vomiting ceases, the persistence of volume, potassium, and chloride depletion triggers maintenance of the alkalosis because these conditions promote HCO3 − reabsorption. Correction of the contracted ECFV with NaCl and repair of K+ deficits with KCl correct the acid-base disorder by restoring the ability of the kidney to excrete the excess bicarbonate. Renal Origin  •  diuretics  (See also Chap. 265) Diuretics such as thiazides and loop diuretics (furosemide, bumetanide, torsemide) increase excretion of salt and acutely diminish the ECFV without alter­ ing the total body bicarbonate content. The serum [HCO3 −] increases because the reduced ECFV “contracts” around the [HCO3 −] in plasma (contraction alkalosis). The chronic administration of diuretics tends

to generate an alkalosis by increasing distal salt delivery so that both K+ and H+ secretion are stimulated. The alkalosis is maintained by persis­ tence of the contraction of the ECFV, secondary hyperaldosteronism, K+ deficiency, and the direct effect of the diuretic (as long as diuretic administration continues). Discontinuing the diuretic and providing isotonic saline to correct the ECFV deficit will repair the alkalosis. SOLUTE LOSING DISORDERS: BARTTER’S AND GITELMAN’S SYNDROMES 

See Chap. 327. NON-REABSORBABLE ANIONS AND MAGNESIUM DEFICIENCY  Admin­ istration of large quantities of the penicillin derivatives carbenicillin or ticarcillin causes their non-reabsorbable anions to appear in the distal tubule, causing an increase in the transepithelial potential difference in the collecting tubule. The more negative potential difference increases both H+ and K+ secretion across the apical membrane. Mg2+ deficiency may occur with chronic administration of thiazide diuretics, alcohol­ ism, and malnutrition. In Gitelman’s syndrome, the development of hypokalemic alkalosis occurs through stimulation of renin and aldo­ sterone secretion to enhance distal acidification. POTASSIUM DEPLETION  Chronic K+ depletion, as a result of extreme dietary potassium restriction, diuretics, or alcohol abuse, may initiate metabolic alkalosis by increasing urinary net acid excretion. Potas­ sium depletion often occurs concurrent with magnesium deficiency in alcoholics with malnutrition. The renal generation of NH4

• (ammonia­ genesis) is upregulated directly by hypokalemia. Chronic K+ deficiency also upregulates the H+, K+-ATPases in the distal tubule and collecting duct to increase K+ absorption while simultaneously increasing H+ secretion. Alkalosis associated with severe K+ depletion is resistant to salt administration, but repair of the K+ deficiency corrects the alkalosis. AFTER TREATMENT OF LACTIC ACIDOSIS OR KETOACIDOSIS  When an underlying stimulus for the generation of lactic acid or ketoacid is corrected, such as correction of shock or severe volume depletion by volume restoration, or with insulin therapy for DKA, the lactate or ketones are metabolized to yield an equivalent amount of HCO3 −. If there have been exogenous sources of HCO3 −, this additional HCO3 − will be additive to that amount generated by organic anion metabolism that together may create a surfeit of HCO3 − (“rebound alkalosis”). POSTHYPERCAPNIA  Prolonged CO2 retention with chronic respira­ tory acidosis enhances renal HCO3 − absorption and the generation of new HCO3 − (increased net acid excretion). Metabolic alkalosis occurs when the elevated Paco2 is abruptly returned toward normal because of residual stimulation of HCO3 − absorption by the prior chronic increase in Paco2. ■ ■METABOLIC ALKALOSIS ASSOCIATED WITH ECFV EXPANSION, HYPERTENSION, AND MINERALOCORTICOID EXCESS An increase in aldosterone may be the result of autonomous primary adrenal overproduction or of secondary aldosterone secretion in response to overproduction of renin by the kidney. Mineralocorti­ coid excess increases net acid excretion and may result in metabolic alkalosis, which is typically exacerbated by associated K+ deficiency. The characteristic salt retention and hypertension are due to upregula­ tion of the epithelial Na+ channel (ENaC) in the collecting tubule in response to aldosterone. The kaliuresis persists because of mineralo­ corticoid excess and stimulation of ENaC, causing an increase in tran­ sepithelial voltage that enhances K+ secretion by the collecting duct. Persistent K+ depletion may cause polydipsia and polyuria. Liddle’s syndrome (Chap. 327) results from an inherited gain-offunction mutation of genes that regulate the collecting duct Na+ chan­ nel, ENaC. This rare monogenic form of hypertension is the result of volume expansion that secondarily suppresses aldosterone elaboration. Patients typically present with hypertension, hypokalemia, and meta­ bolic alkalosis. Symptoms  With metabolic alkalosis, changes in CNS and periph­ eral nervous system function are similar to those of hypocalcemia

(Chap. 421); symptoms include mental confusion; obtundation; and a predisposition to seizures, paresthesias, muscular cramping, tetany, aggravation of arrhythmias, and hypoxemia in chronic obstructive pul­ monary disease. Related electrolyte abnormalities include hypokalemia and hypophosphatemia. TREATMENT Metabolic Alkalosis The first goal of therapy is to correct the underlying stimulus for HCO3 − generation. If primary aldosteronism or Cushing’s syn­ drome is present, correction of the underlying cause will reverse the hypokalemia and alkalosis. [H+] loss by the stomach or kidneys can be mitigated by the use of proton pump inhibitors or the discon­ tinuation of diuretics, respectively. The second aspect of treatment is to eliminate factors that sustain the inappropriate increase in HCO3 − reabsorption, such as ECFV contraction or K+ deficiency. K+ deficits should always be repaired. Isotonic saline is recommended to reverse the alkalosis when ECFV contraction is present. If associ­ ated conditions, such as congestive heart failure, preclude infusion of isotonic saline, renal HCO3 − loss can be accelerated by adminis­ tration of acetazolamide (125–250 mg IV), a carbonic anhydrase inhibitor, which is usually effective in patients with adequate kidney function. Close monitoring is required since acetazolamide triggers urinary K+ losses and may cause hypokalemia that should be cor­ rected promptly. Dilute hydrochloric acid IV (0.1 N HCl) has been advocated in extreme cases of metabolic alkalosis but causes hemo­ lysis and must be delivered slowly in a central vein. This preparation is not available generally and requires preparation by the pharmacy. Because serious errors or harm may occur with dilute HCl infusion, its use is not advised. Therapy in Liddle’s syndrome should include a potassium-sparing diuretic (amiloride or triamterene) to inhibit ENaC and correct both the hypertension and the hypokalemia. RESPIRATORY ACIDOSIS Respiratory acidosis occurs as a result of severe pulmonary disease, respiratory muscle fatigue, or abnormalities in ventilatory control. It is characterized by an elevated Paco2 and reduced pH (Table 58-7). In acute respiratory acidosis, there is a compensatory elevation in HCO3 − (due to cellular buffering mechanisms) that increases the serum [HCO3 –] 1 mmol/L for every 10-mmHg increase in Paco2. In chronic respiratory acidosis (>24 h), renal adaptation increases the [HCO3 −] by 4 mmol/L for every 10-mmHg increase in Paco2. The serum HCO3 − usually does not increase above 38 mmol/L in respiratory acidosis. The clinical features of respiratory acidosis vary according to the severity and duration of the disorder, the underlying disease, and whether there is accompanying hypoxemia. A rapid increase in Paco2 (acute hypercapnia) may cause anxiety, dyspnea, confusion, psychosis, and hallucinations and may progress to coma. Chronic hypercapnia may cause sleep disorders; loss of memory; daytime somnolence; per­ sonality changes; impairment of coordination; and motor disturbances such as tremor, myoclonic jerks, and asterixis. Headaches and other signs that mimic raised intracranial pressure, such as papilledema, abnormal reflexes, and focal muscle weakness, may also occur. Depression of the respiratory center by a variety of drugs, injury, or disease can produce respiratory acidosis. This may occur acutely with general anesthetics, sedatives, and head trauma or chronically with sedatives, alcohol, intracranial tumors, and the syndromes of sleep-

disordered breathing including the primary alveolar and obesityhypoventilation syndromes (Chaps. 296 and 308). Abnormalities or disease in the motor neurons, neuromuscular junction, and skel­ etal muscle can cause hypoventilation via respiratory muscle fatigue. Mechanical ventilation, when not properly adjusted, may result in respiratory acidosis, particularly if CO2 production suddenly rises (because of fever, agitation, sepsis, or overfeeding) or alveolar ventila­ tion decreases because of worsening pulmonary function. High levels of positive end-expiratory pressure in the presence of reduced cardiac output may cause hypercapnia as a result of large increases in alveolar

TABLE 58-7  Respiratory Acid-Base Disorders I. Alkalosis A. Central nervous system stimulation

1. Pain
2. Anxiety
3. Fever
4. Cerebrovascular accident
5. Meningitis, encephalitis
6. Tumor
7. Trauma B. Hypoxemia or tissue hypoxia Acidosis and Alkalosis CHAPTER 58
8. High-altitude acclimatization
9. Pneumonia, pulmonary edema
10. Aspiration
11. Severe anemia C. Drugs or hormones
12. Pregnancy, progesterone
13. Salicylates
14. Cardiac failure D. Stimulation of chest receptors
15. Hemothorax
16. Flail chest
17. Cardiac failure
18. Pulmonary embolism E. Miscellaneous
19. Septicemia
20. Hepatic failure
21. Mechanical hyperventilation
22. Heat exposure
23. Recovery from metabolic acidosis II. Acidosis A. Central
24. Drugs (anesthetics, morphine, sedatives)
25. Stroke
26. Infection B. Airway
27. Obstruction
28. Asthma C. Parenchyma
29. Emphysema
30. Pneumoconiosis
31. Bronchitis
32. Adult respiratory distress syndrome
33. Barotrauma D. Neuromuscular
34. Poliomyelitis
35. Kyphoscoliosis
36. Myasthenia
37. Muscular dystrophies E. Miscellaneous
38. Obesity
39. Hypoventilation
40. Permissive hypercapnia dead space (Chap. 296). Permissive hypercapnia may be used to mini­ mize intrinsic positive end-expiratory pressure in respiratory distress syndrome, but the consequential respiratory acidosis may require administration of NaHCO3 to increase the arterial pH to approximately 7.20. The pH should not be increased to the normal value by NaHCO3 infusion, however. Acute hypercapnia follows sudden occlusion of the upper air­ way or generalized bronchospasm as in severe asthma, anaphylaxis,

inhalational burn, or toxin injury. Chronic hypercapnia and respiratory acidosis occur in end-stage obstructive lung disease. Restrictive disor­ ders involving both the chest wall and the lungs can cause respiratory acidosis because the high metabolic cost of respiration initiates ventila­ tory muscle fatigue. Advanced stages of intrapulmonary and extrapul­ monary restrictive defects present as chronic respiratory acidosis.

The diagnosis of respiratory acidosis requires the measurement of Paco2 and arterial pH. A detailed history and physical examination will typically identify the cause. Pulmonary function studies (Chap. 297), including spirometry, diffusion capacity for carbon monoxide, lung volumes, and arterial Paco2 and O2 saturation, usually make it pos­ sible to determine if respiratory acidosis is secondary to lung disease. The workup for nonpulmonary causes should include a detailed drug history, measurement of hematocrit, and assessment of upper airway, chest wall, pleura, and neuromuscular function. PART 2 Cardinal Manifestations and Presentation of Diseases TREATMENT Respiratory Acidosis The management of respiratory acidosis depends on the severity and rate of onset. Acute respiratory acidosis can be life-threatening, and measures to reverse the underlying cause should be undertaken simultaneously with restoration of adequate alveolar ventilation. This may necessitate tracheal intubation and assisted mechanical ventilation. Oxygen administration should be titrated carefully in patients with severe obstructive pulmonary disease and chronic CO2 retention who are breathing spontaneously (Chap. 307). When oxygen is used injudiciously, these patients may experience progres­ sion of the respiratory acidosis, causing severe acidemia. Aggressive and rapid correction of hypercapnia should be avoided, because the falling Paco2 may provoke the same complications noted with acute respiratory alkalosis (i.e., cardiac arrhythmias, reduced cerebral perfusion, and seizures). The Paco2 should be lowered gradually in chronic respiratory acidosis, aiming to restore the Paco2 to baseline levels and to provide sufficient Cl− and K+ to enhance the renal excretion of HCO3 −. Chronic respiratory acidosis is frequently difficult to correct, but the primary goal is to institute measures that may improve lung function (Chap. 303). RESPIRATORY ALKALOSIS Alveolar hyperventilation decreases Paco2 and increases the HCO3 −/ Paco2 ratio, thus increasing pH (Table 58-7). Nonbicarbonate cellular buffers respond by consuming HCO3 −. Hypocapnia develops when a sufficiently strong ventilatory stimulus causes CO2 output in the lungs to exceed its metabolic production by tissues. Plasma pH and [HCO3 −] appear to vary proportionately with Paco2 over a range from 40–15 mmHg. The relationship between arterial [H+] concentration and Paco2 is ∼0.7 mmol/L per mmHg (or 0.01 pH unit/mmHg), and that for plasma [HCO3 −] is 0.2 mmol/L per mmHg. Hypocapnia sustained for >2–6 h is further compensated by a decrease in renal ammonium and titratable acid excretion and a reduction in filtered HCO3 − reab­ sorption. Full renal adaptation to respiratory alkalosis may take sev­ eral days and requires normal volume status and renal function. The kidneys appear to respond directly to the lowered Paco2 rather than to alkalosis per se. In chronic respiratory alkalosis, a 1-mmHg decrease in Paco2 causes a 0.4- to 0.5-mmol/L decrease in [HCO3 −] and a 0.3-mmol/L decrease in [H+] (or 0.003 unit increase in pH). The effects of respiratory alkalosis vary according to duration and severity but are primarily those of the underlying disease. Reduced cerebral blood flow as a consequence of a rapid decline in Paco2 may cause dizziness, mental confusion, and seizures, even in the absence of hypoxemia. The cardiovascular effects of acute hypocapnia in the conscious human are generally minimal, but in the anesthetized or mechanically ventilated patient, cardiac output and blood pressure may fall because of the depressant effects of anesthesia and positivepressure ventilation on heart rate, systemic resistance, and venous return. Cardiac arrhythmias may occur in patients with heart disease as a

result of changes in oxygen unloading by blood from a left shift in the hemoglobin-oxygen dissociation curve (Bohr effect). Acute respiratory alkalosis causes intracellular shifts of Na+, K+, and PO4 2− and reduces free [Ca2+] by increasing the protein-bound fraction. Hypocapnia-induced hypokalemia is usually minor. Chronic respiratory alkalosis is the most common acid-base distur­ bance in critically ill patients and, when severe, portends a poor prog­ nosis. Many cardiopulmonary disorders manifest respiratory alkalosis in their early to intermediate stages. Normocapnia and hypoxemia in a patient with hyperventilation may herald the onset of rapid respira­ tory failure. Therefore, prompt assessment is necessary to determine if the patient is becoming fatigued. Respiratory alkalosis is also common during mechanical ventilation. The hyperventilation syndrome may be disabling. Paresthesia; cir­ cumoral numbness; chest wall tightness or pain; dizziness; inability to take an adequate breath; and, rarely, tetany may be sufficiently stressful to perpetuate the disorder. Arterial blood-gas analysis demonstrates an acute or chronic respiratory alkalosis, often with hypocapnia in the range of 15–30 mmHg, but without hypoxemia. CNS diseases or injury can produce several patterns of hyperventilation and sustained Paco2 levels of 20–30 mmHg. Hyperthyroidism, high caloric loads, and exercise raise the basal metabolic rate, but ventilation usually increases in proportion so that arterial blood gases are unchanged and respira­ tory alkalosis does not develop. Salicylates are the most common cause of drug-induced respiratory alkalosis because of direct stimulation of the medullary chemoreceptor by salicylates (Chap. 469). In addi­ tion, the methylxanthines, theophylline and aminophylline stimulate ventilation and increase the ventilatory response to CO2. Progesterone increases ventilation and lowers arterial Paco2 by as much as 5–10 mmHg. Therefore, chronic respiratory alkalosis is a common feature of pregnancy. Respiratory alkalosis is also prominent in hepatic failure, and the severity correlates with the degree of hepatic insufficiency. Respiratory alkalosis may be an early finding in gram-negative septice­ mia, often occurring before fever, hypoxemia, or hypotension develops. The diagnosis of respiratory alkalosis depends on measurement of arterial pH and Paco2. The plasma [K+] is often reduced and the [Cl−] increased. In the acute phase, respiratory alkalosis is not associ­ ated with increased renal HCO3 − excretion, but within hours, net acid excretion is reduced. In general, the HCO3 − concentration falls by

2.0 mmol/L for each 10-mmHg decrease in Paco2. Chronic respiratory alkalosis occurs when hypocapnia persists for greater than 3–5 days. The decline in Paco2 reduces the serum [HCO3 −] by 4.0–5 mmol/L for each 10-mmHg decrease in Paco2. It is unusual to observe a plasma HCO3 − <12 mmol/L as a result of a pure respiratory alkalosis. The compensatory reduction in plasma [HCO3 –] is so effective in chronic respiratory alkalosis that the pH may not decline significantly from the normal value. Therefore, chronic respiratory alkalosis is the only acid-base disorder for which compensation can return the pH to the normal value. When the diagnosis of respiratory alkalosis is made, its cause should be investigated. The diagnosis of hyperventilation syndrome is made by exclusion. In difficult cases, it may be important to rule out other conditions such as pulmonary embolism, coronary artery disease, and hyperthyroidism. TREATMENT Respiratory Alkalosis The management of respiratory alkalosis is directed toward allevia­ tion of the underlying disorder. If respiratory alkalosis complicates ventilator management, changes in dead space and tidal volume can minimize the hypocapnia. Patients with the hyperventilation syn­ drome may benefit from reassurance, rebreathing from a paper bag during symptomatic attacks, and attention to underlying psycho­ logical stress. Antidepressants and sedatives are not recommended. β-Adrenergic blockers may ameliorate peripheral manifestations of the hyperadrenergic state.

53 - SECTION 8 Alterations in the Skin

SECTION 8 Alterations in the Skin

■ ■REFERENCES Banerjee T et al: High dietary acid load predicts ESRD among adults with CKD. J Am Soc Nephrol 26:1693, 2015. Berend K et al: Physiological approach to assessment of acid-base disturbances. N Engl J Med 371:1434, 2014. Hamm LL, Dubose TD: Disorders of acid-base balance. In Brenner and Rector’s The Kidney, 11th ed. Yu A et al (eds). Philadelphia, Elsevier, 2020, pp 496–536. Kraut JA, Madias NE: Metabolic acidosis of CKD: An update. Am J Kidney Dis 67:307, 2016. Kraut JA, Madias NE: Re-evaluation of the normal range of serum total CO2 concentration. Clin J Am Soc Nephrol 13:343, 2018. Palmer BF, Clegg DJ: Electrolyte and acid–base disturbances in patients with diabetes mellitus. N Engl J Med 373:548, 2015. Wesson DE et al: Mechanisms of metabolic acidosis-induced kidney injury in chronic kidney disease. J Am Soc Nephrol 31:469, 2020. Section 8 Alterations in the Skin Kim B. Yancey, Thomas J. Lawley

Approach to the Patient

with a Skin Disorder The challenge of examining the skin lies in distinguishing normal from abnormal findings, distinguishing significant findings from trivial ones, and integrating pertinent signs and symptoms into an appropri­ ate differential diagnosis. The fact that the largest organ in the body is visible is both an advantage and a disadvantage to those who examine it. It is advantageous because no special instrumentation is necessary and because the skin can be biopsied with little morbidity. However, the casual observer can be misled by a variety of stimuli and overlook important, subtle signs of skin or systemic disease. For instance, the sometimes minor differences in color and shape that distinguish a melanoma (Fig. 59-1) from a benign nevomelanocytic nevus (Fig. 59-2) can be difficult to recognize. A variety of descriptive terms have been developed that characterize cutaneous lesions (Tables 59-1, 59-2, and 59-3; Fig. 59-3), thereby aiding in their interpretation and in the formulation of a differential diagnosis (Table 59-4). For example, the FIGURE 59-1  Superficial spreading melanoma. This is the most common type of melanoma. Such lesions usually demonstrate asymmetry, border irregularity, color variegation (black, blue, brown, pink, and white), a diameter >6 mm, and a history of change (e.g., an increase in size or development of associated symptoms such as pruritus or pain).

Approach to the Patient with a Skin Disorder CHAPTER 59 FIGURE 59-2  Nevomelanocytic nevus. Nevi are benign proliferations of nevomelanocytes characterized by regularly shaped hyperpigmented macules or papules of a uniform color. TABLE 59-1  Description of Primary Skin Lesions Macule: A flat, colored lesion, <2 cm in diameter, not raised above the surface

of the surrounding skin. A “freckle,” or ephelid, is a prototypical pigmented macule. Patch: A large (>2 cm) flat lesion with a color different from the surrounding skin. This differs from a macule only in size. Papule: A small, solid lesion, <0.5 cm in diameter, raised above the surface of the surrounding skin and thus palpable (e.g., a closed comedone, or whitehead, in acne). Nodule: A larger (0.5–5.0 cm), firm lesion raised above the surface of the surrounding skin. This differs from a papule only in size (e.g., a large dermal nevomelanocytic nevus). Tumor: A solid, raised growth >5 cm in diameter. Plaque: A large (>1 cm), flat-topped, raised lesion; edges may either be distinct (e.g., in psoriasis) or gradually blend with surrounding skin (e.g., in eczematous dermatitis). Vesicle: A small, fluid-filled lesion, <0.5 cm in diameter, raised above the plane of surrounding skin. Fluid is often visible, and the lesions are translucent (e.g., vesicles in allergic contact dermatitis caused by Toxicodendron [poison ivy]). Pustule: A vesicle filled with leukocytes. Note: The presence of pustules does not necessarily signify the existence of an infection. Bulla: A fluid-filled, raised, often translucent lesion >0.5 cm in diameter. Wheal: A raised, erythematous, edematous papule or plaque, usually representing short-lived vasodilation and vasopermeability. Telangiectasia: A dilated, superficial blood vessel. TABLE 59-2  Description of Secondary Skin Lesions Lichenification: A distinctive thickening of the skin that is characterized by accentuated skinfold markings. Scale: Excessive accumulation of stratum corneum. Crust: Dried exudate of body fluids that may be either yellow (i.e., serous crust) or red (i.e., hemorrhagic crust). Erosion: Loss of epidermis without an associated loss of dermis. Ulcer: Loss of epidermis and at least a portion of the underlying dermis. Excoriation: Linear, angular erosions that may be covered by crust and are caused by scratching. Atrophy: An acquired loss of substance. In the skin, this may appear as a depression with intact epidermis (i.e., loss of dermal or subcutaneous tissue) or as sites of shiny, delicate, wrinkled lesions (i.e., epidermal atrophy). Scar: A change in the skin secondary to trauma or inflammation. Sites may be erythematous, hypopigmented, or hyperpigmented depending on their age or character. Sites on hair-bearing areas may be characterized by destruction of hair follicles.

56 - 61 Skin Manifestations of Internal Disease

61 Skin Manifestations of Internal Disease

■ ■FURTHER READING Bolognia JL et al (eds): Dermatology, 4th ed. Philadelphia, Elsevier,

James WD et al (eds): Andrew’s Diseases of the Skin Clinical Dermatology, 13th ed. Philadelphia, Elsevier, 2020. Kang S et al (eds): Fitzpatrick’s Dermatology, 9th ed. New York, McGraw-Hill, 2019. Wolff K et al (eds): Fitzpatrick’s Color Atlas and Synopsis of Clinical Dermatology, 8th ed. New York, McGraw-Hill, 2017. PART 2 Cardinal Manifestations and Presentation of Diseases Jean L. Bolognia, Jonathan S. Leventhal,

Irwin M. Braverman

Skin Manifestations of

Internal Disease It is a generally accepted concept in medicine that the skin can develop signs of internal disease. Therefore, in textbooks of medicine, one finds a chapter describing in detail the major systemic disorders that can be identified by cutaneous signs. The underlying assumption of such a chapter is that the clinician has been able to identify the specific disorder in the patient and needs only to read about it in the textbook. In reality, concise differential diagnoses and the identification of these disorders are actually difficult for nondermatologists because they are not well-versed in the recognition of cutaneous lesions or their spec­ trum of presentations. Therefore, this chapter covers this particular topic of cutaneous medicine not by simply focusing on individual dis­ eases, but by describing the various presenting clinical signs and symp­ toms that point to specific disorders. Concise differential diagnoses will be generated in which the significant diseases will be distinguished from the more common cutaneous disorders that have minimal or no significance with regard to associated internal disease. The latter disorders are reviewed in table form and always need to be excluded when considering the former. For a detailed description of individual diseases, the reader should consult a dermatologic text. PAPULOSQUAMOUS SKIN LESIONS (Table 61-1) When an eruption is characterized by elevated lesions, either papules (<1 cm) or plaques (>1 cm), in association with scale, it is referred to as papulosquamous. The most common papulosqua­ mous diseases—tinea, psoriasis, pityriasis rosea, and lichen planus—are primary cutaneous disorders (Chap. 60). When psoriatic lesions are accompanied by arthritis, the possibility of psoriatic arthritis or reac­ tive arthritis should be considered. A history of oral ulcers, conjuncti­ vitis, uveitis, and/or urethritis points to the latter diagnosis. Lithium, beta blockers, anti-PD-1/PD-L1 antibodies, HIV or streptococcal infections, and a rapid taper of systemic glucocorticoids are known to exacerbate psoriasis; despite being used to treat psoriasis, tumor necro­ sis factor (TNF) inhibitors can paradoxically induce psoriatic lesions. Comorbidities in patients with psoriasis include cardiovascular disease and metabolic syndrome. Whenever the clinical diagnosis of pityriasis rosea or lichen planus is made, it is important to review the patient’s medications because the eruption may resolve by simply discontinuing the offending agent. Pityriasis rosea–like drug eruptions are seen most commonly with angiotensin-converting enzyme (ACE) inhibitors, beta blockers, and metronidazole, whereas the drugs that can produce a lichenoid erup­ tion include thiazides, antimalarials, quinidine, beta blockers, TNF inhibitors, anti-PD-1/PD-L1 antibodies, and ACE inhibitors. In some populations (e.g., Europeans), there is a higher prevalence of hepatitis

TABLE 61-1  Selected Causes of Papulosquamous Skin Lesions

1. Primary cutaneous disorders a. Tineaa—widespread disease may be sign of immunosuppression b. Psoriasisa—widespread or resistant disease may be sign of HIV infection c. Pityriasis roseaa d. Lichen planusa e. Parapsoriasis, small plaque and large plaqueb f. Bowen’s disease (squamous cell carcinoma in situ)c
2. Drugs
3. Systemic diseases a. Lupus erythematosus, primarily subacute or chronic (discoid) lesionsd b. Cutaneous T-cell lymphoma, in particular, mycosis fungoidese c. Secondary syphilis d. Reactive arthritis e. Sarcoidosisf—with scale less common than without scale f. Bazex syndrome (acrokeratosis paraneoplastica)g aDiscussed in detail in Chap. 60; cardiovascular disease and the metabolic syndrome are comorbidities in psoriasis; primarily in Europe, hepatitis C virus is associated with oral lichen planus. bSome authors view large plaque parapsoriasis as a form of early mycosis fungoides. cAssociated with chronic sun exposure more often than exposure to arsenic; usually one or a few lesions. dSee also Red Lesions in “Papulonodular Skin Lesions.” eAlso cutaneous lesions of HTLV-1-associated adult T-cell leukemia/lymphoma. fSee also Red-Brown Lesions in “Papulonodular Skin Lesions.” gPsoriasiform lesions of the helices, nose, and acral sites; squamous cell carcinoma of the upper aerodigestive tract most common underlying malignancy. Abbreviation: HIV, human immunodeficiency virus. C viral infection in patients with oral lichen planus. Lichen planus–like lesions are also observed in chronic graft-versus-host disease. In its early stages, the mycosis fungoides (MF) form of cutaneous T-cell lymphoma (CTCL) may be confused with eczema or psoriasis, but it often eventually fails to respond to appropriate therapy for those inflammatory diseases. MF can develop within lesions of large-plaque parapsoriasis and is suggested by an increase in the thickness of the lesions. The diagnosis of MF is established by skin biopsy in which collections of atypical T lymphocytes are found in the epidermis and dermis and is supported by TCR gene rearrangements. As the disease progresses, cutaneous tumors and lymph node involvement may appear. In secondary syphilis, there are scattered pink to red-brown papules with thin scale. The eruption often involves the palms and soles and can resemble pityriasis rosea. Associated findings are helpful in making the diagnosis and include nonscarring alopecia, annular plaques on the face, mucous patches, condyloma lata (broad-based and moist), and lymphadenopathy, as well as malaise, fever, headache, and myalgias. The interval between the primary chancre and the secondary stage is usually 4–8 weeks, and spontaneous resolution without appropriate therapy occurs. ERYTHRODERMA (Table 61-2) Erythroderma is the term used when the majority of the skin surface is erythematous (red in color). Erythema may be more dif­ ficult to appreciate in darkly pigmented skin. There may be associated scale, erosions, or pustules as well as shedding of the hair and nails. Potential systemic manifestations include fever, chills, hypothermia, reactive lymphadenopathy, peripheral edema, hypoalbuminemia, and high-output cardiac failure. The major etiologies of erythroderma are (1) cutaneous diseases such as psoriasis and dermatitis (Table 61-3); (2) drugs; (3) systemic diseases, most commonly CTCL; and (4) idio­ pathic. In the first three groups, the location and description of the initial lesions, prior to the development of the erythroderma, aid in the diagnosis. For example, a history of red scaly plaques on the elbows and knees would point to psoriasis. It is also important to examine the skin carefully for a migration of the erythema and associated second­ ary changes such as pustules or erosions. Migratory waves of erythema studded with superficial pustules are seen in pustular psoriasis.

TABLE 61-2  Causes of Erythroderma

1. Primary cutaneous disorders a. Psoriasisa b. Dermatitis (atopic > contact >> stasis [with autosensitization] or seborrheic [primarily infants])a c. Pityriasis rubra pilaris
2. Drugs
3. Systemic diseases a. Cutaneous T-cell lymphoma (Sézary syndrome, erythrodermic mycosis fungoides) b. Other lymphomas c. Rarely, late-stage solid tumors, autoimmune bullous diseases
4. Idiopathic (usually older men) aDiscussed in detail in Chap. 60. TABLE 61-3  Erythroderma (Primary Cutaneous Disorders) LOCATION OF INITIAL LESIONS OTHER FINDINGS DIAGNOSTIC AIDS TREATMENT   INITIAL LESIONS Psoriasisa Pink-red, silvery scale, sharply demarcated Elbows, knees, scalp, presacral area, intergluteal fold Nail dystrophy (e.g., pits, oil drop sign), arthritis, pustules, SAPHO syndromeb Dermatitisa Atopic Acute: Erythema, fine scale, crust, indistinct borders, excoriations Chronic: Lichenification (increased skin markings), excoriations Antecubital and popliteal fossae, neck, hands, eyelids Pruritus Personal and/or family history of atopy, including asthma, allergic rhinitis or conjunctivitis, and atopic dermatitis Exclude secondary infection with Staphylococcus aureus or HSV Exclude superimposed irritant or allergic contact dermatitis Contact Local: Erythema, crusting, vesicles, and bullae Depends on offending agent Irritant—onset often within hours Allergic—delayed-type hypersensitivity; lag time of 48 h with rechallenge Patient has history of allergic contact dermatitis to topical agent and then receives systemic medication that is structurally related, e.g., formaldehyde (skin), aspartame (oral) Systemic: Erythema, fine scale, crust Generalized vs major intertriginous zones (especially groin) Seborrheic (rare in adults) Pink-red to pinkorange, greasy scale Scalp, nasolabial folds, eyebrows, intertriginous zones Flares with stress, HIV infection Associated with Parkinson’s disease Stasis (with autosensitization) Erythema, crusting, excoriations Lower extremities Pruritus, lower extremity edema, varicosities, hemosiderin deposits, lipodermatosclerosis History of venous ulcers, thrombophlebitis, and/or cellulitis Exclude cellulitis Exclude superimposed contact dermatitis, e.g., topical neomycin Pityriasis rubra pilaris Orange-red (salmon-colored), perifollicular papules Scalp When generalized, characteristic “skip” areas of uninvolved skin Wax-like palmoplantar keratoderma Exclude cutaneous T-cell lymphoma aDiscussed in detail in Chap. 60. bSAPHO syndrome occurs more commonly in patients with palmoplantar pustulosis than in those with erythrodermic psoriasis. Abbreviations: Ab, antibody; HSV, herpes simplex virus; IL, interleukin; IM, intramuscular; MTX, methotrexate; PUVA, psoralens plus ultraviolet A irradiation; SAPHO, synovitis, acne, pustulosis, hyperostosis, and osteitis (a subtype is chronic recurrent multifocal osteomyelitis); TNF, tumor necrosis factor; UV-A, ultraviolet A irradiation; UV-B, ultraviolet B irradiation.

Drug-induced erythroderma may begin as an exanthematous (mor­ billiform) eruption (Chap. 63) or may arise as diffuse erythema. A number of drugs can produce an erythroderma, including penicil­ lins, sulfonamides, aromatic anticonvulsants (e.g., carbamazepine, phenytoin), and allopurinol. Fever and peripheral eosinophilia often accompany the eruption, and there may also be facial swelling, hepa­ titis, allergic interstitial nephritis, myocarditis, and delayed thyroiditis; this constellation is frequently referred to as drug reaction with eosino­ philia and systemic symptoms (DRESS) or drug-induced hypersensitivity syndrome (DIHS). In addition, these reactions, especially to aromatic anticonvulsants, can lead to a pseudolymphoma syndrome with adenopathy and circulating atypical lymphocytes, while reactions to allopurinol may be accompanied by gastrointestinal bleeding.

Skin Manifestations of Internal Disease CHAPTER 61 The most common malignancy that is associated with erythroderma is CTCL; in some series, up to 25% of the cases of erythroderma were Skin biopsy Topical glucocorticoids, vitamin D analogues, aryl hydrocarbon receptor agonist, PDE4 inhibitor; UV-B (narrowband) > PUVA; oral retinoids; MTX; anti-TNF agents, anti-IL-12/23 Ab, anti-IL-23 Ab, anti-IL-17A, anti-IL-17F, or anti-IL-17 receptor A Ab; TYK2 inhibitor; apremilast; cyclosporine; anti-IL-36 receptor Ab for generalized pustular psoriasis Skin biopsy Topical glucocorticoids, tacrolimus, pimecrolimus, crisaborole, JAK inhibitors, and antipruritics; oral antihistamines for sedation; open wet dressings; UV-B ± UV-A > PUVA; anti-IL-4R alpha Ab, anti-IL-13 Ab; JAK inhibitors, e.g. abrocitinib, upadacitinib; oral/ IM glucocorticoids (short-term); MTX; mycophenolate mofetil; azathioprine; cyclosporine Topical or oral antibiotics Patch testing; repeat open application test Remove irritant or allergen; topical glucocorticoids; oral antihistamines; oral/ IM glucocorticoids (short-term) Patch testing Same as local Skin biopsy Topical glucocorticoids and imidazoles Skin biopsy Topical glucocorticoids; open wet dressings; leg elevation; pressure stockings; pressure wraps if associated ulcers Skin biopsy Isotretinoin or acitretin; MTX; anti-IL-12/23 Ab, anti-IL-23 Ab, anti-TNF agents, anti-IL17A, anti-IL-17F, or -IL-17 receptor A Ab

TABLE 61-4  Causes of Alopecia I. Nonscarring alopecia A. Primary cutaneous disorders

1. Androgenetic alopecia (female pattern, male pattern)
2. Telogen effluvium
3. Alopecia areata
4. Tinea capitis
5. Traumatic alopeciaa
6. Psoriasiform alopecia, including tumor necrosis factor (TNF) inhibitor–induced B. Drugs PART 2 Cardinal Manifestations and Presentation of Diseases
7. Telogen effluvium—see text for most common causes
8. Anagen effluvium—chemotherapeutic agents (e.g., anthracyclines) C. Systemic diseases
9. Systemic lupus erythematosus
10. Secondary syphilis
11. Hypothyroidism
12. Hyperthyroidism
13. Hypopituitarism
14. Deficiencies of protein, biotin, zinc, and perhaps iron II. Scarring alopecia A. Primary cutaneous disorders
15. Cutaneous lupus (chronic discoid lesions)b
16. Lichen planus, including frontal fibrosing alopecia
17. Central centrifugal cicatricial alopecia
18. Folliculitis decalvans
19. Dissecting cellulitis
20. Linear morphea (linear scleroderma)c B. Drugs
21. Chemotherapeutic agents (e.g., taxanes, busulfan) C. Systemic diseases
22. Discoid lesions in the setting of systemic lupus erythematosusb
23. Sarcoidosis
24. Cutaneous metastases aMost patients with trichotillomania or early stages of traction alopecia and some patients with pressure-induced alopecia. bWhile the majority of patients with discoid lesions have only cutaneous disease, these lesions do represent one of the criteria in the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) [2019] and ACR [1982] classification schemes for systemic lupus erythematosus. cCan involve underlying muscles and osseous structures, and rarely in linear morphea of the frontal scalp (en coup de sabre), there is involvement of the meninges and brain. due to CTCL. The patient may progress from isolated plaques and tumors, but more commonly, the erythroderma is present throughout the course of the disease (Sézary syndrome). In Sézary syndrome, there are circulating clonal atypical T lymphocytes, pruritus, and lymphade­ nopathy. In cases of erythroderma where there is no apparent cause (idiopathic), longitudinal evaluation is mandatory to monitor for the possible development of CTCL. ALOPECIA (Table 61-4) The two major forms of alopecia are scarring and non­ scarring. Scarring alopecia is associated with fibrosis, inflammation, and loss of hair follicles. A smooth scalp with a decreased number of follicular openings is usually observed clinically, but in some patients, the changes are seen only in biopsy specimens from affected areas. In nonscarring alopecia, the hair shafts are absent or miniaturized, but the hair follicles are preserved, explaining the reversible nature of nonscar­ ring alopecia. The most common causes of nonscarring alopecia include androge­ netic alopecia, telogen effluvium, alopecia areata, tinea capitis, and the early phase of traumatic alopecia (Table 61-5). In women with andro­ genetic alopecia, an elevation in circulating levels of androgens may be seen as a result of ovarian or adrenal gland dysfunction or neoplasm. When there are signs of virilization, such as a deepened voice and/or

enlarged clitoris, the possibility of an ovarian or adrenal gland tumor should be considered. Exposure to various drugs can also cause diffuse hair loss, usually by inducing a telogen effluvium. An exception is the anagen effluvium observed with chemotherapeutic agents such as daunorubicin. Alope­ cia is a side effect of the following drugs: warfarin, heparin, propyl­ thiouracil, carbimazole, isotretinoin, acitretin, lithium, beta blockers, interferons, colchicine, and amphetamines. Fortunately, spontaneous regrowth usually follows discontinuation of the offending agent. Less commonly, nonscarring alopecia is associated with lupus erythe­ matosus and secondary syphilis. In systemic lupus, there are two forms of alopecia—one is scarring secondary to discoid lesions (see below), and the other is nonscarring. The latter form coincides with flares of systemic disease and may involve the entire scalp or just the frontal scalp, with the appearance of multiple short hairs (“lupus hairs”) as a sign of initial regrowth. Scattered, poorly circumscribed patches of alopecia with a “moth-eaten” appearance are a manifestation of the sec­ ondary stage of syphilis. Diffuse thinning of the hair is also associated with hypothyroidism and hyperthyroidism (Table 61-4). Scarring alopecia is more frequently the result of a primary cutane­ ous disorder such as lichen planus, chronic cutaneous (discoid) lupus, central centrifugal cicatricial alopecia, folliculitis decalvans, or linear scleroderma (morphea) than it is a sign of systemic disease. Although the scarring lesions of discoid lupus can be seen in patients with sys­ temic lupus, in the majority of patients, the disease process is limited to the skin. Less common causes of scarring alopecia include sarcoidosis (see “Papulonodular Skin Lesions,” below), chemotherapeutic agents, and cutaneous metastases. In the early phases of discoid lupus, lichen planus, and folliculitis decalvans, there are circumscribed areas of alopecia. Fibrosis and subsequent loss of hair follicles are observed primarily in the center of these alopecic patches, whereas the inflammatory process is most prominent at the periphery. The areas of active inflammation in dis­ coid lupus are erythematous with scale, whereas the areas of previous inflammation are often hypopigmented with a rim of hyperpigmenta­ tion. In lichen planus, perifollicular macules at the periphery are usually violet-colored. A complete examination of the skin and oral mucosa combined with a biopsy and direct immunofluorescence microscopy of inflamed skin will aid in distinguishing these two entities. The periph­ eral active lesions in folliculitis decalvans are follicular pustules; these patients can develop a reactive arthritis. FIGURATE SKIN LESIONS (Table 61-6) In figurate eruptions, the lesions form rings and arcs that are usually erythematous but can be skin-colored to brown. Most commonly, they are due to primary cutaneous diseases such as tinea, urticaria, granuloma annulare, and erythema annulare centrifugum (Chaps. 60 and 62). An underlying systemic illness is found in a sec­ ond, less common group of migratory annular erythemas. It includes erythema migrans, erythema gyratum repens, erythema marginatum, and necrolytic migratory erythema. In erythema gyratum repens, one sees numerous mobile concentric arcs and wavefronts that resemble the grain in wood. A search for an underlying malignancy is mandatory in a patient with this eruption. Erythema migrans is the cutaneous manifestation of Lyme disease, which is caused by the spirochete Borrelia burgdorferi. In the initial stage (3–30 days after the tick bite, which may go unnoticed), a single annular lesion is usually seen that can expand to ≥10 cm in diameter. Primary EM, as defined by the CDC, has a diameter of ≥5 cm. Within several days, up to half of the patients develop multiple smaller ery­ thematous lesions at sites distant from the bite. Associated symptoms include fever, headache, photophobia, myalgias, arthralgias, and malar rash. Erythema marginatum is seen in patients with rheumatic fever, primarily on the trunk. Lesions are pink-red in color, flat to minimally elevated, and transient. There are additional cutaneous diseases that present as annular eruptions but lack an obvious migratory component. Examples include CTCL, subacute cutaneous lupus, secondary syphilis, and sarcoidosis (see “Papulonodular Skin Lesions,” below).

TABLE 61-5  Nonscarring Alopecia (Primary Cutaneous Disorders)   CLINICAL CHARACTERISTICS PATHOGENESIS TREATMENT Telogen effluvium Diffuse shedding of normal hairs Follows major stress (high fever, severe infection) or change in hormone levels (postpartum) Reversible without treatment Androgenetic alopecia (male pattern; female pattern) Miniaturization of hairs along the midline of the scalp Recession of the anterior scalp line in men and some women Alopecia areata Well-circumscribed, circular areas of hair loss, 2–5 cm in diameter In extensive cases, coalescence of lesions and/or involvement of other hair-bearing surfaces of the body Pitting or sandpapered appearance of the nails Tinea capitis Varies from scaling with minimal hair loss to discrete patches with “black dots” (sites of broken infected hairs) to boggy plaque with pustules (kerion)b Traumatic alopeciac Broken hairs, often of varying lengths Irregular outline in trichotillomania and traction alopecia Fringe sign in traction alopecia aTo date, Food and Drug Administration–approved for men. bScarring alopecia can occur at sites of kerions. cMay also be scarring, especially late-stage traction alopecia. ACNE (Table 61-7) In addition to acne vulgaris and acne rosacea, the two major forms of acne (Chap. 60), there are drugs and systemic diseases that can lead to acneiform eruptions. Patients with the carcinoid syndrome have episodes of flushing of the head, neck, and sometimes the trunk. Resultant skin changes of the TABLE 61-6  Causes of Figurate Skin Lesions I. Primary cutaneous disorders A. Tinea B. Urticaria (primary in ≥90% of patients) C. Granuloma annulare D. Erythema annulare centrifugum E. Psoriasis, annular pustular psoriasis F. Reactive granulomatous dermatitis, which includes interstitial granulomatous drug reaction II. Systemic diseases A. Migratory

1. Erythema migrans (CDC case definition is ≥5 cm in diameter)
2. Urticaria (≤10% of patients)
3. Erythema gyratum repens
4. Erythema marginatum
5. Pustular psoriasis (generalized and annular forms)
6. Necrolytic migratory erythema (glucagonoma syndrome)a B. Nonmigratory (may slowly expand)
7. Subacute cutaneous LE, LE tumidus
8. Sarcoidosis
9. Leprosy (borderline, tuberculoid)
10. Secondary syphilis (especially the face)
11. Cutaneous T-cell lymphoma (especially mycosis fungoides)
12. Interstitial granulomatous dermatitisb
13. Annular erythema of Sjögren’s syndrome aMigratory erythema with erosions; favors lower extremities and girdle area. bUnderlying diseases include rheumatoid arthritis, LE, granulomatosis with polyangiitis, and hematologic disorders, in particular myelodysplasia and chronic myelomonocytic leukemia. Abbreviations: CDC, Centers for Disease Control and Prevention; LE, lupus erythematosus.

Stress causes more of the asynchronous growth cycles of individual hairs to become synchronous; therefore, larger numbers of growing (anagen) hairs simultaneously enter the dying (telogen) phase Observation; discontinue any drugs that have alopecia as a side effect; must exclude underlying metabolic causes, e.g., hypothyroidism, hyperthyroidism Increased sensitivity of affected hairs to the effects of androgens—most common Increased levels of circulating androgens (ovarian or adrenal source in women)—less common If no evidence of hyperandrogenemia, then topical minoxidil; low-dose oral minoxidil; finasteridea; spironolactone (women); hair transplant Skin Manifestations of Internal Disease CHAPTER 61 The germinative zones of the hair follicles are surrounded by T lymphocytes Occasional associated diseases: hyperthyroidism, hypothyroidism, vitiligo, Down syndrome Intralesional glucocorticoids; topical anthralin or tazarotene; topical contact sensitizers; JAK inhibitors; pulse prednisone (e.g., 300 mg orally once a month for 4–6 doses) Invasion of hairs by dermatophytes, most commonly Trichophyton tonsurans Oral griseofulvin or terbinafine plus 2.5% selenium sulfide or ketoconazole shampoo; examine family members Traction with curlers, rubber bands, tight braiding Exposure to heat or chemicals (e.g., hair straighteners) Mechanical pulling (trichotillomania) Discontinuation of offending hair style or chemical treatments; diagnosis of trichotillomania may require observation of shaved hairs (for growth) or biopsy, possibly followed by psychotherapy face, in particular telangiectasias, may mimic the clinical appearance of erythematotelangiectatic acne rosacea. PUSTULAR LESIONS Acneiform eruptions (see “Acne,” above) and folliculitis represent the most common pustular dermatoses. An important consideration in the evaluation of follicular pustules is a determination of the associated pathogen, for example, normal flora (culture-negative), Staphylococcus aureus, Pseudomonas aeruginosa (“hot tub” folliculitis), Malassezia, dermatophytes (Majocchi’s granuloma), and Demodex spp. Noninfec­ tious forms of folliculitis include HIV- or immunosuppression-associated eosinophilic folliculitis and folliculitis secondary to drugs such as glu­ cocorticoids, lithium, and epidermal growth factor receptor (EGFR) or MEK inhibitors. Administration of high-dose systemic glucocorticoids can result in a widespread eruption of follicular pustules on the trunk, characterized by lesions in the same stage of development. With regard to underlying systemic diseases, nonfollicular-based pustules are a characteristic component of pustular psoriasis (sterile) and can be seen in septic emboli of bacterial or fungal origin (see “Purpura,” below). In patients with acute generalized exanthematous pustulosis (AGEP) due primarily to medications (e.g., cephalosporins), there are large TABLE 61-7  Causes of Acneiform Eruptions I. Primary cutaneous disorders A. Acne vulgaris B. Acne rosacea II. Drugs, e.g., anabolic steroids, glucocorticoids, lithium, EGFR inhibitors, HER2 inhibitors, MEK inhibitors, iodides III. Systemic diseases A. Increased androgen production

1. Adrenal origin, e.g., Cushing’s disease, 21-hydroxylase deficiency
2. Ovarian origin, e.g., polycystic ovary syndrome, ovarian hyperthecosis B. Cryptococcosis, disseminated C. Dimorphic fungal infections D. Behçet’s disease Abbreviations: EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor receptor 2; MEK, MAP (mitogen-activated protein) kinase.

areas of erythema studded with multiple sterile pustules in addition to neutrophilia.

TELANGIECTASIAS (Table 61-8) To distinguish the various types of telangiectasias, it is important to examine the shape and configuration of the dilated blood vessels. Linear telangiectasias are seen on the face of patients with actinically damaged skin and acne rosacea, and they are found on the legs of patients with venous hypertension and first appear on the legs in generalized essential telangiectasia. Patients with an unusual form of mastocytosis (telangiectasia macularis eruptiva perstans) and the carcinoid syndrome (see “Acne,” above) also have linear telangiectasias. Lastly, linear telangiectasias are found in areas of cutaneous inflam­ mation. For example, longstanding lesions of discoid lupus frequently have telangiectasias within them. PART 2 Cardinal Manifestations and Presentation of Diseases Poikiloderma is a term used to describe a patch of skin with: (1) reticulated hypo- and hyperpigmentation, (2) wrinkling secondary to epidermal atrophy, and (3) telangiectasias. Poikiloderma does not imply a single disease entity—although it is becoming less common, it is seen in skin damaged by ionizing radiation as well as in patients with autoimmune connective tissue diseases, primarily dermatomyositis (DM), and rare genodermatoses (e.g., Kindler syndrome). In systemic sclerosis (scleroderma), the dilated blood vessels have a unique configuration and are known as mat telangiectasias. The lesions are broad macules that usually measure 2–7 mm in diameter but occasionally are larger. Mats have a polygonal or oval shape, and their erythematous color may appear uniform, but, upon closer inspection, TABLE 61-8  Causes of Telangiectasias I. Primary cutaneous disorders A. Linear/branching

1. Acne rosacea (face)
2. Actinically damaged skin (face, neck, V of chest)
3. Venous hypertension (legs)
4. Generalized essential telangiectasia
5. Cutaneous collagenous vasculopathy
6. Within basal cell carcinomas or cutaneous lymphoma B. Poikiloderma
7. Ionizing radiationa C. Spider angioma
8. Idiopathic
9. Pregnancy II. Systemic diseases A. Linear/branching
10. Carcinoid (head, neck, upper trunk)
11. Ataxia-telangiectasia (bulbar conjunctivae, head and neck)
12. Mastocytosis (within lesions) B. Poikiloderma
13. Dermatomyositis, lupus erythematosus
14. Mycosis fungoides, patch stage
15. Genodermatoses, e.g., xeroderma pigmentosum, Kindler syndrome C. Mat
16. Systemic sclerosis (scleroderma) D. Nailfold
17. Lupus erythematosus
18. Systemic sclerosis (scleroderma)
19. Dermatomyositis
20. Hereditary hemorrhagic telangiectasia E. Papular
21. Hereditary hemorrhagic telangiectasia F. Spider angioma
22. Cirrhosisb
23. Trastuzumab emtansine (may also involve mucosae) aBecoming less common. bDue to hyperestrogenic state.

the erythema is the result of delicate telangiectasias. The most com­ mon locations for mat telangiectasias are the face, oral mucosa, and hands—peripheral sites that are prone to intermittent ischemia. The limited form of systemic sclerosis, also referred to as the CREST (cal­ cinosis cutis, Raynaud’s phenomenon, esophageal dysmotility, sclero­ dactyly, and telangiectasia) variant (Chap. 372), is associated with a chronic course and anticentromere antibodies. Mat telangiectasias are an important clue to the diagnosis of this variant as well as the diffuse form of systemic sclerosis because they may be the only cutaneous finding. Proximal nailfold telangiectasias are pathognomonic signs of the three major autoimmune connective tissue diseases: lupus erythemato­ sus, systemic sclerosis, and DM. They are easily visualized by the naked eye and occur in at least two-thirds of these patients. In both DM and lupus, there is associated nailfold erythema, and in DM, the erythema is often accompanied by “ragged” cuticles and fingertip tenderness. Under 10× magnification or by dermoscopy, the blood vessels in the nailfolds of lupus patients are tortuous and resemble “glomeruli,” whereas in systemic sclerosis and DM, there is a loss of capillary loops and those that remain are markedly dilated. In hereditary hemorrhagic telangiectasia (Osler-Rendu-Weber disease), the lesions usually appear during adolescence (mucosal) and adulthood (cutaneous) and are most commonly seen on the mucous membranes (nasal, orolabial), face, and distal extremities, including under the nails. They represent arteriovenous (AV) mal­ formations of the dermal microvasculature, are dark red in color, and are usually slightly elevated. When the skin is stretched over an individual lesion, an eccentric punctum with radiating legs is seen. Although the degree of systemic involvement varies in this auto­ somal dominant disease (due primarily to mutations in either the endoglin or activin receptor–like kinase gene), the major symptoms are recurrent epistaxis and gastrointestinal bleeding. The fact that these mucosal telangiectasias are actually AV communications helps to explain their tendency to bleed. HYPOPIGMENTATION (Table 61-9) Disorders of hypopigmentation are often classified as either diffuse or localized. The classic example of diffuse hypopigmen­ tation is oculocutaneous albinism (OCA). The most common forms are due to mutations in the tyrosinase gene (type I) or the OCA2 (previously P) gene (type II); patients with type IA OCA have a total lack of enzyme activity. At birth, different forms of OCA can appear similar—white hair, gray-blue eyes, and pink-white skin. However, the patients with no tyrosinase activity maintain this phenotype, whereas those with decreased activity will acquire some pigmentation of the eyes, hair, and skin as they age. The degree of pigment formation is also a function of racial background, and the pigmentary dilution is more readily apparent when patients are compared to their first-degree relatives. The ocular findings in OCA correlate with the degree of hypopigmen­ tation and include decreased visual acuity, nystagmus, photophobia, strabismus, and a lack of normal binocular vision. The differential diagnosis of localized hypomelanosis includes the following primary cutaneous disorders: postinflammatory hypopigmentation, idiopathic guttate hypomelanosis, pityriasis (tinea) versicolor, vitiligo, chemical- or drug-induced leukoderma, nevus depigmentosus (see below), progressive macular hypomelanosis, and piebaldism (Table 61-10). In this group of diseases, the areas of involvement are macules or patches with a decrease or absence of pigmentation. Patients with vitiligo also have an increased incidence of several autoimmune disorders, including Hashimoto’s thyroiditis, Graves’ disease, pernicious anemia, Addison’s disease, uveitis, alope­ cia areata, chronic mucocutaneous candidiasis, and the autoimmune polyendocrine syndromes (types I and II). Diseases of the thyroid gland are the most frequently associated disorders, occurring in up to 30% of patients with vitiligo. Circulating autoantibodies are often found, and the most common ones are antithyroglobulin, antimi­ crosomal, and antithyroid-stimulating hormone receptor antibodies. There are four systemic diseases that should be considered in a patient with skin findings suggestive of vitiligo—systemic sclerosis,

TABLE 61-9  Causes of Hypopigmentation I. Primary cutaneous disorders A. Diffuse

1. Generalized vitiligoa B. Localized
2. Postinflammatory
3. Idiopathic guttate hypomelanosis
4. Pityriasis (tinea) versicolor
5. Vitiligoa
6. Chemical- or drug-induced leukoderma, e.g., topical imiquimod, oral imatinib
7. Nevus depigmentosus and Blaschko-linear hypopigmentation (pigmentary mosaicism)b
8. Progressive macular hypomelanosis
9. Piebaldisma II. Systemic diseases A. Diffuse
10. Oculocutaneous albinismb
11. Hermansky-Pudlak syndromeb,c
12. Chédiak-Higashi syndromeb,d
13. Phenylketonuria B. Localized
14. Systemic sclerosis (scleroderma)e
15. Melanoma-associated vitiligo-like leukoderma, immunotherapyinduced or spontaneouse
16. Sarcoidosis
17. Cutaneous T-cell lymphoma (especially mycosis fungoides)
18. Tuberculoid and indeterminate leprosy
19. Onchocerciasise
20. Blaschko-linear hypopigmentation (pigmentary mosaicism)b,f
21. Incontinentia pigmenti (stage IV)
22. Tuberous sclerosis
23. Waardenburg syndrome and Shah-Waardenburg syndrome
24. Vogt-Koyanagi-Harada syndromee aAbsence of melanocytes in areas of leukoderma; congenital in piebaldism. bNormal number of melanocytes. cPlatelet storage defect and restrictive lung disease secondary to deposits of ceroid-like material or immunodeficiency; due to mutations in β or δ subunit of adaptor-related protein complex 3 as well as subunits of biogenesis of lysosome-related organelles complex (BLOC)-1, -2, and -3. dGiant lysosomal granules and recurrent infections. eCan resemble vitiligo due to acquired complete loss of pigment. fMinority of patients in a nonreferral setting have systemic abnormalities (musculoskeletal, central nervous system, ocular), previously referred to as hypomelanosis of Ito. melanoma-associated leukoderma, onchocerciasis, and Vogt-Koyanagi-

Harada syndrome. The vitiligo-like leukoderma seen in patients with systemic sclerosis has a clinical resemblance to idiopathic vitiligo that has begun to repigment as a result of treatment; that is, perifollicular macules of normal pigmentation are seen within areas of depigmenta­ tion. The basis of this leukoderma is unknown; there is no evidence of inflammation in areas of involvement, but it can resolve if the underlying connective tissue disease becomes inactive. In contrast to idiopathic vitiligo, melanoma-associated vitiligo-like leukoderma often begins on the upper trunk and extensor forearms, and its appearance, if spontaneous, should prompt a search for metastatic disease. It is also seen in patients undergoing immunotherapy for melanoma, including immune checkpoint-blocking antibodies (checkpoint inhibitors), with cytotoxic T lymphocytes presumably recognizing cell surface antigens common to melanoma cells and melanocytes, and is associated with a greater likelihood of a clinical response. A history of aseptic menin­ gitis, nontraumatic uveitis, tinnitus, hearing loss, and/or dysacousia points to the diagnosis of the Vogt-Koyanagi-Harada syndrome. In these patients, the face and scalp are the most common locations of pigment loss. There are two systemic disorders (neurocristopathies) that may have the cutaneous findings of piebaldism (Table 61-9). They are Shah-Waardenburg syndrome and Waardenburg syndrome. A possible

explanation for both disorders is an abnormal embryonic migration or survival of two neural crest–derived elements, one of them being melanocytes and the other myenteric ganglion cells (leading to Hirschsprung disease in Shah-Waardenburg syndrome) or auditory nerve cells (Waardenburg syndrome). The latter syndrome is charac­ terized by congenital sensorineural hearing loss, dystopia canthorum (lateral displacement of the inner canthi but normal interpupillary distance), heterochromic irises, and a broad nasal root, in addition to the piebaldism. The facial dysmorphism can be explained by the neural crest origin of the connective tissues of the head and neck. Patients with Waardenburg syndrome have been shown to have muta­ tions in four genes, including PAX-3 and MITF, three of which encode transcription factors, whereas patients with Hirschsprung disease plus white spotting have mutations in one of three genes—endothelin 3, endothelin B receptor, and the transcription factor SOX10.

