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Pathophysiology and differential diagnosis of neurocardiogenic syncope1
Pathophysiology and Differential Diagnosis of Neurocardiogenic Syncope Blair P. Grubb, Syncope, the transient loss of consciousness and postural tone, is both a sign and a syndrome and may result from very diverse causes. Over the last decade, considerable attention has been focused on neurocardiogenic syncope, also known as vasovagal syncope. Research has demonstrated that the disorder is one aspect of a much broader group of disturbances of the autonomic nervous system that may lead to hypotension, orthostatic intolerance, and ultimately syncope. Recent dis-
“Only if one knows the causes of syncope will he be able to recognize its onset and combat the cause.” —Maimonides (b. 1135– d. 1204)
yncope, defined as the transient loss of consciousness and postural tone, is one of the oldest of S recorded medical problems. Hippocrates is said to have recorded the first description of syncope, and it is from the Greek that we derive this medical term for fainting. Both a sign and a syndrome, syncope may result from very diverse causes. Over the last decade, considerable attention has been focused on one particular cause of syncope—the phenomenon previously called vasovagal syncope. Research into the nature of this disorder has demonstrated that it is only one aspect of a much broader group of disturbances of the autonomic nervous system (ANS) that may lead to hypotension, orthostatic intolerance, and ultimately, syncope. Recent discoveries have caused us to reevaluate our classification of autonomic disorders and to develop a new system that better reflects current knowledge. It is the cardiologist and the clinical cardiac electrophysiologist who are frequently called on to recognize and treat syncope and related disorders. This article reviews these conditions, their pathophysiology, diagnosis, and management.
PHYSIOLOGY OF UPRIGHT POSTURE Although representative of one of the defining aspects of the evolution of Homo sapiens, the adoption of upright posture presented a novel challenge to a blood pressure control system that developed to meet From the Division of Cardiology, Department of Medicine, Medical College of Ohio, Toledo, Ohio. This article may contain discussion of off-label or investigational uses (not yet approved by the FDA) of various therapeutic agents. Please refer to the box provided on page 2Q of this supplement for a disclosure of such agents. Address for reprints: Blair P. Grubb, MD, Medical College of Ohio, Richard D. Ruppert Health Center, Room 0012, 3120 Glendale Avenue, Toledo, Ohio 43614-5809. ©1999 by Excerpta Medica, Inc. All rights reserved.
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coveries have caused us to reevaluate our classification of autonomic disorders and to develop a new system that reflects current knowledge. A basic understanding of syncope and related disorders is essential to diagnosis and proper treatment. This article provides an overview of these conditions, their pathophysiology, and diagnosis. 䊚1999 by Excerpta Medica, Inc. Am J Cardiol 1999;84:3Q–9Q
the requirements of an animal in the dorsal position. Normally, around 25% of the circulating blood volume is in the thorax. Immediately after the assumption of upright posture, gravity produces a downward displacement of roughly 500 mL of blood to the abdomen and lower extremities. Approximately 50% of this amount is redistributed within seconds after standing, and almost one quarter of total blood volume may be involved in the process. The process causes a decrease in venous return to the heart and cardiac filling pressures, and stroke volume may decrease by 40%. After standing, normal subjects achieve orthostatic stabilization in ⱕ1 minute, and a slow decrease in arterial pressure and cardiac filling occurs. This causes activation of the high-pressure receptors of the carotid sinus and aortic arch, as well as the low-pressure receptors of the heart and lungs. The decrease in venous return produces less stretch on mechanoreceptors in the heart, which are linked by unmyelinated vagal afferents in the atria and ventricles.1– 4 These fibers have been found to cause continuous inhibitory actions on the cardiovascular areas of the medulla (the nucleus solitarius).1 As a result, discharge rates decrease and the change in input to the brain stem causes an increase in sympathetic outflow resulting in systemic vasoconstriction. At the same time, the decrease in arterial pressure while upright actuates the highpressure receptors in the carotid sinus, thereby stimulating an increase in heart rate. These early steadystate adaptations to upright posture result in a 10 –15 beats/min increase in heart rate, a 10 mm Hg increase in diastolic pressure, and little or no change in systolic blood pressure. When a person stands, neurohumoral responses are also activated, the amount of which is dependent on the subject’s volume status. As a rule, the lower the volume, the higher the degree of renin–angiotensin–aldosterone system involvement.2 The inability of any of these processes to function adequately or in a coordinated manner can result in a failure of the normal responses to sudden shifts in posture (or their maintenance). Subsequent hypotension may lead to cerebral hypoperfusion, hypoxia, and loss of consciousness. 0002-9149/99/$20.00 PII S0002-9149(99)00691-8
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FIGURE 1. A basic depiction of the disorders of autonomic control associated with orthostatic intolerance. (Reproduced with permission from PACE Pacing Clin Electrophysiol.51)
DISORDERS OF ORTHOSTATIC CONTROL Various disorders of orthostatic control have been identified; although sharing certain characteristics, they are each in many ways unique. In 1996, the American Autonomic Society developed a system to classify these disorders5—a somewhat simplified outline of which is provided in Figure 1. Disorders of orthostatic control are often divided into primary and secondary forms. The primary forms tend to be idiopathic and are further divided into acute and chronic forms. The secondary forms are usually associated with a particular disease or are known to arise secondarily to a known biochemical abnormality. Reflex syncopes: Physicians tend to encounter this group of syncopal syndromes more frequently than other forms. First described by Gower and Sir Thomas Lewis6 as vasovagal syncope, the condition is better known as neurocardiogenic or neurally mediated syncope. Although the exact processes involved in the production remain the subject of considerable debate, some aspects of the mechanisms involved have been identified. Most investigators have felt that a sudden excessive amount of venous pooling during upright posture results in an abrupt decrease in venous return to the heart.3 It appears that this sudden reduction in ventricular volume results in a much more forceful degree of ventricular contraction, which in turn activates a large number of mechanoreceptors that would normally respond only to mechanical stretch. The subsequent surge in afferent neural traffic to the brain stem is thought to mimic the conditions seen in hypertension, thereby eliciting a “paradoxic” withdrawal in sympathetic tone resulting in hypotension and bradycardia.4 Questions have been raised over the validity of this hypothesis. In animal preparations, surgical denervation of the heart did not prevent abrupt sympathetic withdrawal after sudden blood volume reduction.7 Additionally, several investigators have reported that 4Q THE AMERICAN JOURNAL OF CARDIOLOGY姞
