CLINICAL GUIDELINE: Diagnosing Syncope: Part 2: Unexplained Syncope

In the first part of this two-part study [1], the differential diagnosis of syncope was examined with respect to the information provided by results of the history, physical examination, and electrocardiography; an algorithmic approach to the diagnosis of syncope was also introduced. A careful history and physical examination are mandatory in all patients with syncope because they are the keys to determining whether additional diagnostic testing is required. Electrocardiography is recommended for almost all patients with syncope, whereas specialized neurologic testing is suggested only in certain circumstances: for example, computed tomography for patients with focal neurologic signs, electroencephalography for patients with seizure activity, or carotid or transcranial Doppler ultrasonography for patients with carotid bruits or a history of neurovascular symptoms. This paper addresses the workup of patients with syncope that is unexplained by the results of history, physical examination, or surface 12-lead electrocardiography. Unexplained Syncope Syncope that remains unexplained after initial clinical assessment is of considerable concern to the practicing clinician. The algorithm that we developed provides three branches for unexplained syncope: one for patients known to have or suspected of having heart disease, one for elderly patients, and one for patients not known to have or suspected of having heart disease (Figure 1). Figure 1. Algorithm for diagnosing syncope. Branch 1: Unexplained Syncope with Clinical Organic Heart Disease or Abnormal Electrocardiogram Organic heart disease is often known, discovered, or suspected in patients who have sudden or exertional syncope. Evaluation of patients known to have or suspected of having heart disease often begins with echocardiography or an exercise stress test to determine and quantify the degree of heart disease. If the results of these tests are negative, further cardiac testing can often be avoided. If the results are positive, however, subsequent testing may include Holter monitoring or telemetry, signal-averaged electrocardiography, and intracardiac electrophysiologic studies. Echocardiography No studies have been specifically designed to assess the usefulness of echocardiography in syncope. In patients known to have or suspected of having heart disease, patients suspected of having arrhythmias, or patients with abnormal electrocardiograms, echocardiography is an important initial step in diagnostic testing. Unsuspected findings on echocardiography are reported in only 5% to 10% of unselected patients [2]. This yield is similar to that of 12-lead electrocardiography, but echocardiography is 7 times more expensive. The cost-effectiveness of echocardiography in diagnosing the cause of syncope has yet to be determined. Exercise Testing Exercise stress testing can be used for the evaluation of exertional syncope to diagnose ischemia or exercise-induced tachyarrhythmias or to reproduce exercise-associated or postexertional syncope. In one population study of patients with syncope, the yield of the exercise stress test was less than 1% [3]. No data are available to determine the yield for ischemia or exercise-induced tachyarrhythmias or to define the test's usefulness in diagnosing exercise-associated syncope. Tilt-table testing has been used to diagnose neurally mediated syncope, which may manifest as postexertional syncope [4, 5]. Exercise stress testing is recommended if patients have exercise-associated syncope and if the results of clinical evaluation suggest ischemic heart disease. In patients with exertional syncope, echocardiography should be done first to exclude hypertrophic cardiomyopathy. 24-Hour Holter Monitoring We summarize the results of ambulatory monitoring in syncope by determining the presence or absence of arrhythmias in patients who develop symptoms during monitoring [6]. In studies that evaluated syncope or presyncope with 12 or more hours of monitoring and reported on symptoms, 4% of patients had correlation of symptoms with arrhythmias (Table 1) [7-14]. In about 15% of patients, symptoms were not associated with arrhythmias; this finding excluded rhythm disturbance as a cause for syncope in these patients (overall diagnostic yield in 8 studies, 4% + 15% = 19%). No symptoms occurred in approximately 79% of patients, but arrhythmias were found in 14% [7-14]. The causal relation between most of these arrhythmias and syncope is uncertain, although certain uncommon asymptomatic arrhythmias (prolonged sinus pauses, Mobitz type II block, and sustained ventricular tachycardia during sleep) usually prompt appropriate treatment. If no arrhythmias are found and no symptoms occur during monitoring, arrhythmic syncope is not necessarily excluded; this is because of the episodic nature of arrhythmias. In patients with a high pretest likelihood of arrhythmias (for example, patients who have brief loss of consciousness