Neurally Mediated Syncope

Abstract

Neurally mediated syncope is a disorder of the autonomic regulation of postural tone, which results in hypotension, bradycardia, and loss of consciousness. A wide variety of stimuli can trigger this reflex, the most common stimulus being orthostatic stress. Typically, a patient with neurally mediated syncope experiences nausea, lightheadedness, a feeling of warmth, and pallor before abruptly losing consciousness. If the cause of syncope is unclear, a stepwise approach is necessary to arrive at the diagnosis. The diagnosis of neurally mediated syncope can be confirmed by a head-up tilt-table test. Treatment options include behavioral modification and several pharmacologic therapies. For severe recurrent syncope unresponsive to conventional treatment, a pacemaker can be implanted.

Syncope is a sudden loss of postural tone followed by rapid, spontaneous recovery. It affects all ages, from the pediatric to the elderly. Because syncope is a symptom, not a disease, identification of the underlying pathologic process is essential for successful management. Syncope is often caused by an abnormal autonomic response. ¹ Several terms are used to describe this type of syncope, including vasovagal, neurocardiogenic, and neurally mediated syncope (NMS). We prefer the latter term because it indicates the underlying pathologic process. The triggering factor for NMS varies widely and includes orthostatic stress, emotional stress, urination, coughing, swallowing, physical exercise, and stimulation of the carotid sinus in susceptible persons.

Pathophysiology

The human body has a remarkable ability to maintain a stable blood pressure in the presence of ever-changing forces that constantly shift and redistribute the circulating blood volume. To achieve this steady control, reflex mechanisms continuously adjust the cardiac output and vascular tone. Even a simple change in posture, such as standing up, can result in a relatively “empty” ventricle owing to shifting of blood from the thorax to the abdomen and lower extremities. This shift in blood volume can markedly decrease the cardiac output. The decreased output is normally sensed by arterial baroreceptors located in the carotid sinus and aortic arch. ² These receptors transmit signals to the nervous system and result in reflex-increased sympathetic output. In addition, the vascular system responds locally by restricting blood flow to nonvital organs such as the skin, muscles, and adipose tissue, thereby augmenting peripheral resistance. Clinically, this response manifests as an increase in the heart rate (by 10 to 15 beats/min), which is thought to be mediated by increased sympathetic output, and a gradual diastolic-pressure increase of about 10 mmHg, which is probably mediated by local vasoconstriction. ³

Neurally mediated syncope is caused by “hypersensitivity” of the autonomic nervous system, which overresponds to different stimuli. Orthostatic stress is one of the most commonly encountered triggering factors seen in clinical practice. When related to orthostatic stress, syncope is believed to involve the following steps (Fig. 1):

Fig. 1 Steps involved in the development of syncope related to orthostatic stress.

1. The heart is partially emptied as a result of a fluid shift.

2. Activation of the above-described normal sympathetic reflex response results in hypercontractility of the ventricle in an attempt to increase the cardiac output.

3. Cardiac mechanoreceptors, which are usually activated by distension of the heart (for example, in conditions involving severe hypertension), undergo abnormal stimulation. This paradoxical stimulation is believed to result from the combined hypercontractility and emptiness of the ventricle.

4. Abnormal mechanoreceptor stimulation transmits neural signals, as the afferent limb of the abnormal reflex, to the tractus nucleus solitarius in the brainstem.

5. The tractus nucleus solitarius synapses with other centers in the brainstem, which are not clearly understood but may be located in the rostral ventrolateral medulla.

6. Through the efferent limb of this reflex, the para-sympathetic output is increased, and sympathetic output is inhibited, resulting in bradycardia, hypotension, and syncope. ⁴

Experience with NMS in patients with transplanted hearts, which are denervated, suggests that this process is not merely an abnormal reflex arc. ⁵ Cardiac afferents may not be needed to trigger the vasodepressor response; rather, that response may be triggered by receptors in the aorta, in the carotid sinus, and at the pulmonary vascular junctions, or even by direct central nervous system (CNS) output. ³ In addition, several neuroendocrine changes are observed during orthostatic stress. At the time of syncope, a higher level of adrenaline is found in patients with NMS than in normal volunteers. ⁶ Endocrine changes that have been observed during syncope include decreased renin activity and increased opiate, serotonin, vasopressin, and endothelin levels. ⁴ These changes can result in abnormal peripheral vasodilation and predispose the patient to hypotension and syncope. ⁷

Postural hypotension and syncope can result from degenerative changes in 1 or more components of the autonomic nervous system. In these cases, the hypotension is part of a general autonomic disorder that affects many other organs and functions. ^8,9 One form of autonomic dysfunction is postural orthostatic tachycardia syndrome (POTS), ¹⁰ which results from a failure of peripheral vasoconstriction. Patients present with hypotension, fatigue, and dizziness. An important feature of POTS is persistent tachycardia while the patient is upright, which may be misdiagnosed as inappropriate sinus tachycardia.

