Vision

Visual function is generally preserved in autonomic failure. With upright posture and impaired perfusion of the CNS, dimming or tunneling of vision commonly occurs as a transitory phenomenon, usually interpreted as a sign that the patient needs to sit down to avoid passing out. Reduced blood flow in brain areas subserving vision was assumed, but a simpler mechanism may also be partly at work here. Funduscopic examination at this moment of visual change may show a striking diminution in the caliber of vessels in the eyegrounds. It is possible that blood-flow changes in the retinal vasculature contribute to the tunneling of vision in these patients. Intraocular pressure changes greatly in patients with dysautonomias, tracking low with upright posture and hypotension and high with supine posture and hypertension. Pupillary function itself is under autonomic control and therefore often dysfunctional in dysautonomias, but night blindness from inadequate dilation of the pupil in a dark environment is quite rare.

Cardiovascular

Normally when one stands, systolic blood pressure falls about 10 mm Hg, and diastolic pressure increases 5 mm Hg. Heart rate rises 5 to 20 beats per minute (bpm). A fall in blood pressure of 20/10 mm Hg or more in the first 3 minutes of standing defines orthostatic hypotension (Consensus Committee of the American Autonomic Society and the American Academy of Neurology, 1996). If there is not a fall in blood pressure of 20/10 on standing, but the patient is symptomatic and experiencing tachycardia, orthostatic intolerance is present, qualifying as POTS if the heart rate rise is greater than 30 bpm in the first 10 minutes in the upright position (Schondorf and Low, 1993). The most common symptoms of orthostatic hypotension are dizziness, dimming of vision, and discomfort in the neck and head. Orthostatic hypotension is greatest, and hence most easily detected, in the hour after ingesting a large breakfast. Carbohydrate acts as a depressor more than protein or fat. It is important to note that a majority of patients with orthostatic hypotension will not have the usual expected symptoms and may present with falls only (Arbogast et al., 2009), so it is vital to not rely solely on symptom reports in the elderly population.

In the emergency room, the most common causes of acute hypotension may be bleeding, infection, shock, and dehydration. However, even with bleeding and dehydration, the normal rise in diastolic pressure will be even greater than normal, resulting in a very narrowed pulse pressure rather than the drop in diastolic pressure seen with true orthostatic hypotension due to autonomic failure. Chronic orthostatic hypotension is usually never due to one of those causes and is easily recognizable by (1) the clear drop in diastolic pressure that accompanies the systolic drop, and (2) relative absence of related symptoms. Chronic orthostatic hypotension often reflects a serious underlying structural disorder with poor prognosis.

Among 100 consecutive patients seen for chronic orthostatic hypotension at one center, about two-thirds had an identifiable structural dysautonomia. Causes included MSA (Shy-Drager syndrome), autonomic neuropathy, pure autonomic failure (Bradbury-Eggleston syndrome), several genetic disorders, amyloidosis, diabetes mellitus, or malignancy (especially bronchogenic carcinoma). Causes of hypotension in the face of normal autonomic function include antidepressant therapy, diuretic abuse, mast cell activation disorder, dumping syndrome, and deconditioning. It is noteworthy that congestive heart failure improves rather than impairs orthostatic tolerance.

Pulmonary

Lung function is generally preserved in autonomic failure. Patients with MSA frequently experience sleep apnea, and in consequence of these apneic spells, major perturbations in blood pressure may arise acutely. This is in part dependent on the role of carbon dioxide in determining blood pressure level in autonomic failure. Hypoventilation increases blood pressure in autonomic failure, whereas hyperventilation may lower blood pressure significantly. Patients have occasionally noted improved orthostatic tolerance while breathing through a dead space, although this has never been a recommendation in practice. Because of impaired swallowing in patients with MSA (Seppi et al., 2005), aspiration pneumonia occurs frequently and can be missed because the patient may not manifest the expected fever. With early diagnosis and treatment of aspiration pneumonia, patients often do well, returning to their prior state of health.

Gastrointestinal

Constipation occurs in many patients with autonomic failure, but patients with diabetic dysautonomia may also have frequent and often severe diarrhea as well as significant gastroparesis. The diarrhea itself can prevent adequate blood pressure control because of the associated volatility of blood volume. Special problems sometimes occur in specific dysautonomias. For example, patients with Sjögren syndrome commonly have gastroesophageal reflux and may therefore have an increased risk of esophageal carcinoma. Patients with Chagas disease may have achalasia and enlargement of the esophagus, resulting in vomiting. Achalasia is also present in the 4 “A” syndrome (Allgrove disease) characterized by alacrima, achalasia, ACTH insensitivity, and autonomic neuropathy. This syndrome has been mapped to chromosome 12q13 and produced by mutations in the AAAS gene (Handschug et al., 2001). Patients with some forms of genetic autonomic failure may have strikingly severe gastrointestinal fluid loss and bowel movements 10 or more times every day, which sometimes responds to low doses of clonidine. Postprandial angina may occur with food ingestion, usually without associated ST-T wave changes. Most patients with postprandial angina in practice probably have some degree of dysautonomia, and the depressor effect of food is most prominent in the setting of impaired autonomic reflexes. Postprandial angina tends to occur with upright posture following food (especially carbohydrates). Water intake in association with eating will usually help prevent this symptom.

The gastrointestinal dysfunction in two disorders with significant autonomic involvement, namely PD and diabetes, have been better evaluated and understood. For example, the role of diabetes in gastrointestinal dysmotility has been extensively studied. Some changes in the function of the enteric nervous system in diabetes appear to result from apoptosis of enteric neurons. Oxidative stress may play a role in the cell death process. An imbalance also exists in inhibitory and excitatory neuropeptides. These factors then result in altered gut mucosa (Chandrasekharan and Srinivasan, 2007). PD is also associated with gastrointestinal problems, affecting swallowing disorders that may lead to aspiration. Salivation is not increased or may even be decreased in these patients. From early on, individuals with PD may develop delayed gastric emptying, which later in the disease may affect jejunal absorption of levodopa. Gastric emptying of liquids is usually not delayed (Goetze et al., 2006) in PD, so alternatives when giving levodopa are a liquid solution or administering it directly into the jejunum (Jost, 2010). Constipation is also very common in this disorder and represents the most common “autonomic” manifestation of PD, affecting 70% to 80% of patients. Often, severe constipation develops before the more typical symptoms of PD are noticed (Korczyn, 1990; Jost, 2010); the cause is multifactorial. Many of the medications prescribed to treat PD, mainly anticholinergics and (perhaps more controversial) levodopa, may worsen constipation, but they are not the cause, since constipation is usually present before the diagnosis of PD is made and therefore before the onset of medications. Constipation is thought to be due to degeneration of central and peripheral parasympathetic nuclei (Jost, 2010).

Other less well-characterized dysautonomias also have gastrointestinal symptoms. Individuals with POTS complain of bloating, early satiety, nausea, pain, and alternating diarrhea and constipation (Sandroni et al., 1999). In fact, more than half of the children and adults with POTS have gastrointestinal complaints, usually reporting epigastric or lower-abdominal discomfort. Children with POTS seem to suffer nausea and vomiting more often than adults, but these findings were present in both groups (Ojha et al., 2011). Interestingly, coming from the other direction, many with functional gastrointestinal problems also have cardiovascular autonomic dysfunction, primarily sympathetic. In adults, three-eighths also had parasympathetic involvement, which was not present in the pediatric group. Neuropathy was common in both groups (Camilleri and Fealey, 1990; Chelimsky and Chelimsky, 2001). Importantly, when both a functional gastrointestinal disorder and POTS are present, the gastrointestinal symptoms may resolve with treatment of the orthostatic intolerance (Sullivan et al., 2005). The cause of the gastrointestinal symptoms in POTS in unclear and may be related to blood pooling in either the lower extremities or abdomen. Electrical activity of the stomach in POTS changes from supine to the upright position (Safder et al., 2009), suggesting either lack of accommodation or gastroparesis while upright (Buchwald et al., 1987). Cyclic vomiting syndrome (CVS) has also been associated with autonomic dysfunction, and both pediatric and adult sufferers usually have POTS associated with an autonomic neuropathy (Chelimsky and Chelimsky, 2007; Venkatesan et al., 2010).

Urinary Tract

In structural disorders, a reversal of the usual pattern of urine output occurs. Nocturia is brought on by recumbency and the attendant increase in blood pressure (Mathias et al., 2002). The weight loss during the night is often 2 to 4 pounds, and the reduction in blood volume that results partially accounts for the reduction in orthostatic tolerance seen on arising each morning. The bladder is often directly involved in dysautonomias. This autonomic involvement presents as urgency, retention, incontinence, and frequency. Urological evaluation often suggests prostatic hypertrophy in men, and surgery may be a consideration. Such surgery rarely helps patients with autonomic dysfunction and should only be considered after careful consultation between the urologist and neurologist to ascertain whether a physical obstruction is truly playing a major role. Unfortunately, the α₁-antagonist class of drugs commonly used to treat prostatic hypertrophy can worsen orthostatic hypotension; conversely, the α₁-agonist, midodrine, used to increase blood pressure, may occasionally increase bladder symptoms. With urine retention, urinary tract infections occur commonly. With autonomic failure, plasma renin levels are often quite low, probably because sympathetic regulation of the kidney is impaired. However, renal function is usually well preserved in most forms of autonomic failure, although not in dopamine β-hydroxylase deficiency, in which significant renal failure occurs in adulthood.

Urinary symptoms in functional disorders manifest urgency and frequency more often than incontinence and retention. For example, interstitial cystitis patients may void up to 60 times daily, and are sometimes bathroom bound. They complain of urgency, frequency, and bladder pain that worsens as the bladder fills. Treatment is generally unsatisfactory.

Sexual Function

Erectile dysfunction is often the first sign of a dysautonomia in men. Most commonly, this is predominately parasympathetic in origin and proves very difficult to treat with medication. Sildenafil (Viagra), even when cautiously employed, runs the risk of inducing severe hypotension. Yohimbine may help the mildly affected patient. When a specifically sympathetic involvement is present, as in dopamine β-hydroxylase deficiency, erectile dysfunction may be normal, but retrograde ejaculation occurs. In these patients, therapy with droxidopa, which restores norepinephrine, may permit antegrade ejaculation. Little information exists concerning the effects of the autonomic system on female sexual function. However, menstrual function is usually normal, and in patients of childbearing age, conception and childbirth are frequent.

Blood

With severe autonomic failure, mild anemia, often with hematocrit in the range of 33 to 38, is common. This is due to inadequate levels of erythropoietin and responds to treatment with this hormone.

Sweating Abnormalities

Increases or decreases in sweating occur with disturbances of autonomic thermoregulatory function (Fealey, 2008; Low, 1997). Hyperhidrosis refers to conditions in which sweating is excessive for a given stimulus. It can be general or localized. General hyperhidrosis can be primary (episodic hypothermia with hyperhidrosis, or Shapiro syndrome) or secondary to other disorders. Typically, hyperhidrosis is episodic. Dramatic hyperhidrosis may occur in pheochromocytoma. Tumors may produce cytokines, which provoke fever and consequently sweating. Hyperhidrosis also occurs in powerful sympathetic excitation, such as delirium tremens or in the pressor surges of baroreflex failure.

