Blair P. Grubb, MD, FACC
A 32-year-old woman presents after suffering a series of syncopal events. During one of these events she fractured her shoulder. Each of the episodes has occurred while she was standing, and in each case she experienced a sensation of light-headedness lasting 2 or 3 seconds followed by an abrupt loss of consciousness during which she would fall to the ground. The actual loss of consciousness was brief (less than 2-3 minutes) and was usually not associated with injury. After each syncopal event the patient was mildly confused for a brief period and was severely fatigued. Bystanders who have observed some of her events report that she suddenly becomes pale and often becomes “stiff and sometimes shakes.” Physical examination is unremarkable. There are no orthostatic changes in heart rate or blood pressure. An electrocardiogram, echocardiogram, and electroencephalogram are all within normal limits. During head upright tilt table testing, at minute 15 of upright tilt she complains of light-headedness followed by an abrupt loss of consciousness. At the time of syncope her blood pressure fell from 120/80 mm Hg to 60/40 mm Hg and was associated with a 5-second period of asystole. She regained consciousness after being returned to the supine position. She reported that this episode felt identical to those she had experienced clinically. The patient was educated as to the nature of her condition, and therapeutic options were discussed.
ETIOLOGY AND PATHOPHYSIOLOGY
Syncope is defined as a loss of consciousness and postural tone with spontaneous recovery.1 Both a symptom and sign, syncope may be the sole warning prior to an episode of sudden death.2 Even when the cause is benign, recurrent syncope can result in injury and provoke a degree of functional and emotional impairment similar to that seen in other chronic debilitating disorders.3 Neurocardiogenic (or vasovagal) syncope is the most common of a group of disorders known as reflex (or naturally mediated) syncopes. These are characterized by a sudden failure of the autonomic nervous system (ANS) to maintain blood pressure (and on occasion heart rate) at levels sufficient to maintain cerebral perfusion and consciousness. Other types of reflex syncopes include carotid sinus hypersensitivity and syncope brought on by activities such as coughing, swallowing, defecation, and urination.4
While the exact etiology is still uncertain, it is currently felt that neurocardiogenic syncope occurs in people who are predisposed to these events as a consequence of excessive peripheral venous pooling which results in a sudden decline in peripheral venous return to the heart. The lack of volume produces a “hypercontractile” state in the heart, which causes activation of cardiac mechanoreceptors that normally are stimulated only by stretch. This generates an abrupt increase in afferent neural input to the brain, which duplicates the situation normally seen in severe hypertension, resulting in a sudden withdrawal of sympathetic nerve activity. This action produces an apparent “paradoxical” reflex, causing bradycardia and a drop in peripheral vascular resistance and resulting in systemic hypotension which, if sufficiently profound, leads to cerebral hypoperfusion and syncope. In the susceptible individual, activation of other mechanoreceptor beds in the body (such as those found in the rectum, bladder, lungs, and esophagus) can produce similar responses.
Neurocardiogenic syncope can be brought on by being in a warm environment, prolonged standing, pain, fear, and emotional distress. Prodromal symptoms include light-headedness, sweating, headache, fatigue, visual disturbances, feeling cold or hot, and nausea. External signs may include paleness, dilation of the pupils, yawning, and unsteady gait. While most patients will experience some kind of prodrome a significant number (often older patients) will not, in which case syncope may result in a fall with the risk of subsequent physical trauma. The actual loss of consciousness is usually short, often between 30 seconds and several minutes, (however in older patients it maybe longer). Some patients may experience body rigidity and stiffness (or even tonic–clonic-like activity in some) during an episode. Recovery is usually fairly rapid, with only mild confusion afterward. Following an episode the patient may exhibit pallor and experience weakness, headache, and fatigue.
A comprehensive history and physical examination are vital to the diagnosis, which necessitates excluding cardiovascular or neurologic disease. Patients should be queried as to any family history of cardiac disease or sudden death. Information should be obtained as to the frequency of events and the conditions under which they occur. Bystander descriptions are also quite helpful. The finding of a cardiac murmur or focal neurologic sign requires further evaluation by echocardiography or magnetic resonance imaging (MRI). We routinely obtain a 12-lead electrocardiogram on all patients and echocardiography if there is any question that the heart is normal.
