Syncope Resulting from Autonomic Insufficiency Syndromes Associated with Orthostatic Intolerance

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SYNCOPE RESULTING FROM AUTONOMIC INSUFFICIENCY SYNDROMES ASSOCIATED WITH ORTHOSTATIC INTOLERANCE Blair P. Grubb, MD, FACC, and Daniel J. Kosinski, MD, FACC

Only if one knows the causes of syncope will he be able to recognize its onset and combat the cause. Maimonides (1135-1204 c.e.)

Throughout the ages, sudden unpredictable loss of consciousness has plagued patients and frustrated and fascinated physicians. Hippocrates is credited with having made the first description of syncope; the medical term for fainting is derived from the Greek term syncoptein (to cut short). Recurrent syncope may be a sign or a symptom and may occur as a result of a wide variety of different causes. In the 1990s, a substantial amount of research was devoted to syncope resulting from sudden periods of centrally mediated hypotension, a phenomenon initially referred to as vusovugul syncope. Extensive investigations into the nature of this disorder soon uncovered that it represents only one aspect of a broad, heterogeneous group of disturbances of the autonomic nervous system that can result in hypotension, orthostatic intolerance, and often syncope. This flood of new information has caused investigators to reassess the classification of autonomic disorders and to develop the current level of understanding. The new system of classification attempts to be practical and useful clinically (however, any such attempt at classifying natural phenomena has its limitations). This article provides Supported, in part, by a grant from the Sheller Globe Foundation.

From the Division of Cardiology, Department of Medicine, The Medical College of Ohio, Toledo, Ohio

MEDICAL CLINICS OF NORTH AMERICA VOLUME 85 NUMBER 2 * MARCH 2001

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a brief overview of these disorders, their pathophysiology, and management.

BASIC CONCEPTS IN AUTONOMIC FUNCTION One of the most significant moments in the long process of human evolution was the adoption of upright posture. Although greatly enhancing mobility, the upright stance placed a unique burden on a blood pressure control system that previously had been developed to meet the needs of an animal in the dorsal position. Modern humans display an enhanced susceptibility to the effects of gravity on the circulatory system. The human brain is located in a somewhat precarious position in regards to vascular perfusion and oxygenation. The autonomic nervous system is the principal source of the immediate and long-term responses to sudden positional change.2 In the normal adult, roughly 25% to 30% of the body’s blood volume is in the thorax while supine. On assumption of upright posture, there is an immediate gravity-induced downward displacement of 300 to 800 mL of blood to the abdomen and the dependent e~tremities.~~ Almost 50% of this fall occurs within seconds of standing, and 25% of the entire circulating blood volume may be involved in the process. This pronounced redistribution in blood volume produces a fall in venous return to the heart. Because the heart cannot pump out more than flows in, the cardiac stroke volume may drop by 40% owing to a decline in filling pressure. After upright posture has been achieved, orthostatic stabilization usually takes place in less than 1 minute, during which a slow decrease in arterial pressure and cardiac filling occurs. This decrease produces activation of the high-pressure receptors located in the carotid sinus and the aortic arch, in addition to the low-pressure receptors located in the heart and lungs. The reduction in venous return also causes less stretch on the mechanoreceptors of the heart, which are joined by unmyelinated vagal afferents in the atria and ventricles. These fibers have been shown to exert a tonic inhibitory action on the cardiovascular centers located in the medulla oblongata (in particular to the area referred to as the nucleus tructus soliturius). Consequently, cardiac discharge rates decline, and the alteration in impulse frequency to the brain stem results in an augmentation of sympathetic outflow producing systemic vasoconstriction. Concomitantly the reduction in arterial pressure while upright activates the high-pressure receptors located in the carotid sinus, provoking a rise in heart rate. These initial steady-state compensations to upright posture produce a 10- to 15-beat/min increase in heart rate, approximately less than 10 mm Hg increase in diastolic blood pressure, and relatively little or no change in systolic blood pressure. As standing continues, various neurohumoral responses are activated to a degree that seems dependent on the person’s volume Generally the lower the volume, the greater the degree of the renin-