Diagnosis

Typically, a patient with NMS initially experiences warmth, nausea, and lightheadedness and may exhibit pallor before abruptly losing consciousness. ¹¹ However, occasional patients may not exhibit any symptoms at all. Before the diagnosis of NMS can be established, other causes must be ruled out by means of a thorough history, a careful physical examination, and appropriate clinical tests. In about half of the cases, the cause of syncope can be identified during the initial clinical evaluation, and no further testing is needed to make the diagnosis. ¹² When the cause is not clear, a stepwise approach is necessary for determining the diagnosis. ¹³ The differential diagnosis includes syncope associated with cardiac diseases and arrhythmias such as life-threatening ventricular dysrhythmia. Screening methods for heart disease include electrocardiography, stress testing, nuclear imaging, and echocardiography. If an arrhythmia is suspected, 24-hour Holter or long-term event monitoring, with either an external device or an implantable device with memory, may help establish the diagnosis. ¹⁴ Invasive electrophysiologic studies can be performed to clarify whether the syncope is caused by an arrhythmia such as ventricular tachycardia, supraventricular tachycardia, sinus node dysfunction, or intracardiac conduction delay. ¹⁵

If NMS is suspected in the absence of structural heart disease, a head-up tilt-table (HUTT) test is performed to confirm the diagnosis. ¹⁶ This is a provocative test in which the patient undergoes an orthostatic challenge designed to determine his or her susceptibility to syncope. During the test, resuscitative equipment should be available. With the patient in a fasting state, the head of the table is tilted upward to an angle of 60 to 80 degrees while hemodynamic and electrocardiographic monitoring is performed. The blood pressure is measured beat by beat with noninvasive techniques. The test is continued for 30 to 45 minutes unless hemodynamic collapse occurs earlier. If the patient's condition remains stable during this period, carotid-sinus massage is performed with the patient upright. If the findings are negative for NMS, a provocative agent such as nitroglycerin or isopro-terenol is administered, and tilting is continued for another 10 to 15 minutes. The result is considered positive if the original symptoms are reproduced with objective evidence of an abrupt blood pressure decrease or bradycardia (or both).

Another pattern of response to the HUTT test is observed in patients with autonomic failure who may show progressive hypotension as the blood pools in the lower extremities. Milder forms of autonomic failure (POTS) compensate for venous pooling by suddenly increasing the heart rate (by >30 beats/min, up to 120 beats/min), usually within the first 5 minutes. The blood pressure tends to decrease only slightly. ¹⁰

The specificity and sensitivity of the HUTT test are hard to determine because of methodologic differences in the test's performance. The absence of a “gold standard” also makes it difficult to determine normal versus abnormal results. Nevertheless, with “normal” volunteers and with patients who have a history typical of NMS, the reported specificity is about 90%, and the reported sensitivity ranges from 32% to 85%. ¹⁷ When a provocative agent is used, the sensitivity increases while the specificity decreases. Reproducibility of the results ranges from 35% to 85%. ¹⁷ In a recent study that assessed the reproducibility of the HUTT test using sublingual nitroglycerine as a provocative agent, the reproducibility of an initially negative test result was 83%, and that of an initially positive test result was 79%; the overall clinical reproducibility was 77%. ¹⁸

Treatment

Several strategies are available for treating NMS. The patient should be assured of the condition's benign nature. ¹⁹ However, NMS can affect the patient's quality of life and can pose a hazard during driving or in certain high-risk occupations. The condition may be controlled by an increased fluid and salt intake and avoidance of triggering factors such as dehydration, extreme heat, alcohol consumption, and prolonged standing. ²⁰ For patients with frequent episodes, orthostatic tilt training may be useful. ²¹

Because no single large, randomized study has been undertaken to evaluate the best treatment options for NMS, medical therapy is based on a number of small, mostly nonrandomized clinical studies. Drug studies are hampered by the unpredictable nature of the syncopal episodes. The choice of therapeutic agent should be tailored to each patient, taking into account the age of the patient, any concurrent medical conditions, and the safety and side effects of each agent. Beta blockers are the preferred initial agents. Alternatively, midodrine, selective serotonin uptake inhibitors, or fludrocortisone may be administered. Controversy exists regarding the benefit of other medicines such as theophylline or anticholinergic agents (e.g., disopyramide). The optimal duration of treatment is hard to determine. In patients at low risk for occupational injury, treatment for a defined period such as 12 months is reasonable. ²² In many of these cases, syncope will not recur. In patients with a high risk of syncope-related injury, the duration of treatment must be tailored individually.

Beta Blockers. Because beta blockers such as metoprolol or atenolol ^23–25 are effective and safe, with relatively few side effects, they are preferred for initial therapy. In preventing hypotension and bradycardia, these drugs' paradoxical effect is believed to arise from their blockage of catecholamines, which sensitize the receptors of the afferent limb of the reflex. If severe bradycardia develops during therapy with conventional beta blockers, the use of an agent with intrinsic sympathomimetic action (such as pindolol) may alleviate symptoms while having fewer adverse effects on the heart rate. ²⁶ Potential side effects of beta blocker therapy include fatigue, depression, and sexual dysfunction.