Referral for localized hyperhidrosis (Table 77.1) is often to the neurologist. Evidence exists of enhanced sweat gland innervation coupled with increased activity of sympathetic fibers passing through T2-T4. This is especially prominent in young people. Perhaps 25% of such individuals have a positive family history of hyperhidrosis. Axillary or palmar hyperhidrosis may be so severe as to interfere with normal activities and social interactions. Several therapeutic modalities may help (Table 77.2). A major limitation in therapy of hyperhidrosis is achieving sufficient muscarinic antagonism on sweat glands without incurring unacceptable levels of muscarinic blockade elsewhere—for example, in the heart. Local application of botulinum toxin to affected skin may also be quite effective but requires repeat injections at 3- to 12-month intervals (Saadia et al., 2001). In addition, blockade of the sympathetic ganglia using pharmacological injections, radiofrequency ablations, or endoscopic gangliotomy can be very effective (Atkinson and Fealey, 2003).

Table 77.1 Pathological Hyperhidrosis Differential Diagnosis and Some Causes of Localized Hyperhidrosis

Condition	Pathophysiological Mechanism of Sweating
Essential hyperhidrosis	Excessive physiological and emotional sweating affecting hands, feet, and axillae • Type 1: rest of body sweats normally • Type 2: coexists with large areas of anhidrosis; probable contribution from adrenergic-mediated sweating as well as cholinergic; symmetrical distribution

Perilesional and compensatory hyperhidrosis Central and/or peripheral denervation of large numbers of sweat glands produces increased sweat secretion in those remaining innervated; often asymmetrical distribution Gustatory sweating Resprouting of secretomotor axons to supply denervated sweat glands Post cerebral infarct Loss of contralateral inhibition with cortical and upper brainstem infarction Autonomic dysreflexia Uninhibited segmental somatosympathetic reflex; recent drug prescription; includes nifedipine and sublingual captopril Complex regional pain syndrome Localized sympathetic sudomotor hyperactivity; probably axon reflex vs. direct irritation/infiltration of sympathetic preganglionic or postganglionic fibers Paroxysmal localized hyperhidrosis Myopathic: ? transiently decreased hypothalamic setpoint temperature; responsive to clonidine, a centrally acting, α₂-adrenergic agonist

Table 77.2 Treatment Measures for Primary Hyperhidrosis

Topical Rx	20% Aluminum chloride hexahydrate in anhydrous ethyl alcohol (Drysol). Apply half-strength to dry skin daily or every other day, mornings, and wash off.	Irritation of skin; less effective on palms and soles, which may require occlusive (plastic wrap) technique
Tanning Rx, iontophoresis	Glutaraldehyde (2%-10%) solution; apply 2-4 times/week as needed.	Stains skin brown; for soles of feet only
	For palms/soles; 15-30 mA current, 20 min. at start. Drionic battery-run unit or galvanic generator needed; 3-6 treatments/week for total of 10-15 treatments initially; 1-2 treatments/week maintenance.	Shocks, tingling may occur Difficult to use in axilla Drionic unit not effective when batteries low
Anticholinergic	Glycopyrrolate (Robinul/Robinul Forte) at 1-2 mg PO tid as needed; for intermittent/adjunctive treatment.	Dry mouth, blurred vision Contraindicated: glaucoma, GI tract obstruction, GU tract obstruction
Clonidine	Useful for paroxysmal localized (e.g., hemibody) hyperhidrosis; 0.1-0.3 mg PO tid or as TTS patch (0.1-0.3 mg/day) weekly.	Somnolence, hypotension, constipation, nausea, rash, impotence, agitation
Excision	Second and third thoracic ganglionic sympathectomy (palmar hyperhidrosis), sweat glands (axillary liposuction); recent preference is for T2 sympathectomy to limit compensatory hyperhidrosis.	Homer syndrome, dry skin, transient dysesthetic pain Postoperative scar or infection Compensatory hyperhidrosis of trunk, pelvis, legs, and feet
Botox	50-100 mU of botulinum toxin A into each axilla or body area treated; high doses (200 mU) prolong effect; can be repeated.	Injection discomfort, variable Duration of effect 3-12 months Expensive Mild grip weakness when palm is treated Contraindicated in pregnancy, NMJ disease

GI, Gastrointestinal; GU, genitourinary; mU, mouse units; NMJ, neuromuscular junction; PO, orally; Rx, prescription; tid, three times daily.

Adapted from Fealey, R.D., 2004. Disorders of sweating, in: Robertson, D., Biaggioni, I., Burnstock, G., et al. (Eds.), Primer on the Autonomic Nervous System, second ed. Elsevier, New York, pp. 354-357.

Idiopathic hyperhidrosis must be distinguished from compensatory hyperhidrosis due to lower body hypohidrosis, common in dysautonomias (Klein et al., 2003), which may paradoxically be described by patients as excessive sweating in the upper body. Patients who lose their ability to perspire over most of their body may preserve it in the neck and facial area and perspire disproportionately in these areas, which captures attention more than the loss of sweating elsewhere. In this setting, the hyperhidrosis actually mandates an evaluation for the reason for the anhidrosis, usually a structural dysautonomia of some type. Loss of sweating does not require specific medical therapy, but rather practical advice such as staying well hydrated, avoiding alcohol, and avoiding hot conditions. One of the most effective home remedies is a “wet shirt”: A tee shirt soaked in warm water and wrung out thoroughly before putting on provides some artificial perspiration that lasts 30 to 90 minutes in a hot environment. The associated surface cooling is striking and greatly increases the functional capacity of patients who must be in a hot environment.

Orthostatic Test

Orthostatic symptoms are usually the most debilitating aspect of autonomic dysfunction readily amenable to therapy. For this reason, the blood pressure and heart rate response to upright posture is the starting point of any autonomic laboratory evaluation. In healthy human subjects, the cardiovascular effect of upright posture has been well defined (Low, 1997). Upon active assumption of the upright posture by standing, the vigorous contraction of large muscles leads to a transitory muscle vasodilation and a minor fall in arterial pressure for which the reflexes do not immediately compensate. However, this short-lived depressor phase is not usually seen with passive (tilt-table) upright posture. Immediately after 70- or 90-degree head-up tilt, approximately 500 mL of blood move into the veins of the legs and approximately 250 mL into the buttocks and pelvic area. A rapid vagally mediated increase in heart rate occurs, followed by a sympathetically mediated further increase. As right ventricular stroke volume declines, a depletion of blood from the pulmonary reservoir occurs, and central blood volume falls. Stroke volume falls, and cardiac output decreases about 20%. With this decline in cardiac output, blood pressure is maintained by vasoconstriction that reduces splanchnic, renal, and skeletal muscle blood flow especially, but other circulations as well.

In the orthostatic test, mild autonomic impairment usually leads to dramatic tachycardia, with relatively little change in blood pressure. In the presence of a still-functioning baroreflex, the increased heart rate can compensate for mild peripheral denervation, thus preventing a significant decrement in blood pressure. With moderate autonomic neuropathy, the tachycardia may still be present but may be unable to compensate completely, and mild orthostatic hypotension may occur. As the neuropathy becomes more severe, the orthostatic fall in blood pressure becomes progressively greater, and the ability of the efferent autonomic system to manifest a tachycardia is progressively attenuated. In severe autonomic failure, the fall in blood pressure may be greater than 100 mm Hg, yet the heart rate rises little or not at all. Orthostatic tolerance is challenged by a number of factors. Important among them are food ingestion, high environmental temperature, hyperventilation, endogenous vasodilators, and many pharmacological agents. If no abnormality in orthostatic blood pressure or heart rate is detected in the hour after ingestion of a large meal, autonomic neuropathy of sufficient severity to cause cardiovascular instability is effectively excluded.

An important aspect of evaluating responses to orthostasis is the rapid reduction in total blood volume that occurs physiologically. It is not unusual for a 12% fall in plasma volume to occur within 10 minutes of assumption of the upright posture as fluid moves from the vascular compartment into the extravascular space (Jacob et al., 2005). This accounts for the delay in appearance of symptoms in patients with mild autonomic impairment for some minutes after the actual assumption of upright posture. Therefore, the long-stand (30 minutes) test, or Schellong test, is a much more severe orthostatic stress than the short-stand (5 minutes) test commonly employed.

Tilt-Table Testing

Many investigators prefer the use of upright tilt to the orthostatic test to evaluate these variables. In general, analogous but not identical results are obtained. The use of upright tilt is widely used in syncope evaluation. Although no proof exists that upright tilt offers any diagnostic advantage over carefully obtained standing blood pressure and heart rate data, many investigators use tilt because of its convenience, its capacity to calibrate the gravity stimulus, its embrace by third-party payers, and its safety to the patient. In addition, the tilt test may add sensitivity if done at 70 degrees or less, by reducing the activity of the calf and thigh muscle pump and by preventing any CNS stimulus to vasoconstriction that would occur with active standing.

Sweat Testing

Although hypohidrosis rarely dominates a patient’s dysautonomia, assessment of sudomotor function is often helpful in testing for autonomic impairment (Low, 2004). Widely used tests include the thermoregulatory sweat test (TST), quantitative sudomotor axon reflex test (QSART), and sympathetic skin response (SSR).

Pharmacological Tests

Information about prevailing sympathetic and parasympathetic activation as well as denervation hypersensitivity can be achieved by use of muscarinic and adrenergic agonists and antagonists (Robertson et al., 2004). Tables 77.4 and 77.5 provide instructive examples of how biochemical and physiological tests may be combined to make novel diagnostic discoveries.

Reflex Syncope

Although reflex syncope is probably the most common cause of loss of consciousness, it is useful to consider the more global group of disorders that fall under “transitory loss of consciousness.” This differential diagnosis can be narrowed through three decision points. The first question the clinician should develop is whether true loss of consciousness occurred, with consequent loss of memory for a short time period. If this is not the case, considerations include a fall, a vertiginous spell, an episode of near loss of consciousness, and a pseudoseizure, but not true syncope. However, if consciousness was lost, the second consideration is whether the cause was loss of brain perfusion. If this is not the case, syncope is again excluded, and possible etiologies include a true epileptic seizure (often marked by motor manifestations, tongue biting, eyes open during the episode, and a prolonged postictal period), syncopal migraine (usually followed by a throbbing headache accompanied by photophobia, phonophobia, and nausea) or a disorder of cerebrospinal fluid (CSF) flow (e.g., colloid cyst of the third ventricle).

When loss of perfusion is the cause of loss of consciousness, the broad diagnosis is syncope, and the third issue is determining the cause, such as a cardiac arrhythmia, pulmonary embolus, or cardiovascular structural cause, or true reflex vasodilation. Only the last entity is termed reflex syncope. Reflex syncope (transitory loss of consciousness due to loss of brain perfusion as a protective reflex) occurs at least once in 50% of healthy young adults, usually as an emotional faint with a well-recognized precipitating stimulus. Such syncope requires no medical evaluation. Syncope in the absence of a precipitating stimulus is a relatively common medical problem encountered in the office and emergency department.

Syncope of any type is defined as sudden transitory loss of consciousness with spontaneous recovery that is associated with a loss of postural tone (Mathias et al., 2001). Syncope accounts for more than 1% of hospital admissions. The causes of syncope range from benign to life threatening. The common underlying mechanism of syncope is a transitory decrease in cerebral perfusion. Reflex syncope (fainting) is the most common type of syncope, especially in patients without evidence of structural heart disease (Benditt, 2006; Strickberger et al., 2006). Reflex syncope most commonly occurs while the patient is standing but also occurs while seated and occasionally even while lying during sleep (Jardine et al., 2006). Finally, it can occur with exercise (at initiation or at peak exercise) or with emotional/psychological triggers (e.g., phlebotomy).

Unlike most conditions discussed in this chapter, reflex syncope is episodic. Between episodes, most patients appear to have normal cardiovascular function. The precise cause of reflex syncope is not understood. The history and physical examination is the key to diagnosis. A clinical diagnosis can be made with these alone in most cases. Usually the focus is on excluding more malignant causes of syncope, especially by defining circumstances surrounding the episode of syncope, assessing symptoms before and after the event, and obtaining any collateral history from witnesses. The history may sometimes implicate structural heart disease or coexisting medical conditions that point away from reflex syncope. Medications may provoke syncope, and a family history of sudden death may point to an arrhythmic cause. Historical features suggesting reflex syncope include female gender, younger age, associated warmth and diaphoresis, nausea or palpitation, and postsyncopal fatigue. A long interval between spells (from the first lifetime spell) also suggests reflex syncope.

