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(Circulation. 1995;92:1332-1335.)
© 1995 American Heart Association, Inc.

Articles

Electrophysiological Testing

The Final Court of Appeal for Diagnosis of Syncope?

George J. Klein, MD; Bernard J. Gersh, MBCLB DPhil; Raymond Yee, MD

From the Department of Medicine, University of Western Ontario, London, Ontario, Canada, and the Cardiology Division, Georgetown University Medical Center, Washington, DC, USA.

Correspondence to Dr George J. Klein, University Hospital, 339 Windermere Rd, London, Ontario, Canada N6A 5A5.

Key Words: diagnosis • electrophysiology • tachyarrhythmias • syncope

	Introduction

Top Introduction Diagnostic Evaluation Invasive Electrophysiological... Conclusions Based on... Assessment of Therapeutic... Unresolved Issues References

 
Unexplained syncope is a relatively frequent cause of admission to emergency departments, and it continues to pose a clinical dilemma, despite the development of new diagnostic techniques.^{1 2 3 4 5 6} For the patient, the syndrome is a source of morbidity and, to a lesser extent, mortality. Recurrences may have a substantial and deleterious effect on lifestyle, the sense of physical well-being, and employment opportunities. Understandably, the search for treatable or preventable causes and identification of cost-effective approaches to syncope continue to remain a focus of clinical interest.

	Diagnostic Evaluation

Top Introduction Diagnostic Evaluation Invasive Electrophysiological... Conclusions Based on... Assessment of Therapeutic... Unresolved Issues References

 
The cause of a syncopal episode is frequently problematic if the diagnosis is not evident after the initial clinical and laboratory assessment.^{1 2 3 4 5 6} The major obstacle to diagnosis is the periodic and unpredictable frequency of events, with months and years separating spells and a high spontaneous remission rate.⁷ This creates a prohibitive barrier for recording of the ECG during a spontaneous episode in most patients, and even aggressive and prolonged ECG monitoring may yield only a 16% diagnosis rate over a 6-month period.⁵ Perhaps the most valuable clinical tools for the diagnosis of syncope are the clinical history and, in some patients, the use of additional tests to identify structural heart disease. An abnormal ECG frequently is present in patients with syncope but rarely identifies the specific cause. Prolonged ambulatory monitoring has been used widely as a diagnostic tool, but most frequently it identifies nonspecific arrhythmias in the absence of symptoms. Despite the widespread acceptance of ambulatory monitoring as a key aspect of our diagnostic armamentarium for syncope, documentation of significant arrhythmias or syncope during ambulatory monitoring is extremely rare. The use of patient-activated recorders is most productive in motivated patients who experience relatively frequent episodes.

	Invasive Electrophysiological Testing

Top Introduction Diagnostic Evaluation Invasive Electrophysiological... Conclusions Based on... Assessment of Therapeutic... Unresolved Issues References

 
In the absence of an ECG tracing or other record during spontaneous syncope, the only diagnostic gold standard, clinicians may rely on abnormal laboratory results to provide a presumptive diagnosis for initiating therapy. The goals of tilt testing and electrophysiological testing are to provoke symptoms under controlled conditions to arrive at a diagnosis. Reproducing symptoms can be more convincing than recording asymptomatic abnormalities, especially if a unique prodrome is reproduced. Reproducing symptoms is still a surrogate for the spontaneous event, however, and it is readily appreciated that sudden loss of consciousness in an individual may be subjectively similar regardless of the mode of induction.

On the basis of the premise that most cardiogenic syncope is related to an arrhythmia, tachyarrhythmia, or bradyarrhythmia, electrophysiological testing has great intuitive appeal. Intracardiac recording can measure conduction time over the AV node and His-Purkinje system.^{8 9} Pacing and extrastimuli can assess the response of the sinus node to overdrive stimulation and stress the AV conduction system.¹⁰ Many "clinical" arrhythmias, including those due to AV reentry, AV node reentry, and monomorphic ventricular tachycardia, can be reproducibly induced in the electrophysiology laboratory.^{11 12} In patients with unexplained syncope, however, there is no diagnostic gold standard to assess the validity of the result.⁵ The abnormalities observed are generally accepted as "specific" or "diagnostic" if markedly abnormal or if the abnormality is infrequently seen in healthy persons, as with sustained monomorphic ventricular tachycardia (VT). Since the earliest studies using electrophysiological studies for syncope,^{13 14 15 16} many investigators have described their clinical results with this technique for syncope patients after noninvasive attempts have failed.^{17 18 19 20 21 22 23 24 25 26 27 28 29 30} Table 1 summarizes some larger studies in the range of 100 patients. All these studies have described abnormalities, most frequently sustained VT, that have been defined as "diagnostic," have based treatment on these abnormalities, and have reported the results of therapy. Patients who had negative study results had therapy withheld or were treated empirically. Table 1 demonstrates many of the complexities involved in analyzing the use of electrophysiological testing in the diagnosis of syncope. The overall impressions are that test results are positive in 50% of patients and that half the study population has organic heart disease. The likelihood of recurrence is low in patients who had positive test results (and who presumably were receiving electrophysiological testing-guided therapy). On the other hand, the results at first glance for patients who tested negative appear to be similar, with the exception of a lower cardiovascular disease mortality in this group as a manifestation of a lower incidence of underlying structural heart disease.