Alpha Agonists. These drugs exert their effect peripherally by increasing vascular resistance and decreasing vascular capacitance. Potential side effects of alpha agonists include hypertension, paresthesia, urinary retention, “goose bumps,” hyperactivity, dizziness, tremor, and nervousness. A prototype of this drug group is midodrine, which has proved to be effective in randomized clinical trials. ^27,28 However, patient compliance with therapy may be difficult because the medication must be taken 3 times a day. Midodrine does not cross the blood-brain barrier, so it should have no CNS effects.

Selective Serotonin Reuptake Inhibitors. Serotonin is a CNS neurotransmitter that regulates many functions, including those of the cardiovascular system. In animals, intravenous or intracerebral injection of 5-hydroxy-tryptophan, the precursor of serotonin, abruptly lowers the blood pressure and heart rate. ²⁹ Pretreatment with selective serotonin reuptake inhibitors leads to an initial increase in the concentration of extracellular serotonin, which, in turn, causes downregulation of postsynaptic receptor density. This change is postulated to prevent overstimulation of the postsynaptic area by a surge of serotonin. ³⁰ Paroxetine, ³¹ fluoxetine, ³² and sertraline ³³ are selective serotonin reuptake inhibitors useful in treating NMS. Although generally well tolerated, these drugs may cause anxiety, headache, or insomnia in some patients.

Fludrocortisone. Fludrocortisone is a mineralocorticoid that increases blood volume by augmenting renal sodium absorption. By sensitizing alpha-adrenergic receptors, it may also increase the vasoconstrictive peripheral vascular response. ³⁴ This agent has been studied and found beneficial, mainly in pediatric groups. ³⁵ Adverse effects include hypertension, peripheral edema, depression, and acne formation.

Anticholinergic Agents. Disopyramide, scopolamine, ³⁶ and propantheline ³⁷ counteract the high level of vagal activity associated with NMS. Side effects include dry mouth, blurred vision, confusion, disorientation, and urinary difficulty.

Pacemaker Therapy. Pacing is useful in patients with hypersensitive carotid sinus syndrome and neurally mediated symptoms associated with severe, recurrent syncopal episodes. ^38,39 According to guidelines published by the American College of Cardiology/American Heart Association, the following condition is considered a class I indication (Table I) for pacemaker therapy: recurrent syncope caused by carotid sinus stimulation ⁴⁰ when minimal carotid sinus pressure induces ventricular asystole lasting for more than 3 seconds in the absence of medication that depresses sinus-node or AV conduction. In contrast, recurrent syncope without a clear provocative event and with a hypersensitive cardioinhibitory response is considered a class IIa indication for pacemaker implantation. Neurally mediated syncope, with severe bradycardia reproduced during HUTT testing with or without a provocative agent, is a class IIb indication. In contrast, vague symptoms (dizziness or lightheadedness) in the absence of syncope are a class III indication. In the North American neurally mediated pacemaker study, ³⁹ which involved 54 patients with frequent syncopal spells and positive HUTT results, recurrence of syncope was significantly reduced in patients with pacemakers (22%) versus those without pacemakers (70%). Nevertheless, in patients with frequent syncope, pacing tends to be reserved until other therapies have been exhausted. Pacemakers are generally more useful in patients who have a cardioinhibitory, rather than a vasodepressor, response. However, bradycardia induced by HUTT testing does not necessarily predict a beneficial response to pacemaker therapy, and the length of asystole should not be a criterion for pacemaker implantation.

Table I. American College of Cardiology/American Heart Association Guidelines for Pacemaker Implantation in Patients with Syncope

Conclusion

Neurally mediated syncope includes a heterogeneous group of disorders characterized by an abnormal autonomic response that results in hypotension, bradycardia, and temporary loss of consciousness. Because syncope can herald various disease processes, patients with this symptom should undergo a thorough evaluation designed to identify the underlying pathologic process. Although HUTT testing is effective for diagnosing NMS, it is limited by its moderate sensitivity.

Several options are available for treating NMS. The physician's awareness and the patient's education are essential elements of medical care. Beta blockers are the first line of pharmacologic therapy. Alternative agents include alpha agonists, serotonin uptake inhibitors, fludrocortisone, and anticholinergic agents. Therapy is guided by symptom recurrence and the pharmacologic side-effect profile. If symptoms are severe and medical treatment options have been exhausted, pacemaker implantation may be considered.

More research is needed to further define the patho-logic mechanism of NMS and to expand its diagnostic and treatment options.

Acknowledgment

The authors thank Virginia D. Fairchild, medical editor, for helping to prepare this manuscript.