Natural history of patients with unexplained syncope and a nondiagnostic electrophysiologic study

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Natural History of Patients With Unexplained Syncope and a Nondiagnostic Electrophysiologic Study JEFFREY A . KUSHNER, MD, WILLIAM H . KOU, MD, ALAN H . KADISH, MD, FRED MORADY, MD, FACC Ann Arbor, Michigan

The purpose of this study was to define the natural history of 99 patients with unexplained syncope who underwent an electrophysiologic test that either was entirely normal or demonstrated nonspecific abnormalities that were nondiagnostic (inducible polymorphic ventricular tachycardia or ventricular fibrillation, a mildly prolonged sinus node recovery time of < s, a His-ventricular interval of 55 to 99 ms or supraventricular tachycardia not associated with hypotension) . The mean age (±SD) of the patients was 56 ± 19 years; structural heart disease was present in 47 patients and absent in 5 . Complete follow-up was available in 95 patients. During 0 ± 11 months of follow-up, patients ( %) died suddenly, 19 patients ( 0%) had recurrent syncope and 74 patients (78%) had no further episodes of syncope . Among the 19 patients who continued to have syncope after

Many studies have demonstrated the diagnostic value of electrophysiologic testing in patients who have syncope that is unexplained despite a complete clinical evaluation (1-10) . The most commonly found abnormalities of diagnostic value in these patients have been monomorphic ventricular tachycardia, conduction abnormalities in the His-Purkinje system and sinus node dysfunction . However, even in patients who have documented clinical evidence of these abnormalities, the electrophysiologic study at times may be unrevealing (11-16) . Therefore, it is possible that some patients with unexplained syncope caused by an occult arrhythmia may have a false negative electrophysiologic study . These patients would be expected to have a poor prognosis, with

the electrophysiologic testing, the cause of syncope was established clinically in 4 and was found to be high degree atrioventricular (AV) block ( patients) or sinus node dysfunction ( patients) . No clinical or laboratory findings distinguished patients who had sudden death or syncope during follow-up from patients who did not . In conclusion, in patients with unexplained syncope who undergo an electrophysiologic test that is nondiagnostic 1) the incidence of sudden death is low ( %) ; ) the remission rate of syncope is high (80%) ; 3) the electrophysiologic test may be documented to have been falsely negative in >_ 0% of patients who continue to have syncope, syncope in these patients being caused by AV block or sinus node dysfunction ; and 4) patients at risk of sudden death or recurrent syncope, or both, cannot be readily identified prospectively . (J Am Coll Cardiol 1989;14 :391-6)

sudden death or recurrent episodes of syncope during follow-up . The purpose of the present study was to define the natural history of a large group of patients with unexplained syncope whose electrophysiologic test was nondiagnostic . We were particularly interested in how often these patients had an outcome indicative of a false negative electrophysiologic test : sudden death or documented arrhythmias during follow-up . In addition, our purpose was to determine whether potentially high risk patients can be identified within the group of patients with unexplained syncope who have a nondiagnostic electrophysiologic test .

Methods Selection of patients . The study group consisted of 99 consecutive patients who had unexplained syncope and From the Division of Cardiology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan . Manuscript received November 9, 1988 ; revised manuscript received February 15, 1989, accepted March 8, 1989 .

Address for reprints : Fred Morady, MD, Division of Cardiology, University Hospital, 1500 East Medical Center Drive, UH B1F 45-00 , Ann Arbor, Michigan 48109-00 . ©1989 by the American College of Cardiology

nondiagnostic findings in an electrophysiologic study performed at our institution between July 1984 and July 1987 . Syncope was defined as abrupt and transient loss of consciousness unrelated to trauma . Complete clinical, neurologic and noninvasive cardiac evaluation in each patient had 0735-1097/89/$3 .50



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KUSHNER ET AL . UNEXPLAINED SYNCOPE