The physical examination should focus on ruling out structural heart disease and focal neurological lesions. One widely used maneuver is carotid sinus massage. The current technique involves performing up to 10 seconds of massage to the carotid sinus in both the supine and upright posture, with a positive result requiring a drop in blood pressure or heart rate with an associated reproduction of presenting symptoms. This procedure is associated with a low rate of neurological complications.

Tilt-table testing has been widely used in evaluating syncope since the late 1980s. These tests subject patients to head-up tilt at angles of 60 to 80 degrees and aim to induce either syncope or intense presyncope, with reproduction of presenting symptoms. Passive tilt tests simply use upright tilt for up to 45 minutes to induce vasovagal syncope (sensitivity ≈ 40%, specificity ≈ 90%). Provocative tilt tests use a combination of orthostatic stress and drugs such as isoproterenol, nitroglycerin, or adenosine to provoke syncope with a slightly higher sensitivity but reduced specificity. Little agreement exists about the best protocol, and protocols are used less and less. Many physicians are more comfortable treating patients if a diagnosis is suggested by a tilt-table test. Recent studies with implantable loop recorders have called the value of tilt testing into question. The International Study on Syncope of Uncertain Etiology (ISSUE) investigators have recently reported that in the absence of significant structural heart disease, patients with tilt-positive syncope and tilt-negative syncope have similar patterns of recurrence (34% in each group over a follow-up of 3–15 months), with electrocardiographic (ECG) recording during episodes consistent with reflex syncope. Despite these recent data, tilt-table testing is still frequently used to evaluate recurrent reflex syncope. Tilt tests are contraindicated in patients with severe aortic or mitral stenosis or critical coronary or cerebral artery stenosis.

Some people with reflex syncope faint only once or twice and rarely seek medical attention. Medical attention is usually sought for syncope when it becomes a recurring and troublesome disorder. Most patients do very well after assessment, with only a 25% to 30% likelihood of syncope recurrence after tilt testing in patients who receive neither drugs nor a device. The cause for this apparently great reduction in syncope frequency may be spontaneous remission, reassurance, or advice about the pathophysiology of syncope and postural maneuvers to prevent it. However, patients with a greater frequency of historical syncopal spells are more likely to faint in follow-up. The time to the first recurrence of syncope after tilt testing is a simple and individualized measure of eventual syncope frequency, because those patients who faint early after a tilt test tend to continue to faint more frequently.

Many patients can simply be reassured about the usual benign course of reflex syncope and instructed to avoid those situations that precipitate fainting. The use of support stockings or increased salt intake may help. In young non-hypertensive patients, the most frequently affected, we utilize 2 grams of salt in the morning and 2 grams in the early afternoon. Most salt is excreted by a normal kidney within 3 to 4 hours. Patients should be taught to recognize an impending faint and urged to lie down (or sit down if that is not possible) quickly. This will not be enough for some patients, and other treatment options such as physical countermaneuvers (Wieling et al., 2004) and tilt training (Ector et al., 1998) may be necessary. These are covered in detail in the treatment section of the chapter, as are pharmacological and other interventions.

Syncopal Migraine

A subgroup of patients with syncope respond poorly to the usual management of salt supplementation and tilt training. On further questioning, these patients may consistently experience a headache with migrainous features immediately prior to or after the syncopal spell. A recent review suggests that this entity, sometimes also termed basilar migraine, may be far more common than previously suspected, accounting for about one-third of patients with syncope referred to an autonomic specialist (presumably a more complex group of patients based on the referral bias) (Curfman et al., 2011). The importance of identifying this diagnosis is its prompt response to anti-migrainous medications such as verapamil and topiramate, in this author’s experience. Further identifying features include an increased duration of loss of consciousness (up to 15 minutes in this series), and longer time to full recovery, as might be expected in a migrainous mechanism.

Carotid Sinus Hypersensitivity

Carotid sinus hypersensitivity is defined as an asystole of 3 seconds, a fall in systolic pressure of 50 mm Hg, or both in response to carotid artery massage in a patient with otherwise unexplained dizziness or syncope (Fenton et al., 2000; Mathias et al., 2001). Estimates are that 35 to 100 patients per million per year present with this condition. Although the condition has been ensconced in the medical literature since the era of Soma Weiss (1898-1942), its definition remains controversial, in part because diagnosis is by manual massage of the carotid sinus, with its inherent variability. The test should be performed with the patient supine during continuous ECG and blood pressure monitoring and recording. Longitudinal massage should be performed for 5 seconds over the site of maximal pulsation of the right carotid sinus, located between the superior border of the thyroid cartilage and the angle of the mandible. If no response is elicited, the massage is sometimes repeated on the left side supine and ultimately also on the right and then left sides with upright tilt. Unfortunately, improved practical methods for diagnosis have not emerged. Clinically, a history may exist of syncopal symptoms associated with neck pressure, a tight collar, turning the head, shaving, or swallowing; syncope may also occur spontaneously. Hypotension, bradycardia, or both may dominate the clinical picture. The form in which bradycardia predominates may be improved by demand pacing. Some patients with carotid sinus syncope ultimately require surgical denervation. Occasionally, additional symptoms of headache, dizziness, vertigo, paresthesias, homonymous hemianopsia, and hemiplegia occur in the absence of measured blood pressure or heart rate change, but this may reflect another mechanism such as a migrainous or ischemic process; the older literature terms this phenomenon Weiss-Baker syndrome.

Keep in mind that carotid sinus massage is not without risk. In our practice, we encounter a patient every 2 or 3 years who suffers a large stroke immediately after massage on the appropriate side. This presumably reflects an undetected active atherosclerotic plaque with some clot accumulation. We therefore recommend ultrasound of the carotid prior to performing carotid sinus massage on anyone older than age 40.

Gravity-Induced Loss of Consciousness

Gravity-induced loss of consciousness (G-LOC; acceleration stress) during aerial maneuvers is a special kind of syncope seen occasionally in aircraft pilots when the aircraft pulls up quickly after descent, during which gravitational forces may be greatly increased. G-LOC occurs in at least 25% of pilots flying high-performance aircraft. Incapacitation of 30 seconds or longer may cause fatal accidents during aerial combat maneuvers. Because pilots are in an upright seated position, the vertical distance between the head and the heart is approximately 14 inches (35 cm). At about 4G, without an antigravity suit or use of the antigravity straining maneuver, blood flow to the brain will cease, and the individual loses consciousness and may then experience jerking movements of the arms or legs. With resolution of acceleration stress, consciousness recovers over the succeeding 10 to 60 seconds, but confusion may persist for 1 to 2 minutes, and impaired pilot performance may persist considerably longer.

Postural Tachycardia Syndrome

POTS is defined as an increase of at least 30 bpm on standing, associated with symptoms of sympathetic activation (Freeman et al., 2002; Jacob et al., 2000; Low et al., 1997). Orthostatic symptoms include light-headedness, palpitations, tremulousness, visual changes, discomfort or throbbing of the head, poor concentration, tiredness, weakness, and occasionally fainting. Usually, little or no fall in blood pressure occurs on standing (Shibao et al., 2005), and this characteristic should probably be incorporated into the definition. Patients may also have an elevated plasma norepinephrine concentration of 600 pg/mL or more on standing. Standing plasma norepinephrine levels greater than 2000 pg/mL occur, and such patients require careful study to exclude pheochromocytoma. Many POTS patients also have a bluish-red discoloration of skin in the lower extremities on standing. A reduced plasma volume of about 500 mL is often present.

POTS is estimated to affect 250,000 to 500,000 Americans and causes a wide range of disabilities (Benrud-Larson et al., 2002). A 4 : 1 female preponderance exists, typically in the 15- to 45-year age group. Symptom severity is sometimes catamenial. Possible reasons for these cyclical changes include an estrogen-dependent change in plasma volume or a direct estrogen receptor–mediated modulation of vascular reactivity. Other than essential hypertension, POTS is the most common chronic disorder of cardiovascular homeostasis. It is commonly encountered and accounts for frequent referrals to centers specializing in autonomic disorders.

The etiology of POTS is unknown; indeed, the condition has many different names (Box 77.3) and probably many causes. For many years, such patients were considered deconditioned and encouraged to pursue a vigorous exercise regimen. Although such regimens can be quite effective (Fu et al., 2010), it is nonetheless clear that the disorder did not arise from mere deconditioning. The onset of POTS may be abrupt, suddenly disabling a prior marathon runner or Olympic athlete, and often occurs in the wake of a viral infection, pregnancy, or major surgical procedure, encouraging consideration of an autoimmune etiology.

It is important to view POTS not as a disease but as a syndrome, a final common pathway by which many pathophysiological processes may present. The fundamental deficit appears to be anything that reduces the effectiveness of venous return to the heart. Some of these are simple mechanical problems that do not involve the autonomic nervous system at all, such as congenital absence of venous valves or hypermobility disorders (e.g., Ehlers-Danlos syndrome) (Gazit et al., 2003; Rowe et al., 1999) where presumably an inadequate recoil of venous elastic tissue exists to propel adequate volume back to the great veins. Other observations in patients with POTS have included the presence of autonomic neuropathy, termed neuropathic postural tachycardia syndrome (Al-Shekhlee et al., 2005), and the presence of very high adrenergic responsiveness, termed hyperadrenergic postural tachycardia syndrome, as shown in Fig. 77.2. It is not clear that these two processes are mutually exclusive. Other investigators have divided POTS into low, normal, and high blood-flow rates (Fouad et al., 1986; Stewart et al., 2007) and have found different levels of venous compliance in the three types.

Other potential pathophysiological causes include excessive venous pooling, a gravity-dependent fluid shift, diminished plasma volume or red cell mass, and dysfunction of the norepinephrine transporter. In rare specific cases, a genetic disorder has been identified. The clearest example is the illustrative but quite rare form of POTS due to norepinephrine transporter deficiency. This derives from a unique A453P mutation yielding loss of gene function. The norepinephrine transporter clears norepinephrine from the synaptic cleft. Its absence leads to a rise in synaptic and plasma norepinephrine levels with sympathetic hyperactivity (Shannon et al., 2000a).

Mastocytosis may underlie POTS in some individuals (Shibao et al., 2005). The cause may be an increased number or an increased responsiveness of mast cells. Release of histamine and prostaglandin D₂ into the circulation dominate the clinical picture. Characteristic chronic skin changes (erythematous acneiform papular lesions) occur in a minority of patients, but red flushing and urticaria are common during attacks. Palpitations, with or without chest pain, headaches, nausea, vomiting, diarrhea, and dyspnea may occur. Perhaps 25% of cases are familial (autosomal dominant). Many patients respond well to treatment with H₁ and H₂ antagonists, but some have severe attacks with hypotension, requiring treatment by epinephrine infusion. Increases in blood pressure also occur. During severe attacks, disturbances in mental status may seem out of proportion to the hypotension. Patients may also seem to be unconscious for 5 to 20 minutes after syncope, but they may indicate after recovery that they heard what was said to them in the minutes after syncope but were unable to speak or reply to questions. Along with histamine and prostaglandin D₂, substantial quantities of heparin are present in mast cells; during attacks, sometimes enough heparin is released to increase the partial thromboplastin time.

