Arrhythmogenic epilepsy: an hypothesis

Arrhythmogenic

epilepsy:

an hypothesis

Edward L. C. Pritchett, M.D.* James 0. McNamara, M.D.** John J. Gallagher, M.D.*** Durham,

N. C.

Table

Spontaneous paroxysmal supraventricular tachycardia (PSVT) can almost always be reproduced in patients with this arrhythmia by programmed stimulation in the electrophysiology laboratory.lm3 The arrhythmia may be caused by reentry within the atrioventricular (AV) node, reentry within the sinus node, or reentry using an accessory A-V pathway.3, 4 We recently studied two patients who had multiple arrhythmias including PSVT. Electrophysiologic mechanisms for the arrhythmias could not be demonstrated by programmed stimulation in either patient. Both patients were found to have epileptiform abnormalities demonstrated by electroencephalogram (EEG). A primary neurologic abnormality was the probable cause for the arrhythmias in these patients. Case reports Patient No. Clinical

student

Patient No. 1 was a 21-year-old he was referred to Duke University

Sinus cycle, msec. (beats/min.) PA interval (msec.) AH interval (msec.) HV interval (msec.) QRS morphology

college in April,

From the Divisions of Cardiology and Neurology of the Department Medicine, Duke University Medical Center, Durham, N. C. Supported Centers

I

I.

history.

when

of

in part by Grant RR-30 from the General Clinical Research Branch, Division of Health Resources, Bethesda, Md.

Received

for publication

June

14, 1979.

Accepted

for publication

July

18, 1979.

Send correspondence to: Edward L. C. Pritchett, sity Medical Center, Dept. of Medicine, Division Disease, Durham, N. C. 27710.

M.D., Duke Univerof Cardiovascular

*Dr. Pritchett is the recipient of NHLBI Young Investigator Research Award HL 21347. Dr. Pritchett is Assistant Professor of Medicine, Division of Cardiology, and Associate Director of the Clinical Electrophysiology Laboratory, Duke University Medical Center. **Assistant tor, The tal.

Professor of Medicine, Epilepsy Center, Durham

Division of Neurology, Veterans Administration

and

DirecHospi-

***This work was done during Dr. Gallagher’s tenure as an Established Investigator of the American Heart Association. Dr. Gallagher is Associate Professor of Medicine, Division of Cardiology, and Director, the Clinical Electrophysiology Laboratory, Duke University Medical center.

0002~8703/80/110683

+ 06$00.60/O

0 1980

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C. V. Mosby

I. Conduction intervals

Co.

Patient 1 730 (82/min.)

Patient 2

I 465

(129/min.)

40 60

20 50

40

45

normal

normal

1978, for treatment of cardiac arrhythmias. His first recollection of symptoms suggestive of tachycardia occurred in October, 1976. At that time he was bowling and experienced dizziness and dyspnea. A nurse was present and stated that his pulse was “very fast.” The episode terminated abruptly after 30 minutes. Two weeks later he experienced palpitations, dyspnea, and nausea in a restaurant. Observers reported that he lost consciousness for approximately 10 minutes but was not incontinent and did not have tonic or clonic seizures. He awoke and returned home where his mother felt his pulse and noted that it was approximately 200 beats/minute. He continued to have two or three attacks of altered consciousness per msonth between October, 1976, and July, 1977. Some attacks were accompanied by palpitations; other similar episodes were not. In July, 1977, a Holter monitor recording demonstrated two episodes of supraventricular tachycardia (Fig. 1) that caused no symptoms. During tachycardia the QRS morphology was normal. He was treated with digoxin, propranolol, quinidine, and combinations of these drugs, but none modified the frequency or severity of tachycardia or dizziness. He was referred for further evaluation and treatment. The vital signs were normal, and the cardiovascular and neurologic systems were normal by clinical examination. An electrocardiogram recorded at the time of admission was normal. The patient had four hospital admissions between April and August, 1978. During these hospitalizations, he had continuous monitoring of his electrocardiogram in the Coronary Care Unit. Holter monitor recordings were also made. The dominant arrhythmia was sinus arrest with an ectopic atria1 pacemaker at a rate slower than the sinus rate. The patient had no symptoms and no spontaneous tachycardias while in the hospital. I?esults of electrophysiologic testing. Basic A-V conduction intervals are shown in Table I. Sinus node recovery times’ were normal. The A-V conduction system in the antegrade

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ritchett,

~c~arna~a,

and Gallagher

RA PACING CL=500 A. 400 HI-H2

(msec) 300

8.

