Evaluation and Management of Autonomic Nervous System Disorders

Evaluation and Management of Autonomic Nervous System Disorders Caroline M. Klein, M.D., Ph.D. 1 ABSTRACT Autonomic nervous system dysfunction may manifest with a variety of symptoms, with orthostatic intolerance (including orthostatic hypotension or tachycardia) and sweating abnormalities (increased or decreased sweating) being common problems requiring medical evaluation and treatment. Determination of the underlying diagnosis for these symptoms is critical in terms of classification of the disorder and its prognosis. Recent advances in evaluation of patients with these conditions and treatment modalities have enabled physicians to improve overall management of patients with these disorders. These advances include testing for ganglionic acetylcholine receptor antibody in patients with suspected autoimmune autonomic neuropathy and use of pyridostigmine for treatment of patients with orthostatic hypotension or tachycardia. KEYWORDS: Dysautonomia, orthostatic hypotension, postural tachycardia syndrome Autonomic nervous system dysfunction may manifest clinically with a variety of symptoms, including orthostatic intolerance (due to either orthostatic hypotension or inappropriate tachycardia), change in sweating, gastrointestinal complaints, pupillary abnormalities, sexual dysfunction, bladder dysfunction, or secretomotor changes (dry eyes or dry mouth). Depending on the clinical setting, these symptoms may represent a limited autonomic disorder, such as autoimmune autonomic neuropathy, or indicate the onset of generalized autonomic failure as part of a neurodegenerative process, such as pure autonomic failure or multiple system atrophy (Shy-Drager syndrome). One must determine if there is autonomic dysfunction, its extent and severity, and what other clinical features help to establish the overall diagnosis for the patient. Accurate characterization of an autonomic disorder and its underlying pathogenesis is necessary for planning management strategies and long-term prognosis. Orthostatic intolerance and syncope, for example, may be due to a variety of underlying causes, including orthostatic hypotension, orthostatic tachycardia (which may be secondary to volume depletion, deconditioning, anemia, hyperthyroidism, anxiety, or postural tachycardia syndrome only the latter of which is an autonomic disorder), or neurocardiogenic or vasovagal (reflex) syncope. Autonomic symptoms have a wide variety of causes, some of which are more common (neurocardiogenic or reflex syncope) than others (pure autonomic failure, multiple system atrophy, autoimmune autonomic neuropathy). CLINICAL FEATURES Orthostatic Intolerance Orthostatic intolerance, as a broad definition, includes a variety of symptoms, which occur when the patient changes body position, specifically from lying down to 1 Department of Neurology, The University of North Carolina School of Medicine, Chapel Hill, North Carolina. Address for correspondence and reprint requests: Caroline M. Klein, M.D., Ph.D., Assistant Professor, Department of Neurology, The University of North Carolina School of Medicine, 3114 Bioinformatics, Campus Box 7025, Chapel Hill, NC 27599-7025 (e-mail: kleinc@neurology.unc.edu). Neuromuscular Disorders; Guest Editor, Ted M. Burns, M.D. Semin Neurol 2008;28:195 204. Copyright # 2008 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI 10.1055/s-2008-1062263. ISSN 0271-8235. 195

196 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008 sitting, or most likely, standing upright. Physiologically, due to gravitational forces, there is an abrupt shift in blood volume and consequently venous return to the heart with change in body position, which is compensated for in the normal patient by virtue of intact baroreflex mechanisms. Patients may develop symptoms of dizziness, lightheadedness, blurred or tunnel vision, headache, chest discomfort, nausea, cognitive slowing, posterior cervical and shoulder pain, and diaphoresis with change in body position. In elderly patients (age 65 or older), these symptoms may not be immediately apparent to the patient, but instead occur as a subtle but consistent change in mental status noted by caregivers whenever the patient is in an upright posture. In the most extreme circumstances, syncope or temporary loss of consciousness may actually occur. These symptoms may be reported in patients that have orthostatic hypotension or orthostatic tachycardia. In both cases, determining whether the symptoms are secondary to systemic causes such as anemia, dehydration, relative deconditioning, or hyperthyroidism (with orthostatic tachycardia) is important. It is also important to determine whether lightheadedness or vertigo occurs when the patient reports dizziness, and whether the dizziness ever occurs in a supine position or with rapid change in head position, in which case the symptoms may be due to vestibulopathy. How frequently the symptoms occur (daily versus