Skin Manifestations of Internal Disease CHAPTER 61 In tuberous sclerosis, the earliest cutaneous sign is macular hypomel­ anosis, referred to as an ash leaf spot. These lesions are often present at birth and are usually multiple; however, detection may require Wood’s lamp examination, especially in lightly pigmented individu­ als. The pigment within them is reduced, but not absent. The average size is 1–3 cm, and the common shapes are polygonal and lance-ovate. Examination of the patient for additional cutaneous signs such as multiple angiofibromas of the face (adenoma sebaceum), ungual and intraoral fibromas, fibrous cephalic plaques, and connective tissue nevi (shagreen patches) is recommended. It is important to remember that an ash leaf spot on the scalp will result in a circumscribed patch of lightly pigmented hair. Internal manifestations include seizures, intel­ lectual impairment, central nervous system (CNS) and retinal ham­ artomas, pulmonary lymphangioleiomyomatosis (women), bilateral renal angiomyolipomas, and myocardial rhabdomyomas. The latter can be detected in up to 60% of children (<18 years) with tuberous sclerosis by echocardiography. Nevus depigmentosus is a stable, well-circumscribed hypomelanosis that is present at birth. There is usually a single oval or rectangular lesion, but when there are multiple lesions, the possibility of tuberous sclerosis needs to be considered. In Blaschko-linear hypopigmentation, also referred to as linear nevoid hypopigmentation and pigmentary mosaicism, streaks and swirls of hypopigmentation are observed; these terms have replaced hypomelanosis of Ito. Up to one-third of patients in a tertiary care setting had associated abnormalities involv­ ing the musculoskeletal system (asymmetry), the CNS (seizures and intellectual disability), and the eyes (strabismus and hypertelorism). Genetic mosaicism has been detected in these patients (e.g. activating mutations in MTOR), lending support to the hypothesis that the cuta­ neous pattern is the result of the migration of two clones of primordial melanocytes, each with a different pigment potential. Localized areas of decreased pigmentation are commonly seen as a result of cutaneous inflammation (Table 61-10) and have been observed in the skin overlying active lesions of sarcoidosis (see “Papu­ lonodular Skin Lesions,” below) as well as in CTCL. Cutaneous infec­ tions also present as disorders of hypopigmentation, and in tuberculoid leprosy, there are a few asymmetric patches of hypomelanosis that have associated anesthesia, anhidrosis, and alopecia. Biopsy specimens of the palpable border show dermal granulomas that contain rare, if any, Mycobacterium leprae organisms. HYPERPIGMENTATION (Table 61-11) Disorders of hyperpigmentation are also divided into two major groups—localized and diffuse. The localized forms are due to an epidermal alteration, a proliferation of melanocytes, or an increase in pigment production. Both acanthosis nigricans and sebor­ rheic keratoses belong to the first group. Acanthosis nigricans can be a reflection of an internal malignancy, most commonly of the gastroin­ testinal tract, and it appears as velvety hyperpigmentation, primarily in flexural areas. However, in the majority of patients, acanthosis nigricans is associated with obesity and insulin resistance, although it may be a reflection of an endocrinopathy such as acromegaly, Cush­ ing’s syndrome, polycystic ovary syndrome, or insulin-resistant dia­ betes mellitus (type A, type B, and lipodystrophic forms). Seborrheic

TABLE 61-10  Hypopigmentation (Primary Cutaneous Disorders, Localized) WOOD’S LAMP EXAMINATION (UV-A; PEAK = 365 NM) SKIN BIOPSY SPECIMEN PATHOGENESIS TREATMENT   CLINICAL CHARACTERISTICS Postinflammatory hypopigmentation Can develop within active lesions, as in subacute cutaneous lupus, or after the lesion fades, as in atopic dermatitis Depends on particular disease Usually less enhancement than in vitiligo PART 2 Cardinal Manifestations and Presentation of Diseases Idiopathic guttate hypomelanosis Common; acquired; usually

2–4 mm in diameter Shins and extensor forearms Less enhancement than vitiligo Pityriasis (tinea) versicolora Common disorder Upper trunk and neck (shawl-like distribution), body folds Young adults Macules have fine white scale when scratched Golden fluorescence Hyphal forms and budding yeast in stratum corneum Vitiligo Acquired; progressive Symmetric areas of complete pigment loss Periorificial—around mouth, nose, eyes, nipples, umbilicus, anus Other areas—flexor wrists, extensor distal extremities Segmental form is less common—unilateral, dermatomal-like More apparent Chalk-white Chemical- or drug-induced leukoderma Similar appearance to vitiligo Often begins on hands when associated with chemical exposure Satellite lesions in areas not exposed to chemicals More apparent Chalk-white Piebaldism Autosomal dominant Congenital, stable White forelock Areas of amelanosis contain normally pigmented and hyperpigmented macules of various sizes Symmetric involvement of central forehead, ventral trunk, and mid regions of upper and lower extremities Enhancement of leukoderma and hyperpigmented macules aIf potassium hydroxide (KOH) examination of scale is negative, consider the possibility of progressive macular hypomelanosis. Abbreviations: MBEH, monobenzylether of hydroquinone; PUVA, psoralens plus ultraviolet A irradiation; UV-B, ultraviolet B irradiation. keratoses are common lesions, but in one rare clinical setting, they are a sign of systemic disease, and that setting is the sudden appearance of multiple lesions, often with an inflammatory base and in association with acrochordons (skin tags) and acanthosis nigricans. This is termed the sign of Leser-Trélat and alerts the clinician to search for an internal malignancy. A proliferation of melanocytes results in the following pigmented lesions: lentigo, melanocytic nevus, and melanoma (Chap. 81). In an adult, the majority of lentigines are related to sun exposure, which explains their distribution. However, in the Peutz-Jeghers

Type of inflammatory infiltrate depends on specific disease Block in transfer of melanin from melanocytes to keratinocytes could be secondary to edema or decrease in contact time Destruction of melanocytes if inflammatory cells attack basal layer of epidermis Treat underlying inflammatory disease Abrupt decrease in epidermal melanin content Possible somatic mutations as a reflection of aging or UV exposure None Invasion of stratum corneum by the yeast Malassezia Yeast is lipophilic and produces C9 and C11 dicarboxylic acids, which

in vitro inhibit tyrosinase Selenium sulfide 2.5% shampoo; topical imidazoles; oral fluconazole Absence of melanocytes in well-developed lesions Mild inflammation Autoimmune phenomenon that results in destruction of melanocytes—primarily cellular (circulating skinhoming autoreactive T cells) Topical glucocorticoids, calcineurin inhibitors, JAK inhibitors; UV-B (narrowband) > PUVA; oral JAK inhibitors; transplants, if stable; depigmentation (topical MBEH), if widespread and treatment-resistant Decreased number or absence of melanocytes Exposure to chemicals that selectively destroy melanocytes, in particular phenols and catechols (germicides; rubber products) or ingestion of drugs such as imatinib Release of cellular antigens and activation of circulating lymphocytes may explain satellite phenomenon Possible inhibition of KIT receptor Avoid exposure to offending agent, then treat as vitiligo Drug-induced variant may undergo repigmentation when medication is discontinued Amelanotic areas—few to no melanocytes Defect in migration of melanoblasts from neural crest to involved skin or failure of melanoblasts to survive or differentiate in these areas Mutations within the KIT protooncogene that encodes the tyrosine kinase receptor for stem cell growth factor (kit ligand) None; occasionally transplants and LEOPARD (lentigines; ECG abnormalities, primarily conduc­ tion defects; ocular hypertelorism; pulmonary stenosis and subaortic valvular stenosis; abnormal genitalia [cryptorchidism, hypospadias]; retardation of growth; and deafness [sensorineural]) syndromes, len­ tigines do serve as a clue to systemic disease. In LEOPARD/Noonan with multiple lentigines syndrome, hundreds of lentigines develop dur­ ing childhood and are scattered over the entire surface of the body. The lentigines in patients with Peutz-Jeghers syndrome (PJS) are located primarily around the nose and mouth, on the hands and feet, and within the oral cavity. While the pigmented macules on the face may

TABLE 61-11  Causes of Hyperpigmentation I. Primary cutaneous disorders A. Localized

1. Epidermal alteration a. Seborrheic keratosis b. Pigmented actinic keratosis
2. Proliferation of melanocytes a. Lentigo b. Melanocytic nevus (mole) c. Melanoma
3. Increased pigment production a. Ephelide (freckle) b. Café au lait macule c. Postinflammatory hyperpigmentation (also dermal) d. Melasma (also dermal)
4. Dermal pigmentation a. Fixed drug eruption B. Localized and diffuse
5. Drugs (e.g., minocycline, hydroxychloroquine, bleomycin) II. Systemic diseases A. Localized
6. Epidermal alteration a. Acanthosis nigricans (insulin resistance > other endocrine disorders, paraneoplastic) b. Seborrheic keratoses (sign of Leser-Trélat)
7. Proliferation of melanocytes a. Lentigines (Peutz-Jeghers and LEOPARD/Noonan with multiple lentigines syndromes; xeroderma pigmentosum) b. Melanocytic nevi (Carney complex [LAMB and NAME syndromes])a
8. Increased pigment production a. Café au lait macules (neurofibromatosis, Legius syndrome, McCune-Albright syndromeb) b. Urticaria pigmentosac
9. Dermal pigmentation a. Incontinentia pigmenti (stage III) b. Dyskeratosis congenita
10. Dermal deposits a. Exogenous ochronosis b. Localized argyria B. Diffuse
11. Endocrinopathies a. Addison’s disease b. Nelson’s syndrome c. Ectopic ACTH syndrome d. Hyperthyroidism
12. Metabolic a. Porphyria cutanea tarda b. Hemochromatosis c. Vitamin B12, folate deficiency d. Pellagra e. Malabsorption, including Whipple’s disease
13. Melanosis secondary to metastatic melanoma
14. Autoimmune a. Primary biliary cholangitis b. Systemic sclerosis (scleroderma) c. POEMS syndrome d. Eosinophilia-myalgia syndromed
15. Drugs (e.g., cyclophosphamide) and metals (e.g., silver) aAlso lentigines. bPolyostotic fibrous dysplasia. cSee also “Papulonodular Skin Lesions.” dLate 1980s. Abbreviations: ACTH, adrenocorticotropic hormone; LAMB, lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi; LEOPARD, lentigines, ECG abnormalities, ocular hypertelorism, pulmonary stenosis and subaortic valvular stenosis, abnormal genitalia, retardation of growth, and deafness (sensorineural); NAME, nevi, atrial myxoma, myxoid neurofibroma, and ephelides (freckles); POEMS, polyneuropathy, organomegaly, endocrinopathies, M-protein, and skin changes.

fade with age, the oral lesions persist. However, similar intraoral lesions are also seen in Addison’s disease, in Laugier-Hunziker syndrome (no internal manifestations), and as a normal finding in darkly pigmented individuals. Patients with PJS, an autosomal dominant syndrome due to mutations in a novel serine threonine kinase gene, have multiple benign polyps of the gastrointestinal tract, testicular or ovarian tumors, and an increased risk of developing gastrointestinal (primarily colon) and pancreatic cancers.

In the Carney complex, numerous lentigines are also seen, but they are in association with cardiac myxomas. This autosomal dominant disorder is also known as the LAMB (lentigines, atrial myxomas, mucocutaneous myxomas, and blue nevi) syndrome or NAME (nevi, atrial myxoma, myxoid neurofibroma, and ephelides [freckles]) syn­ drome. These patients can also have evidence of endocrine overactivity in the form of Cushing’s syndrome (primary pigmented nodular adre­ nocortical disease) and acromegaly. Skin Manifestations of Internal Disease CHAPTER 61 The third type of localized hyperpigmentation is due to a local increase in pigment production, and it includes ephelides and café au lait macules (CALMs). While a single CALM can be seen in up to 10% of the normal population, the presence of multiple or largesized CALMs raises the possibility of an associated genodermatosis, for example, neurofibromatosis (NF) or McCune-Albright syndrome. CALMs are flat, uniformly brown in color (usually two shades darker than uninvolved skin), and can vary in size from 0.5 to 12+ cm. More than 90% of adult patients with type I NF will have six or more CALMs measuring ≥1.5 cm in diameter. Additional findings are discussed in the section on neurofibromas (see “Papulonodular Skin Lesions,” below). In comparison with NF, the CALMs in patients with McCuneAlbright syndrome (polyostotic fibrous dysplasia with precocious puberty in females due to mosaicism for an activating mutation in a G protein [Gsα] gene) are usually larger, are more irregular in outline, and tend to respect the midline. In incontinentia pigmenti, dyskeratosis congenita, and bleomycin pigmentation, the areas of localized hyperpigmentation form a pattern— swirls and streaks in the first, reticulated in the second, and flagellate in the third. In dyskeratosis congenita, atrophic reticulated hyperpig­ mentation is seen on the neck, trunk, and thighs and is accompanied by nail dystrophy, pancytopenia, and leukoplakia of the oral and anal mucosae. The latter often develops into squamous cell carcinoma. In addition to the flagellate pigmentation (linear streaks) on the trunk, patients receiving bleomycin often have hyperpigmentation overlying the elbows, knees, and small joints of the hand. Localized hyperpigmentation is seen as a side effect of several other systemic medications, including those that produce fixed drug reac­ tions (nonsteroidal anti-inflammatory drugs [NSAIDs], sulfonamides, and tetracyclines) and those that can complex with melanin or iron (antimalarials and minocycline). Fixed drug eruptions recur in the exact same location as circular areas of erythema that can become bul­ lous and then resolve as macular brown circles. The eruption usually appears within hours of readministration of the offending agent, and common locations include the genitalia, distal extremities, and perioral region. Chloroquine and hydroxychloroquine produce gray-brown to blue-black discoloration of the shins, hard palate, and face, while blue macules (often misdiagnosed as bruises) can be seen most commonly on the lower extremities and in sites of inflammation with prolonged minocycline administration. Estrogen in oral contraceptives can induce melasma—symmetric brown patches on the face, especially the cheeks, upper lip, and forehead. Similar changes are seen in pregnancy and in patients receiving phenytoin. In the diffuse forms of hyperpigmentation, the darkening of the skin may be of equal intensity over the entire body or may be accen­ tuated in sun-exposed areas. The causes of diffuse hyperpigmenta­ tion can be divided into four major groups—endocrine, metabolic, autoimmune, and drugs. The endocrinopathies that frequently have associated hyperpigmentation include Addison’s disease, Nel­ son’s syndrome, and ectopic adrenocorticotropic hormone (ACTH) syndrome. In these diseases, the increased pigmentation is diffuse but is accentuated in sun-exposed areas, as well as in the palmar creases, sites of friction, and scars. An overproduction of the pituitary

hormones α-MSH (melanocyte-stimulating hormone) and ACTH can lead to an increase in melanocyte activity. These peptides are products of the proopiomelanocortin gene and exhibit homology; for example, α-MSH and ACTH share 13 amino acids. A minority of patients with Cushing’s disease or hyperthyroidism have generalized hyperpigmentation.

The metabolic causes of hyperpigmentation include porphyria cuta­ nea tarda (PCT), hemochromatosis, vitamin B12 deficiency, folic acid deficiency, pellagra, and malabsorption, including Whipple’s disease. In patients with PCT (see “Vesicles/Bullae,” below), the skin darkening is seen in sun-exposed areas and is a reflection of the photoreactive prop­ erties of porphyrins. The increased level of iron in the skin of patients with types 1 and 2 hemochromatosis stimulates melanin pigment production and leads to the classic bronze color. Patients with pellagra have a brown discoloration of the skin, especially in sun-exposed areas, as a result of nicotinic acid (niacin) deficiency. In the areas of increased pigmentation, there is a thin, varnish-like scale. These changes are also seen in patients who are vitamin B6 deficient, have functioning carcinoid tumors (increased consumption of niacin), or take isoniazid. Approximately 50% of the patients with Whipple’s disease have an associated generalized hyperpigmentation in association with diarrhea, weight loss, arthritis, and lymphadenopathy. A diffuse, slate-blue to gray-brown color is seen in patients with melanosis secondary to meta­ static melanoma. The color reflects widespread deposition of melanin within the dermis as a result of the high concentration of circulating melanin precursors. PART 2 Cardinal Manifestations and Presentation of Diseases Of the autoimmune diseases associated with diffuse hyperpigmen­ tation, primary biliary cholangitis and systemic sclerosis are the most common, and occasionally, both disorders are seen in the same patient. The skin is dark brown in color, especially in sun-exposed areas. In primary biliary cholangitis, the hyperpigmentation is accompanied by pruritus, jaundice, and xanthomas, whereas in systemic sclerosis, it is accompanied by sclerosis of the extremities, face, and, less commonly, the trunk. Additional clues to the diagnosis of systemic sclerosis are mat and cuticular telangiectasias, calcinosis cutis, Raynaud’s phe­ nomenon, and distal ulcerations (see “Telangiectasias,” above). The differential diagnosis of cutaneous sclerosis with hyperpigmentation includes POEMS (polyneuropathy; organomegaly [liver, spleen, lymph nodes]; endocrinopathies [impotence, gynecomastia]; M-protein; and skin changes) syndrome. The skin changes include hyperpigmentation, induration, hypertrichosis, angiomas, clubbing, and facial lipoatrophy. Diffuse hyperpigmentation that is due to drugs or metals can result from one of several mechanisms—induction of melanin pig­ ment formation, complexing of the drug or its metabolites to melanin, and deposits of the drug in the dermis. Busulfan, cyclophosphamide, 5-fluorouracil, and inorganic arsenic induce pigment production. Complexes containing melanin or iron plus the drug or its metabolites are seen in patients receiving minocycline, and a diffuse, brown-gray, muddy appearance within sun-exposed areas may develop, in addition to pigmentation of the mucous membranes, teeth, nails, bones, and thyroid. Administration of amiodarone can result in both a phototoxic eruption (exaggerated sunburn) and/or a slate-gray to violaceous dis­ coloration of sun-exposed skin. Biopsy specimens of the latter show yellow-brown granules in dermal macrophages, which represent intra­ lysosomal accumulations of lipids, amiodarone, and its metabolites. Actual deposits of a particular drug or metal in the skin are seen with silver (argyria), where the skin appears blue-gray in color; gold (chrysi­ asis), where the skin has a brown to blue-gray color; and clofazimine, where the skin appears reddish brown. The associated pigmentation is accentuated in sun-exposed areas, and discoloration of the eye is seen with gold (sclerae) and clofazimine (conjunctivae). VESICLES/BULLAE (Table 61-12) Depending on their size, cutaneous blisters are referred to as vesicles (<1 cm) or bullae (>1 cm). The primary autoimmune blistering disorders include pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, bullous pemphigoid, gestational pemphigoid, cicatricial pemphigoid, epidermolysis bullosa acquisita, linear IgA bul­ lous dermatosis (LABD), and dermatitis herpetiformis (Chap. 62).

TABLE 61-12  Causes of Vesicles/Bullae I. Primary mucocutaneous diseases A. Primary blistering diseases (autoimmune)

1. Pemphigus, foliaceus and vulgarisa
2. Bullous pemphigoidb
3. Gestational pemphigoidb
4. Cicatricial pemphigoidb
5. Dermatitis herpetiformisb,c
6. Linear IgA bullous dermatosisb
7. Epidermolysis bullosa acquisitab,d B. Secondary blistering diseases
8. Contact dermatitisa,b
9. Erythema multiformee
10. Stevens-Johnson syndromee
11. Toxic epidermal necrolysise
12. Bullous fixed drug eruption, including generalized variante
13. Pseudoporphyria, drug- or tanning booth–induced C. Infections
14. Varicella-zoster virusa,f
15. Herpes simplex virusa,f
16. Enteroviruses, e.g., hand-foot-and-mouth diseasef
17. SARS-CoV-2
18. Staphylococcal scalded-skin syndromea,g
19. Bullous impetigoa
20. Bullous tinea II. Systemic diseases A. Autoimmune
21. Paraneoplastic pemphigusa (bronchiolitis obliterans)
22. Bullous systemic lupus erythematosus B. Infections
23. Cutaneous embolib C. Metabolic
24. Diabetic bullaea,b
25. Porphyria cutanea tardab
26. Porphyria variegatab
27. Bullous dermatosis of hemodialysisb (less often associated with peritoneal dialysis and also referred to as pseudoporphyria) D. Ischemia
28. Coma bullae E. Secondary blistering diseases
29. Toxic epidermal necrolysise (respiratory and gastrointestinal tracts can be involved)
30. Edema bullae (venous hypertension, congestive heart failure) aIntraepidermal. bSubepidermal. cAssociated with gluten enteropathy. dAssociated with inflammatory bowel disease. eDegeneration of cells within the basal layer of the epidermis can give impression split is subepidermal. fAlso systemic. gIn adults, associated with renal failure and immunocompromised state. Vesicles and bullae are also seen in contact dermatitis, both allergic and irritant forms (Chap. 60). When there is a linear arrangement of vesicular lesions, an exogenous cause or herpes zoster should be suspected. Bullous disease secondary to the ingestion of drugs can take one of several forms, including phototoxic eruptions, isolated bul­ lae, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) (Chap. 63). Clinically, phototoxic eruptions resemble an exag­ gerated sunburn with diffuse erythema and bullae in sun-exposed areas. The most commonly associated drugs are doxycycline, quino­ lones, voriconazole, thiazides, NSAIDs, vemurafenib, and psoralens. The development of a phototoxic eruption is dependent on the doses of both the drug and ultraviolet (UV)-A irradiation. Toxic epidermal necrolysis is characterized by bullae that arise on widespread areas of tender erythema and then slough. This results in large areas of denuded skin. The associated morbidity, such as sepsis, and mortality rates are relatively high and are a function of the extent of

epidermal necrosis. In addition, these patients may also have involve­ ment of the mucous membranes and respiratory and intestinal tracts. Drugs are the primary cause of TEN, and the most common offenders are aromatic anticonvulsants (phenytoin, barbiturates, carbamazepine), sulfonamides, aminopenicillins, allopurinol, and NSAIDs. Generalized bullous fixed drug eruption, severe acute graft-versus-host disease (grade 4), vancomycin-induced LABD, and flares of cutaneous lupus can also resemble TEN. In erythema multiforme (EM), the primary lesions are pink-red macules and edematous papules, the centers of which may become vesicular. In contrast to a morbilliform exanthem, the clue to the diag­ nosis of EM, and especially SJS, is the development of a “dusky” violet color in the center of the lesions. Target lesions are also characteristic of EM and arise as a result of active centers and borders in combination with centrifugal spread. However, target lesions need not be present to make the diagnosis of EM. EM has been subdivided into two major groups: (1) EM minor due to herpes simplex virus (HSV); and (2) EM major due to HSV, Mycoplasma pneumonia, or, occasionally, other viruses, Chlamydia, or drugs. Involvement of the mucous membranes (ocular, nasal, oral, and genital) is seen more commonly in the latter form, and in patients with Mycoplasma pneumoniae–induced rash and mucositis (MIRM)/reactive infectious mucocutaneous eruption (RIME), there may be minimal cutaneous involvement. Hemorrhagic crusts of the lips are characteris­ tic of EM major and SJS as well as herpes simplex, pemphigus vulgaris, and paraneoplastic pemphigus. Fever, malaise, myalgias, sore throat, and cough may precede or accompany the eruption. The lesions of EM usually resolve over 2–4 weeks but may be recurrent, especially when due to HSV. In addition to HSV (in which lesions usually appear 7–12 days after the viral eruption), EM can also follow vaccinations, radiation therapy, and exposure to environmental toxins, including the oleoresin in poison ivy. Induction of SJS is most often due to drugs, especially sulfonamides, aromatic anticonvulsants, lamotrigine, aminopenicillins, and nonnu­ cleoside reverse transcriptase inhibitors (e.g., nevirapine). Widespread dusky macules and significant mucosal involvement are characteristic of SJS, and the cutaneous lesions may or may not develop epidermal detachment. If the latter occurs, by definition, it is limited to <10% of the body surface area (BSA). Greater involvement leads to the diagno­ sis of SJS/TEN overlap (10–30% BSA) or TEN (>30% BSA). In addition to primary blistering disorders and hypersensitivity reactions, bacterial and viral infections can lead to vesicles and bullae. The most common infectious agents are HSV (Chap. 197), varicella-zoster virus (Chap. 198), and S. aureus (Chap. 152). Staphylococcal scalded-skin syndrome (SSSS) and bullous impetigo are two blistering disorders associated with staphylococcal (phage group II) infection. In SSSS, the initial findings are redness and ten­ derness of the central face, neck, trunk, and intertriginous zones. This is followed by short-lived flaccid bullae and a slough or exfoliation of the superficial epidermis. Crusted areas then develop, characteristically around the mouth in a radial pattern. SSSS is distinguished from TEN by the following features: younger age group (primarily infants and toddlers), more superficial site of blister formation, no oral lesions, shorter course, lower morbidity and mortality rates, and an association with staphylococcal exfoliative toxin (“exfoliatin”), not drugs. A rapid diagnosis of SSSS versus TEN can be made by a frozen section of the blister roof or exfoliative cytology of the blister contents. In SSSS, the site of staphylococcal infection is usually extracutaneous (conjunctivi­ tis, rhinorrhea, otitis media, pharyngitis, tonsillitis), and the cutaneous lesions are sterile, whereas in bullous impetigo, the skin lesions are the site of infection. Impetigo is more localized than SSSS and usually presents with honey-colored crusts. Occasionally, superficial purulent blisters also form. Cutaneous emboli from gram-negative infections may present as isolated bullae, but the base of the lesion is purpuric or necrotic, and it may develop into an ulcer (see “Purpura,” below). Several metabolic disorders are associated with blister formation, including diabetes mellitus, renal failure, and porphyria. Local hypox­ emia secondary to decreased cutaneous blood flow can also produce blisters, which explains the presence of bullae over pressure points

in comatose patients (coma bullae). In diabetes mellitus, tense bullae with clear sterile viscous fluid arise on normal skin. The lesions can be as large as 6 cm in diameter and are located on the distal extremities. There are several types of porphyria, but the most common form with cutaneous findings is porphyria cutanea tarda (PCT). In sun-exposed areas (primarily the hands), the skin is very fragile, with trauma lead­ ing to erosions mixed with tense vesicles. These lesions then heal with scarring and formation of milia; the latter are firm, 1- to 2-mm white or yellow papules that represent epidermoid cysts. Associated findings can include hypertrichosis of the lateral malar region (men) or face (women) and, in sun-exposed areas, hyperpigmentation and firm scle­ rotic plaques. An elevated level of urinary uroporphyrins confirms the diagnosis and is due to a decrease in uroporphyrinogen decarboxylase activity. PCT can be exacerbated by alcohol, hemochromatosis and other forms of iron overload, chlorinated hydrocarbons, hepatitis C virus and HIV infections, and hepatomas.

Skin Manifestations of Internal Disease CHAPTER 61 The differential diagnosis of PCT includes (1) porphyria variegata— the skin signs of PCT plus the systemic findings of acute intermittent porphyria; it has a diagnostic plasma porphyrin fluorescence emission at 626 nm; (2) drug-induced pseudoporphyria—the clinical and histo­ logic findings are similar to PCT, but porphyrins are normal; etiologic agents include naproxen and other NSAIDs, furosemide, tetracycline, and voriconazole; (3) bullous dermatosis of hemodialysis—the same appearance as PCT, but porphyrins are usually normal or occasion­ ally borderline elevated; patients have chronic renal failure and are on hemodialysis; (4) PCT associated with hepatomas and hemodialysis; and (5) epidermolysis bullosa acquisita (Chap. 62). EXANTHEMS (Table 61-13) Exanthems are characterized by an acute generalized eruption. The most common presentation is erythematous macules and papules (morbilliform) and less often confluent blanching erythema (scarlatiniform). Morbilliform eruptions are usually due to either drugs or viral infections. For example, up to 5% of patients receiving penicil­ lins, sulfonamides, phenytoin, or nevirapine will develop a maculo­ papular eruption. Accompanying signs may include pruritus, fever, eosinophilia, transaminitis, and transient lymphadenopathy (Chap. 63).

TABLE 61-13  Causes of Exanthems I. Morbilliform A. Drugs B. Viral

1. Rubeola (measles)
2. Rubella
3. Erythema infectiosum (erythema of cheeks; reticulated on extremities)
4. Epstein-Barr virus, echovirus, coxsackievirus, CMV, adenovirus, HHV-6/HHV-7a, SARS-CoV-2, dengue, chikungunya, and West Nile virus infections
5. HIV seroconversion exanthem (plus mucosal ulcerations) C. Bacterial
6. Typhoid fever
7. Early secondary syphilis
8. Early Rickettsia infections
9. Early meningococcemia
10. Ehrlichiosis D. Acute graft-versus-host disease E. Kawasaki disease II. Scarlatiniform A. Scarlet fever B. Toxic shock syndrome C. Kawasaki disease D. Early staphylococcal scalded-skin syndrome aPrimary infection in infants and reactivation in the setting of immunosuppression. Abbreviations: CMV, cytomegalovirus; HHV, human herpesvirus; HIV, human immunodeficiency virus; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

Similar maculopapular eruptions are seen in the classic childhood viral exanthems, including (1) rubeola (measles)—a prodrome of coryza, cough, and conjunctivitis followed by Koplik’s spots on the buccal mucosa; the eruption begins behind the ears, at the hairline, and on the forehead and then spreads down the body, often becoming confluent; (2) rubella—the eruption begins on the forehead and face and then spreads down the body; it resolves in the same order and is associated with retroauricular and suboccipital lymphadenopathy; and (3) erythema infectiosum (fifth disease)—erythema of the cheeks is fol­ lowed by a reticulated pattern on the extremities; it is secondary to a parvovirus B19 infection, and an associated arthritis is seen in adults.

Both measles and rubella can occur in unvaccinated adults, and an atypical form of measles is seen in adults immunized with either killed measles vaccine or killed vaccine followed in time by live vaccine. In contrast to classic measles, the eruption of atypical measles begins on the palms, soles, wrists, and ankles, and the lesions may become pur­ puric. The patient with atypical measles can have pulmonary involve­ ment and be quite ill. Rubelliform and roseoliform eruptions are also associated with Epstein-Barr virus (5–15% of patients), echovirus, coxsackievirus, cytomegalovirus, adenovirus, SARS-CoV-2, dengue, chi­ kungunya, and West Nile virus infections. While detection of specific IgM antibodies or fourfold elevations in IgG antibodies often allows the proper diagnosis, polymerase chain reaction (PCR) has gradually replaced serologic assays. Occasionally, a maculopapular drug eruption is a reflection of an underlying viral infection. For example, ~95% of the patients with infectious mononucleosis who are given ampicillin will develop a rash. PART 2 Cardinal Manifestations and Presentation of Diseases Of note, early in the course of infections with Rickettsia and menin­ gococcus, prior to the development of petechiae and purpura, the lesions may be erythematous macules and papules. This is also the case in chickenpox prior to the development of vesicles. Maculopapu­ lar eruptions are associated with early HIV infection, early secondary syphilis, typhoid fever, and acute graft-versus-host disease. In the last, lesions frequently begin on the dorsal hands, forearms, and upper trunk; the macular rose spots of typhoid fever involve primarily the anterior trunk. The prototypic scarlatiniform eruption is seen in scarlet fever and is due to an erythrogenic toxin produced by bacteriophage-containing group A β-hemolytic streptococci, most commonly in the setting of pharyngitis. This eruption is characterized by diffuse erythema, which begins on the neck and upper trunk, and red follicular puncta. Addi­ tional findings include a white strawberry tongue (white coating with red papillae) followed by a red strawberry tongue (red tongue with red papillae); petechiae of the palate; a facial flush with circumoral pallor; linear petechiae in the antecubital fossae; and desquamation of the involved skin, palms, and soles 5–20 days after onset of the eruption. A similar desquamation of the palms and soles is seen in toxic shock syndrome (TSS), in Kawasaki disease, and after severe febrile illnesses. Certain strains of staphylococci also produce an erythrotoxin that leads to the same clinical findings as in streptococcal scarlet fever, except that the anti-streptolysin O or DNase B titers are not elevated. In toxic shock syndrome, staphylococcal (phage group I) infections produce an exotoxin (TSST-1) that causes the fever and rash as well as enterotoxins. Initially, the majority of cases were reported in men­ struating women who were using tampons. However, other sites of infection, including wounds and nasal packing, can lead to TSS. The diagnosis of TSS is based on clinical criteria (Chap. 152), and three of these involve mucocutaneous sites (diffuse erythema of the skin, des­ quamation of the palms and soles 1–2 weeks after onset of illness, and involvement of the mucous membranes). The latter is characterized as hyperemia of the vagina, oropharynx, or conjunctivae. Similar systemic findings have been described in streptococcal toxic shock syndrome (Chap. 153), and although an exanthem is seen less often than in TSS due to a staphylococcal infection, the underlying infection is often in the soft tissue (e.g., cellulitis). The cutaneous eruption in Kawasaki disease (Chap. 375) is poly­ morphous, but the two most common forms are morbilliform and scarlatiniform. Additional mucocutaneous findings include bilateral conjunctival injection; erythema and edema of the hands and feet

followed by desquamation; and diffuse erythema of the oropharynx, red strawberry tongue, and dry fissured lips. This clinical picture can resemble TSS and scarlet fever, but clues to the diagnosis of Kawasaki disease are cervical lymphadenopathy, cheilitis, and thrombocyto­ sis. The most serious associated systemic finding in this disease is coronary aneurysms secondary to arteritis. Seen primarily in children, SARS-CoV-2–associated multisystem inflammatory syndrome must be distinguished from Kawasaki disease. Scarlatiniform eruptions are also seen in the early phase of SSSS (see “Vesicles/Bullae,” above), in young adults with Arcanobacterium haemolyticum infection, and as reactions to drugs. URTICARIA (Table 61-14) Urticaria (hives) are transient lesions that are com­ posed of a central wheal surrounded by an erythematous halo or flare. Individual lesions are round, oval, or figurate and are often pruritic. Acute and chronic urticarias have a wide variety of allergic etiologies and reflect edema in the dermis. Urticarial lesions can also be seen in patients with mastocytosis (urticaria pigmentosa), hypo- or hyperthy­ roidism, Schnitzler’s syndrome, and systemic-onset juvenile idiopathic arthritis (Still’s disease). In both juvenile- and adult-onset Still’s disease, the lesions coincide with the fever spike, are transient, and are due to dermal infiltrates of neutrophils; the latter is also referred to as neutro­ philic urticarial dermatosis. The common physical urticarias include dermographism, solar urti­ caria, cold urticaria, and cholinergic urticaria. Patients with dermogra­ phism exhibit linear wheals following minor pressure or scratching of the skin and may be a contributing factor to pruritic dermatoses. It is a common disorder, affecting ~5% of the population. Solar urticaria char­ acteristically occurs within minutes of sun exposure and is a skin sign of one systemic disease—erythropoietic protoporphyria. In addition to the urticaria, these patients have subtle pitted scarring of the nose and hands. Cold urticaria is precipitated by exposure to the cold, and therefore, exposed areas are usually affected. In occasional patients, the disease is associated with abnormal circulating proteins—more com­ monly cryoglobulins and less commonly cryofibrinogens. Additional systemic symptoms include wheezing and syncope, thus explaining the need for these patients to avoid swimming in cold water. Autosomal dominantly inherited cold urticaria is associated with dysfunction of cryopyrin. Cholinergic urticaria is precipitated by heat, exercise, or emotion and is characterized by small wheals with relatively large flares. It is occasionally associated with wheezing. Whereas urticarias are the result of dermal edema, subcutaneous edema leads to the clinical picture of angioedema. Sites of involvement include the eyelids, lips, tongue, larynx, and gastrointestinal tract as well as the subcutaneous tissue. Angioedema occurs alone or in com­ bination with urticaria, including urticarial vasculitis and the physical urticarias. Both acquired and hereditary (autosomal dominant) forms TABLE 61-14  Causes of Urticaria and Angioedema I. Primary cutaneous disorders A. Acute and chronic urticariaa B. Physical urticaria

1. Dermographism
2. Solar urticariab
3. Cold urticariab
4. Cholinergic urticariab C. Angioedema (hereditary and acquired)b,c II. Systemic diseases A. Urticarial vasculitis B. Hepatitis B or C viral infection, SARS-CoV-2 infection C. Serum sickness D. Angioedema (hereditary and acquired) aA small minority develop anaphylaxis. bAlso systemic. cAcquired angioedema can be idiopathic, associated with a lymphoproliferative disorder, or due to a drug, e.g., angiotensin-converting enzyme (ACE) inhibitors. Abbreviation: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

of angioedema occur (Chap. 366), and in the latter, urticaria is rarely, if ever, seen. Urticarial vasculitis is an immune complex disease that may be con­ fused with simple urticaria. In contrast to simple urticaria, individual lesions tend to last longer than 24 h and usually develop central pete­ chiae that can be observed even after the urticarial phase has resolved. The patient may also complain of burning rather than pruritus. On biopsy, there is a leukocytoclastic vasculitis of the small dermal blood vessels. Although urticarial vasculitis may be idiopathic in origin, it can be a reflection of an underlying systemic illness such as lupus ery­ thematosus, Sjögren’s syndrome, or hereditary complement deficiency. There is a spectrum of urticarial vasculitis that ranges from purely cutaneous to multisystem involvement. The most common systemic signs and symptoms are arthralgias and/or arthritis, nephritis, and crampy abdominal pain, with asthma and chronic obstructive lung disease seen less often. Hypocomplementemia occurs in one- to twothirds of patients, even in the idiopathic cases. Urticarial vasculitis can also be seen in patients with hepatitis B and hepatitis C infections and serum sickness but is usually not seen in serum sickness–like illnesses (e.g., due to cefaclor, minocycline). PAPULONODULAR SKIN LESIONS (Table 61-15) In the papulonodular diseases, the lesions are elevated above the surface of the skin and may coalesce to form larger plaques. The location, consistency, and color of the lesions are the keys to their diagnosis; this section is organized on the basis of color. ■ ■WHITE LESIONS In calcinosis cutis, there are firm white to white-yellow papules with an irregular surface. When the contents are expressed, a chalky white material is seen. Dystrophic calcification is seen at sites of previous inflammation or damage to the skin. It develops in acne scars as well as on the distal extremities of patients with systemic sclerosis and in the subcutaneous tissue and intermuscular fascial planes in DM. The latter is more extensive and is more commonly seen in children. A previous or current elevated calcium phosphate product, most commonly due to secondary hyperparathyroidism in the setting of renal failure, can lead to nodules of metastatic calcinosis cutis, which tend to be subcu­ taneous and periarticular. These patients can also develop calcification of muscular arteries and subsequent ischemic necrosis (calciphylaxis). Osteoma cutis, in the form of small papules, most commonly occurs on the face of individuals with a history of acne vulgaris, whereas platelike lesions occur in rare genetic syndromes. ■ ■SKIN-COLORED LESIONS There are several types of skin-colored lesions, including epidermoid cysts, lipomas, rheumatoid nodules, neurofibromas, angiofibromas, neuromas, and adnexal tumors such as tricholemmomas. Both epi­ dermoid cysts and lipomas are very common mobile subcutaneous nodules—the former are rubbery and drain cheeselike material (sebum and keratin) if incised. Lipomas are also rubbery and somewhat lobu­ lated on palpation. When extensive facial epidermoid cysts develop during childhood or there is a family history of such lesions, the patient should be examined for other signs of Gardner syndrome, including osteomas and desmoid tumors. Rheumatoid nodules are firm 0.5- to 4-cm nodules that favor the extensor aspect of joints, especially the elbows. They are seen in ~20% of patients with rheumatoid arthritis and ~5% of patients with Still’s disease. Biopsies of the nodules show palisading granulomas. Similar lesions that are smaller and shorterlived are seen in rheumatic fever. Subcutaneous granuloma annulare is sometimes misdiagnosed as rheumatoid nodules. Neurofibromas (benign Schwann cell tumors) are soft papules or nodules that exhibit the “button-hole” sign; that is, they invaginate into the skin with pressure in a manner similar to a hernia. Single lesions are seen in normal individuals, but multiple neurofibromas, usually in combination with six or more CALMs measuring >1.5 cm (see “Hyper­ pigmentation,” above), axillary freckling, and multiple Lisch nodules, are seen in von Recklinghausen’s disease (NF type I) (Chap. 95). In some patients, the neurofibromas are localized and unilateral due to somatic mosaicism.

TABLE 61-15  Papulonodular Skin Lesions According to Color Groups I. White A. Calcinosis cutis B. Osteoma cutis (also skin-colored or blue) II. Skin-colored A. Rheumatoid nodules B. Neurofibromas (von Recklinghausen’s disease [NF1]) C. Angiofibromas (tuberous sclerosis, MEN syndrome, type 1; also pink-red) D. Neuromas (MEN syndrome, type 2b) E. Adnexal tumors

1. Basal cell carcinomas (basal cell nevus syndrome)
2. Tricholemmomas (Cowden disease)
3. Fibrofolliculomas (Birt-Hogg-Dubé syndrome) F. Osteomas (arise in skull and jaw in Gardner syndrome) G. Primary cutaneous disorders Skin Manifestations of Internal Disease CHAPTER 61
4. Epidermal inclusion cystsa
5. Lipomas III. Pink/translucentb A. Amyloidosis, primary systemic B. Papular mucinosis/scleromyxedema C. Multicentric reticulohistiocytosis IV. Yellow A. Xanthomas B. Tophi C. Necrobiosis lipoidica D. Pseudoxanthoma elasticum E. Sebaceous adenomas (Muir-Torre syndrome) V. Redb A. Papules
6. Angiokeratomas (Fabry disease and related lysosomal storage diseases)c
7. Bacillary angiomatosis (primarily in AIDS) B. Papules/plaques
8. Cutaneous lupus erythematosus
9. Lymphoma cutis
10. Leukemia cutis
11. Sweet syndrome C. Nodules
12. Panniculitis
13. Medium-sized vessel vasculitis (e.g., cutaneous polyarteritis nodosa/cutaneous arteritis) D. Primary cutaneous disorders
14. Arthropod bites
15. Cherry hemangiomas
16. Infections, e.g., streptococcal cellulitis, sporotrichosis
17. Polymorphous light eruption
18. Cutaneous lymphoid hyperplasia (lymphocytoma cutis, pseudolymphoma) VI. Red-brownb A. Sarcoidosis B. Urticaria pigmentosa C. Erythema elevatum diutinum (chronic leukocytoclastic vasculitis) D. Lupus vulgaris VII. Blueb A. Venous malformations (e.g., blue rubber bleb syndrome) B. Primary cutaneous disorders
19. Venous lake
20. Blue nevus VIII. Violaceous A. Lupus pernio (sarcoidosis) B. Lymphoma cutis C. Cutaneous lupus erythematosus IX. Purple A. Kaposi’s sarcoma, acral angiodermatitis (pseudo-Kaposi’s sarcoma) B. Angiosarcoma C. Palpable purpura (see Table 61-16) D. Primary cutaneous disorders
21. Angiokeratomas of the scrotum and vulva X. Brown-blackd XI. Any color A. Metastases aIf multiple with childhood onset, consider Gardner syndrome. bMay have darker hue in more darkly pigmented individuals. cMore widespread, especially lower trunk and girdle region, and often red-purple in color. dSee also “Hyperpigmentation.” Abbreviations: MEN, multiple endocrine neoplasia; NF1, neurofibromatosis type 1.

Angiofibromas are firm pink-red to skin-colored papules that mea­ sure from 3 mm to 1.5 cm in diameter. When multiple lesions are located on the central cheeks (adenoma sebaceum), the patient should be evaluated for tuberous sclerosis or multiple endocrine neoplasia (MEN) syndrome, type 1. The former is an autosomal disorder due to mutations in two different genes, and the associated findings are dis­ cussed in the section on ash leaf spots as well as in Chap. 95.

Neuromas (benign proliferations of nerve fibers) are also firm, skin-colored papules. They are more commonly found at sites of amputations and in rudimentary polydactyly. However, when there are multiple neuromas on the eyelids, lips, distal tongue, and/or oral mucosa, the patient should be investigated for other signs of MEN syndrome, type 2b. Associated findings include marfanoid habitus, protuberant lips, intestinal ganglioneuromas, and medullary thyroid carcinoma (>75% of patients; Chap. 400). PART 2 Cardinal Manifestations and Presentation of Diseases Adnexal tumors are derived from pluripotent cells of the epider­ mis that can differentiate toward hair, sebaceous, apocrine or eccrine glands, or remain undifferentiated. Basal cell carcinomas (BCCs) are examples of adnexal tumors that have little or no evidence of differenti­ ation. Clinically, they are translucent papules with rolled borders, telan­ giectasias, and central erosion. BCCs commonly arise in sun-damaged skin of the head and neck as well as the upper trunk. When a patient has multiple BCCs, especially prior to age 30, the possibility of the basal cell nevus syndrome should be raised. It is inherited as an autosomal dominant trait and is associated with jaw cysts, palmar and plantar pits, frontal bossing, medulloblastomas, and calcification of the falx cerebri and diaphragma sellae. Tricholemmomas are also skin-colored adnexal tumors but differentiate toward hair follicles and can have a wartlike appearance. The presence of multiple tricholemmomas on the face and cobblestoning of the oral mucosa points to the diagnosis of Cowden disease (PTEN hamartoma tumor syndrome) due to mutations in the phosphatase and tensin homolog (PTEN) gene. Internal organ involve­ ment (in decreasing order of frequency) includes fibrocystic disease and carcinoma of the breast, adenomas and carcinomas of the thyroid, genitourinary carcinomas, and gastrointestinal polyposis. Keratoses of the palms, soles, and dorsal aspect of the hands are also seen. Fibrofol­ liculomas are skin-colored to white, smooth papules that favor the face, ears, and neck and, when multiple, are associated with Birt-Hogg-Dubé syndrome, which is associated with renal lesions including cancer as well as pulmonary cysts (Chap. 90). ■ ■PINK LESIONS The cutaneous lesions associated with primary systemic amyloidosis are often pink to pink-orange in color and translucent. Common locations are the face, especially the periorbital and perioral regions, and flexural areas. On biopsy, homogeneous deposits of amyloid are seen in the dermis and in the walls of blood vessels; the latter lead to an increase in vessel wall fragility. As a result, petechiae and purpura develop in clini­ cally normal skin as well as in lesional skin following minor trauma, hence the term pinch purpura. Amyloid deposits are also seen in the striated muscle of the tongue and result in macroglossia. Even though specific mucocutaneous lesions are present in only ~30% of the patients with primary systemic (AL) amyloidosis, the diagnosis can be made via histologic examination of abdominal sub­ cutaneous fat, in conjunction with a serum free light chain assay. By special staining, amyloid deposits can be seen around blood vessels or individual fat cells. There are also three forms of amyloidosis that are limited to the skin and that should not be construed as cutaneous lesions of systemic amyloidosis. They are macular amyloidosis (upper back), lichen amyloidosis (usually lower extremities), and nodular amyloidosis. In macular and lichen amyloidosis, lesions are hyperpig­ mented and the deposits are composed of altered epidermal keratin. Early-onset macular and lichen amyloidosis have been associated with MEN syndrome, type 2a. Patients with multicentric reticulohistiocytosis also have pink-colored papules and nodules on the face and mucous membranes as well as on the extensor surface of the hands and forearms. They have a poly­ arthritis that can mimic rheumatoid arthritis clinically. On histologic examination, the papules have characteristic giant cells that are not

seen in biopsies of rheumatoid nodules. Pink to skin-colored papules that are firm, 2–5 mm in diameter, and often in a linear arrangement are seen in patients with papular mucinosis. This disease is also referred to as scleromyxedema. The latter name comes from the induration of the face and extremities that may accompany the papular eruption. Biopsy specimens of the papules show localized mucin deposition, and serum protein electrophoresis plus immunofixation electrophoresis demonstrates a monoclonal spike of IgG, usually with a λ light chain. ■ ■YELLOW LESIONS Several systemic disorders are characterized by yellow-colored cutane­ ous papules or plaques—hyperlipidemia (xanthomas), gout (tophi), diabetes (necrobiosis lipoidica), pseudoxanthoma elasticum, and MuirTorre syndrome (sebaceous tumors). Eruptive xanthomas are the most common form of xanthomas and are associated with hypertriglyceride­ mia (primarily hyperlipoproteinemia types I, IV, and V). Crops of yel­ low papules with erythematous halos occur primarily on the extensor surfaces of the extremities and the buttocks, and they spontaneously involute with a fall in serum triglycerides. Types II and III result in one or more of the following types of xanthoma: xanthelasma, tendon xan­ thomas, and plane xanthomas. Xanthelasma are found on the eyelids, whereas tendon xanthomas are frequently associated with the Achilles and extensor finger tendons; plane xanthomas are flat and favor the palmar creases and flexural folds. Tuberous xanthomas are frequently associated with hypercholesterolemia; however, they are also seen in patients with hypertriglyceridemia and are found most frequently over the large joints or hand. Biopsy specimens of xanthomas show collec­ tions of lipid-containing macrophages (foam cells). Patients with several disorders, including biliary cirrhosis, can have a secondary form of hyperlipidemia with associated tuberous and plane xanthomas. However, patients with plasma cell dyscrasias have nor­ molipemic plane xanthomas. This latter form of xanthoma may be ≥12 cm in diameter and is most frequently seen on the neck, upper trunk, and flexural folds. It is important to note that the most common set­ ting for eruptive xanthomas is uncontrolled diabetes mellitus. The least specific sign for hyperlipidemia is xanthelasma, because at least 50% of the patients with this finding have normal lipid profiles. In tophaceous gout, there are deposits of monosodium urate in the skin around the joints, particularly those of the hands and feet. Addi­ tional sites of tophi formation include the helix of the ear and the olec­ ranon and prepatellar bursae. The lesions are firm, yellow to yellow-white in color, and occasionally discharge a chalky material. Their size varies from 1 mm to 7 cm, and the diagnosis can be established by polarized light microscopy of the aspirated contents of a tophus. Lesions of nec­ robiosis lipoidica are found primarily on the shins (90%), and patients can have diabetes mellitus or develop it subsequently. Characteristic findings include a central yellow color, atrophy (transparency), telan­ giectasias, and a red to red-brown border. Ulcerations can also develop within the plaques. Biopsy specimens show necrobiosis of collagen and granulomatous inflammation. In pseudoxanthoma elasticum (PXE), due to mutations in the gene ABCC6, there is an abnormal deposition of calcium on the elastic fibers of the skin, eye, and blood vessels. In the skin, the flexural areas such as the neck, axillae, antecubital fossae, and inguinal area are the pri­ mary sites of involvement. Yellow papules coalesce to form reticulated plaques that have an appearance similar to that of plucked chicken skin. In severely affected skin, hanging, redundant folds develop. Biopsy specimens of involved skin show swollen and irregularly clumped elastic fibers with deposits of calcium. In the eye, the calcium deposits in Bruch’s membrane lead to angioid streaks and choroiditis; in the arteries of the heart, kidney, gastrointestinal tract, and extremities, the deposits lead to angina, hypertension, gastrointestinal bleeding, and claudication, respectively. Adnexal tumors that have differentiated toward sebaceous glands include sebaceous adenoma, sebaceous carcinoma, and sebaceous hyperplasia. Except for sebaceous hyperplasia, which is commonly seen on the face, these tumors are fairly rare. Patients with Muir-Torre syndrome have one or more sebaceous adenoma(s), and they can also have sebaceous carcinomas and sebaceous hyperplasia as well

as keratoacanthomas. As a variant of Lynch syndrome, the internal manifestations of Muir-Torre syndrome include multiple carcinomas of the gastrointestinal tract (primarily colon) as well as cancers of the genitourinary tract. ■ ■RED LESIONS Cutaneous lesions that are red in color have a wide variety of etiologies; in an attempt to simplify their identification, they will be subdivided into papules, papules/plaques, and subcutaneous nodules. Common red papules include arthropod bites and cherry hemangiomas; the latter are small, bright-red, dome-shaped papules that represent a benign proliferation of capillaries. In patients with AIDS (Chap. 208), the development of multiple red hemangioma-like lesions points to bacil­ lary angiomatosis, and biopsy specimens show clusters of bacilli that stain positively with the Warthin-Starry stain; the pathogens have been identified as Bartonella henselae and Bartonella quintana. Dissemi­ nated visceral disease is seen primarily in immunocompromised hosts but can occur in immunocompetent individuals. Multiple angiokeratomas are seen in Fabry disease, an X-linked recessive lysosomal storage disease that is due to a deficiency of α-galactosidase A. The lesions are red to red-purple in color and can be quite small in size (1–3 mm), with the most common location being the lower trunk. Associated findings include chronic renal disease, peripheral neuropathy, and corneal opacities (cornea verticillata). While electron photomicrographs demonstrate lamellar lipid depos­ its in dermal fibroblasts, pericytes, and endothelial cells, nowadays, genetic analysis is more frequently performed for diagnosis. Wide­ spread acute eruptions of erythematous papules are discussed in the section on exanthems. There are several infectious diseases that present as erythematous papules or nodules in a lymphocutaneous or sporotrichoid pattern, that is, in a linear arrangement along the lymphatic channels. The two most common etiologies are Sporothrix schenckii (sporotrichosis) and the atypical mycobacterium Mycobacterium marinum. The organisms are introduced as a result of trauma, and a primary inoculation site is often seen in addition to the lymphatic nodules. Additional causes include Nocardia, Leishmania, and other atypical mycobacteria and dimorphic fungi; culture or PCR of lesional tissue will aid in the diagnosis. The diseases that are characterized by erythematous plaques with scale are reviewed in the papulosquamous section, and the various forms of dermatitis are discussed in the section on erythroderma. Additional disorders in the differential diagnosis of red papules/ plaques include cellulitis, polymorphous light eruption (PMLE), cuta­ neous lymphoid hyperplasia (lymphocytoma cutis), cutaneous lupus, lymphoma cutis, and leukemia cutis. The first three diseases represent primary cutaneous disorders, although cellulitis may be accompanied by a bacteremia. PMLE is characterized by erythematous papules and plaques in a primarily sun-exposed distribution—dorsum of the hand, extensor forearm, and upper trunk. Lesions follow exposure to UV-B and/or UV-A, and in higher latitudes, PMLE is most severe in the late spring and early summer. A process referred to as “hardening” occurs with continued UV exposure, and the eruption fades spontaneously, but in temperate climates, it recurs the next spring. PMLE must be differentiated from cutaneous lupus, and this is accomplished by observation of the natural history, histologic examination, and some­ times direct immunofluorescence of the lesions. Cutaneous lymphoid hyperplasia (pseudolymphoma) is a benign polyclonal proliferation of lymphocytes within the skin that presents as infiltrated pink-red to red-purple papules and plaques; it must be distinguished from lym­ phoma cutis. Several types of red plaques are seen in patients with systemic lupus, including (1) erythematous urticarial plaques across the cheeks and nose in the classic butterfly rash; (2) erythematous discoid lesions with fine or “carpet-tack” scale, telangiectasias, central hypopigmentation, peripheral hyperpigmentation, follicular plugging, and atrophy located on the scalp, face, external ears, arms, and upper trunk; and (3) psoria­ siform or annular lesions of subacute cutaneous lupus with hypopig­ mented centers located primarily on the extensor arms and upper

trunk. Additional mucocutaneous findings include (1) a violaceous flush on the face and V of the neck; (2) photosensitivity; (3) urticarial vasculitis (see “Urticaria,” above); (4) lupus panniculitis (see below); (5) diffuse alopecia; (6) alopecia secondary to discoid lesions; (7) proximal nailfold telangiectasias and erythema; (8) EM- or TEN-like lesions that may become bullous; (9) oral or nasal ulcers; (10) livedo reticularis; and (11) distal ulcerations secondary to Raynaud’s phenomenon, vasculitis, or livedoid vasculopathy. Patients with only discoid lesions usually have the form of lupus that is limited to the skin. However, up to 10–15% of these patients eventually develop systemic lupus. Direct immunofluorescence of involved skin, in particular discoid lesions, shows deposits of IgG or IgM and C3 in a granular distribution along the dermal-epidermal junction.

Skin Manifestations of Internal Disease CHAPTER 61 In lymphoma cutis, there is a clonal proliferation of malignant lym­ phocytes within the skin, and the clinical appearance resembles that of cutaneous lymphoid hyperplasia—infiltrated pink-red to red-purple papules and plaques. Lymphoma cutis can occur anywhere on the surface of the skin, whereas the sites of predilection for lymphocy­ tomas include the malar ridge, tip of the nose, and earlobes. Patients with non-Hodgkin’s lymphomas have specific cutaneous lesions more often than those with Hodgkin’s lymphoma, and, occasionally, the skin nodules precede the development of extracutaneous non-Hodgkin’s lymphoma or represent the only site of involvement (e.g., primary cutaneous B-cell lymphoma). Arcuate lesions are sometimes seen in lymphoma and lymphocytoma cutis as well as in CTCL. Adult T-cell leukemia/lymphoma that develops in association with HTLV-1 infection is characterized by cutaneous plaques, hypercalcemia, and circulating CD25+ lymphocytes. Leukemia cutis has the same appear­ ance as lymphoma cutis, and specific lesions are seen more commonly in monocytic leukemias than in lymphocytic or granulocytic leuke­ mias. Cutaneous chloromas (granulocytic sarcomas) may precede the appearance of circulating blasts in acute myelogenous leukemia and, as such, represent a form of aleukemic leukemia cutis. Sweet syndrome is characterized by pink-red to red-brown edema­ tous plaques that are frequently painful and occur primarily on the head, neck, and upper extremities. The patients also have fever, neu­ trophilia, and a dense dermal infiltrate of neutrophils in the lesions. In ~10% of the patients, there is an associated malignancy, most com­ monly acute myelogenous leukemia. Sweet syndrome has also been reported with myelodysplasia, inflammatory bowel disease, systemic lupus erythematosus, and solid tumors (primarily of the genitourinary tract) as well as drugs (e.g., granulocyte colony-stimulating factor [G-CSF], hypomethylating agents, all-trans-retinoic acid). The dif­ ferential diagnosis includes neutrophilic eccrine hidradenitis; bullous forms of pyoderma gangrenosum; and, occasionally, cellulitis. Extra­ cutaneous sites of involvement include joints, muscles, eyes, kidneys (proteinuria, occasionally glomerulonephritis), and lungs (neutrophilic infiltrates). The idiopathic form of Sweet syndrome is seen more often in women, following a respiratory tract infection. Common causes of erythematous subcutaneous nodules include inflamed epidermoid cysts, acne cysts, and furuncles. Panniculitis, an inflammation of the fat, also presents as subcutaneous nodules and is frequently a sign of systemic disease. There are several forms of pan­ niculitis, including erythema nodosum, erythema induratum/nodu­ lar vasculitis, lupus panniculitis, lipodermatosclerosis, α1-antitrypsin deficiency, factitial, and fat necrosis secondary to pancreatic disease. Except for erythema nodosum, these lesions may break down and ulcerate or heal with a scar. The shin is the most common location for the nodules of erythema nodosum, whereas the calf is the most common location for lesions of erythema induratum. In erythema nodosum, the nodules are initially red but then develop a blue bruiselike color as they resolve. Patients with erythema nodosum but no underlying systemic illness can still have fever, malaise, leukocytosis, arthralgias, and/or arthritis. However, the possibility of an underlying illness should be excluded, and the most common associations are streptococcal infections, upper respiratory viral infections, sarcoidosis, and inflammatory bowel disease, in addition to drugs (oral contracep­ tives, sulfonamides, penicillins, bromides, iodides, BRAF inhibitors). Less common associations include bacterial gastroenteritis (Yersinia,

Salmonella) and coccidioidomycosis followed by pregnancy, Sweet syndrome, tuberculosis, histoplasmosis, brucellosis, and infections with Chlamydophilia pneumoniae, Chlamydia trachomatis, Mycoplasma pneumoniae, or hepatitis B virus.