failed to disclose a likely cause of syncope . Patients who had a history suggestive of situational vasodepressor- or neurally mediated syncope and patients with carotid sinus hypersensitivity were excluded . The 99 patients in this study were part of a larger group of 160 patients who, after providing informed consent, underwent electrophysiologic testing for evaluation of unexplained syncope . The stimulation protocol has been described previously (17) ; programmed ventricular stimulation was performed with one to three extrastimuli at two basic drive cycle lengths (400 and either 500 or 600 ms) and at two right ventricular sites . One or more abnormalities presumed to be related to the cause of syncope were identified in 61 of the 160 patients . These abnormalities consisted of inducible monomorphic ventricular tachycardia, a sinus node recovery time > s, an infranodal conduction interval (HV) >100 ms, pathologic infranodal block during atrial pacing or inducible supraventricular tachycardia associated with hypotension . The 99 patients who are the subjects of the present study had none of these abnormalities ; their electrophysiologic study either was entirely normal or demonstrated an abnormality considered to be nonspecific and not diagnostic of the cause of syncope . These nondiagnostic abnormalities consisted of inducible polymorphic ventricular tachycardia or ventricular fibrillation, a mildly prolonged sinus node recovery time (< s), an HV interval of 55 to 99 ms or supraventricular tachycardia not associated with hypotension . Clinical characteristics . There were 61 men and 38 women with a mean age (±SD) of 56 ± 19 years and a history of 3 . ± 5 episodes of syncope . Twenty-six patients had coronary artery disease, 1 had mitral valve prolapse, 6 had dilated cardiomyopathy, 3 had valvular heart disease and 5 had no evidence of structural heart disease . The mean left ventricular ejection fraction was 0 .36 ± 0 .08 among the patients who had structural heart disease . Continuous ambulatory electrocardiographic (ECG) monitoring demonstrated 3 to 8 beat runs of asymptomatic nonsustained ventricular tachycardia in 1 patients, and occasional (average of <30/h) or frequent (average of ?30/h) ventricular premature depolarizations in 3 and 18 patients, respectively . The 1 lead ECG demonstrated bundle branch block in eight patients . Treatment . Seventy-seven of the 99 patients in this study did not receive any specific treatment directed to the prevention of syncope . Among the other patients, antiarrhythmic drug therapy with quinidine, disopyramide or mexiletine was instituted for the treatment of ventricular premature dipolarizations in 1 and for the treatment of atrial fibrillation in . Anticholinergic drug therapy directed toward possible neurally mediated syncope was instituted in five patients ; two patients were treated empirically with phenytoin for a possible seizure disorder and one patient was

treated empirically with aspirin for possible transient ischemic episodes . Follow-up. The patients were followed up by one of us or by the referring physician . Complete follow-up was available in 95 of the 99 patients ; the mean duration of follow-up was 0 ± 11 months (range 3 to 4 months) . All surviving patients were interviewed in person or by telephone by one of us . If the patient had died, a family member was interviewed . Pertinent information also was obtained from the patients' personal physicians . Sudden death was defined as death that occurred during sleep or within an hour of the onset of unexpected collapse . Analysis of data . Data were analyzed with use of Student's t test, Fisher's exact test or chi-square analysis . The time course of recurrent syncope and sudden death during follow-up was determined by generating a survival curve with the Kaplan-Meier product-limit method . A p value <0 .05 was considered significant .

Results General results . During 0 ± 11 months of follow-up (range 3 to 4 months), patients ( %) died suddenly, 19 ( 0%) had recurrent syncope and 74 (78%) had no further episodes of syncope . Sudden death . Among the 95 patients with complete follow-up information, patients died suddenly . One patient was an 80 year old man with coronary artery disease, a left ventricular ejection fraction of 0 .34, atrial fibrillation and an episode of unexplained syncope . Electrophysiologic testing demonstrated no abnormalities other than atrial fibrillation . A 4 h ambulatory ECG demonstrated occasional ventricular premature depolarizations and atrial fibrillation with a ventricular rate of 80 to 110 beats/min . He was treated with verapamil and had no further episodes of syncope, but died suddenly while walking 9 months after electrophysiologic testing . The second patient was a 58 year old man with a history of chronic alcohol abuse and no evidence of structural heart disease . Electrophysiologic testing performed after three episodes of unexplained syncope demonstrated sustained polymorphic ventricular tachycardia induced by programmed ventricular stimulation with triple extrastimuli . A 4 h ambulatory ECG demonstrated no arrhythmias other than rare atrial and ventricular premature depolarizations, and the patient was not treated with antiarrhythmic drugs . Eighteen months after electrophysiologic testing, he had another episode of syncope and died in his sleep several days later . Recurrent syncope . Nineteen ( 0%) of 93 patients who did not die suddenly during follow-up had one or more episodes of syncope (mean 1 .8 ± 1 .7) after the electrophysiologic study ; these episodes did not result in any significant injury . The time course of recurrent syncope and sudden death after electrophysiologic testing is shown in Figure 1 .