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ERP = 217 FRP= 328

?-14- 77

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100

200

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500

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63.CS PACING CL=500 Fig. 1. Holter monitor recording, Patient No. 1. Paizel A was recorded during sleep and shows supraventricular tachycardia with a rate of 166/minute. Panel B was also recorded during sleep and shows sinus rhythm. Panel C was recorded in the early morning and shows supraventricular tachycardia at a rate of 136/minute. The patient was resting quietly at the time Panel C was recorded and experienced no symptoms. and retrograde directions was assessed by fixed rate pacing and the extrastimulus technique” (Fig. 2), using stimulation sites in the right atrium, coronary sinus (left atrium), and right ventricle. The A-V conduction system was normal, and no tachycardia was induced during the study. findings. Electroencephalographic The background rhythms of the EEG consisted of a well-developed and well modulated alpha rhythm at a frequency of 9 Hz. The major abnormality detected was repetitive epiieptiform discharges consisting of both sharp and spike wave transients arising from the lateral aspect of the right mid- and anterior temporal regions. These findings would provide the basis for a diagnosis of epilepsy of temporal lobe origin in symptomatic patients. No cardiac arrhythmias occurred during simultaneous monitoring of the EEG and electrocardiogram. Clinical course. The patient was treated initially with phenytoin 100 mg three times daily but symptoms persisted. He then was treated with carbamazepine 400 mg twice a day. On this dose, a carbamazepine level (drawn 12 hours after the preceding dose) was 4.3 mcg./ml. After one month of therapy, neurologic symptoms and all symptomatic arrhythmias had resolved. A 24-hour Holter monitor recording showed only sinus rhythm.

~lini~~~

history

No. 2. Patient No. 2 was a 15-year-old white male who was referred to Duke University in October, 1976, for treatment of cardiac arrhythmias. His prenatal and perinatal Patient

HI -Hz (msec) 300

ERP (241 FRP1329

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I

100

200

I

AI-AZ A.W.

300

1

1

400

500

(msec)

M88709

2. Refractory periods of the atrioventricular node, Patient No. 1. Punel A, right atria1 pacing. The refractory period curve, the effective refractory period, and the functional refractory period are all normal. Panel B, coronary sinus pacing. the curve is similar to the curve obtained during right atria1 pacing. Atria1 refractoriness prevented exact measurement of the refractory periods of the AV node during coronary sinus pacing. ERP = effective refractory period; FRP = functional refractory period. Fig.

history was unremarkable. His mother commented that as an infant he appeared to have a rapid heart rate, but exact rates were not recorded. At age 12 he had an episode of loss of consciousness. He was taken to a hospital emergency room where a diagnosis of atriai flutter was made. He was begun on digoxin. One month later he had a second episode of loss of consciousness. Both bradycardia and tachycardia were

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Arrhythmogenic

Fig.