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angiotensin-aldosterone activation. If any of the aforementioned processes are unable to function in an adequate (or coordinated) manner, the normal responses that allow for the assumption and maintenance of upright posture fail. This failure is manifested by postural hypotension, which, if sufficiently pronounced, can lead to cerebral hypoperfusion, hypoxia, and ultimately loss of consciousness. DISORDERS OF ORTHOSTATIC REGULATION

Many different disturbances in orthostatic regulation have been identified. Although these disorders share many characteristics, each is in its own way unique. Any system used to classify natural phenomena is by its nature arbitrary and open to debate and periodic revision. A simplified version of the system worked out by the American Autonomic Society is presented in Figure 1.22 Disorders of orthostatic regulation also may be subgrouped into primary and secondary forms. The primary disorders tend to be idiopathic in nature and are divided further into acute and chronic varieties. The secondary forms occur in association with a particular disease process or are known to arise from a known structural or biochemical abnormality. REFLEX SYNCOPE

Most physicians have encountered reflex syncope more frequently than the other types. The first descriptions of reflex syncope have been attributed to Gower and Lewis, who used the term vasovagal syncope (currently the terms neurocardiogenic syncope and vasovugal syncope are refer red).^ Although patients of any age can be affected, the form of syncope most commonly occurs in young people. Although the exact processes involved in causing syncope are not known, a basic understanding of the process has emerged.I9A sudden amount of peripheral venous pooling brought on by prolonged upright posture is surmised to lead to an abrupt decline in venous return to the heart. This sudden fall in ventricular volume is thought to result in a much more forceful level of ventricular contraction, which, in turn, causes activation of many mechanoreceptors that normally respond only to mechanical stretch. The resultant surge in afferent neural traffic to the brain stem is thought to mimic the conditions that normally would be seen during hypertension, provoking an apparently paradoxic sympathetic withdrawal that results in hypotension and bradycardia. More detailed descriptions of this process can be found el~ewhere.~,'~ Other types of stimuli, such as strong emotion or epileptic discharges, may elicit identical responses. This fact suggests that these individuals display an inherent increase in sensitivity to such stimuli, and these episodes are believed to represent a hypersensitive autonomic system that overresponds to various stressors. During the passive orthostatic stress of head-upright tilt-table testing, such indi-

Secondary

Figure 1. Autonomic insufficiency syndromes associated with orthostatic intolerance.

Primary

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viduals exhibit an abrupt profound fall in blood pressure that often is followed by a fall in heart rate (occasionally to the point of asystole). Sutton and Petersen30 reported that the sequence of physiologic responses seen during neurocardiogenic syncope and carotid sinus hypersensitivity are nearly identical and may be different aspects of the same disorder. In such a predisposed individual, rapid mechanoreceptor activation from any site (blood vessels, bladder, rectum, or chest) could provoke similar responses.18 PRIMARY AUTONOMIC FAILURE SYNDROMES

In contrast to the intermittent periods of hypotension seen in reflex syncope (in which patients are fairly asymptomatic between episodes), a second group of patients develop orthostatic intolerance resulting from a failure of the autonomic nervous system to function under normal circumstances. Assuming upright posture, the patient with autonomic failure is not able to make or maintain the gravity-mediated decline in venous return. This failure to adapt may be caused by a disturbance in the afferent or efferent (or both) limbs of the baroreflex or from diminished end-organ responsiveness to vasoconstrictive signals. When this failure is severe, classic orthostatic hypotension results. Many patients with autonomic nervous system failure develop a somewhat slower progressive decline in blood pressure (once referred to as delayed orthostatic hypotension). The longer these patients are upright, the more blood pools in the mesentery and lower extremities, and failure to compensate produces a progressive decline in blood pressure, leading ultimately to cerebral hypoperfusion and loss of consciousness. When this pattern is observed during tilt-table testing, it is referred to as a dysautonornic response. In contrast to patients suffering from reflex syncope, patients suffering from autonomic failure syndromes have many other complaints relating to autonomic disturbances in other organ systems. Chronic Autonomic lnsufficiency

