The causes of syncope include cardiovascular disorders, disorders of vascular tone or blood volume, and cerebrovascular disorders. The relative incidence of these categories varies with the clinical site from which the patients are selected; in hospitalized patients, syncope is most often a result of a cardiovascular disorder, whereas in the emergency room, other causes of syncope predominate.4 In many cases, the cause of syncope may be multifactorial. Furthermore, in up to 50% of cases, the cause of syncope cannot be determined with certainty even after a rigorous evaluation.
Recent studies document the widely divergent risks of death that are associated with an episode of syncope, ranging from those that are benign to cardiac arrhythmias that are potentially lethal.9 Syncope caused by cardiovascular disorders is associated with the highest risk for death, approaching 50% over 5 years and 30% in the first year after diagnosis.4 Furthermore, among patients with certain cardiac diseases, including hypertrophic cardiomyopathy, the long QT syndrome, and others, those with syncope are at greater risk for death.10 The mortality is lower among patients with syncope from other causes (30% over 5 years and < 10% in the first year), but still substantial. Syncope that is not associated with cardiac disease and is of undetermined cause is usually associated with the lowest mortality (6%-10% over 3 years and 24% over 5 years).2,4,7 Syncope can impact quality of life for patients and their families, particularly when it occurs abruptly without warning and is recurrent, or when it is likely to occur in relationship to certain activities. In such cases, patients may need to adjust their lifestyle or change occupation.
For prognostic and therapeutic reasons, it is important to distinguish syncope from other causes of transient loss of consciousness, including seizures, psychogenic seizures, hypoglycemia, pharmacologic agents, and trauma. In some cases, this may prove difficult because reduced cerebral blood flow associated with syncope can cause tonic-clonic movements similar to those that occur with certain seizures. In one study, syncope had been misdiagnosed as seizures in 38% of patients who continued to have episodes despite adequate anticonvulsant therapy.11
Syncope can occur from either severe obstruction of cardiac output or disturbances of cardiac rhythm.4,12,13,14,15,16,17,18,19,20,21,22,23,24 Obstructive lesions and arrhythmias frequently coexist; indeed, one abnormality may accentuate the effects of the other. Table 90–1 lists the cardiovascular disorders that may be associated with syncope.
TABLE 90–1.Cardiac Disorders Associated with Syncope ||Download (.pdf) TABLE 90–1. Cardiac Disorders Associated with Syncope
| Aortic stenosis |
| Hypertrophic cardiomyopathy |
| Mitral stenosis |
| Prosthetic mitral or aortic valve malfunction |
| Atrial myxoma |
| Pulmonary embolism |
| Pulmonary hypertension |
| Tetralogy of Fallot |
| Cardiac tamponade |
| Sinoatrial disease |
| Atrioventricular block |
| Supraventricular tachyarrhythmias |
| Ventricular tachycardia |
| Pacemaker disorders |
Syncope Related to Obstruction of Cardiac Output
Obstruction to cardiac output in the left or right side of the heart may cause syncope. The relationship of syncope to exertion may provide clues to the etiology. Loss of consciousness during or immediately after exertion can occur with any of the cardiac causes of syncope, but is particularly common and may be the presenting symptom in patients with certain obstructive lesions, including aortic stenosis and hypertrophic cardiomyopathy. Studies suggest that in such patients, failure of cardiac output to increase adequately during exercise together with a reflex decrease in peripheral vascular resistance may play a role.25 Nonexertional syncope related to acute decreases in preload or afterload, or to inotropic stimulation, may also occur in either aortic stenosis or hypertrophic cardiomyopathy (see Chaps. 47 and 59). Transient arrhythmias can also induce syncope in patients with obstructive lesions. Syncope is an ominous sign in patients with hypertrophic cardiomyopathy, portending a significant risk for sudden cardiac death.10,25,26,27 Syncope in patients with aortic stenosis suggests that the obstruction is severe.
Malfunction of a left-sided prosthetic heart valve can produce transient and profound obstruction to blood flow resulting in syncope (see Chap. 52). Mitral stenosis can produce cardiac syncope, but usually does so only when tachycardia or other arrhythmias occur (see Chap. 50). A left atrial myxoma may cause syncope by obstructing left ventricular filling. In some cases, the obstruction of left ventricular inflow is posturally induced.