hours

3. Paroxysmal supraventricular tachycardia, when its termination was recorded on this

Patient monitor

described at the time of the second attack. Phenobarbital 30 mg. orally twice daily was added to digoxin, and propranolol 10 mg. orally twice a ‘day was begun in 1975. He continued to have dizzy spells, bradycardia, and tachycardia. He lost consciousness again in December, 1975, was taken to a hospital emergency room, and was found to have a rapid supraventricular tachycardia. Phenobarbital was increased to 30 mg. three times daily and propranolol was increased to 20 mg. also three times a day. Quinidine 200 mg. four times daily was begun in February, 1976, and digoxin and phenobarbital were continued. In September, 1976, he again lost consciousness. His heart rate recorded by the school nurse was 180 beats/minute. He was admitted to a hospital, and PSVT converting to sinus rhythm was recorded on a monitor lead (Fig. 3). He was referred for further evaluation and treatment. The vital signs were normal, and the cardiovascular and neurologic systems were normal by clinical examination. An electrocardiogram recorded at the time of admission was normal. During the course of hospitalization the patient was observed with continuous ECG monitoring in the Coronary Care Unit. A variety of arrhythmias were documented, including sinus tachycardia (rate 210 beats/minute), sinus arrest (2.6 second pauses), junctional rhythm with retrograde block, junctional rhythm with retrograde conduction, multifocal ventricular tachycardia, first-degree atrioventricular (A-V) block, Mobitz Type I second-degree A-V block, and high grade A-V block. During periods of sinus rhythm, there were frequent episodes of sinus arrest follo’wed by appearance of an ectopic atria1 pacemaker at a rate slower than the sinus rate (similar to the rhythm recorded in Patient No. 1). No symptoms occurred during arrhythmias. Results of electrophysiologic testing. Basic conduction intervals (Table I) and sinus node reclovery times were normal. Using stimulation sites in the right atrium and right ventricle, electrophysiologic tests were performed. The A-V conduction system was tested with fixed rate pacing and the extrastimulus technique. The A-V conduction system was normal and no tachycardia was initiated. Electroencephalogram findings. The background rhythms of the EEG consisted of a well-developed alpha rhythm at a frequency of 9 Hz. The principal abnormalities consisted of: (1) irregular intermittent theta and delta transients in the left temporal regions throughout the waking record, and (2)

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No. 2. This tachycardia had been present for over lead. The last QRS was the result of a sinus beat.

epilepsy

12

bilaterally synchronous 3 to 4 per second spike and wave discharges maximal in amplitude in the frontal and central regions (Fig. 4). Despite the focal theta and delta transients in the left temporal region, no focal (as opposed to bilaterally synchronous) cortical spiking was detected. The focal slowing suggested the presence of a structural lesion in the left temporal region. The synchronous spike wave discharges would be consistent with a diagnosis of cortical reticular epilepsy in a symptomatic patient. Supraventricular tachycardia was detected by simultaneous monitoring of the electrocardiogram during the EEG. However, the supraventricular tachycardia did not reflect a consistent temporal relation to occurrence of EEG abnormalities. Clinical course. A ventricular demand pacemaker was implanted in October, 1976. He began taking phenytoin 100 mg. three times a day. He continued to have supraventricular tachycardia. Treatment with digoxin 0.25 mg. three times daily was begun. Supraventricular arrhythmias persisted and digoxin was discontinued and propranolol and a combination of propranolol and disopyramide were tried. No combination of drugs prevented tachycardia, but the patient did not have another episode of loss of consciousness. The patient was found dead in a swimming pool in April, 1978. At the time of death, the pacemaker was functioning normally. The brain was normal at autopsy.

Discussion

The ages of these patients and several other factors strongly suggest that the arrhythmias in th.ese two patients did not cause the neurologic symptoms. Paroxysmal supraventricular tachycardia is not usually associated with syncope in children,? and one patient had episodes of dizziness and disorientation which were not accompanied by palpitations. Also during episodes of loss of consciousness accompanied by tachycardia, the tachycardia persisted after consciousness returned. Neurologic symptoms secondary to an arrhythmia usually last as long as the arrhythmia does or until the victim has fallen to a recumbent position.8 When consciousness returned, our patients were able to resume normal activities (in

685

Sen= 15,uVlmm

EEG

-----I -

Fig. 4. Epileptiform tracing.