A wide variety of disorders may produce varying degrees of autonomic insufficiency, a partial listing of which can be found in Table 1. Because chronic forms of autonomic insufficiency are more common than acute forms, these are addressed first. The chronic idiopathic form of this disorder initially was described by Bradbury and Eggleston5 in 1925. They called this entity idiopathic orthostatic hypotension because of its apparent lack of association with other gross neurologic features. This term does not represent accurately, however, the fact that there usually is a general state of autonomic failure present with disruptions in bladder, sudomotor, gastrointestinal, and sexual function that occur together with orthostatic hypotension. The American Autonomic Society refers to the disorder as pure autonomic failure (PAF).26Although the exact cause of

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Table 1. AUTONOMIC DISORDERS ASSOCIATED WITH ORTHOSTATIC INTOLERANCE Primary Autonomic Disorders Acute pandysautonomia Pure autonomic failure Multiple system atrophy Parkinsonian Pyramidal/cerebellar Mixed Reflex syncopes Neurocardiogenic syncope Carotid sinus hypersensitivity Secondary Autonomic Failure Central origin Cerebral cancer Multiple sclerosis Age related Syringobulbia Peripheral forms Afferent Guillain-Bar& syndrome Tabes dorsalis Holmes-Adie syndrome Efferent Diabetes mellitus Nerve growth factor deficiency Dopamine P-hydroxylase deficiency Afferent/ efferent Familial dysautonomia Spinal origin Transverse myelitis Syringomyelia Spinal tumors Other causes Renal failure Paraneoplastic syndromes Autoimmune/collagen vascular disease Human immunodeficiency virus infection Amvloidosis

PAF remains enigmatic, some researchers have postulated that there is a degeneration of the peripheral postganglionic autonomic neurons. Although the condition is observed most frequently in older adults, it can affect patients of all ages, including children. A second form of chronic autonomic failure was described in 1960 by Shy and Drager.28In comparison with PAF, this condition is a much more severe and devastating disorder. Not only is profound orthostatic hypotension present, but also there is progressive rectal and urinary incontinence, loss of sweating, external ocular palsy, iris atrophy, rigidity, tremors, and impotence. Distal muscle wasting and muscle fasciculations may occur late in the disease. To identify this complex multisystem degenerative disorder more accurately, the American Autonomic Society

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has named this entity multiple system atrophy (MSA).26Investigations have led to the division of MSA into three major clinical subtypes. The first subgroup consists of patients who display parkinsonian features (also called the striatonigral degeneration form). The second subgroup consists of patients with cerebellar or pyramidal features (referred to as the cerebellar or olivopontocerebellar atrophy/degenerative form). A third subgroup displays a combination of features from both forms. It sometimes is difficult to distinguish the parkinsonian form of MSA from classic idiopathic Parkinson’s disease. Reports have found that 7% to 22% of patients thought to have Parkinson’s disease during life were found at autopsy to have neuropathologic features consistent with MSA.17 Although the average age of onset of MSA is in the 50s to 70s, there are rare patients in whom the disease may appear in the late 30s.