intermittently) and whether there is any diurnal variation (worse in the morning, for example, which commonly occurs in patients with orthostatic hypotension) in the symptoms are important clinical features. Sweating Abnormalities Sudomotor or sweating changes can also be features of autonomic dysfunction, implying changes in sweating not related directly to symptoms of orthostatic intolerance or presyncope. Patients may report either increased or excessive sweating, or decreased sweat output and heat intolerance, either globally, segmentally, or patchy in distribution. Many patients with distal sweat loss report increased sweat output, which may occur as a compensatory response in unaffected areas such as the head and upper torso, but which is perceived by the patient as excessive sweating. Sudomotor dysfunction may be due to abnormalities in central control mechanisms (as in multiple system atrophy), or more commonly in patients with autonomic peripheral neuropathy, either as an isolated abnormality of postganglionic sympathetic nerve fibers only in hypohidrosis or global anhidrosis, or as part of a more generalized autonomic neuropathy, either primary (autoimmune autonomic neuropathy) or secondary (amyloidosis, diabetic peripheral neuropathy, or small fiber sensory neuropathy due to Sjögren s syndrome) in nature. Secretomotor Symptoms Secretomotor symptoms include sicca symptoms of dry eyes (xerophthalmia) and dry mouth (xerostomia). Patients do not usually volunteer these symptoms unless they are severe, but with careful questioning, they may be elicited. Dysfunction of autonomic innervation may be seen in autonomic neuropathies or part of generalized autonomic failure, although more commonly seen in the former. Gastrointestinal Symptoms Gastrointestinal symptoms may include early satiety, abdominal cramping after meals, frequent diarrhea or constipation (or alternating bouts of both), nausea and/ or vomiting with meals. Genitourinary Symptoms Bladder dysfunction, in relation to autonomic disorders, may include urinary incontinence, urinary frequency/ urgency, and symptoms of urinary retention. Male patients may report symptoms of erectile dysfunction, and both male and female patients may report decreased libido and inability to achieve orgasm with autonomic dysfunction. Sleep Disorders A subset of patients may report sleep disturbances as part of their presentation of autonomic nervous system dysfunction. Specifically, patients with nightmares and rapid eye movement (REM)-behavioral sleep disturbances may have associated autonomic dysfunction in the setting of a diagnosis of multiple system atrophy. PATHOGENESIS The recent report by Vernino et al 1 regarding isolation of a serum antibody against ganglionic acetylcholine receptors has led to better understanding and further characterization of the pathogenesis of autonomic neuropathies, specifically autoimmune autonomic neuropathy, which was previously called idiopathic autonomic neuropathy. Across a spectrum of patients with autonomic disorders ranging from idiopathic autonomic neuropathy to diabetic autonomic neuropathy to postural orthostatic tachycardia syndrome to pure autonomic failure to multiple system atrophy high levels of seropositivity for this antibody were found. Ganglionic acetylcholine receptor antibodies were found in 40% of patients with idiopathic or paraneoplastic autonomic neuropathy and in a smaller percentage of patients with postural orthostatic tachycardia syndrome or diabetic autonomic neuropathy (< 10% for each group). Patients with other autonomic disorders were seronegative. The

EVALUATION AND MANAGEMENT OF AUTONOMIC NERVOUS SYSTEM DISORDERS/KLEIN 197 subgroup of patients with idiopathic autonomic neuropathy with seropositivity for ganglionic acetylcholine receptor antibody were later further characterized by their clinical features, including sicca complex, pupillary light abnormalities, upper gastrointestinal symptoms, and neurogenic bladder, in addition to orthostatic hypotension, suggesting prominent cholinergic nerve fiber dysfunction in this patient population. 2,3 Patients with more limited forms of autoimmune autonomic neuropathy (diabetic autonomic neuropathy, isolated gastrointestinal dysmotility, postural tachycardia syndrome) were found to have lower, but positive, titers of this antibody. 4 These antibodies are not found in healthy control subjects, 4 so that their presence appears to have not only diagnostic value but also to provide information regarding pathogenesis in these patients, particularly those with very high titers of antibody. Indeed, further testing with animal models has provided evidence of pathogenicity. 1,5,6 The pathophysiology of postural orthostatic tachycardia syndrome (POTS) remains poorly understood, but what has evolved with clinical experience with these patients is that this is truly a syndrome and not a specific diagnosis, meaning that the underlying pathogenesis is variable, and different subgroups of patients who meet the established diagnostic criteria have different underlying causes. 