Many patients with POTS have a relatively mild disorder that may improve over succeeding weeks and months. However, in some the symptoms are more severe, the duration of the illness may be longer, and the expected recovery may not occur. Overall, the majority of patients with POTS improve sufficiently to require no therapy after 5 years.

POTS is not a stand-alone disorder. Although specific data are still forthcoming, POTS has several comorbidities in both children and adults, such as chronic fatigue syndrome (Freeman and Komaroff, 1997; Schondorf and Freeman, 1999) and migraine. Most patients with POTS have multisystem involvement including sleep problems, upper and lower gastrointestinal complaints, headaches with migrainous features, chronic pain in various locations, Raynaud-like symptoms, and severe fatigue (Ojha et al., 2011). POTS highlights the striking contrast between structural and functional autonomic disorders. Patients with this disorder generally voice many complaints involving several systems, whereas those with severe orthostatic hypotension (mean fall of 90 mm Hg in systolic blood pressure) frequently have minimal or no symptoms at all (Arbogast et al., 2009).

The interactions of deconditioning, sleep disturbance, chronic fatigue, and POTS itself are difficult to assess. Perhaps more challenging is the fact that many patients with POTS respond to their illness by reducing physical activity, and upon presentation to physicians, they therefore have POTS and are deconditioned. In individual patients, several therapies may prove helpful (Shannon et al., 2002), including propranolol 10 to 20 mg three times daily; increased dietary salt; fludrocortisone 0.1 mg orally daily; clonidine 0.05 mg once or twice daily; and midodrine 5 mg orally twice daily. Finally, some patients benefit from an exercise program. This should be approached cautiously, beginning in the most severe patients with no more than “orthostatic exercise,” standing against a wall for incrementally increased periods each day. Therapy is discussed in more detail in the treatment section.

Functional Gastrointestinal Disorders

Despite highly varied presenting symptom complexes, current understanding suggests a biopsychosocial model as the underlying process for most functional gastrointestinal disorders (FGID). This model contains three main components, a genetic/environmental predisposition, pathophysiological changes, and a psychological contribution. It is important to understand that the psychological contribution is not considered to be the cause of these disorders, but rather a comorbid process either primary or secondary to the functional pain disorder. Twin and other genetic studies have demonstrated both a genetic and an environmental predisposition to the development of these disorders (Kalantar et al., 2003; Locke et al., 2000). Genetic factors have included the genotype for reduced interleukin (IL)-10 (antiinflammatory cytokine) production, certain SERT polymorphisms (Yeo et al., 2004), increased messenger ribonucleic acid (mRNA) expression of p11 (a protein critical to 5-HT_1B receptor function) in the sigmoid biopsies of IBS-C (Camilleri et al., 2007), and α₂-adrenoceptor polymorphism that affects motility (Kim et al., 2004). Environment plays a role through learned behavior from parents who seek more frequent medical attention. For example, children of patients with IBS utilize more healthcare resources than children of healthy control parents (Levy et al., 2000).

Psychological elements are often present, but these factors do not define and are not required for the diagnosis of FGID. They are modulators of the patient’s experience and perhaps of treatment response. These psychological factors will also influence healthcare seeking. It is important to also consider that these individuals are frequently diagnosed as “having a psychological problem” and may not have received an appropriate diagnosis, treatment, or plan. This lack of diagnostic clarity itself in the context of a prolonged illness may contribute to psychological dysfunction.

Altered motility in the context of stress may play a role in IBS, though these mild abnormalities do not usually explain the disorder. We have also found that gastric electrical activity becomes abnormal in the upright position in children with POTS (a disorder with overlapping symptoms with FGID) (Safder et al., 2010). This may explain the frequent symptom of nausea. Hyperalgesia is very common, from increased rectal sensation to distention of anal balloons to increased sensitivity and discomfort with normal physiological functions (Munakata et al., 1997; Naliboff et al., 1997). The role of either increased intestinal bacterial in the foregut (small-bowel bacterial overgrowth) or altered bacteria is well documented. Some IBS sufferers have small-bowel bacterial overgrowth; others do not fulfill the classic definition for this disease but have greater numbers of bacteria than healthy controls. Furthermore, the use of nonabsorbable antibiotics like rifaximin often improves gastrointestinal symptoms (Pimentel et al., 2000; Posserud et al., 2007). The role of bacteria in the pathogenesis of IBS is further supported by (1) the fact that a third of patients with IBS or dyspepsia describe their symptoms as having begun after an acute enteric infection (Mearin et al., 2005), and (2) that about a quarter of patients who suffer an acute gastrointestinal illness will then develop an FGID (Gwee et al., 1999). More recently, these disorders that were originally defined by the absence of anatomical or inflammatory markers are now found to have increased inflammatory cells (Chadwick et al., 2002).

It is not the goal of this chapter to enumerate every functional disorder, but to list those most commonly encountered in a general neurologist’s practice. IBS is defined as 3 months of abdominal discomfort relieved by a bowel movement or associated with a change in bowel movement frequency or consistency and occurs in 10% to 20% of the general population. Chronic idiopathic nausea also occurs with some frequency. Finally, CVS is characterized by episodes of vomiting alternating with normal baseline health. Though less frequent than other disorders, it sometimes falls in the province of the neurologist because it is highly responsive to antimigrainous strategies, in particular triptans, dihydroergotamine infusion, and prevention using verapamil or tricyclic agents. This disorder has been associated with a mitochondrial polymorphism, and CoQ10 and l-carnitine supplementation may be highly beneficial in some patients (Boles et al., 2005; Ropper, 1994).

Autonomic Storm and Takotsubo Cardiomyopathy

Emotional stress can cause cardiac injury and sometimes death. Until recently, neurologists have emphasized this connection more than cardiologists. Dr. Martin Samuels has been an especially forceful advocate for the study of this phenomenon (Samuels, 2007). Autonomic storms following cerebral catastrophe may have dramatic physical findings and sometimes ECG abnormalities. Indeed, some of the most dramatic T-wave inversions in the intensive care unit are observed in such patients (Rabinstein et al., 2004). The terminology for these autonomic storms is somewhat chaotic because of lack of systematic study and a profusion of names for the condition. These hypersympathetic states have been termed paroxysmal sympathetic storms, autonomic storms, diencephalic seizures, diencephalic epilepsy, autonomic dysreflexia, or simply dysautonomia. In their extreme form, such autonomic storms result in acute alterations in body temperature, blood pressure, heart rate, respiratory rate, sweating, and muscle tone. They occur with severe head trauma, in post-resuscitation encephalopathy, in intracerebral hemorrhage, with brain tumors, and sometimes in hydrocephalus. Immediately after such a catastrophe, a massive catecholamine surge occurs that can induce seizures, neurogenic pulmonary edema, and myocardial injury. Excessive sympathetic outflow declines or goes away within a few days in most patients, but some patients develop recurrent paroxysms of sympathetic overactivity for weeks or months (Rabinstein et al., 2004).

The pathophysiology of these autonomic storms remains uncertain, but heightened activity of diencephalic or brainstem sympathoexcitatory pathways appears to be the major substrate of these episodes. Autonomic storms may be much more common than suggested by the surprisingly sparse reports in the literature. Clinical features of autonomic storms include tachycardia, hypertension (often with widening of the pulse pressure), fever, tachypnea, sweating, flushing, and pupillary dilation. Intracranial pressure increases during the episodes, with the autonomic dysfunction usually preceding the rise in intracranial pressure. The basis for the diagnosis of autonomic storm is the characteristic dysautonomic spells in a patient with acute intracranial disease. It must be distinguished from other conditions such as neuroleptic malignant syndrome, serotonergic syndrome, malignant hyperthermia, and lethal catatonia. Additional disorders that may manifest sudden unexplained autonomic hyperactivity include Guillain-Barré syndrome (Ropper, 1994) and myelopathy. Severe hypertension, but bradycardia rather than tachycardia, are characteristic of the Cushing reflex syndrome, which occurs in patients with compression of the brainstem.

Takotsubo “Broken Heart” Syndrome

A less dramatic but analogous condition has been recognized in postmenopausal women (Gold et al., 2005; Kurisu et al., 2002; Wittstein et al., 2005). It mimics myocardial infarction and is characterized by chest pain and shortness of breath. It was described initially in Japan as tako tsubo (octopus trap) syndrome and in the United States as apical ballooning syndrome or broken heart syndrome (Wittstein et al., 2005). The first two names describe the appearance of the left ventricle on imaging; it seems to stretch, balloon out, and weaken (Fig. 77.3). The third name derives from the severe emotional stress, such as loss of a family member, that may trigger the condition. In approximately 20% of patients, the inciting factor seems to be severe physical stress such as trauma, surgery, or severe pain. Other names for takotsubo cardiomyopathy are neurogenic myocardial stunning, catecholaminergic myocardial stunning, and stress-induced cardiomyopathy.

Patients with takotsubo cardiomyopathy do not have coronary artery occlusion or coronary artery spasm during their presentation, but two-thirds have abnormal myocardial blood flow, apparently due to dysfunction in the microvasculature of the heart. Diagnosis is from nonspecific ST-T abnormalities, ST elevation, or QT prolongation with large negative T waves, often occurring over days in succession (Fig. 77.4). Common markers of myocardial infarction (troponin, creatine kinase) are only slightly raised, confirming that there is more stunning of the heart than permanent heart muscle damage. Plasma and urinary catecholamines are typically elevated (Wittstein et al., 2005). The reason this syndrome occurs in some individuals but not others seeming to suffer comparable levels of stress remains unknown. Treatment is supportive, and while 95% of patients experience complete recovery, approximately 10% will have recurrence over a 4-year period.

The pathophysiology of myocardial stunning probably derives from exaggerated calcium influx into the myocardial cells due to excessive norepinephrine release into the myocardium. Norepinephrine activates release of cyclic adenosine monophosphate (c-AMP), which in turn activates a calcium channel allowing calcium influx and potassium outflow. The potassium outflow may account for the frequently encountered peaked T waves seen on ECG. Pathological examination of the heart muscle reveals coagulative myocytolysis (also known as myofibrillar degeneration or contraction band necrosis) characterized by cell death in a hypercontracted state and abnormal cross-band formations. Similar lesions can be induced in animal models through stimulation of the lateral hypothalamus, limbic cortex, mesencephalic reticular formation, and stellate ganglia (Samuels, 2007).

Familial Dysautonomia

Familial dysautonomia (FD, also referred to as Riley-Day syndrome in the older literature) occurs predominantly in individuals of Ashkenazi Jewish extraction carrying mutations in the IB kinase–associated protein gene (IKBKAP). The mutations cause impaired expression of the normal protein product IB kinase–associated protein (IKAP). IKAP deficiency may impair normal expression of neurotransmitters (Axelrod et al., 2006; Axelrod and Hilz, 2003). FD is part of a group of disorders termed hereditary sensory and autonomic neuropathies (HSANs) and is classified as HSAN III in this scheme. HSAN I and V are the other members of the group, with predominant involvement of small sensory and autonomic fibers, where loss of pain sensation is a major clinical issue. Other HSANs involve larger and generally nonautonomic fibers.

FD patients have inadequate development and limited survival of sensory and autonomic neurons. Although the literature has generally emphasized efferent sympathetic involvement, more recent studies suggest that the predominant pathophysiology originates from loss of afferent nerve function, particularly baroreceptor information (Norcliffe-Kaufmann et al., 2010) but also likely including visceral and chemoceptor information (Bernardi et al., 2003). Peripheral nerves demonstrate a reduction in the unmyelinated and small myelinated neuronal populations. In addition, there is evidence of impaired CNS myelination, especially in the optic radiation and middle cerebellar peduncle, which probably accounts for patients’ frequent visual complaints and ataxia (Axelrod et al., 2010).