View this table: [in this window] [in a new window]   Table 1. Electrophysiological Testing in Syncope

	Conclusions Based on Electrophysiological Testing

Top Introduction Diagnostic Evaluation Invasive Electrophysiological... Conclusions Based on... Assessment of Therapeutic... Unresolved Issues References

 
A great deal has been learned from these studies. (1) The yield of abnormalities is higher in patients with heart disease, and the test is most productive in this group. (2) Patients who have positive electrophysiological study results (generally VT) have a poorer prognosis than those who tested negative (Table 1). Since patients with inducible VT have more severe heart disease and left ventricular dysfunction, the independent contribution of this variable has not been rigidly established. (3) Patients in whom therapy is predicted to be effective fare better than their counterparts who do not have predictive therapy in many^{17 20 23 25 27 28 29} but not all studies.^{18 19 22 30} If patients who do not have predicted effective therapy have a poor prognosis, it is uncertain whether this is related to absence of therapy or to identification of a higher-risk group whose VT cannot be suppressed adequately. (4) Every clinician performing these studies has been impressed by dramatic individual cases in which frequent episodes of syncope are eliminated after identification and treatment of the offending problem.

	Assessment of Therapeutic Efficacy: Statistical Limitations

Top Introduction Diagnostic Evaluation Invasive Electrophysiological... Conclusions Based on... Assessment of Therapeutic... Unresolved Issues References

 
In most patients, assessment of the efficacy of therapy is hampered by the sporadic nature of syncopal events, the temporal proximity of the study, and the initiation of therapy to the most recent episode. The last reason is frequently the precipitant of the evaluation that consequently led to the introduction of therapy The effect of treatment on subsequent outcome is difficult to analyze statistically unless follow-up is lengthy or unless the patient has a history of frequent episodes occurring consistently over a prolonged period, which is an uncommon clinical syndrome. This circumstance is likely to bias the data in favor of a "favorable" response to therapy without a recurrence, but it may be a reflection of selection bias, in that the majority of patients would have had a recent episode before the electrophysiology study and would be reasonably expected to be free of recurrence for some time after the study. This could be entirely unrelated to the treatment instituted.

	Unresolved Issues

Top Introduction Diagnostic Evaluation Invasive Electrophysiological... Conclusions Based on... Assessment of Therapeutic... Unresolved Issues References

 
The American Heart Association and the American College of Cardiology³¹ recommend electrophysiological testing if a diagnosis is not obtained by noninvasive techniques, especially in the patient with organic heart disease. But electrophysiological testing has significant shortcomings as a "court of last appeal" in this patient population (Table 2): (1) Inspection of Table 1 reveals that 14% to 70% of patients will have a nondiagnostic study performed. The tilt test has been used widely to screen patients for vasodepressor syncope, and routine use of this test (which was not used for any study in Table 1) undoubtedly would have improved diagnostic yield. In a study specifically addressing the yields of both electrophysiology studies and tilt tests, 26% of patients remained undiagnosed after both studies.³² Although these patients are said to have a good prognosis, it is small consolation to the individual faced with the specter of recurrent spells, which may limit their choice of occupation, recreational activities, and ability to drive. (2) Patients with severe organic heart disease and the elderly frequently have multiple abnormalities pointing to potential bradycardia or tachycardia.^{5 33} These abnormalities are not definitive, and since therapy is often invasive and complex (eg, permanent pacemaker implantation, antitachycardia devices, or antiarrhythmic drugs), the abnormal results place the physician and the patient in a quandary. Unfortunately, the specificity of these findings is unknown. (3) Diagnostic yield for patients with intermittent AV block and sinus node dysfunction may be low.^{34 35} (4) Criteria for a "specific" abnormality have been established on reasonable principles but without rigid validation and with many gray areas. For example, are "borderline" abnormalities meaningful? Is sustained monomorphic VT at cycle length 180 as meaningful as that at cycle length 300, or is it "ventricular flutter" and not specific? Is a His-ventricular (HV) time diagnostic at 80 milliseconds but nonspecific at 70 milliseconds? What is the specificity? (5) How is organic heart disease defined? It is well established that clinical sustained monomorphic VT is induced most reliably and reproducibly in patients who have coronary artery disease and previous infarction and is induced considerably less reliably in other patients.⁴ Should electrophysiological testing be restricted to this group? Does noninducibility in a patient with valvular heart disease and left ventricular dilatation rule out ventricular tachycardia as a cause of syncope? (6) Does electrophysiological testing provide data that result in cure of syncope? Although such testing clearly does in individuals and may do so in general, this is difficult to prove with available data. Table 1 shows a "cure" rate of 84% in patients who tested positive and a cure rate of 78% in those who tested negative. It is reasonable to argue that a positive study selects a "sicker" group of patients who might otherwise have had an even lower cure rate. However, this clearly cannot be proved by treating all patients who tested positive and is not evident from data currently available. (7) Does electrophysiologically guided therapy improve the mortality rate in patients who experience syncope? The mortality rate in patients who have syncope and accompanying significant heart disease is high (Table 1), and electrophysiological testing is recommended in this group with the implicit hope that mortality can be prevented.³¹ Again, Table 1 shows that patients who tested positive continue to have a high mortality rate. Smaller studies have suggested that positive electrophysiology studies may identify higher-risk patients, but the mortality rate appears to be related to severity of heart disease and is not clearly altered by electrophysiological testing.^{30 36} It is certainly arguable that the mortality rate in the electrophysiological study groups who tested positive in Table 1 would have been higher if patients were not treated, but this is not established clearly. Rules of evidence have been described for grading the quality of a "recommendation" on the basis of available data from level 1 (best) through level 5 (most tenuous).³⁷ Electrophysiological testing for syncope is supported at best by level 4 evidence, since neither randomized nor concurrent cohort comparison data are available to validate the utility of this test for preventing syncope and reducing the mortality rate.