neurocardiogenic syncope can occur in patients who have undergone orthotopic heart transplantation.8 Vasodilators have also been reported to provoke syncope in heart transplant patients9; however, some degree of vagal afferent reinnervation of donor hearts has also been reported to occur.8 The activation of ventricular mechanoreceptors is not the only mechanism shown to provoke neurocardiogenic syncope. In a cat model, it has been shown that direct electrical stimulation of the anterior cingulate gyrus of the limbic system can produce a vasovagal response.10 In humans, it has long been observed that syncope can be provoked by strong emotions or by stimuli such as injury or the sight of blood. Phenomena such as temporal lobe epilepsy may also produce vasovagal episodes.11 These findings suggest that the higher neural centers may play a role in the production of neurocardiogenic syncope.3 The term vasovagal was initially used to describe this type of faint because parasympathetic influences were thought to be predominant. Although relative parasympathetic activity is somewhat enhanced during syncope (producing the observed bradycardia), the primary mechanism resulting in loss of consciousness is vasodilation leading to hypotension. Several investigators have observed that although the administration of atropine (or cardiac pacing) can eliminate the bradycardia, it rarely prevents syncope.12 ¨ berg and Thore´n13 provided the first in-depth O analysis of the neurophysiologic mechanisms occurring in neurocardiogenic syncope. Using an openchest cat preparation subjected to sudden hypovolemia, they observed that a significant initial tachycardia was an important component of ventricular mechanoreceptor activation. Later, investigators used microelectrodes placed in peroneal nerve fascicles to record peripheral ANS activity during neurocardiogenic syncope.14 They found that sympathetic activity initially increases and is followed by a pronounced decrease at the onset of syncope. Sra et al15 have reported that
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during the initial phases of head upright tilt, plasma epinephrine and norepinephrine levels increase, whereas at the onset of syncope, plasma norepinephrine levels decrease and epinephrine levels increase. These findings support the concept that an initial decrease in blood volume occurring as a consequence of peripheral venous pooling causes a reflex increase in sympathetic output producing a tachycardia and peripheral vasoconstriction in an attempt to maintain normal hemodynamics. However, this increase in sympathetic output may sensitize and facilitate the activation of the cardiac mechanoreceptors that reportedly play a large role in the production of neurocardiogenic syncope.4 The sudden increase in neural traffic that occurs with very vigorous ventricular contraction (or by C-fiber activation from myocardial ischemia and reperfusion) produces an abrupt, centrally mediated reduction in sympathetic activity, with peripheral sympathetic inhibition and vasodilation. Recently, it has been suggested that some aspect of diminished ␣-receptor responsiveness or increased -receptor sensitivity may be involved in the process.16,17 Although the central mechanisms that contribute to the production of neurocardiogenic syncope are unclear, studies have focused principally on the role of 2 substances: endogenous opiates and serotonin (5-hydroxytryptamine or 5-HT). Using rat models, a body of evidence has been generated suggesting that the vasodepressor response to acute hemorrhage may be mediated by endogenous opiates.17 In rabbit models, renal sympathetic nerve activity is inhibited if opiate receptor antagonists are given at the time of acute hypotensive hemorrhage.18 Additionally, it has been observed that intracisternal administration of nalaxone, an antagonist of opiate receptors, can diminish the vasodilatory response observed during acute blood loss in rabbits.19 Two human studies have demonstrated notable increases in plasma -endorphin levels before tilt-induced syncope.20,21 However, opiate antagonists did not prevent lower body negative pressure–induced syncope.22 Serotonin is a neurotransmitter implicated in the pathophysiologic processes leading to neurocardiogenic syncope.23 A biologic amine that is widely distributed throughout the central nervous system (CNS), serotonin plays an important role in blood pressure regulation.24 If serotonin is directly applied to the brain via the lateral ventricles, it produces a reduction in efferent sympathetic activity, whereas direct application to the nucleus solitarius produces parasympathetic stimulation, sympathetic withdrawal, and bradycardia. Administration of intracerebroventricular serotonin causes hypotension, inhibition of renal sympathetic nerve activity, and stimulation of adrenal sympathetic nerve activity.25 Serotonin is also important in the modulation of acute responses to acute hemorrhage.23 Several studies have demonstrated that the serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, and paroxetine) can be an effective preventive therapy for neurocardiogenic syncope.26 –28 These agents selectively prevent the reuptake of serotonin at the synaptic
cleft: the serotonin levels increase, 5-HT release is diminished, and impulse transmission velocity increases, which results in a decrease in postsynaptic receptor density. This down-regulation appears to blunt the responses to rapid shifts in central serotonin levels and thereby reduces the ability for such surges to result in abrupt sympathetic withdrawal. A recent double-blind, randomized, placebo-controlled study demonstrated that paroxetine significantly improved symptoms in patients who had recurrent neurocardiogenic syncope (p ⬍0.0001).28 Sutton and Petersen29 have observed that responses seen during neurocardiogenic syncope and carotid sinus hypersensitivity are very similar and may be different aspects of the same disorder. In a predisposed individual, rapid mechanoreceptor activation from any site or cause (e.g., blood, bladder, cough) could elicit similar responses.30 Primary disorders in autonomic failure: In contrast to the intermittent episodes of orthostatic intolerance caused by reflex syncopes in which the ANS appears to function normally despite the intermittent and apparently “hypersensitive” reflex responses, another type of orthostatic intolerance occurs when the ANS appears to be failing. When upright, patients with autonomic failure are unable to compensate for the decrease in venous return. This failure to compensate results from a failure in the afferent and/or efferent limbs of the baroreflex, or from reduced end-organ responsiveness to vasoconstrictors. When this failure becomes severe, frank orthostatic hypotension occurs. However, even in the absence of frank orthostatic hypotension, patients with a failing ANS may demonstrate a progressive type of orthostatic hypotension: As blood pools in the lower extremities with prolonged periods of upright posture, blood pressure continues to decrease. This has been described as a dysautonomic response to upright posture. In contrast to patients with reflex syncopes who tend to have few symptoms referable to the ANS in between syncopal episodes, patients with autonomic failure often have other symptoms of autonomic dysfunction in between episodes of syncope. Chronic autonomic dysfunction: Various disorders may cause varying degrees of autonomic disturbance, some of which are listed in Table I.31 The physician is more likely to encounter the chronic forms of autonomic failure than their acute counterparts. The first report of chronic autonomic failure was the groundbreaking study by Bradbury and Eggleston32 in 1925, in which they labeled the condition “idiopathic orthostatic hypotension” because of an apparent lack of other neurologic features. Since then, however, it has been observed that these patients exhibit a generalized state of autonomic dysfunction that is manifested by orthostatic hypotension and syncope as well as disturbances in bowel, bladder, thermoregulatory, sudomotor, and sexual function.33,34 The American Autonomic Society has named this disorder pure autonomic failure (PAF).5,35 Although its cause remains unknown, several investigators have postulated that there is a degeneration of the peripheral postgangli-
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TABLE I Autonomic Disorders Associated with Orthostatic Intolerance I.