Postural Orthostatic Tachycardia Syndrome

A milder form of autonomic insufficiency occurs that is referred to as the postural orthostatic tachycardia syndrome (POTS)?7The major feature of this disorder is a persistent sinus tachycardia while in the upright position (that may achieve rates of 2-160 beats/min). Patients experience palpitations, severe fatigue, exercise intolerance, near-syncope, tremor, and lightheadedness or dizziness. Many patients complain that they always feel cold, while they are unable to tolerate extreme heat. At headupright tilt-table testing, these patients show a sudden increase in heart rate of greater than 30 beats/min in the first 5 to 10 minutes or achieve a maximum heart rate of 120 beats/min or greater associated with only modest reductions in blood pressure. At present, two major forms of POTS have been identified. The most common is called the partial dysautonomic form. With this form, there appears to be a failure of the peripheral vasculature to vasoconstrict appropriately during orthostatic stress, which is compensated for by an excessive increase in heart rate. A second form appears to be due to baroreflex failure that does not provide an adequate breaking of the initial increase in heart rate that occurs during upright posture. Patients with this form, referred to as the central beta-hypersensitivity form, show an excessive increase in supine heart rate in response to a low-dose isoproterenol infusion. Some investigators postulate that POTS represents the earliest type of autonomic dysfunction, and 10% of these patients may progress later to pure autonomic failure. It is important to distinguish these patients from patients suffering from inappropriate sinus tachycardia because radiofrequency modification of the sinus node may worsen POTS patients, leaving them with profound orthostatic hypotension. One group reported finding a gene defect that predisposes patients to POTS, producing defective norepinephrine transport.ll There appears to be some overlap between POTS and chronic fatigue syndr~me.~

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Acute Autonomic Dysfunction

Although acute autonomic dysfunction syndromes are uncommon, acute autonomic neuropathy resulting in orthostatic hypotension is frighteningly dramatic in presentation.8 Patients present with a sudden, severe, and diffuse failure of the sympathetic and parasympathetic nervous systems, sparing the somatic nerve fibers. Frequently, these patients tend to be young and before their illness were quite healthy. The onset of the illness can be rapid, and patients often can relate the exact day symptoms began. Most of these patients relate having suffered a febrile illness (presumed to be viral) that preceded the onset of symptoms, suggesting a possible autoimmune aspect of the disorder. Disruption of sympathetic nervous system function is so severe that orthostatic hypotension of such a degree occurs that patients are unable to sit upright without losing consciousness. Patients usually lose the ability to sweat. Parasympathetic disruption produces a dry mouth and eyes as well as disturbances in bowel and bladder function. Patients frequently experience abdominal pain and bloating, in addition to nausea, vomiting, and severe constipation (that may occasionally alternate with diarrhea). One interesting feature of this disorder is that many patients have a relatively fixed heart rate of approximately 50 beats/min associated with chronotropic incompetence. Another striking feature is a tendency for the pupils to be dilated and to respond poorly to light. The prognosis of these patients varies markedly; some have complete recoveries, whereas others have a chronic debilitating course. Many patients are left with residual defects. AUTONOMIC FAILURE SECONDARY TO OTHER DISORDERS

A wide variety of disorders may produce varying degrees of disruption in autonomic function (see Table 1). It is important to determine whether an autonomic disorder is primary in nature or part of another illness. Several rare enzymatic disorders have been identified that can produce disruptions in autonomic function. Examples are isolated phydroxylase deficiency as well as nerve growth factor deficiency (that results in p-hydroxylase deficiency), dopa decarboxylase deficiency, and reductions in certain sensory neuropeptides. Diffuse systemic illnesses, such as renal failure, cancer, and acquired immunodeficiency syndrome (AIDS), may cause hypotension and syncope. Studies have shown a link between orthostatic hypotension and Alzheimer’s d i ~ e a s e . ~ One of the most important things to remember is the vast number of pharmacologic agents that may cause or worsen orthostatic hypotension (see the accompanying box). Chief among these are the peripherally acting vasodilatory agents, such as the angiotensin-converting enzyme inhibitors prazosin, hydralazine, and guanethidine. p-Blocking agents may worsen syncope in some patients. The authors have observed an

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increased frequency of dysautonomic syncope in patients suffering from congestive heart failure. In this group, the combination of a low cardiac output and volume depletion secondary to diuretics and vasodilator therapy interferes with the body’s mechanisms for adapting to upright posture. Centrally acting agents, such as the tricyclic antidepressants, reserpine, and methyldopa, also may exacerbate otherwise mild hypotension.