7 11 There is a subgroup of these patients with neuropathic POTS, meaning that they appear to have a limited autonomic neuropathy underlying their condition as demonstrated by distal abnormalities on quantitative sudomotor testing and patchy denervation of sympathetic nerve fibers to the blood vessels in the lower extremities and the kidneys leading to hypovolemia and abnormal vasoconstriction patterns as a cause for the postural tachycardia. 8,11,12 A less common form is that due to an increase in sympathetic outflow from the central nervous system, leading to a hyperadrenergic state and orthostatic hypertension. 8 11 Finally, a genetic mutation in the norepinephrine transporter protein has been identified in a kindred of patients with postural tachycardia syndrome, leading to a peripherally generated hyperadrenergic state. 8 Whether other genetic mutations or polymorphisms are present in the general population of patients with postural tachycardia syndrome remains to be determined. 13 An interesting and clinically challenging subgroup of patients with dysautonomia exhibits chronic autonomic failure with not only orthostatic hypotension but also with supine hypertension. This combination may be seen in patients with multiple system atrophy or pure autonomic failure or in patients with Parkinson s disease and orthostatic hypotension. 14 Although the exact underlying pathophysiology is unknown, speculation is that it may be due to a combination of baroreflex desensitization and residual serum catecholamines interacting with hypersensitive peripheral adrenergic receptors. 14 Goldstein et al 15 found lower baroreflexcardiovagal gain in patients with autonomic failure and supine hypertension and lower plasma norepinephrine levels. Whereas patients with pure autonomic failure have peripheral sympathetic denervation, those with multiple system atrophy have central sympathetic denervation; but both groups of patients very commonly have the combination of supine hypertension and orthostatic hypotension, presumably as a result of baroreflex failure from differing etiologies. 15 CLASSIFICATION Dysautonomias can be classified into general categories based on their basic pathology (Table 1). Autonomic neuropathy may occur as a very limited condition, such as idiopathic hypo- or hyperhidrosis, limited impaired gastrointestinal motility, as part of a more generalized neuropathy such as with diabetic autonomic neuropathy, 12,16 or autonomic neuropathy in the setting of amyloidosis 12 or associated with Sjögren s syndrome, 17 or sicca complex. 12,16,18 In addition, there are hereditary autonomic and sensory neuropathies. 12,16 Autoimmune Table 1 Classification of Dysautonomias by Symptomatology AAN POTS MSA PD þ OH CIA PAF Orthostatic hypotension þþ þþ þþ þþ Orthostatic tachycardia þþþ Secretomotor symptoms þþþ þ / þ þ/ þþ Pupillary abnormalities þþ þ / Gastrointestinal symptoms þþþ þ þ þ þ / Genitourinary symptoms þþ þ / þþ þþ þ/ Sleep disorder þþþ þ CNS involvement þ/ þþþ þþþ PNS involvement þ þ/ Sudomotor abnormality þþ þ þþ þ þþþ þþ AAN, autoimmune autonomic neuropathy; POTS, postural orthostatic tachycardia syndrome; MSA, multiple system atrophy; PD þ OH, Parkinson s disease with orthostatic hypotension; CIA, chronic idiopathic anhidrosis; PAF, pure autonomic failure; CNS, central nervous system; PNS, peripheral nervous system.

198 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008 autonomic neuropathy, as recently highlighted, typically has an acute or subacute (less than 3 months) onset and may be limited or generalized. 2,3,12 Paraneoplastic autonomic neuropathy associated with occult malignancy may also occur, although rarely. 12,16 Lambert-Eaton myasthenic syndrome is associated with autonomic dysfunction as well, presumably on the basis of a paraneoplastic syndrome or neurological autoimmunity secondary to calcium channel antibodies. 1,4,19 Chronic autonomic disorders leading to generalized autonomic failure may be due to central neurodegenerative conditions, such as Parkinson s disease with orthostatic hypotension or multiple system atrophy. These conditions are progressive in their course, with a relatively shorter prognosis for patients with multiple system atrophy. Studies evaluating sympathetic innervation to the heart with radioisotope neuroimaging techniques demonstrate preserved innervation in patients with multiple system atrophy in contrast to Parkinson s disease, where there is absence of sympathetic innervation to the heart. 7,20,21 So, although these two neurological conditions may share some clinical features, including autonomic failure, the underlying pathogenesis may be different, with preganglionic lesions in the case of multiple system atrophy and lesions in postganglionic sympathetic nerve fibers in Parkinson s disease with autonomic failure. 