Primary autonomic disorders A. Acute pandysautonomia B. Reflex syncopes 1. Neurocardiogenic syncope 2. Carotid sinus hypersensitivity C. Pure autonomic failure D. Multiple system atrophy 1. Parkinsonian 2. Cerebellar/pyramidal 3. Mixed D. Postural orthostatic tachycardia syndrome II. Secondary autonomic failure A. Central origin 1. Cerebral cancer 2. Multiple sclerosis 3. Age-related 4. Syringobulbia B. Peripheral forms 1. Afferent a. Guillain-Barre´ syndrome b. Tabes dorsalis c. Holmes-Adie syndrome 2. Efferent a. Diabetes mellitus b. Nerve growth factor deficiency c. Dopamine -hydroxylase deficiency 3. Afferent/efferent a. Familial dysautonomia 4. Spinal origin a. Transverse myelitis b. Syringomyelia c. Spinal tumors 5. Other causes a. Renal failure b. Paraneoplastic syndromes c. Autoimmune/collagen vascular disease d. Human immunodeficiency virus infection e. Amyloidosis Adapted with permission from Neurology.31
onic autonomic neurons.36 The condition is more common in older adults, but it can occur in almost any age group, including children. Another type of autonomic failure was reported in 1960 in a landmark study by Shy and Drager.37 The degenerative disorder known as multiple system atrophy is manifested by severe orthostatic hypotension, progressive urinary and rectal incontinence, loss of sweating, iris atrophy, external ocular palsy, impotence, rigidity, and tremors. Muscle fasciculations and distal muscle wasting may occur late in the disorder. The American Autonomic Society has divided multiple system atrophy into 3 major subtypes.38 The first group of patients demonstrates tremor that is similar to Parkinson’s disease (sometimes called striatonigral degeneration). A second group displays mainly cerebellar and/or pyramidal symptoms (the olivopontocerebellar atrophy/degeneration form). A third group displays aspects of both types. An autopsy study found that 7–22% of patients thought to have Parkinson’s disease actually had neuropathologic findings diagnostic for multiple system atrophy.39 Whereas most multiple system atrophy patients do not present until 6Q THE AMERICAN JOURNAL OF CARDIOLOGY姞
somewhere between the fifth and seventh decade of life, some begin to have symptoms in their late 30s. Recently, attention has been focused on a milder form of chronic autonomic failure that is referred to as postural orthostatic tachycardia syndrome (POTS).40 The hallmark of POTS is a persistent tachycardia while upright, sometimes reaching rates of ⱖ160 beats/min, associated with severe fatigue, near-syncope, exercise intolerance, and lightheadedness or dizziness. Many patients complain of always being cold yet unable to tolerate extreme heat. During head upright tilt, these patients display a sudden increase in heart rate ⬎30 beats/min within the first 5 minutes or achieve a maximum heart rate of 120 beats/min associated with only mildly reduced blood pressure. The mechanism underlying this condition appears to be a failure of the peripheral vasculature to appropriately vasoconstrict under orthostatic stress, which is compensated for by an excessive increase in heart rate. Streeten et al41 have suggested that POTS represents the earliest sign of autonomic dysfunction, and some patients have later progressed to PAF. It is important to recognize this disorder—patients with POTS have been misdiagnosed as having an inappropriate sinus tachycardia and have undergone radio frequency modification of the sinoatrial node, resulting in profound orthostatic hypotension. Patients with POTS may also be misdiagnosed as having chronic fatigue syndrome; recent reports indicate that a great deal of overlap exists between these disorders.42 Acute autonomic dysfunction: Although rare, the acute autonomic neuropathies that produce hypotension and syncope are frequently dramatic in presentation.43 The disorders are acute in most patients and demonstrate severe and widespread failure of the sympathetic and parasympathetic systems while leaving the somatic fibers unaffected. Many of these patients tend to be young and very healthy before the illness. The development of the illness is surprisingly rapid, and patients can frequently identify the exact day their symptoms began. Interestingly, many of these individuals report having had a febrile illness, presumed to be viral, before the onset of symptoms, which suggests an autoimmune component to the disorder. Function of the sympathetic nervous system is often so severely disrupted, and orthostatic hypotension so extreme, that patients cannot even sit upright in bed without fainting. Patients often lose their ability to sweat, have bowel and bladder dysfunction, and frequently complain of bloating, nausea, vomiting, and abdominal pain. Constipation is common and sometimes will alternate with diarrhea. Interestingly, the heart rate is often fixed at 40 –50 beats/min, associated with complete chronotropic incompetence. The pupils are often dilated and poorly reactive to light. Patients may experience several syncopal episodes daily. The long-term prognosis of these patients is variable—some have complete recoveries, whereas others have a chronic debilitating course. Patients are often left with significant residual defects.
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TABLE II Pharmacologic Agents that May Cause or Worsen Orthostatic Intolerance ● ● ● ● ● ● ● ● ● ● ● ● ●
␣-Receptor blockers ACE inhibitors -Blockers Bromocriptine Calcium channel blockers Diuretics Ethanol Ganglionic blocking agents Hydralazine Nitrates Opiates Phenothiazine Tricyclic antidepressants Adapted from Syncope: Mechanisms and Management.3
Secondary disorders in autonomic failure: Autonomic dysfunction can be part of a larger disorder; in occasional patients, several conditions coexist that produce synergistic detrimental effects on autonomic function. Over the last decade, several enzymatic abnormalities have been identified that can result in autonomic disruption. Principal among these is isolated dopamine -hydroxylase deficiency syndrome, a condition that is now easily treated by replacement therapy.44,45 Additional deficiency syndromes involving nerve growth factor, monoamine oxidase, aromatic L-amino decarboxylase, and some sensory neuropeptides may all result in autonomic failure and hypotension.46 Diffuse systemic illnesses such as renal failure, cancer, or acquired immunodeficiency syndrome may all cause hypotension and syncope. Studies have also demonstrated a link between orthostatic hypotension and Alzheimer’s disease.47 Numerous pharmacologic agents may cause or worsen orthostatic hypotension (Table II), particularly peripherally acting vasodilatory agents, such as angiotensin-converting enzyme inhibitors, prazosin, hydralazine, and guanethidine. Although effective in neurocardiogenic syncope, -blocking agents can worsen syncope in some patients. Lately, we have observed an increased frequency of dysautonomic syncope in patients with congestive heart failure. In this group, the combination of low cardiac output and volume depletion due to diuretics and vasodilator therapy interferes with the body’s mechanisms for adapting to upright posture. Centrally acting agents, such as tricyclic antidepressants, reserpine, and methyldopa, may also exacerbate otherwise mild hypotension. In dysautonomic disorders (as opposed to the reflex syncopes), hypotensive syncope is but one aspect of a broader constellation of symptoms relating to autonomic failure. The physician should, therefore, provide the patient with realistic expectations about which symptoms can and cannot be eliminated. Both physician and patient should be aware that these disorders can be progressive in nature and that therapies may have to be altered over time.