Obstruction in the pulmonary vasculature as a result of pulmonary artery hypertension, pulmonary stenosis, or pulmonary embolism can cause syncope. Pulmonary embolism as a cause of syncope should be suspected in paraplegic patients and in those who have been at prolonged bedrest.28,29 In tetralogy of Fallot, because the right ventricular outflow obstruction is often fixed, the magnitude of flow through the right-to-left shunt increases when systemic resistance falls during exertion. This shunting can result in marked arterial hypoxia, which may precipitate syncope. Cardiac tamponade, which affects both the right and the left sides of the heart, rarely causes syncope. The likelihood of syncope is increased by concomitant arrhythmias.
Syncope Related to Cardiac Arrhythmia
Arrhythmias are a common cause of syncope and must be considered in any patient, particularly when cardiac disease is present. Either extreme of ventricular rate (bradycardia or tachycardia) can depress cardiac output to the point of critical hypotension with cerebral hypoperfusion and syncope. The arrhythmias that produce syncope most often are caused by sinoatrial disease (bradycardia, exit block, or pauses), high-grade atrioventricular (AV) block, and ventricular tachycardia. Although arrhythmias are usually secondary to disorders such as ischemic heart disease, cardiomyopathy, valvular heart disease, and primary conduction system disease, they can on occasion occur in the absence of apparent heart disease.
Primary degenerative disease of the sinus node and the specialized conduction tissue is the most common cause of sinoatrial disease (sick sinus syndrome; see Chap. 86). The sick sinus syndrome may be manifested by persistent or episodic sinus bradycardia or sinoatrial exit block, often with impaired junctional escape rhythm. The presence of alternating sinus bradycardia or sinoatrial block with atrial tachyarrhythmias is referred to as the bradycardia-tachycardia syndrome. Syncope often occurs with asystole or bradycardia at the termination of tachycardia because of overdrive suppression of the sinoatrial and junctional pacemakers.30 AV and intraventricular conduction defects are more prevalent in the sick sinus syndrome and, along with ventricular tachyarrhythmias, may be responsible for syncope in these patients.21
High-grade AV block may be a result of disease of either the AV node or the His-Purkinje system. Conduction block in the AV node is usually associated with a junctional pacemaker, a normal QRS complex, and a heart rate that can sustain blood pressure adequate to maintain consciousness, whereas AV block as a result of His-Purkinje system disease is usually associated with a wide-complex idioventricular escape rhythm that may be too slow to maintain adequate blood pressure. Bifascicular block in the presence of a prolonged PR interval suggests that His-Purkinje system disease is present and is associated with a substantial risk of developing high-grade AV block and syncope. Progression to high-grade AV block in patients with bifascicular block and a normal PR interval is less common.
Sinus bradycardia, AV block, or cardiac asystole may be mediated by reflex vagal mechanisms and have been observed in a variety of disease states or during diagnostic procedures. Transient sinus bradycardia or AV block also can occur in apparently healthy young individuals, certain of whom may have mitral valve prolapse.22
Supraventricular tachyarrhythmias rarely cause syncope unless they occur in the presence of other abnormalities that decrease cerebral perfusion (decreased cardiac output because of structural heart disease, a neurocardiogenic reaction, disorders of vascular control, or reduced blood volume). As is the case for other causes of syncope, a neurocardiogenic reaction may be precipitated by the hemodynamic effects of arrhythmias.31 In such cases, syncope may be related to vasomotor factors and not be solely a result of heart rate.30,31 Syncope can occur in patients with Wolff-Parkinson-White (WPW) syndrome who experience atrial fibrillation and a very rapid ventricular rate as a consequence of conduction across an accessory atrioventricular connection.
Ventricular tachycardia is the most common arrhythmic cause of syncope and often occurs in the setting of structural heart disease. In the United States, ventricular tachycardia is usually associated with previous myocardial infarction and depressed left ventricular (LV) ejection fraction, but it can occur also in nonischemic cardiomyopathy.