7,20,22 Pure autonomic failure, in contrast, is a very slowly progressive dysautonomia without symptoms or signs of central nervous system involvement. In this condition, sympathetic innervation to the heart is reduced 20 22 and patients have low supine or resting plasma norepinephrine concentrations. 20,22,23 Of these three causes for generalized autonomic failure, pure autonomic failure has, overall, the best prognosis. 9,23 Mabuchi et al 23 recently compared retrospectively a small group of patients with pure autonomic failure and compared them to patients with multiple system atrophy. They found that patients with pure autonomic failure presented initially with orthostatic intolerance or sudomotor abnormalities followed by constipation and syncope, with urinary complaints occurring much later in their course, and respiratory involvement not being affected. In contrast, patients with multiple system atrophy had early urinary tract dysfunction, followed by sudomotor abnormalities and orthostatic hypotension, with respiratory problems occurring late in the clinical course. Postural orthostatic tachycardia syndrome leads to orthostatic intolerance and may be due to peripheral or central pathological mechanisms, as noted previously. In general, it is a condition that predominantly affects female patients between the ages of 15 and 50 years of age, and in most patients it is a self-limited or monophasic illness. 10 12 It may manifest with more generalized autonomic dysfunction, including orthostatic hypotension, in younger patients. 10 It may occur after a prodromal illness, surgery, or trauma, lending to speculation that some forms of this syndrome may have an autoimmune basis. A retrospective review of 152 patients evaluated over 10 years at the Mayo Clinic found that 15% of 42 patients of the group tested had positive ganglionic acetylcholine receptor antibodies. 11 Neurocardiogenic or reflex syncope may occur in patients with postural orthostatic tachycardia syndrome or in patients without other symptoms or signs of autonomic dysfunction. Reflex syncope and carotid sinus hypersensitivity are more common causes of syncope and are generally self-limited conditions. 9,24 DIAGNOSTIC APPROACH Patients with symptoms suggestive of autonomic dysfunction require a thorough evaluation, starting with a history and physical examination, including neurological examination. In all patients, performance of bedside orthostatic blood pressure and heart rate monitoring is important. Supine parameters should be obtained after the patient has rested quietly for a few minutes, followed by standing upright, if possible, with obtaining and recording blood pressure immediately upon standing, then repeating the process for the next 2 to 3 minutes with a pulse rate obtained at the end of the standing period. It is best to use a manual blood pressure cuff to obtain these measurements, as it is more accurate than most automated devices. In addition, bedside assessment of heart rate response to deep breathing can be easily judged by having the patient breathe in and out at a rate of six breaths per minute (5 seconds for inspiration, 5 seconds for expiration) while palpating the patient s pulse rate. Part of the physical examination should include notation of dry oral mucous membranes, dry skin, skin temperature, vasomotor changes (i.e., acrocyanosis or livedo reticularis), and peripheral edema of the extremities. Further autonomic testing is valuable in obtaining objective and reproducible assessment of autonomic impairment. 25 This testing may include heart rate response to deep breathing and peripheral skin potentials, which can be performed on many standard electromyography (EMG) machines. However, peripheral skin potential responses are sometimes difficult to elicit and are the end result of a centrally stimulated autonomic response to startle. Standardized autonomic testing of cardiovascular reflex pathways (beat-to-beat monitoring of heart rate response to deep breathing and Valsalva maneuver, and to head-up tilt table testing), in addition to direct iontophoretic stimulation of postganglionic sympathetic nerve fibers to measure sudomotor function, is also available and accomplished with minimal discomfort to the patient in an autonomic laboratory with testing expertise. A minimum of 5 minutes of head-up tilt table testing is able to capture abnormalities in the