CLINICAL FEATURES In these conditions, normal cardiovascular regulation is disturbed, resulting in postural hypotension. Although orthostatic hypotension was once defined as a ⬎20 mm Hg decrease in systolic blood pressure over a 3-minute period after standing upright, a smaller decrease in blood pressure associated with symptoms can be just as important. A large percentage of patients will display a slow, steady decrease in blood pressure over a longer period of time (around 10 –15 minutes) that can be quite symptomatic. Whether patients experience symptoms depends as much on the rate of decrease in pressure as on the absolute degree of change. Loss of consciousness in dysautonomic syncope tends to be slow and gradual, and usually occurs when patients are walking or standing. However, many older patients do not seem to perceive a decrease in pressure, report little or no prodrome before syncope, and describe the episodes as “drop attacks.” Individuals who do experience prodromes describe a variety of symptoms such as dizziness, blurred vision, “seeing stars,” and tunnel vision. Unlike neurocardiogenic syncope, bradycardia and diaphoresis are uncommon in dysautonomic syncopal episodes. 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, will exacerbate hypotension. In time, some patients may develop a relatively fixed heart rate that shows little response to postural change or exercise. In addition, some patients will develop a syndrome of supine hypertension that alternates with upright hypotension, presumably due to a failure to vasodilate when prone. Patients with this combination of supine hypertension and upright hypotension can be quite difficult to treat. At times, distinguishing the disorders can be difficult because there may be a considerable degree of overlap between them (Figure 2)—not unlike the situation seen with various forms of chronic obstructive lung disease.
EVALUATION OF PATIENTS The cornerstone of evaluation is a detailed history and physical examination. Table III describes some historical features to which clinicians should pay particular attention. When do syncopal or near-syncopal episodes occur and when did they begin? How often do they 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 history and physical examination that includes a concise neurologic examination will have a greater diagnostic yield than a battery of laboratory tests. Diagnostic tests should be used sparingly, directed by the history and physical examinations, to confirm clinical impressions. Any drugs patients are taking that could produce hypotension should be identified. This includes pharmaceuticals, over-the-counter medications, herbal
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FIGURE 2. Delineation of the interrelation among autonomic disorders associated with orthostatic intolerance. Differentiating the various disorders can be difficult given the significant overlap between them. (Reproduced with permission from Pacing Clin Electrophysiol.51)
remedies, illicit drugs, and alcohol. In women, symptoms may vary with the menstrual cycle; also, an otherwise mild tendency toward autonomic dysfunction can be exacerbated by the onset of menopause. Because the autonomic areas of the brain are not accessible for direct measurement, one must measure the responses of various organ systems to different physiologic or pharmacologic challenges. Recent advances permit the determination of serum, urine, and cerebrospinal fluid levels of some autonomic neuromodulators and neurotransmitters. Foremost, however, is blood pressure and heart rate response to positional change, with measurements taken while patients are supine, sitting, and standing. The exact change in pressure considered to be significant is still under discussion, but is usually felt to be a 20 –30 mm Hg decrease in systolic pressure and a 10 –15 mm Hg
TABLE III Evaluation of Syncope: Patient History ● ● ● ● ● ● ● ● ● ● ● ●
Consider characteristics and length of episodes Define episodes as completely as possible using patient and witnessed accounts Consider the events that trigger episodes Consider specific aspects of the history (e.g., back pain, shortness of breath, angina) Assess the relationship to meals, alcohol, drugs Consider the relation to exercise, body position, posture, and emotional state Consider number, frequency, and timing of previous episodes Prodromal symptoms can help secure a diagnosis Postsyncopal symptoms (symptoms on awakening) can provide important diagnostic clues Consider concomitant disease (especially cardiac) Consider medications Consider family history of death or syncope
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FIGURE 3. Heart rate and blood pressure patterns observed in abnormal responses to head-up tilt-table testing. (Adapted from Syncope: Mechanisms and Management.3)
decrease in diastolic pressure. When patients are standing, blood pressure should be taken with the arm extended horizontally to avoid the possible hydrostatic effects of the fluid column of the arm. Tilt-table testing may also be useful in these patients because it allows the physician to assess autonomic and hemodynamic responses to upright posture over a longer period of time. In addition, passive head-up tilt provides a greater orthostatic challenge than active standing. The use of postural muscles in the abdomen and lower extremities during active standing limits venous pooling; however, these muscles are not used during passive head-up tilt, so venous pooling occurs to a greater degree.48 A number of other autonomic tests are available and are quite useful in selected patients.36,49,50 It is useful to distinguish between broad response patterns as outlined in Figure 3. The classic neurocardiogenic or vasovagal response is characterized by a sudden decrease in blood pressure, often followed by a decrease in heart rate (Figure 3A). The dysautonomic response demonstrates a gradual but progressive decrease in blood pressure to hypotensive levels
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leading to loss of consciousness (Figure 3B). The third pattern is characteristic of POTS (Figure 3C). Originally, we defined this group as exhibiting an increase in heart rate of at least 30 beats/min (or a maximum heart rate of 120 beats/min) within the first 10 minutes of passive upright tilt, which is usually not associated with profound hypotension. Recently, we realized there are probably subgroups within the POTS population and are working to better categorize these groups of patients.
SUMMARY The disorders of autonomic control associated with orthostatic intolerance are a diverse group of infirmities that can result in syncope and near-syncope. A basic understanding of the disorders is essential to diagnosis and proper treatment. Ongoing studies should better define the spectrum of these disorders and enable better diagnostic and treatment modalities.
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PACE Pacing Clin Electrophysiol 1993;16:458 – 464. 27. Grubb BP, Samoil D, Kosinski D, Kip K, Brewster P. Use of sertraline hydrochloride in the treatment of refractory neurocardiogenic syncope in children and adolescents. J Am Coll Cardiol 1994;24:490 – 494. 28. Di Girolamo E, Di Iorio C, Sabatini P, Leonzio L, Barbone C, Barsotti A. Effects of paroxetine hydrochloride, a selective serotonin reuptake inhibitor, on refractory vasovagal syncope: a randomized, double-blind, placebo-controlled study. J Am Coll Cardiol 1999;33:1227–1230. 29. Sutton R, Petersen ME. The clinical spectrum of neurocardiogenic syncope. J Cardiovasc Electrophysiol 1995;6:569 –576. 30. Kosinski D. Miscellaneous causes of syncope. In: Grubb BP, Olshansky B, eds. Syncope: Mechanisms and Management. Armonk, NY: Futura Publishing, 1998. 31. Mathias CJ. Orthostatic hypotension: causes, mechanisms, and influencing factors. Neurology 1995;45(4, suppl 5):S6 –S11. 32. Bradbury S, Eggleston C. Postural hypotension: a report of three cases. Am Heart J 1925;1:73– 86. 33. Freeman R. Pure autonomic failure. In: Robertson D, Biaggioni I, eds. Disorders of the Autonomic Nervous System. London: Harwood Academic Press, 1995:83–105. 34. Ziegler MG, Lake CR, Kopin IJ. The sympathetic-nervous-system defect in primary orthostatic hypotension. N Engl J Med 1977;296:293–297. 35. Robertson D, Polinsky R., eds. Primer on the Autonomic Nervous System. San Diego: Academic Press, 1996. 36. Freeman R. Pure autonomic failure. In: Robertson D, Biaggioni I, eds. Disorders of the Autonomic Nervous System. London: Harwood Academic Publishers, 1995:61– 82. 37. Shy GM, Drager GA. A neurologic syndrome associated with orthostatic hypotension. Arch Neurol 1960;3:511–527. 38. Mathias CJ. The classification and nomenclature of autonomic disorders— ending chaos, restoring conflict and hopefully achieving clarity. (Editorial.) Clin Auton Res 1995;5:307–310. 