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InternalMed_Harrison. FIgURE 453e-3 T2-weighted (fluid-attenuated inversion recovery) magnetic resonance imaging showing hyperintensity in the cortex in a patient with sporadic CJD. This so-called “cortical ribboning” along with increased intensity in the basal ganglia on T2or diffusion-weighted imaging can aid in the diagnosis of Creutzfeldt-Jakob disease. proper clinical setting, diagnosis is facilitated. However, some cases of sCJD do not show this typical pattern, and other early diagnostic approaches are still needed. CSF is nearly always normal but may show protein elevation and, rarely, mild pleocytosis. Although the stress protein 14-3-3 is elevated in the CSF of some patients with CJD, similar elevations of 14-3-3 are found in patients with other disorders; thus this elevation is not specific. Similarly, elevations of CSF neuron-specific enolase and tau occur in CJD but lack specificity for diagnosis.


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InternalMed_Harrison. The EEG is often useful in the diagnosis of CJD, although only approximately 60% of individuals show the typical pattern. During the early phase of CJD, the EEG is usually normal or shows only scattered theta activity. In most advanced cases, repetitive, high-voltage, triphasic, and polyphasic sharp discharges are seen, but in many cases their presence is transient. The presence of these stereotyped periodic bursts of <200 ms in duration, occurring every 1–2 s, makes the diagnosis of CJD very likely. These discharges are frequently but not always symmetric; there may be a one-sided predominance in amplitude. As CJD progresses, normal background rhythms become fragmentary and slower.


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InternalMed_Harrison. Although CJD should not be considered either contagious or communicable, it is transmissible. The risk of accidental inoculation by aerosols is very small; nonetheless, procedures producing aerosols should be performed in certified biosafety cabinets. Biosafety level 2 practices, containment equipment, and facilities are recommended by the Centers for Disease Control and Prevention and the National Institutes of Health. The primary problem in caring for patients with CJD is the inadvertent infection of health care workers by needle and stab wounds. Electroencephalographic and electromyographic needles should not be reused after studies on patients with CJD have been performed.


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InternalMed_Harrison. There is no reason for pathologists or other morgue employees to resist performing autopsies on patients whose clinical diagnosis was CJD. Standard microbiologic practices outlined here, along with specific recommendations for decontamination, seem to be adequate precautions for the care of patients with CJD and the handling of infected specimens.


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InternalMed_Harrison. Prions are extremely resistant to common inactivation procedures, and there is some disagreement about the optimal conditions for sterilization. Some investigators recommend treating CJD-contaminated materials once with 1 N NaOH at room temperature, but we believe this procedure may be inadequate for sterilization. Autoclaving at 134°C for 5 h or treatment with 2 N NaOH for several hours is recommended for sterilization of prions. The term sterilization implies complete destruction of prions; any residual infectivity can be hazardous. Recent studies show that sCJD prions bound to stainless steel surfaces are resistant to inactivation by autoclaving at 134°C for 2 h; exposure of bound prions to an acidic detergent solution prior to autoclaving rendered prions susceptible to inactivation.


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InternalMed_Harrison. There is no known effective therapy for preventing or treating CJD. The finding that phenothiazines and acridines inhibit PrPSc formation in cultured cells led to clinical studies of quinacrine in CJD patients. Unfortunately, quinacrine failed to slow the rate of cognitive decline in CJD, possibly because therapeutic concentrations in the brain were not achieved. Although inhibition of the P-glycoprotein (Pgp) transport system resulted in substantially increased quinacrine levels in the brains of mice, the prion incubation times were not extended by treatment with the drug. Whether such an approach can be used to treat CJD remains to be established.


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InternalMed_Harrison. Like the acridines, anti-PrP antibodies have been shown to eliminate PrPSc from cultured cells. Additionally, such antibodies in mice, either administered by injection or produced from a transgene, have been shown to prevent prion disease when prions are introduced by a peripheral route, such as intraperitoneal inoculation. Unfortunately, the antibodies were ineffective in mice inoculated intracerebrally with prions. Several drugs, including pentosan polysulfate as well as porphyrin and phenylhydrazine derivatives, delay the onset of disease in animals inoculated intracerebrally with prions if the drugs are given intracerebrally beginning soon after inoculation. There is a rapidly expanding body of literature demonstrating that in addition to PrP, other proteins including amyloid beta (Aβ), tau, α-synuclein, and huntingtin can all becomes prions (Chap. 444e).


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InternalMed_Harrison. Experimental studies have shown that transgenic mice expressing mutant amyloid precursor protein (APP) develop amyloid plaques containing fibrils composed of the Aβ peptide approximately a year after inoculation with synthetic Aβ peptides polymerized into amyloid fibrils or extracts prepared from the brains of patients with AD. Mutant tau aggregates in transgenic mice and cultured cells can trigger the aggregation of tau into fibrils that resemble those found in neurofibrillary tangles and Pick bodies. Such tangles have been found in AD, FTDs, Pick’s disease, and some cases of posttraumatic brain injury, all of which are likely to be caused by the prion isoforms of Aβ and/or tau.


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InternalMed_Harrison. In patients with advanced PD who received grafts of fetal substantia nigral neurons, Lewy bodies containing β-sheet–rich α-synuclein were identified in grafted cells approximately 10 years after transplantation, arguing for the axonal transport of misfolded α-synuclein crossing into grafted neurons, where it initiated aggregation of nascent α-synuclein into fibrils that coalesced into Lewy bodies. These findings combined with studies of multiple system atrophy (MSA) argue that the synucleinopathies are caused by prions. Brain homogenates from MSA patients injected into transgenic mice transmitted lethal neurodegeneration in approximately 3 months; moreover, recombinant synuclein injected into wild-type mice initiated the deposition of synuclein fibrils.


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InternalMed_Harrison. In summary, a wealth of evidence continues to accumulate arguing that proteins causing AD, PD, FTDs, ALS, and even HD acquire alternative conformations that become self-propagating. Each of these neurodegenerative diseases is caused by a different protein that undergoes a conformational transformation to become a prion. Prions explain many of the features that the neurodegenerative diseases have in common: (1) incidence increases with age, (2) steady progression over years, (3) spread from one region of the CNS to another, (4) protein deposits consisting of amyloid fibrils, and (5) late onset of inherited forms of the neurodegenerative diseases. Notably, amyloid plaques containing PrPSc are a nonobligatory feature of PrP prion disease in humans and animals. Furthermore, amyloid plaques in AD do not correlate with the level of dementia; however, the level of soluble (oligomeric) Aβ peptide does correlate with memory loss and other intellectual deficits.


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InternalMed_Harrison. Disorders of the autonomic Nervous system Phillip A. Low, John W. Engstrom The autonomic nervous system (ANS) innervates the entire neuraxis and influences all organ systems. It regulates blood pressure (BP), 454 heart rate, sleep, and bladder and bowel function. It operates automatically; its full importance becomes recognized only when ANS function is compromised, resulting in dysautonomia. Hypothalamic disorders that cause disturbances in homeostasis are discussed in Chaps. 23 and 401e. The activity of the ANS is regulated by central neurons responsive to diverse afferent inputs. After central integration of afferent information, autonomic outflow is adjusted to permit the functioning of the major organ systems in accordance with the needs of the whole organism. Connections between the cerebral cortex and the autonomic centers in the brainstem coordinate autonomic outflow with higher mental functions.


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InternalMed_Harrison. The preganglionic neurons of the parasympathetic nervous system leave the central nervous system (CNS) in the third, seventh, ninth, and tenth cranial nerves as well as the second and third sacral nerves, while the preganglionic neurons of the sympathetic nervous system exit the spinal cord between the first thoracic and the second lumbar segments (Fig. 454-1). These are thinly myelinated. The postganglionic neurons, located in ganglia outside the CNS, give rise to the postganglionic unmyelinated autonomic nerves that innervate organs and tissues throughout the body. Responses to sympathetic and parasympathetic stimulation are frequently antagonistic (Table 454-1), reflecting highly coordinated interactions within the CNS; the resultant changes in parasympathetic and sympathetic activity provide more precise control of autonomic responses than could be achieved by the modulation of a single system.


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InternalMed_Harrison. Acetylcholine (ACh) is the preganglionic neurotransmitter for both divisions of the ANS as well as the postganglionic neurotransmitter from cranial nerves III, VII, IX, X from T1-L2 and from sacral nerves 2 and 3 Preganglionic fibers Postganglionic fibers in the heart wall FIGURE 454-1 Schematic representation of the autonomic nervous system. (From M Moskowitz: Clin Endocrinol Metab 6:77, 1977.) of the parasympathetic neurons; the preganglionic receptors are nicotinic, and the postganglionic are muscarinic in type. Norepinephrine (NE) is the neurotransmitter of the postganglionic sympathetic neurons, except for cholinergic neurons innervating the eccrine sweat glands.


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InternalMed_Harrison. Disorders of the ANS may result from pathology of either the CNS or the peripheral nervous system (PNS) (Table 454-2). Signs and symptoms may result from interruption of the afferent limb, CNS tone tone) Bowel motility Decreased motility Increased Lung Bronchodilation Bronchoconstriction Sweat glands Sweating — Pupils Dilation Constriction Adrenal glands Catecholamine release — Sexual function Ejaculation, orgasm Erection Lacrimal glands — Tearing Parotid glands — Salivation processing centers, or efferent limb of reflex arcs controlling autonomic responses. For example, a lesion of the medulla produced by a posterior fossa tumor can impair BP responses to postural changes and result in orthostatic hypotension (OH). OH can also be caused by lesions of the spinal cord or peripheral vasomotor nerve fibers (e.g., diabetic autonomic neuropathy). Lesions of the efferent limb cause the most consistent and severe OH. The site of reflex interruption is usually established by the clinical


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InternalMed_Harrison. nerve fibers (e.g., diabetic autonomic neuropathy). Lesions of the efferent limb cause the most consistent and severe OH. The site of reflex interruption is usually established by the clinical context in which the dysautonomia arises, combined with judicious use of ANS testing and neuroimaging studies. The presence or absence of CNS signs, association with sensory or motor polyneuropathy, medical illnesses, medication use, and family history are often important considerations. Some syndromes do not fit easily into any classification scheme.


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InternalMed_Harrison. Clinical manifestations can result from loss of function, overactivity, or dysregulation of autonomic circuits. Disorders of autonomic function should be considered in patients with unexplained OH, syncope, sleep dysfunction, altered sweating (hyperhidrosis or hypohidrosis), impotence, constipation or other gastrointestinal symptoms (bloating, I. Autonomic disorders with brain involvement A. Associated with multisystem degeneration 1. Multisystem degeneration: autonomic failure clinically prominent a. b. Parkinson’s disease with autonomic failure c. 2. Multisystem degeneration: autonomic failure clinically not usually prominent a. b. Other extrapyramidal disorders (inherited spinocerebellar atrophies, progressive supranuclear palsy, corticobasal degeneration, Machado-Joseph disease, fragile X syndrome [FXTAS]) B. Unassociated with multisystem degeneration (focal CNS disorders) 1. Disorders mainly due to cerebral cortex involvement a. b. c.