Ventricular tachycardia may also cause syncope in patients with normal left ventricular function (ie, long QT syndrome, Brugada syndrome, right ventricular outflow tract ventricular tachycardia, arrhythmogenic right ventricular cardiomyopathy [ARVC], and idiopathic left ventricular tachycardia).32,33,34,35 Syncope is considered to be an ominous sign, portending a high risk for sudden cardiac arrest in patients with long QT syndrome, Brugada syndrome, and ARVC.
Torsade de pointes can cause syncope in patients with either congenital or acquired long QT syndrome (see Chap. 85). A normal QT interval does not preclude the diagnosis of long QT syndrome, because prolongation of repolarization can be intermittent. In some heritable forms of the syndrome, QT prolongation and ventricular tachycardia can be triggered by exercise or a startle response.36,37 Although a number of drugs can prolong ventricular repolarization, the most frequent causes of acquired long QT syndrome are antiarrhythmic drugs (types Ia and III) and electrolyte disorders (hypokalemia and hypomagnesemia). A pause preceding the onset of tachycardia is common, because the early afterdepolarizations thought to be responsible for torsade de pointes in some long QT syndrome patients are bradycardia dependent.23,37,38
A variety of other drugs may produce or aggravate arrhythmias, resulting in syncope or presyncope. Type Ic antiarrhythmic drugs may cause ventricular arrhythmias in patients with structural heart disease. β-Adrenoceptor antagonists, calcium-channel blockers, digoxin, sotalol, and amiodarone are some of the agents that most commonly cause significant sinus bradycardia or AV block. Theophylline and β agonists, used for therapy of chronic obstructive pulmonary disease, may precipitate ventricular or supraventricular arrhythmias. Therapy with diuretics can cause hypokalemia and hypomagnesemia. Both caffeine and alcohol may precipitate either atrial or ventricular tachyarrhythmias.
In the patient who has an artificial ventricular pacemaker, near syncope or syncope may be secondary to pacemaker malfunction or to the pacemaker syndrome (see Chap. 89). Dual-chamber pacemakers can produce pacemaker-mediated tachycardias when there is retrograde conduction of the ventricular impulse to the atria. Improvements in technology have reduced the incidence of this complication.39,40
Disorders of Vascular Control or Blood Volume
Disorders of vascular control or blood volume that can cause syncope include the reflex syncopes and a number of causes for orthostatic intolerance (Table 90–2).41,42 Under normal circumstances, systemic blood pressure is regulated by a complex process that includes the musculature, the venous valves, the autonomic nervous system, and the renin-aldosterone-angiotensin system. Knowledge of these processes is a prerequisite to understanding the disorders of vascular control or blood volume that can cause syncope.
TABLE 90–2.Disorders of Vascular Control and Blood Volume ||Download (.pdf) TABLE 90–2. Disorders of Vascular Control and Blood Volume
|Reflex syncope |
| Neurocardiogenic (vasovagal) |
| Situational |
| Carotid sinus hypersensitivity |
|Orthostatic intolerance |
| Autonomic nervous system disorders |
| Primary autonomic failure |
| Pure autonomic failure |
| Multiple system atrophy |
| Postural orthostatic tachycardia syndrome |
| Peripheral or partial dysautonomic |
| Hyperadrenergic |
| Acute autonomic failure |
| Secondary autonomic failure |
| Amyloidosis |
| Diabetes |
| Sarcoidosis |
| Renal failure |
| Cancer |
| Nerve growth factor deficiency |
| β-Hydroxylase deficiency |
| Pharmacologic agents |
| Certain heavy metals |
| Mercury |
| Lead |
| Arsenic |
| Iron |
|Intravascular volume depletion |
| Anemia |
| Blood loss |
| Dehydration |
| Diuretics |
|Venous pooling/vasodilation |
| Prolonged bed rest |
| Prolonged weightlessness |
| Pregnancy |
| Venous varicosities |
| Pharmacologic agents |
| Hyperbradykininism |
| Mastocytosis |
| Carcinoid syndrome |
Maintenance of Postural Blood Pressure
A principal stress imposed while standing is produced by gravity displacing venous blood downward to a level below the heart. Although the renin-aldosterone-angiotensin system regulates long-term blood pressure responses to upright posture, the autonomic nervous system provides the majority of the short- and medium-term responses to postural change.43
In the normal supine individual, approximately one quarter of the blood volume is in the thorax. On standing, there is a gravity-mediated displacement of between 300 and 800 mL of blood to both the dependent extremities and the inferior mesenteric area.44 Approximately 50% of this displacement occurs within the first few seconds of standing, resulting in a drop in venous return to the heart and a mean fall in stroke volume of approximately 40%.44 In the normal subject, accommodation to this change in posture occurs in less than 1 minute.