39. Bannister R. Multiple system atrophy and pure autonomic failure. In: Low PA, ed. Clinical Autonomic Disorders. Boston: Little Brown & Co, 1993:517–526. 40. Grubb BP, Kosinski D, Boehm K, Kip K. The postural orthostatic tachycardia syndrome: a neurocardiogenic variant identified during head up tilt table testing. PACE Pacing Clin Electrophysiol 1997;20:2205–2212. 41. Streeten DH, Anderson GH Jr, Richardson R, Thomas FD. Abnormal orthostatic changes in blood pressure and heart rate in subjects with intact sympathetic nervous function: evidence for excessive venous pooling. J Lab Clin Med 1988;111:326 –335. 42. Bou-Holaigah I, Rowe PC, Kan J, Calkins H. The relationship between neurally mediated hypotension and the chronic fatigue syndrome. JAMA 1995; 274:961–967. 43. Grubb BP, Kosinski D. Acute pandysautonomic syncope. Eur J Cardiac Pacing Electrophysiol 1997;7:10 –14. 44. Gentric A, Fouilhoux A, Caroff M, Mottier D, Jouquan J. Dopamine -hydroxylase deficiency responsible for severe dysautonomic orthostatic hypotension in an elderly patient. J Am Geriatr Soc 1993;41:550 –551. 45. Robertson D, Goldberg MR, Onrot J, Hollister AS, Wiley R, Thompson JG Jr, Robertson RM. Isolated failure of autonomic noradrenergic neurotransmission: evidence for impaired beta-hydroxylation of dopamine. N Engl J Med 1986;314:1494 –1497. 46. Robertson D, Haile V, Perry SE, Robertson RM, Phillips JA III, Biaggioni I. Dopamine beta-hydroxylase deficiency: a genetic disorder of cardiovascular regulation. Hypertension 1991;18:1– 8. 47. Passant U, Warkentin S, Karlson S, Nilsson K, Edvinsson L, Gustafson L. Orthostatic hypotension in organic dementia: relationship between blood pressure, cortical blood flow and symptoms. Clin Auton Res 1996;6:29 –36. 48. Grubb BP, Kosinski D. Tilt table testing: concepts and limitations. PACE Pacing Clin Electrophysiol 1997;20:781–787. 49. Bannister R, Mathias C, eds. Autonomic Failure: Textbook of Clinical Disorders of the Autonomic Nervous System. Oxford, UK: Oxford Medical Publications, 1992. 50. Grubb BP, Olshansky B, eds. Syncope: Mechanisms and Management. Armonk, NY: Futura Publishing, 1998. 51. Grubb BP, Karas B. Clinical disorders of the autonomic nervous system associated with orthostatic intolerance: an overview of classification, clinical evaluation, and management. PACE Pacing Clin Electrophysiol 1999;22:798 – 810.
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“Only if one knows the causes of syncope will he be able to recognize its onset and combat the cause.” —Maimonides (b. 1135– d. 1204)
yncope, defined as the transient loss of consciousness and postural tone, is one of the oldest of S recorded medical problems. Hippocrates is said to have recorded the first description of syncope, and it is from the Greek that we derive this medical term for fainting. Both a sign and a syndrome, syncope may result from very diverse causes. Over the last decade, considerable attention has been focused on one particular cause of syncope—the phenomenon previously called vasovagal syncope. Research into the nature of this disorder has demonstrated that it is only one aspect of a much broader group of disturbances of the autonomic nervous system (ANS) that may lead to hypotension, orthostatic intolerance, and ultimately, syncope. Recent discoveries have caused us to reevaluate our classification of autonomic disorders and to develop a new system that better reflects current knowledge. It is the cardiologist and the clinical cardiac electrophysiologist who are frequently called on to recognize and treat syncope and related disorders. This article reviews these conditions, their pathophysiology, diagnosis, and management.
PHYSIOLOGY OF UPRIGHT POSTURE Although representative of one of the defining aspects of the evolution of Homo sapiens, the adoption of upright posture presented a novel challenge to a blood pressure control system that developed to meet From the Division of Cardiology, Department of Medicine, Medical College of Ohio, Toledo, Ohio. This article may contain discussion of off-label or investigational uses (not yet approved by the FDA) of various therapeutic agents. Please refer to the box provided on page 2Q of this supplement for a disclosure of such agents. Address for reprints: Blair P. Grubb, MD, Medical College of Ohio, Richard D. Ruppert Health Center, Room 0012, 3120 Glendale Avenue, Toledo, Ohio 43614-5809. ©1999 by Excerpta Medica, Inc. All rights reserved.
MD
coveries have caused us to reevaluate our classification of autonomic disorders and to develop a new system that reflects current knowledge. A basic understanding of syncope and related disorders is essential to diagnosis and proper treatment. This article provides an overview of these conditions, their pathophysiology, and diagnosis. 䊚1999 by Excerpta Medica, Inc. Am J Cardiol 1999;84:3Q–9Q
the requirements of an animal in the dorsal position. Normally, around 25% of the circulating blood volume is in the thorax. Immediately after the assumption of upright posture, gravity produces a downward displacement of roughly 500 mL of blood to the abdomen and lower extremities. Approximately 50% of this amount is redistributed within seconds after standing, and almost one quarter of total blood volume may be involved in the process. The process causes a decrease in venous return to the heart and cardiac filling pressures, and stroke volume may decrease by 40%. After standing, normal subjects achieve orthostatic stabilization in ⱕ1 minute, and a slow decrease in arterial pressure and cardiac filling occurs. This causes activation of the high-pressure receptors of the carotid sinus and aortic arch, as well as the low-pressure receptors of the heart and lungs. The decrease in venous return produces less stretch on mechanoreceptors in the heart, which are linked by unmyelinated vagal afferents in the atria and ventricles.1– 4 These fibers have been found to cause continuous inhibitory actions on the cardiovascular areas of the medulla (the nucleus solitarius).1 As a result, discharge rates decrease and the change in input to the brain stem causes an increase in sympathetic outflow resulting in systemic vasoconstriction. At the same time, the decrease in arterial pressure while upright actuates the highpressure receptors in the carotid sinus, thereby stimulating an increase in heart rate. These early steadystate adaptations to upright posture result in a 10 –15 beats/min increase in heart rate, a 10 mm Hg increase in diastolic pressure, and little or no change in systolic blood pressure. When a person stands, neurohumoral responses are also activated, the amount of which is dependent on the subject’s volume status. As a rule, the lower the volume, the higher the degree of renin–angiotensin–aldosterone system involvement.2 The inability of any of these processes to function adequately or in a coordinated manner can result in a failure of the normal responses to sudden shifts in posture (or their maintenance). Subsequent hypotension may lead to cerebral hypoperfusion, hypoxia, and loss of consciousness. 0002-9149/99/$20.00 PII S0002-9149(99)00691-8
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FIGURE 1. A basic depiction of the disorders of autonomic control associated with orthostatic intolerance. (Reproduced with permission from PACE Pacing Clin Electrophysiol.51)
DISORDERS OF ORTHOSTATIC CONTROL Various disorders of orthostatic control have been identified; although sharing certain characteristics, they are each in many ways unique. In 1996, the American Autonomic Society developed a system to classify these disorders5—a somewhat simplified outline of which is provided in Figure 1. Disorders of orthostatic control are often divided into primary and secondary forms. The primary forms tend to be idiopathic and are further divided into acute and chronic forms. The secondary forms are usually associated with a particular disease or are known to arise secondarily to a known biochemical abnormality. Reflex syncopes: Physicians tend to encounter this group of syncopal syndromes more frequently than other forms. First described by Gower and Sir Thomas Lewis6 as vasovagal syncope, the condition is better known as neurocardiogenic or neurally mediated syncope. Although the exact processes involved in the production remain the subject of considerable debate, some aspects of the mechanisms involved have been identified. Most investigators have felt that a sudden excessive amount of venous pooling during upright posture results in an abrupt decrease in venous return to the heart.3 It appears that this sudden reduction in ventricular volume results in a much more forceful degree of ventricular contraction, which in turn activates a large number of mechanoreceptors that would normally respond only to mechanical stretch. The subsequent surge in afferent neural traffic to the brain stem is thought to mimic the conditions seen in hypertension, thereby eliciting a “paradoxic” withdrawal in sympathetic tone resulting in hypotension and bradycardia.4 Questions have been raised over the validity of this hypothesis. In animal preparations, surgical denervation of the heart did not prevent abrupt sympathetic withdrawal after sudden blood volume reduction.7 Additionally, several investigators have reported that 4Q THE AMERICAN JOURNAL OF CARDIOLOGY姞