The diagnosis of FD is suspected clinically based on a fairly classical presentation of decreased pain and temperature perception, with relative preservation of large-fiber sensory function such as proprioception and touch sensation, labile autonomic responses, hyporeflexia, alacrima, poor oropharyngeal coordination, and absence of lingual fungiform papillae serving the taste modality of sweet. Histamine injection produces no widespread flare response but a very circumscribed response, usually measuring less than 2 to 3 cm in diameter, because of the absence of C-fibers that mediate the neuroinflammatory response.

Autonomic disturbances are very prominent and impose great impediments to function, especially in the neonatal period. Feeding difficulties result from poor oral coordination. Recurrent misdirection, especially of liquids, and frequent gastroesophageal reflux put the patient at risk for aspiration and chronic lung disease. Emotional or physical stress or even arousal from sleep can trigger episodes of nausea and vomiting. These episodes (dysautonomic crises) are usually associated with agitation, tachycardia, and hypertension. Vasomotor and cardiovascular perturbations, manifesting as erythematous skin blotching and hyperhidrosis, occur with excitation or eating.

Patients with FD can have either extreme hypertension or profound postural hypotension without compensatory tachycardia. Supersensitivity to cholinergic and adrenergic agents is present. Relative insensitivity to hypoxemia limits the ability to cope with pneumonia or travel to high altitudes. Ensuing hypoxemia may lead to hypotension, bradyarrhythmia, and syncope. Delayed development is common, but intelligence is usually within normal ranges.

Identification of the gene defect has not yet led to curative therapy (Tutaj et al., 2006). Preventive and supportive strategies include measures to maintain eye moisture, fundoplication with gastrostomy to provide nutrition and avoid risk of aspiration, use of central agents such as benzodiazepines and clonidine to control vomiting and the dysautonomic crisis, and fludrocortisone and midodrine to combat cardiovascular lability (Freeman, 2003). The result of these improved supportive measures is that approximately half of FD patients now reach adulthood.

Baroreflex Failure

Acute baroreflex failure, perhaps the most dramatic neurological disorder of blood pressure regulation, may display stress-induced systolic blood pressure surges of more than 300 mm Hg. It provides evidence of the great capability of the human CNS to generate unbuffered cardiovascular excitation (Ketch et al., 2002; Timmers et al., 2003) (Fig. 77.5). The clinical syndrome resembles pheochromocytoma more than a typical dysautonomia. Human baroreflexes defend against excessive peaks or dips in blood pressure. Baroreflex failure occurs when afferent baroreceptive input via the vagus or glossopharyngeal nerves or their central connections becomes impaired. Wide excursions of blood pressure and heart rate result. Such excursions may derive from endogenous factors such as anger or drowsiness, which result in high and low pressures, respectively. They may also derive from exogenous factors such as environmental stressors like excessive cold or bright light.

Acute baroreflex impairment may produce hypertensive crisis. Over succeeding days to weeks, or in the absence of an acute event, volatile hypertension with periods of hypotension occurs; some individuals after months to years ultimately develop orthostatic hypotension. Usually bilateral destruction of baroreflex afferent function results in concomitant destruction of much efferent vagal function. Loss of vagal parasympathetic tone to the heart prevents bradycardia during stimuli that would ordinarily elicit parasympathetic activation (e.g., sedation, sleep). However, if the baroreflex failure occurs with relative sparing of the parasympathetic efferent vagal fibers, sleep or sedation may lead to malignant vagotonia with severe bradycardia and hypotension and episodes of sinus arrest.

Pure Autonomic Failure

The term pure autonomic failure (PAF) once encompassed many causes of autonomic failure and orthostatic hypotension (Box 77.4). This term is now restricted to a synucleinopathy with synuclein found within Lewy bodies confined to autonomic ganglia, presenting in mid- to late life (Low, 1997; Mathias et al., 2002; Robertson et al., 2004). The adrenal medulla is relatively spared. The initial feature in men is impotence, but the symptom that usually brings patients to the physician is orthostatic hypotension manifesting as unsteadiness or faintness on standing. It is worst in the morning and improves as the day progresses. Supine hypertension may occur during the night while supine. Meals, exercise, fever, or environmental heat make orthostatic hypotension more severe. Other complaints include orthostatic pain in the neck, shoulders, or occiput, relieved by lying down. Although orthostatic hypotension is defined as a decline in systolic blood pressure of 20 mm Hg and diastolic blood pressure of 10 mm Hg after at least 1 minute of standing, most PAF patients have a decrease in systolic blood pressure of 50 mm Hg or greater. This hypotension may be so severe that convulsive near-syncope occurs in a small portion of affected patients. A single measurement of upright blood pressure that does not meet the above criteria does not exclude the diagnosis. Several measurements of orthostatic blood pressure are required. About 5% of PAF patients have what appears to be angina pectoris, usually in the absence of significant angiographically demonstrable coronary atherosclerosis. PAF patients tolerate high altitude very poorly, perhaps because they hyperventilate in this situation. Even with severe supine hypertension, cardiac function can be preserved and contractility may even rise (Mathias et al., 2002; Robertson et al., 2004).

A reduced basal metabolic rate is typical. Hypohidrosis or at least an asymmetrical distribution of sweating is usually present. Nocturia is an invariable accompaniment of PAF and may cause the patient to get up as many as five times a night to pass substantial amounts of urine. This is due to nocturnal vascular redistribution in the microgravitational environment, as is typical of any patient with severe orthostatic hypotension. Urinary hesitancy, urgency, dribbling, and occasional incontinence may also occur. Some patients develop urine retention and may have repeated urinary tract infections in consequence. It is noteworthy that patients with PAF do not usually experience as high a fever as healthy persons, but any fever will significantly lower their blood pressure and consequently decrease their functional capacity. A sudden decline in functional mobility in a patient with PAF is suggestive of an occult infection, often of the urinary tract.

PAF patients have greatly reduced levels of catecholamines. Plasma and urinary norepinephrine levels are usually markedly reduced, sometimes to 10% of normal. Plasma norepinephrine concentrations are always less than 200 pg/mL and often under 100 pg/mL. Plasma levels of epinephrine are also reduced but usually to a lesser extent than norepinephrine. Dopamine levels in urine are usually about 50% of normal values. Marked hypersensitivity to all pressor and depressor stimuli exists (Table 77.6).

Table 77.6 Stimuli on Blood Pressure in Autonomic Failure

Depressor	Pressor
Standing	Lying
Food	Water
Hyperventilation	Hypoventilation
Exercise	Water immersion
Straining	Abdominal binding
Fever, environmental heat

Lewy bodies characterize the pathology of PAF, along with a loss of cells in the intermediolateral column of the spinal cord and a loss of catecholamine uptake and catecholamine fluorescence in sympathetic postganglionic neurons. PAF is less disabling than MSA and PD because of the absence of cerebellar, striatal, pyramidal, or extrapyramidal dysfunction. Patients should understand the relatively benign nature of PAF but need to learn to live within the limitations imparted by their symptoms. They have a generally good outlook, and many live for 20 years or more after the onset of disease. The most common cause of death in these patients is pulmonary embolus or intercurrent infection. The incidence of both myocardial infarction and stroke appears significantly reduced in PAF.

Autoimmune Autonomic Ganglionopathy

Also known as autoimmune autonomic neuropathy (AAN) and acute pandysautonomia (Vernino et al., 2000), autoimmune autonomic ganglionopathy typically strikes a previously healthy individual. Severe generalized sympathetic and parasympathetic autonomic failure unfolds over a few days to a few weeks. Orthostatic hypotension, fixed heart rate, anhidrosis, dry mouth, dry eyes, sexual dysfunction, constipation, and impaired pupillary function are present (Vernino et al., 2000). Anorexia, early satiety, postprandial abdominal pain and vomiting, constipation, or diarrhea may also be present. The spectrum and severity of dysautonomia is quite variable, however. Motor and sensory nerve abnormalities are typically absent. The most convincing evidence of an autoimmune pathogenesis is the demonstration of ganglionic nicotinic acetylcholine receptor (AChR) antibodies in high titers in a large proportion of these patients, the correlation of antibody level with dysautonomia severity, and the response of this disorder to intravenous globulin and plasma exchange (Vernino, 2005). Animal studies have demonstrated passive transfer of the disorder with infusion of patient serum. Recent work has confirmed antibody-mediated impairment of synaptic transmission in autonomic ganglia (Vernino et al., 2000).

Like other autoimmune disorders, autoimmune autonomic ganglionopathy may occur in a postinfectious or postsurgical setting, in the context of other autoimmune disorders such as autoimmune thyroiditis, with pernicious anemia or type 1 diabetes, as a result of a monoclonal antibody, or as a paraneoplastic disorder. Typical malignancies include small-cell carcinoma of the lung, breast cancer, lymphoma, and a scattering of other cancers. An elevated level of serum ganglionic AChR antibody is specific for the diagnosis, but its absence does not rule it out, since not all antibodies are detectable by current methodology. Particularly suggestive of this disorder are the spectrum of neurogenic bladder, impaired pupillary function, gastroparesis, dry eyes, and dry mouth.

Treatment includes plasma exchange or intravenous immunoglobulin. Partial but incomplete improvement over time is typical. Only a third of patients experience major functional improvement of autonomic deficits. Some patients with a more insidious and progressive form (rather than the typical subacute monophasic presentation) may be clinically indistinguishable from PAF. It is quite likely many other antibodies play a role in the production of autonomic disorders, such as antibodies to muscarinic cholinergic receptors, α-adrenergic receptors, and β-adrenergic receptors. This would typically involve dysfunction of a very selective type, involving either pure adrenergic or pure cholinergic failure, or isolated gastrointestinal dysmotility.

Autonomic Neuropathy

Autonomic neuropathy may occur in isolation, or more frequently as a part of a small-fiber neuropathy involving both autonomic and small unmyelinated or thinly myelinated sensory nerves. In this case, the typical presentation will include distal burning pain and changes in color of the distal limb reflecting poor vasomotor control. These symptoms may be quite disabling in their own right and particularly bothersome at night, interfering with sleep. Autonomic nerve involvement will typically affect erectile function first, may then affect bowel or bladder function with constipation or urgency, followed by parasympathetic glandular function resulting in dry eyes or mouth, and ultimately lead to orthostatic hypotension.

Causes of autonomic and small-fiber neuropathy include diabetes or metabolic syndrome in about half of cases. Although traditional teaching might suggest that diabetic autonomic neuropathy would only occur in patients with long-standing diabetes, this is clearly no longer the case. Involvement of autonomic nerves and autonomic Schwann cells is probably an immune-mediated process that occurs at the time diabetes develops, or may antedate glucose intolerance by several months or years. In one study (Hoffman-Snyder et al., 2006), more than half of patients presenting with a small-fiber neuropathy of unknown cause had occult glucose intolerance, with over a quarter being diagnosed with frank diabetes for the first time as a result of their neuropathic presentation. Neuropathy associated with diabetes treatment is increasingly recognized as well (Freeman et al., 2010) and may result from too rapid a drop in sugar levels. The triad of rapid-onset neuropathic symptoms, unexplained weight loss (probably due to diabetic gastroparesis), and new treatment initiation for diabetes should prompt strong consideration for this diagnosis, which may respond to steroid treatment early in its course (Said et al., 2003).

Sjögren syndrome (keratoconjunctivitis sicca) is probably the second most frequent cause of small-fiber neuropathy after diabetes and may present with dryness of the eyes, ears, nose, mouth, and vagina, with associated renal tubular acidosis, mononeuritis multiplex, achlorhydria, and often associated collagen disorders. Dysautonomia is relatively common from ganglionitis or cumulative mononeuritis multiplex lesions involving autonomic areas. Both primary and secondary Sjögren syndrome patients (60%) may have autoantibodies against the M₃ muscarinic receptor and impaired parasympathetic stimulation of bladder (Wang et al., 2004).