Immediately on standing, muscle contractions in the legs, abdomen, and arms, in concert with the venous valvular system, support blood pressure by facilitating venous return.44,45 However, this alone is insufficient to maintain venous return and systemic blood pressure. The reduction in venous return with upright posture is followed by a slow progressive fall in arterial pressure and cardiac filling that produces less stretch and reduces the discharge rate of aortic arch and carotid sinus baroreceptors. Fibers from these mechanoreceptors travel with unmyelinated vagal fibers from the atria and the ventricles to the nucleus tractus solitarii and other areas of the medulla that modulate vascular tone. In the resting supine position, impulses from these fibers increase efferent parasympathetic activity and have an inhibitory effect on efferent sympathetic activity to the heart. After standing, the drop in arterial pressure receptor firing in the carotid sinuses decreases efferent vagal activity and increases efferent sympathetic activity, producing a reflex increase in heart rate and peripheral vasoconstriction. As a result, assumption of upright posture results in a 10 to 15 bpm increase in heart rate, minimal change in systolic blood pressure, and an approximately 10 mm Hg increase in diastolic blood pressure.46
Any inability of this complex process to respond adequately or in a coordinated manner may result in varying degrees of postural hypotension and ultimately loss of consciousness. Failure of one component may be compensated for by increased action of another component. For example, a failure of the peripheral vasculature to constrict during upright posture may be compensated for by increased heart rate and myocardial contractility sufficient to maintain blood pressure. Nonetheless, compensatory mechanisms may not be sufficient, or may not be sustainable over long periods of time. Furthermore, compensatory mechanisms, if not modulated, may result in orthostatic hypertension and inappropriate sinus tachycardia.
In each of the reflex syncopes, there is a sudden failure of the autonomic nervous system to maintain sufficient vascular tone during periods of gravitational stress resulting in hypotension (and sometimes bradycardia). The two types most commonly encountered are neurocardiogenic (vasodepressor or vasovagal) syncope and the carotid sinus syndrome.47 The other forms of reflex syncope are frequently grouped together under the term situational because they occur in association with specific activities or conditions (such as micturition, defecation, swallowing, coughing, postprandial). It is important to realize that the reflexes responsible for neurocardiogenic syncope are normal; healthy individuals will experience neurocardiogenic syncope in the setting of a stimulus that is sufficiently strong and prolonged. However, some individuals develop neurocardiogenic syncope frequently and with relatively little provocation, suggesting that disorders of autonomic control exist.
Neurocardiogenic syncope can be quite diverse in presentation and tends to occur more often in young people.48 The episodes often include three stages: a prodrome (nausea, sweating, lightheadedness, or visual alterations), abrupt loss of consciousness, and rapid recovery without a postictal state. However, close to one-third of patients (often elderly) experience little if any prodrome and report a sudden loss of consciousness (drop attack).