neurocardiogenic syncope can occur in patients who have undergone orthotopic heart transplantation.8 Vasodilators have also been reported to provoke syncope in heart transplant patients9; however, some degree of vagal afferent reinnervation of donor hearts has also been reported to occur.8 The activation of ventricular mechanoreceptors is not the only mechanism shown to provoke neurocardiogenic syncope. In a cat model, it has been shown that direct electrical stimulation of the anterior cingulate gyrus of the limbic system can produce a vasovagal response.10 In humans, it has long been observed that syncope can be provoked by strong emotions or by stimuli such as injury or the sight of blood. Phenomena such as temporal lobe epilepsy may also produce vasovagal episodes.11 These findings suggest that the higher neural centers may play a role in the production of neurocardiogenic syncope.3 The term vasovagal was initially used to describe this type of faint because parasympathetic influences were thought to be predominant. Although relative parasympathetic activity is somewhat enhanced during syncope (producing the observed bradycardia), the primary mechanism resulting in loss of consciousness is vasodilation leading to hypotension. Several investigators have observed that although the administration of atropine (or cardiac pacing) can eliminate the bradycardia, it rarely prevents syncope.12 ¨ berg and Thore´n13 provided the first in-depth O analysis of the neurophysiologic mechanisms occurring in neurocardiogenic syncope. Using an openchest cat preparation subjected to sudden hypovolemia, they observed that a significant initial tachycardia was an important component of ventricular mechanoreceptor activation. Later, investigators used microelectrodes placed in peroneal nerve fascicles to record peripheral ANS activity during neurocardiogenic syncope.14 They found that sympathetic activity initially increases and is followed by a pronounced decrease at the onset of syncope. Sra et al15 have reported that
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during the initial phases of head upright tilt, plasma epinephrine and norepinephrine levels increase, whereas at the onset of syncope, plasma norepinephrine levels decrease and epinephrine levels increase. These findings support the concept that an initial decrease in blood volume occurring as a consequence of peripheral venous pooling causes a reflex increase in sympathetic output producing a tachycardia and peripheral vasoconstriction in an attempt to maintain normal hemodynamics. However, this increase in sympathetic output may sensitize and facilitate the activation of the cardiac mechanoreceptors that reportedly play a large role in the production of neurocardiogenic syncope.4 The sudden increase in neural traffic that occurs with very vigorous ventricular contraction (or by C-fiber activation from myocardial ischemia and reperfusion) produces an abrupt, centrally mediated reduction in sympathetic activity, with peripheral sympathetic inhibition and vasodilation. Recently, it has been suggested that some aspect of diminished ␣-receptor responsiveness or increased -receptor sensitivity may be involved in the process.16,17 Although the central mechanisms that contribute to the production of neurocardiogenic syncope are unclear, studies have focused principally on the role of 2 substances: endogenous opiates and serotonin (5-hydroxytryptamine or 5-HT). Using rat models, a body of evidence has been generated suggesting that the vasodepressor response to acute hemorrhage may be mediated by endogenous opiates.17 In rabbit models, renal sympathetic nerve activity is inhibited if opiate receptor antagonists are given at the time of acute hypotensive hemorrhage.18 Additionally, it has been observed that intracisternal administration of nalaxone, an antagonist of opiate receptors, can diminish the vasodilatory response observed during acute blood loss in rabbits.19 Two human studies have demonstrated notable increases in plasma -endorphin levels before tilt-induced syncope.20,21 However, opiate antagonists did not prevent lower body negative pressure–induced syncope.22 Serotonin is a neurotransmitter implicated in the pathophysiologic processes leading to neurocardiogenic syncope.23 A biologic amine that is widely distributed throughout the central nervous system (CNS), serotonin plays an important role in blood pressure regulation.24 If serotonin is directly applied to the brain via the lateral ventricles, it produces a reduction in efferent sympathetic activity, whereas direct application to the nucleus solitarius produces parasympathetic stimulation, sympathetic withdrawal, and bradycardia. Administration of intracerebroventricular serotonin causes hypotension, inhibition of renal sympathetic nerve activity, and stimulation of adrenal sympathetic nerve activity.25 Serotonin is also important in the modulation of acute responses to acute hemorrhage.23 Several studies have demonstrated that the serotonin reuptake inhibitors (e.g., fluoxetine, sertraline, and paroxetine) can be an effective preventive therapy for neurocardiogenic syncope.26 –28 These agents selectively prevent the reuptake of serotonin at the synaptic
cleft: the serotonin levels increase, 5-HT release is diminished, and impulse transmission velocity increases, which results in a decrease in postsynaptic receptor density. This down-regulation appears to blunt the responses to rapid shifts in central serotonin levels and thereby reduces the ability for such surges to result in abrupt sympathetic withdrawal. A recent double-blind, randomized, placebo-controlled study demonstrated that paroxetine significantly improved symptoms in patients who had recurrent neurocardiogenic syncope (p ⬍0.0001).28 Sutton and Petersen29 have observed that responses seen during neurocardiogenic syncope and carotid sinus hypersensitivity are very similar and may be different aspects of the same disorder. In a predisposed individual, rapid mechanoreceptor activation from any site or cause (e.g., blood, bladder, cough) could elicit similar responses.30 Primary disorders in autonomic failure: In contrast to the intermittent episodes of orthostatic intolerance caused by reflex syncopes in which the ANS appears to function normally despite the intermittent and apparently “hypersensitive” reflex responses, another type of orthostatic intolerance occurs when the ANS appears to be failing. When upright, patients with autonomic failure are unable to compensate for the decrease in venous return. This failure to compensate results from a failure in the afferent and/or efferent limbs of the baroreflex, or from reduced end-organ responsiveness to vasoconstrictors. When this failure becomes severe, frank orthostatic hypotension occurs. However, even in the absence of frank orthostatic hypotension, patients with a failing ANS may demonstrate a progressive type of orthostatic hypotension: As blood pools in the lower extremities with prolonged periods of upright posture, blood pressure continues to decrease. This has been described as a dysautonomic response to upright posture. In contrast to patients with reflex syncopes who tend to have few symptoms referable to the ANS in between syncopal episodes, patients with autonomic failure often have other symptoms of autonomic dysfunction in between episodes of syncope. Chronic autonomic dysfunction: Various disorders may cause varying degrees of autonomic disturbance, some of which are listed in Table I.31 The physician is more likely to encounter the chronic forms of autonomic failure than their acute counterparts. The first report of chronic autonomic failure was the groundbreaking study by Bradbury and Eggleston32 in 1925, in which they labeled the condition “idiopathic orthostatic hypotension” because of an apparent lack of other neurologic features. Since then, however, it has been observed that these patients exhibit a generalized state of autonomic dysfunction that is manifested by orthostatic hypotension and syncope as well as disturbances in bowel, bladder, thermoregulatory, sudomotor, and sexual function.33,34 The American Autonomic Society has named this disorder pure autonomic failure (PAF).5,35 Although its cause remains unknown, several investigators have postulated that there is a degeneration of the peripheral postgangli-
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TABLE I Autonomic Disorders Associated with Orthostatic Intolerance I.