Erythema induratum and nodular vasculitis have overlapping fea­ tures clinically and histologically, and whether they represent two sepa­ rate entities or the ends of a single disease spectrum is a point of debate; in general, the latter is usually idiopathic and the former is associated with the presence of Mycobacterium tuberculosis DNA by PCR within skin lesions. The lesions of lupus panniculitis are found primarily on the cheeks, upper arms, and buttocks (sites of abundant fat) and are seen in both the cutaneous and systemic forms of lupus. The overly­ ing skin may be normal, erythematous, or have the changes of discoid lupus. The subcutaneous fat necrosis that is associated with pancreatic disease is presumably secondary to circulating lipases and is seen in patients with pancreatic carcinoma as well as in patients with acute and chronic pancreatitis. In this disorder, there may be an associated arthritis, fever, and inflammation of visceral fat. Histologic examina­ tion of deep incisional biopsy specimens will aid in the diagnosis of the particular type of panniculitis. PART 2 Cardinal Manifestations and Presentation of Diseases Subcutaneous erythematous nodules are also seen in cutaneous polyarteritis nodosa and as a manifestation of systemic vasculitis when there is involvement of medium-sized vessels, for example, systemic polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis, or granulomatosis with polyangiitis (Chap. 375). Cutaneous polyarteritis nodosa, more recently referred to as cutaneous arteritis, presents with painful subcutaneous nodules and ulcers within a red-purple, netlike pattern of livedo reticularis. The latter is due to slowed blood flow through the superficial horizontal venous plexus. The majority of lesions are found on the lower extremities, and while arthralgias and myalgias may accompany cutaneous polyarteritis nodosa, there is no evidence of systemic involvement. In both the cutaneous and systemic forms of vasculitis, skin biopsy specimens of the associated nodules will show the changes characteristic of a necrotizing vasculitis and/or granulomatous inflammation. ■ ■RED-BROWN LESIONS The cutaneous lesions in sarcoidosis (Chap. 379) are classically red to red-brown in color, and with diascopy (pressure with a glass slide), a yellow-brown residual color is observed that is secondary to the granulomatous infiltrate. The waxy papules and plaques may be found anywhere on the skin, but the face is the most common location. Usu­ ally there are no surface changes, but occasionally, the lesions will have scale. Biopsy specimens of the papules show “naked” granulomas in the dermis, that is, granulomas surrounded by a minimal number of lymphocytes. Other cutaneous findings in sarcoidosis include annular lesions with an atrophic or scaly center, papules within scars, hypopig­ mented papules and plaques, subcutaneous plaques, alopecia, acquired ichthyosis, erythema nodosum, and lupus pernio (see below). The differential diagnosis of sarcoidosis includes foreign-body granulomas produced by chemicals such as beryllium and zirconium, late secondary syphilis, reactive granulomatous dermatitis, and lupus vulgaris. Lupus vulgaris is a form of cutaneous tuberculosis that is seen in previously infected and sensitized individuals. There is often underlying active tuberculosis elsewhere, usually in the lungs or lymph nodes. Lesions occur primarily in the head and neck region and are red-brown plaques with a yellow-brown color on diascopy. Secondary scarring can develop within the central portion of the plaques. Cultures or PCR analysis of the lesions should be performed, along with an interferon γ release assay of peripheral blood, because it is rare for the acid-fast stain to show bacilli within the dermal granulomas. A generalized distribution of red-brown macules and papules is seen in the maculopapular form of mastocytosis, also known as urticaria pigmentosa (Chap. 366). Each lesion represents a collection of mast cells in the dermis, with hyperpigmentation of the overlying epidermis. Stimuli such as rubbing cause these mast cells to degranulate, and this leads to the formation of localized urticaria (Darier’s sign). Additional symptoms can result from mast cell degranulation and include head­ ache, flushing, diarrhea, and pruritus. Mast cells also infiltrate various

organs such as the liver, spleen, and gastrointestinal tract, and accu­ mulations of mast cells in the bones may produce either osteosclerotic or osteolytic lesions on radiographs. In the majority of these patients, however, the internal involvement remains indolent. A subtype of chronic cutaneous small-vessel vasculitis, erythema elevatum diutinum (EED), also presents with papules that are red-brown in color. The papules coalesce into plaques on the extensor surfaces of knees, elbows, and the small joints of the hand. Flares of EED have been associated with streptococcal infections. ■ ■BLUE LESIONS Lesions that are blue in color are the result of vascular ectasias, hyper­ plasias, and tumors or melanin pigment within the dermis. Venous lakes (ectasias) are compressible dark-blue lesions that are found com­ monly in the head and neck region. Venous malformations are also compressible blue papulonodules and plaques that can occur anywhere on the body, including the oral mucosa. When there are multiple papu­ lonodules rather than a single congenital lesion, the patient may have the blue rubber bleb syndrome or Maffucci’s syndrome due to muta­ tions in TEK or IDH1, respectively. Patients with the blue rubber bleb syndrome also have vascular anomalies of the gastrointestinal tract that may bleed, whereas patients with Maffucci’s syndrome have associated osteochondromas. Blue nevi (moles) are seen when there are collec­ tions of pigment-producing nevus cells in the dermis. These benign papular lesions are dome-shaped and occur most commonly on the dorsum of the hand or foot or in the head and neck or presacral region. ■ ■VIOLACEOUS LESIONS Violaceous papules and plaques are seen in lupus pernio, lymphoma cutis, and cutaneous lupus. Lupus pernio is a particular type of sarcoid­ osis that involves the tip and alar rim of the nose as well as the earlobes, with lesions that are violaceous in color rather than red-brown. This form of sarcoidosis is associated with involvement of the upper respira­ tory tract. The plaques of lymphoma cutis and cutaneous lupus may be red or violaceous in color and were discussed above. ■ ■PURPLE LESIONS Purple-colored papules and plaques are seen in vascular tumors, such as Kaposi’s sarcoma (Chap. 208) and angiosarcoma, and when there is extravasation of red blood cells into the skin in association with inflammation, as in palpable purpura (see “Purpura,” below). Patients with congenital or acquired AV fistulas and venous hypertension can develop purple papules on the lower extremities that can resemble Kaposi’s sarcoma clinically and histologically; this condition is referred to as pseudo-Kaposi’s sarcoma (acral angiodermatitis). Angiosarcoma is found most commonly on the scalp and face of elderly patients or within areas of chronic lymphedema and presents as purple papules and plaques. In the head and neck region, the tumor often extends beyond the clinically defined borders and may be accompanied by facial edema. ■ ■BROWN AND BLACK LESIONS Brown- and black-colored papules are reviewed in “Hyperpigmenta­ tion,” above. ■ ■CUTANEOUS METASTASES These are discussed last because they can have a wide range of colors. Most commonly, they present as either firm, skin-colored subcuta­ neous nodules or firm, red to red-brown papulonodules, whereas metastatic melanoma can be pink, blue, or black in color. Cutaneous metastases develop from hematogenous or lymphatic spread and are most often due to the following primary carcinomas: in men, mela­ noma, oropharynx, lung, and colon; and in women, breast, melanoma, and ovary. These metastatic lesions may be the initial presentation of the carcinoma, especially when the primary site is the lung. PURPURA (Table 61-16) Purpura are seen when there is an extravasation of red blood cells into the dermis and, as a result, the lesions do not blanch with pressure. This is in contrast to those erythematous or violet-colored

TABLE 61-16  Causes of Purpura I. Primary cutaneous disorders A. Nonpalpable

1. Trauma
2. Solar (actinic, senile) purpura
3. Steroid purpura
4. Stasis purpura due to venous hypertension
5. Capillaritis
6. Livedoid vasculopathy in the setting of venous hypertensiona II. Drugs (e.g., antiplatelet agents, anticoagulants) III. Systemic diseases A. Nonpalpable
7. Clotting disturbances a. Thrombocytopenia (including ITP) b. Abnormal platelet function c. Clotting factor defects
8. Vascular fragility a. Amyloidosis (within normal-appearing skin) b. Ehlers-Danlos syndrome c. Scurvy
9. Thrombi a. Disseminated intravascular coagulation, purpura fulminans b. Warfarin (Coumadin)-induced necrosis c. Heparin-induced thrombocytopenia and thrombosis d. Antiphospholipid antibody syndrome e. Monoclonal cryoglobulinemia f. Vasculopathy induced by levamisole-adulterated cocaineb g. SARS-CoV-2 infection h. Thrombotic thrombocytopenic purpura i. Thrombocytosis j. Homozygous protein C or protein S deficiency
10. Emboli a. Cholesterol b. Fat
11. Possible immune complex a. Gardner-Diamond syndrome (autoerythrocyte sensitivity) b. Waldenström’s hypergammaglobulinemic purpura
12. Calciphylaxis B. Palpable
13. Vasculitis a. Cutaneous small-vessel vasculitis, including in the setting of systemic vasculitides
14. Embolic a. Acute meningococcemia b. Disseminated gonococcal infection c. Rocky Mountain spotted fever d. Ecthyma gangrenosum aAlso associated with underlying disorders that lead to hypercoagulability/ thrombophilia, e.g., factor V Leiden, protein C dysfunction/deficiency. bCombined vasculopathy/vasculitis can be seen. cBacterial (including rickettsial), fungal, or parasitic. Abbreviations: ITP, idiopathic thrombocytopenic purpura; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. lesions that are due to localized vasodilatation—they do blanch with pressure. Purpura (≥3 mm) and petechiae (≤2 mm) are divided into two major groups: palpable and nonpalpable (macular). The most fre­ quent causes of nonpalpable purpura and petechiae are primary cuta­ neous disorders such as trauma, solar (actinic) purpura, stasis purpura, and capillaritis. Less common causes are steroid purpura and livedoid vasculopathy (see “Ulcers,” below). Solar purpura are seen primarily on the extensor forearms, whereas steroid purpura secondary to potent topical glucocorticoids or endogenous or exogenous Cushing’s syn­ drome can be more widespread. In both cases, there is alteration of the

supporting connective tissue that surrounds the dermal blood vessels. In contrast, the petechiae that result from capillaritis are found primar­ ily on the lower extremities. In capillaritis, there is an extravasation of erythrocytes as a result of perivascular lymphocytic inflammation. The petechiae are bright red, 1–2 mm in size, and scattered within yellow-

brown patches. The yellow-brown color is caused by hemosiderin deposits within the dermis.

Systemic causes of nonpalpable purpura fall into several categories, and those secondary to clotting disturbances and vascular fragility will be discussed first. The former group includes thrombocytopenia (Chap. 120), abnormal platelet function as is seen in uremia, and clot­ ting factor defects. The initial site of presentation for thrombocytope­ nia-induced petechiae is the distal lower extremity. Capillary fragility leads to nonpalpable purpura in patients with systemic amyloidosis (see “Papulonodular Skin Lesions,” above), disorders of collagen produc­ tion such as Ehlers-Danlos syndrome, and scurvy. In scurvy, there are flattened corkscrew hairs with surrounding perifollicular hemorrhage on the lower extremities, in addition to gingivitis. Vitamin C is a cofac­ tor for lysyl hydroxylase, an enzyme involved in the posttranslational modification of procollagen that is necessary for cross-link formation. Skin Manifestations of Internal Disease CHAPTER 61 In contrast to the previous group of disorders, the noninflammatory purpura seen in the following group of diseases are associated with thrombi formation within vessels and have a retiform configuration. It is important to note that these thrombi are demonstrable in skin biopsy specimens. This group of disorders includes disseminated intravascu­ lar coagulation (DIC), monoclonal cryoglobulinemia, thrombocytosis, thrombotic thrombocytopenic purpura, antiphospholipid antibody syndrome, and reactions to warfarin and heparin (heparin-induced thrombocytopenia and thrombosis). DIC is triggered by several types of infection (gram-negative, gram-positive, viral, and rickettsial) as well as by tissue injury and neoplasms. Widespread purpura and hem­ orrhagic infarcts of the distal extremities are seen. Similar lesions are found in purpura fulminans, which is a form of DIC associated with fever and hypotension that occurs more commonly in children fol­ lowing an infectious illness such as varicella, scarlet fever, or an upper respiratory tract infection. In both disorders, hemorrhagic bullae can develop in involved skin. Monoclonal cryoglobulinemia is associated with plasma cell dyscra­ sias, chronic lymphocytic leukemia, and lymphoma. Purpura, primar­ ily of the lower extremities, and hemorrhagic infarcts of the fingers, toes, nose, and ears are seen in these patients. Exacerbations of disease activity can follow cold exposure or an increase in serum viscosity. Biopsy specimens show precipitates of the cryoglobulin within dermal vessels. Similar deposits have been found in the lung, brain, and renal glomeruli. Patients with thrombotic thrombocytopenic purpura can also have hemorrhagic infarcts as a result of intravascular thromboses. Additional signs include microangiopathic hemolytic anemia and fluc­ tuating neurologic abnormalities, especially headaches and confusion. Administration of warfarin can result in painful areas of erythema that become purpuric and then necrotic with an adherent black eschar; the condition is also referred to as Coumadin-induced necrosis. This reaction is seen more often in women and in areas with abundant subcutaneous fat—breasts, abdomen, buttocks, thighs, and calves. The erythema and purpura develop between the third and tenth day of therapy, most likely as a result of a transient imbalance in the levels of anticoagulant and procoagulant vitamin K–dependent factors. Contin­ ued therapy does not exacerbate preexisting lesions, and patients with an inherited or acquired deficiency of protein C are at increased risk for this particular reaction as well as for purpura fulminans and calciphy­ laxis. The latter can have a similar clinical appearance. Purpura secondary to cholesterol emboli are usually seen on the lower extremities of patients with atherosclerotic vascular disease. They often follow anticoagulant therapy or an invasive vascular proce­ dure such as an arteriogram but also occur spontaneously from disin­ tegration of atheromatous plaques. Associated findings include livedo reticularis, gangrene, cyanosis, ischemic ulcerations, and peripheral eosinophilia. Multiple step sections of the biopsy specimen may be necessary to demonstrate the cholesterol clefts within the vessels. Pete­ chiae are also an important sign of fat embolism and occur primarily on

the upper body 2–3 days after a major injury. By using special fixatives, the emboli can be demonstrated in biopsy specimens of the petechiae. Rarely, emboli of tumor or thrombus are seen in patients with atrial myxomas and marantic endocarditis.

In the Gardner-Diamond syndrome (autoerythrocyte sensitivity), female patients develop large ecchymoses within areas of painful, warm erythema. Intradermal injections of autologous erythrocytes or phos­ phatidyl serine derived from the red cell membrane can reproduce the lesions in some patients; however, there are instances where a reaction is seen at an injection site of the forearm but not in the midback region. The latter has led some observers to view Gardner-Diamond syndrome as a cutaneous manifestation of severe emotional stress. More recently, the possibility of platelet dysfunction (as assessed via aggregation stud­ ies) has been raised. Waldenström’s hypergammaglobulinemic purpura, more recently referred to as recurrent macular vasculitis in hypergam­ maglobulinemia, is a chronic disorder characterized by recurrent crops of petechiae and larger purpuric macules on the lower extremities. There are circulating complexes of IgG or IgA rheumatoid factor, and exacerbations are associated with prolonged standing or walking. Patients may have an underlying autoimmune connective tissue dis­ ease, e.g., Sjögren’s syndrome. PART 2 Cardinal Manifestations and Presentation of Diseases Palpable purpura are further subdivided into vasculitic and embolic. In the group of vasculitic disorders, cutaneous small-vessel vasculitis, also known as leukocytoclastic vasculitis (LCV), is the one most com­ monly associated with palpable purpura (Chap. 375). Underlying etiologies include drugs (e.g., antibiotics), infections (e.g., hepatitis C virus), and autoimmune connective tissue diseases (e.g., rheumatoid arthritis, Sjögren’s syndrome, lupus). Henoch-Schönlein purpura (HSP) is a subtype of acute LCV that is seen more commonly in children and adolescents following an upper respiratory infection. The majority of lesions are found on the lower extremities and buttocks. Systemic manifestations include fever, arthralgias (primarily of the knees and ankles), abdominal pain, gastrointestinal bleeding, and nephritis. Direct immunofluorescence examination shows deposits of IgA within dermal blood vessel walls. Renal disease is of particular concern in adults with IgA vasculitis. Several types of infectious emboli can give rise to palpable purpura. These embolic lesions are usually irregular in outline as opposed to the lesions of LCV, which are circular in outline. The irregular outline is indicative of a cutaneous infarct, and the size corresponds to the area of skin that received its blood supply from that particular arteriole or artery. The palpable purpura in LCV are circular because the eryth­ rocytes simply diffuse out evenly from the postcapillary venules as a result of inflammation. Infectious emboli are most commonly due to gram-negative cocci (meningococcus, gonococcus), gram-negative rods (Enterobacteriaceae), and gram-positive cocci (Staphylococcus). Additional causes include Rickettsia and, in immunocompromised patients, Aspergillus and other opportunistic fungi. The embolic lesions in acute meningococcemia are found primarily on the trunk, lower extremities, and sites of pressure, and a gunmetal-gray color often develops within them. Their size varies from a few millime­ ters to several centimeters, and the organisms can be cultured from the lesions. Associated findings include a preceding upper respiratory tract infection; fever; meningitis; DIC; and, in some patients, a deficiency of the terminal components of complement. In disseminated gonococcal infection (arthritis-dermatitis syndrome), a small number of inflam­ matory papules and vesicopustules, often with central purpura or hemorrhagic necrosis, are found on the distal extremities. Additional symptoms include arthralgias, tenosynovitis, and fever. To establish the diagnosis, a Gram stain of these lesions should be performed. Rocky Mountain spotted fever is a tick-borne disease that is caused by Rickettsia rickettsii. A several-day history of fever, chills, severe head­ ache, and photophobia precedes the onset of the cutaneous eruption. The initial lesions are erythematous macules and papules on the wrists, ankles, palms, and soles. With time, the lesions spread centripetally and become purpuric. Lesions of ecthyma gangrenosum begin as edematous, erythematous papules or plaques and then develop central purpura and necrosis. Bullae formation also occurs in these lesions, and they are frequently

found in the girdle region. The organism that is classically associated with ecthyma gangrenosum is Pseudomonas aeruginosa, but other gram-negative rods such as Klebsiella, Escherichia coli, and Serratia can produce similar lesions. In immunocompromised hosts, the list of potential pathogens is expanded to include Candida and other oppor­ tunistic fungi (e.g., Aspergillus, Fusarium). ULCERS The approach to the patient with a cutaneous ulcer is outlined in Table 61-17. Peripheral vascular diseases of the extremities are reviewed in Chap. 292, as is Raynaud’s phenomenon. Livedoid vasculopathy (livedoid vasculitis; atrophie blanche) repre­ sents a combination of a vasculopathy plus intravascular thrombosis. Purpuric lesions and livedo reticularis are found in association with painful ulcerations of the lower extremities. These ulcers are often TABLE 61-17  Causes of Mucocutaneous Ulcers I. Primary cutaneous disorders A. Peripheral vascular disease (Chap. 292)

1. Venous
2. Arteriala B. Livedoid vasculopathy in the setting of venous hypertensionb C. Squamous cell carcinoma (e.g., within scars), basal cell carcinomas D. Infections, e.g., ecthyma caused by Streptococcus (Chap. 153) E. Physical, e.g., trauma, pressure F. Drugs, e.g., hydroxyurea II. Systemic diseases A. Lower legs
3. Small-vessel and medium-vessel vasculitisc
4. Hemoglobinopathies (Chap. 103)
5. Cryoglobulinemia,c cryofibrinogenemia
6. Cholesterol embolia,c
7. Necrobiosis lipoidicad
8. Antiphospholipid syndrome (Chap. 121)
9. Neuropathice (Chap. 415)
10. Panniculitis
11. Kaposi’s sarcoma, acral angiodermatitis (pseudo-Kaposi’s sarcoma)
12. Diffuse dermal angiomatosis B. Hands and feet
13. Raynaud’s phenomenon (Chap. 292)
14. Buerger disease C. Generalized
15. Pyoderma gangrenosum, but most commonly legs
16. Calciphylaxis (Chap. 422)
17. Infections, e.g., dimorphic fungi, leishmaniasis
18. Lymphoma D. Face, especially perioral, and anogenital
19. Chronic herpes simplexf III. Mucosal A. Aphthae B. Drug-induced mucositis C. Behçet’s disease (Chap. 376) D. Erythema multiforme major, Stevens-Johnson syndrome, TEN E. Primary blistering disorders (Chap. 62) F. Lupus erythematosus, lichen planus, lichenoid GVHD G. Inflammatory bowel disease H. Acute HIV infection I. Reactive arthritis aUnderlying atherosclerosis. bAlso associated with underlying disorders that lead to hypercoagulability/thrombophilia, e.g., factor V Leiden, protein C dysfunction/ deficiency, antiphospholipid antibodies. cReviewed in section on purpura. dReviewed in section on papulonodular skin lesions. eFavors plantar surface of the foot. fSign of immunosuppression. Abbreviations: GVHD, graft versus host disease; HIV, human immunodeficiency virus; TEN, toxic epidermal necrolysis.

57 - 62 Immunologically Mediated Skin Diseases

62 Immunologically Mediated Skin Diseases

slow to heal, but when they do, irregularly shaped white scars form. The majority of cases are secondary to venous hypertension, but pos­ sible underlying illnesses include disorders of hypercoagulability, for example, antiphospholipid syndrome and factor V Leiden (Chaps. 122 and 369). In pyoderma gangrenosum, the border of untreated active ulcers has a characteristic appearance consisting of an undermined necrotic violaceous edge and a peripheral erythematous halo. The ulcers often begin as pustules that then expand rather rapidly to a size as large as 20 cm. Although these lesions are most commonly found on the lower extremities, they can arise anywhere on the surface of the body, including at sites of trauma (pathergy). An estimated 30–50% of cases are idiopathic, and the most common associated disorder is inflamma­ tory bowel disease. Less commonly, pyoderma gangrenosum is asso­ ciated with seropositive rheumatoid arthritis, myelodysplasia, acute myelogenous leukemia, a monoclonal gammopathy (usually IgA), or an autoinflammatory disorder. Because the histology of pyoderma gan­ grenosum may be nonspecific (dermal infiltrate of neutrophils when in untreated state), the diagnosis requires clinicopathologic correlation, in particular, the exclusion of similar-appearing ulcers such as vasculitis, Meleney’s ulcer (synergistic infection at a site of trauma or surgery), dimorphic fungi, cutaneous amebiasis, spider bites, and factitial. In the hematologic disorders, the ulcers may be more superficial with a pustulobullous border, and these lesions provide a connection between classic pyoderma gangrenosum and acute febrile neutrophilic derma­ tosis (Sweet syndrome). FEVER AND RASH The major considerations in a patient with a fever and a rash are inflammatory diseases versus infectious diseases. In the hospital set­ ting, the most common scenario is a patient who has a drug rash plus a fever secondary to an underlying infection. However, it should be emphasized that a drug reaction can lead to both a cutaneous eruption and a fever (“drug fever”), especially in the setting of DRESS, AGEP, or serum sickness–like reaction. Additional inflammatory diseases that are often associated with a fever include pustular psoriasis, erythro­ derma, and Sweet syndrome. Lyme disease, secondary syphilis, and viral and bacterial exanthems (see “Exanthems,” above) are examples of infectious diseases that produce a rash and a fever. Lastly, it is impor­ tant to determine whether or not the cutaneous lesions represent septic emboli (see “Purpura,” above). Such lesions usually have evidence of ischemia in the form of purpura, necrosis, or impending necrosis (gunmetal-gray color). In the patient with thrombocytopenia, however, purpura can be seen in inflammatory reactions such as morbilliform drug eruptions and infectious lesions. In addition, because of venous hypertension, lesions of a morbilliform drug eruption that are below the knee can be purpuric. ■ ■FURTHER READING Bolognia JL, Schaffer JV, Cerroni L (eds): Dermatology, 5th ed. Philadelphia, Elsevier, 2024. Callen JP et al (eds): Dermatological Signs of Systemic Disease, 5th ed. Edinburgh, Elsevier, 2017. Fazel N (ed): Oral Signs of Systemic Disease. Switzerland, Springer, 2019. Kurtzman D: Rheumatologic dermatology. Clin Dermatol 36:439, 2018. Taylor SC et al (eds): Taylor and Kelly’s Dermatology for Skin of Color, 2nd ed. New York, McGraw-Hill, 2016.

Kim B. Yancey, Benjamin F. Chong,

Thomas J. Lawley

Immunologically

Mediated Skin Diseases A number of immunologically mediated skin diseases and immuno­ logically mediated systemic disorders with cutaneous manifestations are now recognized as distinct entities with consistent clinical, his­ tologic, and immunopathologic findings. Clinically, these disorders are characterized by morbidity (pain, pruritus, disfigurement) and, in some instances, risk of mortality (largely due to loss of epidermal barrier function and/or secondary infection). The major features of the more common immunologically mediated skin diseases are sum­ marized in this chapter (Table 62-1), as are autoimmune systemic disorders with cutaneous manifestations. Immunologically Mediated Skin Diseases CHAPTER 62 AUTOIMMUNE CUTANEOUS DISEASES ■ ■PEMPHIGUS VULGARIS Pemphigus refers to a group of autoantibody-mediated intraepidermal blistering diseases characterized by loss of cohesion between epidermal cells (a process termed acantholysis). Manual pressure to the skin of these patients may elicit the separation of the epidermis (Nikolsky’s sign). This finding, while characteristic of pemphigus, is not specific to this group of disorders and is also seen in toxic epidermal necrolysis, Stevens-Johnson syndrome, and a few other skin diseases. Pemphigus vulgaris (PV) is a mucocutaneous blistering disease that predominantly occurs in patients >40 years of age. PV typically begins on mucosal surfaces and often progresses to involve the skin. This dis­ ease is characterized by fragile, flaccid blisters that rupture to produce extensive denudation of mucous membranes and skin (Fig. 62-1). The mouth, scalp, face, neck, axilla, groin, and trunk are typically involved. PV may be associated with severe skin pain; some patients experience pruritus as well. Lesions usually heal without scarring except at sites complicated by secondary infection or mechanically induced dermal wounds. Postinflammatory hyperpigmentation is usually present for some time at sites of healed lesions. Biopsies of early lesions demonstrate intraepidermal vesicle formation secondary to loss of cohesion between epidermal cells (i.e., acantholytic blisters). Blister cavities contain acantholytic epi­ dermal cells, which appear as round homogeneous cells containing hyperchromatic nuclei. Basal keratinocytes remain attached to the epidermal basement membrane; hence, blister formation takes place within the suprabasal portion of the epidermis. Lesional skin may contain focal collections of intraepidermal eosinophils within blister cavities; dermal alterations are slight, often limited to an eosino­ phil-predominant leukocytic infiltrate. Direct immunofluorescence microscopy of lesional or intact patient skin shows deposits of IgG on the surface of keratinocytes; deposits of complement components are typically found in lesional but not in uninvolved skin. Deposits of IgG on keratinocytes are derived from circulating autoantibodies to cell-surface autoantigens. Such circulating autoantibodies can be demonstrated in 80–90% of PV patients by indirect immunofluores­ cence microscopy; monkey esophagus is the optimal substrate for these studies. Patients with PV have IgG autoantibodies to desmo­ gleins (Dsgs), transmembrane desmosomal glycoproteins that belong to the cadherin family of calcium-dependent adhesion molecules. Such autoantibodies can be precisely quantitated by enzyme-linked immunosorbent assay (ELISA). Patients with early PV (i.e., mucosal disease) have IgG autoantibodies to Dsg3; patients with advanced PV (i.e., mucocutaneous disease) have IgG autoantibodies to both Dsg3 and Dsg1. Experimental studies have shown that autoanti­ bodies from patients with PV are pathogenic (i.e., responsible for blister formation) and that their titer correlates with disease activity.

TABLE 62-1  Immunologically Mediated Blistering Diseases DISEASE CLINICAL MANIFESTATIONS HISTOLOGY IMMUNOPATHOLOGY AUTOANTIGENSa Pemphigus vulgaris Oromucosal lesions, flaccid blisters, denuded skin Acantholytic blister formed in suprabasal layer of epidermis Pemphigus foliaceus Crusts and shallow erosions on scalp, central face, upper chest, and back Acantholytic blister formed in superficial layer of epidermis Paraneoplastic pemphigus Painful stomatitis with papulosquamous or lichenoid eruptions that may progress to blisters Acantholysis, keratinocyte necrosis, and vacuolar interface dermatitis PART 2 Cardinal Manifestations and Presentation of Diseases Bullous pemphigoid Large tense blisters on flexor surfaces and trunk Subepidermal blister with eosinophil-rich infiltrate Pemphigoid gestationis Pruritic, urticarial plaques rimmed by vesicles and bullae on the trunk and extremities Teardrop-shaped, subepidermal blisters in dermal papillae; eosinophil-rich infiltrate Dermatitis herpetiformis Extremely pruritic small papules and vesicles on elbows, knees, buttocks, and posterior neck Subepidermal blister with neutrophils in dermal papillae Linear IgA disease Pruritic papulovesicles on extensor surfaces; occasionally larger, arciform blisters Subepidermal blister with neutrophil-rich infiltrate Epidermolysis bullosa acquisita Blisters, erosions, scars, and milia on sites exposed to trauma; widespread, inflammatory, tense blisters may be seen initially Subepidermal blister that may or may not include a leukocytic infiltrate Mucous membrane pemphigoid Erosive and/or blistering lesions of mucous membranes and possibly the skin; scarring of some sites Subepidermal blister that may or may not include a leukocytic infiltrate aAutoantigens bound by these patients’ autoantibodies are defined as follows: Dsg1, desmoglein 1; Dsg3, desmoglein 3; BPAG1, bullous pemphigoid antigen 1; BPAG2, bullous pemphigoid antigen 2. Abbreviation: BMZ, basement membrane zone. Recent studies have shown that the anti-Dsg autoantibody profile in these patients’ sera as well as the tissue distribution of Dsg3 and Dsg1 determine the site of blister formation in patients with PV. Coexpression of Dsg3 and Dsg1 by epidermal cells protects against pathogenic IgG antibodies to either of these cadherins but not against pathogenic autoantibodies to both. PV can be life-threatening. Prior to the availability of glucocor­ ticoids, mortality rates ranged from 60% to 90%; the current figure is ~5%. Common causes of morbidity and death are infection and complications of treatment. Bad prognostic factors include advanced age, widespread involvement, and the requirement for high doses of glucocorticoids (with or without other immunosuppressive agents) for control of disease. The course of PV in individual patients is variable and difficult to predict. Some patients experience remis­ sion, while others may require long-term treatment or succumb to complications of their disease or its treatment. The mainstay of treatment is systemic glucocorticoids alone or in combination with other immunosuppressive agents. Patients with moderate to severe PV are usually started on prednisone at doses ≤1 mg/kg per day (single morning dose). If new lesions continue to appear after 1–2 weeks of treatment, the dose of prednisone may need to be increased and/ or combined with another immunosuppressive agent. Among these, rituximab in combination with prednisone often achieves remission (though maintenance therapy may be required to prevent relapse). Other immunosuppressive agents sometimes combined with pred­ nisone to treat PV include azathioprine, mycophenolate mofetil, or cyclophosphamide. Patients with severe, treatment-resistant disease may derive benefit from plasmapheresis (six high-volume exchanges [i.e., 2–3 L per exchange] over ~2 weeks) and/or IV immunoglobulin (IVIg). It is important to bring severe or progressive disease under control quickly in order to lessen the severity and/or duration of this disorder. Increasingly, rituximab and daily glucocorticoids are used early in PV patients to avert the development of advanced and/or treatment-resistant disease.

Cell surface deposits of IgG on keratinocytes Dsg3 (plus Dsg1 in patients with skin involvement) Cell surface deposits of IgG on keratinocytes Dsg1 Cell surface deposits of IgG and C3 on keratinocytes and (variably) similar immunoreactants in epidermal BMZ Plakin protein family members and desmosomal cadherins (see text for details) Linear band of IgG and/or C3 in epidermal BMZ BPAG1, BPAG2 Linear band of C3 in epidermal BMZ BPAG2 (plus BPAG1 in some patients) Granular deposits of IgA in dermal papillae Epidermal transglutaminase Linear band of IgA in epidermal BMZ BPAG2 (see text for specific details) Linear band of IgG and/or C3 in epidermal BMZ Type VII collagen Linear band of IgG, IgA, and/or C3 in epidermal BMZ BPAG2, laminin-332, or others ■ ■PEMPHIGUS FOLIACEUS Pemphigus foliaceus (PF) is distinguished from PV by several features. In PF, acantholytic blisters are located high within the epidermis, usu­ ally just beneath the stratum corneum. Hence, PF is a more superfi­ cial blistering disease than PV. The distribution of lesions in the two disorders is much the same, except that in PF mucous membranes are almost always spared. Patients with PF rarely have intact blisters but rather exhibit shallow erosions associated with erythema, scale, and crust formation. Mild cases of PF can resemble severe seborrheic dermatitis; severe PF may cause extensive exfoliation. Sun exposure (ultraviolet irradiation) may be an aggravating factor. PF has immunopathologic features in common with PV. Specifically, direct immunofluorescence microscopy of perilesional skin demon­ strates IgG on the surface of keratinocytes. Similarly, patients with PF have circulating IgG autoantibodies directed against the surface of keratinocytes. In PF, autoantibodies are directed against Dsg1, a 160kDa desmosomal cadherin. These autoantibodies can be quantitated by ELISA. As noted for PV, the autoantibody profile in patients with PF (i.e., anti-Dsg1 IgG) and the tissue distribution of this autoantigen (i.e., expression in oral mucosa that is compensated by coexpression of Dsg3) are thought to account for the distribution of lesions in this disease. Endemic forms of PF are found in south-central rural Brazil, where the disease is known as fogo salvagem (FS), as well as in selected sites in Latin America and Tunisia. Endemic PF, like other forms of this disease, is mediated by IgG autoantibodies to Dsg1. Clusters of FS overlap with those of leishmaniasis, a disease transmitted by bites of the sand fly Lutzomyia longipalis. Studies have shown that sand fly salivary antigens (specifically, the LJM11 salivary protein) are recognized by IgG autoantibodies from FS patients (as well as by monoclonal anti­ bodies to Dsg1 derived from these patients). The demonstration that mice immunized with LJM11 produce antibodies to Dsg1 suggests that insect bites may deliver salivary antigens, initiate a cross-reactive humoral immune response, and lead to FS in genetically susceptible individuals.

A B FIGURE 62-1  Pemphigus vulgaris. A. Flaccid bullae are easily ruptured, resulting in multiple erosions and crusted plaques. B. Involvement of the oral mucosa, which is almost invariable, may present with erosions on the gingiva, buccal mucosa, palate, posterior pharynx, or tongue. (Courtesy of Robert Swerlick, MD; with permission.) Although pemphigus has been associated with several autoimmune diseases, its association with thymoma and/or myasthenia gravis is particularly notable. To date, >30 cases of thymoma and/or myasthenia gravis have been reported in association with pemphigus, usually with PF. Patients may also develop pemphigus as a consequence of drug exposure; drug-induced pemphigus usually resembles PF rather than PV. Drugs containing a thiol group in their chemical structure (e.g., penicillamine, captopril, enalapril) are most commonly associated with drug-induced pemphigus. Nonthiol drugs linked to pemphigus include penicillins, cephalosporins, and piroxicam. Some cases of drug-induced pemphigus are durable and require treatment with systemic glucocor­ ticoids and/or immunosuppressive agents. PF is generally a less severe disease than PV and usually carries a better prognosis. Localized disease can sometimes be treated with topical or intralesional glucocorticoids; more active cases can usually be controlled with systemic glucocorticoids either alone or in com­ bination with other immunosuppressive agents. Patients with severe, treatment-resistant disease may require more aggressive interventions, as described above for patients with PV.

■ ■PARANEOPLASTIC PEMPHIGUS Paraneoplastic pemphigus (PNP) is an autoimmune acantholytic mucocutaneous disease associated with an occult or confirmed neoplasm. Patients with PNP typically have painful stomatitis in association with papulosquamous and/or lichenoid eruptions that often progress to blisters. Palm and sole involvement are common in these patients and raise the possibility that prior reports of neoplasia-

associated erythema multiforme may have represented unrecognized cases of PNP. Biopsies of lesional skin from these patients show varying combinations of acantholysis, keratinocyte necrosis, and vacuolar-interface dermatitis. Direct immunofluorescence microscopy of a patient’s skin shows deposits of IgG and complement on the surface of keratinocytes and (variably) similar immunoreactants in the epidermal basement membrane zone. Patients with PNP have IgG autoantibodies to cytoplasmic proteins that are members of the pla­ kin family (e.g., desmoplakins I and II, bullous pemphigoid antigen [BPAG] 1, envoplakin, periplakin, and plectin) and to other proteins (e.g., Dsg1, Dsg3, and α2-macroglobulin like-1). Passive transfer studies have shown that autoantibodies from patients with PNP are pathogenic in animal models.

Immunologically Mediated Skin Diseases CHAPTER 62 The predominant neoplasms associated with PNP are non-Hodgkin’s lymphoma, chronic lymphocytic leukemia, thymoma, spindle cell tumors, Waldenström’s macroglobulinemia, and Castleman’s disease; the last-mentioned neoplasm is particularly common among children with PNP. Rare cases of seronegative PNP have been reported in patients with B-cell malignancies previously treated with rituximab. In addition to severe skin lesions, many patients with PNP develop life-threatening bronchiolitis obliterans. PNP is generally resistant to conventional therapies (i.e., those used to treat PV); rarely, a patient’s disease may ameliorate or even remit following ablation or removal of underlying neoplasms. ■ ■BULLOUS PEMPHIGOID Bullous pemphigoid (BP) is a polymorphic autoimmune subepidermal blistering disease usually seen in the elderly. Initial lesions may consist of urticarial plaques; most patients eventually display tense vesicles or blisters on either normal-appearing or erythematous skin (Fig. 62-2). The lesions are usually distributed over the lower abdomen, groin, and flexor surface of the extremities; oral mucosal lesions are found in some patients. Pruritus may be nonexistent or severe. As lesions evolve, tense blisters tend to rupture and be replaced by erosions with or with­ out surmounting crust. Nontraumatized blisters heal without scarring. FIGURE 62-2  Bullous pemphigoid with tense vesicles and bullae on erythematous, urticarial bases. (Courtesy of the Yale Resident’s Slide Collection; with permission.)

The major histocompatibility complex class II allele HLA-DQβ1∗0301 is prevalent in patients with BP. Though most cases occur sporadically, BP can be triggered by medications (e.g., furosemide, dipeptidyl peptidase-4 inhibitors, immune checkpoint inhibitors), ultraviolet light, or ionizing radiation. Several studies have shown that BP is associated with neurologic diseases (e.g., stroke, dementia, Parkinson’s disease, and multiple sclerosis).

Biopsies of early lesional skin demonstrate subepidermal blisters and histologic features that roughly correlate with the clinical character of the lesion under study. Lesions on normal-appearing skin generally contain a sparse perivascular leukocytic infiltrate with some eosino­ phils; conversely, biopsies of inflammatory lesions typically show an eosinophil-rich infiltrate at sites of vesicle formation and in perivas­ cular areas. In addition to eosinophils, cell-rich lesions also contain mononuclear cells and neutrophils. It is not possible to distinguish BP from other subepidermal blistering diseases by routine histologic studies alone. PART 2 Cardinal Manifestations and Presentation of Diseases Direct immunofluorescence microscopy of normal-appearing per­ ilesional skin from patients with BP shows linear deposits of IgG and/ or C3 in the epidermal basement membrane. The sera of ~70% of these patients contain circulating IgG autoantibodies that bind the epidermal basement membrane of normal human skin in indirect immunofluo­ rescence microscopy. IgG from an even higher percentage of patients reacts with the epidermal side of 1 M NaCl split skin (an alternative immunofluorescence microscopy test substrate used to distinguish circulating IgG autoantibodies to the basement membrane in patients with BP from those in patients with similar, yet different, subepidermal blistering diseases; see below). In BP, circulating autoantibodies recog­ nize 230- and 180-kDa hemidesmosome-associated proteins in basal keratinocytes (i.e., BPAG1 and BPAG2, respectively). Autoantibodies to BPAG2 are thought to deposit in situ, activate complement, produce dermal mast-cell degranulation, and generate granulocyte-rich infil­ trates that cause tissue damage and blister formation. BP may persist for months to years, with exacerbations or remis­ sions. Extensive involvement may result in widespread erosions and compromise cutaneous integrity; elderly and/or debilitated patients may die. Local or minimal disease can sometimes be controlled with potent topical glucocorticoids alone; more extensive lesions generally respond to systemic glucocorticoids either alone or in combination with other agents. Adjuncts to systemic glucocorticoids include doxy­ cycline, azathioprine, mycophenolate mofetil, and rituximab. ■ ■PEMPHIGOID GESTATIONIS Pemphigoid gestationis (PG), also known as herpes gestationis, is a rare, nonviral, subepidermal blistering disease of pregnancy and the puerperium. PG may begin during any trimester of pregnancy or present shortly after delivery. Lesions are usually distributed over the abdomen, trunk, and extremities; mucous membrane lesions are rare. Skin lesions in these patients may be quite polymorphic and consist of erythematous urticarial papules and plaques, vesiculopapules, and/ or frank bullae. Lesions are almost always extremely pruritic. Severe exacerbations of PG frequently follow delivery, typically within 24–48 h. PG tends to recur in subsequent pregnancies, often beginning earlier during such gestations. Brief flare-ups of disease may occur with resumption of menses and may develop in patients later exposed to oral contraceptives. Occasionally, infants of affected mothers have transient skin lesions. Biopsies of early lesional skin show teardrop-shaped subepidermal vesicles forming in dermal papillae in association with an eosinophil-rich leukocytic infiltrate. Differentiation of PG from other subepidermal bullous diseases by light microscopy is difficult. However, direct immunofluorescence microscopy of perilesional skin from PG patients reveals the immunopathologic hallmark of this disorder: linear depos­ its of C3 in the epidermal basement membrane. These deposits develop as a consequence of complement activation produced by low-titer IgG anti–basement membrane autoantibodies directed against BPAG2, the same hemidesmosome-associated protein that is targeted by auto­ antibodies in patients with BP—a subepidermal bullous disease that resembles PG clinically, histologically, and immunopathologically.

The goals of therapy in patients with PG are to prevent the devel­ opment of new lesions, relieve intense pruritus, and care for erosions at sites of blister formation. Many patients require treatment with moderate doses of daily glucocorticoids (i.e., 20–40 mg of prednisone) at some point in their course. Mild cases (or brief flare-ups) may be controlled by vigorous use of potent topical glucocorticoids. Infants born of mothers with PG appear to be at increased risk of being born slightly premature or “small for dates.” Current evidence suggests that there is no difference in the incidence of uncomplicated live births between PG patients treated with systemic glucocorticoids and those managed more conservatively. If systemic glucocorticoids are admin­ istered, newborns are at risk for development of reversible adrenal insufficiency. ■ ■DERMATITIS HERPETIFORMIS Dermatitis herpetiformis (DH) is an intensely pruritic, papulovesicular skin disease characterized by lesions symmetrically distributed over extensor surfaces (i.e., elbows, knees, buttocks, back, scalp, and pos­ terior neck) (see Fig. 59-8). Primary lesions in this disorder consist of papules, papulovesicles, or urticarial plaques. Because pruritus is prominent, patients may present with excoriations and crusted papules but no observable primary lesions. Patients sometimes report that their pruritus has a distinctive burning or stinging component; the onset of such local symptoms reliably heralds the development of distinct clinical lesions 12–24 h later. Almost all DH patients have associated, usually subclinical, gluten-sensitive enteropathy (Chap. 336), and

90% express the HLA-B8/DRw3 and HLA-DQw2 haplotypes. DH may present at any age, including in childhood; onset in the second to fourth decades is most common. The disease is typically chronic. Biopsy of early lesional skin reveals neutrophil-rich infiltrates within dermal papillae. Neutrophils, fibrin, edema, and microvesicle forma­ tion at these sites are characteristic of early disease. Older lesions may demonstrate nonspecific features of a subepidermal bulla or an excori­ ated papule. Because the clinical and histologic features of this disease can be variable and resemble those of other subepidermal blistering disorders, the diagnosis is confirmed by direct immunofluorescence microscopy of normal-appearing perilesional skin. Such studies dem­ onstrate granular deposits of IgA (with or without complement com­ ponents) in the papillary dermis and along the epidermal basement membrane zone. IgA deposits in the skin are unaffected by control of disease with medication; however, these immunoreactants diminish in intensity or disappear in patients maintained for long periods on a strict gluten-free diet (see below). Patients with DH have granular deposits of IgA in their epidermal basement membrane zone and should be distinguished from individuals with linear IgA deposits at this site (see below). Although most DH patients do not report overt gastrointestinal symptoms or have laboratory evidence of malabsorption, biopsies of the small bowel usually reveal blunting of intestinal villi and a lympho­ cytic infiltrate in the lamina propria. As is true for patients with celiac disease, this gastrointestinal abnormality can be reversed by a glutenfree diet. Moreover, if maintained, this diet alone may control the skin disease and eventuate in clearance of IgA deposits from these patients’ epidermal basement membrane zones. Subsequent gluten exposure in such patients alters the morphology of their small bowel, elicits a flare-up of their skin disease, and is associated with the reappearance of IgA in their epidermal basement membrane zones. As in patients with celiac disease, dietary gluten sensitivity in patients with DH is associated with IgA anti-endomysial autoantibodies that target tissue transglutaminase. Studies indicate that patients with DH also have high-avidity IgA autoantibodies to epidermal transglutaminase and that the latter is co-localized with granular deposits of IgA in the papil­ lary dermis of DH patients. Patients with DH also have an increased incidence of thyroid abnormalities, achlorhydria, atrophic gastritis, and autoantibodies to gastric parietal cells. These associations likely relate to the high frequency of the HLA-B8/DRw3 haplotype in these patients, since this marker is commonly linked to autoimmune disor­ ders. The mainstay of treatment of DH is dapsone, a sulfone. Patients respond rapidly (24–48 h) to dapsone but require careful pretreatment

evaluation (e.g., screening for glucose-6-phosphate dehydrogenase deficiency) and close follow-up to ensure that complications are avoided or controlled. All patients taking dapsone at ≥100 mg/d will have some hemolysis and methemoglobinemia, which are expected pharmacologic side effects of this agent. Gluten restriction can control DH and lessen dapsone requirements; this diet must rigidly exclude gluten to be of maximal benefit. Many months of dietary restriction may be necessary before a beneficial result is achieved. Good dietary counseling by a trained dietitian is essential. ■ ■LINEAR IGA DISEASE Linear IgA disease, once considered a variant form of DH, is actually a separate and distinct entity. Clinically, patients with linear IgA disease may resemble individuals with DH, BP, or other subepidermal blister­ ing diseases. Lesions typically consist of papulovesicles, bullae, and/or urticarial plaques that develop predominantly on central or flexural sites. Oral mucosal involvement occurs in some patients. Severe pru­ ritus resembles that seen in patients with DH. Patients with linear IgA disease do not have an increased frequency of the HLA-B8/DRw3 hap­ lotype or an associated enteropathy and therefore are not candidates for treatment with a gluten-free diet. Histologic alterations in early lesions may be virtually indistinguish­ able from those in DH. However, direct immunofluorescence micros­ copy of normal-appearing perilesional skin reveals a linear band of IgA (and often C3) in the epidermal basement membrane zone. Most patients with linear IgA disease have circulating IgA anti-basement membrane autoantibodies directed against neoepitopes in the pro­ teolytically processed extracellular domain of BPAG2. These patients generally respond to treatment with dapsone (50–200 mg/d) alone or in combination with low daily doses of prednisone. ■ ■EPIDERMOLYSIS BULLOSA ACQUISITA Epidermolysis bullosa acquisita (EBA) is a rare, noninherited, poly­ morphic, chronic, subepidermal blistering disease. (The inherited form is discussed in Chap. 425.) Patients with classic or noninflam­ matory EBA have blisters on noninflamed skin, atrophic scars, milia, nail dystrophy, hair loss, and oral lesions. Because lesions generally occur at sites exposed to minor trauma, classic EBA is considered a mechanobullous disease. Other patients with EBA have widespread inflammatory scarring and bullous lesions that resemble severe BP. Inflammatory EBA may evolve into the classic, noninflammatory form of this disease. Rarely, patients present with lesions that pre­ dominate on mucous membranes. The HLA-DR2 haplotype is found with increased frequency in EBA patients. Studies suggest that EBA is sometimes associated with inflammatory bowel disease (especially Crohn’s disease). The histology of lesional skin varies with the character of the lesion being studied. Noninflammatory bullae are subepidermal, feature a sparse leukocytic infiltrate, and resemble the lesions in patients with porphyria cutanea tarda. Inflammatory lesions consist of

neutrophil-rich subepidermal blisters. EBA patients have continu­ ous deposits of IgG (and frequently C3) in a linear pattern within the epidermal basement membrane zone. Ultrastructurally, these immunoreactants are found in the sublamina densa region in associa­ tion with anchoring fibrils. Approximately 50% of EBA patients have demonstrable circulating IgG anti-basement membrane autoantibodies directed against type VII collagen—the collagen species that makes up anchoring fibrils. Such IgG autoantibodies bind the dermal side of 1 M NaCl split skin (in contrast to IgG autoantibodies in patients with BP). Studies have shown that passive transfer of experimental or patient IgG against type VII collagen can produce lesions in mice that clinically, histologically, and immunopathologically resemble those in patients with EBA. Treatment of EBA is generally unsatisfactory. Some patients with inflammatory EBA may respond to systemic glucocorticoids, either alone or in combination with immunosuppressive agents. Other patients (especially those with neutrophil-rich inflammatory lesions) may respond to dapsone. The chronic, noninflammatory form of EBA is largely resistant to treatment, although some patients may respond

to prednisone in combination with rituximab, cyclosporine, mycophe­ nolate mofetil, azathioprine, or IVIg.

■ ■MUCOUS MEMBRANE PEMPHIGOID Mucous membrane pemphigoid (MMP) is a rare, acquired, subepithe­ lial immunobullous disease characterized by erosive lesions of mucous membranes and skin that result in scarring of at least some sites of involvement. Common sites include the oral mucosa (especially the gingiva) and conjunctiva; other sites that may be affected include the nasopharyngeal, laryngeal, esophageal, and anogenital mucosa. Skin lesions (present in about one-third of patients) tend to predominate on the scalp, face, and upper trunk and generally consist of a few scat­ tered erosions or tense blisters on an erythematous or urticarial base. MMP is typically a chronic and progressive disorder. Serious compli­ cations may arise as a consequence of ocular, laryngeal, esophageal, or anogenital lesions. Erosive conjunctivitis may result in shortened fornices, symblepharon, ankyloblepharon, entropion, corneal opaci­ ties, and (in severe cases) blindness. Similarly, erosive lesions of the larynx may cause hoarseness, pain, and tissue loss that, if unrecognized and untreated, may eventuate in complete destruction of the airway. Esophageal lesions may result in stenosis and/or strictures that could place patients at risk for aspiration. Strictures may also complicate anogenital involvement. Immunologically Mediated Skin Diseases CHAPTER 62 Biopsies of lesional tissue generally show subepithelial vesicu­ lobullae and a mononuclear leukocytic infiltrate. Neutrophils and eosinophils may be seen in biopsies of early lesions; older lesions may demonstrate a scant leukocytic infiltrate and fibrosis. Direct immu­ nofluorescence microscopy of perilesional tissue typically reveals deposits of IgG, IgA, and/or C3 in the epidermal basement membrane. Because many patients with MMP exhibit no evidence of circulating anti-basement membrane autoantibodies, testing of perilesional skin is important diagnostically. Although MMP was once thought to be a single nosologic entity, it is now largely regarded as a disease pheno­ type that may develop as a consequence of an autoimmune reaction to a variety of molecules in the epidermal basement membrane (e.g., BPAG2, laminin-332, type VII collagen, α6β4 integrin) and other anti­ gens yet to be completely defined. Studies suggest that MMP patients with autoantibodies to laminin-332 have an increased relative risk for cancer. Treatment of MMP is largely dependent upon the sites of involvement. Due to potentially severe complications, patients with ocular, laryngeal, esophageal, and/or anogenital involvement require aggressive systemic treatment with dapsone, prednisone, or the latter in combination with other immunosuppressive agents (e.g., rituximab, azathioprine, mycophenolate mofetil, or cyclophosphamide), or IVIg. Less threatening forms of the disease may be managed with topical or intralesional glucocorticoids. AUTOIMMUNE SYSTEMIC DISEASES WITH PROMINENT CUTANEOUS FEATURES ■ ■DERMATOMYOSITIS The cutaneous manifestations of dermatomyositis (Chap. 377) are often distinctive but at times may resemble those of systemic lupus erythematosus (SLE) (Chap. 368), scleroderma (Chap. 372), or other overlapping connective tissue diseases (Chap. 372). The extent and severity of cutaneous disease may or may not correlate with the extent and severity of the myositis. The cutaneous manifestations of dermato­ myositis are similar, whether the disease appears in children or in the elderly, except that calcification of subcutaneous tissue is a common late sequela in childhood dermatomyositis. Dermatomyositis may be associated with interstitial lung disease or cancer. The cutaneous signs of dermatomyositis may precede or follow the development of myositis by weeks to years. Cases lacking muscle involvement (i.e., dermatomyositis sine myositis or amyopathic derma­ tomyositis) have been reported. The most common manifestation is a purple-red discoloration of the upper eyelids, sometimes associated with scaling (“heliotrope” erythema; Fig. 62-3) and periorbital edema. Erythema on the cheeks and nose in a “butterfly” distribution may resemble the malar eruption of SLE. Erythematous or violaceous thin,

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 62-3  Dermatomyositis. Periorbital violaceous erythema characterizes the classic heliotrope rash. (Courtesy of James Krell, MD; with permission.) scaly plaques are common on the upper trunk and neck (shawl sign), the scalp, lateral aspects of the thighs (holster sign), and the extensor surfaces of the forearms and hands (tendon streaking). Approximately one-third of patients have violaceous, flat-topped papules over the dor­ sal interphalangeal joints that are pathognomonic of dermatomyositis (Gottron’s papules) (Fig. 62-4). Thin violaceous papules and plaques on the elbows and knees of patients with dermatomyositis are referred to as Gottron’s sign. These lesions can be contrasted with the erythema and scaling on the dorsum of the fingers that spares the skin over the interphalangeal joints of some SLE patients. Periungual telangiectasias and edema may be prominent in patients with dermatomyositis. Other patients, particularly those with long-standing disease, develop areas of hypopigmentation, hyperpigmentation, mild atrophy, and telangi­ ectasia known as poikiloderma. Poikiloderma is rare in both SLE and FIGURE 62-4  Dermatomyositis showing involvement of the hands with erythematous flat-topped papules over the joints (i.e., Gottron’s papules) as well as periungual erythema and telangiectasias. (Courtesy of Justin Cheeley, MD; with permission.)

scleroderma and thus can serve as a clinical sign that distinguishes dermatomyositis from these two diseases. Cutaneous changes may be similar in dermatomyositis and various overlap syndromes where thickening and binding down of the skin of the hands (sclerodactyly) as well as Raynaud’s phenomenon can be seen. However, the presence of severe muscle disease, Gottron’s papules, heliotrope erythema, and poikiloderma serves to distinguish patients with dermatomyositis. Skin biopsy of the erythematous, scaling lesions of dermatomyositis may reveal only mild nonspecific inflammation, but sometimes may show changes indistinguishable from those found in cutaneous lupus erythe­ matosus (LE), including epidermal atrophy, hydropic degeneration of basal keratinocytes, and dermal changes consisting of interstitial mucin deposition and a mild mononuclear cell perivascular infiltrate. Direct immunofluorescence microscopy of lesional skin is usually negative, although granular deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone have been described in some patients. Treatment should be stratified based on the relative severity of disease. Topical treatments include glucocorticoids, sunscreens, and aggressive photoprotective measures. Treatment of systemic disease includes antimalarials (though some patients may develop a drug eruption upon initiation of therapy) or systemic glucocorticoids in conjunction with methotrexate, mycophenolate mofetil, azathioprine, rituximab, or IVIg. ■ ■LUPUS ERYTHEMATOSUS The cutaneous manifestations of LE (Chap. 368) can be divided into acute, subacute, and chronic types. Acute cutaneous LE is characterized by erythema of the nose and malar eminences in a “butterfly” distribu­ tion (Fig. 62-5A). The erythema is often sudden in onset, accompanied by edema and fine scale, and correlated with systemic involvement. Patients may have widespread involvement of the face as well as ery­ thema and scaling of the extensor surfaces of the extremities and upper chest (Fig. 62-5B). These acute lesions, while sometimes evanescent, usually last for days and are often associated with exacerbations of systemic disease. Skin biopsy of acute lesions typically shows hydropic degeneration of basal keratinocytes, dermal edema, and (in some cases) a sparse perivascular infiltrate of mononuclear cells in the upper dermis as well as dermal mucin. Direct immunofluorescence micros­ copy of lesional skin frequently reveals deposits of immunoglobulin(s) and complement in the epidermal basement membrane zone. Treat­ ment of cutaneous disease includes topical glucocorticoids, aggressive photoprotection, antimalarials, and control of systemic disease. Treat­ ment of systemic disease associated with acute cutaneous LE includes systemic glucocorticoids in conjunction with antimalarials and other immunosuppressive agents. Subacute cutaneous lupus erythematosus (SCLE) is characterized by a widespread photosensitive, nonscarring eruption. In most patients, renal and central nervous system involvement is mild or absent. SCLE may present as a papulosquamous eruption that resembles psoriasis or as annular polycyclic lesions. In the papulosquamous form, discrete erythematous papules arise on the upper back, upper chest, shoulders, extensor surfaces of the arms, and dorsum of the hands; lesions are uncommon on the central face and the flexor surfaces of the arms as well as below the waist. These slightly scaling papules tend to merge into plaques. The annular form involves the same areas and presents with erythematous papules that evolve into oval, circular, or poly­ cyclic lesions. The lesions of SCLE are more widespread than those in patients with discoid LE and have less tendency for scarring. In many patients with SCLE, drugs (e.g., hydrochlorothiazide, calcium channel blockers, antifungals, proton pump inhibitors) may induce or exacerbate disease. Skin biopsy typically reveals epidermal changes that include atrophy, hydropic degeneration of basal keratinocytes, and apoptosis accompanied by an infiltrate of mononuclear cells in the upper dermis. Direct immunofluorescence microscopy of lesional skin reveals deposits of immunoglobulin(s) in the epidermal basement membrane zone in about one-half of these cases. A particulate pattern of IgG deposition throughout the epidermis has been associated with SCLE. Most SCLE patients have anti-Ro autoantibodies. Local therapy alone is usually unsuccessful. Most patients require treatment with

A B FIGURE 62-5  Acute cutaneous lupus erythematosus (LE). A. Acute cutaneous LE on the face, showing prominent, scaly, malar erythema. Involvement of other sun-exposed sites is also common. B. Acute cutaneous LE on the upper chest, demonstrating brightly erythematous and slightly edematous papules and plaques. (Courtesy of Robert Swerlick, MD; with permission.) aminoquinoline antimalarial drugs. Low-dose therapy with oral glu­ cocorticoids is sometimes necessary. Photoprotective measures against both ultraviolet B and ultraviolet A wavelengths are very important. Chronic cutaneous LE has multiple subtypes; discoid LE (DLE) is the most common. DLE is characterized by discrete lesions, most often found on the face, scalp, and/or external ears. It is unusual to see DLE lesions below the neck without lesions above the neck. The lesions are erythematous papules or plaques with a thick, adherent scale that occludes hair follicles (follicular plugging). When the scale is removed, its underside shows small excrescences that correlate with the openings of hair follicles (so-called “carpet tacking”), a finding relatively specific for DLE. Long-standing lesions develop central atrophy, scarring, and hypopigmentation but frequently have erythematous, sometimes raised borders (Fig. 62-6). These lesions persist for years and tend to expand slowly. Up to 20% of patients with DLE eventually meet the American College of Rheumatology criteria for SLE, but lower percentages of DLE patients develop SLE under the Systemic Lupus International Collaborating Clinics classification criteria and European League Against Rheumatism and American College of Rheumatology classification criteria. Typical discoid lesions are frequently seen in patients with SLE. Biopsy of DLE lesions shows hyperkeratosis, follicular plugging, atrophy of the epidermis, hydropic degeneration of basal keratinocytes, thickening of the epidermal basement membrane zone,

Immunologically Mediated Skin Diseases CHAPTER 62 FIGURE 62-6  Discoid lupus erythematosus (DLE). Erythematous to violaceous, dyspigmented, atrophic plaques with scarring of the face and scalp. (Courtesy of Robert Swerlick, MD; with permission.) dermal mucin, and a mononuclear cell infiltrate adjacent to epidermal, adnexal, and microvascular basement membranes. Direct immuno­ fluorescence microscopy demonstrates immunoglobulin(s) and com­ plement deposits at the basement membrane zone in ~90% of cases. Treatment is focused on control of local cutaneous disease and consists mainly of photoprotection and topical or intralesional glucocorticoids. If local therapy is ineffective, use of aminoquinoline antimalarial agents may be indicated. ■ ■SCLERODERMA AND MORPHEA The skin changes of scleroderma (Chap. 372) may be limited or dif­ fuse. In both instances, disease usually begins on the fingers, hands, toes, feet, and face, with episodes of recurrent nonpitting edema. Sclerosis of the skin commences distally on the fingers (sclerodac­ tyly) and spreads proximally, usually accompanied by resorption of bone of the fingertips, which may have punched out ulcers, stellate scars, or areas of hemorrhage (Fig. 62-7). The fingers may shrink and become sausage-shaped, and, because the fingernails are usually unaffected, they may curve over the end of the fingertips. Periungual telangiectasias are usually present, but periungual erythema is rare. In diffuse disease, the extremities show contractures and calcinosis cutis; facial involvement includes a smooth, unwrinkled brow, taut skin over the nose, shrinkage of tissue around the mouth, and perioral radial FIGURE 62-7  Scleroderma showing acral sclerosis, matlike telangiectasias, and focal digital ulcers.  (Courtesy of Justin Cheeley, MD; with permission.)