Pharmacologic Agents That May Cause or Worsen Orthostatic Intolerance

Angiotensin-convertingenzyme inhibitors a-Receptor blockers Calcium channel blockers p-Blockers Phenothiazines Tricyclic antidepressants Bromocriptine Ethanol Opiates Diuretics Hydralazine Ganglionic blocking agents Nitrates Sildenafil citrate Monoamine oxidase inhibitors

Clinical Features

The principal feature that all of the disorders causing autonomic failure share is that normal cardiovascular regulation is disturbed resulting in postural hypotension. Although orthostatic hypotension has been defined as a greater than 20 mm Hg fall in systolic blood pressure over a 3-minute period after standing upright, a smaller drop in blood pressure associated with symptoms can be just as important. A large percentage of these patients display a slow, steady fall in blood pressure over a longer time frame (around 10 to 15 minutes) that can be quite symptomatic. Whether the patient experiences symptoms depends as much on the rate of fall in pressure as on the absolute degree of change. The loss of consciousness in the dysautonomic patient tends to be slow and gradual, usually occurring when the patient is walking or standing. Many older patients do not seem to perceive this decline in pressure, however, and report little or no prodrome before syncope and describe these episodes as drop attacks. Patients who do experience prodromes describe a wide variety of symptoms, such as dizziness, blurring of

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vision, seeing stars, and tunnel vision. A distinguishing feature between neurocardiogenic and dysautonomic syncope is that in the latter, bradycardia and diaphoresis are uncommon during an episode. Dysautonomic syncope tends to be more common in the early morning hours. Any factor that enhances peripheral venous pooling, such as extreme heat, fatigue, or alcohol ingestion, exacerbates hypotension. As time goes on, some patients may develop a relatively fixed heart rate that shows little response to postural change or exercise. Some patients develop a syndrome of supine hypertension that alternates with upright hypotension, presumably secondary to a failure to vasodilate when prone. Patients suffering from this combination of supine hypertension and upright hypotension can be difficult to treat. Sometimes distinguishing between these disorders can be difficult because there may be a considerable degree of overlap between them (a situation similar to that seen with the various forms of chronic obstructive lung disease) (Fig. 2). Evaluation of Patients

The cornerstone of evaluation is a detailed history and physical examination. When do syncopal or near-syncopal episodes occur, and when did they begin? How often do these episodes occur? Is there a pattern to the events or any known precipitating factors? What are episodes like to the patient, and how do they appear to bystanders? What other organ systems are involved? Other than syncope, what symptom bothers the patient most? A careful and concise history and

Figure 2. Considerable degree of overlap between the various autonomic disorders associated with orthostatic intolerance.

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physical examination (which must include a concise neurologic examination) has a greater diagnostic yield than the mindless ordering of multiple tests. Laboratory examinations should be obtained in a careful and directed manner, based on history and physical examination findings, to confirm one’s clinical impressions. It is beyond the scope of this article to review every autonomic disorder and the various tests used in evaluation. The interested reader is directed to several excellent texts on the subject.l,14, 20, 24, 26 Any drugs that the patient is taking that could produce hypotension should be identified (see previous box), including prescription drugs, over-thecounter medications, and herbal remedies. When a young person presents with symptoms of autonomic dysfunction, the potential use of illicit drugs or alcohol should be considered. In women, symptoms may vary with the menstrual cycle, or an otherwise mild tendency toward autonomic dysfunction may be exacerbated by the onset of menopause. Because the autonomic areas of the brain are not accessible to direct measurement, one must measure the responses of various organ systems to various physiologic or pharmacologic challenges. Advances have allowed for the determination of serum urine and cerebrospinal fluid levels of some autonomic neuromodulators and neurotransmitters. Foremost, however, is the determination of the blood pressure and heart rate response to positional change, with measurements taken while supine, sitting, and standing. The exact change in pressure considered to be significant is undetermined but usually is considered to be 20 to 30 mm Hg systolic and 10 to 15 mm Hg diastolic. When the patient is standing, pressure determination should be performed with the arm extended horizontally (to avoid the possible hydrostatic effects of the fluid column of the arm). Because the body’s responses to active standing differ from those of passive tilting, the authors also frequently perform tilt-table testing on these patients, the details of which are given el~ewhere.~ The response pattern seen during tilt can be helpful in determining the type of autonomic disorder (Fig. 3). Many other autonomic tests are available and are useful in selected patients.’, 14, 20, 24 Therapeutic Options