View this table: [in this window] [in a new window]   Table 2. Unresolved Issues in Electrophysiological Testing for Syncope

Invasive electrophysiological testing for the diagnosis of syncope has been embraced enthusiastically by the electrophysiological community. The optimistic descriptor "diagnostic yield" is preferred in many publications over the alternative designation of "yield of abnormal results," and "sensitivity" is used with the assumption that the abnormal test result is the cause of syncope. Research has been focused to provide noninvasive predictors of a positive study^{21 26 38 39} rather than to validate the meaning of a positive test. This is not surprising, given the relative futility of other diagnostic techniques and the attractions of electrophysiological testing, which include a comprehensive assessment of the conduction system and the inducibility of supraventricular or ventricular arrhythmia. Nonetheless, although the logic of this diagnostic strategy, which has been in place for almost 15 years, is indisputable, the sensitivity and specificity of electrophysiological testing and the results of test-guided therapy on the recurrence of syncope have not been subjected to rigorous scrutiny.

A major impediment to the evaluation of treatments that are based on this approach is the understandable reluctance of physicians to use placebo therapy, particularly in patients with syncope and underlying structural heart disease. Emerging technological advances would suggest that this is a trial whose time has now come (Figure). High-risk patients could be treated with implantable defibrillators or pacemakers that have the diagnostic capability to record subsequent events. This, in turn, would validate the result of the electrophysiological test that initially dictated the therapy. Patients can be randomized to therapy or no therapy if they are considered to be at low risk of sudden death.⁴⁰ Alternatively, such patients could be randomized prospectively to strategies that did or did not incorporate electrophysiological testing. In patients with presumed vasodepressor syncope, there are conflicting data concerning the utility of pharmacological therapy that are based on the results of repeat tilt-table testing.^{41 42} A positive tilt test result may expose a tendency toward vasodepressor syncope in an individual but does not prove that this caused syncope. The long-term reproducibility of a positive tilt test result is not clear.⁴² A large, multicenter trial is needed to assess our ability to treat this troublesome condition with pharmacological therapy and ways of assessing therapeutic efficacy ahead of time. The quest for diagnostic gold standards can be reestablished by a new technique that is capable of long-term ambulatory ECG monitoring for periods of months and years, as opposed to days and weeks.^{43 44} This will be extremely helpful in the evaluation of patients who test negative and have sporadic episodes of syncope.

View larger version (18K): [in this window] [in a new window]   Figure 1. Potential framework for a randomized trial. ICD indicates implantable cardioverter defibrillator.

In conclusion, the limitations of current strategies to diagnose and treat syncope have been appreciated by many contributors to the field.^{3 4 5 7 16 19 20 28 30 34 35 36} It is time to achieve the next milestone in our understanding and management of this problem, which is vexing for both physician and patient.

	Acknowledgments

 
This study was supported in part by the Heart and Stroke Foundation of Ontario (Canada).

	Footnotes

 
Dr G.J. Klein is a Career Investigator for the Heart and Stroke Foundation of Ontario (Canada).

Received February 9, 1995; revision received March 23, 1995; accepted March 26, 1995.

	References

Top Introduction Diagnostic Evaluation Invasive Electrophysiological... Conclusions Based on... Assessment of Therapeutic... Unresolved Issues References

 

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This Article Extract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Klein, G. J. Articles by Yee, R. Search for Related Content PubMed PubMed Citation Articles by Klein, G. J. Articles by Yee, R.