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63 Cutaneous Drug Reactions

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 62-8  Development of an expressionless, masklike facies in a patient with scleroderma. (Courtesy of Thomas J. Lawley, MD; with permission.) furrowing (Fig. 62-8). Matlike telangiectasias are often present, par­ ticularly on the face and hands. Involved skin feels indurated, smooth, and bound to underlying structures; hyper- and hypopigmentation are common as well. Raynaud’s phenomenon (i.e., cold-induced blanch­ ing, cyanosis, and reactive hyperemia) is documented in almost all patients and can precede development of scleroderma by many years. The combination of calcinosis cutis, Raynaud’s phenomenon, esopha­ geal dysmotility, sclerodactyly, and telangiectasias has been termed as the CREST syndrome. Anti-centromere autoantibodies have been reported in a very high percentage of patients with CREST syndrome but in only a small minority of patients with scleroderma. Skin biopsy reveals thickening of the dermis, homogenization of collagen bundles, atrophic pilosebaceous and eccrine glands, and a sparse mononuclear cell infiltrate in the dermis and subcutaneous fat. Direct immunofluo­ rescence microscopy of lesional skin is usually negative. Treatments for cutaneous disease include emollients, antipruritics, and phototherapy (UVA1 [ultraviolet A1 irradiation] or PUVA [psoralens + ultraviolet A irradiation]). Treatment of systemic disease includes vascular modify­ ing agents, immunosuppressives, and antifibrotics. Morphea is characterized by localized thickening and sclerosis of skin; it dominates on the trunk. This disorder may affect children or adults. Morphea begins as erythematous or flesh-colored plaques that become sclerotic, develop central hypopigmentation, and have an erythematous border. In most cases, patients have one or a few lesions, and the disease is termed circumscribed morphea. In some patients, widespread cutaneous lesions may occur without systemic involvement (generalized morphea). Many adults with generalized morphea have concomitant rheumatic or other autoimmune disorders. Skin biopsy of morphea is generally indistinguishable from that of scleroderma. Scleroderma and morphea are usually quite resistant to therapy. For this reason, physical therapy to prevent joint contractures and to maintain function is employed and is often helpful. Treatment options for early, rapidly progressive disease include phototherapy (UVA1 or PUVA) or methotrexate alone or in combination with daily glucocorticoids. Diffuse fasciitis with eosinophilia is a clinical entity that can some­ times be confused with scleroderma. There is usually a sudden onset of swelling, induration, and erythema of the extremities, frequently following significant physical exertion, initiation of hemodialysis, exposure to certain medications, or other triggers. The proximal por­ tions of the extremities (upper arms, forearms, thighs, calves) are more often involved than are the hands and feet. While the skin is indurated, it usually displays a woody, dimpled, or “pseudocellulite” appearance

rather than being bound down as in scleroderma; contractures may occur early secondary to fascial involvement. The latter may also cause muscle groups to be separated and veins to appear depressed (i.e., the “groove sign”). These skin findings are accompanied by peripheralblood eosinophilia, increased erythrocyte sedimentation rate, and sometimes hypergammaglobulinemia. Deep biopsy of affected areas of skin reveals inflammation and thickening of the deep fascia over­ lying muscle. An inflammatory infiltrate composed of eosinophils and mononuclear cells is usually found. Patients with eosinophilic fasciitis appear to be at increased risk for developing bone marrow failure or other hematologic abnormalities. While the ultimate course of eosinophilic fasciitis is variable, most patients respond favorably to treatment with prednisone. Relapses may occur and require treatment with prednisone in combination with other immunosuppressive or immunomodulatory agents. The eosinophilia-myalgia syndrome, a disorder with epidemic num­ bers of cases reported in 1989 and linked to ingestion of l-tryptophan manufactured by a single company in Japan, is a multisystem disor­ der characterized by debilitating myalgias and absolute eosinophilia in association with varying combinations of arthralgias, pulmonary symptoms, and peripheral edema. In a later phase (3–6 months after initial symptoms), these patients often develop localized scleroderma­ tous skin changes, weight loss, and/or neuropathy (Chap. 372). ■ ■FURTHER READING Bolognia JL et al (eds): Dermatology, 4th ed. Philadelphia, Elsevier, 2018. Ellebrecht CT et al: Pemphigus and pemphigoid. J Invest Dermatol 142:907, 2022. Hammers CM, Stanley JR: Mechanisms of disease: Pemphigus and bullous pemphigoid. Annu Rev Pathol 11:175, 2016. Kang S et al (eds): Fitzpatrick’s Dermatology, 9th ed. New York, McGraw-Hill, 2019.

Cutaneous Drug

Reactions Robert G. Micheletti, Misha Rosenbach,

Elizabeth J. Phillips, Bruce U. Wintroub,

Kanade Shinkai Cutaneous reactions are the most frequent adverse reactions to medications, representing 10–15% of reported adverse drug reac­ tions. Most are benign, but a few can be life threatening. Prompt recognition of severe reactions, drug withdrawal, and appropri­ ate therapeutic interventions can minimize toxicity. This chapter focuses on adverse cutaneous reactions to systemic medications; it covers their incidence, patterns, and pathogenesis, and provides some practical guidelines on treatment, assessment of causality, and future use of drugs. USE OF PRESCRIPTION DRUGS IN

THE UNITED STATES In the United States, more than 6.7 billion prescriptions for >20,000 drug products are dispensed annually. Hospital inpatients alone annu­ ally receive about 120 million courses of drug therapy, and approxi­ mately two-thirds of adult Americans receive prescription drugs on a regular outpatient basis. Adverse effects of a prescription medication may result in 4.5 million urgent or emergency care visits and over 7000 deaths each year in the United States. Many patients use over-thecounter medicines that may cause adverse cutaneous reactions.

INCIDENCE OF CUTANEOUS REACTIONS Several prospective studies reported that acute cutaneous reactions to drugs affect between 2.2 and 10 per 1000 hospitalized patients. Reac­ tions usually occur a few days to 4 weeks after initiation of therapy. In a series of 48,005 inpatients over a 20-year period, morbilliform rash (91%) and urticaria (6%) were the most frequent skin reactions, and antimicrobials, radiocontrast, and nonsteroidal anti-inflammatory drugs (NSAIDs) were the most common drug associations. Severe hypersensitivity reactions to medications have been reported to occur in between 1 in 1000 and 2 per million users, depending on the reac­ tion type. Although rare, severe cutaneous reactions to drugs have an important impact on health because of significant sequelae; in addi­ tion, they may require hospitalization, increase the duration of hospital stay, or be life-threatening. Some populations are at increased risk of drug reactions, including elderly patients, patients with autoimmune disease, hematopoietic stem cell transplant recipients, and those with acute Epstein-Barr virus (EBV) or human immunodeficiency virus (HIV) infection. The pathophysiology underlying this association may be related to immune dysregulation. Individuals with advanced HIV disease that is not virologically suppressed (e.g., CD4+ T lymphocyte count <200 cells/μL) have a 40- to 50-fold increased risk of adverse reactions to sulfamethoxazole (Chap. 208) and increased risk of severe hypersensitivity reactions to medications overall. In addition to acute eruptions, a variety of skin diseases can be induced or exacerbated by medications (e.g., pruritus, pigmentation, nail or hair disorders, psoriasis, bullous pemphigoid, photosensitivity, and even cutaneous neoplasms). These drug reactions are not frequent; however, neither their incidence nor their impact on public health has been evaluated. PATHOGENESIS OF DRUG REACTIONS Adverse cutaneous responses to drugs can arise as a result of immuno­ logic or nonimmunologic mechanisms. ■ ■NONIMMUNOLOGIC DRUG REACTIONS Examples of nonimmunologic cutaneous drug reactions are pig­ mentary changes due to dermal accumulation of medications or their metabolites or alteration of hair follicles by antimetabolites and TABLE 63-1  Revised Classification of Adverse Drug Reactions Based on Immune Pathway TYPE KEY PATHWAY KEY IMMUNE MEDIATORS ADVERSE DRUG REACTION TYPE Antibody Mediated Type I IgE, immediate IgE, B cells, TH2, ILC2 (IL-4,IL-5, IL-9, IL-13) Mast cells, basophils Type II IgG-mediated cytotoxicity IgG, B cells, IgM Phagocytes, neutrophils, macrophages Complement-dependent cytotoxicity, NK (antibodydependent cellular cytotoxicity) Type III Immune complexes IgG + antigen (immune complexes) B cells, IgM, IgG Complement, basophils, mast cells, platelets, Neutrophils, monocytes, macrophages Cell-Mediated (T-cell mediated) (Delayed Hypersensitivity) Type IVa (T1) T lymphocyte–mediated macrophage inflammation and cytotoxic functions of T cells TH1 cells, ILC1, Tc1, NK (IFN-γ, TNF-α, granzyme B, perforins, granulysin) Macrophages (granulomas) Type IVb (T2) T lymphocyte–mediated eosinophil inflammation TH2 cells, ILC2, Tc2, NK-T (IL-4, IL-5, IL-9, IL-13, IL-31) Eosinophils, B cells, mast cells/basophils Type IVc (T3) T lymphocyte–mediated neutrophil inflammation TH17, ILC3, Tc17 (IL17, IL-22, IL-23, CXCL8, GM-CSF) Neutrophils Abbreviations: AGEP, acute generalized exanthematous pustulosis; DIHS, drug-induced hypersensitivity syndrome; DRESS, drug reaction with eosinophilia and systemic symptoms. GM-CSF, granulocyte-macrophage colony-stimulating factor; IFN, interferon; IL, interleukin; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; TNF, tumor necrosis factor; Ig, immunoglobulin; ILC1/2/3, innate lymphoid cells type 1/2/3; NK, natural killer cell, NK-T, natural killer T cell. T1/T2/T3, type 1/2/3 immune response; Tc1/2/17, cytotoxic lymphocyte type 1/2/17. Th, T helper lymphocytes. Source: Adapted from M Jutel, et al. Allergy 78:2851, 2023.

signaling inhibitors. These side effects are predictable and sometimes can be prevented.

■ ■IMMUNOLOGIC DRUG REACTIONS Evidence suggests a direct immunologic basis for most acute drug eruptions. Drug reactions such as urticaria or anaphylaxis may result from immediate release of preformed mediators. Such reactions may be antibody-mediated through an adaptive immune response. Alterna­ tively, they may result from complement activation or direct activation of a mast cell receptor such as the mast-related G-protein–coupled receptor-2 (MRGPRX2) that is not associated with immune memory. T-cell–mediated reactions typically manifest with a delayed exanthem. Drug-specific CD4+ and CD8+ T-cell clones can be derived from the blood or from skin lesions of such patients, suggesting these T cells mediate drug allergy in an antigen-specific manner. For severe cutane­ ous adverse reactions (SCARs) such as drug-induced hypersensitivity syndrome (DIHS), also known as drug reaction with eosinophilia and systemic symptoms (DRESS), and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), drug presentation to T cells is major histocompatibility complex (MHC)-restricted and likely involves drugpeptide complex recognition by specific T-cell receptors (TCRs). Cutaneous Drug Reactions CHAPTER 63 Once a drug has induced an immune response, the phenotype of the reaction is determined by the nature of effectors: cytotoxic (CD8+) T cells in blistering and certain hypersensitivity reactions, chemokines for reactions mediated by neutrophils or eosinophils, and B-cell col­ laboration for production of specific antibodies for urticarial reactions. There has been consideration for reclassification of hypersensitivity reactions into antibody and cell-mediated processes that are directly driven by inflammation and the immune system, tissue driven mecha­ nisms, and those mediated through a direct response to chemicals (Table 63-1 and Fig. 63-1). Immediate Reactions  Immediate reactions depend on the release of mediators of inflammation by tissue mast cells or circulating basophils. These mediators include histamine, leukotrienes, prosta­ glandins, bradykinins, platelet-activating factor, enzymes, and pro­ teoglycans. Drugs can trigger mediator release either directly through non–IgE-mediated mast cell activation (formerly “pseudoallergic” or Acute urticaria, angioedema, anaphylaxis Drug-induced cytopenia (e.g. hemolysis, thrombocytopenia secondary to penicillin) Serum sickness, Arthus reaction, drug-induced vasculitis and lupus SJS/TEN, erythema multiforme, allergic contact dermatitis, fixed drug eruption, drug induced liver injury DIHS/DRESS Morbilliform eruption AGEP

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 63-1  Clinical manifestations and mechanisms of immune-mediated cutaneous drug reactions. Antibody-mediated reactions include IgE-mediated reactions, cytotoxic reactions, and immune complex reactions. IgE-mediated reactions, also classified as type I immediate reactions, require a period of prior exposure and sensitization to a drug (e.g., penicillin). Drug-specific IgE is bound to high-affinity IgE receptors on mast cells and then cross-linked by the drug. This leads to activation of mast cells and release of mediators including tryptase and histamine, which are responsible for clinical symptoms such as urticaria, hypotension, bronchospasm, and anaphylaxis. In type II cytotoxic reactions, antibodies target the cell membrane of red or white blood cells and platelets, leading to cell destruction and cytopenia. In type III immune complex reactions, antibodies react with a drug protein carrier forming soluble immune complexes. This leads to complement activation and deposition, ultimately leading to tissue damage and small vessel vasculitis. Cell- (T-cell) mediated reactions generally occur more than 6 hours after the first exposure to a drug. In these reactions, an antigen presenting cell processes peptides modified by the drug and presents them in the antigen binding groove of HLA for recognition by the T-cell receptor on CD8+ or CD4+ T cells, which leads to activation of T cells and release of specific cytokines (dependent on the specific reaction). Specific cytokine and cellular features defining these reactions are shown in Table 63-1, and specific clinical features and causative drugs are listed in Table 63-3. (From M Castells et al: Penicillin allergy. N Engl J Med 381:2338. Copyright © (2019) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.)

Cutaneous Drug Reactions CHAPTER 63 “anaphylactoid” reaction) or through IgE-specific antibodies. These reactions usually manifest in the skin and gastrointestinal, respira­ tory, and cardiovascular systems (Chap. 364). Primary symptoms and signs include pruritus, urticaria, nausea, vomiting, abdominal cramps, bronchospasm, laryngeal edema, and, occasionally, anaphylactic shock with hypotension and death. They occur within minutes of drug exposure. Aspirin, NSAIDs, radiocontrast media, opiates, and some antibiotics (fluoroquinolones, vancomycin) are frequent causes of non–IgE-mediated mast cell activation, which can occur on first exposure, is dose-related, and can be variable in occurrence with mul­ tiple exposures over time. Penicillins and cephalosporins (e.g., cefazo­ lin) are the most frequent causes of IgE-dependent reactions to drugs, requiring prior sensitization. When IgE-mediated reactions occur, they typically occur secondary to a haptenated product of the parent drug or metabolite but occasionally can be due to an IgE-mediated response against an inactive excipient of the drug (e.g., polyethylene glycol 3350 in injectable methylprednisolone acetate). Release of mediators is triggered when polyvalent drug protein conjugates cross-link IgE mol­ ecules fixed to sensitized cells. Certain routes of administration favor different clinical patterns (e.g., gastrointestinal effects from oral route, circulatory effects from intravenous route). Immune Complex–Dependent Reactions  Serum sickness is produced by tissue deposition of circulating immune complexes with consumption of complement. It is characterized by the triad of fever, arthritis, and urticarial, papular, or purpuric rash with accompanying hypocomplementemia and nephritis (Chap. 375). First described fol­ lowing administration of nonhuman sera, it currently occurs in the setting of monoclonal antibodies and similar medications. In classic serum sickness, symptoms develop 6 or more days after drug exposure, the latent period representing the time needed to synthesize antibody. Vasculitis, a relatively rare complication of drugs, may also be a result of immune complex deposition (Chap. 375). Clinically similar “serum sickness–like” reactions (SSLRs) may be associated with penicillin, cefaclor, amoxicillin, trimethoprim/sulfamethoxazole, and monoclonal antibodies such as infliximab, rituximab, and omalizumab. The mecha­ nism of this reaction is unknown but is unrelated to immune complex formation and complement activation, and systemic involvement is rare. Whereas serum sickness most commonly occurs in adults, SSLR is more frequently observed in children in the setting of a concurrent viral illness. It is now recognized that most children who experience SSLR in association with a β-lactam antibiotic will not have a repeat reaction on rechallenge with the same drug. Delayed Hypersensitivity  While not completely understood, delayed hypersensitivity directed by drug antigen–driven T cells is an important mechanism underlying the most common drug eruptions, specifically morbilliform eruptions and also rare and severe cutaneous and systemic forms, such as DIHS/DRESS, acute generalized exan­ thematous pustulosis (AGEP), and SJS/TEN (Table 63-1). Drug-specific T cells have been detected in some of these reactions. Drugs themselves are not independently antigenic, and the specific drug-altered antigens mediating delayed hypersensitivity reactions have not been identified. In SJS/TEN, the immune response is triggered by the presentation of a drug-antigen by a keratinocyte or other antigen presenting cell (APC) expressing a risk HLA class I allele. A specific T-cell receptor (TCR) expressed by CD8+ T cells enriched in the skin recognizes this drugHLA complex, leading to activation and release of cytolytic peptides such as granulysin that are thought to be the main mediators of kera­ tinocyte death. In the case of carbamazepine-related SJS/TEN, studies have identified cytotoxic T lymphocytes (CTLs) reactive to carbamaze­ pine that use highly restricted V-alpha and V-beta TCR repertoires in affected patients. This TCR restriction is shared among patients with carbamazepine SJS/TEN restricted by HLA-B15:02 and other B75 serotypes but is not found in carbamazepine-tolerant individuals or individuals with carbamazepine-related DIHS/DRESS. The specific mechanisms by which medications activate T cells and by which a memory T-cell response is maintained despite the absence of the drug are unknown. The hapten-prohapten model suggests that antigens driving these reactions may be the drug or a metabolite that covalently binds to endogenous proteins, presented in association with HLA molecules to T cells through the classic antigen presentation pathway. The pharmacologic interaction (p-i) model proposes that the drug/metabolite-altered antigen binds noncovalently to the risk HLA or TCR without undergoing classical antigen processing. Compelling evidence exists that abacavir activates CD8+ T cells through an altered peptide repertoire model whereby abacavir binds within the antigen binding cleft of HLA-B57:01 and alters the repertoire of self-peptides that are seen as immunogenic. Functional data and x-ray crystallog­ raphy solving the crystal structure of abacavir bound to synthetic or natural peptide and HLA-B57:01 support this model. It is still puzzling how memory T-cell responses to small-molecule drugs are preserved over time in the absence of reexposure. Independent of existing mod­ els of T-cell activation, a heterologous immunity model proposes that a cross-reactive memory T-cell response occurs between HLA class I restricted immunity to a prevalent pathogen early in life (such as a common virotope) and response to a drug-altered self-peptide restricted by the same HLA class I allele. ■ ■GENETIC FACTORS AND CUTANEOUS DRUG REACTIONS Current knowledge suggests that genetic determinants may pre­ dispose individuals to severe drug reactions by affecting immune responses to drugs and, in some cases, through altered drug metabolism. Associations between T-cell–mediated delayed drug hypersensitivities and specific class I HLA alleles suggest a key role for immune mechanisms, especially those leading to severe skin or sys­ temic organ involvement, such as SJS/TEN, DIHS/DRESS, abacavir hypersensitivity (AHS), drug-induced liver injury, pancreatitis, or agranulocytosis. Hypersensitivity to the anti-HIV medication abacavir is strongly associated with HLA-B57:01. HLA-B57:01 has 100% nega­ tive predictive value for the development of AHS, and routine prepre­ scription screening for HLA-B57:01 has eliminated AHS as a clinical entity (Chap. 208). In Taiwan, within a homogeneous Han Chinese population, a strong association was observed between SJS/TEN (but not DIHS/DRESS) related to carbamazepine and HLA-B15:02. In the same population, a strong association was found between HLA-B∗58:01 and both DIHS/DRESS and SJS/TEN associated with allopurinol. Other notable HLA associations include HLA-B13:01 and dapsone or sulfonamide antibiotic-induced DIHS/DRESS and SJS/TEN, as well as HLA-A32:01 and vancomycin-induced DIHS/DRESS. These associa­ tions are drug and phenotype specific; that is, HLA-specific T-cell stimulation by medications leads to distinct reactions. However, while these HLA associations are extremely strong, the presence of a risk HLA allele alone is not sufficient to cause severe drug hypersensitivity reactions. Other factors outside of the MHC, such as drug metabolism (e.g., CYP2C93 slow metabolism status and risk of phenytoin-induced morbilliform drug eruption, DIHS/DRESS, and SJS/TEN), are also important. The entirety of genetic and ecological factors that define why the majority of individuals carrying an HLA risk allele remain drug-tolerant and those factors that drive risk for specific drug hyper­ sensitivity reactions are not known at this time. ■ ■GLOBAL CONSIDERATIONS The PREDICT-1 study was a randomized, double-blind clinical trial of real-time preprescription HLA-B57:01 screening versus the previous standard of care of no screening that provided the basis for the utility of HLA-B57:01 screening to prevent AHS. If an HLA risk allele is present, it seems to have the same implication regardless of the population. This generalizability across populations, the fact that self-identified race is a social rather than biological construct, and greater availability of less costly single-HLA assays with a shorter turnaround time argue against targeted genetic screening on the basis of self-identified race. The American College of Rheumatology has recommended HLA-B∗58:01 screening of Han Chinese patients prescribed allopurinol; however, HLA-B*58:01 does not have 100% negative predictive value for allopu­ rinol DIHS/DRESS or SJS/TEN in other populations, and safety moni­ toring and risk counseling remain imperative. To date, screening for a single HLA (but not multiple HLA haplotypes) in specific populations

has been determined to be cost-effective (e.g., HLA-B∗1301 screening in Chinese patients with leprosy treated with dapsone). Genetic testing for specific HLA haplotypes is becoming more widely available, and its utility will increase as mechanistic factors driving drug hypersensitiv­ ity and tolerance are elucidated. Further data are needed to clarify the role of genetic and other testing beyond screening (e.g., in diagnosis) in order to optimize cost-effectiveness, utility, and benefit.

CLINICAL PRESENTATION OF

CUTANEOUS DRUG REACTIONS ■ ■NONIMMUNE CUTANEOUS REACTIONS PART 2 Cardinal Manifestations and Presentation of Diseases Exacerbation or Induction of Dermatologic Diseases  A variety of drugs can exacerbate preexisting diseases or induce—or unmask—a disease that may or may not disappear after withdrawal of the inducing medication. For example, NSAIDs, lithium, beta block­ ers, tumor necrosis factor (TNF) antagonists, interferon (IFN) α, and angiotensin-converting enzyme (ACE) inhibitors can exacerbate plaque psoriasis, whereas antimalarials and withdrawal of systemic glucocorticoids can worsen pustular psoriasis. The situation of TNF-α inhibitors is unusual, as this class of medications is used to treat pso­ riasis; however, they may paradoxically induce psoriasis (especially palmoplantar) in patients being treated for other conditions. Acne may be induced by glucocorticoids, androgens, lithium, and anti­ depressants. Follicular papular or pustular eruptions of the face and trunk resembling acne frequently occur with epidermal growth factor receptor (EGFR) antagonists, mitogen-activated protein kinase (MEK) inhibitors, tyrosine kinase (TK) inhibitors, and other targeted inhibi­ tors. With EGFR antagonists, the severity of the eruption correlates with a better anticancer effect. This rash is typically responsive to and prevented by tetracycline antibiotics. Several medications induce or exacerbate autoimmune disease. Checkpoint inhibitors induce a wide array of systemic autoimmune reactions, including in skin (see below). Interleukin (IL) 2, IFN-α, and anti-TNF-α are associated with new-onset systemic lupus erythema­ tosus (SLE). Drug-induced lupus is classically marked by antinuclear and antihistone antibodies and, in some cases, anti-double-stranded DNA (D-penicillamine, anti-TNF-α) or perinuclear antineutrophil cytoplasmic antibodies (p-ANCA) (minocycline). Subacute cutaneous lupus erythematosus (SCLE) can be induced by a growing list of drugs, including thiazide diuretics, proton pump inhibitors, TNF inhibitors, terbinafine, and minocycline (Fig. 63-2). Drug-induced dermato­ myositis may rarely occur with TNF inhibitors or capecitabine, and FIGURE 63-2  Subcutaneous lupus erythematosus due to medication. 

flares have been reported in association with the herbal supplement spirulina. Hydroxyurea can induce skin findings of dermatomyositis. IFN and TNF inhibitors, as well as BRAF inhibitors and checkpoint inhibitors, can induce granulomatous disease and sarcoidosis. Autoim­ mune blistering diseases may be drug induced as well: pemphigus by D-penicillamine and ACE inhibitors; bullous pemphigoid by furose­ mide and, increasingly, by DPP4 inhibitors and PD-1 inhibitors; and linear IgA bullous dermatosis by vancomycin. Other medications may cause highly specific cutaneous reactions. Gadolinium contrast has been associated with nephrogenic systemic fibrosis, a condition of sclerosing skin and rare internal organ involvement, in the setting of renal compromise. Granulocyte colony-stimulating factor, azacitidine, all-trans-retinoic acid, the FLT3 inhibitor class of drugs, and (rarely) levamisole-contaminated cocaine may induce neutrophilic dermatoses. The hypothesis that a drug may be responsible should always be con­ sidered, even after treatment is complete. In addition, reactions may develop in cases of long-term medication therapy due to changes in dosing or host metabolism. Resolution of the cutaneous reaction may be delayed upon discontinuation of the medication. Photosensitivity Eruptions  Photosensitivity eruptions are usu­ ally most marked in sun-exposed areas, but they may extend to sun-protected sites. The mechanism is almost always phototoxicity. Phototoxic reactions resemble sunburn and can occur with first expo­ sure to a drug. Blistering may occur in drug-related pseudoporphyria, most commonly with NSAIDs. The severity of the reaction depends on the tissue level of the drug, its efficiency as a photosensitizer, and the extent of exposure to the activating wavelengths of ultraviolet (UV) light (Chap. 64). Common orally administered photosensitizing drugs include fluoroquinolones, tetracycline antibiotics, and trimethoprim/

sulfamethoxazole. Other drugs less frequently implicated are chlor­ promazine, thiazides, NSAIDs, and BRAF inhibitors. Voriconazole may result in severe photosensitivity, accelerated photoaging, and cutaneous carcinogenesis. Hydrochlorothiazide may be associated with increased nonmelanoma skin cancer in some populations. Because UV-A and visible light, which trigger these reactions, are not easily absorbed by nonopaque sunscreens and are transmitted through window glass, photosensitivity reactions may be difficult to prevent. Photosensitivity reactions abate with removal of either the drug or UV radiation, use of sunscreens that block UV-A light, and treatment of the reaction as one would a sunburn. Rarely, individuals develop persistent reactivity to light, necessitating long-term avoidance of sun exposure. Some chemotherapeutic agents, such as methotrexate, can induce a UV-recall reaction characterized by an erythematous, slightly scaly eruption at sites of prior severe photosensitivity reactions. Pigmentation Changes  Drugs, either systemic or topical, may cause a variety of pigmentary changes in the skin by triggering mela­ nocyte production of melanin (as in the case of oral contraceptives causing melasma) or due to deposition of drug or drug metabolites. Long-term minocycline or amiodarone exposure may cause blue-gray pigmentation. Phenothiazine, gold, and bismuth result in gray-brown pigmentation of sun-exposed areas. Numerous cancer chemotherapeu­ tic agents may be associated with characteristic patterns of pigmenta­ tion (e.g., bleomycin, busulfan, daunorubicin, cyclophosphamide, hydroxyurea, fluorouracil, and methotrexate). Clofazimine causes a drug-induced lipofuscinosis with characteristic red-brown coloration. Hyperpigmentation of the face, mucous membranes, and pretibial and subungual areas occurs with antimalarials. Quinacrine causes general­ ized yellow discoloration. Pigmentation changes may also occur in mucous membranes (busulfan, bismuth), conjunctiva (chlorproma­ zine, thioridazine, imipramine, clomipramine), nails (zidovudine, doxorubicin, cyclophosphamide, bleomycin, fluorouracil, hydroxy­ urea), hair, and teeth (tetracyclines). Warfarin Necrosis of Skin  This rare reaction (0.01–0.1%) usu­ ally occurs between the third and tenth days of therapy with war­ farin, usually in women. Common sites are breasts, thighs, and buttocks (Fig. 63-3). Lesions are sharply demarcated, erythematous,

FIGURE 63-3  Warfarin necrosis involving the breasts. or purpuric, and may progress to form large, hemorrhagic bullae with necrosis and eschar formation. Warfarin anticoagulation in protein C or S deficiency causes an additional reduction in already low circulating levels of endogenous anticoagulants, permitting temporary hypercoagulability and throm­ bosis in the cutaneous microvasculature, with consequent areas of necrosis. Heparin-induced necrosis may have clinically similar fea­ tures but is probably due to heparin-induced platelet aggregation with subsequent occlusion of blood vessels; it can affect areas adjacent to the injection site or more distant sites if infused. Levamisole-tainted cocaine (and more recently, opiates) can induce similar skin necrosis; however, the distribution tends to involve the ears and cheeks predomi­ nantly, with stellate or retiform purpura. Patients may have abnormal white blood cell counts and may be dual P- and C-ANCA positive. Drug-Induced Hair Disorders  •  DRUG-INDUCED HAIR LOSS 

Medications may affect hair follicles at two different phases of their growth cycle: anagen (growth) or telogen (resting). Anagen effluvium occurs within days of drug administration, especially with antimetabo­ lite or other chemotherapeutic drugs. In contrast, in telogen effluvium, the delay is 2–4 months following initiation of a new medication. Both present as diffuse, nonscarring alopecia, most often reversible after discontinuation of the responsible agent. A considerable number of drugs have been associated with hair loss. These include antineoplastic agents (alkylating agents, bleomycin, vinca alkaloids, platinum compounds), anticonvulsants (carbamaze­ pine, valproate), beta blockers, antidepressants, antithyroid drugs, IFNs, oral contraceptives, and cholesterol-lowering agents. DRUG-INDUCED HAIR GROWTH  Medications may also cause hair growth. Hirsutism is an excessive growth of terminal hair with mascu­ line hair growth pattern in a female, most often on the face and trunk, due to androgenic stimulation of hormone-sensitive hair follicles (anabolic steroids, oral contraceptives, testosterone, corticotropin). Hypertrichosis is a distinct pattern of hair growth, not in a masculine pattern, typically located on the forehead and temporal regions of the face. Drugs responsible for hypertrichosis include anti-inflammatory drugs, glucocorticoids, vasodilators (diazoxide, minoxidil), diuretics (acetazolamide), anticonvulsants (phenytoin), immunosuppressive agents (cyclosporine A), psoralens, and zidovudine. Changes in hair color or structure are uncommon adverse effects from medications. Hair discoloration may occur with chloroquine, IFN-α, chemotherapeutic agents, and tyrosine kinase inhibitors. Changes in hair structure have been observed in patients given EGFR inhibitors, BRAF inhibitors, tyrosine kinase inhibitors, and acitretin. Drug-Induced Nail Disorders  Drug-related nail disorders usu­ ally involve all 20 nails and need months to resolve after withdrawal of the medication. The pathogenesis is most often toxic. Drug-induced nail changes include Beau lines (transverse depression of the nail plate), onycholysis (detachment of the distal part of the nail plate), onychoma­ desis (detachment of the proximal part of the nail plate), pigmentation, and paronychia (inflammation of periungual skin).

ONYCHOLYSIS  Onycholysis occurs with tetracyclines, fluoroquino­ lones, retinoids, NSAIDs, and others, including many chemotherapeu­ tic agents, and may be triggered by exposure to sunlight.

ONYCHOMADESIS  Onychomadesis is caused by temporary arrest of nail matrix mitotic activity. Common drugs reported to induce onychomadesis include carbamazepine, lithium, retinoids, and chemo­ therapeutic agents such as taxanes. PARONYCHIA  Paronychia and multiple pyogenic granulomas with progressive and painful periungual abscess of fingers and toes are side effects of systemic retinoids, lamivudine, indinavir, and EGFR inhibitors. Cutaneous Drug Reactions CHAPTER 63 NAIL DISCOLORATION  Some drugs—including anthracyclines, tax­ anes, fluorouracil, psoralens, and zidovudine—may induce nail bed hyperpigmentation through melanocyte stimulation. It appears to be reversible and dose dependent. Toxic Erythema of Chemotherapy and Other Chemotherapy Reactions  Because many agents used in cancer chemotherapy inhibit cell division, rapidly proliferating elements of the skin, includ­ ing hair, mucous membranes, and appendages, are sensitive to their effects. A broad spectrum of chemotherapy-related skin toxicities has been reported, including neutrophilic eccrine hidradenitis, sterile cel­ lulitis, exfoliative dermatitis, and flexural erythema. These reactions are best characterized under the unifying term “toxic erythema of chemotherapy” (TEC) (Fig. 63-4). Acral erythema is marked by dys­ esthesia and an erythematous, edematous eruption of the palms and soles. Common causes include cytarabine, doxorubicin, methotrexate, hydroxyurea, fluorouracil, and capecitabine. The introduction of many new monoclonal antibody and smallmolecule signaling inhibitors for the treatment of cancer has been accompanied by numerous reports of skin and hair toxicity; only the most common of these are mentioned here. EGFR antagonists induce follicular eruptions and nail toxicity after a mean interval of 10 days in a majority of patients. Xerosis, eczematous eruptions, acneiform erup­ tions, and pruritus are common. Erlotinib is associated with marked hair textural changes. Sorafenib, a tyrosine kinase inhibitor, may result in follicular eruptions and focal bullous eruptions at palmoplantar, flexural sites, or areas of pressure or friction. BRAF inhibitors are asso­ ciated with photosensitivity, palmoplantar hyperkeratosis, hair curling, dyskeratotic (Grover-like) rash, hyperkeratotic benign cutaneous neo­ plasms, and keratoacanthoma-like squamous cell carcinomas. The immune checkpoint inhibitor (ICI) class of drugs (including anti-CTLA-4, anti-PD-1, and anti-PD-L1 agents) can induce a wide range of cutaneous eruptions, including lichenoid, eczematous, granu­ lomatous, papulosquamous, bullous, vitiligo-like, alopecic, and pan­ niculitic eruptions. Mucocutaneous immune-related adverse events (irAEs) to ICIs typically occur early and are the most common of potentially multiorgan reactions, occurring in 30–60% of patients. The onset may be as early as a few weeks after initiating the ICI and FIGURE 63-4  Toxic erythema of chemotherapy.

as late as 1 year or more after initiation. The incidence of irAEs dif­ fers between the distinct ICI medications and is most frequent with combination therapy with anti-CTLA-4 and anti-PD-1 agents. Severe irAEs (grade 3 or 4, including DIHS/DRESS, SJS/TEN-like, and bullous reactions involving over 30% body surface area) are rare, occurring in 2–3% of patients with ICI monotherapy and up to 15% with com­ bined ICI therapy. The rates of irAEs may also differ between patient populations depending on the type of malignancy being treated. These reactions are largely T-cell–mediated, which informs the approach to management. Whereas milder reactions may be managed with topical corticosteroids, more severe reactions may require oral corticosteroids or other systemic immunomodulatory or immunosuppressive medi­ cations, including biologic agents. In some cases of severe reactions, including lichenoid bullous and SJS/TEN-like reactions, rechallenge of the ICI may be possible. A clear history of all new medications intro­ duced within the few days to 2 months preceding the reaction should be taken, as case reports of ICIs increasing the risk of small-molecule SCAR have emerged. There are some data, largely retrospective studies, supporting the notion that mucocutaneous irAEs may be associated with improved prognosis and survival.

PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■IMMUNE CUTANEOUS REACTIONS: COMMON Morbilliform Drug Eruption  Morbilliform or maculopapular drug eruptions (Fig. 63-5) are the most common of all drug-induced reactions, often start on the trunk or intertriginous areas, and consist of blanching erythematous macules and papules that are symmetric and confluent. Nonblanching, dusky, or bright-red macules, as well as mucosal involvement, should raise concern for a more severe reac­ tion. Facial involvement in morbilliform eruptions is also uncommon, and the presence of extensive facial lesions with facial edema suggests DIHS/DRESS. Diagnosis of morbilliform eruptions is rarely assisted by laboratory testing or skin biopsy. Morbilliform drug eruptions may be associated with moderate to severe pruritus and fever. A viral exanthem is a differential diagnostic consideration, especially in children, and graft-versus-host disease is also a consideration in the proper clinical setting. Absence of enan­ thems; absence of ear, nose, throat, and upper respiratory tract symp­ toms; and polymorphism of the skin lesions support a drug rather than a viral eruption. Common offenders include aminopenicillins, cephalosporins, antibacterial sulfonamides, allopurinol, and antiepi­ leptic drugs. Beta blockers, calcium channel blockers, and ACE inhibi­ tors are rarely the culprit; however, any drug can cause a morbilliform exanthem. Certain medications carry very high rates of morbilliform eruption, including nevirapine and lamotrigine, even in the absence of DIHS/DRESS reactions. Lamotrigine morbilliform rash is associated with higher starting doses, rapid dose escalation, concomitant use of valproate (which increases lamotrigine levels and half-life), and use in children. Morbilliform drug eruptions usually develop within 1 week of initia­ tion of therapy and last less than 2 weeks. Occasionally, these eruptions FIGURE 63-5  Morbilliform drug eruption.

resolve despite continued use of the responsible drug. Because the erup­ tion may also worsen, the suspect drug should be discontinued unless it is essential. It is important to note that the rash may continue to prog­ ress for a few days up to 1 week following medication discontinuation. Oral antihistamines and emollients may help relieve pruritus. Short courses of potent topical glucocorticoids can reduce inflammation and symptoms. Systemic glucocorticoid treatment is rarely indicated. Pruritus  Pruritus is associated with almost all drug eruptions and, in some cases, may represent the only symptom of the adverse cutaneous reaction. It may be alleviated by antihistamines such as hydroxyzine or diphenhydramine. Pruritus stemming from specific medications may require distinct treatment, such as selective opiate antagonists for opiate-related pruritus. Urticaria/Angioedema/Anaphylaxis  Urticaria, the second most frequent type of cutaneous reaction to drugs, is characterized by pruritic, red wheals of varying size rarely lasting more than 24 hours. It has been observed in association with nearly all drugs, most frequently aspirin, NSAIDs, penicillin, and blood products. However, medications account for no more than 10–20% of acute urticaria cases. Deep edema within dermal and subcutaneous tissues is known as angioedema and may involve respiratory and gastrointestinal mucous membranes. Urti­ caria and angioedema may be part of a life-threatening anaphylactic reaction. Drug-induced urticaria may be caused by three mechanisms: an IgE-dependent mechanism, circulating immune complexes (serum sickness), and nonimmunologic activation of effector pathways. IgE-

dependent urticarial reactions usually occur within 36 hours of drug exposure but can occur within minutes. Immune complex–induced urticaria associated with serum sickness reactions usually occurs 6–12 days after first exposure. In this syndrome, the urticarial eruption (typically polycyclic plaques over distal joints) may be accompanied by fever, hematuria, arthralgias, hepatic dysfunction, and neurologic symptoms. Certain drugs, such as NSAIDs, ACE inhibitors, angiotensin II antago­ nists, radiographic dye, and opiates, may induce urticarial reactions, angioedema, and anaphylaxis in the absence of drug-specific antibod­ ies (non–IgE-mediated mast cell activation) through direct mast cell degranulation. Non–IgE-mediated mast cell activation associated with fluoroquinolones, vancomycin, radiocontrast dye, opiates, and other medications that share a tetrahydroisoquinolone (THIQ) moiety is now thought to be mediated through their interaction and activation of the MRGPRX2 receptor on mast cells. Expression of MRGPRX2 is also increased in the skin of patients with severe chronic spontaneous urticaria (CSU), and patients with CSU are more likely to be labeled as allergic to multiple drugs. Radiocontrast agents are a common cause of urticaria through non–IgE-mediated mast cell activation and, in rare cases, can cause anaphylaxis. High-osmolality radiocontrast media are about five times more likely to induce urticaria (1%) or anaphylaxis than are newer low-osmolality media. About one-third of those with mild reactions to previous exposure react on reexposure. Pretreatment with prednisone and diphenhydramine reduces reaction rates. The treatment of urticaria or angioedema depends on the sever­ ity of the reaction. In severe cases with respiratory or cardiovascular compromise, epinephrine and intravenous glucocorticoids are the mainstay of therapy. For patients with urticaria without symptoms of angioedema or anaphylaxis, drug withdrawal and oral antihistamines are usually sufficient. Future drug avoidance is recommended; rechal­ lenge, especially in individuals with severe reactions, should only occur in an intensive care setting. Vancomycin is a small-molecule ligand for MRGPRX2 and is also associated with an infusional form of non– IgE-mediated mast cell activation now termed vancomycin flushing syndrome (VFS) or vancomycin infusion reaction (VIR). This infusion syndrome is a rate- and dose-dependent histamine-related reaction characterized by flushing, diffuse urticarial or morbilliform eruption, tachycardia, and hypotension. In rare cases, cardiac arrest may be asso­ ciated with rapid intravenous (IV) infusion of the medication. It is pre­ vented by slowing the infusion and premedicating with antihistamines.

FIGURE 63-6  Allergic contact dermatitis (bullous) due to adhesive tape. Irritant/Allergic Contact Dermatitis  Patients using topical medications may develop an irritant or allergic contact dermatitis to the medication itself or to a preservative or other component of the formulation. Reactions to neomycin sulfate, bacitracin, polymyxin B, and benzalkonium are common, and co-sensitization is common due to their shared presence in multiple products such as ointments and eyedrops. Contact dermatitis may be seen to adhesive tapes, leading to irritation or blisters around ports and IV sites (Fig. 63-6). Harsh disinfectant skin cleansers may lead to localized irritant dermatitis. Systemic contact dermatitis can occur when an individual is sensitized to a contact allergen and later exposed to that same medication or a potentially cross-reactive medication systemically. The most common associated medications are corticosteroids, aminoglycoside antibiotics, and aminophylline. Symmetric drug-related intertriginous and flexural exanthema (SDRIFE) causes well-demarcated erythema in the inter­ triginous and flexural areas in patients without a previous history of cutaneous sensitization. It is commonly associated with aminopenicil­ lins, β-lactams, and chemotherapeutic agents. Fixed Drug Eruption  This uncommon reaction is character­ ized by one or more sharply demarcated, dull red-to-brown lesions, sometimes with central dusky violaceous erythema and central bulla (Fig. 63-7). Hyperpigmentation during healing is characteristic, often persists after resolution of the acute inflammation, and can be more pronounced in patients with more richly pigmented skin types. With rechallenge, the process recurs in the same (fixed) locations but may spread to new areas as well. Lesions often involve the lips, hands, FIGURE 63-7  Fixed drug eruption.

legs, face, genitalia, and oral mucosa, and cause a burning sensation. Most patients have multiple flat lesions. Fixed drug eruption has been associated with pseudoephedrine (frequently a nonpigmenting reac­ tion), phenolphthalein (in laxatives), sulfonamides, tetracyclines, flu­ conazole, NSAIDs, barbiturates, and others. A severe and uncommon variant of fixed drug eruption, generalized bullous fixed drug eruption, involves the development of multiple bullous lesions comprising at least 10% body surface area (BSA). It is considered a SCAR due to its high BSA involvement and mortality that can exceed 20%.

■ ■IMMUNE CUTANEOUS REACTIONS:

RARE AND SEVERE Cutaneous Drug Reactions CHAPTER 63 Drug-Induced Hypersensitivity Syndrome/Drug Reaction with Eosinophilia and Systemic Symptoms  DIHS and DRESS are used interchangeably; however, eosinophilia is an inconsistent and sometimes late laboratory finding. The histopathologic features of DIHS/DRESS are nonspecific and can be indistinguishable from mor­ billiform drug eruption. There are mixtures of CD4 and CD8 T cells in the skin, and TH2 cells express CD134 and produce cytokines such as IL-4, IL-5, IL-10, IL-13, and eotaxin. Type 2 innate lymphocytes (ILC2) produce IL-5 that promotes activation and migration of eosinophils. Tregs and dendritic cells produce IFN-γ, TNF-α, and CCL17 (serum thymus and activation-regulated chemokine [TARC]), which fuels the systemic presentation. Clinically, DIHS/DRESS presents with a prodrome of fever and flu-like symptoms for several days, followed by the appearance of an extensive rash usually involving the face (Fig. 63-8). The rash of DIHS/DRESS is polymorphic. It is usually morbilliform, but can also be exfoliative, lichenoid, urticarial, eczematous, pustular, or a combi­ nation of multiple morphologies. Increased severity of DIHS/DRESS is associated with purpuric and erythema multiforme-like cutaneous presentations. Facial swelling and hand/foot swelling are often present and are also associated with severity. Systemic manifestations include lymphadenopathy, fever, and leukocytosis (often with eosinophilia or atypical lymphocytosis), as well as hepatitis, nephritis, pneumonitis, myositis, and gastroenteritis, in descending order. Distinct patterns of timing of onset and organ involvement may exist for specific medica­ tions. For example, allopurinol classically induces DIHS/DRESS with renal involvement; cardiac and lung involvement are more common FIGURE 63-8  Drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS).

with minocycline; and some medications typically do not induce eosinophilia (dapsone, lamotrigine). The cutaneous reaction usually begins 2–8 weeks after the drug is started and persists after drug ces­ sation, with a prolonged resolution period. Signs and symptoms may continue for several weeks, especially those associated with hepatitis, while disease relapse or recrudescence can occur, particularly upon weaning corticosteroids. The eruption recurs with rechallenge, and cross-reactions among aromatic anticonvulsants, including phenytoin, carbamazepine, and phenobarbital, are common. Other drugs caus­ ing DIHS/DRESS include vancomycin, antibacterial sulfonamides, and other antibiotics. Hypersensitivity to reactive drug metabolites, hydroxylamine for sulfamethoxazole and arene oxide for aromatic anti­ convulsants, may be involved in the pathogenesis of DIHS. Research suggests inciting drugs may reactivate quiescent human herpes viruses, including herpesviruses 6 and 7, EBV, and cytomegalovirus (CMV), resulting in expansion of viral-specific CD8+ T lymphocytes and sub­ sequent end-organ damage. Viral reactivation, particularly with CMV, may be associated with a worse clinical prognosis. Mortality rates as high as 10% have been reported, with most fatalities resulting from liver failure; however, clinical experience and results of a large, unpub­ lished cohort suggest mortality is likely closer to 2%. Systemic gluco­ corticoids (1.5–2 mg/kg/d prednisone equivalent) should be started and tapered slowly over 8–12 weeks, during which time clinical symp­ toms and labs (including complete blood count with differential, basic metabolic panel, and liver function tests) should be followed carefully. A steroid-sparing agent such as mycophenolate mofetil, IV immuno­ globulin, or cyclosporine may be indicated in cases of rapid recurrence upon steroid taper. A role for newer, targeted biologic therapies, such as inhibitors of IL-5 and the JAK-STAT pathway, is under investiga­ tion. In all cases, immediate withdrawal of all potential culprit drugs is essential. Given the severe complications and potentially delayed pre­ sentation of myocarditis, patients should undergo cardiac evaluation in cases of severe DIHS/DRESS or if heart involvement is suspected due to hypotension or arrhythmia. Patients should be closely monitored for resolution of organ dysfunction and for development of late-onset autoimmune sequelae, such as thyroiditis, lupus, and diabetes.

PART 2 Cardinal Manifestations and Presentation of Diseases Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis 

SJS/TEN is a disease spectrum characterized by blisters and mucosal/ epidermal detachment resulting from full-thickness epidermal necro­ sis. The term Stevens-Johnson syndrome (SJS) describes cases in which the total BSA of blistering and eventual detachment is <10% (Figs. 63-9 to 63-11). The term Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) overlap is used to describe cases with 10–30% BSA epider­ mal detachment (Fig. 63-12), and the term toxic epidermal necrolysis (TEN) is used to describe cases with >30% BSA detachment (Figs. 63-13 and 63-14). Other blistering eruptions with concomitant mucositis may be confused with SJS/TEN. Erythema multiforme (EM) associated with FIGURE 63-9  Stevens-Johnson syndrome (SJS).

FIGURE 63-10  SJS-TEN overlap. herpes simplex virus is characterized by painful mucosal erosions and target lesions, typically with an acral distribution and limited skin detachment. Mycoplasma and other respiratory infections in children cause a clinically distinct presentation with prominent mucositis and limited cutaneous involvement. The term reactive infectious mucocuta­ neous eruption (RIME) is used to help differentiate this clinical entity. Patients with SJS/TEN initially present with fever >39°C (102.2°F); sore throat; conjunctivitis; and acute onset of painful dusky, atypical, FIGURE 63-11  Toxic epidermal necrolysis, hand.

FIGURE 63-12  Toxic epidermal necrolysis. target-like lesions (Figs. 63-13 and 63-14). Cancer and renal insuf­ ficiency are associated with a poor prognosis, as are older age and greater extent of epidermal detachment. At least 10% of those with SJS and 30% of those with TEN die from the disease. Drugs that most com­ monly cause SJS/TEN are sulfonamide antibiotics, allopurinol, antiepi­ leptics (e.g., lamotrigine, phenytoin, carbamazepine), oxicam NSAIDs, β-lactam and other antibiotics, and nevirapine. Frozen-section skin biopsy may aid in rapid diagnosis. At this time, there is no consensus on the most effective treatment for SJS/TEN. The best outcomes stem from early diagnosis, immediate discontinuation of the suspected drug, and meticulous supportive ther­ apy in an intensive care or burn unit. Fluid management, atraumatic wound care, infection prevention and treatment, and ophthalmologic FIGURE 63-13  Target-like lesion in SJS.

Cutaneous Drug Reactions CHAPTER 63 FIGURE 63-14  Atypical target-like lesion in SJS. and respiratory support are critical. Early administration of systemic glucocorticoids, intravenous immunoglobulin, cyclosporine, or etaner­ cept may improve disease outcomes, but randomized studies to evalu­ ate potential therapies are lacking and difficult to perform. Pustular Eruptions  AGEP is a rare reaction pattern affecting 3–5 people per million per year. It is thought to be secondary to medication exposure in >90% of cases (Fig. 63-15). Patients typically present with diffuse erythema or erythroderma, as well as fever and neutrophilia. One to two days later, innumerable pinpoint pustules develop overly­ ing the erythema. The pustules are most pronounced in flexural and body fold areas; however, they may become generalized and, when coalescent, can lead to superficial erosion. In such cases, differentiat­ ing the eruption from SJS in its initial stages may be difficult, although in AGEP any erosions are more superficial, and prominent mucosal involvement is lacking. In AGEP, both keratinocytes and T cells produce cytokines such as IL-8, IL-36a, and granulocyte-macrophage colony-stimulating factor (GM-CSF) that attract neutrophils to the skin, culminating in sterile pustule formation in the epidermis and neutrophilia in the peripheral blood. Skin biopsy shows collections of neutrophils and sparse necrotic keratinocytes in the upper part of the epidermis, unlike the full-thickness epidermal necrosis that characterizes SJS. Before the pustules appear, AGEP may also mimic DIHS/DRESS due to the prominent fever and erythroderma. The principal differential diagnosis for AGEP is acute pustular psoriasis, which has an identical clinical and histologic appearance. Many patients with AGEP have a personal or family history of pso­ riasis. AGEP classically begins within 24–48 hours of drug exposure, although it may occur as much as 1–3 weeks later particularly with medications such as hydroxychloroquine or terbinafine. AGEP has FIGURE 63-15  Acute generalized exanthematous pustulosis.

been associated with β-lactam antibiotics, calcium channel blockers, macrolide antibiotics, and other inciting agents (including radiocon­ trast and dialysates). Patch testing with the responsible drug often results in a localized pustular eruption mimicking the original reaction.

Overlap Hypersensitivity Syndromes  An important concept in the clinical approach to severe drug eruptions is the existence of “overlap syndromes,” most notably DIHS with TEN-like features, DIHS/DRESS with pustular eruption (AGEP-like), and AGEP with TEN-like features. In case series of AGEP, 50% of cases had TEN-like or DIHS/DRESS-like features, and 20% of cases had mucosal involve­ ment resembling SJS/TEN. In one study, up to 20% of all severe drug eruptions had overlap features, suggesting that AGEP, DIHS/DRESS, and SJS/TEN can represent a clinical spectrum with some common pathophysiologic mechanisms. Designation of a single diagnosis based on cutaneous and extracutaneous involvement may not always be pos­ sible in cases of hypersensitivity; in such instances, treatment should be geared toward addressing the dominant clinical features as they evolve. The timing of rash onset with respect to drug administration, which is usually much more delayed in DIHS/DRESS than AGEP or SJS/TEN, and the presence of systemic manifestations such as hepatitis are help­ ful clues to that diagnosis. PART 2 Cardinal Manifestations and Presentation of Diseases Vasculitis  Cutaneous small-vessel vasculitis (CSVV) typically pres­ ents with purpuric papules and macules involving the lower extremi­ ties and other dependent areas (Fig. 63-16) (Chap. 375). Pustular and hemorrhagic vesicles as well as rounded ulcers also occur. Importantly, vasculitis may involve other organs, including the kidneys, joints, gastrointestinal tract, and lungs, necessitating a thorough clinical evaluation for systemic involvement. Drugs are implicated as a cause of roughly 15% of all cases of CSVV. Antibiotics, particularly β-lactams, are commonly implicated; however, almost any drug can cause vascu­ litis. Vasculitis may also be idiopathic or due to underlying infection, connective tissue disease, or (rarely) malignancy. Rare but important types of drug-induced vasculitis include druginduced ANCA vasculitis. Such patients commonly present with cutaneous manifestations but can develop the full range of symptoms associated with ANCA-associated vasculitis, including crescentic glo­ merulonephritis and alveolar hemorrhage. Propylthiouracil, methima­ zole, and hydralazine are common culprits. Drug-induced polyarteritis nodosa has been associated with long-term exposure to minocycline. The presence of perivascular eosinophils on skin biopsy can be a clue to possible drug etiology. FIGURE 63-16  Cutaneous small-vessel vasculitis (CSVV, leukocytoclastic vasculitis).