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InternalMed_Harrison. B. Unassociated with multisystem degeneration (focal CNS disorders) 1. Disorders mainly due to cerebral cortex involvement a. b. c. Cerebral infarction of the insula 2. Disorders of the limbic and paralimbic circuits a. Shapiro’s syndrome (agenesis of corpus callosum, hyperhidrosis, hypothermia) b. c. 3. Disorders of the hypothalamus a. b. c. d. e. f. Antidiuretic hormone (ADH) syndromes (diabetes insipidus, inappropriate ADH secretion) g. Disturbances of temperature regulation (hyperthermia, hypothermia) h. Disturbances of sexual function i. Disturbances of appetite j. Disturbances of BP/HR and gastric function k. 4. Disorders of the brainstem and cerebellum a. b. c. Disorders of BP control (hypertension, hypotension) d. e. f. g. h. i. II. Autonomic disorders with spinal cord involvement A. B. C. D. E. Amyotrophic lateral sclerosisF. Tetanus G. H. III. A. 1. Subacute autoimmune autonomic ganglionopathy (AAG) a. b. c. d. e.


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InternalMed_Harrison. A. B. C. D. E. Amyotrophic lateral sclerosisF. Tetanus G. H. III. A. 1. Subacute autoimmune autonomic ganglionopathy (AAG) a. b. c. d. e. Drug induced autonomic neuropathies-stimulants, drug withdrawal, vasoconstrictor, vasodilators, beta-receptor antagonists, betaagonists f. g. B. 1. 2. a. b. c. d. Sensory neuronopathy with autonomic failure e. f. Diabetic, uremic, or nutritional deficiency g. Dysautonomia of old age 3. Disorders of reduced orthostatic intolerance: reflex syncope, POTS, associated with prolonged bed rest, associated with space flight, chronic fatigue Abbreviations: BP, blood pressure; CNS, central nervous system; HR, heart rate; POTS, postural orthostatic tachycardia syndrome. Source: PA Low et al: Mayo Clin Proc 70:617, 1995.


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InternalMed_Harrison. nausea, vomiting of old food, diarrhea), or bladder disorders (urinary frequency, hesitancy, or incontinence). Symptoms may be widespread or regional in distribution. An autonomic history focuses on systemic functions (BP, heart rate, sleep, fever, sweating) and involvement of individual organ systems (pupils, bowel, bladder, sexual function). The autonomic symptom profile is a self-report questionnaire that can be used for formal assessment. It is also important to recognize the modulating effects of age. For example, OH typically produces lightheadedness in the young, whereas cognitive slowing is more common in the elderly. Specific symptoms of orthostatic intolerance are diverse (Table 454-3). Autonomic symptoms may vary dramatically, reflecting the dynamic nature of autonomic control over homeostatic function. For example, OH might be manifest only in the early morning, following a meal, with exercise, or with raised ambient temperature, depending on the regional vascular bed


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InternalMed_Harrison. over homeostatic function. For example, OH might be manifest only in the early morning, following a meal, with exercise, or with raised ambient temperature, depending on the regional vascular bed affected by the dysautonomia.


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InternalMed_Harrison. Early symptoms may be overlooked. Impotence, although not specific for autonomic failure, often heralds autonomic failure in men and may precede other symptoms by years (Chap. 67). A decrease in the frequency of spontaneous early morning erections may occur months before loss of nocturnal penile tumescence and development of total impotence. Bladder dysfunction may appear early in men and women, particularly in those with a CNS etiology. Cold feet may indicate increased peripheral vasomotor constriction. Brain and spinal cord disease above the level of the lumbar spine results first in urinary frequency and small bladder volumes and eventually in incontinence (upper motor neuron or spastic bladder). By contrast, PNS disease of autonomic nerve fibers results in large bladder volumes, urinary frequency, and overflow incontinence (lower motor neuron flaccid bladder). Measurement of bladder volume (postvoid residual) is a useful bedside test for distinguishing between upper and lower


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InternalMed_Harrison. frequency, and overflow incontinence (lower motor neuron flaccid bladder). Measurement of bladder volume (postvoid residual) is a useful bedside test for distinguishing between upper and lower motor neuron bladder dysfunction in the early stages of dysautonomia. Gastrointestinal autonomic dysfunction typically presents as severe constipation. Diarrhea may develop (typically in diabetes mellitus) due to rapid transit of contents or uncoordinated small-bowel motor activity, or on an osmotic basis from bacterial overgrowth associated with small-bowel stasis. Impaired glandular secretory function may cause difficulty with food intake due to decreased salivation or eye irritation due to decreased lacrimation. Occasionally, temperature elevation and vasodilation can result from anhidrosis because sweating is normally important for heat dissipation (Chap. 23). Lack of sweating after a hot bath, during exercise, or on a hot day can suggest sudomotor failure.


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InternalMed_Harrison. OH (also called orthostatic or postural hypotension) is perhaps the most disabling feature of autonomic dysfunction. The prevalence of OH is relatively high, especially when OH associated with aging and diabetes mellitus is included (Table 454-4). OH can cause a variety of symptoms, including dimming or loss of vision, lightheadedness, diaphoresis, diminished hearing, pallor, and weakness. Syncope results when the drop in BP impairs cerebral perfusion. Other manifestations of impaired baroreflexes are supine hypertension, a heart rate that is fixed regardless of posture, postprandial hypotension, and an excessively high nocturnal BP. Many patients with OH have a preceding


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InternalMed_Harrison. Aging 14–20% Diabetic neuropathy 10% Other autonomic neuropathies 10–50 per 100,000 Multiple system atrophy 5–15 per 100,000 Pure autonomic failure 10–30 per 100,000 diagnosis of hypertension or have concomitant supine hypertension, reflecting the great importance of baroreflexes in maintaining postural and supine normotension. The appearance of OH in patients receiving antihypertensive treatment may indicate overtreatment or the onset of an autonomic disorder. The most common causes of OH are not neurologic in origin; these must be distinguished from the neurogenic causes (Table 454-5). Neurocardiogenic and cardiac causes of syncope are considered in Chap. 27. APPROACH TO THE PATIENT:


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InternalMed_Harrison. APPROACH TO THE PATIENT: The first step in the evaluation of symptomatic OH is the exclusion of treatable causes. The history should include a review of medications that may affect the ANS (Table 454-6). The main classes of drugs that may cause OH are diuretics, antihypertensives, antidepressants, ethanol, narcotics, insulin, dopamine agonists, barbiturates, and calcium channel-blocking agents. However, the precipitation of OH by medications may also be the first sign of an underlying autonomic disorder. The history may reveal an underlying cause for symptoms (e.g., diabetes, Parkinson’s disease) or specific underlying mechanisms (e.g., cardiac pump failure, reduced intravascular volume). The relationship of symptoms to meals (splanchnic pooling), standing on awakening in the morning (intravascular volume depletion), ambient warming (vasodilatation), or exercise (muscle arteriolar vasodilatation) NoNNeuroGeNiC Causes of orthostatiC hypoteNsioN


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InternalMed_Harrison. NoNNeuroGeNiC Causes of orthostatiC hypoteNsioN Myocarditis Postprandial dilation of splanchnic vessel beds Constrictive pericarditis Vigorous exercise with dilation of Tachyarrhythmias Heat: hot environment, hot show-Bradyarrhythmias ers and baths, fever Salt-losing nephropathy Reduced intravascular volume Antihypertensives Straining or heavy lifting, urination, Diuretics defecation Vasodilators: nitrates, hydralazine Dehydration Alphaand beta-blocking agents Diarrhea, emesis Central nervous system sedatives: Hemorrhage barbiturates, opiates Burns Tricyclic antidepressants Metabolic Phenothiazines Adrenocortical insufficiency Hypoaldosteronism Pheochromocytoma Severe potassium depletion Disorders of the Autonomic Nervous System Abbreviations: CCBs, calcium channel blockers; HCTZ, hydrochlorothiazide; SSRIs, selective serotonin reuptake inhibitors. should be sought. Standing time to first symptom and to presyncope (Chap. 27) should be followed for management.


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InternalMed_Harrison. Physical examination includes measurement of supine and standing pulse and BP. OH is defined as a sustained drop in systolic (≥20 mmHg) or diastolic (≥10 mmHg) BP after 2–3 min of standing. In nonneurogenic causes of OH (such as hypovolemia), the BP drop is accompanied by a compensatory increase in heart rate of >15 beats/min. A clue that the patient has neurogenic OH is the aggravation or precipitation of OH by autonomic stressors (a meal, hot bath, or exercise). Neurologic examination should include mental status (neurodegenerative disorders), cranial nerves (impaired downgaze with progressive supranuclear palsy; abnormal pupils with Horner’s or Adie’s syndrome), motor tone (Parkinson’s disease and parkinsonism), and sensation (polyneuropathies). In patients without a clear diagnosis initially, follow-up evaluations every few months or whenever symptoms worsen may reveal the underlying cause.


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InternalMed_Harrison. Disorders of autonomic function should be considered in patients with symptoms of altered sweating (hyperhidrosis or hypohidrosis), gastroparesis (bloating, nausea, vomiting of old food), impotence, constipation, or bladder disturbances (urinary frequency, hesitancy, or incontinence). Autonomic function tests are helpful to document abnormalities when findings on history and examination are inconclusive; to detect subclinical involvement; or to follow the course of an autonomic disorder.


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InternalMed_Harrison. Heart Rate Variation with Deep Breathing This tests the parasympathetic component of cardiovascular reflexes via the vagus nerve. Results are influenced by multiple factors including the subject’s position (recumbent, sitting, or standing), rate and depth of respiration (6 breaths per minute and a forced vital capacity [FVC] >1.5 L are optimal), age, medications, weight, and degree of hypocapnia. Interpretation of results requires comparison of test data with results from age-matched controls collected under identical test conditions. For example, the lower limit of normal heart rate variation with deep breathing in persons <20 years is >15–20 beats/min, but for persons over age 60 it is 5–8 beats/min. Heart rate variation with deep breathing (respiratory sinus arrhythmia) is abolished by the muscarinic ACh receptor antagonist atropine but is unaffected by sympathetic postganglionic blockade (e.g., propranolol).