Other causes include multiple immunological disorders such as monoclonal protein–related neuropathy (with or without a plasma cell cancer), paraneoplastic autonomic neuropathy, postinfectious causes, and autonomic neuropathy related to various collagen vascular disorders such as lupus or rheumatoid arthritis. Infectious causes include herpes zoster, Lyme disease, and syphilis. Finally, a host of rarer metabolic and infiltrative disorders such as α-galactosidase deficiency (Fabry disease), porphyria, heavy metal poisoning, and other drugs and toxins discussed later can be responsible.

Drug-Induced Dysautonomia

Approximately 10% of drugs used in clinical practice derive their usefulness from their effect on the autonomic nervous system (Benowitz, 2004; Low et al., 2004). Moreover, at least 25% of drugs may, with overdose or toxicity, exert unwanted effects on the autonomic nervous system. These observations account for the importance physicians must attach to recognition of drug-induced autonomic impairment.

The mechanism by which drugs cause orthostatic hypotension include blood volume depletion; sympathoplegic effects causing impairment in maintenance of vascular resistance, venous tone, or cardiac output; and direct vasodilatation, which lowers vascular resistance or venous tone. Vasodilators may act directly on the vasculature or indirectly by blocking the renin-angiotensin or vasopressin systems. When drugs induce orthostatic hypotension by depleting the blood volume or by vasodilation alone, there is compensatory baroreflex-mediated sympathetic activation—that is, tachycardia, palpations, sweating, and increased circulating catecholamines. This presentation has been termed hyperadrenergic orthostatic hypotension. When drugs that impair central sympathetic outflow cause orthostatic hypotension, the expected sympathetic reflex response blunts or is absent (hypoadrenergic orthostatic hypotension).

Some drugs may cause reflex syncope (vasovagal syncope), especially those that produce hyperadrenergic orthostatic hypotension by vasodilation. Typically such patients have an initial period of reflex tachycardia after assuming an upright posture, followed by sudden bradycardia and hypotension with signs and symptoms of cerebral hypoperfusion and parasympathetic activation. Activation of afferent ventricular mechanoreceptors, owing to the intense myocardial contractile state, may contribute to the mechanism of syncope, increasing parasympathetic and inhibiting sympathetic responses, resulting in bradycardia and vasodilation with little or no increase in plasma norepinephrine (although plasma epinephrine may increase greatly). This effect occurs in the clinical laboratory after administering isoproterenol as a stressor to patients during upright tilt testing.

Elderly patients are especially at risk for drug-induced orthostatic hypotension, which is an important cause of syncope and falls in this population. Typically, drug-induced orthostatic hypotension in the elderly results from therapeutic use of sedatives, hypnotics, antidepressants, diuretics, antihypertensive drugs, nitrates, or antidepressants. Risk factors are less vigorous cardiovascular health, impaired baroreceptor function, and the increased number of prescription drugs they may be taking. Tricyclic antidepressants and other norepinephrine blocking agents are the most common unsuspected cause. The effect of tricyclic antidepressants on blood pressure may come on slowly and may require more than a week after discontinuation to go away completely. Other drugs commonly involved are trimethaphan, guanadrel, clonidine, and α-adrenoreceptor blockers. Chronic frequent marijuana use and excessive phenylpropanolamine use may occasionally lead to hypotension, but these are more prominent in the young.

Usually autonomic effects of drugs are readily reversible on discontinuation, but several drugs may produce permanent injury to autonomic nerves. Wernicke encephalopathy occurs with chronic alcohol abuse, is commonly associated with orthostatic hypotension that occurs without an adequate compensatory tachycardia, and is associated with an impaired cold pressor response together with hypersensitivity to infused catecholamines. Oncological agents such as vincristine and cisplatin can cause autonomic dysfunction and orthostatic hypotension, from which recovery may occur over several months. Cisplatin causes both autonomic neuropathy and salt wasting, thus giving rise to orthostatic hypotension by two different mechanisms. Paclitaxel and other chemotherapeutic agents in this class are particularly toxic to the autonomic nervous system. Most patients will get some degree of dysautonomia, which remains asymptomatic. In a minority, the autonomic neuropathy is so profound that blood pressure cannot be maintained, and the drug has to be discontinued. Metronidazole has also been associated with an autonomic neuropathy in doses that usually exceed 3 grams. In our experience, metronidazole toxicity usually occurs in the context of another risk factor such as diabetes or an already-present mild autonomic neuropathy that becomes markedly exacerbated by the drug. The medication should be immediately discontinued as soon as an autonomic neuropathy is uncovered. In addition, it should be avoided in patients with an extant autonomic neuropathy.

Oligohidrosis has been reported in a small number of patients receiving zonisamide, and in a proportion of these patients, hyperthermia has occurred (Low et al., 2004). Production of ciguatera toxin is by dinoflagellates consumed by reef fish. The presenting features of intoxication (most commonly after ingestion of barracuda, red snapper, or grouper) include vomiting, abdominal pain, myalgias, weakness, pruritus, and paresthesias of the mouth, face, and extremities. A peculiar “hot-and-cold reversal” occurs in which cold objects feel hot and vice versa. Cardiovascular features include bradycardia, hypotension, and in some cases, severe orthostatic hypotension. Increased vagal tone characterizes the nature of the autonomic disturbance. The bradycardia and, in part, the orthostatic hypotension reverse with atropine. The orthostatic hypotension is reversible in most cases, resolving within 4 to 6 weeks. Vacor is a toxin associated with severe autonomic neuropathy.

Dopamine β-Hydroxylase Deficiency

Dopamine β-hydroxylase (DBH) deficiency is due to selective absence of norepinephrine and all its metabolites (Robertson et al., 2005). It is described in only a few patients but has a disproportionate importance because it illuminates human noradrenergic function. Affected patients have absent sympathetic noradrenergic function but normal parasympathetic and sympathetic cholinergic function. DBH-deficient patients exhibit profound orthostatic hypotension. Although present from birth, the disorder is often unrecognized until adulthood. Symptoms in the perinatal period include vomiting, dehydration, hypotension, hypothermia, and profound hypoglycemia requiring repeated hospitalization. Exercise capacity is poor. By early adulthood, individuals have profound orthostatic hypotension, greatly reduced exercise tolerance, ptosis of the eyelids, and supine nasal stuffiness. Presyncopal symptoms include dizziness, blurred vision, dyspnea, nuchal discomfort, and chest pain. Neuropsychiatric symptoms are surprisingly mild. CNS abnormalities are not a consideration before diagnosis driven by the orthostatic hypotension. During adult life, some DBH-deficient patients develop renal function abnormalities, including raised blood urea nitrogen and creatinine levels. Life expectancy is uncertain but appears near normal.

The diagnosis is clinical, based on the findings of orthostatic hypotension, intact sweating, ptosis of the eyelids, and arched palate. Biochemical features include minimal or undetectable plasma, CSF, and urinary norepinephrine and epinephrine and a fivefold to tenfold elevation of plasma dopamine, a finding pathognomonic of DBH deficiency. Patients lack urinary normetanephrine, metanephrine, and vanillylmandelic acid. The molecular basis of DBH deficiency has been elucidated (Kim et al., 2002).

Menkes Kinky Hair Syndrome (Trichopolydystrophy, X-linked Copper Deficiency)

DBH is a copper-containing enzyme, and congenital disorders of impaired copper metabolism may present with certain features similar to DBH deficiency. Male infants with Menkes kinky hair syndrome (see Chapter 65) present with stubby, tangled, sparse hair (often white or gray in color), pudgy cheeks, spasticity, seizures, hypothermia, retarded growth, and decreased visual function. Subdural hematoma, jaundice, and osteoporosis also occur. The abnormality in copper handling leads to defective DBH functional efficiency. The incidence is between 1 in 50,000 and 1 in 100,000.

DBH deficiency is the first neurotransmitter defect with a uniquely efficacious replacement strategy. Administration of droxidopa (l-threo-3,4-dihydroxyphenylserine), or LDOPS (Freeman et al., 1999; Kaufmann et al., 2003), alleviates the orthostatic hypotension and other symptoms. Individuals do not respond well to standard therapeutic approaches for autonomic failure. Surgery can correct ptosis. Renal function should be assessed every 3 years or more often if function decreases.

Multiple System Atrophy

MSA, also known as Shy-Drager syndrome, is a progressive neurodegenerative disorder encompassing autonomic, extrapyramidal, cerebellar, and pyramidal features (Parikh et al., 2002; Seppi et al., 2005; Wenning et al., 2004). Extrapyramidal involvement (termed MSA-P, for parkinsonian) is about threefold more common than cerebellar involvement (termed MSA-C for cerebellar). Occasional patients feature both types. The pathological hallmark of MSA is neuronal loss and gliosis within multiple sites in the brain, intermediolateral columns, and the Onuf nucleus, with characteristic glial cytoplasmic inclusions (GCIs) containing α-synuclein and ubiquitin. These inclusions are quite distinct from Lewy bodies, which also contain ubiquitin in several respects:

The average age of onset is 53 years; no confirmed cases exist under age 30, and onset beyond age 70 is rare. No gender predilection exists. MSA has a prevalence of 0.4 per 100,000 individuals. In some patients, the disease presents as orthostatic hypotension or urinary tract symptoms, but in other cases, extrapyramidal or cerebellar symptoms predominate in the early stages. When orthostatic hypotension antedates other neurological involvement, differentiation from autonomic neuropathy, PD, diffuse Lewy body disease, or PAF may be difficult (Geser et al., 2005; Kaufmann et al., 2004; Seppi et al., 2005). Even when there is full-blown parkinsonism and severe dysautonomia, MSA and PD are difficult to separate and cannot be separated on the basis of autonomic testing alone (Riley and Chelimsky, 2003). Other clinical features are better predictors of a diagnosis of MSA, such as poor response to dopamine agonists or l-dopa, absence of significant dementia, absence of tremor, and falls early in the disease course.

The clinical picture is usually dominated by three major issues: a dysautonomia manifested by severe orthostatic hypotension and severe (most often lower motor neuron) urinary dysfunction, and their motor system disturbance that results in wheelchair requirement early in the course of the disorder. Patients may have multiple other related complaints including impotence, slurred speech, sleep apnea, vivid nightmares, orthostatic headache, neck pain, dimming of vision, and leg discomfort. Several specific clinical features may help in the diagnosis of MSA. Patients frequently note emotional lability, with short (sometimes only 1 or 2 minutes) episodes of crying due to happiness or sadness in response to a relatively minor environmental stimulus, such as a song or an event in a television program or movie. This is usually self-limited but may be a harbinger of depression and requires treatment with a selective serotonin reuptake inhibitor. Patients sometimes have periodic gasping respirations punctuating the medical interview. They only last a few seconds and are not generally deep but seem labored. Finally, many patients discontinue the use of nicotine-containing products at the onset of their disease. It sometimes appears that they no longer enjoy the nicotine. Ultimately, nicotine may provoke or worsen tremor. Finally some patients will complain of intermittent diplopia, particularly in MSA-C.

Orthostatic hypotension is usually severe, and treatment is frequently complicated by supine hypertension. Supine plasma norepinephrine levels are often near normal in patients with MSA but do not rise appropriately on standing, as expected in a disorder involving central pathways. This contrasts with the low plasma norepinephrine found in the ganglionic disorder, PAF. The reduction in the lying-to-standing norepinephrine level change in MSA results from both lower than normal secretion with standing, and higher than normal secretion when supine. This accounts for the sometimes severe supine hypertension seen in MSA (Shannon et al., 2000b). Thus MSA does not reflect only a reduction of required autonomic outflow but an inversion of central autonomic regulation.