EVALUATION AND MANAGEMENT OF AUTONOMIC NERVOUS SYSTEM DISORDERS/KLEIN 199 majority of patients with orthostatic hypotension, 26 although some investigators propose that an additional population of patients with delayed orthostatic hypotension may be missed on standard tilt table testing unless the duration of the tilt is extended beyond 10 minutes. 27 Autonomic function testing is particularly useful in patients with suspected subclinical autonomic involvement, as in patients with diabetes who present with complaints of orthostatic intolerance but who may have more generalized autonomic failure with testing. Likewise, in patients with postural orthostatic tachycardia syndrome, autonomic function testing may not only confirm the diagnosis on head-up tilt table testing, but also provide evidence of a hyperadrenergic state and a limited autonomic neuropathy with sudomotor testing. Additional testing may also be directed in areas of clinically symptomatic autonomic dysfunction, including urodynamic studies for bladder complaints and gastrointestinal motility studies for patients. Additional screening laboratory tests should include complete blood count for anemia, serum protein electrophoresis with immunofixation and free light chain analysis for patients with peripheral neuropathy and possible primary systemic amyloidosis, testing for Sjögren s antibodies, and testing for ganglionic acetylcholine receptor antibodies in patients with possible autoimmune autonomic neuropathy. Obtaining supine and standing plasma catecholamine levels is not critical for diagnosis but may be helpful in distinguishing patients with multiple system atrophy versus pure autonomic failure, as the former has normal levels of norepinephrine, whereas in pure autonomic failure the patient s plasma norepinephrine levels are reduced. 20 A baseline electrocardiogram (ECG) and possibly additional cardiac evaluation, such as Holter monitoring or echocardiogram, may be indicated in patients with orthostatic intolerance or syncope. Testing for sicca complex symptoms (Schirmer s testing for xerophthalmia, minor salivary gland lip biopsy for xerostomia) may be indicated in patients with suspected Sjögren s syndrome, particularly if the serological testing for anti-ssa and anti-ssb antibodies is negative. A 24-hour urine sodium excretion test is useful in patients with orthostatic intolerance to determine if their daily salt and fluid intake is adequate to maintain euvolemia. The target sodium excretion is 170 mmol/l per 24 hours, with a target urine output volume between 2000 and 2500 ml per 24 hours. 12 For patients with suspected supine hypertension in addition to orthostatic hypotension, a 24-hour ambulatory blood pressure monitor may be useful to document this abnormality, as its presence may alter management decisions. TREATMENT One of the most important aspects of treatment of patients with dysautonomia is careful education of patients and their family members or caregivers about the nature of their condition and the approach to treatment. Symptoms of dysautonomia, especially blood pressure and heart rate, tend to fluctuate and are impacted by a variety of other influences. Therefore, patients and their families need to be aware of interventions that should be done routinely to help stabilize the patient, and those which may be adjusted depending on the circumstances. 9 For example, patients with orthostatic intolerance, from either tachycardia or hypotension, should always maintain adequate salt and fluid intake daily, elevate the head of their bed 4 to 6 inches, and avoid situations that may precipitate or worsen their symptoms. 16,28 On the other hand, dosing of medications to treat these conditions in some cases may work optimally by day-to-day adjustments, with higher dosages being given on certain days or certain times of the day, depending on the medication and the patient s diagnosis. Other medications need to be taken regularly as prescribed for optimal benefit. With appropriate education and understanding of these issues on the part of the patient and their caregivers, the quality of life in patients with dysautonomia can be substantially improved, in most cases. Nonpharmacological Treatment A variety of approaches can be instituted for patients with dysautonomia, particularly those with orthostatic intolerance (Table 2). Encouraging patients to maintain adequate daily salt and fluid intake is critical, 10,16,29 and can be easily monitored by checking 24-hour urinary sodium excretion. In patients who are maintaining adequate salt and fluid intake, the 24-hour urinary sodium excretion should be greater than 150 and ideally greater than 170 mmol or meq per 24 hours, 12 with a total 24-hour urinary output volume Table 2 Nonpharmacological Management of Dysautonomias Orthostatic intolerance Adequate daily salt and fluid intake Head of bed elevated 4 6 inches Lower body resistance isometric training exercises Compression stockings or abdominal binder Eat smaller, more frequent meals Plan daily activities to occur later in the day Arise to standing upright slowly Secretomotor symptoms Artificial tears Over-the-counter oral mucous membrane moisturizers Punctal plugging or cauterization Sudomotor symptoms External cooling devices Avoidance of warm/hot environments if heat intolerance Use of antiperspirants (Drysol) for excessive sweating