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InternalMed_Harrison. Valsalva Response This response (Table 454-7) assesses the integrity of the baroreflex control of heart rate (parasympathetic) and BP (adrenergic). Under normal conditions, increases in BP at the carotid bulb trigger a reduction in heart rate (increased vagal tone), and decreases in BP trigger an increase in heart rate (reduced vagal tone). The Valsalva response is tested in the supine position. The subject exhales against a closed glottis (or into a manometer maintaining a constant expiratory pressure of 40 mmHg) for 15 s while measuring changes in heart rate and beat-to-beat BP. There are four phases of the BP and heart rate response to the Valsalva maneuver. Phases I and III are mechanical and related to changes in intrathoracic and intraabdominal pressure. In early phase II, reduced venous return results in a fall in stroke volume and BP, counteracted by a combination of reflex tachycardia and increased total peripheral resistance. Increased total peripheral resistance arrests the


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InternalMed_Harrison. return results in a fall in stroke volume and BP, counteracted by a combination of reflex tachycardia and increased total peripheral resistance. Increased total peripheral resistance arrests the BP drop ~5–8 s after the onset of the maneuver. Late phase II begins with a progressive rise in BP toward or above baseline. Venous return and cardiac output return to normal in phase


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InternalMed_Harrison. IV. Persistent peripheral arteriolar vasoconstriction and increased cardiac adrenergic tone result in a temporary BP overshoot and phase IV bradycardia (mediated by the baroreceptor reflex). Autonomic function during the Valsalva maneuver can be measured using beat-to-beat BP or heart rate changes. The Valsalva ratio is defined as the maximum phase II tachycardia divided by the minimum phase IV bradycardia (Table 454-8). The ratio reflects the integrity of the entire baroreceptor reflex arc and of sympathetic efferents to blood vessels.


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InternalMed_Harrison. Sudomotor Function Sweating is induced by release of ACh from sympathetic postganglionic fibers. The quantitative sudomotor axon reflex test (QSART) is a measure of regional autonomic function mediated by ACh-induced sweating. A reduced or absent response indicates a lesion of the postganglionic sudomotor axon. For example, sweating may be reduced in the feet as a result of distal polyneuropathy (e.g., diabetes). The thermoregulatory sweat test (TST) is a qualitative measure of regional sweat production in response to an elevation of body temperature under controlled conditions. An indicator powder placed on the anterior surface of the body changes color with sweat production during temperature Abbreviations: BPBB, beat-to-beat blood pressure; HRDB, heart rate response to deep breathing; HUT, head-up tilt; QSART, quantitative sudomotor axon reflex test; VM, Valsalva maneuver.


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InternalMed_Harrison. Abbreviations: BPBB, beat-to-beat blood pressure; HRDB, heart rate response to deep breathing; HUT, head-up tilt; QSART, quantitative sudomotor axon reflex test; VM, Valsalva maneuver. elevation. The pattern of color change is a measure of regional sweat secretion. A postganglionic lesion is present if both QSART and TST show absent sweating. In a preganglionic lesion, the QSART is normal but TST shows anhidrosis. Orthostatic BP Recordings Beat-to-beat BP measurements determined in supine, 70° tilt, and tilt-back positions are useful to quantitate orthostatic failure of BP control. Allow a 20-min period of rest in the supine position before assessing changes in BP during tilting. The BP change combined with heart rate monitoring is useful for the evaluation of patients with suspected OH or unexplained syncope.


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InternalMed_Harrison. Tilt Table Testing for Syncope The great majority of patients with syncope do not have autonomic failure. Tilt table testing can be used to make the diagnosis of vasovagal syncope with sensitivity, specificity, and reproducibility. A standardized protocol is used that specifies the tilt apparatus, angle and duration of tilt, and procedure for provocation of vasodilation (e.g., sublingual or spray nitroglycerin). A positive nitroglycerin-stimulated test predicts recurrence of syncope. Recommendations for the performance of tilt studies for syncope have been incorporated in consensus guidelines. MULTIPLE SYSTEM ATROPHY (CHAP. 449)


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InternalMed_Harrison. Multiple system atrophy (MSA) is an entity that comprises autonomic failure (OH or a neurogenic bladder) and either parkinsonism (MSA-p) or a cerebellar syndrome (MSA-c). MSA-p is the more common form; the parkinsonism is atypical in that it is usually unassociated with significant tremor or a response to levodopa. Symptomatic OH within 1 year of onset of parkinsonism predicts eventual development of MSA-p in 75% of patients. There is a very high frequency of impotence in men. Although autonomic abnormalities are common in advanced Parkinson’s disease (Chap. 449), the severity and distribution of autonomic failure are more severe and generalized in MSA. Brain magnetic resonance imaging (MRI) is a useful diagnostic adjunct: in MSA-p, iron deposition in the striatum may be evident as T2 hypointensity, and in MSA-c, cerebellar atrophy is present with a characteristic T2 hyperintense signal (“hot cross buns sign”) in the pons (Fig. 454-2). Cardiac postganglionic adrenergic innervation,


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InternalMed_Harrison. and in MSA-c, cerebellar atrophy is present with a characteristic T2 hyperintense signal (“hot cross buns sign”) in the pons (Fig. 454-2). Cardiac postganglionic adrenergic innervation, measured by uptake of fluorodopamine on positron emission tomography, is markedly impaired in the dysautonomia of Parkinson’s disease (PD) but is usually normal in MSA. Neuropathologic changes include neuronal loss and gliosis in many CNS regions, including the brainstem, cerebellum, striatum, and intermediolateral cell column of the thoracolumbar spinal cord.


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InternalMed_Harrison. FIGURE 454-2 Multiple system atrophy, cerebellar type (MSA-c). Axial T2-weighted magnetic resonance image at the level of the pons shows a characteristic hyperintense signal, the “hot cross buns” sign. This appearance can also be seen in some spinocerebellar atrophies, as well as other neurodegenerative conditions affecting the brainstem.


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InternalMed_Harrison. MSA is uncommon, with a prevalence estimated at 2–5 per 100,000 individuals. Onset is typically in the mid-fifties, men are slightly more often affected than women, and most cases are sporadic. The diagnosis should be considered in adults over the age of 30 years who present with OH or urinary incontinence and either parkinsonism that is poorly responsive to dopamine replacement or a cerebellar syndrome. MSA generally progresses relentlessly to death 7–10 years after onset, but survival beyond 15 years has been reported. Factors that predict a worse prognosis include rapid progression of disability, bladder dysfunction, female gender, the MSA-p subtype, and an older age at onset. Attempts to slow the progression of MSA have thus far been unsuccessful, including trials of lithium, growth hormone, riluzole, rasagiline, minocycline, and a recent trail of rifampicin.


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InternalMed_Harrison. Management is symptomatic for neurogenic OH (see below), sleep disorders including laryngeal stridor, and gastrointestinal (GI) and urinary dysfunction. GI management includes frequent small meals, soft diet, stool softeners, and bulk agents. Gastroparesis is difficult to treat; metoclopramide stimulates gastric emptying but worsens parkinsonism by blocking central dopamine receptors. The peripheral dopamine (D2 and D3) receptor antagonist domperidone has been used patients with various GI conditions in many countries and is now available in the United States through the U.S. Food and Drug Administration’s (FDA) Expanded Access to Investigational Drugs program. Autonomic dysfunction is also a common feature in dementia with Lewy bodies (Chap. 448); the severity is usually less than that found in MSA or PD. In multiple sclerosis (MS; Chap. 458), autonomic complications reflect the CNS location of MS involvement and generally worsen with disease duration and disability.


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InternalMed_Harrison. Spinal cord lesions from any cause may result in focal autonomic deficits or autonomic hyperreflexia (e.g., spinal cord transection or hemisection) affecting bowel, bladder, sexual, temperature-regulation, or cardiovascular functions. Quadriparetic patients exhibit both supine hypertension and OH after upward tilting. Autonomic dysreflexia describes a dramatic increase in BP in patients with traumatic spinal cord lesions above the T6 level, often in response to stimulation of the bladder, skin, or muscles. A distended or obstructed bladder, suprapubic palpation, catheter insertion, and urinary infection are common triggers. Associated symptoms can include facial flushing, headache, hypertension, or piloerection. Potential complications


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InternalMed_Harrison. Disorders of the Autonomic Nervous System 2642 include intracranial vasospasm or hemorrhage, cardiac arrhythmia, and death. Awareness of the syndrome, identifying the trigger, and careful monitoring of BP during procedures in patients with acute or chronic spinal cord injury are essential. In patients with supine hypertension, BP can be lowered by tilting the head upward or sitting the patient up. Vasodilator drugs may be used to treat acute elevations in BP. Clonidine can be used prophylactically to reduce the hypertension resulting from bladder stimulation. Dangerous increases or decreases in body temperature may result from an inability to experience the sensory accompaniments of heat or cold exposure or control peripheral vasoconstriction or sweating below the level of the spinal cord injury.


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InternalMed_Harrison. Peripheral neuropathies (Chap. 459) are the most common cause of chronic autonomic insufficiency. Polyneuropathies that affect small myelinated and unmyelinated fibers of the sympathetic and parasympathetic nerves commonly occur in diabetes mellitus, amyloidosis, chronic alcoholism, porphyria, and Guillain-Barré syndrome. Neuromuscular junction disorders with autonomic involvement include botulism and Lambert-Eaton syndrome (Chap. 461).


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InternalMed_Harrison. Diabetes Mellitus Autonomic neuropathy in patients with diabetes increases the mortality rate 1.5to 3-fold, even after adjusting for other cardiovascular risk factors. Estimates of 5-year mortality risk among these patients range from 15 to 53%. Although many deaths are due to secondary vascular disease, there are patients who specifically suffer cardiac arrest due to autonomic neuropathy. The autonomic involvement is also predictive of other complications including renal disease, stroke, and sleep apnea. Diabetes mellitus is discussed in Chaps. 417–419.


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InternalMed_Harrison. Amyloidosis Autonomic neuropathy occurs in both sporadic and familial forms of amyloidosis (Chap. 137). The AL (immunoglobulin light chain) type is associated with primary amyloidosis or amyloidosis secondary to multiple myeloma. The ATTR type, with transthyretin as the primary protein component, is responsible for the most common form of inherited amyloidosis. Although patients usually present with a distal painful polyneuropathy accompanied by sensory loss, autonomic insufficiency can precede the development of the polyneuropathy or occur in isolation. The diagnosis can be made by protein electrophoresis of blood and urine, tissue biopsy (abdominal fat pad, rectal mucosa, or sural nerve) to search for amyloid deposits, and genetic testing for transthyretin mutations in familial cases. Treatment of familial cases with liver transplantation can be successful. The response of primary amyloidosis to melphalan and stem cell transplantation has been mixed. Death is usually due to cardiac


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InternalMed_Harrison. of familial cases with liver transplantation can be successful. The response of primary amyloidosis to melphalan and stem cell transplantation has been mixed. Death is usually due to cardiac or renal involvement. Postmortem studies reveal amyloid deposition in many organs, including two sites that contribute to autonomic failure: intraneural blood vessels and autonomic ganglia. Pathologic examination reveals a loss of both unmyelinated and myelinated nerve fibers.


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InternalMed_Harrison. Alcoholic Neuropathy Abnormalities in parasympathetic vagal and efferent sympathetic function are usually mild in alcoholic polyneuropathy. OH is usually due to brainstem involvement, rather than injury to the PNS. Impotence is a major problem, but concurrent gonadal hormone abnormalities may play a role in this symptom. Clinical symptoms of autonomic failure generally appear only when the stocking-glove polyneuropathy is severe, and there is usually coexisting Wernicke’s encephalopathy (Chap. 330). Autonomic involvement may contribute to the high mortality rates associated with alcoholism (Chap. 467).