A complete discussion of the treatment options available is beyond the scope of this article; however, some basic principles are outlined briefly (Table 2).7 One of the physician’s most important tasks is to identify whether hypotensive syncope is primary or secondary in nature and to determine if there are any potentially reversible causes (i.e., drugs, anemia, volume depletion). It is important to educate the patient and family as to the nature of the problem. Teaching the patient to avoid aggravating factors (such as extreme heat, dehydration, and alcohol consumption) as well as recognize any prodromal symptoms and assuming a recumbent position at their onset are extremely helpful measures. Nonpharmacologic therapies include sleeping with the head of the

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.c

I

Figure 3. The response pattern during tilt can help determine the type of autonomic disorder. A, Neurocardiogenic. B, Dysautonomic response. C,Postural orthostatic tachycardia. Solid line = blood pressure, dotted line = heart rate.

bed upright (about 6 to 12 inches) and elastic support hose (at least 30 to 40 mm Hg ankle counterpressure). Biofeedback has proved useful in selected patients. Aerobic reconditioning is an important part of therapy; in many patients, this is best done using water activities. In some patients with these disorders, building lower extremity muscle strength is useful, and spending progressively longer periods of time upright (tilt training) can be helpful. Pharmacotherapy should be used cautiously and should be tailored to fit the needs of the patient based on the type of autonomic disorder being treated as well as coexisting symptoms and conditions. Virtually

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Table 2. TREATMENT OPTIONS Therapy

Method or Dose

Head-up tilt of bed Elastic support hose

45" head-up tilt of bed (often need footboard) Require at least 30-40 mm Hg ankle counterpressure; work best if waist high Diet Fluid intake of 2-2.5 L/d; sodium intake of 150-250 mEq/d Exercise Aerobic exercise (mild) may aid venous return. Water exercise particularly helpful Fludrocortisone Begin at 0.1-0.2 mg/d; may work up to doses not exceeding 0.4 mg/d Methylphenidate 5-10 mg orally 3 times/d given with meals, give last dose before 6 P.M. Midodrine 2.5-10 mg every 2-4 h; may use 40 mg/d Clonidine 0.14.3 mg orally 2 times/d or patches placed l / w k Yohimbine 8 mg orally 2-3 times/d Ephedrine 12.5-25 mg orally 3 times/d sulfate Fluoxetine 10-20 mg orally daily (requires 4-6 wk of therapy) Erythropoietin 4000 IU subcutaneously twice a week Pindolol 2.5-5.0 mg orally 2-3 times/d Desmopressin

An analogue of vasopressin used

Common Problems

Hypotension, sliding off bed, leg cramps Uncomfortable, hot, difficult to get on Supine hypertension, peripheral edema May lower blood pressure if done too vigorously Hypokalemia, hypomagnesemia, peripheral edema, weight gain, congestive heart failure Agitation, tremor, insomnia, supine hypertension Nausea, supine hypertension Dry mouth, bradycardia, hypotension Diarrhea, anxiety, nervousness Tachycardia, tremor, supine hypertension Nausea, anorexia, diarrhea Requires injections, burning at site, increase hematocrit, CVA Hypotension, congestive heart failure, bradycardia Hyponatremia

as a nasal spray CVA

=

Cerebrovascular accident.

any drug used in treatment occasionally can worsen symptoms (a

prosyncopal effect). In neurocardiogenic syncope, many reports have found that pblocker therapy is effective, presumably because its negative inotropic effects lessen the degree of cardiac mechanoreceptor activation associated with abrupt falls in venous return. The increase in peripheral vascular resistance that accompanies unopposed P-blockade may contribute to its therapeutic effects. p-Blockade has not been found to be as useful in other forms of reflex syncope, and this therapy may be detrimental in the dysautonomic syndromes. A useful agent in patients with dysautonomic syncope (and in younger patients with neurocardiogenic syncope) is the mineralocorticoid agent, fludrocortisone. It results not only in fluid and sodium retention, but also appears to raise pressure through an indirect vasoconstrictive effect resulting from sensitization