with short or absent prodrome, an abnormal electrocardiogram, or organic heart disease), further evaluation for arrhythmias should be pursued by event monitoring or electrophysiologic studies. Table 1. Yield of Prolonged Electrocardiographic (Holter) Monitoring in Syncope Only one study evaluated the effect of duration of monitoring on diagnostic yield [7]. Extending monitoring to 72 hours increased the number of arrhythmias detected (14.7% on the first day, an additional 11.1% the second day, and an additional 4.2% the third day) but not the yield for arrhythmias associated with symptoms. A 24-hour Holter monitor or inpatient telemetry is recommended when symptoms suggest arrhythmic syncope (brief loss of consciousness, no prodrome, palpitations with syncope) and in patients who have syncope of unexplained cause, heart disease, or an abnormal electrocardiogram. Loop monitoring may be a reasonable alternative in patients with recurrent syncope and a normal heart. Intracardiac Electrophysiologic Studies Although they are relatively safe in patients with syncope [15], electrophysiologic studies are expensive and invasive. Such studies are associated with low risks for pulmonary embolism, cardiac perforation, arteriovenous fistulae, and myocardial infarction (cumulative risk < 3%) [16]. Electrophysiologic studies use electric stimulation and monitoring to discover conduction abnormalities that predispose patients to bradyarrhythmias and to determine a patient's propensity for developing tachyarrhythmias (both ventricular and supraventricular). Most protocols for programmed stimulation include three extrastimuli at one or two ventricular sites. More aggressive protocols, including the use of isoproterenol, may increase the sensitivity but decrease the specificity of tests for detecting tachyarrhythmias. The most important outcome of electrophysiologic testing is the diagnosis of ventricular tachycardia. Other potentially important diagnostic outcomes include supraventricular tachycardias and bradyarrhythmias. Because only a few studies have used 24-hour Holter monitoring to confirm results of electrophysiologic studies [17, 18], the true diagnostic yield of this testing is generally unknown. Nevertheless, it is agreed that the results of an electrophysiologic test are considered positive if the test uncovers any of the following: 1) sustained monomorphic ventricular tachycardia [not including polymorphic ventricular tachycardia or ventricular fibrillation, which may be nonspecific responses], 2) a prolonged corrected sinus node recovery time longer than 1000 milliseconds, 3) markedly prolonged HV intervals longer than 90 milliseconds, 4) spontaneous or induced infra-Hisian block, and 5) supraventricular tachycardia with hypotension. For the accompanying analysis, we used the above definitions wherever possible, excluding supraventricular tachycardias (which are relatively uncommon outcomes of electrophysiologic testing in syncope and can be diagnosed by other means). Our primary purpose was to classify study results to determine predictors of positive results on electrophysiologic studies. Key predictors that we assessed were presence of organic heart disease and brady-arrhythmic abnormalities (such as conduction-system disease) found on 12-lead electrocardiography. Fourteen studies evaluating 1423 patients provided information on electrophysiologic outcomes but had insufficient detail to assess the importance of organic heart disease and baseline electrocardiography [19-32]. Heart disease was present in slightly more than half of the patients. Ventricular tachycardia was diagnosed in 14%, whereas a bradycardic outcome was observed in 21%. Because some patients (about 10%) had both tachycardic and bradycardic outcomes, the overall diagnostic yield in these studies (in which a high prevalence of patients had organic heart disease) was approximately 32% [14% ventricular tachycardia + 21% bradycardias 10% x (14 + 21)]. Table 2 summarizes eight additional studies in which the contribution of organic heart disease to a positive test result could be assessed [15, 17, 18, 33-37]. In these studies, 625 patients underwent electrophysiologic testing for syncope. Of the 406 patients with organic heart disease or an abnormal electrocardiogram, 21% had ventricular tachycardia and 34% had a bradycardia during the electrophysiologic study. Of the 219 patients with normal hearts, only 1% had ventricular tachycardia and 10% had a documented bradycardia (P < 0.001 for both comparisons). In these studies, approximately 14% of patients who could be given a diagnosis had both ventricular tachycardia and bradycardia. Thus, the diagnostic yield of electrophysiologic studies was almost 50% in patients with organic heart disease and about 10% in patients with a normal heart. Table 2. Diagnostic Yield of Intracardiac Electrophysiologic Studies in Syncope: Importance of Organic Heart Disease* These data are further elucidated by Table 3, which describes six referral st