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InternalMed_Harrison. Porphyria (Chap. 430) Autonomic dysfunction is most extensively documented in acute intermittent porphyria but can also occur with variegate porphyria and hereditary coproporphyria. Autonomic symptoms include tachycardia, sweating, urinary retention, abdominal pain, nausea and vomiting, insomnia, hypertension, and (less commonly) hypotension. Another prominent symptom is anxiety. Abnormal autonomic function can occur both during acute attacks and during remissions. Elevated catecholamine levels during acute attacks correlate with the degree of tachycardia and hypertension that is present.


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InternalMed_Harrison. Guillain-Barré Syndrome (Chap. 460) BP fluctuations and arrhythmias from autonomic instability can be severe. It is estimated that between 2 and 10% of patients with severe Guillain-Barré syndrome suffer fatal cardiovascular collapse. GI autonomic involvement, sphincter disturbances, abnormal sweating, and pupillary dysfunction can also occur. Demyelination has been described in the vagus and glossopharyngeal nerves, the sympathetic chain, and the white rami communicantes. Interestingly, the degree of autonomic involvement appears to be independent of the severity of motor or sensory neuropathy. Acute autonomic and sensory neuropathy is a variant that spares the motor system and presents with neurogenic OH and varying degrees of sensory loss. It is treated similarly to Guillain-Barré syndrome, but prognosis is less favorable, with persistent severe sensory deficits and variable degrees of OH in many patients.


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InternalMed_Harrison. Autoimmune Autonomic Ganglionopathy (AAG) This disorder presents with the subacute development of autonomic disturbances including OH, enteric neuropathy (gastroparesis, ileus, constipation/diarrhea), flaccid bladder, and cholinergic failure (e.g., loss of sweating, sicca complex, and a tonic pupil). A chronic form of AAG resembles pure autonomic failure (see below). Autoantibodies against the ganglionic ACh receptor (A3 AChR), which are present in approximately half of patients, are considered diagnostic of AAG. Pathology shows preferential involvement of small unmyelinated nerve fibers, with sparing of larger myelinated ones. Onset of the neuropathy follows a viral infection in approximately half of cases. Up to one-third of untreated patients experience significant functional improvement over time. Immunotherapies that have been reported to be helpful include plasmapheresis, intravenous immune globulin, glucocorticoids, azathioprine, rituximab, and mycophenolate mofetil. OH,


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InternalMed_Harrison. over time. Immunotherapies that have been reported to be helpful include plasmapheresis, intravenous immune globulin, glucocorticoids, azathioprine, rituximab, and mycophenolate mofetil. OH, gastroparesis, and sicca symptoms can be managed symptomatically.


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InternalMed_Harrison. AAG can also occur on a paraneoplastic basis, with adenocarcinoma or small-cell carcinoma of the lung, lymphoma, or thymoma being the most common (Chap. 122). In the paraneoplastic cases, distinctive additional features, such as cerebellar involvement or dementia, may be present (see Tables 122-1, 122-2, and 122-3). The neoplasm may be occult and possibly suppressed by the autoantibody. Botulism Botulinum toxin binds presynaptically to cholinergic nerve terminals and, after uptake into the cytosol, blocks ACh release. This acute cholinergic neuropathy presents as motor paralysis and autonomic disturbances that include blurred vision, dry mouth, nausea, unreactive or sluggishly reactive pupils, constipation, and urinary retention (Chap. 178).


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InternalMed_Harrison. This sporadic syndrome consists of postural hypotension, impotence, bladder dysfunction, and impaired sweating. The disorder begins in midlife and occurs in women more often than men. The symptoms can be disabling, but the disease does not shorten life span. The clinical and pharmacologic characteristics suggest primary involvement of postganglionic sympathetic neurons. A severe reduction in the density of neurons within sympathetic ganglia results in low supine plasma NE levels and noradrenergic supersensitivity. Some patients who are initially labeled with this diagnosis subsequently go on to develop AAG or MSA. Skin biopsies can demonstrate phosphorylated α-synuclein inclusions in postganglionic sympathetic adrenergic and cholinergic nerve fibers from some individuals with PAF, distinguishing them from AAG and suggesting that PAF is a synucleinopathy; patients with PD also have α-synuclein inclusions in sympathetic nerve biopsies.


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InternalMed_Harrison. This syndrome is characterized by symptomatic orthostatic intolerance without OH, accompanied by either an increase in heart rate to >120 beats/min or an increase of 30 beats/min with standing that subsides on sitting or lying down. Women are affected approximately five times more often than men, and most develop the syndrome between the ages of 15 and 50. Presyncopal symptoms (lightheadedness, weakness, blurred vision) combined with symptoms of autonomic overactivity (palpitations, tremulousness, nausea) are common. Recurrent unexplained episodes of dysautonomia and fatigue also occur. The pathogenesis is unclear, but there is increasing evidence for sympathetic denervation distally in the legs with preserved cardiovascular function. Hypovolemia, venous pooling, impaired brainstem regulation, or increased sympathetic activity may play a role. Optimal treatment is uncertain, but expansion of fluid volume with water, salt, and fludrocortisone can be helpful as initial interventions. If


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InternalMed_Harrison. or increased sympathetic activity may play a role. Optimal treatment is uncertain, but expansion of fluid volume with water, salt, and fludrocortisone can be helpful as initial interventions. If this approach is inadequate, then midodrine, pyridostigmine, phenobarbital, beta blockers, or clonidine can be tried. Reconditioning and a sustained exercise program are important adjuncts to treatment.


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InternalMed_Harrison. There are five known hereditary sensory and autonomic neuropathies (HSAN I–V). The most important autonomic variants are HSAN I and HSAN III. HSAN I is dominantly inherited and often presents as a distal small-fiber neuropathy (burning feet syndrome) associated with sensory loss and foot ulcers. The most common responsible gene, on chromosome 9q, is SPTLC1. SPTLC is an important enzyme in the regulation of ceramide. Cells from HSAN I patients with the mutation produce higher-than-normal levels of glucosyl ceramide, perhaps triggering apoptosis. HSAN III (Riley-Day syndrome; familial dysautonomia) is an autosomal recessive disorder of Ashkenazi Jewish children and adults and is much less prevalent than HSAN I. Decreased tearing, hyperhidrosis, reduced sensitivity to pain, areflexia, absent fungiform papillae on the tongue, and labile BP may be present. Episodic abdominal crises and fever are common. Pathologic examination of nerves reveals a loss of sympathetic, parasympathetic, and


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InternalMed_Harrison. fungiform papillae on the tongue, and labile BP may be present. Episodic abdominal crises and fever are common. Pathologic examination of nerves reveals a loss of sympathetic, parasympathetic, and sensory neurons. The defective gene, IKBKAP, may prevent normal transcription of important molecules in neural development.


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InternalMed_Harrison. This syndrome presents with excess sweating of the palms of the hands and soles of the feet beginning in childhood or early adulthood. The condition tends to improve with age. The disorder affects 0.6–1.0% of the population. The etiology is unclear, but there may be a genetic component because 25% of patients have a positive family history. The condition can be socially embarrassing (e.g., shaking hands) or even disabling (e.g., inability to write without soiling the paper). Topical antiperspirants are occasionally helpful. More useful are potent anticholinergic drugs such as glycopyrrolate (1–2 mg PO tid). T2 ganglionectomy or sympathectomy is successful in >90% of patients with palmar hyperhidrosis. The advent of endoscopic transaxillary T2 sympathectomy has lowered the complication rate of the procedure. The most common postoperative complication is compensatory hyperhidrosis, which improves spontaneously over months. Other potential complications include recurrent hyperhidrosis


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InternalMed_Harrison. of the procedure. The most common postoperative complication is compensatory hyperhidrosis, which improves spontaneously over months. Other potential complications include recurrent hyperhidrosis (16%), Horner’s syndrome (<2%), gustatory sweating, wound infection, hemothorax, and intercostal neuralgia. Local injection of botulinum toxin has also been used to block cholinergic, postganglionic sympathetic fibers to sweat glands in patients with palmar hyperhidrosis. This approach is limited by the need for repetitive injections (the effect usually lasts 4 months before waning).


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InternalMed_Harrison. The physician may be confronted occasionally with an acute state of sympathetic overactivity.


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InternalMed_Harrison. An autonomic storm is an acute state of sustained sympathetic surge that results in variable combinations of alterations in BP and heart rate, body temperature, respiration, and sweating. Causes of autonomic storm include brain and spinal cord injury, toxins and drugs, autonomic neuropathy, and chemodectomas (e.g., pheochromocytoma). Brain injury is the most common cause of autonomic storm and typically follows severe head trauma and postresuscitation encephalopathy anoxic-ischemic brain injury. Autonomic storm can also occur with other acute intracranial lesions such as hemorrhage, cerebral infarction, rapidly expanding tumors, subarachnoid hemor-2643 rhage, hydrocephalus, or (less commonly) an acute spinal cord lesion. The most consistent setting is that of an acute intracranial catastrophe of sufficient size and rapidity to produce a massive catecholaminergic surge. The surge can cause seizures, neurogenic pulmonary edema, and myocardial injury. Manifestations include fever,


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InternalMed_Harrison. of sufficient size and rapidity to produce a massive catecholaminergic surge. The surge can cause seizures, neurogenic pulmonary edema, and myocardial injury. Manifestations include fever, tachycardia, hypertension, tachypnea, hyperhidrosis, pupillary dilatation, and flushing. Lesions of the afferent limb of the baroreflex can result in milder recurrent autonomic storms; many of these follow neck irradiation.


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InternalMed_Harrison. Drugs and toxins may also be responsible, including sympathomimetics such as phenylpropanolamine, cocaine, amphetamines, and tricyclic antidepressants; tetanus; and, less often, botulinum toxin. Cocaine, including “crack,” can cause a hypertensive state with CNS hyperstimulation. Tricyclic overdose, such as from amitriptyline, can cause flushing, hypertension, tachycardia, fever, mydriasis, anhidrosis, and a toxic psychosis. The hyperadrenergic state associated with Guillain-Barré syndrome can produce a moderate autonomic storm. Pheochromocytoma presents with a paroxysmal or sustained hyperadrenergic state, headache, hyperhidrosis, palpitations, anxiety, tremulousness, and hypertension. Neuroleptic malignant syndrome refers to a syndrome of muscle rigidity, hyperthermia, and hypertension in psychotic patients treated with phenothiazines (Chap. 449). Management of autonomic storm includes ruling out other causes of autonomic instability, including malignant hyperthermia, porphyria, and


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InternalMed_Harrison. psychotic patients treated with phenothiazines (Chap. 449). Management of autonomic storm includes ruling out other causes of autonomic instability, including malignant hyperthermia, porphyria, and seizures. Sepsis and encephalitis need to be excluded with appropriate studies. An electroencephalogram (EEG) should be done to search for seizure activity; MRI of the brain and spine is often necessary. The patient should be managed in an intensive care unit. Management with morphine sulphate (10 mg every 4 h) and labetalol (100–200 mg twice daily) may be helpful. Supportive treatment may need to be maintained for several weeks. For chronic and milder autonomic storm, propranolol and/or clonidine can be effective.