Involvement of the bladder occurs in most patients. The pathophysiology is complex, resulting from pathological changes in bladder-control elements at several levels in the neuraxis. Early complaints of urgency, frequency, and nocturia reflect dysfunction in upper motor neuron circuits, including loss of neuromelatonin-containing neurons in the striatum and loss of neurons in the cerebellum, raphe nuclei, and frontal cortex. The later picture is dominated by overflow incontinence, more consistent with a “lower motor neuron bladder,” most likely reflecting the destruction of cells in the Onuf parasympathetic nucleus of the sacral spinal cord. Post-void residuals steadily increase from year 1 to year 5 of the disease (Ito et al., 2006). In fact, a large post-void residual in a patient with a Parkinson-like disorder suggests MSA rather than PD (Hahn and Ebersbach, 2005). Failure of bladder emptying is further compromised by loss of intermediolateral horn preganglionic sympathetic innervation to the bladder, which results in loss of control of both the sphincter and collapse of the bladder neck (Kirby et al., 1986), which remains open in 53% of patients (Sakakibara et al., 2001). Detailed reviews of the subject have been published (Fowler et al., 2008, 2010).

Prognosis in MSA is poor; 10-year survival is rare. The autonomic abnormalities are seldom the direct cause of death. Some patients develop laryngeal stridor and difficulty swallowing, which can lead to aspiration pneumonia. Some MSA patients have sleep apnea, and in some cases, this may lead to a critical loss of respiratory drive, the so-called Ondine’s curse. The most common causes of death in patients with MSA are pulmonary embolus, apnea, and intercurrent infection.

The pathophysiology of MSA is unknown, and no cure exists, so management continues to be symptomatic (Freeman et al., 1999; Hussain et al., 2001; Jordan and Biaggioni, 2002; Wenning et al., 2005). This includes treatment of the depression, tremor, gait disturbances, orthostatic hypotension, and possible self-catheterization when urine retention is severe. However, in the last 5 years, several promising developments have occurred. A transgenic mouse model that closely mimics the disorder was developed by splicing the α-synuclein gene in front of a myelin basic protein promoter (Shults et al., 2005). Further, rifampicin was shown to inhibit aggregation of α-synuclein in vitro and in this mouse model, leading to a National Institutes of Health–sponsored trial of rifampicin in MSA begun in 2011. A trial of intravenous globulin has now been completed, and the results are pending. Finally, an international trial of the antiparkinsonian drug, rasagiline, an inhibitor of monoamine oxidase type B, has just enrolled its last patient and will be following the cohort for 1 year.

Parkinson Disease

From a clinical perspective, the autonomic manifestations of PD are virtually indistinguishable from those of MSA. Although some authors report a difference between the results of autonomic testing in MSA and PD (Chelimsky, 2008; Lipp et al., 2009), these studies compared patients with nonequivalent burdens of autonomic dysfunction, being much worse in MSA than in PD. Clearly, more severe abnormalities occur in patients with more severe clinical dysautonomia, causing patients with MSA to appear more severe in their test results than patients with PD. When patients in the PD group are matched with those of the MSA group for severity of autonomic involvement, autonomic testing cannot distinguish MSA from PD (Riley and Chelimsky, 2003). The autonomic dysfunction of PD can be astoundingly severe. Although autonomic dysfunction is clearly more prevalent in MSA than in PD, when a patient presents to the office with severe orthostatic hypotension and a PD-like syndrome, PD is more likely, simply because PD is so much more common than MSA (1000 per 100,000 versus 0.4 per 100,000) (Bonuccelli et al., 2003).

The pathophysiology of autonomic dysfunction in PD is different than in MSA. Whereas MSA exclusively involves central networks and nuclei, the Lewy bodies of PD directly involve ganglia, and hence postganglionic neurons, with degeneration of peripheral autonomic fibers. One may therefore see reduction in axon reflex sweating more frequently in PD than in MSA, though this is not always reliable. In addition, increased response to sympathetic agonists such as midodrine due to denervation supersensitivity may occur, but again this is inconsistent. Finally, this peripheral predilection in PD is the basis for the denervation seen on metaiodobenzylguanidine (MIBG) scanning of the heart, which has been touted as a diagnostic test to distinguish PD from MSA (Goldstein et al., 2009), though others do not find the same results (Geser et al., 2011). The rationale is that uptake of this compound, a congener of norepinephrine, into noradrenergic-rich tissues such as the heart will be impaired in conditions such as PAF and PD, but is comparatively normal in MSA. Finally, some authors have advocated sphincter EMG as a method of distinction, since the lower motor neuron is involved in MSA, resulting in polyphasic and bizarre motor units in this disorder but normal motor units in PD (Fowler, 2001).

Clinical classification may provide the best method at this point in time. In the recent epidemiological trial of MSA with classification based on clinical criteria, over 100 patients were classified correctly when the classification was compared to autopsy findings.

Myelopathy

Because sympathetic outflow (T1-L2/3) and sacral parasympathetic outflow descend in the spinal cord, cord lesions commonly result in substantial autonomic impairment. This may occur in both spinal cord injury and other disorders such as multiple sclerosis (Fowler et al., 2010), neuromyelitis optica, or spinal cord lesions of any other cause. In cervical and high thoracic levels, most sympathetic and sacral parasympathetic outflow is lost (Mathias, 2004, 2006). Following spinal cord injury, the initial response is hypoexcitability (spinal shock) with flaccid paralysis, impaired tendon reflexes, and spinal autonomic dysfunction presenting as atonic bladder and bowel, vasodilation, and absent spinal autonomic reflexes. This stage lasts days to weeks, and then activity below the transected cord returns. Chronically, a quite distinct autonomic dysfunction emerges (Critchley et al., 2003).

Whereas blood pressure is low following acute high thoracic cord injury, in the chronic stage, blood pressure relates to the level of the spinal lesion. It is lower in high cord lesions and rises to near normal as the lesion descends. Severe hypertension may occur during autonomic dysreflexia (Head-Riddoch syndrome) after stimulation below the level of the lesion. This may occur from pressure sores, from abdominal viscera, by bladder contraction or irritation from a urethral catheter, or even from skeletal muscle contraction such as muscle spasm. Any of these may elicit dramatic blood pressure elevation. These changes occur from activation below the cord lesion, whereas sweating and cutaneous dilation occurs above the lesion. During autonomic dysreflexia, sympathetic nerve activity is increased. Impaired baroreflex function no doubt contributes to these effects, including the hypersensitivity to pressor and depressor agents.

Considerable morbidity occurs in autonomic dysreflexia, with severe sweating and headache; more ominously, even intracranial hemorrhage occurs. Management consists of preventing initiation of the increased sympathetic discharge. High cord lesions are associated with warm (vasodilated) skin below the lesion. The nasal stuffiness from vasodilation in the nasal mucosa is Guttmann sign. There is susceptibility to hypothermia because, in addition to being unable to constrict the cutaneous circulation, shivering diminishes. However, in certain circumstances the reverse occurs, causing hyperthermia because of the inability to sweat and vasodilate in the periphery, which would normally induce heat loss.

Environmental temperature therefore needs to be carefully controlled. Hyperthermia responds to sponge bathing, the efficacy of which is enhanced by fanning. In severe cases, ice-cooled saline by intravenous infusion or urinary bladder irrigation is occasionally required. The sympathetic skin response can be useful in assessing spinal cord injury (Cariga et al., 2002). Activation of supraspinal centers and descending sudomotor neural pathways in the spinal cord are necessary for the SSR. It is absent in the feet in low spinal injuries and absent in the hand region in high spinal injuries. The presence or absence of the SSR, in addition to motor and sensory evaluation, can be a marker of spinal cord autonomic involvement and may improve classification of the extent of spinal functional deficits. The SSR can also test spinal cord sudomotor centers isolated from the brainstem that are capable of generating an SSR.

In early cord injury, vagal hyperactivity may cause excessive gastric acid secretion, with ulceration and hemorrhage (Mathias, 2002). H₂ antagonists or proton pump inhibitors may be useful in such patients. In high lesions, paralytic ileus may occur, especially after ingestion of solid food. Colon dysfunction occurs commonly but may be amenable to bowel training, modification of diet, mild laxatives, and stool softeners. Urine retention, distension, and overflow occur early after cord injury. Intermittent catheterization should be used in the early stages. Persistent infection in various sites may cause secondary amyloidosis with renal infiltration and damage.

In men, both erectile and ejaculatory failure occur in early cord injury. Conversely, in the chronic phase, priapism may occur during autonomic dysreflexia. Ejaculation is often retrograde. Various approaches that include electrical stimulation and collection of seminal fluid have been used for artificial insemination. Sildenafil (Viagra) is effective for erection in spinal injuries and autonomic failure (Hussain et al., 2001). In women, menstrual cycle disruption occurs in early cord injury. Recovery is usually within a year, and successful pregnancy has occurred in both tetraplegic and paraplegic women. In high cord lesions, uterine contractions may evoke severe autonomic dysreflexia. Such patients are particularly prone to seizures and sometimes to cerebral hemorrhage in response to very severe hypertension. These individuals require antihypertensive therapy as well as medication for seizure control.

Aortic Stenosis

With bicuspid aortic valves, patients may develop aortic stenosis late in life. This may lead to syncopal episodes, especially with exertion. Intracardiac pressure may be high even when the cuff blood pressure is low, as when syncope occurs. Echocardiography provides definitive diagnosis.

Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy is an asymmetrical hypertrophy of the heart ventricles. Inheritance may be autosomal dominant, but at least half of cases are sporadic. It is the most common genetic cardiac disease. Systolic function is preserved, but left ventricular outflow obstruction at rest occurs in 20% of patients and may lead to syncope, palpitations, shortness of breath, and sudden death. The echocardiogram is diagnostic.

Subclavian Steal Syndrome (Millikan-Siekert Syndrome)

Basilar artery insufficiency results from subclavian steal; exercise of the left arm precipitates neurological symptoms including syncope, facial paresthesia, headache, and transitory loss of vision. It is due to reversal of blood flow from the vertebrobasilar system into the subclavian system.

Innominate Artery Syndrome

Innominate artery syndrome may present with apparently low blood pressure in the right arm but be otherwise asymptomatic. It is detected by disparities of blood pressure in the two arms. However, occasionally subclavian steal occurs with proximal subclavian artery stenosis and retrograde perfusion of the vertebral artery to the distal subclavian artery.

Sick Sinus Syndrome (Short Syndrome)

Sick sinus syndrome presents with alternating bradycardia and tachycardia. A sick sinus node is abnormally susceptible to the suppressive influence of ectopic atrial activity. It usually occurs in women after age 60, more than half of whom may experience syncope.

Glossopharyngeal Neuralgia (Weisenberg Syndrome)

Glossopharyngeal neuralgia presents as a unilateral episodic hypotension and bradycardia in association with severe paroxysmal pain beginning in the tonsillar region, lateral pharynx, or base of the tongue and radiating deeply into the ear. Eating or talking elicits the neuralgia. This disorder sometimes occurs in the wake of injury or tumor in the neck. It may respond to treatment with yohimbine, but some patients seem very resistant to therapy. If all else fails, division of the nerve at the area of emergence from the cranium may be required.

Inferior Vena Cava Syndrome (Supine Hypotensive Syndrome)

Inferior vena cava syndrome occurs in the last month of pregnancy in as many as 10% of women. Assumption of the supine position causes a sudden fall in systolic blood pressure, nausea, and vomiting. Tachycardia is associated. The probable cause is decreased venous return, and hence cardiac output, from compression of the inferior vena cava by the gravid uterus.