Primary autonomic disorders A. Acute pandysautonomia B. Reflex syncopes 1. Neurocardiogenic syncope 2. Carotid sinus hypersensitivity C. Pure autonomic failure D. Multiple system atrophy 1. Parkinsonian 2. Cerebellar/pyramidal 3. Mixed D. Postural orthostatic tachycardia syndrome II. Secondary autonomic failure A. Central origin 1. Cerebral cancer 2. Multiple sclerosis 3. Age-related 4. Syringobulbia B. Peripheral forms 1. Afferent a. Guillain-Barre´ syndrome b. Tabes dorsalis c. Holmes-Adie syndrome 2. Efferent a. Diabetes mellitus b. Nerve growth factor deficiency c. Dopamine -hydroxylase deficiency 3. Afferent/efferent a. Familial dysautonomia 4. Spinal origin a. Transverse myelitis b. Syringomyelia c. Spinal tumors 5. Other causes a. Renal failure b. Paraneoplastic syndromes c. Autoimmune/collagen vascular disease d. Human immunodeficiency virus infection e. Amyloidosis Adapted with permission from Neurology.31
onic autonomic neurons.36 The condition is more common in older adults, but it can occur in almost any age group, including children. Another type of autonomic failure was reported in 1960 in a landmark study by Shy and Drager.37 The degenerative disorder known as multiple system atrophy is manifested by severe orthostatic hypotension, progressive urinary and rectal incontinence, loss of sweating, iris atrophy, external ocular palsy, impotence, rigidity, and tremors. Muscle fasciculations and distal muscle wasting may occur late in the disorder. The American Autonomic Society has divided multiple system atrophy into 3 major subtypes.38 The first group of patients demonstrates tremor that is similar to Parkinson’s disease (sometimes called striatonigral degeneration). A second group displays mainly cerebellar and/or pyramidal symptoms (the olivopontocerebellar atrophy/degeneration form). A third group displays aspects of both types. An autopsy study found that 7–22% of patients thought to have Parkinson’s disease actually had neuropathologic findings diagnostic for multiple system atrophy.39 Whereas most multiple system atrophy patients do not present until 6Q THE AMERICAN JOURNAL OF CARDIOLOGY姞
somewhere between the fifth and seventh decade of life, some begin to have symptoms in their late 30s. Recently, attention has been focused on a milder form of chronic autonomic failure that is referred to as postural orthostatic tachycardia syndrome (POTS).40 The hallmark of POTS is a persistent tachycardia while upright, sometimes reaching rates of ⱖ160 beats/min, associated with severe fatigue, near-syncope, exercise intolerance, and lightheadedness or dizziness. Many patients complain of always being cold yet unable to tolerate extreme heat. During head upright tilt, these patients display a sudden increase in heart rate ⬎30 beats/min within the first 5 minutes or achieve a maximum heart rate of 120 beats/min associated with only mildly reduced blood pressure. The mechanism underlying this condition appears to be a failure of the peripheral vasculature to appropriately vasoconstrict under orthostatic stress, which is compensated for by an excessive increase in heart rate. Streeten et al41 have suggested that POTS represents the earliest sign of autonomic dysfunction, and some patients have later progressed to PAF. It is important to recognize this disorder—patients with POTS have been misdiagnosed as having an inappropriate sinus tachycardia and have undergone radio frequency modification of the sinoatrial node, resulting in profound orthostatic hypotension. Patients with POTS may also be misdiagnosed as having chronic fatigue syndrome; recent reports indicate that a great deal of overlap exists between these disorders.42 Acute autonomic dysfunction: Although rare, the acute autonomic neuropathies that produce hypotension and syncope are frequently dramatic in presentation.43 The disorders are acute in most patients and demonstrate severe and widespread failure of the sympathetic and parasympathetic systems while leaving the somatic fibers unaffected. Many of these patients tend to be young and very healthy before the illness. The development of the illness is surprisingly rapid, and patients can frequently identify the exact day their symptoms began. Interestingly, many of these individuals report having had a febrile illness, presumed to be viral, before the onset of symptoms, which suggests an autoimmune component to the disorder. Function of the sympathetic nervous system is often so severely disrupted, and orthostatic hypotension so extreme, that patients cannot even sit upright in bed without fainting. Patients often lose their ability to sweat, have bowel and bladder dysfunction, and frequently complain of bloating, nausea, vomiting, and abdominal pain. Constipation is common and sometimes will alternate with diarrhea. Interestingly, the heart rate is often fixed at 40 –50 beats/min, associated with complete chronotropic incompetence. The pupils are often dilated and poorly reactive to light. Patients may experience several syncopal episodes daily. The long-term prognosis of these patients is variable—some have complete recoveries, whereas others have a chronic debilitating course. Patients are often left with significant residual defects.