The etiology of neurocardiogenic syncope is poorly understood. It can be provoked by prolonged standing, warm environments, emotional distress, and pain, although episodes can occur also without an identifiable trigger.48 Many episodes of neurocardiogenic syncope are provoked by prolonged orthostatic stress.49,50,51 Gravity-mediated displacement of blood and venous pooling in dependent areas decreases venous return to the heart, resulting in a reflex-mediated increase in myocardial contractility that activates ventricular mechanoreceptors that would normally fire only during stretch.50 This sudden increase in neural traffic to the medulla appears to mimic the conditions seen in hypertension, resulting in a “paradoxic” decrease in sympathetic activity that results in hypotension (vasodepressor response), and in some cases, an increase in vagal efferent activity that results in bradycardia.51 Other nonorthostatic stimuli (such as fear, fright, or epileptic discharges) can provoke virtually identical responses, suggesting that these patients may have an inherent predisposition to these events.48 During head upright tilt-table testing, individuals susceptible to neurocardiogenic syncope demonstrate a precipitous fall in blood pressure that is frequently (but not always) followed by a fall in heart rate (on occasion to the point of asystole).47
Carotid Sinus Hypersensitivity
Syncope caused by carotid sinus hypersensitivity is most common in men ≥ 50 years old and is precipitated by pressure on the carotid sinus baroreceptors, typically in the setting of shaving, a tight collar, or turning the head to one side. Activation of carotid sinus baroreceptors gives rise to impulses to the medulla oblongata that, in turn, activate efferent sympathetic nerve fibers to the heart and blood vessels, cardiac vagal efferent nerve fibers, or both. In patients with carotid sinus hypersensitivity, these responses may cause sinus arrest or AV block (a cardioinhibitory response), vasodilatation (a vasodepressor response), or both (a mixed response). The underlying mechanisms responsible for the syndrome are not clear, and validated diagnostic criteria do not exist.
Some investigators have noted that the hemodynamic responses observed in neurocardiogenic syncope and carotid sinus hypersensitivity are similar, suggesting that the two syndromes may represent different aspects of the same condition.52 Others have proposed that each of the reflex syncopes may occur in predisposed individuals when rapid activation of neuroreceptors from multiple sites (esophagus, bladder, rectum, or cough) activates a similar response.51 Recent observations concerning defecation syncope support this.47 What seems to distinguish the reflex syncopes from the other autonomic syndromes is that between episodes of syncope these patients rarely complain of symptoms referable to the autonomic nervous system. Consequently, in the reflex syncopes, the autonomic nervous system functions normally, despite being at times “hypersensitive,” in contrast to other conditions wherein the autonomic system appears to “fail,” operating at a level insufficient for the body’s needs, and thereby resulting in drawing levels of orthostatic intolerance.47
Syndromes of Orthostatic Intolerance
Orthostatic hypotension may occur as a result of hypovolemia or disturbances in vascular control (see Table 90–2). The latter may occur because of agents that affect the vasculature directly or to primary or secondary abnormalities of autonomic control. During the past two decades, several autonomic disorders have been identified that can impact vascular control and cause syncope.47 The system presented here corresponds with that developed by the American Autonomic Society and the Heart Rhythm Society and attempts to present these disorders in a clinically useful framework.41,42 Primary autonomic disorders that affect vascular control are often idiopathic, occur in the absence of other disease states that affect the autonomic nervous system, and may follow either an acute or chronic course. In contrast, the secondary forms occur in conjunction with another illness (such as amyloidosis or diabetes), in the setting of a known biochemical or structural alteration, or following exposure to various drugs or toxins (heavy metals, alcohol, or some chemotherapeutic agents) (Tables 90–2 and 90–3).41,42
TABLE 90–3.Pharmacologic Agents That May Cause or Worsen Orthostatic Intolerance ||Download (.pdf) TABLE 90–3. Pharmacologic Agents That May Cause or Worsen Orthostatic Intolerance