D.X ,,,.pM

LlF = 1.0 Hz HLF = 70 Hz

discharges

on EEG

on Patient

No. 2. Supraventricular

one case to drive a car) even though tachycardia persisted. Paroxysmal supraventricular tachycardia was a prominent arrhythmia recorded in both patients, but three features of the arrhythmia were unusual. As noted above, PSVT rarely causes loss of consciousness.7 Also, common antiarrhythmic drugs failed to alter the frequency, duration, or severity of attacks. In addition, no etiology could be found for the PSVT and when electrophysiologic other arrhythmias studies were done. This arrhythmia has been studied intensively with electrophysiologic techniques for several years. The etiology can be demonstrated by laboratory methods in approxi-

686

tachycardia

is present

throughout

the

mately 90% of patients in whom PSVT occurs spontaneous1y.‘-3 Both the presence of neurologic symptoms even without arrhythmias and the unusual features of the PSVT led us to consider alternate explanations in these patients referred for cardiac evaluations. A primary neurologic abnormality causing seizures and subsequent initiation of arrhythmias was an hypothesis that would explain all the findings. Epileptiform discharges on the scalp EEG of both patients supported this diagnostic hypothesis. A correlation between the EEG abnormalities and the cardiac arrhythmias would provide important evidence implicating the epileptiform

Arrhythmogenic

discharges as a cause for the cardiac arrhythmias. Despite the occurrence of the cardiac arrhythmia during EEG monitoring in Patient No. 2, such a correlation was not established. This finding is not surprising in light of two facts. First, even when abnormally excitable neural tissue lies in immediate proximity to the scalp (e.g., epilepsia partialis eontinuans arising from precentral gyrus), a close correlation between epileptiform discharges on EEG and the clinical seizure can be established in less than 50% of cases9 Second, accurate sampli:ng of epileptiform activity in depths of the brain by sampling scalp EEG is exceedingly difficult. Since the brain regions implicated by stimulation studies as causing arrhythmias are remote from the scalp (e.g., diencephalon and orbital frontal cortex),“, I1 difficulties in establishing a close correlation would be expected. Thus the failure to establish a one-to-one relationship between the PSVT and the scalp EEG abnormalities in no way excludes seizures as a cause of the arrhythmias. Walsh and colleagues’2 described a patient in whom a supraventricular arrhythmia occurred immediately following the onset of epileptiform discharges on the EEG. Unfortunately, electrophysiologic testing of that patient was not done, and the absence of an intrinsic cardiac abnormality can not be assumed. Abolition of both the arrhythmia and the neurologic symptoms in Patient No. 1 by a single antiepileptic agent, carbamazepine, is consistent with the primary neurologic cause of a cardiac arrhythmia postulated. Carbamazepine has some antiarrhythmic effects on ventricular tachycardia induced by digitalis or coronary artery ligation in dogs.‘” It is, however, also related to the tricyclic antidepressants that have arrhythmogenic potential in man.14 The effect of carbamazepine on arrhythmias in humans is not known. The findings in our two patients in which arrhythmias appeared to be secondary to partial seizures strengthen the argument that some arrhythmias have a nerual origin. Arrhythmias have been induced by stimulation of the diencephalon of experimental animals,‘“, I1 and bradycardia’j and tachycardia16 have been reported in humans with epilepsy. Recent investigation of the neural influence on arrhythmias has identified an important role for psychologic stress9, I’. I8 Potentially lethal arrhythmias have been linked to

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epilepsy

psychologic stress in two patients who had no known cardia.c abnormalities.‘*. I9 Future study of the origin of arrhythmias may include studies of the neurologic system. Summary

This report describes a clinical syndrome of arrhythmias that may have neural origin. Two patients presented with episodes of loss of consciousness, disorientation, and paroxysmal supraventricular tachycardia (PSVT). One patient reported experiencing neurologic symptoms without tachycardia. When electrophysiologic testing with intracardiac recordings and programmed stimulation yielded no abnormalities that could account for the arrhythmias, a primary neurologic abnormality was sought. The electroencephalograms of both patients showed epileptiform discharges that supported this hypothesis. Arrhythmias and neurologic symptoms were controlled by treatment with the antiepileptic drug carbamazepine in one patient. Findings in these two patients suggest that in some patients arrhythmias may be a manifestation of seizures. REFERENCES 1.

2.

3.

4.

5.

6.