200 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008 of between 2000 and 2500 ml. This requires patients to consume between 5 and 10 g of salt per day and to drinkbetween2and3loffluidperday.patients should be encouraged to read food packaging labels and to use drinking containers of known volumes to estimate what amounts of salt and fluid they are consuming daily. The 24-hour urinary sodium measurement should ideally be done when the patient s salt and fluid intake are at steady state in terms of their day-to-day consumption pattern, and can be easily checked during times when the patient s symptoms may be worsening and it needs to be determined if the patient is maintaining the target consumption levels. Patients should limit caffeine-containing beverages because of their diuretic effect and try to use various commercially available fitness waters or beverages containing sodium to reach their daily goal. Recent studies have shown that simply drinking 300 to 500 ml of water has an acute effect on blood pressure, even beyond simple volume expansion. 16,30 32 Mechanical elevation of the head of the patient s bed is important to diminish natriuresis, which occurs particularly in patients with orthostatic hypotension overnight, leading to increased urinary output and worsening the drop in blood pressure when the patient gets up the following morning. 9,12,14,33 This should be done with cinder blocks under the head of the bed frame to maintain a constant elevation of at least 4 inches above the horizontal when the patient is lying in bed. Use of compression stockings is also important in patients with orthostatic intolerance. 9,10,12,14,16,33,34 These stockings are available in a variety of forms, and it has generally been found that stockings that extend from toes to mid-thigh provide the best benefit, although some patients find putting on such stockings daily cumbersome, and this reduces compliance. Patients should be strongly encouraged to wear these stockings as much as possible, especially on days when they are more symptomatic, as that is when they will add the most benefit. A moderate degree of compression, between 30 and 40 mm Hg, for the stockings is ideal, 10 although again any degree of compression is better than the patient not wearing anything. In elderly patients with arthritis or other medical issues that may reduce grip strength and their ability to pull on compression stockings, a milder degree of compression, 15 to 20 mm Hg, can be considered. Abdominal binders to reduce blood pooling in the splanchnic vascular beds can also be used successfully in selected patients. 12,14,33 An exercise program for patients, including aerobic and isometric exercises, is important for maximizing lower body muscle tone, which improves venous return in the upright posture. 9,10,33 Depending on the patient, simple exercises such as repetitively standing on tiptoes to contract calf muscles or performing repetitive deep knee bends. These movements can be translated into physical counter-maneuvers the patient can use when he or she experiences presyncopal symptoms and cannot immediately sit down to try and abort an impending syncope. 33 In other patients, a more formal exercise program using an exercise bench can be done with even better results. In some cases, institution of an exercise program can be implemented under the guidance of a physical therapist. Pharmacological Treatment Pharmacological treatment for dysautonomia has been primarily focused on treatment of patients with orthostatic intolerance (Table 3). Medication should only be prescribed to treat patients who are symptomatic (or for patients whose standing systolic blood pressure is 80 mm Hg or lower who may not be symptomatic but who are at increased risk of syncope) and who have adequately Table 3 Pharmacological Treatment of Dysautonomias Orthostatic intolerance orthostatic hypotension Pyridostigmine, 15 60 mg TID or SR 180 mg daily Midodrine 2.5 15 mg TID Fludrocortisone 0.1 0.2 mg daily or every other day DDAVP (Desmopressin) 0.2 0.4 mg daily at bedtime Erythropoietin 2000 10,000 units subcutaneously, weekly, titrated for hematocrit of 50% Orthostatic intolerance orthostatic tachycardia Pyridostigmine, 15 60 mg TID or SR 180 mg daily b blocker (metoprolol, nadolol, propranolol) Midodrine 2.5 15 mg TID Fludrocortisone 0.1 0.2 mg daily or every other day Selective serotonin reuptake inhibitors (SSRIs) Erythropoietin 2000 10,000 units subcutaneously, weekly, titrated to hematocrit of 50% Phenobarbital 15 60 mg qhs Autoimmune autonomic neuropathy Plasmapheresis Intravenous immunoglobulin, repeated courses if necessary Oral prednisone or other immunosuppressants for chronic recurrence Sudomotor abnormalities Hypo/anhidrosis o Intravenous methylprednisolone or oral prednisone if skin biopsy demonstrates inflammatory response associated with sweat glands Hyperhidrosis o Botulinum toxin A subcutaneous injections, if localized to palmar or axillary regions o Oral anticholinergic agents, including amitriptyline 10 50 mg at bedtime, glycopyrrolate 1 2 mg TID orally or 0.5 4% compounded cream TID, scopolamine patch; hyoscyamine 0.125 0.25 mg every 4 hours; belladonna tincture TID, three times a day; SR, sustained release; qhs, at bedtime.