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TABLE II Pharmacologic Agents that May Cause or Worsen Orthostatic Intolerance ● ● ● ● ● ● ● ● ● ● ● ● ●
␣-Receptor blockers ACE inhibitors -Blockers Bromocriptine Calcium channel blockers Diuretics Ethanol Ganglionic blocking agents Hydralazine Nitrates Opiates Phenothiazine Tricyclic antidepressants Adapted from Syncope: Mechanisms and Management.3
Secondary disorders in autonomic failure: Autonomic dysfunction can be part of a larger disorder; in occasional patients, several conditions coexist that produce synergistic detrimental effects on autonomic function. Over the last decade, several enzymatic abnormalities have been identified that can result in autonomic disruption. Principal among these is isolated dopamine -hydroxylase deficiency syndrome, a condition that is now easily treated by replacement therapy.44,45 Additional deficiency syndromes involving nerve growth factor, monoamine oxidase, aromatic L-amino decarboxylase, and some sensory neuropeptides may all result in autonomic failure and hypotension.46 Diffuse systemic illnesses such as renal failure, cancer, or acquired immunodeficiency syndrome may all cause hypotension and syncope. Studies have also demonstrated a link between orthostatic hypotension and Alzheimer’s disease.47 Numerous pharmacologic agents may cause or worsen orthostatic hypotension (Table II), particularly peripherally acting vasodilatory agents, such as angiotensin-converting enzyme inhibitors, prazosin, hydralazine, and guanethidine. Although effective in neurocardiogenic syncope, -blocking agents can worsen syncope in some patients. Lately, we have observed an increased frequency of dysautonomic syncope in patients with congestive heart failure. In this group, the combination of low cardiac output and volume depletion due to diuretics and vasodilator therapy interferes with the body’s mechanisms for adapting to upright posture. Centrally acting agents, such as tricyclic antidepressants, reserpine, and methyldopa, may also exacerbate otherwise mild hypotension. In dysautonomic disorders (as opposed to the reflex syncopes), hypotensive syncope is but one aspect of a broader constellation of symptoms relating to autonomic failure. The physician should, therefore, provide the patient with realistic expectations about which symptoms can and cannot be eliminated. Both physician and patient should be aware that these disorders can be progressive in nature and that therapies may have to be altered over time.
CLINICAL FEATURES In these conditions, normal cardiovascular regulation is disturbed, resulting in postural hypotension. Although orthostatic hypotension was once defined as a ⬎20 mm Hg decrease in systolic blood pressure over a 3-minute period after standing upright, a smaller decrease in blood pressure associated with symptoms can be just as important. A large percentage of patients will display a slow, steady decrease in blood pressure over a longer period of time (around 10 –15 minutes) that can be quite symptomatic. Whether patients experience symptoms depends as much on the rate of decrease in pressure as on the absolute degree of change. Loss of consciousness in dysautonomic syncope tends to be slow and gradual, and usually occurs when patients are walking or standing. However, many older patients do not seem to perceive a decrease in pressure, report little or no prodrome before syncope, and describe the episodes as “drop attacks.” Individuals who do experience prodromes describe a variety of symptoms such as dizziness, blurred vision, “seeing stars,” and tunnel vision. Unlike neurocardiogenic syncope, bradycardia and diaphoresis are uncommon in dysautonomic syncopal episodes. 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, will exacerbate hypotension. In time, some patients may develop a relatively fixed heart rate that shows little response to postural change or exercise. In addition, some patients will develop a syndrome of supine hypertension that alternates with upright hypotension, presumably due to a failure to vasodilate when prone. Patients with this combination of supine hypertension and upright hypotension can be quite difficult to treat. At times, distinguishing the disorders can be difficult because there may be a considerable degree of overlap between them (Figure 2)—not unlike the situation seen with various forms of chronic obstructive lung disease.
EVALUATION OF PATIENTS The cornerstone of evaluation is a detailed history and physical examination. Table III describes some historical features to which clinicians should pay particular attention. When do syncopal or near-syncopal episodes occur and when did they begin? How often do they 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 history and physical examination that includes a concise neurologic examination will have a greater diagnostic yield than a battery of laboratory tests. Diagnostic tests should be used sparingly, directed by the history and physical examinations, to confirm clinical impressions. Any drugs patients are taking that could produce hypotension should be identified. This includes pharmaceuticals, over-the-counter medications, herbal
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FIGURE 2. Delineation of the interrelation among autonomic disorders associated with orthostatic intolerance. Differentiating the various disorders can be difficult given the significant overlap between them. (Reproduced with permission from Pacing Clin Electrophysiol.51)
remedies, illicit drugs, and alcohol. In women, symptoms may vary with the menstrual cycle; also, an otherwise mild tendency toward autonomic dysfunction can be exacerbated by the onset of menopause. Because the autonomic areas of the brain are not accessible for direct measurement, one must measure the responses of various organ systems to different physiologic or pharmacologic challenges. Recent advances permit the determination of serum, urine, and cerebrospinal fluid levels of some autonomic neuromodulators and neurotransmitters. Foremost, however, is blood pressure and heart rate response to positional change, with measurements taken while patients are supine, sitting, and standing. The exact change in pressure considered to be significant is still under discussion, but is usually felt to be a 20 –30 mm Hg decrease in systolic pressure and a 10 –15 mm Hg
TABLE III Evaluation of Syncope: Patient History ● ● ● ● ● ● ● ● ● ● ● ●
Consider characteristics and length of episodes Define episodes as completely as possible using patient and witnessed accounts Consider the events that trigger episodes Consider specific aspects of the history (e.g., back pain, shortness of breath, angina) Assess the relationship to meals, alcohol, drugs Consider the relation to exercise, body position, posture, and emotional state Consider number, frequency, and timing of previous episodes Prodromal symptoms can help secure a diagnosis Postsyncopal symptoms (symptoms on awakening) can provide important diagnostic clues Consider concomitant disease (especially cardiac) Consider medications Consider family history of death or syncope
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FIGURE 3. Heart rate and blood pressure patterns observed in abnormal responses to head-up tilt-table testing. (Adapted from Syncope: Mechanisms and Management.3)
decrease in diastolic pressure. When patients are standing, blood pressure should be taken with the arm extended horizontally to avoid the possible hydrostatic effects of the fluid column of the arm. Tilt-table testing may also be useful in these patients because it allows the physician to assess autonomic and hemodynamic responses to upright posture over a longer period of time. In addition, passive head-up tilt provides a greater orthostatic challenge than active standing. The use of postural muscles in the abdomen and lower extremities during active standing limits venous pooling; however, these muscles are not used during passive head-up tilt, so venous pooling occurs to a greater degree.48 A number of other autonomic tests are available and are quite useful in selected patients.36,49,50 It is useful to distinguish between broad response patterns as outlined in Figure 3. The classic neurocardiogenic or vasovagal response is characterized by a sudden decrease in blood pressure, often followed by a decrease in heart rate (Figure 3A). The dysautonomic response demonstrates a gradual but progressive decrease in blood pressure to hypotensive levels
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leading to loss of consciousness (Figure 3B). The third pattern is characteristic of POTS (Figure 3C). Originally, we defined this group as exhibiting an increase in heart rate of at least 30 beats/min (or a maximum heart rate of 120 beats/min) within the first 10 minutes of passive upright tilt, which is usually not associated with profound hypotension. Recently, we realized there are probably subgroups within the POTS population and are working to better categorize these groups of patients.
SUMMARY The disorders of autonomic control associated with orthostatic intolerance are a diverse group of infirmities that can result in syncope and near-syncope. A basic understanding of the disorders is essential to diagnosis and proper treatment. Ongoing studies should better define the spectrum of these disorders and enable better diagnostic and treatment modalities.
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A SYMPOSIUM: TREATMENT FOR PATIENTS WITH VASOVAGAL SYNCOPE
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