|Angiotensin-converting enzyme inhibitors |
|α-Receptor blockers |
|Calcium channel blockers |
|Tricyclic antidepressants |
|Ganglionic-blocking agents |
|Sildenafil citrate |
|Monoamine oxidase inhibitors |
|Chemotherapeutic agents |
| Vincristine |
| Vinblastine |
Primary Causes of Autonomic Failure
Bradbury and Eggleston first reported an autonomic failure syndrome in 1925, coining the term idiopathic orthostatic hypotension to describe the disorder.53 In the interim, it has become apparent that this term insufficiently describes the diffuse state of autonomic failure present in these patients, as evidence by impaired bladder, bowel, thermoregulatory, motor, and sexual function (all in the absence of somatic nerve involvement). Currently the condition is referred to as pure autonomic failure (PAF).54 Onset of symptoms in PAF is usually between ages 50 and 75 years, and affects twice as many men as women.55 PAF is manifested by orthostatic hypotension, syncope, and near syncope, neurocardiogenic bladder, constipation, heat intolerance, inability to sweat, and erectile dysfunction. Typically, the onset of symptoms is gradual and insidious, often with sensations of positional weakness, lightheadedness, and dizziness.56 Male patients often report that the earliest signs of PAF were erectile dysfunction and diminished libido; women often report that their earliest symptoms were urinary retention and incontinence.57 Although not the initial symptom, syncope may be the event that prompts the patient to seek medical attention. Whereas PAF may result in severe functional impairment, it infrequently leads to death.57
Multiple system atrophy (MSA) is a more severe form of autonomic failure, first reported by Shy and Drager in 1960.58 In contrast to PAF, these patients display not only significant orthostatic hypotension, but also urinary and rectal incontinence, anhidrosis, iris atrophy, external ocular palsy, erectile dysfunction, rigidity, and tremor. As with PAF, the condition is twice as common in men as women, and usually starts in the fifth and sixth decades of life.55 Although MSA may initially be indistinguishable from PAF, patients with MSA eventually experience somatic nervous system involvement.59
MSA is subclassified into three groups according to the somatic system involvement.55,56 Group I patients exhibit a muscle tremor similar to that seen in Parkinson disease (also referred to by some as suffering from striatonigral degeneration).60 As opposed to patients with true Parkinson disease, MSA patients display more rigidity than tremor and the tremor usually lacks the “lead pipe” or “cogwheel” rigidity observed in Parkinson disease.61,62 Patients with the parkinsonism form of MSA often show a loss of facial expression as well as limb akinesia.
Group II (olivopontocerebellar degenerative atrophy) patients demonstrate pronounced cerebellar and/or pyramidal signs and symptoms.63 These patients display both gait disturbance and a truncal ataxia severe enough to prevent standing without assistance. They may have a mild intention tremor and severe slurring of speech with impaired diction. Group III (mixed) patients display features of both the parkinsonian and cerebellar groups.59
The frequency of MSA may be underappreciated, as an autopsy study found that between 7% and 22% of patients thought to have Parkinson disease during life had neuropathologic changes consistent with the disorder.61 MSA is relentlessly progressive, with the vast majority of patients dying within 5 to 8 years after onset of the illness (although occasional patients have been reported to have lived up to 20 years).56 Aspiration, apnea, and respiratory failure are the most frequent terminal events.
Postural Orthostatic Tachycardia Syndrome
Postural orthostatic tachycardia syndrome (POTS) is a somewhat less severe autonomic insufficiency in which heart rate increases excessively in response to upright posture.64 There are two primary forms of the disorder. The more common type is referred to as the peripheral (or partial) dysautonomic form.65 These individuals appear to suffer from an inability to increase adequately peripheral vascular resistance in the face of continuing orthostatic stress. This leads to a greater than normal amount of blood pooling in the dependent areas of the body (including the mesenteric vasculature), which is then compensated for by an excessive increase in both heart rate and myocardial contractibility.