to

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± 1 months of follow-up after the nondiagnostic electroyear old

KUSHNER ET AL . UNEXPLAINED SYNCOPE

393

nondiagnostic electrophysiologic test, 1 underwent a second test 7 months after the first . This patient was a 6 man with coronary artery disease who had an HV interval of 70 ms without other abnormalities during the first electrophysiologic study . During the second study, the HV interval was 100 ms . A permanent pacemaker was implanted and the patient has had no further episodes of syncope during 6 months of follow-up . Remission of syncope . Among the 93 patients who did not die suddenly, 74 (80%) had no recurrences of syncope during

Figure 1 . Time course of sudden death and recurrent syncope after nondiagnostic electrophysiologic test in 95 patients for whom follow-up information was available . The proportion of patients free of sudden death and recurrent syncope is plotted against the duration of follow-up . The numbers in brackets refer to the population size at the corresponding points in time .

The cause of syncope was established on a clinical basis in 4 of the 19 patients who had recurrent syncope after the nondiagnostic electrophysiologic test . Two patients were documented to have intermittent third degree AV block with an idioventricular escape at a rate of 0 to 30 beats/min months after the test . One of these patients was a 67 year old man who at the time of testing had left bundle branch block, an HV interval of 70 ms and no infranodal block during incremental atrial pacing to the point of AV node Wenckebach block at a cycle length of 400 ms . The other patient was a 35 year old woman with idiopathic dilated cardiomyopathy and a left ventricular ejection fraction of 0 . 8 . During electrophysiologic study, this patient manifested a normal QRS duration, a normal HV interval of 50 ms and no infranodal block during incremental atrial pacing to the point of AV node Wenckebach block at a cycle length of 430 ms . Both patients underwent implantation of a permanent pace9 maker and neither has had further syncope during 1 months of follow-up . Two additional patients were documented to have a significant bradyarrhythmia . One was a 9 year old man without structural heart disease who was noted to have a 4 s sinus pause during continuous telemetric ECG monitoring I day after an electrophysiologic study demonstrated a normal sinus node recovery time and no other abnormalities . The second patient was a 76 year old woman with coronary artery disease who presented to the hospital with a functional bradycardia at a rate of 5 beats/min and hypotension after experiencing syncope I month after electrophysiologic testing demonstrated a normal sinus node recovery time and no other abnormalities . Both patients received a permanent pacemaker and have had no further episodes of syncope during 8 to 6 months of follow-up . Among the 19 patients who had recurrent syncope after a

physiologic test . Before the test, these 74 patients had experienced a mean of 3 .8 ± 5 episodes of syncope over 1 to 58 months . Included among these 74 patients are 11 who died during follow-up from a documented nonarrhythmic cause . Life table analysis demonstrated that 67% of patients remained free of recurrent syncope and sudden death at 4 months of follow-up (Fig . 1) . Comparison of patients with and without recurrent syncope or sudden death (Table 1) . The 1 patients who experienced recurrent syncope or who died suddenly during follow-up were compared with the 74 patients who did not experience syncope or sudden death after electrophysiologic testing . There were no significant differences between the two groups of patients in age, gender, incidence of structural heart disease, mean left ventricular ejection fraction, incidence of bundle branch block, occurrence of nonsustained ventricular tachycardia or ventricular premature depolarizations during ambulatory ECG monitoring, mean HV interval or incidence of inducible polymorphic ventricular tachycardia or ventricular fibrillation . Discussion Main findings . This study evaluated the outcome of a large group of patients with and without structural heart disease who had unexplained syncope and who underwent an electrophysiologic test that was not helpful in elucidating the cause of syncope . The major findings in this group of patients followed during up to 3 years of followup after testing were that 1) there was a low incidence rate ( %) of sudden death ; ) 80% of patients had no further episodes of syncope ; 3) among the patients who continued to have syncope, the electrophysiologic test was documented to be falsely negative in approximately 0% of patients (the documented abnormalities that were not detected during testing were intermittent high degree AV block and marked sinus slowing or sinus arrest) ; and 4) there were no clinical or laboratory findings that distinguished patients who died suddenly or had recurrent syncope from patients who had an uneventful follow-up . Sudden death . The low incidence of sudden death in this study indicates that a nondiagnostic electrophysiologic test in patients with unexplained syncope identifies a group of