MANAGEMENT OF THE PATIENT WITH SUSPECTED DRUG ERUPTION There are four main questions to answer regarding a suspected drug eruption:

1. Is the observed rash caused by a medication?
2. Is the reaction severe or evolving with systemic manifestations?
3. Which drug or drugs are suspected, and should they be withdrawn?
4. What recommendation can be made for future medication use? ■ ■EARLY DIAGNOSIS OF SEVERE ERUPTIONS Rapid recognition of potentially serious or life-threatening reactions is paramount. In this regard, a suspected drug eruption is best defined initially by whether or not it is one of these entities (e.g., SJS/TEN, DIHS/DRESS). Table 63-2 lists clinical and laboratory features that, if present, suggest the presence of a severe reaction. Table 63-3 lists the most important of these reactions, along with their key features and commonly associated medications. Any concern for a serious reaction should prompt immediate consultation with the appropriate specialist (e.g., a dermatologist or allergist and immunologist) and/or referral of the patient to a specialized center. ■ ■CONFIRMATION OF DRUG REACTION The probability of drug etiology varies with the timing and pattern of the reaction. The latency period, or time from starting a drug until reaction onset, provides important context regarding the clinical phe­ notype. Immediate reactions typically occur within 6 hours of medi­ cation exposure, while delayed reactions generally occur days after the first exposure but can occur within hours following rechallenge. Morbilliform eruptions are usually viral in children and drug-induced in adults. Among severe reactions, drugs account for 10–20% of ana­ phylaxis and vasculitis and between 70% and 90% of AGEP, DIHS/ DRESS, and SJS/TEN. Skin biopsy helps characterize the reaction but does not inform drug causality. Blood counts and liver and renal func­ tion tests are important for evaluating organ involvement. The findings of mild elevation of liver enzymes and eosinophil count are frequent but not specific for a drug reaction. Blood tests that could identify an alternative cause, serologic tests (to rule out drug-induced lupus), and serology or polymerase chain reaction for infections may be of great diagnostic importance. TABLE 63-2  Clinical and Laboratory Findings Suggestive of Severe Cutaneous Adverse Drug Reaction Cutaneous Generalized rash Dusky or target-like lesions Purpura Blisters or epidermal detachment Positive Nikolsky sign Skin pain Skin necrosis Erosions of the mucous membranes Facial or acral edema Swelling of the lips or tongue General Fever Enlarged lymph nodes Arthralgias or arthritis Tachycardia, hypotension Shortness of breath, hoarseness, wheezing Laboratory Results Eosinophil count >1000/μL Leukopenia or leukocytosis with atypical lymphocytes Abnormal liver or kidney function tests From The New England Journal of Medicine, JC Roujeau, RS Stern: Severe adverse cutaneous reactions to drugs. 331, 1272-1285. Copyright © (1994) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

TABLE 63-3  Clinical Features of Severe Cutaneous Drug Reactions DIAGNOSIS MUCOSAL LESIONS TYPICAL SKIN LESIONS Stevens-Johnson syndrome (SJS) Erosions usually of two or more sites Dusky macules or atypical targets evolve into small blisters; rare areas of confluence; detachment ≤10% body surface area Toxic epidermal necrolysis (TEN)a Erosions usually of two or more sites Individual lesions like those in SJS evolving into confluent dusky erythema; large sheets of necrotic epidermis; total detachment of >30% body surface area Drug-induced hypersensitivity syndrome/drug rash with eosinophilia and systemic symptoms (DIHS/DRESS) Mucositis reported in up to 30% Diffuse, deep red morbilliform eruption with facial involvement; facial and acral swelling Acute generalized exanthematous pustulosis (AGEP) Oral erosions in perhaps 20% Diffuse erythematous eruption; innumerable pinpoint pustules with preference for body folds; superficial peeling or erosions Serum sickness or serum sickness–like reaction Absent Urticarial rash, often serpiginous or polycyclic; purpuric eruption along the sides of the feet and hands is characteristic Anticoagulant-induced necrosis Infrequent Purpura and necrosis, especially of central, fatty areas Angioedema Often involved Swelling, erythema, and discomfort of skin and subcutaneous tissue, generally associated with urticaria Note: SJS-TEN overlap is characterized by detachment of 10–30% of body surface area. From The New England Journal of Medicine, JC Roujeau, RS Stern: Severe adverse cutaneous reactions to drugs. 331, 1272-1285. Copyright © (1994) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society. ■ ■WHAT DRUG(S) TO SUSPECT AND WITHDRAW Most drug eruptions occur during the first course of treatment with a new medication. A notable exception is IgE-mediated urticaria and anaphylaxis that require presensitization and develop a few minutes to hours after rechallenge. Characteristic timing of onset of delayed hypersensitivity reactions following drug administration is as fol­ lows: 4–14 days for morbilliform drug eruption, 2–4 days for AGEP, 1.5 days to 3 weeks for AHS, 5–28 days for SJS/TEN, and 14–48 days for DIHS (Fig. 63-17). A drug timeline, compiling comprehensive information of all current and past prescription and nonprescription medications/supplements and the timing of administration rela­ tive to the rash, is a key diagnostic tool for identifying the inciting drug. Medications introduced for the first time in the relevant time frame are prime suspects. Two other important elements to suspect causality at this stage are (1) previous experience with the drug (or related members of the same pharmacologic class) and (2) alternative etiologic candidates. The decision to continue or discontinue any medication depends on the severity of the reaction, the severity of the primary disease under­ going treatment, the degree of suspicion of causality, and the feasibility of finding an alternative safer treatment. In any potentially fatal drug reaction, elimination of all possible suspect drugs and unnecessary medications should be immediately attempted. Some rashes may resolve when “treating through” a benign drug-related eruption. The decision to treat through an eruption should, however, remain the exception based on a higher benefit-risk ratio and withdrawal of every suspect drug the general rule. On the other hand, drugs that are associ­ ated with a low pretest probability of a hypersensitivity reaction and are important for the patient (e.g., antihypertensive agents), or have been tolerated by the patient for more than 12 weeks, generally should not be quickly withdrawn. This approach may permit judicious use of these agents in the future. ■ ■RECOMMENDATION FOR FUTURE USE OF DRUGS The aims are to (1) prevent the recurrence of the drug eruption and (2) avoid compromising future treatment by inaccurately excluding otherwise useful medications.

FREQUENT SIGNS AND SYMPTOMS MOST COMMON CULPRIT DRUGS Most cases involve fever Trimethoprim-sulfamethoxazole, allopurinol, anticonvulsants, β-lactam antibiotics, nonsteroidal anti-inflammatory drugs (NSAIDs) Fever, leukopenia Same as for SJS Cutaneous Drug Reactions CHAPTER 63 Fever, lymphadenopathy; eosinophilia, atypical lymphocytosis, hepatitis, nephritis, myocarditis Anticonvulsants, sulfonamides, allopurinol, minocycline, vancomycin High fever, leukocytosis (neutrophilia), hypocalcemia b-Lactam antibiotics, macrolide antibiotics, calcium channel blockers, IV contrast Fever, arthralgias, lymphadenopathy Antithymocyte globulin, anti-toxins, rituximab, other monoclonal antibodies; cefaclor, penicillin, amoxicillin, trimethoprim-sulfamethoxazole Ischemic pain in affected areas Warfarin, heparin Stridor, respiratory distress, cardiovascular collapse Angiotensin-converting enzyme (ACE) inhibitors, NSAIDs, contrast dye A thorough assessment of drug causality is based on timing of the reaction, evaluation of other possible causes, and effect of drug withdrawal or continuation. The RegiSCAR group has proposed the Algorithm of Drug Causality for Epidermal Necrolysis (ALDEN) to rank likelihood of drug causality in SJS/TEN; validation of this and other instruments, such as the Naranjo adverse drug reaction prob­ ability scale, is limited. Medication(s) with a “definite” or “probable” causality should be contraindicated, a warning card or medical alert tag (e.g., wristband) should be given to the patient, and the drugs should be listed in the patient’s medical chart as serious allergic reactions war­ ranting permanent drug avoidance. ■ ■CROSS-SENSITIVITY Because of possible cross-sensitivity among chemically related drugs, many physicians recommend avoidance of not only the medication that induced the reaction but also all drugs of the same pharmacologic class. There are two types of cross-sensitivity. Reactions that depend on a pharmacologic interaction may occur with all drugs that target the same pathway, whether the drugs are structurally similar or not. This is the case with angioedema caused by COX-1 inhibitors (aspirin/ NSAIDs) and ACE inhibitors. In this situation, the risk of recurrence varies from drug to drug in a particular class; however, avoidance of all drugs in the class is usually recommended. Immune recognition of structurally related drugs is the second mechanism by which crosssensitivity occurs. A classic example is hypersensitivity to aromatic antiepileptics (barbiturates, phenytoin, carbamazepine) with up to 50% of patients who reacted to one drug reacting to a second. For other drugs, in vitro and in vivo data have suggested that cross-reactivity exists only between compounds with very similar chemical structures. Sulfamethoxazole-specific lymphocytes may be activated by other antibacterial sulfonamides but not diuretics, antidiabetic drugs, or anti-COX2 NSAIDs that have a sulfonamide group (SO2-NH2) but do not share the N4 substituted aryl-amine or the aromatic ring at N1 characteristic of antibacterial sulfonamides. Though it has been previously reported that 10% of patients with penicillin allergies will also develop allergic reactions to cephalosporin class antibiotics, the cross-reactivity is now thought to be mainly driven by the shared R1

Morbilliform drug eruption (benign exanthem) Fixed drug eruption Drug-induced lupus or vasculitis Serum sickness–like reaction Drug-induced interstitial nephritis Non-IgE-mediated mast-cell activation IgE (<6 hours) Drug reaction with eosinophilia & systemic symptoms AGEP PART 2 Cardinal Manifestations and Presentation of Diseases Stevens-Johnson syndrome & toxic epidermal necrolysis Abacavir hypersensitivity Weeks following initiation of the medication

FIGURE 63-17  Timeline of drug hypersensitivity reactions. Drug reactions differ in their latency period, which is the time from first ingestion of a medication to the time a reaction occurs. For IgE- and non–IgE-mediated reactions, these are typically immediate and occur less than 6 hours from ingestion. Delayed reactions typically occur several hours to days or even weeks following first ingestion. The latency period can be a valuable clue to the clinical phenotype of the drug reaction and the culprit drug. For example, acute generalized exanthematous pustulosis (AGEP) associated with antibiotics typically occurs within 24–48 hours, whereas when AGEP is associated with hydroxychloroquine, it may take up to 3 weeks. Drug-induced hypersensitivity syndrome (DIHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) to most drugs has a latency period of 2–3 weeks, although shorter latencies associated with β-lactam antibiotics have been described. Because multiple drugs are frequently started together in a complex medical patient, a timeline outlining all medications taken at the first time symptoms of a reaction occur and documentation of the evolution of these symptoms in relation to initiation of specific medications are valuable in clinical phenotype and drug causality assessment. (Reproduced with permission from DA Khan et al: Drug allergy: A 2022 practice parameter update. J Allerg Clin Immun 150:1333, 2022, Figure 1.) side chain between specific aminopenicillins and aminocephalospo­ rins. The fact that more than 95% of patients labeled with a penicillin allergy do not have a true allergy and that cross-reactivity between penicillins and unrelated cephalosporin is less than 2% means severe reactions are very rare. Data suggest that although the risk of developing a drug eruption to another drug is increased in persons with a prior reaction, “crosssensitivity” is probably not the explanation. For example, those with a history of an allergic-like reaction to penicillin are at greater risk of devel­ oping a reaction to antibacterial sulfonamides than to cephalosporins. These data suggest the list of drugs to avoid after a drug reaction should be limited to the causative one(s) and to a few very similar medications. Because of growing evidence that some severe cutaneous reactions to drugs are associated with HLA genes that are inherited co-dominantly (one set of alleles is active from each parent), consideration should be given to counsel first-degree family members of patients with severe cutaneous reactions about genetic testing and potential medication avoidance. ■ ■ROLE OF TESTING FOR CAUSALITY

AND DRUG RECHALLENGE The usefulness of laboratory tests, skin-prick, or patch testing to deter­ mine causality is highly dependent on the specific medication and clinical phenotype of the drug hypersensitivity reaction. Many in vitro immuno­ logic assays have been developed for research purposes; however, the pre­ dictive value of these tests has not been validated in large series of affected patients. In some cases, where the benefit of treatment outweighs the risk of rechallenge, diagnostic rechallenge may be appropriate, even for drugs with high rates of adverse reactions. Supportive data from resource-poor settings suggest careful sequential additive rechallenge can be achieved with anti-tuberculous medications, with immediate high-dose methyl­ prednisolone rescue used successfully to abort any reaction. Skin-prick testing has clinical value in specific settings. In patients with a history suggesting immediate IgE-mediated reactions to penicillin, skin-prick testing with the specific culprit penicillins and

Drug-induced liver injury major and minor determinants of penicillins or cephalosporins has proven useful for identifying patients at risk of anaphylactic reac­ tions to these agents. Negative skin tests do not totally rule out IgEmediated reactivity; however, the risk of anaphylaxis in response to penicillin administration in patients with negative skin tests is about 1%. In contrast, two-thirds of patients with a positive skin test experi­ ence an allergic response upon rechallenge. The skin tests themselves carry a small risk of anaphylaxis in patients who have had recent IgE-mediated reactions. Many patients with childhood reactions to antibiotics such as penicillin were never allergic, and even true IgE-mediated responses are thought to wane over time. For low-risk penicillin allergic adults and children with remote histories or whose history consisted of cutaneous symptoms only (e.g., urticaria) and where symptoms resolved without treatment, evidence currently sup­ ports direct oral challenge with a penicillin without preceding skin testing. This approach of direct oral challenge has also been applied to remove the allergy label to low-risk reactions associated with sul­ fonamides and other antibiotics. For patients with delayed-type hypersensitivity, the clinical utility of skin tests is dependent on the clinical phenotype of the reaction. Evidence and standardization of approaches including the concen­ tration of medications used in skin and patch testing are needed as the lower concentrations used in prick and intradermal testing for immediate IgE-mediated reactions may have limited utility for dosedependent T-cell–mediated reactions. At least one of a combination of several tests (prick, patch, and intradermal) is positive in 50–70% of patients with a delayed reaction “definitely” attributed to a single medication. This low sensitivity corresponds to the observation that readministration of drugs with negative skin testing results in erup­ tions in 17% of cases. Desensitization can be considered in those with a history of reaction to a medication that must be used again. Efficacy of such procedures has been demonstrated in cases of immediate reaction to penicillin and positive skin tests, anaphylactic reactions to platinum chemotherapy, and delayed reactions to sulfonamides in patients with AIDS. Desensitization is often successful in HIV-infected patients with morbilliform eruptions

60 - SECTION 9 Hematologic Alterations

SECTION 9 Hematologic Alterations

Section 9 Hematologic Alterations Dan L. Longo

Interpreting Peripheral

Blood Smears Some of the relevant findings in peripheral blood, enlarged lymph nodes, and bone marrow are illustrated in this chapter. Systematic his­ tologic examination of the bone marrow and lymph nodes is beyond the scope of a general medicine textbook. However, every internist should know how to examine a peripheral blood smear. The examination of a peripheral blood smear is one of the most informative exercises a physician can perform. Although advances in automated technology have made the examination of a peripheral blood smear by a physician seem less important, the technology is not a completely satisfactory replacement for a blood smear interpretation by a trained medical professional who also knows the patient’s clinical history, family history, social history, and physical findings. It is useful to ask the laboratory to generate a Wright’s-stained peripheral blood smear and examine it. A normal peripheral blood smear is shown in Figure 65-1. The best place to examine blood cell morphology is the feath­ ered edge of the blood smear where red cells lie in a single layer, side by side, just barely touching one another but not overlapping. The author’s approach is to look at the smallest cellular elements, the platelets, first and work his way up in size to red cells and then white cells. Using an oil immersion lens that magnifies the cells 100-fold, one counts the platelets in five to six fields, averages the number per field, and multiplies by 20,000 to get a rough estimate of the platelet count. The platelets are usually 1–2 μm in diameter and have a blue granulated appearance. There is usually 1 platelet for every 20 or so red cells. Of course, the automated counter is much more accurate, but gross disparities between the automated and manual counts should be assessed. Large platelets may be a sign of rapid platelet turnover, as young platelets are often larger than old ones; alternatively, certain rare inherited syndromes can produce large platelets. If the platelet count is low, the absence of large (young) platelets may be an indicator of marrow production problems. Platelet clumping visible on the smear can be associated with falsely low automated platelet counts. Clumping may be caused by the anticoagulant into which the blood is drawn. Similarly, neutrophil fragmentation can be a source of falsely elevated automated platelet counts. The absence of platelet granules may be an artifact of the handling of the blood or may indicate marrow disease or a rare congenital anomaly, gray platelet syndrome. Elevated platelet counts usually signify a myeloproliferative disorder or a reaction to systemic inflammation. Next one examines the red blood cells. One can gauge their size by comparing the red cell to the nucleus of a small lymphocyte. Both are normally about 8-μm wide. Red cells that are smaller than the small lymphocyte nucleus may be microcytic; those larger than the small lymphocyte nucleus may be macrocytic. Macrocytic cells also tend to be more oval than spherical in shape and are sometimes called mac­ roovalocytes. The automated mean corpuscular volume (MCV) can assist in making a classification. However, some patients may have both iron and vitamin B12 deficiency, which will produce an MCV in the normal range but wide variation in red cell size. When the red cells vary greatly in size, anisocytosis is said to be present. When the red cells vary greatly in shape, poikilocytosis is said to be present. The electronic cell counter provides an independent assessment of vari­ ability in red cell size. It measures the range of red cell volumes and reports the results as “red cell distribution width” (RDW). This value is calculated from the MCV; thus, cell width is not being measured

but cell volume is. The term is derived from the curve displaying the frequency of cells at each volume, also called the distribution. The width of red cell volume distribution curve is what determines the RDW. The RDW is calculated as follows: RDW = (standard deviation of MCV ÷ mean MCV) × 100. In the presence of morphologic aniso­ cytosis, RDW (normally 11–14%) increases to 15–18%. The RDW is useful in at least two clinical settings. In patients with microcytic anemia, the differential diagnosis is generally between iron deficiency and thalassemia. In thalassemia, the small red cells are generally of uniform size with a normal small RDW. In iron deficiency, the size variability and the RDW are large. In addition, a large RDW can sug­ gest a dimorphic anemia when a chronic atrophic gastritis can pro­ duce both vitamin B12 malabsorption to produce macrocytic anemia and blood loss to produce iron deficiency. In such settings, RDW is also large. An elevated RDW also has been reported as a risk factor for all-cause mortality in population-based studies, a finding that is unexplained currently.

Interpreting Peripheral Blood Smears CHAPTER 65 After red cell size is assessed, one examines the hemoglobin con­ tent of the cells. They are either normal in color (normochromic) or pale in color (hypochromic). They are never “hyperchromic.” If more than the normal amount of hemoglobin is made, the cells get larger—they do not become darker. In addition to hemoglobin con­ tent, the red cells are examined for inclusions. Red cell inclusions are the following:

1. Basophilic stippling—diffuse fine or coarse blue dots in the red cell usually representing RNA residue—especially common in lead poisoning
2. Howell-Jolly bodies—dense blue circular inclusions that repre­ sent nuclear remnants—their presence implies defective splenic function
3. Nuclei—red cells may be released or pushed out of the marrow pre­ maturely before nuclear extrusion—often implies a myelophthisic process or a vigorous narrow response to anemia, usually hemolytic anemia
4. Parasites—red cell parasites include malaria and babesia (Chaps. A2 and A6)
5. Polychromatophilia—the red cell cytoplasm has a bluish hue, reflect­ ing the persistence of ribosomes still actively making hemoglobin in a young red cell Vital stains are necessary to see precipitated hemoglobin called Heinz bodies. Red cells can take on a variety of different shapes. All abnormally shaped red cells are poikilocytes. Small red cells without the central pallor are spherocytes; they can be seen in hereditary spherocytosis, hemolytic anemias of other causes, and clostridial sepsis. Dacrocytes are teardrop-shaped cells that can be seen in hemolytic anemias, severe iron deficiency, thalassemias, myelofibrosis, and myelodys­ plastic syndromes. Schistocytes are helmet-shaped cells that reflect microangiopathic hemolytic anemia or fragmentation on an artificial heart valve. Echinocytes are spiculated red cells with the spikes evenly spaced; they can represent an artifact of abnormal drying of the blood smear or reflect changes in stored blood. They also can be seen in renal failure and malnutrition and are often reversible. Acanthocytes are spiculated red cells with the spikes irregularly distributed. This process tends to be irreversible and reflects underlying renal disease, abetalipoproteinemia, or splenectomy. Elliptocytes are ellipticalshaped red cells that can reflect an inherited defect in the red cell membrane, but they also are seen in iron deficiency, myelodysplastic syndromes, megaloblastic anemia, and thalassemias. Stomatocytes are red cells in which the area of central pallor takes on the morphology of a slit instead of the usual round shape. Stomatocytes can indicate an inherited red cell membrane defect and also can be seen in alco­ holism. Target cells have an area of central pallor that contains a dense center, or bull’s eye. These cells are seen classically in thalassemia, but they are also present in iron deficiency, cholestatic liver disease, and some hemoglobinopathies. They also can be generated artifactually by improper slide making.

61 - 65 Interpreting Peripheral Blood Smears

65 Interpreting Peripheral Blood Smears

Section 9 Hematologic Alterations Dan L. Longo

Interpreting Peripheral

Blood Smears Some of the relevant findings in peripheral blood, enlarged lymph nodes, and bone marrow are illustrated in this chapter. Systematic his­ tologic examination of the bone marrow and lymph nodes is beyond the scope of a general medicine textbook. However, every internist should know how to examine a peripheral blood smear. The examination of a peripheral blood smear is one of the most informative exercises a physician can perform. Although advances in automated technology have made the examination of a peripheral blood smear by a physician seem less important, the technology is not a completely satisfactory replacement for a blood smear interpretation by a trained medical professional who also knows the patient’s clinical history, family history, social history, and physical findings. It is useful to ask the laboratory to generate a Wright’s-stained peripheral blood smear and examine it. A normal peripheral blood smear is shown in Figure 65-1. The best place to examine blood cell morphology is the feath­ ered edge of the blood smear where red cells lie in a single layer, side by side, just barely touching one another but not overlapping. The author’s approach is to look at the smallest cellular elements, the platelets, first and work his way up in size to red cells and then white cells. Using an oil immersion lens that magnifies the cells 100-fold, one counts the platelets in five to six fields, averages the number per field, and multiplies by 20,000 to get a rough estimate of the platelet count. The platelets are usually 1–2 μm in diameter and have a blue granulated appearance. There is usually 1 platelet for every 20 or so red cells. Of course, the automated counter is much more accurate, but gross disparities between the automated and manual counts should be assessed. Large platelets may be a sign of rapid platelet turnover, as young platelets are often larger than old ones; alternatively, certain rare inherited syndromes can produce large platelets. If the platelet count is low, the absence of large (young) platelets may be an indicator of marrow production problems. Platelet clumping visible on the smear can be associated with falsely low automated platelet counts. Clumping may be caused by the anticoagulant into which the blood is drawn. Similarly, neutrophil fragmentation can be a source of falsely elevated automated platelet counts. The absence of platelet granules may be an artifact of the handling of the blood or may indicate marrow disease or a rare congenital anomaly, gray platelet syndrome. Elevated platelet counts usually signify a myeloproliferative disorder or a reaction to systemic inflammation. Next one examines the red blood cells. One can gauge their size by comparing the red cell to the nucleus of a small lymphocyte. Both are normally about 8-μm wide. Red cells that are smaller than the small lymphocyte nucleus may be microcytic; those larger than the small lymphocyte nucleus may be macrocytic. Macrocytic cells also tend to be more oval than spherical in shape and are sometimes called mac­ roovalocytes. The automated mean corpuscular volume (MCV) can assist in making a classification. However, some patients may have both iron and vitamin B12 deficiency, which will produce an MCV in the normal range but wide variation in red cell size. When the red cells vary greatly in size, anisocytosis is said to be present. When the red cells vary greatly in shape, poikilocytosis is said to be present. The electronic cell counter provides an independent assessment of vari­ ability in red cell size. It measures the range of red cell volumes and reports the results as “red cell distribution width” (RDW). This value is calculated from the MCV; thus, cell width is not being measured

but cell volume is. The term is derived from the curve displaying the frequency of cells at each volume, also called the distribution. The width of red cell volume distribution curve is what determines the RDW. The RDW is calculated as follows: RDW = (standard deviation of MCV ÷ mean MCV) × 100. In the presence of morphologic aniso­ cytosis, RDW (normally 11–14%) increases to 15–18%. The RDW is useful in at least two clinical settings. In patients with microcytic anemia, the differential diagnosis is generally between iron deficiency and thalassemia. In thalassemia, the small red cells are generally of uniform size with a normal small RDW. In iron deficiency, the size variability and the RDW are large. In addition, a large RDW can sug­ gest a dimorphic anemia when a chronic atrophic gastritis can pro­ duce both vitamin B12 malabsorption to produce macrocytic anemia and blood loss to produce iron deficiency. In such settings, RDW is also large. An elevated RDW also has been reported as a risk factor for all-cause mortality in population-based studies, a finding that is unexplained currently.

Interpreting Peripheral Blood Smears CHAPTER 65 After red cell size is assessed, one examines the hemoglobin con­ tent of the cells. They are either normal in color (normochromic) or pale in color (hypochromic). They are never “hyperchromic.” If more than the normal amount of hemoglobin is made, the cells get larger—they do not become darker. In addition to hemoglobin con­ tent, the red cells are examined for inclusions. Red cell inclusions are the following:

1. Basophilic stippling—diffuse fine or coarse blue dots in the red cell usually representing RNA residue—especially common in lead poisoning
2. Howell-Jolly bodies—dense blue circular inclusions that repre­ sent nuclear remnants—their presence implies defective splenic function
3. Nuclei—red cells may be released or pushed out of the marrow pre­ maturely before nuclear extrusion—often implies a myelophthisic process or a vigorous narrow response to anemia, usually hemolytic anemia
4. Parasites—red cell parasites include malaria and babesia (Chaps. A2 and A6)
5. Polychromatophilia—the red cell cytoplasm has a bluish hue, reflect­ ing the persistence of ribosomes still actively making hemoglobin in a young red cell Vital stains are necessary to see precipitated hemoglobin called Heinz bodies. Red cells can take on a variety of different shapes. All abnormally shaped red cells are poikilocytes. Small red cells without the central pallor are spherocytes; they can be seen in hereditary spherocytosis, hemolytic anemias of other causes, and clostridial sepsis. Dacrocytes are teardrop-shaped cells that can be seen in hemolytic anemias, severe iron deficiency, thalassemias, myelofibrosis, and myelodys­ plastic syndromes. Schistocytes are helmet-shaped cells that reflect microangiopathic hemolytic anemia or fragmentation on an artificial heart valve. Echinocytes are spiculated red cells with the spikes evenly spaced; they can represent an artifact of abnormal drying of the blood smear or reflect changes in stored blood. They also can be seen in renal failure and malnutrition and are often reversible. Acanthocytes are spiculated red cells with the spikes irregularly distributed. This process tends to be irreversible and reflects underlying renal disease, abetalipoproteinemia, or splenectomy. Elliptocytes are ellipticalshaped red cells that can reflect an inherited defect in the red cell membrane, but they also are seen in iron deficiency, myelodysplastic syndromes, megaloblastic anemia, and thalassemias. Stomatocytes are red cells in which the area of central pallor takes on the morphology of a slit instead of the usual round shape. Stomatocytes can indicate an inherited red cell membrane defect and also can be seen in alco­ holism. Target cells have an area of central pallor that contains a dense center, or bull’s eye. These cells are seen classically in thalassemia, but they are also present in iron deficiency, cholestatic liver disease, and some hemoglobinopathies. They also can be generated artifactually by improper slide making.

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 65-1  Normal peripheral blood smear. Small lymphocyte in center of field. Note that the diameter of the red blood cell is similar to the diameter of the small lymphocyte nucleus. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault, Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-2  Reticulocyte count preparation. This new methylene blue–stained blood smear shows large numbers of heavily stained reticulocytes (the cells containing the dark blue–staining RNA precipitates). (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-3  Hypochromic microcytic anemia of iron deficiency. Small lymphocyte in field helps assess the red blood cell size. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

FIGURE 65-4  Iron deficiency anemia next to normal red blood cells. Microcytes (right panel) are smaller than normal red blood cells (cell diameter <7 μm) and may or may not be poorly hemoglobinized (hypochromic). (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault, Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-5  Polychromatophilia. Note large red cells with light purple coloring. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-6  Macrocytosis. These cells are both larger than normal (mean corpuscular volume >100) and somewhat oval in shape. Some morphologists call these cells macroovalocytes. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

FIGURE 65-7  Hypersegmented neutrophils. Hypersegmented neutrophils (multilobed polymorphonuclear leukocytes) are larger than normal neutrophils with five or more segmented nuclear lobes. They are commonly seen with folic acid or vitamin B12 deficiency. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-8  Spherocytosis. Note small hyperchromatic cells without the usual clear area in the center. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-9  Rouleaux formation. Small lymphocyte in center of field. These red cells align themselves in stacks and are related to increased serum protein levels. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

Interpreting Peripheral Blood Smears CHAPTER 65 FIGURE 65-10  Red cell agglutination. Small lymphocyte and segmented neutrophil in upper left center. Note irregular collections of aggregated red cells. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-11  Fragmented red cells. Heart valve hemolysis. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-12  Sickle cells. Homozygous sickle cell disease. A nucleated red cell and neutrophil are also in the field. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 65-13  Target cells. Target cells are recognized by the bull’s-eye appearance of the cell. Small numbers of target cells are seen with liver disease and thalassemia. Larger numbers are typical of hemoglobin C disease. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-14  Elliptocytosis. Small lymphocyte in center of field. Elliptical shape of red cells related to weakened membrane structure, usually due to mutations in spectrin. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-15  Stomatocytosis. Red cells characterized by a wide transverse slit or stoma. This often is seen as an artifact in a dehydrated blood smear. These cells can be seen in hemolytic anemias and in conditions in which the red cell is overhydrated or dehydrated. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

FIGURE 65-16  Acanthocytosis. Spiculated red cells are of two types: acanthocytes are contracted dense cells with irregular membrane projections that vary in length and width; echinocytes have small, uniform, and evenly spaced membrane projections. Acanthocytes are present in severe liver disease, in patients with abetalipoproteinemia, and in rare patients with McLeod blood group. Echinocytes are found in patients with severe uremia, in glycolytic red cell enzyme defects, and in microangiopathic hemolytic anemia. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-17  Howell-Jolly bodies. Howell-Jolly bodies are tiny nuclear remnants that normally are removed by the spleen. They appear in the blood after splenectomy (defect in removal) and with maturation/dysplastic disorders (excess production). (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-18  Teardrop cells and nucleated red blood cells characteristic of myelofibrosis. A teardrop-shaped red blood cell (left panel) and a nucleated red blood cell (right panel) as typically seen with myelofibrosis and extramedullary hematopoiesis. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

FIGURE 65-19  Myelofibrosis of the bone marrow. Total replacement of marrow precursors and fat cells by a dense infiltrate of reticulin fibers and collagen (hematoxylin and eosin stain). (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-20  Reticulin stain of marrow myelofibrosis. Silver stain of a myelofibrotic marrow showing an increase in reticulin fibers (black-staining threads). (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-21  Stippled red cell in lead poisoning. Mild hypochromia. Coarsely stippled red cell. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

Interpreting Peripheral Blood Smears CHAPTER 65 FIGURE 65-22  Heinz bodies. Blood mixed with hypotonic solution of crystal violet. The stained material is precipitates of denatured hemoglobin within cells. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-23  Giant platelets. Giant platelets, together with a marked increase in the platelet count, are seen in myeloproliferative disorders, especially primary thrombocythemia. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-24  Normal granulocytes. The normal granulocyte has a segmented nucleus with heavy, clumped chromatin; fine neutrophilic granules are dispersed throughout the cytoplasm. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 65-25  Normal monocytes. The film was prepared from the buffy coat of the blood from a normal donor. L, lymphocyte; M, monocyte; N, neutrophil. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-26  Normal eosinophils. The film was prepared from the buffy coat of the blood from a normal donor. E, eosinophil; L, lymphocyte; N, neutrophil. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGrawHill, 2005.) FIGURE 65-27  Normal basophil. The film was prepared from the buffy coat of the blood from a normal donor. B, basophil; L, lymphocyte. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

FIGURE 65-28  Pelger-Hüet anomaly. In this benign disorder, the majority of granulocytes are bilobed. The nucleus frequently has a spectacle-like, or “pince-nez,” configuration. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-29  Döhle body. Neutrophil band with Döhle body. The neutrophil with a sausage-shaped nucleus in the center of the field is a band form. Döhle bodies are discrete, blue-staining nongranular areas found in the periphery of the cytoplasm of the neutrophil in infections and other toxic states. They represent aggregates of rough endoplasmic reticulum. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 65-30  Chédiak-Higashi disease. Note giant granules in neutrophil. (Source: From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGrawHill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

62 - 66 Anemia and Polycythemia

66 Anemia and Polycythemia

One last feature of the red cells to assess before moving to the white blood cells is the distribution of the red cells on the smear. In most individuals, the cells lie side by side in a single layer. Some patients have red cell clumping (called agglutination) in which the red cells pile upon one another; it is seen in certain paraproteinemias and autoimmune hemolytic anemias. Another abnormal distribution involves red cells lying in single cell rows on top of one another like stacks of coins. This is called rouleaux formation and reflects abnor­ mal serum protein levels. Finally, one examines the white blood cells. Three types of granu­ locytes are usually present: neutrophils, eosinophils, and basophils, in decreasing frequency. Neutrophils are generally the most abundant white cell. They are round, are 10–14 μm wide, and contain a lobulated nucleus with two to five lobes connected by a thin chromatin thread. Bands are immature neutrophils that have not completed nuclear condensation and have a U-shaped nucleus. Bands reflect a left shift in neutrophil maturation in an effort to make more cells more rap­ idly. Neutrophils can provide clues to a variety of conditions. Vacu­ olated neutrophils may be a sign of bacterial sepsis. The presence of 1- to 2-μm blue cytoplasmic inclusions, called Döhle bodies, can reflect infections, burns, or other inflammatory states. If the neutrophil gran­ ules are larger than normal and stain a darker blue, “toxic granulations” are said to be present, and they also suggest a systemic inflammation. The presence of neutrophils with more than five nuclear lobes suggests megaloblastic anemia. Large misshapen granules may reflect the inher­ ited Chédiak-Higashi syndrome. Eosinophils are slightly larger than neutrophils, have bilobed nuclei, and contain large red granules. Diseases of eosinophils are associated with too many of them rather than any morphologic or qualitative change. They normally total less than one-thirtieth the number of neu­ trophils. Basophils are even more rare than eosinophils in the blood. They have large dark blue granules and may be increased as part of chronic myeloid leukemia. Lymphocytes can be present in several morphologic forms. Most common in healthy individuals are small lymphocytes with a small dark nucleus and scarce cytoplasm. In the presence of viral infections, more of the lymphocytes are larger, about the size of neutrophils, with abundant cytoplasm and a less condensed nuclear chromatin. These cells are called reactive lymphocytes. About 1% of lymphocytes are larger and contain blue granules in a light blue cytoplasm; they are called large granular lymphocytes. In chronic lymphoid leukemia, the small lymphocytes are increased in number, and many of them are ruptured in making the blood smear, leaving a smudge of nuclear material without a surrounding cytoplasm or cell membrane; they are called smudge cells and are rare in the absence of chronic lymphoid leukemia. Monocytes are the largest white blood cells, ranging from 15 to 22 μm in diameter. The nucleus can take on a variety of shapes but usually appears to be folded; the cytoplasm is gray. Abnormal cells may appear in the blood. Most often, the abnormal cells originate from neoplasms of bone marrow–derived cells, includ­ ing lymphoid cells, myeloid cells, and occasionally red cells. More rarely, other types of tumors can get access to the bloodstream, and rare epithelial malignant cells may be identified. The chances of seeing such abnormal cells are increased by examining blood smears made from buffy coats, the layer of cells that is visible on top of sedimenting red cells when blood is left in the test tube for an hour. Smears made from finger sticks may include rare endothelial cells. Acknowledgment Figures in this chapter were borrowed from Williams Hematology, 7th edition, M Lichtman et al (eds). New York, McGraw-Hill, 2005; Hematology in General Practice, 4th edition, RS Hillman, KA Ault. New York, McGraw-Hill, 2005.

Thomas G. DeLoughery, Dan L. Longo

Anemia and Polycythemia Anemia is one of the most common medical problems in the world, affecting almost 2 billion people, and it is a significant source of mor­ bidity and reduced quality of life. Many causes of anemia are treatable, and some forms of anemia can be a clue to underlying disorders. Anemia and Polycythemia CHAPTER 66 NORMAL RED CELL PRODUCTION Hematopoiesis is the process by which the formed elements of blood are produced. The process is regulated through a series of steps begin­ ning with the hematopoietic stem cell. Stem cells are capable of pro­ ducing red cells, all classes of granulocytes, monocytes, platelets, and the cells of the immune system. The precise molecular mechanism by which the stem cell becomes committed to a given lineage is not fully defined. However, experiments in mice suggest that erythroid cells come from a common erythroid/megakaryocytic progenitor that does not develop in the absence of expression of the GATA-1 and FOG-1 (friend of GATA-1) transcription factors (Chap. 101). Following lineage commitment, hematopoietic progenitor and precursor cells become increasingly under the regulatory influence of growth factors and hormones. For red cell production, erythropoietin (EPO) is the primary regulatory hormone. EPO is required for the maintenance of committed erythroid progenitor cells that, in the absence of the hormone, undergo programmed cell death (apoptosis). The regulated process of red cell production is erythropoiesis, and its key elements are illustrated in Fig. 66-1. In the bone marrow, the first morphologically recognizable ery­ throid precursor is the pronormoblast. This cell can undergo four to five cell divisions, which result in the production of 16–32 mature red cells. With increased EPO production, or the administration of EPO as a drug, early progenitor cell numbers are amplified and, in turn, give rise to increased numbers of erythrocytes. The regulation of EPO production is linked to tissue oxygenation. In mammals, oxygen is transported to tissues bound to the hemo­ globin contained within circulating red cells. The mature red cell is 8 μm in diameter, anucleate, discoid in shape, and extremely pliable in order to traverse the microcirculation successfully; its membrane integrity is maintained by the intracellular generation of ATP. The biconcave disk provides the greatest amount of surface area for a given volume; this maximizes oxygen delivery. Normal red cell production results in the daily replacement of 0.8–1% of all circulating red cells in the body, since the average red cell lives 100–120 days. The organ responsible for red cell production is called the erythron. The erythron is a dynamic organ made up of a rapidly proliferating pool of marrow erythroid precursor cells and a large mass of mature circulating red Iron folate B12 Erythroid marrow Red cell mass Red cell destruction Erythropoietin Plasma volume Hb Concentration Kidney tissue PO2 O2 Consumption Heart Lungs Vessels Atmospheric O2 levels FIGURE 66-1  The physiologic regulation of red cell production by tissue oxygen tension. Hb, hemoglobin.

Serum erythropoietin (mU/mL)

Normal 9–26 mU/mL PART 2 Cardinal Manifestations and Presentation of Diseases

Hemoglobin (g/dL) FIGURE 66-2  Erythropoietin (EPO) levels in response to anemia. When the hemoglobin level falls to 120 g/L (12 g/dL), plasma EPO levels increase logarithmically. In the presence of chronic kidney disease or chronic inflammation, EPO levels are typically lower than expected for the degree of anemia. As individuals age, the level of EPO needed to sustain normal hemoglobin levels appears to increase. (Reproduced with permission from RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) blood cells. The size of the red cell mass reflects the balance of red cell production and destruction. The physiologic basis of red cell produc­ tion and destruction provides an understanding of the mechanisms that can lead to anemia. The physiologic regulator of red cell production, the glycoprotein hormone EPO, is produced and released by peritubular capillary lining cells within the kidney. These cells are highly specialized epitheliallike cells. A small amount of EPO is produced by hepatocytes. The fundamental stimulus for EPO production is the availability of oxygen (O2) for tissue metabolic needs. Key to EPO gene regulation is hypoxia-

inducible factor (HIF)-1α. In the presence of O2, HIF-1α is hydroxylated at a key proline, allowing HIF-1α to be ubiquitinated and degraded via the proteasome pathway. If O2 becomes limiting, this critical hydrox­ ylation step does not occur, allowing HIF-1α to partner with other proteins, translocate to the nucleus, and upregulate the expression of the EPO gene, among others. Impaired O2 delivery to the kidney can result from a decreased red cell mass (anemia), impaired O2 loading of the hemoglobin molecule, a high O2 affinity mutant hemoglobin (hypoxemia), or, rarely, impaired blood flow to the kidney (e.g., renal artery stenosis). EPO governs the day-to-day production of red cells, and ambient levels of the hormone can be measured in the plasma by sensitive immunoassays with the normal level being 10–25 U/L. When the hemoglobin concentration falls below 100–120 g/L (10–12 g/dL), plasma EPO levels increase in proportion to the severity of the anemia (Fig. 66-2). In circulation, EPO has half-life time of 6–9 h. EPO acts by binding to specific recep­ tors on the surface of marrow erythroid precursors, inducing them to proliferate and to mature. With EPO stimulation, red cell production can increase four- to fivefold within a 1- to 2-week period, but only in the presence of adequate nutrients, especially iron. The functional capacity of the erythron, therefore, requires normal renal production of EPO, a functioning erythroid marrow, and an adequate supply of substrates for hemoglobin synthesis. A defect in any of these key com­ ponents can lead to anemia. APPROACH TO THE DIAGNOSIS OF ANEMIA There are four initial steps in the diagnosis of anemia. The first step is a good history; one should ask about previous episodes of anemia, any previous therapy such as iron pills or transfusions, family history of anemia, and being a blood donor. Attention should also be paid to symptoms of disease that can lead to anemia. For example, diarrhea can be a sign of celiac disease or inflammatory bowel disease. In people who menstruate, a good menstrual history should be taken, including

duration of periods, number of pads/tampons used, and passing large clots. The physical exam should be focused on the consequences of ane­ mia such as a cardiac flow murmur and clues to the cause of the anemia such as the presence of splenomegaly or blood in the stool. A review of the blood smear is a crucial part of any evaluation for anemia as changes in red cell morphology can point to specific causes of anemia. Measuring the number of new red cells—the reticulocyte count—assesses the function of the bone marrow. Both of these tests are discussed in more detail below. ■ ■SIGNS AND SYMPTOMS OF ANEMIA Patients who gradually develop anemia over months can tolerate amaz­ ingly low hemoglobin levels due to compensatory mechanisms. The overall health status of an individual will also determine their response to anemia. Since blood delivers oxygen, many of the clinical signs are related to lack of oxygen delivery, such as tiredness and shortness of breath. On exam, this is manifested by paleness of the mucosa/con­ junctiva and resting tachycardia. If patients have atherosclerosis, they may suffer ischemic symptoms such as angina or transient ischemic attacks/strokes. Also, in cases of nutritional deficiency, there may be symptoms related to that such as pica in iron deficiency or neuropathy in B12 deficiency. In general, the signs and symptoms of anemia are very unreliable in predicting the patient’s hematocrit. ■ ■COMPENSATION FOR ANEMIA The body has a tremendous ability to compensate for anemia. This compensation improves over time, so inherited anemias or those that occur gradually are better tolerated than acute anemias. There are three physiologic compensatory mechanisms for anemia, which are described below. The first compensatory mechanism is an increase in cardiac out­ put. Oxygen delivery to tissues is a function of cardiac output times hemoglobin, so if the hemoglobin is lower, the cardiac output rises to compensate. Therefore, patients with a limited cardiac reserve will have symptoms of anemia at a higher hematocrit than patients with normal cardiac function. This compensatory mechanism can occur within minutes. The second compensatory mechanism is via increased levels of 2,3-disphosphoglyceric acid (2,3-DPG). 2,3-DPG decreases oxygen affinity for hemoglobin by increasing the stability of deoxygenated hemoglobin. While this may seem counterintuitive, this decreased affinity leads to more oxygen delivery in the tissues. The high ambient oxygen tension in the alveoli results in full oxygenation of hemoglobin despite this decreased oxygen affinity. This mechanism takes place over hours to days. Finally, over time, plasma volume increases which preserves cardiac output and maintains blood pressure and in theory may lower blood viscosity. In some cases, this increased plasma volume can overwhelm the heart, leading to edema and other signs of heart failure. This com­ pensation for anemia occurs over weeks. ■ ■LABORATORY TESTING Because most anemia develops slowly, anemia is most often detected by finding low hemoglobin and hematocrit levels on a complete blood count. Current testing of the blood count is performed by electronic cell counters that can directly measure red cell size (mean corpuscular volume [MCV]), number of red cells, and hemoglobin levels with a variety of measurements derived from these values. For example: × Hematocrit = Red cell number/liter MCV

The classic red cell indices reflect red cell size and hemoglobin con­ centration (Table 66-1). The index most commonly used is the MCV because the mean corpuscular hemoglobin and mean corpuscular hemoglobin concentration will trend with the MCV. Normal variations in hemoglobin and hematocrit with age are shown in Table 66-2. A normal peripheral blood smear is shown in Fig. 66-3.

TABLE 66-1  Red Cell Indices NORMAL VALUES COMMENT INDEX FORMULA Mean corpuscular volume (MCV) Hct/RBC

count × 10 85–95 fL RBC size Mean corpuscular hemoglobin concentration Hgb/Hct × 100 33.8–34.2 g/dL Changes very little in most cases of anemia; therefore, of limited value Mean corpuscular hemoglobin (MCH) Hgb/RBC

count × 10 28.5–32.3 pg Varies linearly with MCV; therefore, of limited additional value Abbreviations: Hct, hematocrit; Hgb, hemoglobin; RBC, red blood cell. ■ ■BLOOD SMEAR Blood is one of the few tissues of the body that allows direct visual­ ization. The morphology of the red cell on the blood smear can be a diagnostic clue to a variety of anemias. As a complement to the red cell indices, the blood smear also reveals variations in cell size (aniso­ cytosis) and shape (poikilocytosis). The degree of anisocytosis usually correlates with increases in the red cell distribution width (RDW) or the range of cell sizes. Poikilocytosis suggests a defect in the maturation of red cell precursors in the bone marrow or fragmentation of circu­ lating red cells. The blood smear may also reveal polychromasia—red cells that are slightly larger than normal and grayish blue in color on the Wright-Giemsa stain. These cells are reticulocytes that have been released prematurely from the bone marrow, and their color represents residual amounts of ribosomal RNA. These cells appear in circulation in response to EPO stimulation or to architectural damage of the bone marrow (e.g., fibrosis, infiltration of the marrow by malignant cells) that results in their disordered release from the marrow. The appear­ ance of nucleated red cells, Howell-Jolly bodies, target cells, sickle cells, and other red cell morphology changes may provide clues to specific disorders (Figs. 66-4 to 66-12). (See also Table 66-3 and the Atlas of Hematology, Chap. A6.) ■ ■BURR CELLS Also called echinocytes, these cells have multiple small projections. This can be a laboratory artifact but is most often seen with liver dis­ ease or uremia. ■ ■ELLIPTOCYTES These elongated red cells may be seen most commonly in heredity elliptocytosis or with severe iron deficiency. ■ ■HOWELL-JOLLY BODIES These are small remnants of the red cell nucleus. Usually these are rap­ idly cleared by the spleen, but if the spleen is missing or not function­ ing, these red cell inclusions may be seen. ■ ■HYPOCHROMIA/MICROCYTOSIS These are cells that have larger areas of central pallor than normal. This is a sign of inadequate hemoglobinization of the red cell. This can be seen in iron deficiency, thalassemia, or in the rare sideroblastic anemia. TABLE 66-2  Changes in Normal Hemoglobin/Hematocrit Values with Age, Sex, and Pregnancy AGE/SEX HEMOGLOBIN, g/dL HEMATOCRIT, % At birth

Childhood

Adolescence

Adult man 16 (±2) 47 (±6) Adult woman (menstruating) 13 (±2) 40 (±6) Adult woman (postmenopausal) 14 (±2) 42 (±6) During pregnancy 12 (±2) 37 (±6) Source: From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.

Anemia and Polycythemia CHAPTER 66 FIGURE 66-3  Normal blood smear (Wright stain). High-power field showing normal red cells, a neutrophil, and a few platelets. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) FIGURE 66-4  Severe iron-deficiency anemia. Microcytic and hypochromic red cells smaller than the nucleus of a lymphocyte associated with marked variation in size (anisocytosis) and shape (poikilocytosis). (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) FIGURE 66-5  Macrocytosis. Red cells are larger than a small lymphocyte and well hemoglobinized. Often macrocytes are oval shaped (macro-ovalocytes). (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 66-6  Howell-Jolly bodies. In the absence of a functional spleen, nuclear remnants are not culled from the red cells and remain as small homogeneously staining blue inclusions on Wright stain. (From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.) FIGURE 66-7  Red cell changes in myelofibrosis. The left panel shows a teardropshaped cell. The right panel shows a nucleated red cell. These forms can be seen in myelofibrosis. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) FIGURE 66-8  Target cells. Target cells have a bull’s-eye appearance and are seen in thalassemia and in liver disease. (From M Lichtman et al (eds): Williams Hematology, 7th ed. New York, McGraw-Hill, 2005; RS Hillman, KA Ault: Hematology in General Practice, 4th ed. New York, McGraw-Hill, 2005.)

FIGURE 66-9  Red cell fragmentation. Red cells may become fragmented in the presence of foreign bodies in the circulation, such as mechanical heart valves, or in the setting of thermal injury. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) FIGURE 66-10  Uremia. The red cells in uremia may acquire numerous regularly spaced, small, spiny projections. Such cells, called burr cells or echinocytes, are readily distinguishable from irregularly spiculated acanthocytes shown in Fig. 66-11. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGrawHill, 2010.) FIGURE 66-11  Spur cells. Spur cells are recognized as distorted red cells containing several irregularly distributed thorn-like projections. Cells with this morphologic abnormality are also called acanthocytes. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)

FIGURE 66-12  Reticulocytes. Methylene blue stain demonstrates residual RNA in newly made red cells. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) ■ ■MACRO-OVALOCYTES These are red cells that are larger in size and slightly oval-shaped. This is caused by disruption of DNA synthesis in the developing red cell from B12/folate deficiency, certain drugs, or bone marrow disorders. ■ ■NUCLEATED RED BLOOD CELLS The nucleus of the red cell is cleared by the marrow before being released; any remaining are cleared by the spleen. The presence of nucleated red cells can be seen with asplenia, severe marrow stress such as massive bleeding or hemolysis, and many bone marrow disorders, especially those that disrupt the marrow architecture such as marrow fibrosis. ■ ■SCHISTOCYTES These are fragments of red cells that have been physically disrupted by blockage in the blood vessels by platelets or fibrin strands or by external forces. They can be seen in a wide variety of processes such as thrombotic thrombocytopenic purpura or march hemoglobinuria. ■ ■SICKLE CELLS As the name implies, the blood cells are sickle-shaped. This can be seen in hemoglobin defects, most commonly in sickle cell anemia. TABLE 66-3  Red Cell Morphology   PATHOPHYSIOLOGY DISEASE STATES Macro-ovalocytes Hemoglobin excess (nuclear-cytoplasmic dyssynchrony) B12 and/or folate deficiencies Myelodysplasia Spherocytes Loss of membrane Hereditary spherocytosis Immune hemolytic anemia Hypochromia Hemoglobin deficiency (corresponds to low mean corpuscular hemoglobin concentration) Iron deficiency Thalassemia Sideroblastic anemia Anemia of chronic disease Schistocyte Red blood cell fragmentation Microangiopathic hemolysis Heart-valve hemolysis Sickle cell Hemoglobin polymerization Sickle cell disease Target cell Relative membrane excess Liver disease Thalassemia Hemoglobinopathy Polychromatophilia Persistence of polyribosomes (corresponds to high reticulocyte count) Hemolytic anemia Basophilic stippling Pathologic precipitation of polyribosomes Thalassemia Lead poisoning

■ ■SPHEROCYTES These are cells that on the blood smear lack central pallor as they are spherical and not biconcave disks. This can be caused by any process that leads to the loss of red cell membrane. This membrane loss turns the biconcave disk into a sphere as this is the shape with the least amount of surface area for a given volume. Spherocytes are most commonly seen in autoimmune hemolytic anemia and hereditary spherocytosis.

■ ■SPUR CELLS As opposed to burr cells, spur cells have fewer longer projections from the red cell and are most commonly seen in severe liver disease. They result from cholesterol crystal formation in the red cell membrane due to the abnormal lipid metabolism in liver disease. These crystals get caught in narrow passages of the spleen, resulting in these projections. They can also be seen in asplenic patients and those with McLeod blood group. Anemia and Polycythemia CHAPTER 66 ■ ■TARGET CELLS These can be seen where there is a redundant red cell membrane. In thalassemia, there is less hemoglobin filling the red cell, and in liver disease, there is excess red cell membrane. ■ ■TEARDROP CELLS These are cells that look like a teardrop and are most often seen with disruption of marrow architecture or severe iron deficiency. ■ ■THE RETICULOCYTE COUNT Red cells still contain mRNA for about 24 h after being released by the marrow. This mRNA can be detected by staining, and these cells are called “reticulocytes.” The number of reticulocytes present is a measure of red cell production and is helpful in separating increased destruction from anemias due to impaired red cell production. The oldest method of determining reticulocyte counts is to stain the blood smear with new methylene blue and determine the percentage of red cells that take up the stain; this is the reticulocyte count. However, this needs to be adjusted for the hematocrit as the reticulocyte percent­ age will appear to increase with decreasing blood counts when the abso­ lute count has not actually increased. For example, a reticulocyte count of 1% will increase to 2% with a hematocrit of 23% (Fig. 66-13). There­ fore, the reticulocyte count needs to be corrected for the hematocrit: Corrected reticulocyte count = Measured reticulocyte count × (Patient hematocrit/45%) (Normal hematocrit) Many newer complete blood count machines can directly quantitate the reticulocytes present in a given volume of blood, and this is the absolute reticulocyte count. Since this is per volume, no adjustment for anemia is required. Absolute reticulocyte number = Reticulocyte count/100 × Red blood cell number ■ ■BONE MARROW EXAM The bone marrow may be easily sampled in a bedside procedure and can be helpful in the diagnosis of anemia or other hematologic pro­ cesses. With bone marrow aspiration, the marrow is removed from the posterior iliac spine and stained with Wright’s or Wright-Giemsa stains (photomicrographs of normal marrow [Fig. 66-14], marrow showing 2% reticulocytes 10% reticulocytes 1% reticulocytes FIGURE 66-13  Interpretation of reticulocyte counts. If the absolute reticulocyte count is not provided, the percent reticulocytes must be adjusted based on the hematocrit.

PART 2 Cardinal Manifestations and Presentation of Diseases FIGURE 66-14  Normal bone marrow. This is a low-power view of a section of a normal bone marrow biopsy stained with hematoxylin and eosin (H&E). Note that the nucleated cellular elements account for ∼40–50% and the fat (clear areas) accounts for ∼50–60% of the area. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) erythroid hyperplasia [Fig. 66-15], and marrow showing myeloid hyperplasia [Fig. 66-16] are shown). The biopsy disturbs the marrow architecture but allows for examination of individual cell morphology, determination of a differential cell count, and determination of the myeloid-to-erythroid ratio. This ratio is normally 2.5:1 (range 2:1–5:1). Bone marrow iron stores can be examined by use of an appropriate stain. Samples can also be drawn for specialized testing such as flow cytometry, genetic testing, and/or microbiological testing. For a marrow biopsy, a “core” sample of marrow is removed intact from the iliac spine and then decalcified, sectioned, and stained with hematoxylin and eosin. This technique reveals the undisturbed mar­ row architecture and is useful for the determination of cellularity and the presence of abnormal marrow infiltrates or fibrosis. The normal bone marrow is ~50% cellular (i.e., half hematopoietic cells and half fat cells). In general, the marrow fat percentage is roughly equivalent to the patient’s age. A bone marrow examination is a necessary diagnostic study in situ­ ations where the blood and clinical findings suggest the possibility of marrow infiltration by abnormal or nonhematopoietic elements or the likelihood of generalized marrow dysfunction (e.g., aplastic anemia or myelodysplasia). In most situations, it is necessary to perform both an aspiration and a biopsy. The biopsy should precede the aspiration. If the aspiration is done first, the subsequent biopsy tends to be distorted by the bleeding induced by the aspiration. FIGURE 66-15  Erythroid hyperplasia. This marrow shows an increase in the fraction of cells in the erythroid lineage as might be seen when a normal marrow compensates for acute blood loss or hemolysis. The myeloid/erythroid (M/E) ratio is about 1:1. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.)