Patients with dysautonomic POTS experience constant tachycardia (up to 160 bpm) while standing, and often complain of palpitation, exercise intolerance, fatigue, lightheadedness, cognitive impairment, visual disturbances, dizziness, near syncope, and syncope. Patients may complain of heat intolerance and that they constantly feel cold. Heart rate increases greater than 30 bpm or to a rate greater than 120 bpm, usually with minimal drop in blood pressure during the first 10 minutes of upright tilt.66 Approximately 10% of dysautonomic POTS patients progress to PAF. Dysautonomic POTS often occurs following a viral infection, surgery, or trauma. Recent studies suggest a link between dysautonomic POTS and the joint hypermobility syndrome.47,67
A second primary form of POTS is referred to as the hyperadrenergic, β-hypersensitivity, or central form. This form is thought to be associated with a failure of normal feedback mechanisms above the level of the baroreflex. Whereas the initial heart rate response to postural changes is adequate, the brain appears to be unable to discontinue the response, allowing heart rate to continue to rise. These patients may also be noted to have significant orthostatic hypertension. Although supine serum catecholamine levels are normal, upright levels are often quite elevated (over 600 mg/dL) and these patients often display an excessive response to an infusion of isoproterenol (a greater than 30 bpm increase in response to 1 μg/min). In contrast to patients with the peripheral dysautonomic form, patients with hyperadrenergic POTS complain more often of tremor, hyperhidrosis, diarrhea, panic attacks, and severe migraines headaches. Recent studies in a family with several affected members identified genes that appear to be responsible for hyperadrenergic POTS.68 A defect was found in the genetic code for a protein that functions to recycle norepinephrine in the intra-synaptic cleft, allowing for excessively high serum levels of norepinephrine. Additional studies suggest that there may be several different genetic forms of the disorder.69
Although less common than the other autonomic disorders, acute autonomic failure is dramatic in presentation.70 The onset is surprisingly rapid and is characterized by severe widespread failure of both parasympathetic and sympathetic components of the autonomic nervous system, while the somatic system is unaffected. Patients may have such profound orthostatic hypotension that merely attempting to sit up in bed causes syncope.71 Many suffer from complete anhidrosis and disturbances in bowel and bladder function that result in abdominal pain, cramping, bloating, nausea, and vomiting. Cardiac denervation is common, resulting in a fixed heart rate of 45 to 50 bpm and chronotropic incompetence.72 Most of these patients have high circulating levels of antibodies to adrenergic receptors within the ganglia of the autonomic nervous system, supporting the idea that the disorder is autoimmune in nature.73
Secondary Causes of Autonomic Dysfunction
A wide variety of conditions may cause orthostatic hypotension by disturbing normal autonomic function (see Table 90–2).41,42 Almost any systemic illness that affects multiple organ systems (such as diabetes mellitus, amyloidosis, sarcoidosis, renal failure, and certain cancers) may disrupt autonomic function sufficiently so as to result in orthostatic hypotension and syncope. A subgroup of patients with autonomic failure syndrome (especially diabetic patients) have a combination of supine hypertension and orthostatic hypertension, thought to be caused by a failure to properly vasoconstrict when upright or properly vasodilate when supine.74 It is not uncommon for these patients to exhibit a 100-point fall in systolic blood pressure on standing. In some hypertensive patients, a rapid fall in blood pressure may exceed the brain’s autoregulatory ability to maintain perfusion, causing syncope even though the systemic blood pressure may at the time be in a relatively normal range.75 Some investigators suggest that there may be an association between Alzheimer disease and orthostatic hypotension as a consequence of effects on autonomic control.76 Isolated enzyme abnormalities may also cause orthostatic hypotension, examples of which are nerve growth factor deficiency and β-hydroxylase deficiency.74 In addition, certain pharmacologic agents may either produce or contribute to orthostatic hypotension by interfering with autonomic control (sew Table 90–3).
Additional Causes of Orthostatic Intolerance
Intravascular volume depletion, venous pooling, certain pharmacologic agents, and a number of endogenous vasodilators may cause orthostatic hypotension and syncope. Anemia, acute blood loss, and dehydration may cause intravascular volume depletion. Venous pooling is more common in older individuals who have incompetent venous valves in the lower extremities. Individuals subjected to prolonged periods of bedrest or weightlessness often experience orthostatic hypotension. In addition to those pharmacologic agents that interfere with autonomic vascular control, a number of pharmacologic agents can cause orthostatic hypotension by reducing intravascular volume or causing vasodilatation. Certain endogenous vasodilators may cause syncope when they are present in high concentrations.
The principal feature shared by the syndromes of orthostatic intolerance is a disturbance in cardiovascular regulation sufficiently profound so as to result in orthostatic hypotension. Symptoms, the response to tilt testing (see “Diagnostic Tests” later in the chapter), and the company they keep may assist in differentiating among the disorders. Symptoms are related to both the rate and magnitude of change in blood pressure.