Pancreatic Cholera (Verner-Morrison Syndrome)

Verner-Morrison syndrome is marked by a watery diarrhea associated with an islet cell tumor and electrolyte abnormalities. It may occur with bronchogenic carcinoma or multiple endocrine neoplasia type 1. Secretion of vasoactive intestinal polypeptide is the usual cause of symptoms. In 84% of cases, the origin is the pancreas. A metabolic acidosis is usually present.

Villous Adenoma (McKittrick-Wheelock Syndrome)

McKittrick-Wheelock syndrome arises from the severe dehydration and electrolyte depletion that occurs as a complication of colonic villous adenoma. These adenomas exude large quantities of electrolyte-rich fluid. Severe orthostatic hypotension may occur. A key diagnostic feature is greatly elevated blood urea nitrogen with proportionately lesser elevation of serum creatinine. These findings may resolve almost completely with fluid replacement.

Cortisol Deficiency (Addison Disease)

Hypotension and postural hypotension occur in the late stages of cortisol deficiency, as both aldosterone and cortisol itself play important roles in the maintenance of blood pressure. Aldosterone increases available intravascular volume through renal retention of sodium, while cortisol directly influences both the endothelium and vascular smooth muscle. In endothelium, cortisol inhibits the generation of vasodilators such as nitric oxide and prostacyclin, while it enables pharmacomechanical coupling of agonists such as norepinephrine in vascular smooth muscle. When cortisol is absent, hypotension and vascular collapse due to unresponsiveness of the smooth muscle to any pharmacological agonists ensue, including those given exogenously for resuscitation. In this setting, administration of intravenous glucocorticoids is the only strategy and constitutes a medical emergency (Yang and Zhang, 2004).

Nonpharmacological Interventions for Orthostatic Hypotension

Treatment of orthostasis is primarily nonpharmacological. Many measures can be used for POTS, syncope, and orthostatic hypotension and should be implemented before moving to drugs with approaches that are slightly different for the three disorders. When autonomic reflexes fail, certain physical maneuvers, life habits, and drugs have a much greater effect on blood pressure than they have in normal subjects. This can be used to advantage in patient management. Maintenance of physical conditioning is a fundamental principle of management. This may only be achieved with water aerobics or water jogging in shoulder deep water if orthostasis is advanced. The water reduces the gravitational pull on blood volume to nearly a quarter of its normal value, with cerebral perfusion remaining largely intact. Great care should be exercised when coming out of the water, with return of full gravitational pull combined with a vasodilated muscular system and possibly cutaneous dilation as well depending on water temperature. For this reason, cooler temperatures are preferred. Recumbent bicycling may also be useful.

A range of simple physical maneuvers have been identified that can improve the patient’s ability to stand upright (Krediet et al., 2005; van Dijk et al., 2006); implementation is accomplished with a little education (Fig. 77.7). Physical counter-maneuvers possesses the additional advantage of being entirely under the patient’s control, with all the convenience and self-reliance that derive from this. Such maneuvers use muscle pump action or gravity to improve circulation to the brain and forestall a faint when the person is standing; they include leg crossing, performed by crossing the legs in a scissors pattern. The patient actively stands on both legs. It is likely that this maneuver squeezes venous vessels in the legs and abdomen so that less blood pools there. Leaning forward slightly enhances the benefit of this maneuver. Crossing the legs in the seated posture may have a similar physiological basis and is quite effective, especially for individuals with the most severe orthostatic hypotension, when even the seated posture represents a challenge. One limitation of leg crossing in the upright posture is that the patient may have reduced postural stability and be more likely to fall. In particular, few patients with MSA, for example, can benefit from upright leg crossing because of their balance problems independent of their blood pressure. However, in individuals without extrapyramidal or cerebellar abnormalities, this maneuver is so strikingly useful that many patients will have discovered its value on their own and may have been using it for a number of years before they are even diagnosed with orthostatic hypotension (Wieling et al., 2004).

Squatting is another powerful pressor maneuver. Squatting increases pressure by reducing the capacity of veins in the legs and splanchnic vasculature while also creating a mechanical impediment to arterial circulation to the legs. The usefulness of squatting to forestall a “hypotensive” emergency is very great for many patients with orthostatic hypotension. It is noteworthy, however, that rising from the squatting position sometimes presents difficulties of its own.

Orthostatic (standing) training has been suggested as effective nonpharmacological therapy for patients with recurrent reflex syncope. This treatment involves leaning patients upright with the upper back against a wall and the feet away from the wall about 1 foot (mimicking a 70-degree angle) for 10 to 20 minutes once or twice a day. The maneuver should be performed on a carpeted floor with no sharp angular furniture nearby, in case of a faint. The initial results from this therapy are quite promising, and it has been subjected to an open-label trial with good results (Fowler et al., 2010). Although not proven to work in POTS or orthostatic hypotension, orthostatic training merits being tried for both of these disorders.

Support garments over the lower part of the body benefit patients by acutely increasing blood pressure. Support garments can be used in patients with severe orthostatic hypotension, especially those who live in a relatively cool climate. A disadvantage is that the patients must be willing to take off the garments every time they lie down to preserve their effectiveness in the upright posture. This is a major inconvenience. Many patients also find the garments uncomfortable and “hot.” Some individuals will save the garment for special occasions when they must stand up to speak or to carry out an important but time-limited activity in the upright posture.

Dietary Measures

Drugs

Pacemaker Placement

Permanent dual-chamber pacemakers may sometimes be required for treatment—if, for example, severe bradycardias occur as part of the dysautonomia—but their value in reflex syncope remains controversial. The are currently not recommended, as several trials failed to show significant benefit (Connolly et al., 1999; Mosqueda-Garcia et al., 2000).

Treatment of Supine Hypertension

Supine hypertension may sometimes be a serious problem. The physiology is now better understood. Ganglionic blockade significantly reduces supine pressure, implying that it is actually in part due to inappropriate sympathetic outflow to the vasculature in the supine position (Shannon et al., 2000a, 2000b). Supine hypertension often requires specific treatment with short-acting antihypertensives at bedtime, such as captopril or propranolol. In our practice, we usually treat pressures over 170/95 mm Hg or so, though no data are available as to when to treat this problem. Patients with autonomic failure do not appear to have the usually associated higher risk of stroke because high pressure is episodic rather than continuous, and the main reason to treat is to reduce the risk associated with very high pressures (e.g., cerebral bleed).

Bladder Issues

Early in most dysautonomias, an upper motor neuron spastic bladder dominates the clinical picture, while later a lower motor neuron flaccid process often supervenes. Urodynamics are very helpful in determining the stage of bladder dysfunction. Treatment is usually symptomatic in the early (spastic) phase, and various anticholinergic medications are available to prevent urgency and frequency. If CNS issues such as memory loss are not a problem, older agents such as oxybutynin (Ditropan) or tolterodine (Detrol) are usually adequate. Newer agents have more specific muscarinic receptor specificity and do not cross the blood brain barrier, making them more appropriate when CNS effects should be avoided. Although α-adrenergic antagonists may be helpful in patients with urgency by reducing sphincter pressure, they are relatively contraindicated in patients with orthostatic hypotension, since they will reduce standing arterial pressure and are exact pharmacological opposites of drugs like midodrine.

Treatment of a later-stage low-pressure, flaccid detrusor employs different methods and pharmacology. The primary concern here is ureteral reflux that may lead to irreversible kidney damage. Thus, in contrast to the spastic bladder where management is primarily aimed at patient comfort, the flaccid bladder requires management from the outset to avert ureteral reflux and recurrent urinary tract infections. Management begins by measuring a post-void residual. If over 100 mL, the risk of UTI is high, and emptying measures must be taken. This may include procholinergic medications, such as bethanechol, or acetylcholinesterase inhibitors, such as pyridostigmine, which improve detrusor contractility. If residual is still significantly over 100 mL, clean self-catheterization should be considered. Depending on the residual volume, this may be performed just once in the morning to ensure complete bladder emptying once daily, or upon awakening and before retiring, or if needed, 4 times daily. If possible, it is better to allow the detrusor to work during some of the voids to maintain whatever function is still present as long as possible.

Bowel Issues

Dysmotility associated with dysautonomias leads to upper bowel problems such as gastroparesis and bacterial overgrowth leading to bloating, distention, diarrhea, and lower bowel dysfunction, manifesting primarily as constipation or diarrhea, which may paradoxically be a result of obstipation with overflow stooling. All these issues demand careful thought and evaluation as the basis for appropriate management. For example, if diarrhea were due to constipation and simply treated as such with an antimuscarinic agent, the problem would become worse, not better. PD patients need a laxative approach, and polyethylene glycol (PEG) is at this time the first choice for slow transit or as a first-line treatment in other causes of constipation. It is important to work with a gastroenterologist with expertise in dysmotility. If one is not available, then a general gastroenterologist should be consulted to exclude superimposed structural disorders.

Upper-bowel dysfunction usually manifests as early satiety. It occurs commonly in diabetes and probably accounts for the profound weight loss (may be 30–80 pounds over 1–2 months) associated with acute diabetic autonomic syndromes that may be treatment associated. Two aspects of gastric function may come as a surprise: (1) both sympathetic and parasympathetic nervous systems play key roles in gastric emptying, and pure loss of sympathetic function may lead to severe gastroparesis (Chelimsky et al., 2004); and (2) early satiety may NOT represent poor gastric emptying but rather loss of gastric accommodation (ability of the stomach to expand rapidly in compliance with a meal). To distinguish between these two possibilities, one may use a water-load test (How much water can the patient drink in 5 minutes? [normal > 300 mL] (Sood et al., 2002) and a gastric-emptying test with solid and liquid diet. Upper-bowel dysmotility may benefit from promotility agents such as metoclopramide, 10 mg 2 or 3 times daily. However, metoclopramide is contraindicated in PD, owing to brain barrier passage and central effect. It should also be used with extreme caution because of the risk of tardive dyskinesia. Other motility agents are also available, including erythromycin at an adult dose of 250 mg 2 to 3 times daily. Erythromycin is a motilin agonist that improves gastric emptying and foregut motility. Octreotide is also useful in improving foregut motility, although it may produce delayed gastric emptying. It has some effect in increasing blood pressure and has been used in postprandial hypotension.

Lower-bowel dysfunction may present as constipation or diarrhea. Constipation usually requires a nonstimulating laxative such as PEG or lactulose given in generous doses until bowel function normalizes, when doses can be reduced to routine maintenance levels. Serial radiographs of the abdomen (KUBs) may be helpful in determining residual stool in the colon. When severe constipation with obstipation supervenes and is unresponsive to the standard regimen, a “home cleanout” regimen may be prescribed, consisting of bisacodyl 10 mg (2 × 5 mg tablets), followed by 1 capful of PEG in 8 ounces of liquid every 30 minutes for a total of 8 to 10 doses, followed by another dose of bisacodyl 4 hours later. Lower-bowel dysmotility may also present with diarrhea, with a broader possible set of causes. Diarrhea may actually be a manifestation of obstipation, with liquid stool overflowing around the hard stool in the distal colon. A flat plate abdominal radiograph is diagnostic. Other causes include small-bowel bacterial overgrowth, which may be determined by a hydrogen breath test and responds to antibiotics, in particular rifaximin, which is the current standard of care. Metronidazole should be avoided, since it may cause or worsen an autonomic neuropathy. Finally, primary lower-bowel hypermotility sometimes responds to low-dose clonidine (0.1–0.2 mg) once or twice daily.

In conclusion, autonomic disorders constitute a field in which much growth has occurred in the last decade. The discipline seems poised for an explosion of new understanding, particularly in the area of functional autonomic disorders, where new fundamental links between brain, behavior, and end-organ control may be uncovered.