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InternalMed_Harrison. Other conditions associated with autonomic failure include infections, malignancy, poisoning (organophosphates), and aging. Disorders of the hypothalamus can affect autonomic function and produce abnormalities in temperature control, satiety, sexual function, and circadian rhythms (Chap. 403). The failure to identify a primary role of the ANS in the pathogenesis of these disorders has resulted in a change of nomenclature. The terms complex regional pain syndrome (CRPS) types I and II are now used in place of reflex sympathetic dystrophy (RSD) and causalgia.


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InternalMed_Harrison. CRPS type I is a regional pain syndrome that often develops after tissue injury and most commonly affects one limb. Examples of associated injury include minor shoulder or limb trauma, fractures, myocardial infarction, or stroke. Allodynia (the perception of a nonpainful stimulus as painful), hyperpathia (an exaggerated pain response to a painful stimulus), and spontaneous pain occur. The symptoms are unrelated to the severity of the initial trauma and are not confined to the distribution of a single peripheral nerve. CRPS type II is a regional pain syndrome that develops after injury to a specific peripheral nerve, often a major nerve trunk. Spontaneous pain initially develops within the territory of the affected nerve but eventually may spread outside the nerve distribution.


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InternalMed_Harrison. Pain (usually burning or electrical in quality) is the primary clinical feature of CRPS. Vasomotor dysfunction, sudomotor abnormalities, or focal edema may occur alone or in combination but must be present for diagnosis. Limb pain syndromes that do not meet these criteria are best classified as “limb pain—not otherwise specified.” In CRPS, localized sweating (increased resting sweat output) and changes in blood flow may produce temperature differences between affected and unaffected limbs. CRPS type I (RSD) has been classically divided into three clinical phases. Phase I consists of pain and swelling in the distal extremity occurring within weeks to 3 months after the precipitating event. The


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InternalMed_Harrison. Disorders of the Autonomic Nervous System 2644 pain is diffuse, spontaneous, and either burning, throbbing, or aching in quality. The involved extremity is warm and edematous, and the joints are tender. Increased sweating and hair growth develop. In phase II (3–6 months after onset), thin, shiny, cool skin appears. After an additional 3–6 months (phase III), atrophy of the skin and subcutaneous tissue plus flexion contractures complete the clinical picture. Autonomic testing or bone scans are occasionally useful when the diagnosis is in doubt. The natural history of typical CRPS may be more benign and more variable than previously recognized. A variety of surgical and medical treatments have been developed, with conflicting reports of efficacy. Clinical trials suggest that early mobilization with physical therapy or a brief course of glucocorticoids may be helpful for CRPS type I or II. Other medical treatments include the use of adrenergic blockers, nonsteroidal anti-inflammatory


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InternalMed_Harrison. with physical therapy or a brief course of glucocorticoids may be helpful for CRPS type I or II. Other medical treatments include the use of adrenergic blockers, nonsteroidal anti-inflammatory drugs, calcium channel blockers, phenytoin, opioids, and calcitonin. Stellate ganglion blockade is a commonly used invasive technique that often provides temporary pain relief, but the efficacy of repetitive blocks is uncertain.


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InternalMed_Harrison. Management of autonomic failure is aimed at specific treatment of the cause and alleviation of symptoms. Of particular importance is the removal of drugs or amelioration of underlying conditions that cause or aggravate the autonomic symptoms, especially in the elderly. For example, OH can be caused or aggravated by angiotensin-converting enzyme inhibitors, calcium channel-blocking agents, tricyclic antidepressants, levodopa, alcohol, or insulin. A summary of drugs that can cause OH by class, putative mechanism, and magnitude of the BP drop is shown in Table 454-6.


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InternalMed_Harrison. Only a minority of patients with OH require drug treatment. All patients should be taught the mechanisms of postural normotension (volume status, resistance and capacitance bed, autoregulation) and the nature of orthostatic stressors (time of day and the influence of meals, heat, standing, and exercise). Patients should learn to recognize orthostatic symptoms early (especially subtle cognitive symptoms, weakness, and fatigue) and to modify or avoid activities that provoke episodes. Other helpful measures may include keeping a BP log and dietary education (salt/fluids). Learning physical counter-maneuvers that reduce standing OH and practicing postural and resistance training are helpful measures.


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InternalMed_Harrison. Nonpharmacologic approaches are summarized in Table 454-9. Adequate intake of salt and fluids to produce a voiding volume between 1.5 and 2.5 L of urine (containing >170 meq/L of Na+) each 24 h is essential. Sleeping with the head of the bed elevated will minimize the effects of supine nocturnal hypertension. Prolonged recumbency should be avoided when possible. Patients are advised to sit with legs dangling over the edge of the bed for several minutes before attempting to stand in the morning; other postural stresses should be similarly approached in a gradual manner. One iNitiaL treatmeNt of orthostatiC hypoteNsioN (oh)


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InternalMed_Harrison. Patient education: mechanisms and stressors of OH High-salt diet (10–20 g/d) High-fluid intake (2 L/d) Elevate head of bed 10 cm (4 in.) to minimize supine hypertension Maintain postural stimuli Learn physical counter-maneuvers Compression garments Correct anemia maneuver that can reduce OH is leg-crossing with maintained contraction of leg muscles for 30 s; this compresses leg veins and increases systemic resistance. Compressive garments, such as compression stockings or abdominal binders, are helpful on occasion but uncomfortable for many patients. For transient worsening of OH, drinking two 250-mL (8-oz) glasses of water can raise standing BP 20–30 mmHg for about 2 h, beginning ~20 min after the fluid load. The patient can increase intake of salt and fluids (bouillon treatment), increase use of physical counter-maneuvers (elevate the legs when supine), or temporarily resort to a full-body stocking (compression pressure 30–40 mmHg).


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InternalMed_Harrison. Anemia should be corrected with erythropoietin, administered subcutaneously at doses of 25–75 U/kg three times per week. The hematocrit increases after 2–6 weeks. A weekly maintenance dose is usually necessary. However, the increased intravascular volume that accompanies the rise in hematocrit can exacerbate supine hypertension.


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InternalMed_Harrison. If these measures are not sufficient, pharmacologic treatment may be necessary. Midodrine, a directly acting α1-agonist that does not cross the blood-brain barrier, is effective. It has a duration of action of 2–4 h. The usual dose is 5–10 mg orally tid, but some patients respond best to a decremental dose (e.g., 15 mg on awakening, 10 mg at noon, and 5 mg in the afternoon). Midodrine should not be taken after 6:00 P.M. Side effects include pruritus, uncomfortable piloerection, and supine hypertension especially at higher doses. Droxidopa (Northera) was recently approved by the FDA for treatment of neurogenic OH associated with PAF, PD, or MSA; oral droxidopa is converted to NE and in short-term clinical trails was effective in decreasing symptoms of OH. Pyridostigmine (Mestinon) appears to improve OH without aggravating supine hypertension by enhancing ganglionic transmission (maximal when orthostatic, minimal when supine). Fludrocortisone will reduce OH but aggravates supine


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InternalMed_Harrison. to improve OH without aggravating supine hypertension by enhancing ganglionic transmission (maximal when orthostatic, minimal when supine). Fludrocortisone will reduce OH but aggravates supine hypertension. At doses between 0.1 mg/d and 0.3 mg bid orally, it enhances renal sodium conservation and increases the sensitivity of arterioles to NE. Susceptible patients may develop fluid overload, congestive heart failure, supine hypertension, or hypokalemia. Potassium supplements are often necessary with chronic administration of fludrocortisone. Sustained elevations of supine BP >180/110 mmHg should be avoided. Supine hypertension (>180/110 mmHg) can be self-treated by avoiding the supine position (e.g., sleeping in a recumbent chair) and reducing fludrocortisone. A daily glass of wine, if requested by the patient, can be taken shortly before bedtime. If these simple measures are not adequate, drugs to be considered include oral hydralazine (25 mg qhs), oral nifedipine (Procardia; 10 mg


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InternalMed_Harrison. by the patient, can be taken shortly before bedtime. If these simple measures are not adequate, drugs to be considered include oral hydralazine (25 mg qhs), oral nifedipine (Procardia; 10 mg qhs), or a nitroglycerin patch.


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InternalMed_Harrison. A promising drug combination (atomoxetine and yohimbine) has been studied for use in human subjects with severe OH not responsive to other agents, as can occur is some patients with diabetes and severe autonomic neuropathy not responsive to other medications. The atomoxetine blocks the NE reuptake transporter, and yohimbine blocks α2 receptors that mediate the sympathetic feedback loop for downregulation of BP in response to atomoxetine. The result is a dramatic increase in BP and standing tolerance. This combination is not FDA approved for this purpose. It is possible that the limited drug duration of action can be used to withdraw drug treatment when the patient anticipates becoming supine (e.g., before sleep).


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InternalMed_Harrison. Postprandial OH may respond to several measures. Frequent, small, low-carbohydrate meals may diminish splanchnic shunting of blood after meals and reduce postprandial OH. Prostaglandin inhibitors (ibuprofen or indomethacin) taken with meals or midodrine (10 mg with the meal) can be helpful. The somatostatin analogue octreotide can be useful in the treatment of postprandial syncope by inhibiting the release of GI peptides that have vasodilator and hypotensive effects. The subcutaneous dose ranges from 25 μg bid to 200 μg tid.