EVALUATION AND MANAGEMENT OF AUTONOMIC NERVOUS SYSTEM DISORDERS/KLEIN 201 implemented nonpharmacological measures. For patients with orthostatic hypotension, there are two U.S. Food and Drug Administration (FDA)-approved medications available: fludrocortisone, a synthetic mineralocorticoid, and midodrine, which is an a-adrenergic receptor agonist. 9,14,33,35 Fludrocortisone works to increase salt and thereby water retention, thus increasing plasma volume. It is dosed once or twice daily and, due to its long half-life, may also be dosed on alternate days. Common side effects include hypokalemia, peripheral edema, and increasing intraocular pressure; therefore, it should be used with caution in patients with congestive heart failure or glaucoma. 33 It may also worsen supine hypertension in patients with a combination of supine hypertension and orthostatic hypotension as part of their dysautonomia. Fludrocortisone is not a first-line agent and should be reserved for patients who are unable to maintain adequate daily salt and fluid intake on their own, or for patients with refractory orthostatic hypotension on maximal therapy. 12 The therapeutic dosing range is narrow, with effective doses being between 0.1 and 0.2 mg daily. 12 Midodrine is a peripherally acting a-adrenergic receptor agonist that has a short duration of action, only 4 hours, and is beneficial in patients who can be educated on how the medication affects their blood pressure and when to use it properly to manage their symptoms. Midodrine can be useful in patients with either orthostatic hypotension or tachycardia. It is typically used at much lower doses in patients with postural orthostatic tachycardia, as it has some action on veins and can reduce venous pooling in the lower extremities in these patients, thereby improving their orthostatic symptoms. Side effects of the medication are due to its mechanism of action and include scalp paresthesias and goose bumps due to piloerection at the skin surface, supine hypertension, and urinary retention. 33,35 Patients should be advised not to take the medication within 4 hours of lying supine, as it may lead to supine hypertension. Typically this medication is given in higher doses in the morning, when patients with orthostatic hypotension commonly have more severe symptoms, with lower doses in the afternoon, when orthostatic hypotension is usually less severe, and no doses given within 4 hours of the patient s bedtime. 12,33 Generally, patients may have some control of their doses so that on days when they are more symptomatic and their orthostatic blood pressure drop is more severe, they may take a higher dose of the medication. For patients with severe orthostatic hypotension, taking a dose 30 to 45 minutes before they attempt to get out of bed in the morning can be very helpful, although they must be sure to get up by that time frame or risk worsening supine hypertension once the medication takes effect. 33 Typically, doses of this medication range from 2.5 to 15 mg up to three times a day, with the average dose being 5 to 10 mg three times a day. For the initial dose of the medication, because of the risk of denervation hypersensitivity of the peripheral adrenoreceptors, the patient should take a dose of 2.5 mg while being medically supervised with the patient s blood pressure recorded 2 hours after taking the dose. Pyridostigmine is a medication that has not been FDA-approved for treatment of orthostatic intolerance, but has recently been found to be useful in patients not only with orthostatic hypotension but also patients with orthostatic tachycardia. 36 38 Pyridostigmine (Mestinon) is an acetylcholinesterase inhibitor that is thought to benefit patients with orthostatic hypotension by increasing acetylcholine neurotransmission at peripheral autonomic ganglia, thereby increasing peripheral vasoconstriction via sympathetic nerve fiber transmission. Patients with orthostatic tachycardia benefit from the drug s effect of increasing vagal cardiac input. 36 39 Not only is the medication well-tolerated by most patients, 39 but it also does not worsen supine hypertension. 36 38 Its duration of action is 4 hours, similar to midodrine, so that patients can take up to three doses during the day to help to alleviate symptoms occurring when they are upright. The most common side effects are increased salivation, sweating, and increased gastrointestinal motility, 37,39 all of which are usually beneficial in patients with dysautonomia. 39,40 Rarely patients may experience muscle fasciculations, which are benign and are due to increased neuromuscular junction transmission. The usual dose of the medication is 60 mg up to three times a day, although I usually start patients at a lower dose, such as 15 mg three times a day, titrating to the target dose as needed. Additional medications that have been used in patients with orthostatic hypotension include desmopressin, or DDAVP, which can be administered at night to reduce nocturnal diuresis and, subsequently, orthostatic hypotension in selected patients by its antidiuretic hormonal effect. 28,33,41 However, serum sodium levels and osmolarity must be closely monitored when using this therapy. 33 Erythropoietin subcutaneous injections, given weekly, have also been used successfully and are thought to improve orthostatic intolerance not only by increasing blood volume by increasing red blood cell counts, but also by a direct vasoactive effect on peripheral vasculature. 9,10,16,28,42 For patients with orthostatic hypotension and supine hypertension, striking a balance between these two states is particularly challenging to the clinician and does require vigilance on the part of the patients and their caregivers. Obviously, during the day if the patient has an elevated blood pressure while seated or reclining, then sitting or standing up will bring the blood pressure down again. However, if the blood pressure drops too much and/or the patient becomes symptomatic, then use of medications to increase the patient s blood pressure is required. In contrast, at night, the patient is in a reclined