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Table 1 . Comparison of Patients With and Without Syncope or Sudden Death During Follow-up Recurrent Syncope or Sudden Death No . of patients Age (yr) No . of men Structural heart disease LV ejection fraction Bundle branch block Nonsustained VT during AEM <30 VPDs/h during AEMt >_30 VPDs/h during AEMt HV interval (ms) Inducible polymorphic VT/VF

No Recurrent Syncope or Sudden Death

p Value

1

74

56 ± 19* 10(48%)

55 ± 19

NS

48 (65%n) 36 (49%) 0 .48 ± 0 .13

NS NS NS

11 (5 %) 0 .44 ± 0 .16 1 (5%)

7 (9%)

NS

6( 8%) 4(19%)

15 ( 0%) 19 ( 6%)

NS NS

6( 8%) 48 ± 1

1 06%) 46±9

NS NS

8 (38%)

19( 6%)

NS

*Mean ± SD ; taverage frequency of VPDs during 4 h of monitoring . AEM = ambulatory electrocardiographic monitoring ; HV = His-ventricular ; LV = left ventricular ; NS = not significant ; VF = ventricular fibrillation ; VPD = ventricular premature depolarization ; VT = ventricular tachycardia .

patients that is overall at low risk of dying from a serious

out the possibility of intermittent high degree AV block as

arrhythmia . The actual cause of death in the two patients in

the cause of syncope . One of the two patients who were

this study who died suddenly is not known ; however, even if

documented to have high degree AV block during follow-up

an arrhythmia is assumed to have been the cause of sudden

did not have an underlying bundle branch block . Therefore,

death, the % overall incidence of sudden death in this study

the possibility that AV block is the cause of syncope in

is considerably lower than the

patients who undergo a nondiagnostic electrophysiologic test is not limited to patients with bundle branch block .

4% incidence of sudden

death at 1 year of follow-up in patients who have a cardiovascular cause of syncope (18) . Although it is possible that a

A second electrophysiologic test in a patient who contin-

serious arrhythmia was the cause of syncope among some of

ued to have syncope after the first test demonstrated an

the patients who continued to have syncope but did not die,

increase in the HV interval from 70 to 100 ms . Because a

the low incidence of sudden death over a mean of close to

markedly prolonged HV interval of ? 100 ms is associated

years of follow-up suggests that patients with unexplained

with a high risk of high degree AV block, a permanent

syncope who undergo an electrophysiologic test that is

pacemaker was implanted in this patient ( 6) . No further

nondiagnostic are at low risk of experiencing a lethal ar-

episodes of syncope occurred, suggesting that transient high

rhythmia .

degree AV block may have been the cause of syncope . This case suggests that repeat testing may be of value in patients

One of the factors that determine the sensitivity with which programmed ventricular stimulation reproduces clinically occurring ventricular tachycardia is the number of

who continue to have syncope after an initial nondiagnostic electrophysiologic study .

extrastimuli that are used (19- 3) . The stimulation protocol

Syncope caused by sinus node dysfunction . Despite a

in the present study included triple ventricular extrastimuli

normal sinus node recovery time, two patients were docu-

delivered at two basic drive cycle lengths and at two right

mented to have either a long sinus pause or symptomatic

ventricular sites . Therefore, the conclusion that a nondiag-

junctional bradycardia after the electrophysiologic test .

nostic electrophysiologic study predicts a low risk of sudden

These two cases demonstrate that the sinus node recovery

death in patients with unexplained syncope may not be valid

time may be insensitive in detecting transient sinus node

if the stimulation protocol is less extensive than the one used in this study .

abnormalities . The sensitivity of the sinus node recovery

Syncope caused by AV block . Among 19 patients who continued to have syncope during follow-up, transient high

to be 60% to 70% ( 7- 9) ; therefore, it is not surprising that

degree AV block was documented clinically to be the cause

node abnormalities may have a nondiagnostic electrophysi-

of syncope in

patients . Electrophysiologic testing in these

ologic study . The normal sinus node recovery time suggests

two patients had demonstrated a normal or mildly prolonged

that the documented bradyarrhythmias in the two patients in

HV interval . Prior studies ( 4- 6) have indicated that the

our study may have been a result of extrinsic autonomic

overall risk of high degree AV block is low when the HV interval is normal or only mildly prolonged . However, it is

influence on the sinus node rather than intrinsic sinus node disease .

clear from the present study and from prior reports (1

Remission of syncope . Overall, 80% of patients who did not die suddenly had no recurrences of syncope during

,13) that a normal or mildly prolonged HV interval does not rule

time in detecting the sick sinus syndrome has been reported occasional patients with syncope caused by occult sinus