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InternalMed_Harrison. trigeminal Neuralgia, Bell’s palsy, and other Cranial Nerve Disorders M. Flint Beal, Stephen L. Hauser Symptoms and signs of cranial nerve pathology are common in inter-nal medicine. They often develop in the context of a widespread neu-rologic disturbance, and in such situations, cranial nerve involvement 455 may represent the initial manifestation of the illness. In other disor ders, involvement is largely restricted to one or several cranial nerves; these distinctive disorders are reviewed in this chapter. Disorders of ocular movement are discussed in Chap. 39, disorders of hearing in Chap. 43, and vertigo and disorders of vestibular function in


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InternalMed_Harrison. The trigeminal (fifth cranial) nerve supplies sensation to the skin of the face and anterior half of the head (Fig. 455-1). The motor part innervates the muscles involved in chewing (including masseters and pterygoids) as well as the tensor tympani of the middle ear (hearing especially for high-pitched tones). It is the largest of the cranial nerves. It exits in the lateral midpons and traverses the middle cranial fossa to the semilunar (gasserian, trigeminal) ganglion in Meckel’s cave, where the nerve divides into three divisions (ophthalmic [V1], maxillary [V2], and mandibular [V3]). V1 and V2 traverse the cavernous sinus to exit in the superior orbital fissure and foramen rotundum, located above and below the eye socket respectively; V3 exits through the foramen ovale. The trigeminal nerve is predominantly sensory, and motor innervation is exclusively carried in V3. The cornea is primar- Chap. 28. ily innervated by V1, although an inferior crescent may be V2. Upon


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InternalMed_Harrison. Chap. 28. ily innervated by V1, although an inferior crescent may be V2. Upon Frontal branch of frontal nerve Mesencephalic nucleus of V nerve Main sensory nucleus of V ganglion Main motor nucleus of Vnerve External Nucleus of spinal tract of V rami of infraorbital Mylohyoid nerve and sublingual glands Anterior belly of Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders


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InternalMed_Harrison. FIGURE 455-1 The trigeminal nerve and its branches and sensory distribution on the face. The three major sensory divisions of the trigeminal nerve consist of the ophthalmic, maxillary, and mandibular nerves. (Adapted from Waxman SG: Clinical Neuroanatomy, 26th ed. http://www.accessmedicine.com. Copyright © The McGraw-Hill Companies, Inc. All rights reserved.) 2646 entering the pons, pain and temperature fibers descend ipsilaterally to the upper cervical spinal cord as the spinal tract of V, before synapsing with the spinal nucleus of V; this accounts for the facial numbness that can occur with spinal cord lesions above C2. In the brainstem, the spinal tract of V is also located adjacent to crossed ascending fibers of the spinothalamic tract, producing a “crossed” sensory loss for pain and temperature (ipsilateral face, contralateral arm/trunk/leg) with lesions of the lateral lower brainstem. CN V is also ensheathed by oligodendrocyte-derived, rather than Schwann cell–derived, myelin


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InternalMed_Harrison. temperature (ipsilateral face, contralateral arm/trunk/leg) with lesions of the lateral lower brainstem. CN V is also ensheathed by oligodendrocyte-derived, rather than Schwann cell–derived, myelin for up to 7 mm after it leaves the brainstem, unlike just a few millimeters for other cranial and spinal nerves; this may explain the high frequency of trigeminal neuralgia in multiple sclerosis (Chap. 458), a disorder of oligodendrocyte myelin.


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InternalMed_Harrison. TRIGEMINAL NEURALGIA (TIC DOULOUREUX) Clinical Manifestations Trigeminal neuralgia is characterized by excruciating paroxysms of pain in the lips, gums, cheek, or chin and, very rarely, in the distribution of the ophthalmic division of the fifth nerve. The pain seldom lasts more than a few seconds or a minute or two but may be so intense that the patient winces, hence the term tic. The paroxysms, experienced as single jabs or clusters, tend to recur frequently, both day and night, for several weeks at a time. They may occur spontaneously or with movements of affected areas evoked by speaking, chewing, or smiling. Another characteristic feature is the presence of trigger zones, typically on the face, lips, or tongue, that provoke attacks; patients may report that tactile stimuli—e.g., washing the face, brushing the teeth, or exposure to a draft of air—generate excruciating pain. An essential feature of trigeminal neuralgia is that objective signs of sensory loss cannot be demonstrated


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InternalMed_Harrison. the face, brushing the teeth, or exposure to a draft of air—generate excruciating pain. An essential feature of trigeminal neuralgia is that objective signs of sensory loss cannot be demonstrated on examination.


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InternalMed_Harrison. Trigeminal neuralgia is relatively common, with an estimated annual incidence of 4–8 per 100,000 individuals. Middle-aged and elderly persons are affected primarily, and ~60% of cases occur in women. Onset is typically sudden, and bouts tend to persist for weeks or months before remitting spontaneously. Remissions may be long-lasting, but in most patients, the disorder ultimately recurs.


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InternalMed_Harrison. Pathophysiology Symptoms result from ectopic generation of action potentials in pain-sensitive afferent fibers of the fifth cranial nerve root just before it enters the lateral surface of the pons. Compression or other pathology in the nerve leads to demyelination of large myelinated fibers that do not themselves carry pain sensation but become hyperexcitable and electrically coupled with smaller unmyelinated or poorly myelinated pain fibers in close proximity; this may explain why tactile stimuli, conveyed via the large myelinated fibers, can stimulate paroxysms of pain. Compression of the trigeminal nerve root by a blood vessel, most often the superior cerebellar artery or on occasion a tortuous vein, is now believed to be the source of trigeminal neuralgia in most patients. In cases of vascular compression, age-related brain sagging and increased vascular thickness and tortuosity may explain the prevalence of trigeminal neuralgia in later life.


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InternalMed_Harrison. Differential Diagnosis Trigeminal neuralgia must be distinguished from other causes of face and head pain (Chap. 21) and from pain arising from diseases of the jaw, teeth, or sinuses. Pain from migraine or cluster headache tends to be deep-seated and steady, unlike the superficial stabbing quality of trigeminal neuralgia; rarely, cluster headache is associated with trigeminal neuralgia, a syndrome known as cluster-tic. In temporal arteritis, superficial facial pain is present but is not typically shock-like, the patient frequently complains of myalgias and other systemic symptoms, and an elevated erythrocyte sedimentation rate (ESR) is usually present (Chap. 385). When trigeminal neuralgia develops in a young adult or is bilateral, multiple sclerosis (MS) is a key consideration, and in such cases, the cause is a demyelinating plaque near the root entry zone of the fifth nerve in the pons; often, evidence of facial sensory loss can be found on careful examination. Cases that are


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InternalMed_Harrison. in such cases, the cause is a demyelinating plaque near the root entry zone of the fifth nerve in the pons; often, evidence of facial sensory loss can be found on careful examination. Cases that are secondary to mass lesions—such as aneurysms, neurofibromas, acoustic schwannomas, or meningiomas—usually produce objective signs of sensory loss in the trigeminal nerve distribution (trigeminal neuropathy, see below).


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InternalMed_Harrison. Laboratory Evaluation An ESR is indicated if temporal arteritis is suspected. In typical cases of trigeminal neuralgia, neuroimaging studies are usually unnecessary but may be valuable if MS is a consideration or in assessing overlying vascular lesions in order to plan for decompression surgery.


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InternalMed_Harrison. Drug therapy with carbamazepine is effective in ~50–75% of patients. Carbamazepine should be started as a single daily dose of 100 mg taken with food and increased gradually (by 100 mg daily in divided doses every 1–2 days) until substantial (>50%) pain relief is achieved. Most patients require a maintenance dose of 200 mg qid. Doses >1200 mg daily provide no additional benefit. Dizziness, imbalance, sedation, and rare cases of agranulocytosis are the most important side effects of carbamazepine. If treatment is effective, it is usually continued for 1 month and then tapered as tolerated. Oxcarbazepine (300–1200 mg bid) is an alternative to carbamazepine that has less bone marrow toxicity and probably is equally efficacious. If these agents are not well tolerated or are ineffective, lamotrigine, 400 mg daily, and phenytoin, 300–400 mg daily, are other options. Baclofen may also be tried, either alone or in combination with an anticonvulsant. The initial dose is 5–10 mg tid, gradually


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InternalMed_Harrison. 400 mg daily, and phenytoin, 300–400 mg daily, are other options. Baclofen may also be tried, either alone or in combination with an anticonvulsant. The initial dose is 5–10 mg tid, gradually increasing as needed to 20 mg qid.


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InternalMed_Harrison. If drug treatment fails, surgical therapy should be offered. The most widely used method is currently microvascular decompression to relieve pressure on the trigeminal nerve as it exits the pons. This procedure requires a suboccipital craniotomy. This procedure appears to have a >70% efficacy rate and a low rate of pain recurrence in responders; the response is better for classic tic-like symptoms than for nonlancinating facial pains. In a small number of cases, there is perioperative damage to the eighth or seventh cranial nerves or to the cerebellum or a postoperative cerebrospinal fluid leak syndrome. High-resolution magnetic resonance angiography is useful preoperatively to visualize the relationships between the fifth cranial nerve root and nearby blood vessels.


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InternalMed_Harrison. Gamma knife radiosurgery of the trigeminal nerve root is also used for treatment and results in complete pain relief, sometimes delayed in onset, in more than two-thirds of patients and a low risk of persistent facial numbness; the response is sometimes long-lasting, but recurrent pain develops over 2–3 years in half of patients. Compared with surgical decompression, gamma knife surgery appears to be somewhat less effective but has few serious complications.


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InternalMed_Harrison. Another procedure, radiofrequency thermal rhizotomy, creates a heat lesion of the trigeminal ganglion or nerve. It is used less often now than in the past. Short-term relief is experienced by >95% of patients; however, long-term studies indicate that pain recurs in up to one-third of treated patients. Postoperatively, partial numbness of the face is common, masseter (jaw) weakness may occur especially following bilateral procedures, and corneal denervation with secondary keratitis can follow rhizotomy for first-division trigeminal neuralgia.


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InternalMed_Harrison. A variety of diseases can affect the trigeminal nerve (Table 455-1). Most present with sensory loss on the face or with weakness of the jaw muscles. Deviation of the jaw on opening indicates weakness of the pterygoids on the side to which the jaw deviates. Some cases are due to Sjögren’s syndrome or a collagen-vascular disease such as systemic lupus erythematosus, scleroderma, or mixed connective tissue disease. Among infectious causes, herpes zoster (acute or postherpetic) and leprosy should be considered. Tumors of the middle cranial fossa (meningiomas), of the trigeminal nerve (schwannomas), or of the base of the skull (metastatic tumors) may cause a combination of motor and sensory signs. Lesions in the cavernous sinus can affect the first and second divisions of the trigeminal nerve, and lesions of the superior orbital fissure can affect the first (ophthalmic) division; the accompanying corneal anesthesia increases the risk of ulceration (neurokeratitis).


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InternalMed_Harrison. Isolated sensory loss over the chin (mental neuropathy) can be the only manifestation of systemic malignancy. Rarely, an idiopathic form of trigeminal neuropathy is observed. It is characterized by numbness Nasopharyngeal carcinoma Trauma Guillain-Barré syndrome Sjögren’s syndrome Collagen-vascular diseases Sarcoidosis Leprosy Drugs (stilbamidine, trichloroethylene) Idiopathic trigeminal neuropathy and paresthesias, sometimes bilaterally, with loss of sensation in the territory of the trigeminal nerve but without weakness of the jaw. Gradual recovery is the rule. Tonic spasm of the masticatory muscles, known as trismus, is symptomatic of tetanus (Chap. 177) or may occur in patients treated with phenothiazines. (Fig. 455-2) The seventh cranial nerve supplies all the muscles concerned with facial expression. The sensory component is small (the nervus intermedius); it conveys taste sensation from the anterior Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders


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InternalMed_Harrison. Trigeminal Neuralgia, Bell’s Palsy, and Other Cranial Nerve Disorders Lacrimal gland Sublingual gland Submandibular ganglion Nucleus fasciculus solitarius Motor nucleus VII n. Motor nucleus VI n. Superior salivatory nucleus Fasciculus solitarius Geniculate ganglion Trigeminal ganglion Major superficial petrosal nerve Lingual nerve Chorda tympani To nasal and palatine glands VII n. V n. 123BCA


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InternalMed_Harrison. FIGURE 455-2 The facial nerve. A, B, and C denote lesions of the facial nerve at the a rule) before regeneration occurs, and that it may be stylomastoid foramen, distal and proximal to the geniculate ganglion, respectively. incomplete. The presence of incomplete paralysis in Green lines indicate the parasympathetic fibers, red line indicates motor fibers, and the first week is the most favorable prognostic sign. purple lines indicate visceral afferent fibers (taste). (Adapted from MB Carpenter: Core Text Recurrences are reported in approximately 7% of of Neuroanatomy, 2nd ed. Williams & Wilkins, 1978.) cases.