FIGURE 66-16  Myeloid hyperplasia. This marrow shows an increase in the fraction of cells in the myeloid or granulocytic lineage as might be seen in a normal marrow responding to infection. The myeloid/erythroid (M/E) ratio is >3:1. (From RS Hillman et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010.) General indications for bone marrow examination are:

1. Circulating immature cells (e.g., blasts)
2. Severe pancytopenia
3. Very low reticulocyte counts (<0.1%)
4. Circulating nucleated red blood cells
5. Evidence of marrow infiltration (teardrop red cells, nucleated red blood cells)
6. Staging of certain malignancies (e.g., lymphoma)
7. Unexplained severe anemia ■ ■ANEMIA DEFINITION AND CLASSIFICATION Anemia is simply defined as blood counts below normal for a given population. There are two general ways of classifying anemia (Table 66-4). A time-honored and still practical way is by the size of the red cell, as this can help guide diagnostic workup. Another method is by mechanism of anemia. Anemia classification by red cell size was pioneered by the hema­ tologist Max Wintrobe. In this classification, anemia is grouped by MCV, with those with smaller MCV called microcytic; normal MCV, normocytic; and larger MCV, macrocytic. Microcytic anemia is due to any process that interferes with hemo­ globin production; less hemoglobin leads to smaller red cells. This would include: • Thalassemia: defects of hemoglobin protein synthesis • Iron deficiency: unable to make heme • Anemia of chronic disease: lack of iron delivery to red cell (note: the anemia of chronic disease is often associated with normal red cell volume; the mechanism remains the inhibition of iron reutilization based on cytokine inhibition) • Sideroblastic anemias: defects of heme synthesis Macrocytic anemia may be due to defects in DNA synthesis and has two subdivisions: round macrocytes and oval macrocytes. Oval macrocytes are due to defects in DNA synthesis, while round macro­ cytes are caused by membrane defects. Unlike the limited differential of microcytosis, many processes can lead to macrocytosis. The classic macrocytic anemias are due to B12 and folate deficiency, but these account for a minority of macrocytic anemias. Normocytic anemia includes all other causes of anemia; the broad differential for this classification of anemia is a drawback of this ane­ mia classification scheme. An alternative method of classifying anemias is by mechanism. The absolute reticulocyte count is an important first indicator of mechanism. If reticulocytes are elevated, the mechanism of anemia is increased loss or destruction of red cells. If reticulocytes are low or

TABLE 66-4  Classification of Anemia By Size of Red Cell Microcytic Anemia of inflammation Iron deficiency Sideroblastic Thalassemia Macrocytic Oval Macrocytes Vitamin B12 deficiency Folate deficiency Medications (chemotherapy, some antiseizure medications) Myelodysplasia Round Macrocytes Alcohol use Dysproteinemia Hypothyroidism Hypoxia Liver disease Reticulocytosis Smoking Normocytic Aplastic anemia Endocrinopathies Marrow invasion Myeloma Pure red cell aplasia Renal disease By Mechanism Hyperproduction Bleeding Hemolysis Acquired Autoimmune Mechanical Congenital Hemibrain defect Hemoglobinopathies Enzyme defects Underproduction Nutritional Deficiency Vitamin B12 Copper Folate Iron Vitamin C Absence of Red Cell Precursors Aplastic anemia Pure red cell aplasia Lack of Erythropoietin Anemia of inflammation Renal disease Anemia of aging Marrow Replacement Granulomatous disease Infection Neoplasm Stem Cell Defects Acute leukemia Chronic leukemia Myelodysplasia

inappropriately low for the level of anemia, the mechanism is impaired production of red cells. Impaired production includes:

• Nutritional: deficiencies such as iron or B12 • Marrow replacement by infection, cancer, granulomas • Absence of red cell precursors: aplastic anemia, pure red cell aplasia • Stem cell defects: myelodysplasia • Lack of EPO: renal disease, anemia of inflammation, anemia of aging ■ ■HYPERPRODUCTION: HEMOLYSIS/BLEEDING In general, the finding of an elevated reticulocyte count should raise the suspicion of hemolysis. Hemolysis is where red cell breakdown is accelerated. This can be due to extrinsic causes such as autoimmune hemolytic anemia or processes intrinsic to the red cell such as enzyme defects. Laboratories will show evidence of red cell breakdown includ­ ing high lactate dehydrogenase (LDH; an enzyme found in abundance in red cells), low haptoglobin (a serum protein that salvages free hemoglobin), and increased blood/urine free hemoglobin. Often the blood smear will show evidence of hemolysis with abnormal cells such as schistocytes or spherocytes. Testing is then focused on finding the particular cause of hemolysis. For example, autoimmune hemolytic anemia will present with spherocytes, high LDH, and low haptoglobin; testing will show the presence of autoantibodies on red cells. Anemia and Polycythemia CHAPTER 66 ■ ■UNDERPRODUCTION At least 75% of all cases of anemia are hypoproliferative in nature. The most common cause is mild to moderate iron deficiency or inflammation. ■ ■NUTRITIONAL Production of red cells is dependent on a consistent supply of nutrients. The most vital nutrient is iron; four atoms are required for every hemo­ globin molecule, with about 1 billion iron atoms in every red cell. Iron deficiency is the most common nutritional deficiency worldwide and is very common in premenopausal women due to obligate menstrual losses. The laboratory measurements that reflect the availability of iron for hemoglobin synthesis include the serum iron, the total ironbinding capacity (TIBC), and the percent transferrin saturation. The percent transferrin saturation is derived by dividing the serum iron level (× 100) by the TIBC. The normal serum iron ranges from 9 to

27 μmol/L (50–150 μg/dL), whereas the normal TIBC is 54–64 μmol/L (300–360 μg/dL); the normal transferrin saturation ranges from 25 to 50%. A diurnal variation in the serum iron leads to a variation in the percent transferrin saturation. The serum ferritin is used to evaluate total-body iron stores. Adult males have serum ferritin levels that aver­ age ∼100 μg/L, corresponding to iron stores of ∼1 g. Adult premeno­ pausal females have lower serum ferritin levels averaging 30 μg/L, reflecting lower iron stores (∼300 mg). A serum ferritin less than 30 μg/L indicates depletion of body iron stores. However, ferritin is also an acute-phase reactant and, in the presence of acute or chronic inflammation, may rise several-fold above baseline levels. As a rule, a serum ferritin >200 μg/L means there is at least some iron in tissue stores. The classic finding of iron deficiency in the blood is a microcytic anemia, but this can be absent in early iron deficiency or when other confounding issues are present like liver disease. Laboratory findings show a low serum ferritin and may show a low iron saturation. Vitamin B12 is another crucial nutrient. The red cell requires vitamin B12 in order to synthesize DNA, so deficiency results in impaired DNA synthesis. This leads to the classic hematologic finding of B12 deficiency—macrocytosis. In addition, the neutrophils will show hypersegmentation and the marrow will be remarkably hypercellular with large abnormal red cell precursors. Folate is also required for red cell DNA synthesis; deficiencies pres­ ent similar to B12 deficiency, and these two are grouped together as “megaloblastic anemia.” In countries that supplement flour with folate, deficiencies are rare but may still be seen in those with a very poor diet or severe malabsorption. Other nutrient deficiencies lead to anemia, but these tend to be more unusual. Copper deficiency is often associated with neurologic

disease and neutropenia. Vitamin C deficiency can be associated with severe anemia as well as the classic clinical findings of scurvy.

■ ■MARROW REPLACEMENT Several processes, most notably infections and neoplasms, can invade the marrow and crowd out hematopoietic elements. Many infections can occupy the marrow including infections such as histoplasmosis or tuberculosis. Metastasis to the marrow from any tumor can also lead to anemia. For example, patients with prostate cancer may have their marrow replaced by tumor, leading to severe anemia. More commonly in older patients, multiple myeloma can present with anemia. In many cases of marrow replacement, the blood smear can show a myelophthisic picture with the presence of nucleated red cells, tear­ drop cells, and immature white cells. These findings mandate marrow examination. PART 2 Cardinal Manifestations and Presentation of Diseases ■ ■LACK OF ERYTHROPOIETIN As noted earlier, EPO is essential for red cell production. Since the kidney is the primary source of this hormone, renal disease is often associated with anemia. While anemia is almost always present with a glomerular filtration rate of <30 mL/min/1.73 m2, some patients will be anemic with higher levels of renal function. Certain medications, most notably angiotensin-converting enzyme inhibitors, can also suppress EPO production. Inflammatory cytokines such as tumor necrosis factor can decrease production of EPO. One of the hallmarks of the anemia of inflamma­ tion is a low EPO level for any given degree of anemia. In addition, inflammation will increase levels of hepcidin, which then blocks iron absorption and its release from stores. Anemia is common in people over age 65 years; 11% of community-

dwelling and up to 40% of nursing home residents over age 65 are ane­ mic. Anemia is associated with increased risk of death, hospitalization, and frailty. EPO levels tend to be lower than expected for the degree of anemia, and administration of EPO can increase the hemoglobin level, but it is unclear whether the adverse consequences of anemia are reduced by treatment. ■ ■ABSENCE OF RED CELL PRECURSORS Aplastic anemia is a disease where the marrow is very hypocellular. This can be caused by autoimmune processes, reactions to certain medications, or as a result of toxins/radiation. The bone marrow shows markedly reduced levels of all precursors, and other blood elements such as platelets and neutrophils will be reduced. Pure red cell aplasia is defined as only the red cell precursors in the marrow being reduced. Autoimmune processes that target only the red cell can lead to this, as well as infections with parvovirus B19. The patient will present with a very low reticulocyte count, and the bone marrow will show absent or markedly reduced erythroid cells. ■ ■STEM CELL DEFECTS Finally, processes intrinsic to the marrow can lead to anemia. Primary neoplasms of the marrow such as acute myelogenous leukemia or chronic myelogenous leukemia will often have a component of severe anemia. Patients most often will have elevated white cell counts with immature cells present; rare patients will present only with anemia. Myelodysplastic syndromes are caused by stem cell defects that lead to impaired marrow function. Patients can present with only a mac­ rocytic anemia but can also present with pancytopenia. The natural history can vary; some patients’ courses are measured in years while others rapidly evolve into acute leukemia. Diagnosis of leukemia and myelodysplasia is most often made by bone marrow testing. Currently, the pathologic examination is augmented by molecular testing for mutations that are diagnostic of leukemia or myelodysplasia. ■ ■EVALUATION OF ANEMIA The results of the complete blood count and reticulocyte count together can guide further testing (Fig. 66-17). If the reticulocyte count is high and bleeding has been ruled out, then specific testing for hemolysis can be performed, including LDH, haptoglobin, and direct

antibody testing. If there are clues present on the blood smear such as sickle cells, then focused testing can be done. If the reticulocyte count is not elevated, workup is guided by the MCV. If the MCV is low, a ferritin should be performed, and if normal, then the patient should be assessed for thalassemia. Another clue to distinguishing iron deficiency from thalassemia is the RDW. Iron defi­ ciency is characterized by a high RDW because of anisocytosis. The red cells in thalassemia are more homogeneous in volume and have a low RDW. Anemia of inflammation is a diagnosis of exclusion and usually occurs in the presence of an inflammatory disorder such as cancer or infection. The workup of macrocytosis is guided by the blood smear. If signs of megaloblastic anemia are seen (hypersegmented neutrophils and macro-ovalocytes), then B12 and folate levels should be assessed. Some experts distinguish large round red cells from large oval red cells on smear. If macro-ovalocytes are seen and nutritional tests are normal, this raises the concern for myelodysplasia, and bone marrow testing is the next step. With round macrocytosis, often the history can provide clues, such as presence of liver disease or alcoholism, for example. Workup of normocytic anemia involves assessment of renal func­ tion, EPO levels, and other disease processes that can lead to anemia and consideration of marrow exam if no other cause is apparent. Additional laboratory tests may be of value in confirming specific diagnoses. For details of these tests and how they are applied in spe­ cific disorders, see Chaps. 102 to 106. TREATMENT Anemia While definitive treatment of anemia requires knowing the cause, some patients may need treatment with transfusions to support them during the diagnostic workup. Clear indications for blood transfusion are hypotension or signs of cardiac compromise such as angina. For some patients such as those with bone marrow failure, transfusion may be needed to support them while definitive therapy is being performed. Often, the cause of the anemia is multifactorial. For example, a patient with severe rheumatoid arthritis who has been taking anti-inflammatory drugs may have a hypoproliferative anemia associated with chronic inflammation as well as chronic blood loss associated with intermittent gastrointestinal bleeding. In every circumstance, it is important to evaluate the patient’s iron status fully before and during the treatment of any anemia. Transfusion is discussed in Chap. 118; iron therapy is discussed in Chap. 102; treatment of megaloblastic anemia is discussed in Chap. 104; treatment of other entities is discussed in their respective chap­ ters (sickle cell anemia, Chap. 103; hemolytic anemias, Chap. 105; aplastic anemia and myelodysplasia, Chap. 107). Therapeutic options for the treatment of anemias have expanded dramatically during the past 30 years. Blood component therapy is available and safe. Recombinant EPO as an adjunct to anemia man­ agement has transformed the lives of patients with chronic renal failure on dialysis and reduced transfusion needs of anemic can­ cer patients receiving chemotherapy. Transforming growth factor β inhibitors (anemia associated with myelodysplastic syndrome), complement inhibitors (associated with paroxysmal nocturnal hemoglobinuria), and other therapies are making a difference in the quality of life in selected types of anemia. Eventually, patients with inherited disorders of globin synthesis or mutations in the globin gene, such as sickle cell disease, may benefit from the successful introduction of targeted genetic therapy (Chap. 483). POLYCYTHEMIA Polycythemia is defined as an increase in the hemoglobin above nor­ mal. This increase may be real or only apparent because of a decrease in plasma volume (spurious or relative polycythemia). The term erythro­ cytosis may be used interchangeably with polycythemia, but some draw a distinction between them: erythrocytosis implies documentation of

Low absolute reticulocyte count High absolute reticulocyte count Red cell morphology MCV Normal hypoproliferative Elevated nuclear defects Low cytoplasmic defects Ferritin Normal or elevated Low Anemia of inflammation* Sideroblastic anemia Thalassemia Iron deficiency Look for marrow damage • Infiltration/fibrosis • Aplasia OR stimulation ↓ • Inflammation: ↑ hepcidin, ↓ iron reutilization • Metabolic defect • Renal disease • Aging (↓ EPO) EPO level • BUN/creatinine • SPEP/light chains • Bone marrow exam *MCV may be normal B12/folate deficiency Myelodysplasia Medication effect FIGURE 66-17  The physiologic classification of anemia. BUN, blood urea nitrogen; CBC, complete blood count; EPO, erythropoietin level; MCV, mean corpuscular volume; SPEP, serum protein electrophoresis. increased red cell mass, whereas polycythemia refers to any increase in red cells. Often patients with polycythemia are detected through an incidental finding of elevated hemoglobin or hematocrit levels. Concern that the hemoglobin level may be abnormally high is usu­ ally triggered at 17 g/dL (170 g/L) for men and 15 g/dL (150 g/L) for women. Hematocrit levels of >50% in men or >45% in women may be abnormal. Hematocrit levels of >60% in men and >55% in women are almost invariably associated with an increased red cell mass. Given that the machine that quantitates red cell parameters actually measures hemoglobin concentrations and calculates hematocrits, hemoglobin levels may be a better index. Features of the clinical history that are useful in the differential diagnosis include smoking, currently living at high altitude, a history of diuretic use, congenital heart disease, sleep apnea, or chronic lung dis­ ease. It is also useful to inquire about the use of testosterone, EPO, and SGLT2 (sodium-glucose transport protein 2) inhibitors (gliflozins). Patients with polycythemia may be asymptomatic or experience symptoms related to the increased red cell mass or the underlying disease process that leads to the increased red cell mass. The dominant symptoms from an increased red cell mass are related to hyperviscosity and thrombosis (both venous and arterial), because the blood viscosity increases logarithmically at hematocrit levels of >55%. Manifestations include neurologic symptoms such as vertigo, tinnitus, headache,

Anemia CBC, reticulocyte count Anemia and Polycythemia CHAPTER 66 Hemolysis/ hemorrhage Blood loss Intravascular hemolysis Metabolic defect Membrane abnormality Smear Hemoglobinopathy Round macrocytes Oval macrocytes Immune destruction Alcohol excess Liver disease Hypersegmentation? Fragmentation hemolysis Yes No and visual disturbances. Hypertension is often present. Patients with polycythemia vera may have aquagenic pruritus, symptoms related to hepatosplenomegaly, easy bruising, epistaxis, or bleeding from the gas­ trointestinal tract. Peptic ulcer disease is common. Such patients also may present with digital ischemia, Budd-Chiari syndrome, or hepatic or splenic/mesenteric vein thrombosis. Patients with hypoxemia may develop cyanosis on minimal exertion or have headache, impaired mental acuity, and fatigue. The physical examination usually reveals a ruddy complexion. Splenomegaly favors polycythemia vera as the diagnosis (Chap. 108). The presence of cyanosis or evidence of a right-to-left shunt suggests congenital heart disease presenting in the adult, particularly tetralogy of Fallot or Eisenmenger’s syndrome (Chap. 280). Increased blood viscosity raises pulmonary artery pressure; hypoxemia can lead to increased pulmonary vascular resistance. Together, these factors can produce cor pulmonale. Polycythemia can be spurious (related to a decrease in plasma volume; Gaisbock’s syndrome), primary, or secondary in origin. The secondary causes are nearly all mediated by EPO: either a physiologi­ cally adapted appropriate level based on tissue hypoxia (lung disease, high altitude, carbon monoxide [CO] poisoning, high-affinity hemo­ globinopathy) or an abnormal overproduction (renal cysts, renal artery stenosis, tumors with ectopic EPO production). A rare familial form of

Elevated red cell count, hemoglobin, or hematocrit Obtain prior blood counts If elevated, exclude hypoxia (O2 saturation <93% at rest or exercise) If no prior elevation and asymptomatic, repeat the studies in 1 month If persistent or symptomatic or if elevation is substantial and O2 saturation is normal PART 2 Cardinal Manifestations and Presentation of Diseases Obtain a serum erythropoietin level Normal or low Elevated JAK2, LNK mutation assays (VAF) Renal disease Tumors Chuvash polycythemia (VHL) EGLN1 (PHD2) (HIF-1 alpha) EPAS1 (HIF-2 alpha) High O2 affinity hemoglobin Positive (VAF ≥ 5%) Negative or VAF ≤ 5% Polycythemia vera Polycythemia vera Renal disease Tumors Erythropoietin receptor mutation High O2 affinity hemoglobin FIGURE 66-18  An approach to the differential diagnosis of patients with an elevated hemoglobin (possible polycythemia). VAF, variant allele frequency; VHL, von HippelLindau syndrome. (Reproduced with permission from Jerry L. Spivak.) polycythemia is associated with normal EPO levels but hyperrespon­ sive EPO receptors due to mutations. Rare hemochromatosis (HFE mutations) may have elevated hemoglobin levels. APPROACH TO THE PATIENT Polycythemia As shown in Fig. 66-18, the first step is to search for earlier blood counts that might suggest the chronicity of the increase. Ideally one would document the presence of an increased red cell mass; however, the dependence of this technique on radiolabeled red cells has led to its abandonment. If the red cell mass is normal (<36 mL/kg in men, <32 mL/kg in women), the patient has spurious or relative polycythemia. If the red cell mass is increased (>36 mL/kg

in men, >32 mL/kg in women), serum EPO levels should be measured. It must be acknowledged that measurement of red cell mass is a physiologic approach to distinguishing polycythemia, and because of the use of radionuclide-labeled red cells, it is rarely performed. It is more common to measure EPO levels in a person with an elevated hemoglobin level or hematocrit once it has been documented that the patient is not hypoxic (i.e., O2 saturation is

93%). If EPO levels are low or unmeasurable, the patient most likely has polycythemia vera. A mutation in JAK2 (Val617Phe), a key member of the cytokine intracellular signaling pathway, can be found in 90–95% of patients with polycythemia vera. Many of those without this particular JAK2 mutation have mutations in exon

12. If EPO levels are low, check for JAK2 mutation(s), and perform an abdominal ultrasound to assess spleen size. Tests that support the diagnosis of polycythemia vera include elevated white blood cell count, increased absolute basophil count, and thrombocytosis. In practice, many physicians order EPO levels and assessment for JAK2 mutations at the same time.

If serum EPO levels are elevated, one needs to distinguish whether the elevation is a physiologic response to hypoxia or related to autonomous EPO production. Patients with low arte­ rial O2 saturation (<92%) should be further evaluated for the presence of heart or lung disease, if they are not living at high altitude. Patients with normal O2 saturation who are smokers may have elevated EPO levels because of CO displacement of O2. If carboxyhemoglobin (COHb) levels are high, the diagnosis is “smoker’s polycythemia.” Such patients should be urged to stop smoking. Those who cannot stop smoking require phlebotomy to control their polycythemia. Patients with normal O2 saturation who do not smoke either have an abnormal hemoglobin that does not deliver O2 to the tissues (evaluated by finding elevated O2–hemo­ globin affinity) or have a source of EPO production that is not responding to the normal feedback inhibition. Further workup is dictated by the differential diagnosis of EPO-producing neo­ plasms. Hepatoma, uterine leiomyoma, and renal cancer or cysts are all detectable with abdominopelvic computed tomography scans. Cerebellar hemangiomas may produce EPO, but they pres­ ent with localizing neurologic signs and symptoms rather than polycythemia-related symptoms. ■ ■FURTHER READING Camaschella C: Iron deficiency. Blood 133:30, 2019. Hillman RS et al: Hematology in Clinical Practice, 5th ed. New York, McGraw-Hill, 2010. McMullin MF et al: Guidelines for the diagnosis, investigation and management of polycythaemia/erythrocytosis. Br J Haematol 130:174, 2005. Sankaran VG, Weiss MJ: Anemia: Progress in molecular mechanisms and therapies. Nat Med 21:221, 2015. Spivak JL: How I manage polycythemia vera. Blood 134:341, 2019.

63 - 67 Disorders of Granulocytes and Monocytes

67 Disorders of Granulocytes and Monocytes

Steven M. Holland, John I. Gallin*

Disorders of Granulocytes

and Monocytes Leukocytes, the major cells comprising inflammatory and immune responses, include neutrophils, T and B lymphocytes, natural killer (NK) cells, mononuclear phagocytes (blood monocytes and tissue macrophages), eosinophils, and basophils. These cells have specific functions, such as antibody production by B lymphocytes or destruc­ tion of bacteria by neutrophils, but in no single infectious disease is the exact role of the cell types completely established. Thus, whereas neutrophils are classically thought to be critical to host defense against bacteria, they may also play important roles in defense against viral infections. The blood delivers leukocytes to the various tissues from the bone marrow, where they are produced. Normal blood leukocyte counts are 4.3–10.8 × 109/L, with neutrophils representing 45–74% of the cells, bands 0–4%, lymphocytes 16–45%, monocytes 4–10%, eosinophils 0–7%, and basophils 0–2%. Variation among individuals and among different ethnic groups can be substantial, with lower leukocyte num­ bers for certain African-American ethnic groups. Lower granulocyte numbers in African Americans are often in the 1500–2000/μL range and are generally without sequelae, a condition termed benign ethnic neutropenia. The lower number of granulocytes is associated with null expression of the Duffy antigen receptor for cytokines (DARC) gene, a receptor for Plasmodium vivax, the absence of which conveys resis­ tance to this form of malaria. The various leukocytes are derived from a common stem cell in the bone marrow. Three-fourths of the nucleated cells of bone marrow are committed to the production of leukocytes. Leukocyte maturation in the marrow is under the regulatory control of a number of different factors, known as colony-stimulating factors (CSFs) and interleukins (ILs). Because an alteration in the number and type of leukocytes is often associated with disease processes, total white blood cell (WBC) count (cells per μL) and differential counts are informative. This chapter focuses on neutrophils, monocytes, and eosinophils. Lymphocytes and basophils are discussed in Chaps. 360 and 364, respectively. NEUTROPHILS ■ ■MATURATION Important events in neutrophil life are summarized in Fig. 67-1. In normal humans, neutrophils are produced only in the bone marrow. The minimum number of stem cells necessary to support hematopoi­ esis is estimated to be 400–500 at any one time. Human blood mono­ cytes, tissue macrophages, and stromal cells produce CSFs, hormones required for the growth of monocytes and neutrophils in the bone mar­ row. The hematopoietic system not only produces enough neutrophils (∼1.3 × 1011 cells per 80-kg person per day) to carry out physiologic functions but also has a large reserve stored in the marrow, which can be mobilized in response to inflammation or infection. An increase in the number of blood neutrophils is called neutrophilia, and the pres­ ence of immature cells is termed a shift to the left. A decrease in the number of blood neutrophils is called neutropenia. Neutrophils and monocytes evolve from pluripotent stem cells under the influence of cytokines and CSFs (Fig. 67-2). The prolifera­ tion phase through the metamyelocyte takes about 1 week, while the maturation phase from metamyelocyte to mature neutrophil takes another week. The myeloblast is the first recognizable precursor cell and is followed by the promyelocyte. The promyelocyte evolves when the classic lysosomal granules, called the primary, or azurophil, granules are produced. The primary granules contain hydrolases, elastase, *Deceased

myeloperoxidase, cathepsin G, cationic proteins, and bactericidal/

permeability-increasing protein, which is important for killing gram-

negative bacteria. Azurophil granules also contain defensins, a family of cysteine-rich polypeptides with broad antimicrobial activity against bacteria, fungi, and certain enveloped viruses. The promyelocyte divides to produce the myelocyte, a cell responsible for the synthesis of the specific, or secondary, granules, which contain unique (specific) constituents such as lactoferrin, vitamin B12–binding protein, mem­ brane components of the reduced nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase (NOX2) required for hydrogen peroxide production, histaminase, and receptors for certain chemoattractants and adherence-promoting factors (e.g., CR3) as well as receptors for the basement membrane component, laminin. The secondary granules do not contain acid hydrolases and therefore are not classic lysosomes. Packaging of secondary granule contents during myelopoiesis is con­ trolled by CCAAT/enhancer binding protein-ε (encoded by CEBPE). Secondary granule contents are readily released extracellularly, and their mobilization is important in modulating inflammation. During the final stages of maturation, no cell division occurs, and the cell passes through the metamyelocyte stage and then to the band neutrophil with a sausage-shaped nucleus (Fig. 67-3). As the band cell matures, the nucleus assumes a lobulated configuration. The nucleus of neutrophils normally contains up to four segments (Fig. 67-4). Excessive segmen­ tation (>5 nuclear lobes) may be a manifestation of folate or vitamin B12 deficiency or the congenital neutropenia syndrome of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) described below. The Pelger-Hüet anomaly (Fig. 67-5), an infrequent dominant benign inherited trait caused by heterozygous mutations in the lamin B receptor, results in neutrophils with distinctive bilobed nuclei that must be distinguished from band forms. Acquired bilobed nuclei, pseudo-Pelger-Hüet anomaly, can occur with acute infections or in myelodysplastic syndromes. The physiologic role of the normal multilobed nucleus of neutrophils is unknown, but it may allow great deformation of neutrophils during migration into tissues at sites of inflammation and facilitate production of neutrophil nets.

Disorders of Granulocytes and Monocytes CHAPTER 67 In severe acute bacterial infection, prominent neutrophil cytoplas­ mic granules, called toxic granulations, are occasionally seen. Toxic granulations are immature or abnormally staining azurophil granules. Cytoplasmic inclusions, also called Döhle bodies (Fig. 67-3), can be seen during infection and are fragments of ribosome-rich endoplasmic reticulum. Large neutrophil vacuoles are often present in acute bacte­ rial infection in some viral infections such as COVID-19 and probably represent pinocytosed (internalized) membrane (Fig. 67-6). Neutrophils are heterogeneous in function. Monoclonal antibodies have been developed that recognize only a subset of mature neutro­ phils. The meaning of neutrophil heterogeneity is not known. The morphology of eosinophils is shown in Fig. 67-7. ■ ■MARROW RELEASE AND CIRCULATING COMPARTMENTS Specific signals, including IL-1, tumor necrosis factor α (TNF-α), the CSFs, complement fragments, and chemokines, mobilize leukocytes from the bone marrow and deliver them to the blood in an unstimu­ lated state. Under normal conditions, ∼90% of the neutrophil pool is in the bone marrow, 2–3% in the circulation, and the remainder in the tissues (Fig. 67-8). The circulating pool exists in two dynamic compartments: one freely flowing and one marginated. The freely flowing pool is about one-half the neutrophils in the basal state and is composed of those cells that are in the blood and not in contact with the endothelium. Marginated leukocytes are those that are in close physical contact with the endothelium (Fig. 67-9). In the pulmonary circulation, where an extensive capillary bed (∼1000 capillaries per alveolus) exists, margin­ ation occurs because the capillaries are about the same size as a mature neutrophil. Therefore, neutrophil fluidity and deformability are neces­ sary to make the transit through the pulmonary bed. Increased neutro­ phil rigidity and decreased deformability lead to augmented neutrophil trapping and margination in the lung. In contrast, in the systemic post­ capillary venules, margination is mediated by the interaction of specific

BONE MARROW CIRCULATION Stem cell C3a C5a Histamine Bradykinin Serotonin PART 2 Cardinal Manifestations and Presentation of Diseases PMN Diapedesis G-CSF Steroids Endotoxin Integrins Increased endothelial stickiness Vessel wall IL-1, TNF-α Endothelium FIGURE 67-1  Schematic events in neutrophil production, recruitment, and inflammation. The four cardinal signs of inflammation (rubor, tumor, calor, dolor) are indicated, as are the interactions of neutrophils with other cells and cytokines. G-CSF, granulocyte colony-stimulating factor; IL, interleukin; PMN, polymorphonuclear leukocyte; TNF-α, tumor necrosis factor α. Cell Stage Surface Markersa Characteristics MYELOBLAST CD33, CD13, CD15 Prominent nucleoli PROMYELOCYTE CD33, CD13, CD15 Large cell Primary granules appear MYELOCYTE CD33, CD13, CD15, CD14, CD11b Secondary granules appear METAMYELOCYTE CD33, CD13, CD15, CD14, CD11b Kidney bean– shaped nucleus Condensed, band– shaped nucleus BAND FORM CD33, CD13, CD15, CD14, CD11b, CD10, CD16 Condensed, multilobed nucleus CD33, CD13, CD15, CD14, CD11b, CD10, CD16 NEUTROPHIL aCD = Cluster Determinant; Nucleolus; Primary granule; Secondary granule. FIGURE 67-2  Stages of neutrophil development shown schematically. Granulocyte colonystimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) are critical to this process. Identifying cellular characteristics and specific cell-surface markers are listed for each maturational stage.

Microbial killing tissue damage Activation of other limbs of host defense Redness (Rubor) Edema (Tumor) Pain (Dolor) Warmth (Calor) O2 –, H2O2, .OH, HOCl (bleach) Vasodilation Fluid Leakage Ingestion Chemokines, other chemoattractants Bacteria or fungi Cytokine secretion Fever IL-8, TNF-α, IL-12 Recruitment Selectins Macrophages Lymphocytes cell-surface molecules called selectins. Selectins are glycoproteins expressed on neutrophils and endothelial cells, among others, that cause a low-affinity interaction, resulting in “rolling” of the neutrophil along the endo­ thelial surface. On neutrophils, the molecule L-selectin (cluster determinant [CD] 62L) binds to glycosylated proteins on endothelial cells (e.g., glycosylation-depen­ dent cell adhesion molecule [GlyCAM1] and CD34). Glycoproteins on neutrophils, most importantly sialylLewisx (SLex, CD15s), are targets for binding of selectins expressed on endothelial cells (E-selectin [CD62E] and P-selectin [CD62P]) and other leukocytes. In response to chemotactic stimuli from injured tissues (e.g., com­ plement product C5a, leukotriene B4, IL-8) or bacterial products (e.g., N-formylmethionylleucylphenylalanine [f-met-leu-phe of fMLF]), neutrophil adhesiveness increases through mobilization of intracellular adhesion proteins stored in specific granules to the cell surface, and the cells “stick” to the endothelium through integ­ rins. The integrins are leukocyte glycoproteins that exist as complexes of a common CD18 β chain with CD11a (LFA-1), CD11b (called Mac-1, CR3, or the C3bi recep­ tor), and CD11c (called p150,95 or CR4). CD11a/CD18 and CD11b/CD18 bind to specific endothelial receptors (intercellular adhesion molecules [ICAM] 1 and 2). On cell stimulation, L-selectin is shed from neutro­ phils, and E-selectin increases in the blood, presumably because it is shed from endothelial cells; receptors for chemoattractants and opsonins are mobilized; and the phagocytes orient toward the chemoattractant source in the extravascular space, increase their motile activ­ ity (chemokinesis), and migrate directionally (che­ motaxis) into tissues. The process of migration into tissues is called diapedesis and involves the crawling of neutrophils between postcapillary endothelial cells that open junctions between adjacent cells to permit leuko­ cyte passage. Diapedesis involves platelet/endothelial cell adhesion molecule (PECAM) 1 (CD31), which is expressed on both the emigrating leukocyte and the

FIGURE 67-3  Neutrophil band with Döhle body. The neutrophil with a sausageshaped nucleus in the center of the field is a band form. Döhle bodies (arrow) are discrete, blue-staining, nongranular areas found in the periphery of the cytoplasm of the neutrophil in infections and other toxic states. They represent aggregates of rough endoplasmic reticulum. FIGURE 67-5  Pelger-Hüet anomaly. In this disorder, granulocytes are bilobed. In the benign, genetic form (due to mutations in LBR), most granulocytes have this appearance. In the acquired form, which is associated with myelodysplastic syndrome, it may be more occasional. The nucleus frequently has a spectacle-like, or “pince-nez,” configuration. (Courtesy of Dr. Katherine Calvo, Hematopathology Laboratory, Department of Laboratory Medicine, Clinical Center, NIH.) endothelial cells. The endothelial responses (increased blood flow from increased vasodilation and permeability) are mediated by anaphyla­ toxins (e.g., C3a and C5a) as well as vasodilators such as histamine, bradykinin, serotonin, nitric oxide, vascular endothelial growth factor (VEGF), and prostaglandins E and I. Cytokines regulate some of these processes (e.g., TNF-α induction of VEGF, interferon [IFN] γ inhibi­ tion of prostaglandin E). In the healthy adult, most neutrophils leave the body by migration through the mucous membrane of the oral cavity and especially the gastrointestinal tract. Normally, neutrophils spend a short time in the circulation (half-life, 6–7 h). Senescent neutrophils are cleared from the circulation by macrophages in the lung and spleen. Once in the tissues, neutrophils release enzymes, such as collagenase and elastase, which may help establish abscess cavities. Neutrophils ingest pathogenic materials that have been opsonized by IgG and C3b. Fibro­ nectin and the tetrapeptide tuftsin also facilitate phagocytosis. FIGURE 67-4  Normal granulocyte. The normal granulocyte has a segmented nucleus with heavy, clumped chromatin; fine neutrophilic granules are dispersed throughout the cytoplasm.

Disorders of Granulocytes and Monocytes CHAPTER 67 With phagocytosis comes a burst of oxygen consumption and acti­ vation of the hexose-monophosphate shunt. A membrane-associated NADPH oxidase called NOX2, consisting of membrane and cytosolic components, is assembled and catalyzes the univalent reduction of oxygen to superoxide anion, which is then converted by superoxide dismutase to hydrogen peroxide and other toxic oxygen products (e.g., hydroxyl radical). Hydrogen peroxide + chloride + neutrophil myelo­ peroxidase generates hypochlorous acid (bleach), hypochlorite, and chlorine. These products oxidize and halogenate microorganisms and tumor cells and, when uncontrolled, can damage host tissue. Strongly cationic proteins, defensins, elastase, cathepsins, and probably nitric oxide also participate in microbial killing. Lactoferrin chelates iron, an important growth factor for microorganisms, especially fungi. Other enzymes, such as lysozyme and acid proteases, help digest microbial debris. After 1–4 days in tissues, neutrophils die. The apoptosis of neutrophils is also cytokine-regulated; granulocyte colony-stimulating factor (G-CSF) and IFN-γ prolong their life span. Neutrophil extra­ cellular traps (NETs) consisting of a DNA scaffold decorated with neutrophil-granule derived proteins, such as enzymatically active proteases and antimicrobial peptides, are thought to be formed as a defense mechanism to immobilize invading microorganisms. Under certain conditions, such as in delayed-type hypersensitivity, monocyte accumulation occurs within 6–12 h of initiation of inflammation. Neutrophils, monocytes, microorganisms in various states of diges­ tion, and altered local tissue cells make up the inflammatory exudate, pus. Myeloperoxidase confers the characteristic green color to pus and may participate in turning off the inflammatory process by inactivating chemoattractants and immobilizing phagocytic cells. Neutrophils respond to certain cytokines (IFN-γ, granulocyte-

macrophage colony-stimulating factor [GM-CSF], IL-8) and produce cytokines and chemotactic signals (TNF-α, IL-8, macrophage inflam­ matory protein [MIP] 1) that modulate the inflammatory response. In the presence of fibrinogen, fMLF, or leukotriene B4, IL-8 production by neutrophils is induced, providing autocrine amplification of inflam­ mation. Chemokines (chemoattractant cytokines) are small proteins produced by many different cell types, including endothelial cells, fibroblasts, epithelial cells, neutrophils, and monocytes, that regulate neutrophil, monocyte, eosinophil, and lymphocyte recruitment and activation. Chemokines transduce their signals through heterotrimeric G protein–linked receptors that have seven cell membrane–spanning domains, the same type of cell-surface receptor that mediates the response to the classic chemoattractants fMLF and C5a. Four major groups of chemokines are recognized based on the cysteine structure near the N terminus: C, CC, CXC, and CXXXC. The C chemokine

Normal monocytes A Normal neutrophils COVID-19 neutrophils PART 2 Cardinal Manifestations and Presentation of Diseases B FIGURE 67-6  COVID-19: Vacuolization in peripheral blood monocytes and neutrophils of COVID-19 patients. Peripheral blood smear showing vacuolization in (A) monocytes and (B) neutrophils from hospitalized hypoxemic COVID-19 patients relative to healthy volunteers. Increased vacuoles were noted in ∼80% of monocytes and ∼50% of neutrophils in each COVID-19 patient throughout their hospitalization. lymphotactin is T-cell tropic; CC chemokines such as MIP-1 attract lymphocytes, monocytes, eosinophils, and basophils; CXC cytokines such as IL-8 mainly attract neutrophils; while the CXXXC chemokine fractalkine attracts neutrophils, monocytes, and T cells. Not only do these molecules and their receptors regulate the trafficking and acti­ vation of inflammatory cells, but also specific chemokine receptors serve as co-receptors for HIV infection (Chap. 208), while others have roles in other viral infections (e.g., West Nile virus), susceptibility and response to Candida, and atherogenesis. ■ ■NEUTROPHIL ABNORMALITIES Defects in the neutrophil life cycle can lead to dysfunction and com­ promised host defenses. When inflammation is severely depressed, the clinical result is often recurrent, severe bacterial and fungal infections. Aphthous ulcers of mucous membranes (gray ulcers without pus) and gingivitis and periodontal disease suggest a phagocytic cell disorder. Patients with congenital phagocyte defects can have infections within the first few days of life. Skin, ear, upper and lower respiratory tract, and bone infections are common. Sepsis and meningitis are rare. In some disorders, the frequency of infection is variable, and patients can go for months or even years without major infection. Aggressive man­ agement of these congenital diseases, including hematopoietic stem cell transplantation and gene therapy, has extended the life span of patients well into adulthood. FIGURE 67-7  The normal eosinophil seen here contains large, bright orange granules and usually a bilobed nucleus. (Courtesy of Dr. Katherine Calvo, Hematopathology Laboratory, Department of Laboratory Medicine, Clinical Center, NIH.)

COVID-19 monocytes Neutropenia  The consequences of absent neutrophils are dra­ matic. Susceptibility to infectious diseases increases sharply when neutrophil counts fall to <1000 cells/μL. When the absolute neutrophil count (ANC; band forms and mature neutrophils combined) falls to <500 cells/μL, control of endogenous microbial flora (e.g., mouth, gut) is impaired; when the ANC is <200/μL, the local inflammatory process is absent. Neutropenia can be due to depressed production, increased peripheral destruction, or excessive peripheral pooling. A falling neu­ trophil count or a significant decrease in the number of neutrophils below steady-state levels, together with a failure to increase neutrophil counts in the setting of infection or other challenge, requires investiga­ tion. Acute neutropenia, such as that caused by cancer chemotherapy, is more likely to be associated with increased risk of infection than chronic neutropenia (months to years) that reverses in response to infection or carefully controlled administration of endotoxin (see “Laboratory Diagnosis and Management,” below). Some causes of inherited and acquired neutropenia are listed in Table 67-1. The most common neutropenias are iatrogenic, result­ ing from the use of cytotoxic or immunosuppressive therapies for malignancy or control of autoimmune disorders. These drugs cause Circulating pool Basal Tissue Bone marrow Marginated pool Circulating pool Infection Bone marrow Tissue Marginated pool Circulating pool Epinephrine Bone marrow Tissue Marginated pool Circulating pool Steroids (Acute) Bone marrow Tissue Marginated pool Circulating pool Leukocyte Adhesion Deficiency Bone marrow Tissue Marginated pool FIGURE 67-8  Schematic neutrophil distribution and kinetics between the different anatomic and functional pools.

Pulmonary capillary bed Alveolus Chemotactic factor Free flowing Rolling Systemic circulation postcapillary venules Tight adhesion CD15s CD62L CD18 CD11a,b CD31 CD54 CD102 GlyCAM-1 CD34 CD62P CD62E Activation Chemoattractant FIGURE 67-9  Neutrophil travel through the pulmonary capillaries is dependent on neutrophil deformability. Neutrophil rigidity (e.g., caused by C5a) enhances pulmonary trapping and response to pulmonary pathogens in a way that is not so dependent on cell-surface receptors. Intraalveolar chemotactic factors, such as those caused by certain bacteria (e.g., Streptococcus pneumoniae), lead to diapedesis of neutrophils from the pulmonary capillaries into the alveolar space. Neutrophil interaction with the endothelium of the systemic postcapillary venules is dependent on molecules of attachment. The neutrophil “rolls” along the endothelium using selectins: neutrophil CD15s (sialyl-Lewisx) binds to CD62E (E-selectin) and CD62P (P-selectin) on endothelial cells; CD62L (L-selectin) on neutrophils binds to CD34 and other molecules (e.g., GlyCAM-1) expressed on endothelium. Chemokines or other activation factors stimulate integrin-mediated “tight adhesion”: CD11a/CD18 (LFA-1) and CD11b/CD18 (Mac-1, CR3) bind to CD54 (ICAM-1) and CD102 (ICAM-2) on the endothelium. Diapedesis occurs between endothelial cells: CD31 (PECAM-1) expressed by the emigrating neutrophil interacts with CD31 expressed at the endothelial cell-cell junction. CD, cluster determinant; GlyCAM, glycosylation-dependent cell adhesion molecule; ICAM, intercellular adhesion molecule; PECAM, platelet/ endothelial cell adhesion molecule. neutropenia because they result in decreased production of rapidly growing progenitor (stem) cells of the marrow. Certain antibiotics such as chloramphenicol, trimethoprim-sulfamethoxazole, flucytosine, vidarabine, and the antiretroviral drug zidovudine may cause neutro­ penia by inhibiting proliferation of myeloid precursors. Azathioprine TABLE 67-1  Causes of Neutropenia Decreased Production Drug-induced—alkylating agents (nitrogen mustard, busulfan, chlorambucil, cyclophosphamide); antimetabolites (methotrexate, 6-mercaptopurine, 5-flucytosine); noncytotoxic agents (antibiotics [chloramphenicol, penicillins, sulfonamides], phenothiazines, tranquilizers [meprobamate], anticonvulsants [carbamazepine], antipsychotics [clozapine], certain diuretics, anti-inflammatory agents, antithyroid drugs, many others) Hematologic diseases—idiopathic, cyclic neutropenia, Chédiak-Higashi syndrome, aplastic anemia, infantile genetic disorders (see text) Tumor invasion, myelofibrosis Nutritional deficiency—vitamin B12, folate (especially alcoholics) Infection—tuberculosis, typhoid fever, brucellosis, tularemia, measles, infectious mononucleosis, malaria, viral hepatitis, leishmaniasis, AIDS Peripheral Destruction Antineutrophil antibodies and/or splenic or lung trapping Autoimmune disorders—Felty syndrome, rheumatoid arthritis, lupus erythematosus Drugs as haptens—aminopyrine, α-methyldopa, phenylbutazone, mercurial diuretics, some phenothiazines Granulomatosis with polyangiitis (Wegener) Peripheral Pooling (Transient Neutropenia) Overwhelming bacterial infection (acute endotoxemia) Hemodialysis Cardiopulmonary bypass

and 6-mercaptopurine are metabolized by the enzyme thiopurine methyltrans­ ferase (TMPT); hypofunctional polymor­ phisms that are found in 11% of whites can lead to accumulation of 6-thioguanine and profound marrow toxicity, which is why pharmacogenomic testing is recom­ mended before initiating these drugs. The marrow suppression is generally doserelated and resolves after cessation of the drug.

Disorders of Granulocytes and Monocytes CHAPTER 67 Another important mechanism for iat­ rogenic neutropenia is the effect of drugs that serve as immune haptens and sensitize neutrophils or neutrophil precursors to immune-mediated peripheral destruction. This form of drug-induced neutropenia can be seen within 7 days of exposure to the drug; with previous drug exposure, resulting in preexisting antibodies, neutro­ penia may occur a few hours after adminis­ tration of the drug. Although any drug can cause this form of neutropenia, the most frequent causes are commonly used antibi­ otics, such as sulfa-containing compounds, penicillins, and cephalosporins. Fever and eosinophilia may also be associated with drug reactions, but often these signs are not present. Drug-induced neutropenia can be severe, but discontinuation of the sensitizing drug is sufficient for recovery, which is usually seen within 5–7 days and is complete by 10 days. Readministration of the sensitizing drug should be avoided, because abrupt neutropenia will often result. For this reason, diagnostic challenge should be avoided. Diapedesis Endothelium Nucleus Autoimmune neutropenias caused by circulating antineutrophil antibodies are another form of acquired neutropenia that results in increased destruction of neutrophils. Acquired neutropenia may also be seen with viral infections, including acute infection with HIV. Acquired neutropenia may be cyclic in nature, occurring at intervals of several weeks. Acquired cyclic or stable neutropenia may be associated with an expansion of large granular lymphocytes (LGLs), which may be T cells, NK cells, or NK-like cells. Patients with large granular lym­ phocytosis may have moderate blood and bone marrow lymphocyto­ sis, neutropenia, polyclonal hypergammaglobulinemia, splenomegaly, rheumatoid arthritis, and absence of lymphadenopathy. Such patients may have a chronic and relatively stable course. Recurrent bacterial infections are frequent. Benign and malignant forms of this syndrome occur. In some patients, spontaneous regression has occurred even after 11 years, suggesting an immunoregulatory defect as the basis for at least one form of the disorder. Glucocorticoids, cyclosporine, methotrexate, and monoclonals are commonly used to manage these cytopenias. Hereditary Neutropenias  Hereditary neutropenias are rare and may manifest in early childhood as a profound constant neutropenia or agranulocytosis. Congenital forms of neutropenia include Kost­ mann’s syndrome (neutrophil count <100/μL), which is often fatal and due to mutations in the anti-apoptosis gene HAX-1; severe chronic neutropenia (neutrophil count of 300–1500/μL) due to mutations in neutrophil elastase (ELANE); hereditary cyclic neutropenia or, more appropriately, cyclic hematopoiesis, also due to mutations in neutro­ phil elastase (ELANE); the cartilage-hair hypoplasia syndrome due to mutations in the mitochondrial RNA-processing endoribonuclease RMRP; Shwachman-Diamond syndrome associated with pancreatic insufficiency due to mutations in the Shwachman-Bodian-Diamond syndrome gene SBDS; the WHIM syndrome (warts, hypogamma­ globulinemia, infections, myelokathexis [retention of WBCs in the

marrow]), characterized by neutrophil hypersegmentation and bone marrow myeloid arrest due to mutations in the chemokine receptor CXCR4; and neutropenias associated with other immune defects, such as GATA2 deficiency, X-linked agammaglobulinemia, Wiskott-Aldrich syndrome, and CD40 ligand deficiency. Mutations in the G-CSF recep­ tor can develop in severe congenital neutropenia and are linked to the development of leukemia. Absence of both myeloid and lymphoid cells is seen in reticular dysgenesis, due to mutations in the nuclear genomeencoded mitochondrial enzyme adenylate kinase-2 (AK2).

Maternal factors can be associated with neutropenia in the new­ born. Transplacental transfer of IgG directed against antigens on fetal neutrophils can result in peripheral destruction. Drugs (e.g., thiazides) ingested during pregnancy can cause neutropenia in the newborn by either depressed production or peripheral destruction. PART 2 Cardinal Manifestations and Presentation of Diseases In Felty syndrome—the triad of rheumatoid arthritis, splenomegaly, and neutropenia (Chap. 370)—antibodies can shorten neutrophil life span, while large granular lymphocytes can attack marrow neutrophil precursors. Splenectomy may increase the neutrophil count in Felty syndrome and lower serum neutrophil-binding IgG. Some Felty syn­ drome patients also have autoantibodies to G-CSF, while others have increased numbers of LGLs. Splenomegaly with peripheral trapping and destruction of neutrophils is also seen in lysosomal storage dis­ eases and commonly in portal hypertension. Neutrophilia  Neutrophilia results from increased neutrophil pro­ duction, increased marrow release, or defective margination (Table 67-2). The most important acute cause of neutrophilia is infection. Neutro­ philia from acute infection represents both increased production and increased marrow release. Increased production is also associated with chronic inflammation and certain myeloproliferative diseases. Increased marrow release and mobilization of the marginated leukocyte pool are induced by glucocorticoids. Release of epinephrine, as with vigorous exercise, excitement, or stress, will demarginate neutrophils in the spleen and lungs and double the neutrophil count in minutes. Cigarette smoking can elevate neutrophil counts above the normal range. Leu­ kocytosis with cell counts of 10,000–25,000/μL occurs in response to infection and other forms of acute inflammation and results from both release of the marginated pool and mobilization of marrow reserves. Persistent neutrophilia with cell counts of ≥30,000–50,000/μL is called a leukemoid reaction, a term often used to distinguish this degree of neutrophilia from leukemia. In a leukemoid reaction, the circulating neutrophils are usually mature and not clonally derived. Abnormal Neutrophil Function  Inherited and acquired abnor­ malities of phagocyte function are listed in Table 67-3. The resulting diseases are best considered in terms of the functional defects of adher­ ence, chemotaxis, and microbicidal activity. The distinguishing features of the important inherited disorders of phagocyte function are shown in Table 67-4. TABLE 67-3  Types of Granulocyte and Monocyte Disorders CAUSE OF INDICATED DYSFUNCTION FUNCTION DRUG-INDUCED ACQUIRED INHERITED Adherence-aggregation Aspirin, colchicine, alcohol, glucocorticoids, ibuprofen, piroxicam Neonatal state, hemodialysis Leukocyte adhesion deficiency types 1, 2, and 3 Deformability   Leukemia, neonatal state, diabetes mellitus, immature neutrophils Chemokinesischemotaxis Glucocorticoids (high dose), auranofin, colchicine (weak effect), phenylbutazone, naproxen, indomethacin, interleukin 2 Thermal injury, malignancy, malnutrition, periodontal disease, neonatal state, systemic lupus erythematosus, rheumatoid arthritis, diabetes mellitus, sepsis, influenza virus infection, herpes simplex virus infection, acrodermatitis enteropathica, AIDS Microbicidal activity Colchicine, cyclophosphamide, glucocorticoids (high dose), TNFα-blocking antibodies Leukemia, aplastic anemia, certain neutropenias, tuftsin deficiency, thermal injury, sepsis, neonatal state, diabetes mellitus, malnutrition, AIDS Abbreviations: IFNγ, interferon γ; IL, interleukin; TNF-α, tumor necrosis factor alpha.

TABLE 67-2  Causes of Neutrophilia Increased Production Idiopathic Drug-induced—glucocorticoids, G-CSF Infection—bacterial, fungal, sometimes viral Inflammation—thermal injury, tissue necrosis, myocardial and pulmonary infarction, hypersensitivity states, collagen vascular diseases Myeloproliferative diseases—myelocytic leukemia, myeloid metaplasia, polycythemia vera Increased Marrow Release Glucocorticoids Acute infection (endotoxin) Inflammation—thermal injury Decreased or Defective Margination Drugs—epinephrine, glucocorticoids, nonsteroidal anti-inflammatory agents Stress, excitement, vigorous exercise Leukocyte adhesion deficiency type 1 (CD18); leukocyte adhesion deficiency type 2 (selectin ligand, CD15s); leukocyte adhesion deficiency type 3 (FERMT3) Miscellaneous Metabolic disorders—ketoacidosis, acute renal failure, eclampsia, acute poisoning Drugs—lithium Other—metastatic carcinoma, acute hemorrhage or hemolysis Abbreviation: G-CSF, granulocyte colony-stimulating factor. DISORDERS OF ADHESION  Three main types of leukocyte adhesion deficiency (LAD) have been described. All are autosomal recessive and result in the impairment of neutrophil exit from the circulation to sites of infection, leading to leukocytosis and increased susceptibil­ ity to infection (Fig. 67-9). Patients with LAD 1 have mutations in CD18, the common component of the integrins LFA-1, Mac-1, and p150,95, leading to a defect in tight adhesion between neutrophils and the endothelium. The heterodimer formed by CD18/CD11b (Mac-1) is also the receptor for the complement-derived opsonin C3bi (CR3). The CD18 gene is located on distal chromosome 21q. The severity of the defect determines the severity of clinical disease. Complete lack of expression of the leukocyte integrins results in a severe phenotype in which inflammatory stimuli do not increase the expression of leuko­ cyte integrins on neutrophils or activated T and B cells. Neutrophils (and monocytes) from patients with LAD 1 adhere poorly to endothe­ lial cells and protein-coated surfaces and exhibit defective spreading, aggregation, and chemotaxis. The inability of neutrophils to exit the vasculature to the tissue deprives the tissue macrophage of its expected neutrophil ingestion, leading to macrophage production of IL-23,   Chédiak-Higashi syndrome, neutrophil-specific granule deficiency, WDR1 deficiency, Job’s syndrome (in some patients), Down syndrome, α-mannosidase deficiency, leukocyte adhesion deficiencies, Wiskott-Aldrich syndrome Chédiak-Higashi syndrome, neutrophil-specific granule deficiency, chronic granulomatous disease, defects in IFNγ/IL-12 axis, Anti-IFNγ autoantibodies

TABLE 67-4  Inherited Disorders of Phagocyte Function: Differential Features CLINICAL MANIFESTATIONS CELLULAR OR MOLECULAR DEFECTS DIAGNOSIS Chronic Granulomatous Diseases (70% X-Linked, 30% Autosomal Recessive) Severe infections of skin, ears, lungs, liver, and bone with microorganisms such as Staphylococcus aureus, Burkholderia cepacia complex, Aspergillus spp., Chromobacterium violaceum; often hard to culture organism; excessive inflammation with granulomas, frequent lymph node suppuration; granulomas can obstruct GI or GU tracts; gingivitis, aphthous ulcers Chédiak-Higashi Syndrome (Autosomal Recessive) Recurrent pyogenic infections, especially with S. aureus; many patients get lymphoma-like illness during adolescence; periodontal disease; partial oculocutaneous albinism, nystagmus, progressive peripheral neuropathy, cognitive impairment in some patients Specific Granule Deficiency (Autosomal Recessive and Dominant) Recurrent infections of skin, ears, and sinopulmonary tract; delayed wound healing; decreased inflammation; bleeding diathesis Myeloperoxidase Deficiency (Autosomal Recessive) Clinically normal except in patients with underlying disease such as diabetes mellitus; then candidiasis or other fungal infections Leukocyte Adhesion Deficiency Type 1: Delayed separation of umbilical cord, sustained neutrophilia, recurrent infections of skin and mucosa, gingivitis, periodontal disease Type 2: Cognitive impairment, short stature, Bombay (hh) blood phenotype, recurrent infections, neutrophilia Type 3: Petechial hemorrhage, recurrent infections Impaired signaling for integrin activation resulting in impaired adhesion. Mutations in FERMT3 Phagocyte Activation Defects (X-Linked and Autosomal Recessive) NEMO deficiency: mild hypohidrotic ectodermal dysplasia; broad-based immune defect: pyogenic and encapsulated bacteria, viruses, Pneumocystis, mycobacteria; X-linked IRAK4 and MyD88 deficiency: susceptibility to pyogenic bacteria such as staphylococci, streptococci, clostridia; resistant to Candida; autosomal recessive Hyper IgE–Recurrent Infection Syndrome (Autosomal Dominant) (Job’s Syndrome) Eczematoid or pruritic dermatitis, “cold” skin abscesses, recurrent pneumonias with S. aureus with bronchopleural fistulae and cyst formation, mild eosinophilia, mucocutaneous candidiasis, characteristic facies, restrictive lung disease, scoliosis, delayed primary dental deciduation DOCK8 deficiency (autosomal recessive), severe eczema, atopic dermatitis, cutaneous abscesses, HSV, HPV, and molluscum infections, severe allergies, cancer Mycobacterial Susceptibility (Autosomal Dominant and Recessive Forms) Severe extrapulmonary or disseminated infections with bacille CalmetteGuérin (BCG), nontuberculous mycobacteria, salmonella, histoplasmosis, coccidioidomycosis, poor granuloma formation GATA2 Deficiency (Autosomal Dominant) Persistent or disseminated warts, disseminated mycobacterial disease, low monocytes, NK cells, B cells; hypoplastic myelodysplasia, leukemia, cytogenetic abnormalities, pulmonary alveolar proteinosis Abbreviations: C/EBPε, CCAAT/enhancer binding protein-ε; DHR, dihydrorhodamine (oxidation test); DOCK8, dedicator of cytokinesis 8; GI, gastrointestinal; GU, genitourinary; HPV, human papillomavirus; HSV, herpes simplex virus; IFN, interferon; IL, interleukin; IRAK4, IL-1 receptor–associated kinase 4; LFA-1, leukocyte function– associated antigen 1; MyD88, myeloid differentiation primary response gene 88; NADPH, nicotinamide–adenine dinucleotide phosphate; NBT, nitroblue tetrazolium (dye test); NEMO, NF-κB essential modulator; NF-κB, nuclear factor-κB; NK, natural killer; STAT1–3, signal transducer and activator of transcription 1–3; TLR, Toll-like receptor; TNF, tumor necrosis factor.