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follow-up . Furthermore, life table analysis indicated that the proportion of patients remaining free of recurrent syncope and sudden death was 67% at 4 months of follow-up . Prior studies in smaller numbers of patients have also reported a high apparent remission rate of 44% to 80% in patients with a history of unexplained syncope who have nondiagnostic electrophysiologic test ( ,5,7-9) . The high apparent remission rate suggests that a majority of patients with unexplained syncope and a nondiagnostic electrophysiologic study do not have severe arrhythmias . The explanation for the high apparent remission rate of syncope in this study and in prior studies is unclear . Al-

though patients with a history suggesting situational or vasodepressor syncope were excluded from our study, this type of syncope may not always be associated with typical symptoms . Therefore, it is possible that syncope in some of these patients was caused by a transient autonomic disturbance . It is also possible that syncope had a hysterical basis in some patients who benefited emotionally when they learned that the electrophysiologic testing had demonstrated no serious abnormalities . In addition, the high apparent remission rate may simply be a function of the sporadic and unpredictable nature of syncope ; it is possible that with longer follow-up, syncope will eventually recur in a larger percentage of patients . Risk stratification. There were no clinical or laboratory findings that distinguished patients who died suddenly or experienced syncope during follow-up from patients who did not . Therefore, it may not be possible to readily identify prospectively those patients with unexplained syncope and a nondiagnostic electrophysiologic test who are most likely to require further evaluation . Because the overall incidence of sudden death in this group of patients is low, and because a majority of patients may have no further episodes of syncope, it may be appropriate to direct additional diagnostic testing only toward those patients who experience a recurrence of syncope after electrophysiologic testing . Polymorphic ventricular tachycardia and ventricular fibrillation . The results of prior studies (30-34) have suggested that polymorphic ventricular tachycardia or ventricular fibrillation induced by programmed ventricular stimulation is often a nonspecific finding that does not have clinical significance . In the present study, 38% of patients who died suddenly or had recurrent syncope during follow-up had inducible polymorphic ventricular tachycardia or ventricular fibrillation during electrophysiologic testing ; however, these arrhythmias were also induced in a similar percentage of patients who had an uneventful follow-up . These findings confirm that polymorphic ventricular tachycardia and ventricular fibrillation are nonspecific findings that do not have prognostic significance when induced in patients with unexplained syncope . Limitations of the study . First, four patients were lost to follow-up and their outcome may have affected the conclu-

KUSHNER ET AL . UNEXPLAINED SYNCOPE

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sions of the study . Second, the natural history of the 14 patients who were treated with antiarrhythmic medications may have been influenced by drug therapy . Third, the evaluation before electrophysiologic testing did not include tilt table testing ; evaluation on a tilt table might have allowed detection of patients with neurogenic syncope who did not have a typical history for this type of syncope (35) . Fourth, electrophysiologic testing was repeated in only I of 19 patients who continued to have syncope after the initial test . Therefore, the overall value of a second electrophysiologic test in patients with unexplained syncope and an initial test that is nondiagnostic is unclear . Fifth, signal-averaged electrocardiography was not performed in the patients in this series . The signal-averaged ECG has been reported (36-38) to identify those patients with unexplained syncope who are most likely to have inducible ventricular tachycardia during electrophysiologic testing . It is possible that the signalaveraged ECG could have been of value in identifying patients in this study who died suddenly or had recurrent syncope during follow-up . Conclusions . A nondiagnostic electrophysiologic test in patients who have had unexplained syncope generally is associated with a good prognosis . Although sudden death or recurrent syncope may occur during follow-up, the majority of patients have an uneventful outcome . Electrophysiologic testing occasionally may not detect patients with syncope caused by high degree AV block or sinus node dysfunction, but it does not appear possible to identify prospectively those patients most likely to have a false negative test . In light of the low incidence of sudden death and the high remission rate of syncope during follow-up, there does not appear to be any role for empiric pacemaker implantation or antiarrhythmic drug therapy in patients with syncope and a nondiagnostic electrophysiologic test . In a patient with unexplained syncope and a nondiagnostic electrophysiologic study, it may be appropriate to postpone further evaluation until syncope recurs . If syncope recurs, further diagnostic evaluation with extended ECG monitoring or a second electrophysiologic test may be helpful in detecting patients whose initial test yielded false negative results .

We thank Judy Hanson for excellent secretarial assistance .

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