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InternalMed_Harrison. two-thirds of the tongue and probably cutaneous impulses from the 2647 anterior wall of the external auditory canal. The motor nucleus of the seventh nerve lies anterior and lateral to the abducens nucleus. After leaving the pons, the seventh nerve enters the internal auditory meatus with the acoustic nerve. The nerve continues its course in its own bony channel, the facial canal, and exits from the skull via the stylomastoid foramen. It then passes through the parotid gland and subdivides to supply the facial muscles.


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InternalMed_Harrison. A complete interruption of the facial nerve at the stylomastoid foramen paralyzes all muscles of facial expression. The corner of the mouth droops, the creases and skinfolds are effaced, the forehead is unfurrowed, and the eyelids will not close. Upon attempted closure of the lids, the eye on the paralyzed side rolls upward (Bell’s phenomenon). The lower lid sags and falls away from the conjunctiva, permitting tears to spill over the cheek. Food collects between the teeth and lips, and saliva may dribble from the corner of the mouth. The patient complains of a heaviness or numbness in the face, but sensory loss is rarely demonstrable and taste is intact.


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InternalMed_Harrison. If the lesion is in the middle-ear portion, taste is lost over the anterior two-thirds of the tongue on the same side. If the nerve to the stapedius is interrupted, there is hyperacusis (sensitivity to loud sounds). Lesions in the internal auditory meatus may affect the adjacent auditory and vestibular nerves, causing deafness, tinnitus, or dizziness. Intrapontine lesions that paralyze the face usually affect the abducens nucleus as well, and often the corticospinal and sensory tracts.


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InternalMed_Harrison. If the peripheral facial paralysis has existed for some time and recovery of motor function is incomplete, a continuous diffuse contraction of facial muscles may appear. The palpebral fissure becomes narrowed, and the nasolabial fold deepens. Attempts to move one group of facial muscles may result in contraction of all (associated movements, or synkinesis). Facial spasms, initiated by movements of the face, may develop (hemifacial spasm). Anomalous regeneration of seventh nerve fibers may result in other troublesome phenomena. If fibers originally connected with the orbicularis oculi come to innervate the orbicularis oris, closure of the lids may cause a retraction of the mouth, or if fibers originally connected with muscles of the face later innervate the lacrimal gland, anomalous tearing (“crocodile tears”) may occur with any activity of the facial muscles, such as eating. Another facial synkinesia is triggered by jaw opening, causing closure of the eyelids on the side of the facial


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InternalMed_Harrison. (“crocodile tears”) may occur with any activity of the facial muscles, such as eating. Another facial synkinesia is triggered by jaw opening, causing closure of the eyelids on the side of the facial palsy (jaw-winking).


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InternalMed_Harrison. The most common form of facial paralysis is Bell’s palsy. The annual incidence of this idiopathic disorder is ~25 per 100,000 annually, or about 1 in 60 persons in a lifetime. Risk factors include pregnancy and diabetes mellitus.


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InternalMed_Harrison. Pterygopalatine Clinical Manifestations The onset of Bell’s palsy is ganglion fairly abrupt, with maximal weakness being attained by 48 h as a general rule. Pain behind the ear may precede the paralysis for a day or two. Taste sensation may be lost unilaterally, and hyperacusis may be present. In some cases, there is mild cerebrospinal fluid lymphocytosis. Magnetic resonance imaging (MRI) may reveal swelling and uniform enhancement of the geniculate ganglion and facial nerve and, in some cases, entrapment of the swollen nerve in the temporal bone. Approximately 80% of patients recover within a few weeks or months. Electromyography may be of some prognostic value; evidence of denervation after 10 days indicates there has been axonal degeneration, that there will be a long delay (3 months as 2648 Pathophysiology In acute Bell’s palsy, there is inflammation of the facial nerve with mononuclear cells, consistent with an infectious or immune cause. Herpes simplex virus (HSV) type 1 DNA was


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InternalMed_Harrison. 2648 Pathophysiology In acute Bell’s palsy, there is inflammation of the facial nerve with mononuclear cells, consistent with an infectious or immune cause. Herpes simplex virus (HSV) type 1 DNA was frequently detected in endoneurial fluid and posterior auricular muscle, suggesting that a reactivation of this virus in the geniculate ganglion may be responsible for most cases. Reactivation of varicella-zoster virus is associated with Bell’s palsy in up to one-third of cases and may represent the second most frequent cause. A variety of other viruses have also been implicated less commonly. An increased incidence of Bell’s palsy was also reported among recipients of inactivated intranasal influenza vaccine, and it was hypothesized that this could have resulted from the Escherichia coli enterotoxin used as adjuvant or reactivation of latent virus.


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InternalMed_Harrison. Differential Diagnosis There are many other causes of acute facial palsy that must be considered in the differential diagnosis of Bell’s palsy. Lyme disease can cause unilateral or bilateral facial palsies; in endemic areas, 10% or more of cases of facial palsy are likely due to infection with Borrelia burgdorferi (Chap. 210). The Ramsay Hunt syndrome, caused by reactivation of herpes zoster in the geniculate ganglion, consists of a severe facial palsy associated with a vesicular eruption in the external auditory canal and sometimes in the pharynx and other parts of the cranial integument; often the eighth cranial nerve is affected as well. Facial palsy that is often bilateral occurs in sarcoidosis (Chap.


InternalMed_Harrison

InternalMed_Harrison. 390) and in Guillain-Barré syndrome (Chap. 460). Leprosy frequently involves the facial nerve, and facial neuropathy may also occur in diabetes mellitus, connective tissue diseases including Sjögren’s syndrome, and amyloidosis. The rare Melkersson-Rosenthal syndrome consists of recurrent facial paralysis; recurrent—and eventually permanent—facial (particularly labial) edema; and, less constantly, plication of the tongue. Its cause is unknown. Acoustic neuromas frequently involve the facial nerve by local compression. Infarcts, demyelinating lesions of MS, and tumors are the common pontine lesions that interrupt the facial nerve fibers; other signs of brainstem involvement are usually present. Tumors that invade the temporal bone (carotid body, cholesteatoma, dermoid) may produce a facial palsy, but the onset is insidious and the course progressive.


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InternalMed_Harrison. All these forms of nuclear or peripheral facial palsy must be distinguished from the supranuclear type. In the latter, the frontalis and orbicularis oculi muscles of the forehead are involved less than those of the lower part of the face, since the upper facial muscles are innervated by corticobulbar pathways from both motor cortices, whereas the lower facial muscles are innervated only by the opposite hemisphere. In supranuclear lesions, there may be a dissociation of emotional and voluntary facial movements, and often some degree of paralysis of the arm and leg or an aphasia (in dominant hemisphere lesions) is present.


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InternalMed_Harrison. Laboratory Evaluation The diagnosis of Bell’s palsy can usually be made clinically in patients with (1) a typical presentation, (2) no risk factors or preexisting symptoms for other causes of facial paralysis, (3) absence of cutaneous lesions of herpes zoster in the external ear canal, and (4) a normal neurologic examination with the exception of the facial nerve. Particular attention to the eighth cranial nerve, which courses near to the facial nerve in the pontomedullary junction and in the temporal bone, and to other cranial nerves is essential. In atypical or uncertain cases, an ESR, testing for diabetes mellitus, a Lyme titer, angiotensin-converting enzyme and chest imaging studies for possible sarcoidosis, a lumbar puncture for possible Guillain-Barré syndrome, or MRI scanning may be indicated. MRI often shows swelling and enhancement of the facial nerve in idiopathic Bell’s palsy (Fig. 455-3).


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InternalMed_Harrison. Symptomatic measures include (1) the use of paper tape to depress the upper eyelid during sleep and prevent corneal drying, and (2) massage of the weakened muscles. A course of glucocorticoids, given as prednisone 60–80 mg daily during the first 5 days and then tapered over the next 5 days, modestly shortens the recovery period and improves the functional outcome. Although large and well-controlled randomized trials found no added benefit of the antiviral agents valacyclovir (1000 mg daily for 5–7 days) or acyclovir (400 mg five times daily for 10 days) compared to glucocorticoids alone, some earlier data suggested that combination therapy with prednisone plus valacyclovir might be marginally better than prednisolone alone, especially in patients with severe clinical presentations. For patients with permanent paralysis from Bell’s palsy, a number of cosmetic surgical procedures have been used to restore a relatively symmetric appearance to the face.


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InternalMed_Harrison. Hemifacial spasm consists of painless irregular involuntary contractions on one side of the face. Most cases appear related to vascular compression of the exiting facial nerve in the pons. Other cases develop as a sequela to Bell’s palsy or are secondary to compression and/or demyelination of the nerve by tumor, infection, or MS. Mild cases can be treated with carbamazepine, gabapentin, or, if these drugs fail, baclofen. Local injections of botulinum toxin into affected muscles can relieve spasms for 3–4 months, and the injections can be repeated. Refractory cases due to vascular compression usually respond to surgical decompression of the facial nerve. Blepharospasm is an involuntary recurrent spasm of both eyelids that usually occurs in elderly persons as an isolated phenomenon or with varying degrees of spasm of other facial muscles. Severe, persistent cases of blepharospasm can be treated by local injection of botulinum toxin into the orbicularis oculi. Facial myokymia refers to a


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InternalMed_Harrison. degrees of spasm of other facial muscles. Severe, persistent cases of blepharospasm can be treated by local injection of botulinum toxin into the orbicularis oculi. Facial myokymia refers to a fine rippling activity of the facial muscles; it may be caused by MS or follow Guillain-Barré syndrome (Chap. 460).


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InternalMed_Harrison. FIGURE 455-3 Axial and coronal T1-weighted images after gadolinium with fat suppression demonstrate diffuse smooth linear enhancement of the left facial nerve, involving the genu, tympanic, and mastoid segments within the temporal bone (arrows), without evidence of mass lesion. Although highly suggestive of Bell’s palsy, similar findings may be seen with other etiologies such as Lyme disease, sarcoidosis, and perineural malignant spread.