202 SEMINARS IN NEUROLOGY/VOLUME 28, NUMBER 2 2008 position (head of bed elevated 4 inches) but may have unacceptably high blood pressure even in this position. These patients should record their blood pressure in the resting position in bed before they go to sleep or in the morning before they get out of bed; if their blood pressure is consistently or frequently greater than 180/100 mm Hg, then an antihypertensive medication, ideally one with a short duration of action, might be taken at bedtime so that their orthostatic hypotension is not worsened the following morning. The reason to treat supine hypertension is to reduce adverse long-term effects on the brain and heart caused by 6 to 8 hours of hypertension daily. Commonly used medications include oral hydralazine (10 to 50 mg), clonidine (0.1 mg), and nifedipine (10 to 30 mg) given at bedtime if needed, depending on the patient s blood pressure. 43,44 Nitroglycerin paste (1/2 to 1 inch) may also be used for some patients. 14,43,44 None of these medications are ideal, 43,44 and it is very important to counsel patients that if they use an antihypertensive agent at night, they cannot get up out of bed to urinate due to the increased risk of worsened orthostatic hypotension secondary to the effects of the antihypertensive medication. A urinal at the bedside for male patients and a bedside commode or a bedpan for female patients are the alternatives. For treatment of orthostatic tachycardia, use of b-blocker medications in low dosages to avoid an excessive drop in blood pressure and worsening exercise intolerance is generally effective, 10,11 particularly for patients with a more hyperadrenergic state. Many different b blockers can be used with success, but metoprolol is recommended as it can be administered in either a shortor immediate-acting form or a long-acting form, and both tablet formulations can be divided. Start with a low dosage, such as 12.5 mg once or twice a day, and titrate as tolerated to a target dose of 50 mg of the long-acting formulation once or twice a day. Patients should be monitored closely for orthostatic changes in blood pressure, particularly if their orthostatic intolerance symptoms actually worsen. Caution should be used in patients with a history of asthma. If the patient has a history of severe asthma requiring hospitalization, this type of medication is relatively contraindicated. Low doses of midodrine may also be helpful in selected patients, 10,11 with administration of the medication usually being most effective earlier in the day. Additional choices include low doses of selective serotonin reuptake inhibitors (SSRIs), 9 fludrocortisone 10 and phenobarbital. 11 Pyridostigmine has been recently shown to be of benefit in this population of patients, not only to reduce the patient s orthostatic tachycardia, but also to improve symptoms. 10,36,45 For patients with autoimmune autonomic neuropathy, who commonly have orthostatic hypotension as part of their symptomatology, use of the above therapies is of benefit for symptomatic treatment. In addition, there have been case reports of improvement in patients with immunomodulatory therapy, including plasmapheresis, 46 infusion of intravenous immunoglobulin (IVIg), 47 51 and use of oral immunosuppressive medications for long-term therapy. 49 Interestingly, this approach to therapy has been shown to be of benefit not only in the acute setting, but also in patients who have had symptoms for months or even years. 46,49 Asimilar approach may also be considered in patients with autonomic neuropathy associated with Sjögren s syndrome, as presumably the neuropathic features of this condition are on an autoimmune basis and may respond to immunomodulatory therapy. Clearly, additional research into the benefit of this type of therapy in this population of patients with dysautonomia is needed to determine the best approach and to determine for which patients immunomodulatory therapy may be most successful. Other symptoms of dysautonomia that are amenable to treatment include sudomotor and secretomotor abnormalities. Patients with hypohidrosis should be strongly cautioned about the risks of heat intolerance and the need to avoid hot environmental temperatures. Patients with acute idiopathic anhidrosis or hypohidrosis, which may be a form of limited autonomic neuropathy, should have a skin biopsy performed within the affected region to be examined pathologically for lymphocytic infiltration around sweat glands and their ducts. If positive, then consideration should be given to possible short-term treatment with oral prednisone or intravenous methylprednisolone, based on case reports that this may be effective. 52 Hyperhidrosis, if localized, may respond to treatment with subcutaneous injections of botulinum toxin to denervate sweat glands. 16 Patients with more generalized hyperhidrosis may benefit from oral medications that have a strong anticholinergic side effect, such as amitriptyline or glycopyrrolate. Topical treatments for excessive sweating include aluminum chloride (the active ingredient in antiperspirants) and topical compounded cream formulations of glycopyrrolate. Treatment for secretomotor abnormalities includes punctal plugging for xerophthalmia and use of artificial tears and cyclosporine eye drops locally, and administration of fish oil supplements systemically. Chronic, severe dry eye has a risk of development of corneal abnormalities and should be treated aggressively. 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