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of peripheral alpha receptors, serum potassium and magnesium levels that need to be monitored periodically. Because failure to vasoconstrict the peripheral vessels properly is common to all of these disorders, vasoconstrictive substances can be employed. Initially the authors employed the amphetamine-like agent methylphenidate with excellent results.', Because methylphenidate is a controlled substance with potent central nervous system stimulating activity, however, the authors have limited their use of the drug. An excellent alternative is the new a-stimulating agent, midodrine. It has almost no central nervous system effects or cardiac stimulation, while providing identical degrees of peripheral a-receptor stimulation. Several studies have shown midodrine's efficacy in neurocardiogenic and dysau29 tonomic It has been found that the a,-receptor blocking agent clonidine can elevate blood pressure in dysautonomic patients in whom hypotension is secondary to a severe postganglionic sympathetic lesion.25In patients with severe autonomic failure, the postjunctional vascular au,-receptors (which are plentiful in the venous system) are hypersensitive. In normal individuals, clonidine acts on the central nervous system to lessen sympathetic output and with it blood pressure; in autonomic failure, some patients exhibit little or no sympathetic output, permitting its peripheral actions to become manifest. Many patients with autonomic failure are anemic. A study by Hoeldtke and Streeton16showed that subcutaneous injections of erythropoietin produce dramatic increases in blood pressure while raising blood count. This pressure effect seems to occur independent of the red cell effect.13 A series of animal and human studies have shown that the neurotransmitter serotonin (5-hydroxytryptamine) plays an essential role in the central regulation of blood pressure and heart rate. It has been postulated that some patients with autonomic disorders may have disturbances in central serotonin production or regulation.l0 In support of this concept has been the observation that the serotonin reuptake inhibitors can be effective in the treatment of neurocardiogenic syncope and orthostatic hypotension.6,l5 The exact role of pacemaker therapy in the treatment of these disorders is controversial and beyond the scope of this discussion. Many investigators found that in selected patients pacemaker therapy can be effective in reducing symptoms and may eliminate syncope alt~gether.~ In dysautonomic disorders (as opposed to reflex syncope), hypotensive syncope is one aspect of a broader constellation of symptoms relating to autonomic failure. The physician should not give the patient unrealistic expectations regarding what symptoms can and cannot be eliminated. The physician and patient should remain cognizant that these disorders can be progressive in nature and that therapies may have to be altered over time.

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SUMMARY

The disorders of autonomic control associated with orthostatic intolerance are a diverse group that can result in syncope and near-syncope. A basic understanding of these disorders is essential to diagnosis and proper treatment. Ongoing studies should help to define better the spectrum of these disorders and to elaborate better diagnostic and treatment modalities.

References 1. Bannister R, Mathias C (eds): Autonomic Failure: A Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford, Oxford Medical Publications, 1992 2. Benarroch E: The central autonomic network Functional organization, dysfunction and perspective. Mayo Clinic Proc 68:98€&1001,1993 3. Benditt D, Petersen ME, Luriek K, et al: Cardiac pacing for prevention of recurrent vasovagal syncope. Ann Intern Med 1223204-209,1995 4. Bou-Holaigh I, Rowe P, Kan J, et al: The relationship between neurally mediated hypotension and chronic fatigue syndrome. JAMA 274:961-967,1995 5. Bradbury S, Eggleston C: Postural hypotension: A report of three cases. American Heart Journal 1:73-86, 1925 6. DiGirolamo E, DiIorio C, Sabatani P, et al: Effects of paroxetine hydrochloride, a

7.