No respiratory burst due to impaired of NADPH oxidase in neutrophils, monocytes, and eosinophils. Mutations in CYBB, CYBA, NCF1, NCF2, NCF4, or CYBC1 DHR or NBT test; no superoxide and H2O2 production by neutrophils; immunoblot for NADPH oxidase components; genetic detection Reduced chemotaxis and phagolysosome fusion, increased respiratory burst activity, defective egress from marrow, abnormal skin window; defect in CHS1 Giant primary granules in neutrophils and other granule-bearing cells (Wright stain); genetic detection Disorders of Granulocytes and Monocytes CHAPTER 67 Abnormal chemotaxis, impaired respiratory burst and bacterial killing, failure to upregulate chemotactic and adhesion receptors with stimulation, defect in transcription of granule proteins. Mutations in CEBPE or SMARCD2 Lack of secondary (specific) granules in neutrophils (Wright stain), no neutrophilspecific granule contents (i.e., lactoferrin), no defensins, platelet α granule abnormality; genetic detection No myeloperoxidase due to pre- and posttranslational defects in myeloperoxidase deficiency. Mutations in MPO No peroxidase in neutrophils; genetic detection Impaired phagocyte adherence, aggregation, spreading, chemotaxis, phagocytosis of C3bi-coated particles; defective production of CD18 subunit common to leukocyte integrins. Mutations in ITGB2 Reduced phagocyte surface expression of the CD18-containing integrins with monoclonal antibodies against LFA-1 (CD18/CD11a), Mac-1 or CR3 (CD18/ CD11b), p150,95 (CD18/CD11c); genetic detection Impaired phagocyte rolling along endothelium; due to defects in fucose transporter. Mutations in SLC35C1 Reduced phagocyte surface expression of Sialyl-Lewisx, with monoclonal antibodies against CD15s; genetic detection Reduced signaling for adhesion through integrins; genetic detection Impaired phagocyte activation by IL-1, IL-18, TLR, CD40L, TNF-α leading to problems with inflammation and antibody production. Mutations in IKBKG Poor in vitro response to endotoxin; impaired NF-κB activation; genetic detection Impaired phagocyte activation by endotoxin through TLR and other pathways; TNF-α signaling preserved. Mutations in IRAK4 or MYD88 Poor in vitro response to endotoxin; lack of NF-κB activation by endotoxin; genetic detection Reduced chemotaxis in some patients, reduced memory T and B cells. Mutations in STAT3 Somatic and immune features involving lungs, skeleton, and immune system; serum IgE >2000 IU/mL; genetic testing Impaired T-cell proliferation to mitogens. Mutations in DOCK8 Severe allergies, viral infections, high IgE, eosinophilia, low IgM, progressive lymphopenia, genetic detection Inability to kill intracellular organisms due to low IFN-γ production or response. Mutations in IFN-γ receptors, IL-12 receptors, IL-12 p40, STAT1, NEMO, ISG15, and others Abnormally low or very high levels of IFN-γ receptor 1; functional assays of cytokine production and response; genetic detection Impaired macrophage activity, cytopenias. Mutations in GATA2 Profound circulating monocytopenia, NK and B-cell cytopenias; genetic detection

which induces T-cell production of IL-17, a potent proinflammatory cytokine. These processes conspire to drive inflammation in LAD 1. Patients with LAD 1 have recurrent bacterial infections involving the skin, oral and genital mucosa, and respiratory and intestinal tracts; persistent leukocytosis (resting neutrophil counts of 15,000–20,000/μL) because cells do not marginate; and, in severe cases, a history of delayed separation of the umbilical stump. Infections, especially of the skin, may become necrotic with progressively enlarging borders, slow heal­ ing, and development of dysplastic scars. The most common bacteria are Staphylococcus aureus and enteric gram-negative bacteria. LAD 2 is caused by an abnormality of fucosylation of SLex (CD15s), the ligand on neutrophils that interacts with selectins on endothelial cells and is responsible for neutrophil rolling along the endothelium. Infection susceptibility in LAD 2 appears to be less severe than in LAD 1. LAD 2 is also known as congenital disorder of glycosylation IIc (CDGIIc) due to mutation in a GDP-fucose transporter (SLC35C1). LAD 3 is character­ ized by infection susceptibility, leukocytosis, and petechial hemorrhage due to impaired integrin activation caused by mutations in FERMT3.

PART 2 Cardinal Manifestations and Presentation of Diseases DISORDERS OF NEUTROPHIL GRANULES  The most common neu­ trophil defect is myeloperoxidase deficiency, a primary granule defect inherited as an autosomal recessive trait; the incidence is ∼1 in 2000 persons. Myeloperoxidase deficiency is not associated with clinically compromised defenses unless there is another contributing factor such as diabetes. In myeloperoxidase deficiency, neutrophil microbicidal activity is delayed but not absent. Patients with myeloperoxidase defi­ ciency and diabetes are more susceptible to Candida infections. An acquired form of myeloperoxidase deficiency occurs in myelomono­ cytic leukemia and acute myeloid leukemia. Importantly, myeloper­ oxidase deficiency gives an abnormal dihydrorhodamine (DHR) assay (see chronic granulomatous disease below). Chédiak-Higashi syndrome (CHS) is a rare disease with autosomal recessive inheritance due to defects in the lysosomal transport protein LYST, encoded by the gene CHS1 at 1q42. This protein is required for normal packaging and disbursement of granules. Neutrophils (and all cells containing lysosomes) from patients with CHS characteristically have large granules (Fig. 67-10), making it a systemic disease. Patients with CHS have nystagmus, partial oculocutaneous albinism, and an increased number of infections resulting from many bacterial agents. Some CHS patients develop an “accelerated phase” in childhood with a hemophagocytic syndrome and an aggressive lymphoma requiring FIGURE 67-10  Chédiak-Higashi syndrome. The granulocytes contain huge cytoplasmic granules formed from aggregation and fusion of azurophilic and specific granules. Large abnormal granules are found in other granule-containing cells throughout the body.

bone marrow transplantation. CHS neutrophils and monocytes have impaired chemotaxis and abnormal rates of microbial killing due to slow rates of fusion of the lysosomal granules with phagosomes. NK cell function is also impaired. CHS patients may develop a severe dis­ abling peripheral neuropathy in adulthood. Specific granule deficiency is a rare autosomal recessive disease in which the production of secondary granules and their contents, as well as the primary granule component defensins, is defective. The defect in killing leads to severe bacterial infections. One type of specific granule deficiency is due to a mutation in CEBPE, which regulates expression of granule components. A dominant mutation in CEBPE has also been described. Specific granule deficiency can also be caused by mutations in SMARCD2. CHRONIC GRANULOMATOUS DISEASE  Chronic granulomatous dis­ ease (CGD) is a group of genetic disorders of granulocyte and mono­ cyte oxidative metabolism due to defects in the enzyme NADPH oxidase, also called NOX2. CGD has an incidence of ∼1 in 100,000– 200,000 individuals. In about two-thirds of patients, CGD is inherited as an X-linked recessive trait; the remainder inherit their disease in autosomal recessive patterns. Mutations in the genes encoding the six proteins that allow assembly at the plasma membrane of NOX2 account for all patients with CGD. Two proteins (a 91-kDa protein, abnormal in X-linked CGD, and a 22-kDa protein, absent in one form of autosomal recessive CGD) form the heterodimer cytochrome b-558 in the plasma membrane. The protein essential for reactive oxidant signaling (EROS) is encoded by CYBC1, which is required to transport the 91- and 22-kDa proteins to the endoplasmic reticulum. Three other proteins (40, 47, and 67 kDa, abnormal in the other autosomal reces­ sive forms of CGD) are cytoplasmic and interact with the cytochrome after cell activation to form the NADPH oxidase, which is required for phagocyte hydrogen peroxide production. Therefore, leukocytes from patients with CGD have severely diminished hydrogen perox­ ide production. Patients with CGD characteristically have increased numbers of infections due to a relatively narrow range of microorgan­ isms (in North America, S. aureus, Serratia marsescens, Burkholderia cepacia complex, and Nocardia and Aspergillus species). Outside of North America, Salmonella, tuberculosis, and bacillus CalmetteGuérin (BCG) are important pathogens. When patients with CGD become infected, they often have extensive inflammatory reactions, and suppuration is common despite the administration of appropri­ ate antibiotics. Aphthous ulcers and chronic infection of the nares are often present. Granulomas are frequent and can obstruct the gastroin­ testinal or genitourinary tracts. The excessive inflammation is due to failure to downregulate inflammation, reflecting a failure to inhibit the synthesis of, degradation of, or response to interleukins or chemoat­ tractants, leading to persistent myeloid reaction. Impaired killing of intracellular microorganisms by macrophages may lead to persistent cell-mediated immune activation and granuloma formation. Autoim­ mune complications such as immune thrombocytopenic purpura and juvenile idiopathic arthritis are also increased in CGD. In addition, for unexplained reasons, discoid lupus is more common in X-linked car­ riers. Late complications, including nodular regenerative hyperplasia and portal hypertension, are increasingly recognized in adolescent and adult patients with CGD. Interestingly, patients with CGD have been reported to be protected from atherosclerosis, suggesting an important role for NADPH oxidase (NOX2) in the pathogenesis of this inflamma­ tory disease of arteries. DISORDERS OF PHAGOCYTE ACTIVATION  Phagocytes depend on cell-surface stimulation to induce signals that evoke multiple levels of the inflammatory response, including cytokine synthesis, chemotaxis, and antigen presentation. Mutations affecting the major pathway that signals through NF-κB have been noted in patients with a variety of infection susceptibility syndromes. If the defects are at a very late stage of signal transduction, in the protein critical for NF-κB activation known as the NF-κB essential modulator (NEMO), then affected males develop ectodermal dysplasia and severe immune deficiency with susceptibility to bacteria, fungi, mycobacteria, and viruses. There are several other proteins that interact with NEMO, mutations in which are

autosomal and can be phenocopies of NEMO deficiency. If the defects in NF-κB activation are closer to the cell-surface receptors, in the pro­ teins transducing Toll-like receptor signals, IL-1 receptor–associated kinase 4 (IRAK4), and myeloid differentiation primary response gene 88 (MyD88), then children have a marked susceptibility to pyogenic infections associated with a striking blunting of the febrile and inflam­ matory responses early in life but develop resistance to infection later. The small Rho-family GTPase, RAC2, is involved in actin assem­ bly, intracellular signaling, and superoxide production. Given these multiple roles, it is not surprising that different mutations in RAC2 can have different effects on its functions. Accordingly, different RAC2 mutations present, ranging from early-onset sepsis (constitutively active mutations), to abscesses with impaired superoxide production (dominant negative mutations), to common variable immunodefi­ ciency (hyperactive mutations). MONONUCLEAR PHAGOCYTES The mononuclear phagocyte system is composed of monoblasts, pro­ monocytes, and monocytes, in addition to the structurally diverse tis­ sue macrophages that make up what was previously referred to as the reticuloendothelial system. Monocytes, which leave the circulation by diapedesis more slowly than neutrophils and have a half-life of 12–24 h, migrate into tissues and differentiate into macrophages. Macrophages are long-lived phagocytic cells capable of many of the functions of neutrophils. They are also secretory cells that participate in many immunologic and inflammatory processes distinct from neutrophils. Many tissue macrophages (“big eaters”) arise in the embryonic yolk sac outside of conventional hematopoiesis and then go on to take up residence in tissues. In addition, there are macrophages derived from monocytes, which may have specialized functions suited for specific anatomic locations. Macrophages are particularly abundant in capil­ lary walls of the lung, spleen, liver, and bone marrow, where they function to remove microorganisms and other noxious elements from the blood. Alveolar macrophages, liver Kupffer cells, splenic macro­ phages, peritoneal macrophages, bone marrow macrophages, lym­ phatic macrophages, brain microglial cells, and dendritic macrophages all have specialized functions. Macrophage-secreted products include lysozyme, neutral proteases, acid hydrolases, arginase, complement components, enzyme inhibitors (plasmin, α2-macroglobulin), binding proteins (transferrin, fibronectin, transcobalamin II), nucleosides, and cytokines (TNF-α; IL-1, 8, 12, 18). IL-1 (Chaps. 20 and 360) has many functions, including initiating fever in the hypothalamus, mobilizing leukocytes from the bone marrow, and activating lymphocytes and neutrophils. TNF-α is a pyrogen that duplicates many of the actions of IL-1 and plays an important role in the pathogenesis of gram-negative shock (Chap. 315). TNF-α stimulates production of hydrogen perox­ ide and related toxic oxygen species by macrophages and neutrophils. In addition, TNF-α induces catabolic changes that contribute to the profound wasting (cachexia) associated with many chronic diseases. Other macrophage-secreted products include reactive oxygen and nitrogen metabolites, bioactive lipids (arachidonic acid metabolites and platelet-activating factors), chemokines, CSFs, and factors stimu­ lating fibroblast and vessel proliferation. Macrophages help regulate the replication of lymphocytes and participate in the killing of tumors, viruses, and certain bacteria (Mycobacterium tuberculosis and Listeria monocytogenes). Macrophages are key effector cells in the elimination of intracellular microorganisms. Their ability to fuse to form giant cells that coalesce into granulomas in response to some inflammatory stimuli is important in the elimination of intracellular microbes and is under the control of IFN-γ. Nitric oxide induced by IFN-γ may be an important effector against intracellular parasites, including tuberculo­ sis and Leishmania. Macrophages play an important role in the immune response (Chap. 360). They process and present antigen to lymphocytes and secrete cytokines that modulate and direct lymphocyte development and function. Macrophages participate in autoimmune phenomena by removing immune complexes and other substances from the circula­ tion. Polymorphisms in macrophage receptors for immunoglobulin (FcγRII) determine susceptibility to some infections and autoimmune

diseases. In wound healing, they dispose of senescent cells, and they also contribute to atheroma development. Macrophage elastase medi­ ates development of emphysema from cigarette smoking.

■ ■DISORDERS OF THE MONONUCLEAR PHAGOCYTE SYSTEM Many disorders of neutrophils extend to mononuclear phagocytes. Monocytosis is associated with tuberculosis, brucellosis, subacute bac­ terial endocarditis, Rocky Mountain spotted fever, malaria, and visceral leishmaniasis (kala-azar). Monocytosis also occurs with certain malig­ nancies, leukemias, myeloproliferative syndromes, hemolytic anemias, chronic idiopathic neutropenias, and granulomatous diseases such as sarcoidosis, Crohn disease, and some collagen vascular diseases. Patients with LAD1, hyperimmunoglobulin E–recurrent infection (Job’s) syndrome, CHS, and CGD all have defects in the mononuclear phagocyte system. Disorders of Granulocytes and Monocytes CHAPTER 67 Monocyte cytokine production or response is impaired in some patients with disseminated nontuberculous mycobacterial infection who are not infected with HIV. Genetic defects in the pathways regulated by IFN-γ and IL-12 lead to impaired killing of intracellular bacteria, mycobacteria, salmonellae, and certain viruses (Fig. 67-11). Autoantibodies to IFN-γ, IL-23, and GM-CSF can block critical signals for macrophage intracellular killing and are associated with mycobac­ terial, fungal, and Nocardia infections. Certain viral infections impair mononuclear phagocyte function. For example, influenza virus infection causes abnormal monocyte chemotaxis. Mononuclear phagocytes can be infected by HIV using CCR5, the chemokine receptor that acts as a co-receptor with CD4 for HIV. T lymphocytes produce IFN-γ, which induces FcR expression and phagocytosis and stimulates hydrogen peroxide production by mononuclear phagocytes and neutrophils. In certain diseases, such as AIDS, IFN-γ production may be deficient, whereas in other diseases, such as T-cell lymphomas, excessive release of IFN-γ may be associated with erythrophagocytosis by splenic macrophages. IL-2 IL-2R IFNγ T/NK β1 IL-12R β2 IL-15

? IFNγR STAT1 1 2 GATA2 ISG15 IL-12 IRF8 TNFα AFB Salm. NEMO NRAMP1 MΦ TNFαR TLR LPS CD14 FIGURE 67-11  Lymphocyte-macrophage interactions underlying resistance to mycobacteria and other intracellular pathogens such as Salmonella, Histoplasma, and Coccidioides. Mycobacteria (and others) infect macrophages, leading to the production of IL-12, which activates T or NK cells through its receptor, leading to production of IL-2 and IFN-γ. IFN-γ acts through its receptor on macrophages to upregulate TNF-γ and IL-12 and kill intracellular pathogens. Other critical interacting molecules include signal transducer and activator of transcription 1 (STAT1), interferon regulatory factor 8 (IRF8), GATA2, and ISG15. Mutant forms of the cytokines and receptors shown in bold type have been found in severe cases of nontuberculous mycobacterial infection, salmonellosis, and other intracellular pathogens. AFB, acid-fast bacilli; IFN, interferon; IL, interleukin; NEMO, nuclear factor-κB essential modulator; NK, natural killer; TLR, Toll-like receptor; TNF, tumor necrosis factor.

Autoinflammatory diseases are characterized by abnormal cytokine regulation, leading to excess inflammation in the absence of infection. These diseases can mimic infectious or immunodeficient syndromes. Gain-of-function mutations in the TNF-α receptor cause TNF-α receptor–associated periodic syndrome (TRAPS), which is character­ ized by recurrent fever in the absence of infection, due to persistent stimulation of the TNF-α receptor (Chap. 381). Diseases with abnor­ mal IL-1 regulation leading to fever include familial Mediterranean fever due to mutations in PYRIN. Mutations in cold-induced autoin­ flammatory syndrome 1 (CIAS1) lead to neonatal-onset multisystem autoinflammatory disease, familial cold urticaria, and Muckle-Wells syndrome. The syndrome of pyoderma gangrenosum, acne, and sterile pyogenic arthritis (PAPA syndrome) is caused by mutations in PSTPIP1. In contrast to these syndromes of overexpression of proin­ flammatory cytokines, blockade of TNF-α by the antagonists inflix­ imab, adalimumab, certolizumab, golimumab, or etanercept has been associated with severe infections due to tuberculosis, nontuberculous mycobacteria, and fungi (Chap. 381).

PART 2 Cardinal Manifestations and Presentation of Diseases Monocytopenia occurs with acute infections, with stress, and after treatment with glucocorticoids. Drugs that suppress neutrophil production in the bone marrow can cause monocytopenia. Persistent severe circulating monocytopenia is seen in GATA2 deficiency, even though macrophages are found at the sites of inflammation. Mono­ cytopenia also occurs in aplastic anemia, hairy cell leukemia, acute myeloid leukemia, and as a direct result of myelotoxic drugs. EOSINOPHILS Eosinophils and neutrophils share similar morphology, many lyso­ somal constituents, phagocytic capacity, and oxidative metabolism. Eosinophils express a specific chemoattractant receptor and respond to a specific chemokine, eotaxin, but little is known about their required role. Eosinophils are much longer lived than neutrophils, and unlike neutrophils, tissue eosinophils can recirculate. During most infections, eosinophils appear unimportant. However, in invasive helminthic infections, such as hookworm, schistosomiasis, strongyloidiasis, toxo­ cariasis, trichinosis, filariasis, echinococcosis, and cysticercosis, the eosinophil plays a central role in host defense. Recently, eosinophils have been recognized as important in the host response to tuberculosis. Eosinophils are associated with bronchial asthma, cutaneous allergic reactions, and other hypersensitivity states. The distinctive feature of the red-staining (Wright’s stain) eosino­ phil granule is its crystalline core consisting of an arginine-rich pro­ tein (major basic protein) with histaminase activity, important in host defense against parasites. Eosinophil granules also contain a unique eosinophil peroxidase that catalyzes the oxidation of many substances by hydrogen peroxide and may facilitate killing of microorganisms. Eosinophil peroxidase, in the presence of hydrogen peroxide and halide, initiates mast cell secretion in vitro and thereby promotes inflammation. Eosinophils contain cationic proteins, some of which bind to heparin and reduce its anticoagulant activity. Eosinophil-derived neurotoxin and eosinophil cationic protein are ribonucleases that can kill respiratory syncytial virus. Eosinophil cytoplasm contains CharcotLeyden crystal protein, a hexagonal bipyramidal crystal first observed in a patient with leukemia and then in sputum of patients with asthma; this protein is lysophospholipase and may function to detoxify certain lysophospholipids. Several factors enhance the eosinophil’s function in host defense. T cell–derived factors enhance the ability of eosinophils to kill para­ sites. Mast cell–derived eosinophil chemotactic factor of anaphylaxis (ECFa) increases the number of eosinophil complement receptors and enhances eosinophil killing of parasites. Eosinophil CSFs (e.g., IL-5) produced by macrophages increase eosinophil production in the bone marrow and activate eosinophils to kill parasites. ■ ■EOSINOPHILIA Eosinophilia is the presence of >500 eosinophils per μL of blood and is common in many settings besides parasite infection. Significant tissue eosinophilia can occur without an elevated blood count. A common cause of eosinophilia is allergic reaction to drugs (iodides,

aspirin, sulfonamides, nitrofurantoin, penicillins, and cephalospo­ rins). Allergies such as hay fever, asthma, eczema, serum sickness, allergic vasculitis, and pemphigus are associated with eosinophilia. Eosinophilia also occurs in collagen vascular diseases (e.g., rheuma­ toid arthritis, eosinophilic fasciitis, allergic angiitis, and periarteritis nodosa) and malignancies (e.g., Hodgkin disease; mycosis fungoides; chronic myeloid leukemia; and cancer of the lung, stomach, pan­ creas, ovary, or uterus), as well as in dominant negative STAT3 (Job’s syndrome), DOCK8 deficiency (see below), and CGD. Eosinophilia is commonly present in helminthic infections. IL-5 is the dominant eosinophil growth factor. Therapeutic administration of the cyto­ kines IL-2 or GM-CSF frequently leads to transient eosinophilia. The most dramatic hypereosinophilic syndromes are Loeffler’s syndrome, tropical pulmonary eosinophilia, Loeffler’s endocarditis, eosinophilic leukemia, and idiopathic hypereosinophilic syndrome (50,000–100,000/μL). IL-5 is the dominant eosinophil growth factor and can be specifically inhibited with monoclonal antibodies against it or its receptor. The idiopathic hypereosinophilic syndromes are a heterogeneous group of disorders with the common feature of prolonged eosinophilia of unknown cause and organ system dysfunction, including the heart, central nervous system, kidneys, lungs, gastrointestinal tract, and skin. The bone marrow is involved in all affected individuals, but the most severe complications involve the heart and central nervous system. Clinical manifestations and organ dysfunction are highly variable. Eosinophils are found in the involved tissues and likely cause tissue damage by local deposition of toxic eosinophil proteins such as eosino­ phil cationic protein and major basic protein. In the heart, the patho­ logic changes lead to thrombosis, endocardial fibrosis, and restrictive endomyocardiopathy. The damage to tissues in other organ systems is similar. Some cases are due to mutations involving the platelet-

derived growth factor receptor, and these are extremely sensitive to the tyrosine kinase inhibitor imatinib. Glucocorticoids, hydroxyurea, and IFN-α each have been used successfully, as have therapeutic antibodies against IL-5 or its receptor. Cardiovascular complications are managed aggressively. The eosinophilia-myalgia syndrome is a multisystem disease, with prominent cutaneous, hematologic, and visceral manifestations, that frequently evolves into a chronic course and can occasionally be fatal. The syndrome is characterized by eosinophilia (eosinophil count

1000/μL) and generalized disabling myalgias without other recog­ nized causes. Eosinophilic fasciitis, pneumonitis, and myocarditis; neuropathy culminating in respiratory failure; and encephalopathy may occur. The disease is thought to be caused by ingesting con­ taminants in L-tryptophan–containing products. Eosinophils, lym­ phocytes, macrophages, and fibroblasts accumulate in the affected tissues, but their role in pathogenesis is unclear. Activation of eosino­ phils and fibroblasts and the deposition of eosinophil-derived toxic proteins in affected tissues may contribute. IL-5 and transforming growth factor β have been implicated as potential mediators. Treat­ ment is withdrawal of products containing L-tryptophan and the administration of glucocorticoids. Most patients recover fully, remain stable, or show slow recovery, but the disease can be fatal in up to 5% of patients. Eosinophilic neoplasms are discussed in Chap. 115. ■ ■EOSINOPENIA Eosinopenia occurs with stress, such as acute bacterial infection, and after treatment with glucocorticoids. The mechanism of eosinopenia of acute bacterial infection is unknown but is independent of endogenous glucocorticoids, because it occurs in animals after total adrenalectomy. There is no known adverse effect of eosinopenia. HYPERIMMUNOGLOBULIN E–RECURRENT INFECTION SYNDROME The hyperimmunoglobulin E–recurrent infection syndrome, Job’s syndrome, is a rare multisystem disease in which the immune and somatic systems are affected, including neutrophils, monocytes, T cells, B cells, and osteoclasts. Autosomal dominant negative

mutations in signal transducer and activator of transcription 3 (STAT3) impair normal STAT signaling with broad and profound effects. Patients have characteristic facies with broad nose, kypho­ scoliosis, and eczema. Primary teeth erupt normally but do not deciduate, often requiring extraction. Recurrent sinopulmonary and cutaneous infections tend to elicit much less inflammation than appropriate for the degree of infection, leading to “cold abscesses.” Pneumonias typically cavitate, leading to pneumatoceles. Coronary artery aneurysms are common, as are cerebral demyelinated plaques that accumulate with age. IL-17–producing T cells, which are thought responsible for protection against extracellular and muco­ sal infections, are reduced in Job’s syndrome. Despite very high IgE levels, Job’s patients have only mildly elevated levels of allergy. Patients with autosomal recessive defects in dedicator of cytokinesis 8 (DOCK8) also have very high IgE levels joined to severe allergy, extensive viral susceptibility, and increased rates of cancer. Autoso­ mal dominant gain-of-function (GOF) mutations in STAT3 lead to a disease characterized by onset in childhood of lymphadenopathy, autoimmune cytopenias, multiorgan autoimmunity, infections, and interstitial lung disease. LABORATORY DIAGNOSIS AND MANAGEMENT A complete blood count (CBC) and differential are essential. Careful examination of neutrophils on peripheral blood smears can diagnose CHS and suggest other neutrophil granule abnormalities such as spe­ cific granule deficiency. Bone marrow examination, where indicated, should be accompanied by either gene panel or whole exome/genome sequencing if genetic defects are suspected. Bone marrow reserves (ste­ roid challenge test), marginated circulating pool of cells (epinephrine challenge test), and marginating ability (endotoxin challenge test) are also doable (Fig. 67-8). In vivo assessment of inflammation is possible with a Rebuck skin window test or an in vivo skin blister assay, which measure the ability of leukocytes and inflammatory mediators to accumulate locally in the skin. In vitro tests of phagocyte aggregation, adherence, chemotaxis, phagocytosis, degranulation, and microbicidal activity may help pinpoint cellular or humoral lesions. CGD is detected with either the nitroblue tetrazolium (NBT) dye test or the DHR oxida­ tion test. These tests are based on the ability of products of oxidative metabolism to alter the oxidation states of reporter molecules so that they can be detected microscopically (NBT) or by flow cytometry (DHR). While the DHR is very sensitive for CGD, impaired DHR responses are seen in myeloperoxidase deficiency and with acetamino­ phen ingestion. Patients with leukopenias or leukocyte dysfunction often have delayed inflammatory responses. Therefore, clinical manifestations may be minimal despite overwhelming infection, and unusual infec­ tions must always be suspected. Early signs of infection demand prompt, aggressive culturing for microorganisms, use of antibiotics, and drainage of abscesses. Prolonged courses of antibiotics are often required. In patients with CGD, prophylactic antibiotics (trime­ thoprim-sulfamethoxazole) and antifungals (itraconazole) markedly diminish the frequency of life-threatening infections. Glucocorti­ coids may relieve gastrointestinal or genitourinary tract obstruction by granulomas in patients with CGD. Although TNF-α-blocking agents may markedly relieve inflammatory bowel symptoms, extreme caution must be exercised in their use in CGD inflammatory bowel disease, because it profoundly increases these patients’ already heightened susceptibility to infection. Recombinant human IFN-γ, which nonspecifically stimulates phagocytic cell function, reduces the frequency of infections in patients with CGD by 70% and reduces the severity of infection. This effect of IFN-γ in CGD is additive to the effect of prophylactic antibiotics. The recommended dose is 50 μg/m2 subcutaneously three times weekly. IFN-γ has also been used success­ fully in the treatment of leprosy, nontuberculous mycobacteria, and visceral leishmaniasis.

Rigorous oral hygiene reduces but does not eliminate the dis­ comfort of gingivitis, periodontal disease, and aphthous ulcers; chlorhexidine mouthwash and tooth brushing with a hydrogen peroxide–sodium bicarbonate paste also helps many patients. Oral antifungal agents (fluconazole, itraconazole, voriconazole, posacon­ azole) have reduced mucocutaneous candidiasis in patients with Job’s syndrome. Recombinant G-CSF is useful in the management of certain forms of neutropenia due to depressed neutrophil production, including those related to cancer chemotherapy. Patients with chronic neutropenia with evidence of a good bone marrow reserve need not receive prophylactic antibiotics. Patients with chronic or cyclic neutrophil counts <500/μL may benefit from prophylactic antibiot­ ics and G-CSF during periods of neutropenia. Oral trimethoprimsulfamethoxazole (160/800 mg) twice daily can prevent infection. Increased numbers of fungal infections are not seen in patients with CGD on this regimen. Oral quinolones such as levofloxacin and cip­ rofloxacin are alternatives.

Disorders of Granulocytes and Monocytes CHAPTER 67 In the setting of cytotoxic chemotherapy with severe, persistent lymphocyte dysfunction, trimethoprim-sulfamethoxazole prevents Pneumocystis jirovecii pneumonia. These patients, and patients with phagocytic cell dysfunction, should avoid heavy exposure to airborne soil, dust, or decaying matter (mulch, manure), which are often rich in Nocardia and the spores of Aspergillus and other fungi. Restriction of activities or social contact has no proven role in reducing risk of infec­ tion for phagocyte defects. Although aggressive medical care for many patients with phagocytic disorders can allow them to go for years without a life-threatening infection, there may still be delayed effects of prolonged antimicrobi­ als and other inflammatory complications. Cure of most congenital phagocyte defects is possible by bone marrow transplantation, and rates of success are improving (Chap. 119). The identification of spe­ cific gene defects in patients with LAD1, CGD, and other immunode­ ficiencies has led to gene therapy trials in a number of genetic white cell disorders. ■ ■FURTHER READING Boeltz S et al: To NET or not to NET: Current opinions and state of the science regarding the formation of neutrophil extracellular traps. Cell Death Differ 26:395, 2019. Bousfiha A et al: The 2022 update of IUIS phenotypical classifica­ tion for human inborn errors of immunity. J Clin Immunol 42:1508,

Donko A et al: Interpretation of dihydrorhodamine-1,2,3 flow cytom­ etry in chronic granulomatous disease: An atypical exemplar. J Clin Immunol 42:986, 2022. Donko A et al: Clinical and functional spectrum of RAC2-related immunodeficiency. Blood 143:1476, 2024. Idol RA et al: Neutrophil and macrophage NADPH oxidase 2 differen­ tially control responses to inflammation and to Aspergillus fumigatus in mice. J Immunol 209:1960, 2022. Khoury P et al: Biologic therapy in rare eosinophil-associated disor­ ders: Remaining questions and translational research opportunities. J Leukoc Biol 116:307, 2024. Lazarov T et al: Physiology and diseases of tissue-resident macro­ phages. Nature 618:698, 2023. Ochoa S et al: Genetic susceptibility to fungal infection in children. Curr Opin Pediatr 32:780, 2020. Peiseler M, Kubes P: More friend than foe: the emerging role of neu­ trophils in tissue repair. J Clin Invest 129:2629, 2019. Tangye SG et al: Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 42:1473, 2022. Zerbe CS, Holland SM: Functional neutrophil disorders: Chronic granulomatous disease and beyond. Immunol Rev 322:71, 2024.

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69 Bleeding and Thrombosis

It is suggested that if organ damage is HLH-triggered, lympholytic agents should be considered and a two-step approach is suggested: First, target the cytokine storm and T-cell proliferation with moder­ ately dosed etoposide (75–100 mg/m2), glucocorticoids, and possibly IVIG, and then target the neoplastic disease by specific treatment as soon as organ function has improved to an acceptable degree. Other HLH-directed immunomodulatory agents, such as anakinra, may also be valuable, but results of studies on such therapies are limited. ■ ■MACROPHAGE ACTIVATION SYNDROME Macrophage activation syndrome (MAS) is a life-threatening hyperin­ flammatory complication of rheumatic disease and other autoimmune diseases. It is characterized by an uncontrolled activation and prolif­ eration of T lymphocytes and macrophages and classified among the secondary, acquired forms of HLH because it shares many clinical and laboratory features with both primary and secondary HLH, hence the term MAS-HLH. MAS-HLH is the third most common form of HLH in adults and the second most common in children. In children, it occurs most fre­ quently in individuals with systemic juvenile idiopathic arthritis (sJIA), affecting 10% of these patients, and with systemic lupus erythematosus. In adults, systemic lupus erythematosus is the most common cause, followed by adult-onset Still’s disease, affecting about 5% and 10–15% of these patient groups, respectively. Other causes include systemic vasculitis and inflammatory bowel disease. Clinically, MAS-HLH manifests as fever, liver dysfunction, cytope­ nia, hyperferritinemia, coagulopathy, CNS abnormalities, and, more rarely, hemophagocytosis. Fibrinogen and platelet levels are often higher than in other forms of HLH, due to the inflammatory nature of sJIA. In 2016, MAS-HLH in sJIA patients was defined as a febrile patient with ferritin >684 µg/L and any two of the following: platelet count ≤181 × 109/L, aspartate aminotransferase >48 U/L, fasting tri­ glycerides >1.76 mmol/L (156 mg/dL), and fibrinogen ≤3.6 g/L. Most MAS-HLH flares are reported to be triggered by active disease, but about a third have an infectious trigger. The cytokine pattern in MAS-HLH is characterized by high serum levels of IL-18, distinguish­ ing it from other forms of HLH such as FHL. The mortality rate in MAS-HLH is about 5–10% in children and 10–15% in adults. CNS involvement is frequent and may lead to irre­ versible neurologic damage. Early diagnosis and treatment are therefore crucial. Patients with MAS-HLH may also develop severe pulmonary disease with a high fatality rate, reported to be about 50%, for which the best treatment and prevention still is unknown. The predominant pathology is pulmonary alveolar proteinosis and/or endogenous lipoid pneumonia, but the underlying cause is unknown. ■ ■TREATMENT A common first-line approach is glucocorticoids in high doses, such as intravenous pulse methylprednisolone 30 mg/kg per dose up to a maxi­ mum of 1000 mg/dose once daily for 3–5 days followed by high-dose oral or intravenous glucocorticoids. Cyclosporin A (2–7 mg/kg/d) can be added. IL-1–blocking therapy is also effective, such as with anakinra in a dose of 2–6 mg/kg up to 10 mg/kg per day in divided doses. Expe­ rience with other immunomodulating agents, including tocilizumab, emapalumab, and ruxolitinib, is increasing. In patients with severe disease or CNS involvement despite gluco­ corticoids, cyclosporin A, and/or anakinra, a moderate dose of etopo­ side (50–100 mg/m2 once weekly) can be very effective. ■ ■TRANSPLANT-RELATED AND CHIMERIC ANTIGEN RECEPTOR HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS Other causes of secondary HLH include transplantation, particularly kidney and hematologic transplantations, and novel drugs, such as chimeric antigen receptor (CAR) T cells, bispecific T-cell engagers, and checkpoint inhibitors. HLH with late onset (>30 days) after HSCT is often comparable to infection-associated HLH. Based on other forms of secondary HLH, it is reasonable to start treatment with corticosteroids. As second-line

treatment, favorable response after low-dose etoposide has been reported; one dose of 50–75 mg/m2 may be sufficient.

Increasing use of CAR T-cell therapy and other immune effector cell-based therapies has led to an increasing number of cases with a clinical picture resembling secondary HLH that is distinct from cyto­ kine release syndrome. This HLH-like complication is more frequent when using CD22 CAR T cells, affecting about a third of these patients. Data on treatment results are limited, but anakinra with or without glucocorticoids is suggested as first-line therapy. As second- and thirdline therapy, ruxolitinib, emapalumab, and low-dose etoposide have been suggested. Bleeding and Thrombosis CHAPTER 69 CONCLUSION The survival and biological understanding of primary and secondary HLH have increased dramatically over the past decade(s), but much remains to be learned. Despite being life-threatening and now also treatable, HLH is still markedly underdiagnosed. Numerous lives might be saved by increased awareness of HLH. ■ ■FURTHER READING Daver N et al: A consensus review on malignancy-associated hemo­ phagocytic lymphohistiocytosis in adults. Cancer 123:3229, 2017. Ehl S et al: Recommendations for the use of etoposide-based therapy and bone marrow transplantation for the treatment of HLH: Con­ sensus statements by the HLH Steering Committee of the Histiocyte Society. J Allergy Clin Immunol Pract 6:1508, 2018. Hines MR et al: Consensus-based guidelines for the recognition, diag­ nosis, and management of hemophagocytic lymphohistiocytosis in critically ill children and adults. Crit Care Med 50:860, 2022. La Rosée P et al: Recommendations for the management of hemo­ phagocytic lymphohistiocytosis in adults. Blood 133:2465, 2019. Ramos-Casals M et al: Adult haemophagocytic syndrome. Lancet 383:1503, 2014. Barbara A. Konkle

Bleeding and Thrombosis The human hemostatic system provides a natural balance between pro­ coagulant and anticoagulant forces. The procoagulant forces include platelet adhesion and aggregation and fibrin clot formation; anticoagu­ lant forces include the natural inhibitors of coagulation and fibrinoly­ sis. Under normal circumstances, hemostasis is regulated to promote blood flow; however, it is also prepared to clot blood rapidly to arrest blood flow and prevent exsanguination. After bleeding is successfully halted, the system remodels the damaged vessel to restore normal blood flow. The major components of the hemostatic system, which function in concert, are (1) platelets and other formed elements of blood, such as monocytes and red cells; (2) plasma proteins (the coagu­ lation and fibrinolytic factors and inhibitors); and (3) the vessel wall. STEPS OF NORMAL HEMOSTASIS ■ ■PLATELET PLUG FORMATION On vascular injury, platelets adhere to the site of injury, usually the denuded vascular intimal surface. Platelet adhesion is mediated pri­ marily by von Willebrand factor (VWF), a large multimeric protein present in both plasma and the extracellular matrix of the subendothe­ lial vessel wall, which serves as the primary “molecular glue,” providing

sufficient strength to withstand the high levels of shear stress that would tend to detach them with the flow of blood. Platelet adhesion is also facilitated by direct binding to subendothelial collagen through specific platelet membrane collagen receptors.

Platelet adhesion results in subsequent platelet activation and aggre­ gation. This process is enhanced and amplified by humoral mediators in plasma (e.g., epinephrine, thrombin); mediators released from acti­ vated platelets (e.g., adenosine diphosphate, serotonin); and vessel wall extracellular matrix constituents that come in contact with adherent platelets (e.g., collagen, VWF). Activated platelets undergo the release reaction, during which they secrete contents that further promote aggregation and inhibit the naturally anticoagulant endothelial cell factors. During platelet aggregation (platelet-platelet interaction), addi­ tional platelets are recruited from the circulation to the site of vascular injury, leading to the formation of an occlusive platelet thrombus. The platelet plug is anchored and stabilized by the developing fibrin mesh. PART 2 Cardinal Manifestations and Presentation of Diseases The platelet glycoprotein (Gp) IIb/IIIa (αIIbβ3) complex is the most abundant receptor on the platelet surface. Platelet activation converts the normally inactive Gp IIb/IIIa receptor into an active receptor, enabling binding to fibrinogen and VWF. Because the surface of each platelet has about 50,000 Gp IIb/IIIa–binding sites, numerous acti­ vated platelets recruited to the site of vascular injury can rapidly form an occlusive aggregate by means of a dense network of intercellular fibrinogen bridges. ■ ■FIBRIN CLOT FORMATION Plasma coagulation proteins (clotting factors) normally circulate in plasma in their inactive forms. The sequence of coagulation protein reactions that culminate in the formation of fibrin was originally described as a waterfall or a cascade. Two pathways of blood coagulation have been described in the past: the so-called extrinsic, or tissue factor, pathway and the so-called intrinsic, or contact activation, pathway. We now know that coagulation is normally initiated through tissue factor (TF) exposure and activation through the classic extrinsic pathway but with critically important amplification through elements of the classic intrinsic pathway, as illustrated in Fig. 69-1. These reactions take place on phospholipid surfaces, usually the activated platelet surface. Coagu­ lation testing in the laboratory can reflect other influences due to the artificial nature of the in vitro systems used (see below). The immediate trigger for coagulation is vascular damage that exposes blood to TF that is constitutively expressed on the surfaces of subendothelial cellular components of the vessel wall, such as smooth Vessel injury IX TF VIIa IXa TFPI X Va Xa II (Prothrombin) Fibrinogen Fibrin FIGURE 69-1  Coagulation is initiated by tissue factor (TF) exposure, which, with factor (F) VIIa, activates FIX and FX, which in turn, with FVIII and FV as cofactors, respectively, results in thrombin formation and subsequent conversion of fibrinogen to fibrin. Thrombin activates FXI, FVIII, and FV, amplifying the coagulation signal. Once the TF/FVIIa/ FXa complex is formed, tissue factor pathway inhibitor (TFPI) inhibits the TF/FVIIa pathway, making coagulation dependent on the amplification loop through FIX/FVIII. Coagulation requires calcium (not shown) and takes place on phospholipid surfaces, usually the activated platelet membrane.

muscle cells and fibroblasts. TF is also present in circulating micropar­ ticles, presumably shed from cells including monocytes and platelets. TF binds the serine protease factor VIIa; the complex activates factor X to factor Xa. Alternatively, the complex can indirectly activate factor X by initially converting factor IX to factor IXa, which then activates factor X. The participation of factor XI in hemostasis is not dependent on its activation by factor XIIa but rather on its positive feedback acti­ vation by thrombin. Thus, factor XIa functions in the propagation and amplification, rather than in the initiation, of the coagulation cascade. The role of factor XIIa in activation of factor XI is not fully elucidated, but studies suggest it may be a mechanism to promote thrombosis. Factor Xa can be formed through the actions of either the TF/factor VIIa complex or factor IXa (with factor VIIIa as a cofactor) and converts prothrombin to thrombin, the pivotal protease of the coagulation system. The essential cofactor for this reaction is factor Va, which is produced by thrombin-induced limited proteolysis of factor V. Thrombin is a multifunctional enzyme that converts soluble plasma fibrinogen to an insoluble fibrin matrix. Fibrin polymerization involves an orderly pro­ cess of intermolecular associations (Fig. 69-2). Thrombin also activates factor XIII (fibrin-stabilizing factor) to factor XIIIa, which covalently cross-links and thereby stabilizes the fibrin clot. The assembly of the clotting factors on activated cell membrane surfaces greatly accelerates their reaction rates and also serves to local­ ize blood clotting to sites of vascular injury. The critical cell membrane components, acidic phospholipids, are not normally exposed on rest­ ing cell membrane surfaces. However, when platelets, monocytes, and endothelial cells are activated by vascular injury or inflammatory stimuli, the procoagulant head groups of the membrane anionic phos­ pholipids become translocated to the surfaces of these cells or released as part of microparticles, making them available to support and pro­ mote the plasma coagulation reactions. ANTITHROMBOTIC MECHANISMS Several physiologic antithrombotic mechanisms act in concert to pre­ vent clotting under normal circumstances. These mechanisms operate to preserve blood fluidity and to limit blood clotting to specific focal sites of vascular injury. Endothelial cells have many antithrombotic effects. They produce prostacyclin, nitric oxide, and ectoADPase/ CD39, which act to inhibit platelet binding, secretion, and aggrega­ tion. Endothelial cells produce anticoagulant factors including heparan proteoglycans, TF pathway inhibitor, and thrombomodulin. They also activate fibrinolytic mechanisms through the production of tissue plas­ minogen activator, urokinase, plasmino­ gen activator inhibitors, and annexin-2. Antithrombin is the major plasma pro­ tease inhibitor of thrombin and other clot­ ting factors in coagulation. Antithrombin neutralizes thrombin and other activated coagulation factors by forming a complex between the active site of the enzyme and the reactive center of antithrombin. The rate of formation of these inactivating complexes increases by a factor of sev­ eral thousand in the presence of heparin. Antithrombin inactivation of thrombin and other activated clotting factors occurs physiologically on vascular surfaces, where glycosaminoglycans, including heparan sulfates, are present to catalyze these reactions. Inherited quantitative or qualitative deficiencies of antithrombin lead to a lifelong predisposition to venous thromboembolism (VTE). IX VIIIa XIa X XI Thrombin (IIa) Protein C is a plasma glycoprotein that becomes an anticoagulant when it is activated by thrombin. The thrombininduced activation of protein C occurs physiologically on thrombomodulin, a transmembrane proteoglycan-binding site

A D E D Thrombin Fibrin assembly D E D D E D D E D B D E D D E D D E D Fibrin cross-linking Factor XIIIa D E D D E D D E D C D E D D E D D E D Plasmin D D D E FIGURE 69-2  Fibrin formation and dissolution. (A) Fibrinogen is a trinodular structure consisting of two D domains and one E domain. Thrombin activation results in an ordered lateral assembly of protofibrils (B) with noncovalent associations. Factor XIIIa cross-links the D domains on adjacent molecules (C). Fibrin and fibrinogen (not shown) lysis by plasmin occurs at discrete sites and results in intermediary fibrin(ogen) degradation products (not shown). d-Dimers are the product of complete lysis of fibrin (D), maintaining the cross-linked D domains. for thrombin on endothelial cell surfaces. The binding of protein C to its receptor on endothelial cells places it in proximity to the thrombinthrombomodulin complex, thereby enhancing its activation efficiency. (See Fig. 69-3.) Activated protein C acts as an anticoagulant by cleav­ ing and inactivating activated factors V and VIII. This reaction is accel­ erated by a cofactor, protein S, which, like protein C, is a glycoprotein that undergoes vitamin K–dependent posttranslational modification. Quantitative or qualitative deficiencies of protein C or protein S, or resistance to the action of activated protein C by a specific variant at Protein S Free protein S FVIIIa FVa C4 binding protein Thrombomodulin APC FVIIIi FVi Protein C IIa Endothelial protein C receptor Endothelial cell FIGURE 69-3  The activated protein C pathway in regulation of thrombosis. Thrombin generation results in protein C activation through interaction with thrombomodulin and protein C bound to the endothelial protein C receptor (EPCR). Activated protein C (APC) with free protein S converts activated factors (F) VIII and V to inactivate forms, thus in turn decreasing thrombin generation. C4BP, C4 binding protein; EC, endothelial cell; F, factor; IIa, thrombin; PC, protein C; PS, protein S; TM, thrombomodulin.

its target cleavage site in factor Va (factor V Leiden), lead to hyperco­ agulable states.

Tissue factor pathway inhibitor (TFPI) is a plasma protease inhibi­ tor that regulates the TF-induced extrinsic pathway of coagulation. TFPI inhibits the TF/factor VIIa/factor Xa complex, essentially turning off the TF/factor VIIa initiation of coagulation, which then becomes dependent on the “amplification loop” via factor XI and factor VIII activation by thrombin. TFPI is bound to lipoprotein and can also be released by heparin from endothelial cells, where it is bound to gly­ cosaminoglycans, and from platelets. The heparin-mediated release of TFPI may play a role in the anticoagulant effects of unfractionated and low-molecular-weight heparins. Bleeding and Thrombosis CHAPTER 69 ■ ■THE FIBRINOLYTIC SYSTEM Any thrombin that escapes the inhibitory effects of the physiologic anticoagulant systems is available to convert fibrinogen to fibrin. In response, the endogenous fibrinolytic system is then activated to dispose of intravascular fibrin and thereby maintain or reestablish the patency of the circulation. Just as thrombin is the key protease enzyme of the coagulation system, plasmin is the major protease enzyme of the fibrinolytic system, acting to digest fibrin to fibrin degradation products. The general scheme of fibrinolysis and its control is shown in Fig. 69-4. Clot lysis The plasminogen activators, tissue type plasminogen activator (tPA) and the urokinase-type plasminogen activator (uPA), cleave the Arg560-Val561 bond of plasminogen to generate the active enzyme plasmin. The lysine-binding sites of plasmin (and plasminogen) permit it to bind to fibrin, so that physiologic fibrinolysis is “fibrin specific.” Both plasminogen (through its lysine-binding sites) and tPA possess specific affinity for fibrin and thereby bind selectively to clots. The assembly of a ternary complex, consisting of fibrin, plasminogen, and tPA, promotes the localized interaction between plasminogen and tPA and greatly accelerates the rate of plasminogen activation to plasmin. Moreover, partial degradation of fibrin by plasmin exposes new plas­ minogen and tPA-binding sites in carboxy-terminus lysine residues of fibrin fragments to enhance these reactions further. This creates a highly efficient mechanism to generate plasmin locally on the fibrin clot, which then becomes plasmin’s substrate for digestion to fibrin degradation products. Plasmin cleaves fibrin at distinct sites of the fibrin molecule, leading to the generation of characteristic fibrin fragments during the pro­ cess of fibrinolysis (Fig. 69-2). The sites of plasmin cleavage of fibrin are the same as those in fibrinogen. However, when plasmin acts on covalently cross-linked fibrin, d-dimers are released; hence, d-dimers uPA Plasminogen tPA PAI Plasmin Thrombin α2PI-Plasmin FDPs FIGURE 69-4  A schematic diagram of the fibrinolytic system. Tissue plasminogen activator (tPA) is released from endothelial cells, binds the fibrin clot, and activates plasminogen to plasmin. Release of plasminogen activator inhibitors (PAI-1 and PAI-2) inhibits tPA and urokinase (uPA). Excess fibrin is degraded by plasmin to distinct degradation products [FDPs (d-dimers)]. Any free plasmin is complexed with α2-antiplasmin (α2Pl). PAI, plasminogen activator inhibitor; uPA, urokinase-type plasminogen activator.

can be measured in plasma as a relatively specific test of fibrin (rather than fibrinogen) degradation. d-Dimer assays can be used as sensitive markers of blood clot formation and have been validated for clinical use to exclude the diagnosis of deep venous thrombosis (DVT) and pulmonary embolism in selected populations. d-Dimer levels increase with age. Use of an age-adjusted d-dimer threshold for risk stratifica­ tion results in less additional testing for VTE.

Physiologic regulation of fibrinolysis occurs primarily at three levels: (1) plasminogen activator inhibitors (PAIs), specifically PAI-1 and PAI-2, inhibit the physiologic plasminogen activators; (2) the thrombin-activatable fibrinolysis inhibitor (TAFI) limits fibrinolysis; and (3) α2-antiplasmin inhibits plasmin. PAI-1 is the primary inhibitor of tPA and uPA in plasma. TAFI cleaves the N-terminal lysine residues of fibrin, which aid in localization of plasmin activity. α2-Antiplasmin is the main inhibitor of plasmin in human plasma, inactivating any nonfibrin clot–associated plasmin. PART 2 Cardinal Manifestations and Presentation of Diseases APPROACH TO THE PATIENT Bleeding and Thrombosis CLINICAL PRESENTATION Disorders of hemostasis may be either inherited or acquired. A detailed personal and family history is key in determining the chronicity of symptoms and the likelihood of the disorder being inherited, as well as providing clues to underlying conditions that have contributed to the bleeding or thrombotic state. In addition, the history can give clues as to the etiology by determining (1) the bleeding (mucosal and/or joint) or thrombosis (arterial and/ or venous) site and (2) whether an underlying bleeding or clotting tendency was enhanced by another medical condition or the intro­ duction of medications or dietary supplements. History of Bleeding  A history of bleeding is the most important predictor of bleeding risk. In evaluating a patient for a bleeding disorder, a history of at-risk situations, including the response to past surgeries, should be assessed. Does the patient have a history of spontaneous or trauma/surgery-induced bleeding? Spontaneous hemarthroses are a hallmark of moderate and severe factor VIII and IX deficiency and, in rare circumstances, of other clotting fac­ tor deficiencies. Mucosal bleeding symptoms are more suggestive of underlying platelet disorders or von Willebrand disease (VWD), termed disorders of primary hemostasis or platelet plug formation. Disorders affecting primary hemostasis are shown in Table 69-1. A bleeding score has been validated as a tool to predict patients more likely to have an inherited bleeding disorder, particularly type 1 VWD (International Society on Thrombosis and Haemo­ stasis Bleeding Assessment Tool [www.isth.org/resource/resmgr/ssc/

isth-ssc_bleeding_assessment.pdf]), and a self-administered form has been validated. This is the most useful tool in excluding the diagnosis of a bleeding disorder, thus avoiding unnecessary testing, and is recommended by 2021 guidelines for screening for VWD in primary care. Bleeding symptoms that are more common in patients with bleeding disorders include prolonged bleeding with surgery, dental procedures and extractions, and/or trauma; heavy menstrual bleeding or postpartum hemorrhage; and large bruises (often described with lumps). Easy bruising and heavy menstrual bleeding are common com­ plaints in patients with and without bleeding disorders. Easy bruis­ ing can also be a sign of medical conditions in which there is no identifiable coagulopathy; instead, the conditions are caused by an abnormality of blood vessels or their supporting connective tissues. In Ehlers-Danlos syndrome, there may be posttraumatic bleed­ ing and a history of joint hyperextensibility. Cushing’s syndrome, chronic steroid use, and aging result in changes in skin and sub­ cutaneous tissue, and subcutaneous bleeding occurs in response to minor trauma. The latter has been termed senile purpura. Epistaxis is a common symptom, particularly in children and in dry climates, and may not reflect an underlying bleeding disorder.

TABLE 69-1  Primary Hemostatic (Platelet Plug) Disorders Defects of Platelet Adhesion von Willebrand disease Bernard-Soulier syndrome (absence or dysfunction of platelet Gp Ib-IX-V) Defects of Platelet Aggregation Glanzmann’s thrombasthenia (absence or dysfunction of platelet glycoprotein [Gp] IIb/IIIa) Afibrinogenemia Defects of Platelet Secretion Decreased cyclooxygenase activity   Drug-induced (aspirin, nonsteroidal anti-inflammatory agents, thienopyridines)   Inherited Granule storage pool defects   Inherited   Acquired Nonspecific inherited secretory defects Nonspecific drug effects Uremia Platelet coating (e.g., paraprotein, penicillin) Defect of Platelet Coagulant Activity Scott’s syndrome However, it is the most common symptom in hereditary hemor­ rhagic telangiectasia and in boys with VWD. Clues that epistaxis is a symptom of an underlying bleeding disorder include lack of seasonal variation and bleeding that requires medical evaluation or treatment, including cauterization. Bleeding with eruption of primary teeth is seen in children with more severe bleeding disorders, such as mod­ erate and severe hemophilia. It is uncommon in children with mild bleeding disorders. Patients with disorders of primary hemostasis (platelet adhesion) may have increased bleeding after dental clean­ ings and other procedures that involve gum manipulation. Heavy menstrual bleeding is defined quantitatively as a loss of >80 mL of blood per cycle, based on the quantity of blood loss required to produce iron-deficiency anemia. A complaint of heavy menses is subjective and has a poor correlation with excessive blood loss. Predictors of heavy menstrual bleeding include bleeding resulting in iron-deficiency anemia or a need for blood transfusion, passage of clots >1 inch in diameter, and changing a pad or tampon more than hourly. Heavy menstrual bleeding is a common symp­ tom in women with underlying bleeding disorders and is reported in the majority of women with VWD, factor XI deficiency, platelet function disorders, and hemophilia, including genetic carriers with borderline-normal factor levels. Women with underlying bleeding disorders are more likely to have other bleeding symptoms, includ­ ing bleeding after dental extractions and postoperative and postpar­ tum bleeding, and are much more likely to have heavy menstrual bleeding beginning at menarche than women with heavy menstrual bleeding due to other causes. Heavy menstrual bleeding may result in iron deficiency and is documented to have significant adverse effects on quality of life. Postpartum hemorrhage is a common symptom in women with underlying bleeding disorders. In women with type 1 VWD or hemophilia A in whom levels of VWF and factor VIII often nor­ malize during pregnancy, postpartum hemorrhage may be delayed. Women with a history of postpartum hemorrhage may have a higher risk of recurrence with subsequent pregnancies. Women with underlying bleeding disorders are at risk for other reproduc­ tive tract bleeding, including rupture of ovarian cysts with intraab­ dominal hemorrhage. Tonsillectomy is a major hemostatic challenge, because intact hemostatic mechanisms are essential to prevent excessive bleeding from the tonsillar bed. Bleeding may occur early after surgery or after approximately 7 days postoperatively, with loss of the eschar

at the operative site. Similar delayed bleeding is seen after colonic polyp resection. Gastrointestinal (GI) bleeding and hematuria are usually due to underlying pathology, and procedures to identify and treat the bleeding site should be undertaken, even in patients with known bleeding disorders. VWD, particularly types 2 and 3, is associated with angiodysplasia of the bowel and GI bleeding. Hemarthroses and spontaneous muscle hematomas are char­ acteristic of moderate or severe congenital factor VIII or IX defi­ ciency. They can also be seen in moderate and severe deficiencies of fibrinogen, prothrombin, and factors V, VII, and X. Spontaneous hemarthroses occur rarely in other bleeding disorders except for severe VWD, with associated very low factor VIII levels. Muscle and soft tissue bleeds are also common in acquired factor VIII deficiency. Bleeding into a joint results in severe pain and swelling, as well as loss of function, but is rarely associated with discoloration from bruising around the joint. Life-threatening sites of bleeding include bleeding into the oropharynx, where bleeding can obstruct the air­ way, into the central nervous system, and into the retroperitoneum. Central nervous system bleeding is the major cause of bleedingrelated deaths in patients with severe congenital factor deficiencies. Prohemorrhagic Effects of Medications and Dietary Supple­ ments  Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) that inhibit cyclooxygenase 1 impair primary hemostasis and may exacerbate bleeding from another cause or even unmask a previously occult mild bleeding disorder such as VWD. All NSAIDs, however, can precipitate GI bleeding, which may be more severe in patients with underlying bleeding disorders. The aspirin effect on platelet function lasts for the life of the platelet; however, in indi­ viduals with typical platelet turnover, the functional defect reverts to near-normal within 2–3 days after the last dose. The effect of other NSAIDs is shorter, as the inhibitor effect is reversed when the drug is removed. Inhibitors of the ADP P2Y12 receptor (clopidogrel, prasugrel, and ticagrelor) inhibit ADP-mediated platelet aggregation and, like NSAIDs, can precipitate or exacerbate bleeding symptoms. The risk of bleeding with these drugs is higher than with NSAIDs. Many herbal supplements can impair hemostatic function. Some are more convincingly associated with a bleeding risk than others. Fish oil or concentrated omega-3 fatty acid supplements impair platelet function. They alter platelet biochemistry to produce more PGI3, a more potent platelet inhibitor than prostacyclin (PGI2), and more thromboxane A3, a less potent platelet activator than throm­ boxane A2. In fact, diets naturally rich in omega-3 fatty acids can result in a prolonged bleeding time and abnormal platelet aggre­ gation studies, but the actual associated bleeding risk is unclear. Many supplements have been associated with increased bleeding with surgery and anticoagulant-related bleeding. In patients with unexplained bruising or bleeding, it is prudent to review any new medications or supplements and discontinue those that have been associated with bleeding. Underlying Systemic Diseases That Cause or Exacerbate a Bleeding Tendency  Acquired bleeding disorders are commonly secondary to, or associated with, systemic disease. The clinical evaluation of a patient with a bleeding tendency must therefore include a thorough assessment for evidence of underlying disease. Bruising or mucosal bleeding may be the presenting complaint in liver disease, severe renal impairment, hypothyroidism, paraproteinemias or amyloidosis, and conditions causing bone marrow failure. All coagulation factors are synthesized in the liver, and hepatic failure results in combined factor deficiencies. This is often compounded by thrombocytopenia and portal hypertension. Coagulation factors II, VII, IX, and X and proteins C, S, and Z are dependent on vitamin K for posttranslational modification. Although vitamin K is required in both procoagulant and anticoagulant processes, the phenotype of vitamin K deficiency or the warfarin effect on coagulation is bleeding. The normal blood platelet count is 150,000–450,000/μL. Throm­ bocytopenia results from decreased production, increased destruc­ tion, and/or sequestration. Although the bleeding risk varies

TABLE 69-2  Some Risk Factors for Thrombosis VENOUS VENOUS AND ARTERIAL Inherited   Factor V Leiden   Prothrombin G20210A   Antithrombin deficiency   Protein C deficiency   Protein S deficiency Acquired   Age   Previous thrombosis   Immobilization   Major surgery   Pregnancy and puerperium   Hospitalization   Obesity   Infection   Smoking Inherited   Homocystinuria   Dysfibrinogenemia Acquired   Malignancy   Antiphospholipid antibody syndrome   Hormonal therapy   Polycythemia vera   Essential thrombocythemia   Paroxysmal nocturnal hemoglobinuria   Thrombotic thrombocytopenic purpura   Heparin-induced thrombocytopenia   Disseminated intravascular coagulation   Infection Unknowna Bleeding and Thrombosis CHAPTER 69   Elevated factor II, VIII, IX, XI   Elevated TAFI levels   Low levels of TFPI aUnknown whether risk is inherited or acquired. Abbreviations: APC, activated protein C; TAFI, thrombin-activatable fibrinolysis inhibitor; TFPI, tissue factor pathway inhibitor. somewhat by the reason for the thrombocytopenia, bleeding rarely occurs in isolated thrombocytopenia at counts >50,000/μL and usually not until <10,000–20,000/μL. Coexisting coagulopathies, as is seen in liver failure or disseminated coagulation; infection; platelet-inhibitory drugs; and underlying medical conditions can all increase the risk of bleeding in the thrombocytopenic patient. Most procedures can be performed in patients with a platelet count of 50,000/μL or greater. HISTORY OF THROMBOSIS The risk of thrombosis, like that of bleeding, is influenced by both genetic and environmental factors. The major risk factor for arte­ rial thrombosis is atherosclerosis, whereas for venous thrombosis, the risk factors are immobility, surgery, underlying medical condi­ tions such as malignancy, medications such as hormonal therapy, obesity, and genetic predispositions. Factors that increase risks for venous and for both venous and arterial thromboses are shown in Table 69-2. The most important point in a history related to venous throm­ bosis is determining whether the thrombotic event was idiopathic (meaning there was no clear precipitating factor) or was a precipi­ tated event. In patients without underlying malignancy, having an idiopathic event is the strongest predictor of recurrence of VTE. In patients who have a vague history of thrombosis, a history of being treated with warfarin or other anticoagulants suggests a past DVT. Age is an important risk factor for venous thrombosis—the risk of DVT increases per decade, with an approximate incidence of 1/100,000 per year in early childhood to 1/200 per year among octogenarians. Family history is helpful in determining if there is a genetic predisposition and how strong that predisposition appears to be. A genetic thrombophilia that confers a relatively small increased risk, such as being a heterozygote for the prothrombin G20210A or factor V Leiden mutation, is a minor determinant of risk in an elderly individual undergoing a high-risk surgical procedure. As illustrated in Fig. 69-5, a thrombotic event usually has more than one contributing factor. Predisposing factors must be carefully assessed to determine the risk of recurrent thrombosis and, with consideration of the patient’s bleeding risk, determine the length of anticoagulation. Testing for inherited thrombophilias in adults should be limited to instances where results would change clinical care. Such instances are rare.