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InternalMed_Harrison. Facial hemiatrophy occurs mainly in women and is characterized by a disappearance of fat in the dermal and subcutaneous tissues on one side of the face. It usually begins in adolescence or the early adult years and is slowly progressive. In its advanced form, the affected side of the face is gaunt, and the skin is thin, wrinkled, and brown. The facial hair may turn white and fall out, and the sebaceous glands become atrophic. Bilateral involvement may occur. A limited form of systemic sclerosis (scleroderma) may be the cause of some cases. Treatment is cosmetic, consisting of transplantation of skin and subcutaneous fat.


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InternalMed_Harrison. This form of neuralgia involves the ninth (glossopharyngeal) and sometimes portions of the tenth (vagus) cranial nerves. It resembles trigeminal neuralgia in many respects but is much less common. The pain is intense and paroxysmal; it originates on one side of the throat, approximately in the tonsillar fossa. In some cases, the pain is localized in the ear or may radiate from the throat to the ear because of involvement of the tympanic branch of the glossopharyngeal nerve. Spasms of pain may be initiated by swallowing or coughing. There is no demonstrable motor or sensory deficit; the glossopharyngeal nerve supplies taste sensation to the posterior third of the tongue and, together with the vagus nerve, sensation to the posterior pharynx. Cardiac symptoms—bradycardia or asystole, hypotension, and fainting—have been reported. Glossopharyngeal neuralgia can result from vascular compression, MS, or tumors, but many cases are idiopathic. Medical therapy is similar to that for trigeminal


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InternalMed_Harrison. and fainting—have been reported. Glossopharyngeal neuralgia can result from vascular compression, MS, or tumors, but many cases are idiopathic. Medical therapy is similar to that for trigeminal neuralgia, and carbamazepine is generally the first choice. If drug therapy is unsuccessful, surgical procedures—including microvascular decompression if vascular compression is evident—or rhizotomy of glossopharyngeal and vagal fibers in the jugular bulb is frequently successful.


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InternalMed_Harrison. Glossopharyngeal neuropathy in conjunction with vagus and accessory nerve palsies may occur with herpes zoster infection or with a tumor or aneurysm in the posterior fossa or in the jugular foramen. Hoarseness due to vocal cord paralysis, some difficulty in swallowing, deviation of the soft palate to the intact side, anesthesia of the posterior wall of the pharynx, and weakness of the upper part of the trapezius and sternocleidomastoid muscles make up the jugular foramen syndrome (Table 455-2).


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InternalMed_Harrison. When the intracranial portion of one vagus (tenth cranial) nerve is interrupted, the soft palate droops ipsilaterally and does not rise in phonation. There is loss of the gag reflex on the affected side, as well as of the “curtain movement” of the lateral wall of the pharynx, whereby the faucial pillars move medially as the palate rises in saying “ah.” The voice is hoarse and slightly nasal, and the vocal cord lies immobile midway between abduction and adduction. Loss of sensation at the external auditory meatus and the posterior pinna may also be present. The pharyngeal branches of both vagal nerves may be affected in diphtheria; the voice has a nasal quality, and regurgitation of liquids through the nose occurs during swallowing.


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InternalMed_Harrison. The pharyngeal branches of both vagal nerves may be affected in diphtheria; the voice has a nasal quality, and regurgitation of liquids through the nose occurs during swallowing. Injury to the vagus nerve in the carotid sheath can also occur with carotid dissection or following endarterectomy. The vagus nerve may be involved at the meningeal level by neoplastic and infectious processes and within the medulla by tumors, vascular lesions (e.g., the lateral medullary syndrome), and motor neuron disease. This nerve may be involved by infection with varicella zoster virus. Polymyositis and dermatomyositis, which cause hoarseness and dysphagia by direct involvement of laryngeal and pharyngeal muscles, may be confused with diseases of the vagus nerves. Dysphagia is also a symptom in some patients with myotonic dystrophy. Nonneurologic causes of dysphagia are discussed in Chap. 53.


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InternalMed_Harrison. The recurrent laryngeal nerves, especially the left, are most often damaged as a result of intrathoracic disease. Aneurysm of the aortic arch, an enlarged left atrium, and tumors of the mediastinum and bronchi are much more frequent causes of an isolated vocal cord palsy than are intracranial disorders. However, a substantial number of cases of recurrent laryngeal palsy remain idiopathic.


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InternalMed_Harrison. When confronted with a case of laryngeal palsy, the physician must attempt to determine the site of the lesion. If it is intramedullary, there are usually other signs, such as ipsilateral cerebellar dysfunction, loss of pain and temperature sensation over the ipsilateral face and contralateral arm and leg, and an ipsilateral Horner’s syndrome. If the lesion is extramedullary, the glossopharyngeal and spinal accessory nerves are frequently involved (jugular foramen syndrome). If it is extracranial in the posterior laterocondylar or retroparotid space, there may be a combination of ninth, tenth, eleventh, and twelfth cranial nerve palsies and a Horner’s syndrome (Table 455-2). If there is no sensory loss over the palate and pharynx and no palatal weakness or dysphagia, the lesion is below the origin of the pharyngeal branches, which leave the vagus nerve high in the cervical region; the usual site of disease is then the mediastinum.


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InternalMed_Harrison. Isolated involvement of the accessory (eleventh cranial) nerve can occur anywhere along its route, resulting in partial or complete paralysis of the sternocleidomastoid and trapezius muscles. More commonly, involvement occurs in combination with deficits of the ninth and tenth cranial nerves in the jugular foramen or after exit from the skull (Table 455-2). An idiopathic form of accessory neuropathy, akin to Bell’s palsy, has been described, and it may be recurrent in some cases. Most but not all patients recover.


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InternalMed_Harrison. The hypoglossal (twelfth cranial) nerve supplies the ipsilateral muscles of the tongue. The nucleus of the nerve or its fibers of exit may be involved by intramedullary lesions such as tumor, poliomyelitis, or most often motor neuron disease. Lesions of the basal meninges and the occipital bones (platybasia, invagination of occipital condyles, Paget’s disease) may compress the nerve in its extramedullary course or in the hypoglossal canal. Isolated lesions of unknown cause can occur. Atrophy and fasciculation of the tongue develop weeks to months after interruption of the nerve. s Palsy, and Other Cranial Nerve Disorders


InternalMed_Harrison

InternalMed_Harrison. s Palsy, and Other Cranial Nerve Disorders Several cranial nerves may be affected by the same disease process. In this situation, the main clinical problem is to determine whether the lesion lies within the brainstem or outside it. Lesions that lie on the surface of the brainstem are characterized by involvement of adjacent cranial nerves (often occurring in succession) and late and rather slight involvement of the long sensory and motor pathways and segmental structures lying within the brainstem. The opposite is true of primary lesions within the brainstem. The extramedullary lesion is more likely to cause bone erosion or enlargement of the foramens of exit of cranial nerves. The intramedullary lesion involving cranial nerves often produces a crossed sensory or motor paralysis (cranial nerve signs on one side of the body and tract signs on the opposite side).


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InternalMed_Harrison. Involvement of multiple cranial nerves outside the brainstem is frequently the result of trauma, localized infections including varicellazoster virus, infectious and noninfectious (especially carcinomatous) causes of meningitis (Chaps. 164 and 165), granulomatous diseases such as Wegener’s granulomatosis, Behçet’s disease, vascular disorders including those associated with diabetes, enlarging aneurysms, or locally infiltrating tumors. Among the tumors, nasopharyngeal cancers, lymphomas, neurofibromas, meningiomas, chordomas, cholesteatomas, carcinomas, and sarcomas have all been observed to involve a succession of lower cranial nerves. Owing to their anatomic relationships, the multiple cranial nerve palsies form a number of distinctive syndromes, listed in Table 455-2. Sarcoidosis is the cause of some cases of multiple cranial neuropathy; tuberculosis, the Chiari malformation, platybasia, and basilar invagination of the skull are additional causes. A purely motor disorder without


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InternalMed_Harrison. the cause of some cases of multiple cranial neuropathy; tuberculosis, the Chiari malformation, platybasia, and basilar invagination of the skull are additional causes. A purely motor disorder without atrophy always raises the question of myasthenia gravis (Chap. 461). As noted above, Guillain-Barré syndrome commonly affects the facial nerves bilaterally. In the Fisher variant of the Guillain-Barré syndrome, oculomotor paresis occurs with ataxia and areflexia in the limbs (Chap. 460). Wernicke’s encephalopathy can cause a severe ophthalmoplegia combined with other brainstem signs (Chap. 330).


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InternalMed_Harrison. The cavernous sinus syndrome (Fig. 455-4) is a distinctive and frequently life-threatening disorder. It often presents as orbital or facial pain; orbital swelling and chemosis due to occlusion of the ophthalmic veins; fever; oculomotor neuropathy affecting the third, fourth, and sixth cranial nerves; and trigeminal neuropathy affecting the ophthalmic (V1) and occasionally the maxillary (V2) divisions of the trigeminal nerve. Cavernous sinus thrombosis, often secondary to infection from orbital cellulitis (frequently Staphylococcus aureus), a cutaneous source on the face, or sinusitis (especially with mucormycosis in diabetic patients), is the most frequent cause; other etiologies include Ant. cerebral a. Int. carotid a. Ant. clinoid process Subarachnoid Oculomotor (III) n. Trochlear (IV) n. Ophthalmic (VI) n. Abducens (VI) n. Maxillary (V2) n. Pia Arachnoid Sphenoid sinus


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InternalMed_Harrison. Ant. cerebral a. Int. carotid a. Ant. clinoid process Subarachnoid Oculomotor (III) n. Trochlear (IV) n. Ophthalmic (VI) n. Abducens (VI) n. Maxillary (V2) n. Pia Arachnoid Sphenoid sinus FIGURE 455-4 Anatomy of the cavernous sinus in coronal section, illustrating the location of the cranial nerves in relation to the vascular sinus, internal carotid artery (which loops anteriorly to the section), and surrounding structures. aneurysm of the carotid artery, a carotid-cavernous fistula (orbital bruit may be present), meningioma, nasopharyngeal carcinoma, other tumors, or an idiopathic granulomatous disorder (Tolosa-Hunt syndrome). The two cavernous sinuses directly communicate via intercavernous channels; thus, involvement on one side may extend to become bilateral. Early diagnosis is essential, especially when due to infection, and treatment depends on the underlying etiology.


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InternalMed_Harrison. In infectious cases, prompt administration of broad-spectrum antibiotics, drainage of any abscess cavities, and identification of the offending organism are essential. Anticoagulant therapy may benefit cases of primary thrombosis. Repair or occlusion of the carotid artery may be required for treatment of fistulas or aneurysms. The Tolosa-Hunt syndrome generally responds to glucocorticoids. A dramatic improvement in pain is usually evident within a few days; oral prednisone (60 mg daily) is usually continued for 2 weeks and then gradually tapered over a month, or longer if pain recurs. Occasionally an immunosuppressive medication, such as azathioprine or methotrexate, needs to be added to maintain an initial response to glucocorticoids.