Tilt table testing is the sole medical test for diagnosing neurocardiogenic syncope that has undergone careful evaluation. A positive test is one that elicits a hypotensive response that duplicates the patient’s clinical episodes. Several comprehensive resources have been published on the technical details of tilt table testing, established protocols, (including pharmacologic provocation), and the various patterns of hemodynamic response, to which the interested reader is directed.
Implantable loop recorders are also useful tools in determining whether severe bradycardia or asystole is associated with a syncopal event. The interested reader is directed to Chapter 49 The Implantable Loop Recorder in this book on the subject.
In situations where syncope only occurs in particular circumstances, management principally centers around educating both the patient and their family as to the nature of the disorder and the situations to be avoided, for example, dehydration, extreme heat, prolonged standing, as well as agents that facilitate syncope such as vasodilators and alcohol.
In patients with an adequate prodrome, isometric contractions of the leg and arm muscles can sometimes abort episodes by virtue of activation of the skeletal muscle pump, which seems to augment venous return. Increasing fluid and salt intake may reduce the frequency of syncopal episodes. While a variety of pharmacotherapies are employed to treat neurocardiogenic syncope, only a small number have been prospectively evaluated, and no drug has been approved by the U.S. Food and Drug Administration for the treatment of neurocardiogenic syncope. A list of potential treatments can be found in Table 47-1.
TABLE 47-1 Treatment Modalities for Neurocardiogenic Syncope
Briefly, while β-blockers have been used to prevent neurocardiogenic syncope, some studies have cast doubt on their effectiveness. While most studies have used metoprolol, we prefer nebivolol due to is low side effect profile. Fludrocortisone is a synthetic mineral corticoid that promotes retention of sodium as well as the expansion of central blood volume and sensitization of α-receptors in the peripheral vasculature. Midodrine hydrochloride is a direct α-1 receptor agonist which exerts direct vasoconstrictive effects (methylphenidate may be an acceptable alternative agent). The selective serotonin reuptake inhibitors are sometimes helpful, presumably by their desensitization of central reflexes.
Other treatments undergoing evaluation for refractory patients include octreotide, desmopression, and erythropoietin.
Permanent cardiac pacemaker placement has been advocated as a treatment for medically refractory patients based on the finding that up to one-third of these patients may experience severe bradycardia or asystole during either tilt-induced or spontaneously occurring syncope. While initial controlled studies of pacing were disappointing, it was realized that when pacemakers were placed in patients in whom asystole or bradycardia was documented during syncope using an implantable loop recorder the success rate was much higher (see Chapter 49, The Implantable Loop Recorder).
The recent ISSUE-3 trial was a randomized, double-blind, placebo-controlled trial of pacing in syncope patients with periods of asystole or profound bradycardia documented by an implantable loop recorder.10 Patients were randomized to pacing “on” or pacing “off.” At the end of 2 years, the acute recurrence in the pacemaker “off” group was 57% while the recurrence rate in the pacemaker on group was 25%.
These studies were performed using standard pacing systems that sense heart rate only. However, in neurocardiogenic syncope blood pressure falls first followed by a decline in heart rate. Therefore, in this condition standard pacemakers can only detect an event after it is well underway, offering “too little too late.” The recent development of pacemakers that have the ability to sense blood pressure have addressed this issue. Pacing systems using “closed loop stimulation” (CLS) have been show to be superior to standard pacing systems in preventing neurocardiogenic syncope.11,12 Ongoing studies will help clarify this finding.
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9. Bringole M. Randomized Clinical trials of neurally medicated syncope. J Cardiovasc Electrophysiol. 2003;14(S9):S64-S69.
10. Brignole M, Menozzi C, Moya A, et al. Pacemaker therapy in patients with neutrally medicated syncope and documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE-3): a randomized trial. Circulation. 2012;125:2566-2571.
11. Kanjwal K, Karabin B, Kanjwal Y, Grubb BP. Preliminary observations on the use of closed-loop cardiac pacing in patients with refractory neurocardiogenic syncope. J Interv Card Electrophysiol. 2010;27:69-73.
12. Palmisano P, Zaccaria M, Luzzi G, Nacci F, Anacierio M, Favala S. Closed loop cardiac pacing vs. conventional dual chamber cardiac pacing with specialized sensing and pacing algorithms for syncope prevention in patients with refractory vasovagal syncope: results of a long term follow up. Europace. 2012:14(7):1038-1043.