On occasion, it may be difficult to fully distinguish between the various autonomic nervous system disorders, as there is a considerable degree of overlap between them and because our understanding of mechanisms remains incomplete. In addition, these disorders should be distinguished from neurocardiogenic syncope. Patients with neurocardiogenic syncope tend to experience an abrupt fall in blood pressure that is commonly associated with definitive prodrome. In dysautonomic syncope, the drop in blood pressure tends to be slow and may not be perceived, resulting in a “drop attack” with little or no warning, particularly in older patients.74 Those who experience a prodrome report feeling lightheaded, dizzy, and blurred or tunnel vision. In contrast to reflex syncope, dysautonomic syncope is seldom associated with either bradycardia or diaphoresis.56 Patients with the dysautonomic forms of syncope find that symptoms are more common in the morning after awaking from sleep and are made worse by situations that enhance peripheral venous pooling (extreme heat, fatigue, dehydration, and alcohol). Patients suffering from PAF and MSA may display severe chronotropic incompetence with a relatively fixed heart rate (usually around 50 to 70 bpm).57
A number of cerebrovascular disorders can cause syncope. Syncope can occur in patients with extensive occlusive disease of the origins of the brachiocephalic vessels, such as pulseless disease (eg, aortic arch syndrome and Takayasu arteritis).4,77 With lesser degrees of cerebral occlusive disease, as with atherosclerotic narrowing, transient lowering of arterial pressure such as that immediately following assumption of the upright posture may be followed by vague symptoms suggesting impaired cerebral blood flow. In patients with cerebrovascular occlusive disease, a transient decrease in cardiac output and arterial pressure may provoke syncope at levels of arterial pressure that would otherwise be tolerated (see “Multifactorial Syncope” later in the chapter).
Impairment in, or loss of, consciousness in relation to changing positions of the head, particularly hyperextension and lateral rotation, has been attributed to mechanical narrowing of the vertebral arteries by skeletal deformities of the cervical spine. Such symptoms have been observed in patients with Klippel-Feil deformity, cervical spondylosis, and severe cervical osteoarthritis. Altered consciousness is often preceded by vestibular symptoms. However, when vertigo is a predominant symptom, the syndrome of benign postural vertigo must be considered.
Syncope in the subclavian steal syndrome is caused by major occlusive disease of the subclavian artery proximal to the origin of the vertebral artery. During upper extremity exercise, blood flow is shunted retrograde, by the circle of Willis, to the distal subclavian artery. The consequent decrease in cerebral circulation induces cerebral ischemia.77 This syndrome is suggested by the findings of diminished brachial arterial pressure on the affected side, a bruit that is maximal over the supraclavicular area adjacent to the origin of the vertebral artery, and the induction of symptoms by exercise of the involved extremity.
Although focal neurologic symptoms and signs are the usual neurologic manifestations of cerebral emboli, transient loss of consciousness can be a primary presenting symptom. Syncopal episodes are more likely to occur when atherosclerotic occlusive disease involves the vertebrobasilar system, with compromised perfusion to the medullary arousal center. In vertebrobasilar vascular insufficiency, syncope or presyncope is nearly always preceded by symptoms of vertigo, diplopia, dysarthria, and ataxia. The episodes are generally attributed to microemboli arising from an atherosclerotic plaque, although vasospasm or postural hypotension may contribute.
Syncope of Undetermined Cause
Despite careful diagnostic evaluation, the cause of syncope cannot be defined in as many as 50% of patients.4 Unexplained syncope has a broad spectrum of etiologies. The varying mortality among patients with syncope of undetermined cause likely reflects the varying incidence of undetected cardiac syncope. A certain number of these patients may have experienced syncope from multiple causes.78,79
The cause of syncope is often multifactorial. Patients with structural heart disease or cerebrovascular disease may be predisposed to lose consciousness when blood pressure is compromised because of other causes, such as orthostatic hypotension, a neurocardiogenic reaction, cerebrovascular disease, or an arrhythmia. In addition, patients may have more than one abnormality that alone can cause syncope. In these patients the history may provide clues that enable the clinician to identify the cause of a particular event.