OCP use Leg in cast HRT use Thrombotic risk DVT Thrombosis Surgery PART 2 Cardinal Manifestations and Presentation of Diseases Factor V Leiden Age FIGURE 69-5  Thrombotic risk over time. Shown schematically is an individual’s thrombotic risk over time. An underlying factor V Leiden variant provides a “theoretically” constant increased risk. The thrombotic risk increases with age and, intermittently, with oral contraceptive (OCP) or oral hormone replacement therapy (HRT) use; other events, like major surgery or illness, will increase the risk further. At some point, the cumulative risk may increase to the threshold for thrombosis and result in deep venous thrombosis (DVT). Note: The magnitude and duration of risk portrayed in the figure are meant for example only and may not precisely reflect the relative risk determined by clinical study. (Sources: From BA Konkle, A Schafer, in DP Zipes et al [eds]: Braunwald’s Heart Disease, 7th ed. Philadelphia, Saunders, 2005; from FR Rosendaal: Venous thrombosis: A multicausal disease. Lancet 353:1167, 1999.) LABORATORY EVALUATION Careful history taking and clinical examination are essential com­ ponents in the assessment of bleeding and thrombotic risk. The use of laboratory tests of coagulation complements, but cannot substitute for, clinical assessment. No test exists that provides a global assessment of hemostasis. Thrombin generation assays have not generally provided reproducible results across laboratories. The bleeding time does not predict bleeding risk, and it is not recom­ mended for this indication. Thromboelastography can be useful in guiding intraoperative transfusion and is being explored in other settings but is not broadly applicable for the diagnosis of disorders of hemostasis and thrombosis. For routine preoperative and preprocedure testing, an abnormal prothrombin time (PT) may detect liver disease or vitamin K defi­ ciency that had not been previously appreciated. Studies have not confirmed the usefulness of an activated partial thromboplastin time (aPTT) in preoperative evaluations in patients with a negative bleeding history. The primary use of coagulation testing should be to confirm the presence and type of bleeding disorder in a patient with a suspicious clinical history. Because of the nature of coagulation assays, proper sample acquisition and handling is critical to obtaining valid results. In patients with abnormal coagulation assays who have no bleeding history, repeat studies with attention to these factors frequently results in normal values. Most coagulation assays are performed in sodium citrate anticoagulated plasma that is recalcified for the assay. Because the anticoagulant is in liquid solution and needs to be added to blood in proportion to the plasma volume, incorrectly filled or inadequately mixed blood collection tubes will give errone­ ous results. These vacutainer tubes should be filled to >90% of the recommended fill, which is usually denoted by a line on the tube. An elevated hematocrit (>55%) can result in a false value due to a decreased plasma-to-anticoagulant ratio. Screening Assays  The most commonly used screening tests are the PT, aPTT, and platelet count. The PT assesses the factors I

aPTT HMWK PT PK FXII FVII FXI FIX FVIII FX FV Prothrombin (FII) Fibrinogen (FI) FIGURE 69-6  Coagulation factor activity tested in the activated partial thromboplastin time (aPTT) in red and prothrombin time (PT) in green, or both. F, factor; HMWK, high-molecular-weight kininogen; PK, prekallikrein. (fibrinogen), II (prothrombin), V, VII, and X (Fig. 69-6). The PT measures the time for clot formation of the citrated plasma after recalcification and addition of thromboplastin, a mixture of TF and phospholipids. The sensitivity of the assay varies by the source of thromboplastin. The relationship between defects in secondary hemostasis (fibrin formation) and coagulation test abnormalities is shown in Table 69-3. To adjust for this variability, the overall sensitivity of different thromboplastins to reduction of the vitamin K–dependent clotting factors II, VII, IX, and X in anticoagulation patients is expressed as the International Sensitivity Index (ISI). The international normalized ratio (INR) is determined based on the formula: INR = (PTpatient/PTnormal mean)ISI. The INR was developed to assess stable anticoagulation due to reduction of vitamin K–dependent coagulation factors; it is commonly used in the evaluation of patients with liver disease. Although it does allow comparison between laboratories, reagent sensitivity as used to determine the ISI is not the same in liver disease as with warfarin anticoagulation. In addition, progressive liver failure is associated with variable changes in coagulation fac­ tors; the degree of prolongation of either the PT or the INR only roughly predicts the bleeding risk. Thrombin generation has been shown to be normal in many patients with mild to moderate liver dysfunction. Because the PT only measures one aspect of hemosta­ sis affected by liver dysfunction, we likely overestimate the bleed­ ing risk of a mildly elevated INR in this setting. PT reagents have variable sensitivity to the direct Xa inhibitors, and the PT is usually normal in patients on apixaban. The aPTT assesses the intrinsic and common coagulation path­ ways; factors XI, IX, VIII, X, V, and II; fibrinogen; prekallikrein; high-molecular-weight kininogen; and factor XII (Fig. 69-6). The aPTT reagent contains phospholipids derived from either animal or vegetable sources that function as a platelet substitute in the coagu­ lation pathways and includes an activator of the intrinsic coagula­ tion system, such as nonparticulate ellagic acid or the particulate activators kaolin, celite, or micronized silica. The phospholipid composition of aPTT reagents varies, which influences the sensitivity of individual reagents to clotting factor deficiencies and to inhibitors such as heparin and lupus anticoagu­ lants. Thus, aPTT results will vary from one laboratory to another, and the normal range in the laboratory where the testing occurs

TABLE 69-3  Hemostatic Disorders and Coagulation Test Abnormalities Prolonged Activated Partial Thromboplastin Time (aPTT) No clinical bleeding—↓ factor XII, high-molecular-weight kininogen, prekallikrein Variable, but usually mild, bleeding—↓ factor XI, mild ↓ factor VIII and factor IX Frequent, severe bleeding—severe deficiencies of factors VIII and IX Heparin and direct thrombin inhibitors Prolonged Prothrombin Time (PT) Factor VII deficiency Vitamin K deficiency—early Warfarin anticoagulation Direct Xa inhibitors (rivaroxaban, edoxaban, apixaban—note PT may be normal) Prolonged aPTT and PT Factor II, V, X, or fibrinogen deficiency Vitamin K deficiency—late Direct thrombin inhibitors Prolonged Thrombin Time Heparin or heparin-like inhibitors Direct thrombin inhibitors (e.g., dabigatran, argatroban, bivalirudin) Mild or no bleeding—dysfibrinogenemia Frequent, severe bleeding—afibrinogenemia Prolonged PT and/or aPTT Not Corrected with Mixing with Normal Plasma Bleeding—specific factor inhibitor No symptoms, or clotting and/or pregnancy loss—lupus anticoagulant Disseminated intravascular coagulation Heparin or direct thrombin inhibitor Abnormal Clot Solubility Factor XIII deficiency Inhibitors or defective cross-linking Rapid Clot Lysis Deficiency of α2-antiplasmin or plasminogen activator inhibitor 1 Treatment with fibrinolytic therapy should be used in the interpretation. Local laboratories can relate their aPTT values to the therapeutic heparin anticoagulation by correlating aPTT values with direct measurements of heparin activ­ ity (anti-Xa or protamine titration assays) in samples from heparin­ ized patients, although correlation between these assays is often poor. The aPTT reagent will vary in sensitivity to individual factor deficiencies and usually becomes prolonged with individual factor deficiencies of ≤30–50%. Mixing Studies  Mixing studies are used to evaluate a prolonged aPTT or, less commonly, PT to distinguish between a factor defi­ ciency and an inhibitor. In this assay, normal plasma and patient plasma are mixed in a 1:1 ratio, and the aPTT or PT is determined immediately and after incubation at 37°C for varying times, typi­ cally 30, 60, and/or 120 min. With isolated factor deficiencies, the aPTT will correct with mixing and stay corrected with incubation. With aPTT prolongation due to a lupus anticoagulant, the mixing and incubation will show no correction. In acquired neutralizing factor antibodies, notably an acquired factor VIII inhibitor, the ini­ tial assay may or may not correct immediately after mixing but will prolong or remain prolonged with incubation at 37°C. Failure to correct with mixing can also be due to the presence of other inhibi­ tors or interfering substances such as heparin, fibrin split products, and paraproteins. Specific Factor Assays  Decisions to proceed with specific clot­ ting factor assays will be influenced by the clinical situation and the results of coagulation screening tests. Precise diagnosis and effec­ tive management of inherited and acquired coagulation deficiencies

necessitate quantitation of the relevant factors. When bleeding is severe, specific assays are urgently required to guide appropriate therapy. Individual factor assays are usually performed as modi­ fications of the mixing study, where the patient’s plasma is mixed with plasma deficient in the factor being studied. This will correct all factor deficiencies to >50%, thus making prolongation of clot formation due to a factor deficiency dependent on the factor miss­ ing from the added plasma. Chromogenic assays may also be used. Testing for Antiphospholipid Antibodies  Antibodies to phos­ pholipids (cardiolipin) or phospholipid-binding proteins (β2-microglobulin and others) are detected by enzyme-linked immunosorbent assay (ELISA). When these antibodies interfere with phospholipid-dependent coagulation tests, they are termed lupus anticoagulants. The aPTT has variability sensitivity to lupus anticoagulants, depending in part on the aPTT reagents used. An assay using a sensitive reagent has been termed an LA-PTT. The dilute Russell viper venom test (dRVVT) is a modification of a standard test with the phospholipid reagent decreased, thus increasing the sensitivity to antibodies that interfere with the phos­ pholipid component. These tests, however, are not specific for lupus anticoagulants, because factor deficiencies or other inhibitors will also result in prolongation. Documentation of a lupus anticoagu­ lant requires not only prolongation of a phospholipid-dependent coagulation test but also lack of correction when mixed with nor­ mal plasma and correction with the addition of activated platelet membranes or certain phospholipids (e.g., hexagonal phase). Bleeding and Thrombosis CHAPTER 69 Other Coagulation Tests  The thrombin time and the reptilase time measure fibrinogen conversion to fibrin and are prolonged when the fibrinogen level is low (usually <80–100 mg/dL) or quali­ tatively abnormal, as seen in inherited or acquired dysfibrinogen­ emias, or when fibrin/fibrinogen degradation products interfere. The thrombin time, but not the reptilase time, is prolonged in the presence of heparin. The thrombin time is markedly prolonged in the presence of the direct thrombin inhibitor, dabigatran; a dilute thrombin time is used to assess drug activity. Measurement of anti–factor Xa plasma inhibitory activity is a test frequently used to assess low-molecular-weight heparin (LMWH) levels, as a direct measurement of unfractionated heparin (UFH) activity, or to assess activity of the direct Xa inhibitors rivaroxaban, apixaban, and edox­ aban. Drug in the patient sample inhibits the enzymatic conversion of an Xa-specific chromogenic substrate to colored product by fac­ tor Xa. Standard curves are created using multiple concentrations of the specific drug and are used to calculate the concentration of anti-Xa activity in the patient plasma. Laboratory Testing for Thrombophilia  Laboratory assays to detect thrombophilic states include molecular diagnostics and immuno­ logic and functional assays. These assays vary in their sensitivity and specificity for the condition being tested. Furthermore, acute thrombosis, acute illnesses, inflammatory conditions, pregnancy, and medications affect levels of many coagulation factors and their inhibitors. Antithrombin is decreased by heparin and in the set­ ting of acute thrombosis. Protein C and S levels may be increased in the setting of acute thrombosis and are decreased by warfarin. Antiphospholipid antibodies are frequently transiently positive in acute illness. Testing for genetic thrombophilias should, in general, only be performed when there is a strong family history of throm­ bosis and results would affect clinical decision-making. Because thrombophilia evaluations are usually performed to assess the need to extend anticoagulation, testing, if indicated, should be performed in a steady state, remote from the acute event. Functional assays, but not genetic assays, will be affected by anti­ coagulants including warfarin (for vitamin K–dependent proteins) and thrombin and Xa inhibitors and cannot be interpreted in patients on those drugs. In most instances, when discontinuation of anticoagulation is being considered, drugs can be stopped after the initial 3–6 months of treatment, and testing can be performed at least 3 weeks later.

66 - 70 Enlargement of Lymph Nodes and Spleen

70 Enlargement of Lymph Nodes and Spleen

Measures of Platelet Function  The bleeding time was used in the past to assess platelet function but is nonspecific and it is not recommended for use for this indication. The PFA-100 and similar instruments that measure platelet-dependent coagulation under flow conditions are generally more sensitive and specific for plate­ let disorders and VWD than the bleeding time; however, data are insufficient to support their use to predict bleeding risk or monitor response to therapy, and they will be normal in some patients with platelet disorders or mild VWD. When they are used in the evalua­ tion of a patient with bleeding symptoms, abnormal results require specific testing, such as VWF assays and/or platelet aggregation studies. Because all of these “screening” assays may miss patients with mild bleeding disorders, further studies are needed to define their role in hemostasis testing. PART 2 Cardinal Manifestations and Presentation of Diseases For classic platelet aggregometry, various agonists are added to the patient’s platelet-rich plasma or whole blood, and platelet aggregation is measured. Tests of platelet secretion in response to agonists can also be measured. These remain the gold standard for diagnosis of platelet function disorders. However, they are affected by many factors, including numerous medications, and the associa­ tion between minor defects in these assays and bleeding risk is not clearly established. ■ ■FURTHER READING Baker P et al: Guidelines on the laboratory aspects of assays used in haemostasis and thrombosis. Br J Haematol 191:347, 2020. Connors JM: Thrombophilia testing and venous thrombosis. N Engl J Med 377:12, 2017. Darzi AJ et al: Prognostic factors for VTE and bleeding in hospitalized medical patients: A systematic review and meta-analysis. Blood 135:1788, 2020. Devreese KMJ et al: Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis update of the guidelines for lupus anticoagulant detection and interpretation. J Thromb Haemost 18:2828, 2020. Elbaz C, Sholzberg M: An illustrated review of bleeding assessment tools and common coagulation tests. Res Pract Thromb Haemost 4:761, 2020. Hatfield et al: Dietary supplements and bleeding. Proc (Bayl Univ Med Cent) 35:802, 2022. James PD et al: ASH ISTH NHF WFH 2021 guidelines on the diagno­ sis of von Willebrand disease. Blood Adv 5:280, 2021. Moran J, Bauer KA: Managing thromboembolic risk in patients with hereditary and acquired thrombophilias. Blood 135:344, 2020. Risman RA et al: Fibrinolysis: an illustrated review. Res Pract Thromb Haemost 7:e100081, 2023. Yau JW et al: Endothelial cell control of thrombosis. BMC Cardiovasc Disord 15:130, 2015. Dan L. Longo

Enlargement of Lymph

Nodes and Spleen This chapter is intended to serve as a guide to the evaluation of patients who present with enlargement of the lymph nodes (lymphadenopathy) or the spleen (splenomegaly). Lymphadenopathy is a rather common clinical finding in primary care settings, whereas palpable spleno­ megaly is less so.

LYMPHADENOPATHY Lymphadenopathy may be an incidental finding in patients being examined for various reasons, or it may be a presenting sign or symp­ tom of the patient’s illness. The physician must eventually decide whether the lymphadenopathy is a normal finding or one that requires further study, up to and including biopsy. Soft, flat, submandibular nodes (<1 cm) are often palpable in healthy children and young adults; healthy adults may have palpable inguinal nodes of up to 2 cm, which are considered normal. Further evaluation of these normal nodes is not warranted. In contrast, if the physician believes the node(s) to be abnormal, then pursuit of a more precise diagnosis is needed. APPROACH TO THE PATIENT Lymphadenopathy Lymphadenopathy may be a primary or secondary manifesta­ tion of numerous disorders, as shown in Table 70-1. Many of these disorders are infrequent causes of lymphadenopathy. In primary care practice, more than two-thirds of patients with lymphadenopathy have nonspecific causes or upper respiratory illnesses (viral or bacterial) and <1% have a malignancy. In one study, 84% of patients referred for evaluation of lymphadenopathy had a “benign” diagnosis. The remaining 16% had a malignancy (lymphoma or metastatic adenocarcinoma). Of the patients with benign lymphadenopathy, 63% had a nonspecific or reactive etiol­ ogy (no causative agent found), and the remainder had a specific cause demonstrated, most commonly infectious mononucleosis, toxoplasmosis, or tuberculosis. Thus, the vast majority of patients with lymphadenopathy will have a nonspecific etiology requiring few diagnostic tests. CLINICAL ASSESSMENT The physician will be aided in the pursuit of an explanation for the lymphadenopathy by a careful medical history, physical examina­ tion, selected laboratory tests, and perhaps an excisional lymph node biopsy. The medical history should reveal the setting in which lymphade­ nopathy is occurring. Symptoms such as sore throat, cough, fever, night sweats, fatigue, weight loss, or pain in the nodes should be sought. The patient’s age, sex, occupation, exposure to pets, sexual behavior, and use of drugs such as diphenylhydantoin are other important historic points. For example, children and young adults usually have benign (i.e., nonmalignant) disorders that account for the observed lymphadenopathy such as viral or bacterial upper respiratory infections; infectious mononucleosis; toxoplasmosis; and, in some countries, tuberculosis. In contrast, after age 50, the incidence of malignant disorders increases and that of benign dis­ orders decreases. The physical examination can provide useful clues such as the extent of lymphadenopathy (localized or generalized), size of nodes, texture, presence or absence of nodal tenderness, signs of inflamma­ tion over the node, skin lesions, and splenomegaly. A thorough ear, nose, and throat (ENT) examination is indicated in adult patients with cervical adenopathy and a history of tobacco use. Localized or regional adenopathy implies involvement of a single anatomic area. Generalized adenopathy has been defined as involvement of three or more noncontiguous lymph node areas. Many of the causes of lymphadenopathy (Table 70-1) can produce localized or generalized adenopathy, so this distinction is of limited utility in the differential diagnosis. Nevertheless, generalized lymphadenopathy is frequently associated with nonmalignant disorders such as infectious mono­ nucleosis (Epstein-Barr virus [EBV] or cytomegalovirus [CMV]), toxoplasmosis, AIDS, other viral infections, systemic lupus ery­ thematosus (SLE), and mixed connective tissue disease. Acute and chronic lymphocytic leukemias and malignant lymphomas also produce generalized adenopathy in adults. The site of localized or regional adenopathy may provide a use­ ful clue about the cause. Occipital adenopathy often reflects an

TABLE 70-1  Diseases Associated with Lymphadenopathy

1. Infectious diseases a. Viral—infectious mononucleosis syndromes (EBV, CMV), infectious hepatitis, herpes simplex, herpesvirus-6, varicella-zoster virus, rubella, measles, adenovirus, HIV, epidemic keratoconjunctivitis, vaccinia, herpesvirus-8 b. Bacterial—streptococci, staphylococci, cat-scratch disease, brucellosis, tularemia, plague, chancroid, melioidosis, glanders, tuberculosis, atypical mycobacterial infection, primary and secondary syphilis, diphtheria, leprosy, bartonella c. Fungal—histoplasmosis, coccidioidomycosis, paracoccidioidomycosis d. Chlamydial—lymphogranuloma venereum, trachoma e. Parasitic—toxoplasmosis, leishmaniasis, trypanosomiasis, filariasis f. Rickettsial—scrub typhus, rickettsialpox, Q fever
2. Immunologic diseases a. Rheumatoid arthritis b. Juvenile rheumatoid arthritis c. Mixed connective tissue disease d. Systemic lupus erythematosus e. Dermatomyositis f. Sjögren’s syndrome g. Serum sickness h. Drug hypersensitivity—diphenylhydantoin, hydralazine, allopurinol, primidone, gold, carbamazepine, etc. i. Angioimmunoblastic lymphadenopathy j. Primary biliary cirrhosis k. Graft-versus-host disease l. Silicone-associated m. Autoimmune lymphoproliferative syndrome n. IgG4-related disease o. Immune reconstitution inflammatory syndrome (IRIS)
3. Malignant diseases a. Hematologic—Hodgkin’s disease, non-Hodgkin’s lymphomas, acute or chronic lymphocytic leukemia, hairy cell leukemia, malignant histiocytosis, amyloidosis b. Metastatic—from numerous primary sites
4. Lipid storage diseases—Gaucher’s, Niemann-Pick, Fabry, Tangier
5. Endocrine diseases—hyperthyroidism
6. Passive congestion
7. Other disorders a. Castleman’s disease (giant lymph node hyperplasia) b. Sarcoidosis c. Dermatopathic lymphadenitis d. Lymphomatoid granulomatosis e. Histiocytic necrotizing lymphadenitis (Kikuchi’s disease) f. Sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) g. Mucocutaneous lymph node syndrome (Kawasaki’s disease) h. Histiocytosis X i. Familial Mediterranean fever j. Severe hypertriglyceridemia k. Vascular transformation of sinuses l. Inflammatory pseudotumor of lymph node m. Congestive heart failure Abbreviations: CMV, cytomegalovirus; EBV, Epstein-Barr virus. infection of the scalp, and preauricular adenopathy accompanies conjunctival infections and cat-scratch disease. The most frequent site of regional adenopathy is the neck, and most of the causes are benign—upper respiratory infections, oral and dental lesions, infec­ tious mononucleosis, or other viral illnesses. The chief malignant causes include metastatic cancer from head and neck, breast, lung, and thyroid primaries. Enlargement of supraclavicular and scalene nodes is always abnormal. Because these nodes drain regions of

the lung and retroperitoneal space, they can reflect lymphomas, other cancers, or infectious processes arising in these areas. Vir­ chow’s node is an enlarged left supraclavicular node infiltrated with metastatic cancer from a gastrointestinal primary. Metastases to supraclavicular nodes also occur from lung, breast, testis, or ovarian cancers. Tuberculosis, sarcoidosis, and toxoplasmosis are nonneo­ plastic causes of supraclavicular adenopathy. Axillary adenopathy is usually due to injuries or localized infections of the ipsilateral upper extremity. Malignant causes include melanoma or lymphoma and, in women, breast cancer. Inguinal lymphadenopathy is usually secondary to infections or trauma of the lower extremities and may accompany sexually transmitted diseases such as lymphogranuloma venereum, primary syphilis, genital herpes, or chancroid. These nodes may also be involved by lymphomas and metastatic cancer from primary lesions of the rectum, genitalia, or lower extremities (melanoma). Enlargement of Lymph Nodes and Spleen CHAPTER 70 The size and texture of the lymph node(s) and the presence of pain are useful parameters in evaluating a patient with lymph­ adenopathy. Nodes <1.0 cm2 in area (1.0 cm × 1.0 cm or less) are almost always secondary to benign, nonspecific reactive causes. In one retrospective analysis of younger patients (9–25 years) who had a lymph node biopsy, a maximum diameter of >2 cm served as one discriminant for predicting that the biopsy would reveal malignant or granulomatous disease. Another study showed that a lymph node size of 2.25 cm2 (1.5 cm × 1.5 cm) was the best size limit for distinguishing malignant or granulomatous lymphadenopathy from other causes of lymphadenopathy. Patients with node(s) ≤1.0 cm2 should be observed after excluding infectious mononucleosis and/ or toxoplasmosis unless there are symptoms and signs of an under­ lying systemic illness. The texture of lymph nodes may be described as soft, firm, rub­ bery, hard, discrete, matted, tender, movable, or fixed. Tenderness is found when the capsule is stretched during rapid enlargement, usually secondary to an inflammatory process. Some malignant diseases such as acute leukemia may produce rapid enlargement and pain in the nodes. Nodes involved by lymphoma tend to be large, discrete, symmetric, rubbery, firm, mobile, and nontender. Nodes containing metastatic cancer are often hard, nontender, and nonmovable because of fixation to surrounding tissues. The coexistence of splenomegaly in the patient with lymphadenopathy implies a systemic illness such as infectious mononucleosis, lym­ phoma, acute or chronic leukemia, SLE, sarcoidosis, toxoplasmosis, cat-scratch disease, or other less common hematologic disorders. The patient’s story should provide helpful clues about the underly­ ing systemic illness. Nonsuperficial presentations (thoracic or abdominal) of adenop­ athy are usually detected as the result of a symptom-directed diag­ nostic workup. Thoracic adenopathy may be detected by routine chest radiography or during the workup for superficial adenopathy. It may also be found because the patient complains of a cough or wheezing from airway compression; hoarseness from recurrent laryngeal nerve involvement; dysphagia from esophageal compres­ sion; or swelling of the neck, face, or arms secondary to compres­ sion of the superior vena cava or subclavian vein. The differential diagnosis of mediastinal and hilar adenopathy includes primary lung disorders and systemic illnesses that characteristically involve mediastinal or hilar nodes. In the young, mediastinal adenopathy is associated with infectious mononucleosis and sarcoidosis. In endemic regions, histoplasmosis can cause unilateral paratracheal lymph node involvement that mimics lymphoma. Tuberculosis can also cause unilateral adenopathy. In older patients, the differential diagnosis includes primary lung cancer (especially among smok­ ers), lymphomas, metastatic carcinoma (usually lung), tuberculosis, fungal infection, and sarcoidosis. Enlarged intraabdominal or retroperitoneal nodes are usu­ ally malignant. Although tuberculosis may present as mesenteric lymphadenitis, these masses usually contain lymphomas or, in young men, germ cell tumors.

LABORATORY INVESTIGATION The laboratory investigation of patients with lymphadenopathy must be tailored to elucidate the etiology suspected from the patient’s history and physical findings. One study from a family practice clinic evaluated 249 younger patients with “enlarged lymph nodes, not infected” or “lymphadenitis.” No laboratory studies were obtained in 51%. When studies were performed, the most common were a complete blood count (CBC) (33%), throat culture (16%), chest x-ray (12%), or monospot test (10%). Only eight patients (3%) had a node biopsy, and half of those were normal or reactive. The CBC can provide useful data for the diagnosis of acute or chronic leukemias, EBV or CMV mononucleosis, lymphoma with a leu­ kemic component, pyogenic infections, or immune cytopenias in illnesses such as SLE. Serologic studies may demonstrate antibod­ ies specific to components of EBV, CMV, HIV, and other viruses; Toxoplasma gondii; Brucella; etc. If SLE is suspected, antinuclear and anti-DNA antibody studies are warranted. PART 2 Cardinal Manifestations and Presentation of Diseases The chest x-ray is usually negative, but the presence of a pul­ monary infiltrate or mediastinal lymphadenopathy would suggest tuberculosis, histoplasmosis, sarcoidosis, lymphoma, primary lung cancer, or metastatic cancer and demands further investigation. A variety of imaging techniques (CT, MRI, ultrasound, color Doppler ultrasonography) have been employed to differentiate benign from malignant lymph nodes, especially in patients with head and neck cancer. CT and MRI are comparably accurate (65– 90%) in the diagnosis of metastases to cervical lymph nodes. Ultra­ sonography has been used to determine the long (L) axis, short (S) axis, and a ratio of long to short axis in cervical nodes. An L/S ratio of <2.0 has a sensitivity and a specificity of 95% for distinguishing benign and malignant nodes in patients with head and neck cancer. This ratio has greater specificity and sensitivity than palpation or measurement of either the long or the short axis alone. The indications for lymph node biopsy are imprecise, yet it is a valuable diagnostic tool. The decision to biopsy may be made early in a patient’s evaluation or delayed for up to two weeks. Prompt biopsy should occur if the patient’s history and physical findings suggest a malignancy; examples include a solitary, hard, nontender cervical node in an older patient who is a chronic user of tobacco; supraclavicular adenopathy; and solitary or generalized adenopathy that is firm, movable, and suggestive of lymphoma. If a primary head and neck cancer is suspected as the basis of a solitary, hard cer­ vical node, then a careful ENT examination should be performed. Any mucosal lesion that is suspicious for a primary neoplastic process should be biopsied first. If no mucosal lesion is detected, an excisional biopsy of the largest node should be performed. Fineneedle aspiration should not be performed as the first diagnostic procedure. Most diagnoses require more tissue than such aspiration can provide, and it often delays a definitive diagnosis. Fine-needle aspiration should be reserved for thyroid nodules and for confirma­ tion of relapse in patients whose primary diagnosis is known. If the primary physician is uncertain about whether to proceed to biopsy, consultation with a hematologist or medical oncologist should be helpful. In primary care practices, <5% of lymphadenopathy patients will require a biopsy. That percentage will be considerably larger in referral practices, i.e., hematology, oncology, or ENT. Two groups have reported algorithms that they claim will identify more precisely those lymphadenopathy patients who should have a biopsy. Both reports were retrospective analyses in referral practices. The first study involved patients 9–25 years of age who had a node biopsy performed. Three variables were identified that predicted those young patients with peripheral lymphadenopathy who should undergo biopsy; lymph node size >2 cm in diameter and abnormal chest x-ray had positive predictive values, whereas recent ENT symp­ toms had negative predictive values. The second study evaluated 220 lymphadenopathy patients in a hematology unit and identified five variables (lymph node size, location [supraclavicular or nonsupra­ clavicular], age [>40 years or <40 years], texture [nonhard or hard], and tenderness) that were used in a mathematical model to identify

those patients requiring a biopsy. Positive predictive value was found for age >40 years, supraclavicular location, node size >2.25 cm2, hard texture, and lack of pain or tenderness. Negative predictive value was evident for age <40 years, node size <1.0 cm2, nonhard texture, and tender or painful nodes. Ninety-one percent of those who required biopsy were correctly classified by this model. Because both of these studies were retrospective analyses and one was limited to young patients, it is not known how useful these models would be if applied prospectively in a primary care setting. Most lymphadenopathy patients do not require a biopsy, and at least half require no laboratory studies. If the patient’s history and physical findings point to a benign cause for lymphadenopathy, careful follow-up at a 2- to 4-week interval can be employed. The patient should be instructed to return for reevaluation if there is an increase in the size of the nodes. Antibiotics are not indicated for lymphadenopathy unless strong evidence of a bacterial infection is present. Glucocorticoids should not be used to treat lymphade­ nopathy because their lympholytic effect obscures some diagnoses (lymphoma, leukemia, Castleman’s disease) and they contribute to delayed healing or activation of underlying infections. An excep­ tion to this statement is the life-threatening pharyngeal obstruction by enlarged lymphoid tissue in Waldeyer’s ring that is occasionally seen in infectious mononucleosis. SPLENOMEGALY ■ ■STRUCTURE AND FUNCTION OF THE SPLEEN The spleen is a reticuloendothelial organ that has its embryologic origin in the dorsal mesogastrium at about 5 weeks’ gestation. It arises in a series of hillocks, migrates to its normal adult location in the left upper quadrant (LUQ), and is attached to the stomach via the gastroli­ enal ligament and to the kidney via the lienorenal ligament. When the hillocks fail to unify into a single tissue mass, accessory spleens may develop in around 20% of persons. The function of the spleen has been elusive. Galen believed it was the source of “black bile” or melancholia, and the word hypochondria (literally, beneath the ribs) and the idiom “to vent one’s spleen” attest to the beliefs that the spleen had an impor­ tant influence on the psyche and emotions.* In humans, its normal physiologic roles seem to be the following:

1. Maintenance of quality control over erythrocytes in the red pulp by removal of senescent and defective red blood cells. The spleen accomplishes this function through a unique organization of its parenchyma and vasculature (Fig. 70-1).
2. Synthesis of antibodies in the white pulp.
3. The removal of antibody-coated bacteria and antibody-coated blood cells from the circulation. An increase in these normal functions may result in splenomegaly. The spleen is composed of red pulp and white pulp, which are Malpighi’s terms for the red blood–filled sinuses and reticuloen­ dothelial cell–lined cords and the white lymphoid follicles arrayed within the red pulp matrix. The spleen is in the portal circulation. The reason for this is unknown but may relate to the fact that lower blood pressure allows less rapid flow and minimizes damage to normal erythrocytes. Blood flows into the spleen at a rate of about 150 mL/min through the splenic artery, which ultimately ramifies into central arterioles. Some blood goes from the arterioles to capillar­ ies and then to splenic veins and out of the spleen, but the majority of blood from central arterioles flows into the macrophage-lined sinuses and cords. The blood entering the sinuses reenters the circu­ lation through the splenic venules, but the blood entering the cords is subjected to an inspection of sorts. To return to the circulation, the blood cells in the cords must squeeze through slits in the cord lining to enter the sinuses that lead to the venules. Old and damaged erythrocytes are less deformable and are retained in the cords, where *Reproduced with permission from RS Hillman, KA Ault: Hematology in Clinical Practice, 4th ed. New York, McGraw-Hill; 2005.

Central artery Primary follicle (B-cell area) Secondary follicle with germinal center (B-cell area) Lymphoid T-cell area Marginal lymphoid zone Arterial capillaries Pulp sinus Pulp cord Pulp sinus Pulp cord
Splenic venous system Arterioles Sinusoidal pores Pulp cord Sinusoids Pulp sinuses RE cells To splenic venous system FIGURE 70-1  Schematic spleen structure. The spleen comprises many units of red and white pulp centered around small branches of the splenic artery, called central arteries. White pulp is lymphoid in nature and contains B-cell follicles, a marginal zone around the follicles, and T-cell–rich areas sheathing arterioles. The red pulp areas include pulp sinuses and pulp cords. The cords are dead ends. In order to regain access to the circulation, red blood cells must traverse tiny openings in the sinusoidal lining. Stiff, damaged, or old red cells cannot enter the sinuses. RE, reticuloendothelial. (Bottom portion of figure reproduced with permission from RS Hillman, KA Ault: Hematology in Clinical Practice, 4th ed. New York, McGraw-Hill, 2005.) they are destroyed and their components recycled. Red cell–inclu­ sion bodies such as parasites (Chaps. 231, 232, and A2), nuclear residua (Howell-Jolly bodies, see Fig. 66-6), or denatured hemoglo­ bin (Heinz bodies) are pinched off in the process of passing through the slits, a process called pitting. The culling of dead and damaged cells and the pitting of cells with inclusions appear to occur without significant delay because the blood transit time through the spleen is only slightly slower than in other organs. The spleen is also capable of assisting the host in adapting to its hos­ tile environment. It has at least three adaptive functions: (1) clearance of bacteria and particulates from the blood, (2) the generation of immune responses to certain pathogens, and (3) the generation of cellular components of the blood under circumstances in which the marrow is unable to meet the needs (i.e., extramedullary hematopoiesis). The latter adaptation is a recapitulation of the blood-forming function the spleen plays during gestation. In some animals, the spleen also serves a role in the vascular adaptation to stress because it stores red blood cells (often hemoconcentrated to higher hematocrits than normal) under normal

circumstances and contracts under the influence of β-adrenergic stimu­ lation to provide the animal with an autotransfusion and improved oxygen-carrying capacity. However, the normal human spleen does not sequester or store red blood cells and does not contract in response to sympathetic stimuli. The normal human spleen contains approximately one-third of the total body platelets and a significant number of margin­ ated neutrophils. These sequestered cells are available when needed to respond to bleeding or infection.

APPROACH TO THE PATIENT Splenomegaly Enlargement of Lymph Nodes and Spleen CHAPTER 70 CLINICAL ASSESSMENT The most common symptoms produced by diseases involving the spleen are pain and a heavy sensation in the LUQ. Massive sple­ nomegaly may cause early satiety. Pain may result from acute swelling of the spleen with stretching of the capsule, infarction, or inflammation of the capsule. For many years, it was believed that splenic infarction was clinically silent, which, at times, is true. However, Soma Weiss, in his classic 1942 report of the self-

observations by a Harvard medical student on the clinical course of subacute bacterial endocarditis, documented that severe LUQ and pleuritic chest pain may accompany thromboembolic occlusion of splenic blood flow. Vascular occlusion, with infarction and pain, is commonly seen in children with sickle cell crises. Rupture of the spleen, from either trauma or infiltrative disease that breaks the capsule, may result in intraperitoneal bleeding, shock, and death. The rupture itself may be painless. A palpable spleen is the major physical sign produced by diseases affecting the spleen and suggests enlargement of the organ. The normal spleen weighs <250 g, decreases in size with age, normally lies entirely within the rib cage, has a maximum cephalocaudad diameter of 13 cm by ultrasonography or maximum length of 12 cm and/or width of 7 cm by radionuclide scan, and is usually not palpa­ ble. However, a palpable spleen was found in 3% of 2200 asymptom­ atic, male, freshman college students. Follow-up at 3 years revealed that 30% of those students still had a palpable spleen without any increase in disease prevalence. Ten-year follow-up found no evi­ dence for lymphoid malignancies. Furthermore, in some tropical countries (e.g., New Guinea), the incidence of splenomegaly may reach 60%. Thus, the presence of a palpable spleen does not always equate with presence of disease. Even when disease is present, splenomegaly may not reflect the primary disease but rather a reac­ tion to it. For example, in patients with Hodgkin’s lymphoma, only two-thirds of the palpable spleens show involvement by the cancer. Physical examination of the spleen uses primarily the techniques of palpation and percussion. Inspection may reveal fullness in the LUQ that descends on inspiration, a finding associated with a mas­ sively enlarged spleen. Auscultation may reveal a venous hum or friction rub. Palpation can be accomplished by bimanual palpation, bal­ lotment, and palpation from above (Middleton maneuver). For bimanual palpation, which is at least as reliable as the other tech­ niques, the patient is supine with flexed knees. The examiner’s left hand is placed on the lower rib cage and pulls the skin toward the costal margin, allowing the fingertips of the right hand to feel the tip of the spleen as it descends while the patient inspires slowly, smoothly, and deeply. Palpation is begun with the right hand in the left lower quadrant with gradual movement toward the left costal margin, thereby identifying the lower edge of a massively enlarged spleen. When the spleen tip is felt, the finding is recorded as cen­ timeters below the left costal margin at some arbitrary point, i.e., 10–15 cm, from the midpoint of the umbilicus or the xiphisternal junction. This allows other examiners to compare findings or the initial examiner to determine changes in size over time. Bimanual palpation in the right lateral decubitus position adds nothing to the supine examination.

Percussion for splenic dullness is accomplished with any of three techniques described by Nixon, Castell, or Barkun:

1. Nixon’s method: The patient is placed on the right side so that the spleen lies above the colon and stomach. Percussion begins at the lower level of pulmonary resonance in the posterior axillary line and proceeds diagonally along a perpendicular line toward the lower midanterior costal margin. The upper border of dull­ ness is normally 6–8 cm above the costal margin. Dullness >8 cm in an adult is presumed to indicate splenic enlargement.

2. Castell’s method: With the patient supine, percussion in the lowest intercostal space in the anterior axillary line (8th or 9th) produces a resonant note if the spleen is normal in size. This is true during expiration or full inspiration. A dull percussion note on full inspiration suggests splenomegaly.

3. Percussion of Traube’s semilunar space: The borders of Traube’s PART 2 Cardinal Manifestations and Presentation of Diseases space are the sixth rib superiorly, the left midaxillary line later­ ally, and the left costal margin inferiorly. The patient is supine with the left arm slightly abducted. During normal breathing, this space is percussed from medial to lateral margins, yield­ ing a normal resonant sound. A dull percussion note suggests splenomegaly. Studies comparing methods of percussion and palpation with a standard of ultrasonography or scintigraphy have revealed sensitiv­ ity of 56–71% for palpation and 59–82% for percussion. Reproduc­ ibility among examiners is better for palpation than percussion. Both techniques are less reliable in obese patients or patients who have just eaten. Thus, the physical examination techniques of palpa­ tion and percussion are imprecise at best. It has been suggested that the examiner perform percussion first and, if positive, proceed to palpation; if the spleen is palpable, then one can be reasonably con­ fident that splenomegaly exists. However, not all LUQ masses are enlarged spleens; gastric or colon tumors and pancreatic or renal cysts or tumors can mimic splenomegaly. The presence of an enlarged spleen can be more precisely deter­ mined, if necessary, by liver-spleen radionuclide scan, CT, MRI, or ultrasonography. The latter technique is the current procedure of choice for routine assessment of spleen size (normal = a maximum cephalocaudad diameter of 13 cm) because it has high sensitivity and specificity and is safe, noninvasive, quick, mobile, and less costly. Equipment advances allow ultrasonography to be performed at the bedside with excellent sensitivity and specificity. Nuclear medicine scans are accurate, sensitive, and reliable but are costly, require greater time to generate data, and use immobile equipment. They have the advantage of demonstrating accessory splenic tissue. CT and MRI provide accurate determination of spleen size, but the equipment is immobile and the procedures are expensive. MRI appears to offer no advantage over CT. Changes in spleen structure such as mass lesions, infarcts, inhomogeneous infiltrates, and cysts are more readily assessed by CT, MRI, or ultrasonography. None of these techniques is very reliable in the detection of patchy infiltra­ tion (e.g., Hodgkin’s lymphoma). DIFFERENTIAL DIAGNOSIS Many of the diseases associated with splenomegaly are listed in Table 70-2. They are grouped according to the presumed basic mechanisms responsible for organ enlargement:

4. Hyperplasia or hypertrophy related to a particular splenic func­ tion such as reticuloendothelial hyperplasia (work hypertrophy) in diseases such as hereditary spherocytosis or thalassemia syn­ dromes that require removal of large numbers of defective red blood cells; immune hyperplasia in response to systemic infec­ tion (infectious mononucleosis, subacute bacterial endocarditis) or to immunologic diseases (immune thrombocytopenia, SLE, Felty’s syndrome).

5. Passive congestion due to decreased blood flow from the spleen in conditions that produce portal hypertension (cirrhosis, BuddChiari syndrome, congestive heart failure).

6. Infiltrative diseases of the spleen (lymphomas, metastatic cancer, amyloidosis, Gaucher’s disease, myeloproliferative disorders with extramedullary hematopoiesis). The differential diagnostic possibilities are much fewer when the spleen is “massively enlarged,” palpable >8 cm below the left costal margin, or its drained weight is ≥1000 g (Table 70-3). The vast majority of such patients will have non-Hodgkin’s lym­ phoma, chronic lymphocytic leukemia, hairy cell leukemia, chronic myeloid leukemia, myelofibrosis with myeloid metaplasia, or poly­ cythemia vera. LABORATORY ASSESSMENT The major laboratory abnormalities accompanying splenomegaly are determined by the underlying systemic illness. Erythrocyte counts may be normal, decreased (thalassemia major syndromes, SLE, cirrhosis with portal hypertension), or increased (polycythemia vera). Granulocyte counts may be normal, decreased (Felty’s syndrome, congestive splenomegaly, leukemias), or increased (infections or inflammatory disease, myeloproliferative disorders). Similarly, the platelet count may be normal, decreased when there is enhanced sequestration or destruction of platelets in an enlarged spleen (congestive splenomegaly, Gaucher’s disease, immune thrombocy­ topenia), or increased in the myeloproliferative disorders such as polycythemia vera. The CBC may reveal cytopenia of one or more blood cell types, which should suggest hypersplenism. This condition is character­ ized by splenomegaly, cytopenia(s), normal or hyperplastic bone marrow, and a response to splenectomy. The latter characteristic is less precise because reversal of cytopenia, particularly granulocyto­ penia, is sometimes not sustained after splenectomy. The cytopenias result from increased destruction of the cellular elements secondary to reduced flow of blood through enlarged and congested cords (congestive splenomegaly) or to immune-mediated mechanisms. In hypersplenism, various cell types usually have normal morphol­ ogy on the peripheral blood smear, although the red cells may be spherocytic due to loss of surface area during their longer transit through the enlarged spleen. The increased marrow production of red cells should be reflected as an increased reticulocyte produc­ tion index, although the value may be less than expected due to increased sequestration of reticulocytes in the spleen. The need for additional laboratory studies is dictated by the dif­ ferential diagnosis of the underlying illness of which splenomegaly is a manifestation. SPLENECTOMY Splenectomy is infrequently performed for diagnostic purposes, espe­ cially in the absence of clinical illness or other diagnostic tests that suggest underlying disease. More often, splenectomy is performed for symptom control in patients with massive splenomegaly, for disease control in patients with traumatic splenic rupture, or for correction of cytopenias in patients with hypersplenism or immune-mediated destruction of one or more cellular blood elements. Splenectomy is necessary for staging of patients with Hodgkin’s lymphoma only in those with clinical stage I or II disease in whom radiation therapy alone is contemplated as the treatment. Noninvasive staging of the spleen in Hodgkin’s lymphoma is not a sufficiently reliable basis for treatment decisions because one-third of normal-sized spleens will be involved with Hodgkin’s lymphoma and one-third of enlarged spleens will be tumor-free. The widespread use of systemic therapy to test all stages of Hodgkin’s lymphoma has made staging laparotomy with splenectomy unnecessary. Although splenectomy in chronic myeloid leukemia (CML) does not affect the natural history of disease, removal of the massive spleen usually makes patients significantly more comfortable and simplifies their management by significantly reducing transfusion requirements. The improvements in therapy of CML have reduced the need for splenectomy for symptom control. Splenectomy is an effec­ tive secondary or tertiary treatment for two chronic B-cell leukemias,

TABLE 70-2  Diseases Associated with Splenomegaly Grouped by Pathogenic Mechanism Enlargement Due to Increased Demand for Splenic Function Reticuloendothelial system hyperplasia (for removal of defective erythrocytes)   Malaria   Spherocytosis   Leishmaniasis   Early sickle cell anemia   Trypanosomiasis   Ovalocytosis   Ehrlichiosis   Thalassemia major Disordered immunoregulation   Hemoglobinopathies   Rheumatoid arthritis (Felty’s syndrome)   Paroxysmal nocturnal hemoglobinuria   Systemic lupus erythematosus   Pernicious anemia   Collagen vascular diseases Immune hyperplasia   Serum sickness   Response to infection (viral, bacterial, fungal, parasitic)   Immune hemolytic anemias     Infectious mononucleosis   Immune thrombocytopenias     AIDS   Immune neutropenias     Viral hepatitis   Drug reactions     Cytomegalovirus   Angioimmunoblastic lymphadenopathy     Subacute bacterial endocarditis   Sarcoidosis     Bacterial septicemia   Thyrotoxicosis (benign lymphoid hypertrophy)     Congenital syphilis   Interleukin 2 therapy     Splenic abscess Extramedullary hematopoiesis     Tuberculosis   Myelofibrosis     Histoplasmosis   Marrow damage by toxins, radiation, strontium     Marrow infiltration by tumors, leukemias, Gaucher’s disease Enlargement Due to Abnormal Splenic or Portal Blood Flow Cirrhosis Splenic artery aneurysm Hepatic vein obstruction Hepatic schistosomiasis Portal vein obstruction, intrahepatic or extrahepatic Congestive heart failure Cavernous transformation of the portal vein Hepatic echinococcosis Splenic vein obstruction Portal hypertension (any cause including the above): “Banti’s disease” Infiltration of the Spleen Intracellular or extracellular depositions   Hodgkin’s lymphoma   Amyloidosis   Myeloproliferative syndromes (e.g., polycythemia vera, essential thrombocytosis)   Gaucher’s disease   Angiosarcomas   Niemann-Pick disease   Metastatic tumors (melanoma is most common)   Tangier disease   Eosinophilic granuloma   Hurler’s syndrome and other mucopolysaccharidoses   Histiocytosis X   Hyperlipidemias   Hamartomas Benign and malignant cellular infiltrations   Hemangiomas, fibromas, lymphangiomas   Leukemias (acute, chronic, lymphoid, myeloid, monocytic)   Splenic cysts   Lymphomas   Hemophagocytic lymphohistiocytosis Unknown Etiology Idiopathic splenomegaly Iron-deficiency anemia Berylliosis   hairy cell leukemia and prolymphocytic leukemia, and for the very rare splenic mantle cell or marginal zone lymphoma. Splenectomy in these diseases may be associated with significant tumor regres­ sion in bone marrow and other sites of disease. Similar regressions of systemic disease have been noted after splenic irradiation in some types of lymphoid tumors, especially chronic lymphocytic leukemia TABLE 70-3  Diseases Associated with Massive Splenomegalya Chronic myeloid leukemia Gaucher’s disease Lymphomas Chronic lymphocytic leukemia Hairy cell leukemia Sarcoidosis Myelofibrosis with myeloid metaplasia Autoimmune hemolytic anemia Polycythemia vera Diffuse splenic hemangiomatosis aThe spleen extends >8 cm below left costal margin and/or weighs >1000 g.

Enlargement of Lymph Nodes and Spleen CHAPTER 70 and prolymphocytic leukemia. This has been termed the abscopal effect. Such systemic tumor responses to local therapy directed at the spleen suggest that some hormone or growth factor produced by the spleen may affect tumor cell proliferation, but this conjecture is not yet substantiated. A common therapeutic indication for splenectomy is traumatic or iatrogenic splenic rupture. In a fraction of patients with splenic rupture, peritoneal seeding of splenic fragments can lead to splenosis—the presence of multiple rests of spleen tissue not connected to the portal circulation. This ectopic spleen tissue may cause pain or gastrointestinal obstruction, as in endometriosis. A large number of hematologic, immunologic, and congestive causes of splenomegaly can lead to destruction of one or more cellular blood elements. In the majority of such cases, splenectomy can correct the cytopenias, par­ ticularly anemia and thrombocytopenia. In a large series of patients seen in two tertiary care centers, the indication for splenectomy was diagnostic in 10% of patients, therapeutic in 44%, staging for Hodgkin’s

disease in 20%, and incidental to another procedure in 26%. Perhaps the only contraindication to splenectomy is the presence of marrow failure, in which the enlarged spleen is the only source of hematopoietic tissue.

Often the splenectomy is done by laparoscopy, which is associated with shorter hospital stays and faster recovery than the open proce­ dure; however, concern has emerged that the laparoscopic approach is associated with a higher risk of postoperative portal venous system thrombosis and Budd-Chiari syndrome. The absence of the spleen has minimal long-term effects on the hematologic profile. In the immediate postsplenectomy period, leu­ kocytosis (up to 25,000/μL) and thrombocytosis (up to 1 × 106/μL) may develop, but within 2–3 weeks, blood cell counts and survival of each cell lineage are usually normal. The chronic manifestations of splenectomy are marked variation in size and shape of erythrocytes (anisocytosis, poikilocytosis) and the presence of Howell-Jolly bodies (nuclear remnants), Heinz bodies (denatured hemoglobin), basophilic stippling, and an occasional nucleated erythrocyte in the peripheral blood. When such erythrocyte abnormalities appear in a patient whose spleen has not been removed, one should suspect splenic infiltration by tumor that has interfered with its normal culling and pitting function. PART 2 Cardinal Manifestations and Presentation of Diseases The most serious consequence of splenectomy is increased sus­ ceptibility to bacterial infections, particularly those with capsules such as Streptococcus pneumoniae, Haemophilus influenzae, and some gram-negative enteric organisms. Patients aged <20 years are particu­ larly susceptible to overwhelming sepsis with S. pneumoniae, and the overall actuarial risk of sepsis in patients who have had their spleens removed is about 7% in 10 years. The case-fatality rate for pneumococ­ cal sepsis in splenectomized patients is 50–80%. About 25% of patients without spleens will develop a serious infection at some time in their life. The frequency is highest within the first 3 years after splenectomy. About 15% of the infections are polymicrobial, and lung, skin, and blood are the most common sites. No increased risk of viral infection has been noted in patients who have no spleen. The susceptibility to bacterial infections relates to the inability to remove opsonized bac­ teria from the bloodstream and a defect in making antibodies to

T cell–independent antigens such as the polysaccharide components of bacterial capsules. Pneumococcal vaccine should be administered to all patients 2 weeks before elective splenectomy. The Advisory Committee on Immunization Practices recommends that these patients receive repeat vaccination 5 years after splenectomy. Efficacy has not been proven for this group, and the recommendation discounts the pos­ sibility that administration of the vaccine may actually lower the titer of specific pneumococcal antibodies. A more effective pneumococcal conjugate vaccine that involves T cells in the response is now available (PCV13). The vaccine to Neisseria meningitidis should also be given to patients in whom elective splenectomy is planned. Although efficacy data for H. influenzae type b vaccine are not available for older children or adults, it may be given to patients who have had a splenectomy. Splenectomized patients should be educated to consider any unex­ plained fever as a medical emergency. Prompt medical attention with

evaluation and treatment of suspected bacteremia may be lifesaving. Routine chemoprophylaxis with oral penicillin can result in the emer­ gence of drug-resistant strains and is not recommended. In addition to an increased susceptibility to bacterial infections, splenectomized patients are also more susceptible to the parasitic dis­ ease babesiosis. The splenectomized patient should avoid areas where the parasite Babesia is endemic (e.g., Cape Cod, Massachusetts). Surgical removal of the spleen is an obvious cause of hyposplenism. Patients with sickle cell disease often suffer from autosplenectomy as a result of splenic destruction by the numerous infarcts associated with sickle cell crises during childhood. Indeed, the presence of a palpable spleen in a patient with sickle cell disease after age 5 suggests a coexist­ ing hemoglobinopathy, e.g., thalassemia or hemoglobin C. In addition, patients who receive splenic irradiation for a neoplastic or autoimmune disease are also functionally hyposplenic. The term hyposplenism is preferred to asplenism in referring to the physiologic consequences of splenectomy because asplenia is a rare, specific, and fatal congenital abnormality in which there is a failure of the left side of the coelo­ mic cavity (which includes the splenic anlagen) to develop normally. Infants with asplenia have no spleens, but that is the least of their prob­ lems. The right side of the developing embryo is duplicated on the left so there is liver where the spleen should be, there are two right lungs, and the heart comprises two right atria and two right ventricles. Acknowledgment Patrick H. Henry, MD, friend and mentor now deceased, contributed significantly to the chapter in past editions and much of his work remains in this chapter. ■ ■FURTHER READING Barkun AN et al: The bedside assessment of splenic enlargement. Am J Med 91:512, 1991. Cessford T et al: Comparing physical examination with sono­ graphic versions of the same examination techniques for splenomegaly. J Ultrasound Med 37:1621, 2018. Facchetti F: Tumors of the spleen. Int J Surg Pathol 18:136S, 2010. Girard E et al: Management of splenic and pancreatic trauma. J Visc Surg 153(suppl 4):45, 2016. Kim DK et al: Advisory committee on immunization practices recom­ mended immunization schedule for adults aged 19 years or older— United States, 2017. MMWR 66:136, 2017. Kraus MD et al: The spleen as a diagnostic specimen: A review of ten years’ experience at two tertiary care institutions. Cancer 91:2001, 2001. McIntyre OR, Ebaugh FG Jr: Palpable spleens: Ten-year follow-up. Ann Intern Med 90:130, 1979. Pangalis GA et al: Clinical approach to lymphadenopathy. Semin Oncol 20:570, 1993. Sjoberg BP et al: Splenomegaly: A combined clinical and radiologic approach to the differential diagnosis. Gastroenterol Clin North Am 47:643, 2018.