8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21.

selective serotonin reuptake inhibitor, on refractory vasovagal syncope: A double blind, randomized, placebo controlled study. J Am Coll Cardiol33:1227-1230,1999 Grubb BP: Neurocardiogenic syncope. In Grubb BP, Olshansky B (eds): Syncope: Mechanisms and Management. Armonk, NY, Futura Publishing, 1998, 73-106 Grubb BP, Kosinski D: Acute pandysautonomic syncope. Eur J card Pacing Electrophysiol 710-14, 1997 Grubb BP, Kosinski D: Tilt table testing: Concepts and limitations. Pacing Clin Electrophysiol 20(pt II):781-787, 1997 Grubb BP, Kosinski D Serotonin and syncope: An emerging connection? Eur J Card Pacing Electrophysiol5:306-314, 1996 Grubb BP, Kosinski D, Boehm K, et al: The postural orthostatic tachycardia syndrome: A neurocardiogenic variant identified during head up tilt table testing. Pacing Clin Electrophysiol (in press) Grubb BP, Kosinski D, Mouhaffel A, et al: The use of methylphenidate in the treatment of refractory neurocardiogenic syncope. Pacing Clin Electrophysiol 19:836-840, 1996 Grubb BP, Lachant N, Kosinski D: Erythropoietin as a therapy for severe refractory orthostatic hypotension. Clin Auton Res 4:212, 1994 Grubb BP, Olshansky B (eds): Syncope: Mechanisms and Management. Armonk, NY, Futura Publishing, 1997 Grubb BP, Samoil D, Kosinski D, et al: Fluoxetine hydrochloride for the treatment of severe refractory orthostatic hypotension. Pacing Clin Electrophysiol 16:801-805, 1993 Hoeldtke RD, Streeton DH: Treatment of orthostatic hypotension with erythropoietin. N Engl J Med 329:611415, 1993 Hughes AJ, Daniel DE, Kilford L, et al: Accuracy of clinical diagnosis of idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 55:181-184, 1992 Kosinski D: Miscellaneous causes of syncope. In Grubb BP, Olshansky B (eds): Syncope: Mechanisms and Management. Armonk, NY, Futura Publishing, 1998,297-304 Kosinski D, Grubb BP, Temesy-Armos P: Pathophysiological aspects of neurocardiogenic syncope. Pacing Clin Electrophysiol 18:71&721, 1995 Low P (ed): Clinical Autonomic Disorders. Boston, Little, Brown, 1993 Low P, Gilden J, Freeman R, et al: Efficacy of midodrine vs placebo in neurocardiogenic orthostatic hypotension. JAMA 2771046-1051, 1997

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22. Mathias CJ: The classification and nomenclature of autonomic disorders: Ending chaos, restoring conflict, and hopefully achieving clarity. Clin Auton Res 5:307-310, 1995 23. Passant V, Warkentin S, Karlson, et al: Orthostatic hypotension in organic dementia: Relationship between blood pressure, cortical blood flow, and symptoms. Clin Auton Res 6:29-36, 1996 24. Robertson D, Biaggioni I (eds): Disorders of the Autonomic Nervous System. London, Harwood Academic Publishers, 1995 25. Robertson D, Davis TL: Recent advances in the treatment of orthostatic hypotension. Neurology 5526-532, 1995 26. Robertson D, Polinsky R (eds): A Primer on the Autonomic Nervous System. San Diego, Academic Press, 1996 27. Shannon J, Flattem N, Jordan J, et al: Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 3523541-549,2000 28. Shy GM, Drager GA: A neurologic syndrome associated with orthostatic hypotension. Arch Neurol3511-527,1960 29. Sra J, Maglio C, Biehl M, et al: Efficacy of midodrine hydrochloride in neurocardiogenic syncope refractory to standard therapy. J Cardiovasc Electrophysiol 8:4246, 1997 30. Sutton R, Petersen M: The clinical spectrum of neurocardiogenic syncope. J Cardiovasc Electrophysiol 6:569-576, 1995 31. Wieling W, Lieshout J: Maintenance of postural normotension in humans. In Low P (ed): Clinical Autonomic Disorders. Boston, Little, Brown, 1993, pp 69-73

Address reprint requests to Blair P. Grubb, MD Cardiology, Room 1192 The Medical College of Ohio 3000 Arlington Avenue Toledo, OH 43614