Goldreyer, B. N., and Bigger, J. T.: Site of reentry in paroxysmal supraventricular tachycardia in man, Circulation 43:X, 1971. Denes, P., Wu, D., Dhingra, R. C., Amat-y-Leon, F., Wyndham, C. R. C., and Rosen, K. M.: Dual A-V nodal pathways, Br. Heart J. 37:1069, 1975. Wu, D., Denes, P., Amat-y-Leon, F., Dhingra, R., Wyndham, C. R. C., Bauernfeind, R., Latif, P., and Rosen, K. M.: Clinical electrocardiographic and electrophysiologic observations in patients with paroxysmal supraventricular tachycardia, Am. J. Cardiol. 41:1045, 1978. Pritchett, E. L. C., Gallagher, J. J., Sealy, W. C. Anderson, R., Campbell, R. W. F., Sellers, T. D., Jr., and Wallace, A. G.: Supraventricular tachycardia dependent upon secondary pathways in the absence of ventricular preexcitation, Am. J. Med. 64:214, 1978. Benditt, D. G., Strauss, H. C., Scheinman, M. M., Behar, V. S., and Wallace, A. G.: Analysis of secondary pauses following termination of rapid atria1 pacing in man, Circulation 54:436, 1976. Wit, A. L., Weiss, M. B., Berkowitz, W. D., Rosen, K. M., Steiner, C., and Damato, A. N.: Patterns of atrioventricular conduction in the human heart, Circulation 27:345, 1979. Nadas, A. S., Daeschner, C. W., Roth, A., and Blumenthal, S. L.: Paroxysmal tachycardia in infants and children, Pediatrics 9:167, 1952. Saunders, E. D., and Ord, J. W.: The hemodynamic effects of paroxysmal supraventricular tachycardia in patients with the Wolff-Parkinson-White syndrome, Am. J. Cardiol. 9:223, 1962. Thomas, J. E., Reagan, T. J., and Klass, D. W.: Epilepsia partialis continua. A review of 32 cases, Arch. Neurol. 34:266, 1977.

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Pritehett,

IO. 11.

12.

13.

14.

15.

MeNamara,

and

Gallagher

Lown, B., and Verrier, R. L.: Neural activity and ventricular fibrillation, N. Engl. J. Med. 294:1165, 1976. Fuster, J. M.: and Veinberg, S. 3.: Bioelectrical changes of the heart cycle induced by stimulation of diencephalic regions, Exper. Neural. 2:26, 1960. Walsh, G. O., Masland, W., and Goldensohn, E. S.: Relationship between paroxysmal atria1 tachycardia and paroxysmal cerebral discharges, Bull. Los Angeles Neu1-01. Sot. 3128, 1972. Steiner, C., Wit, A. L., Weiss, M. B., and Damato, A. N.: The antiarrhythmic actions of carbamazepine, J. Pharmacol. Exp. Ther. 173:323, 1970. Livingston, S., Pauli, L. L., and Berman, W.: Carbamazepine (Tegretol) in epilepsy, Dis. Nerv. Syst. 35:103, 1974. Phizackerley, P., Poole, E., and Whitly, 6.: Sinoauricular

16.

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19.

heart block as an epileptic manifestation, Epilepsia 3:89, 1954. Poggiali, I.: Considerazionai su di un case dl tachycardia parossistica con alterazioni eiectroencefalo-grafice, Clinica Pediatrica 53:260, 1971. Lown, B., DeSilva, R. A., and Lenson, R.: Roles of psychologic stress and autonomic nervous system changes in provocation of ventricular premature complexes, Am. 3. Cardiol. 4l:979, 1978. Lown, B., Temte, J. V., Reich, P., Gaughan, C., Regestein, Q., and Hai, M.: Basis for recurring ventricular fibrillation in the absence of coronary heart disease and its management, N. Engl. J. Med. 294:623, 1976. Wellens, H. J. J., Vermeulen, A., and Durrer, D.: Ventricular fibrillation occurring on arousal from sleep by auditory stimuli, Circulation 46:661, 1972.

IMPORTANT INFORMATION FOR AUTHORS All manuscripts for the AMERICAN JOURNAL should be sent to: Dean T. Mason, M.D. Section of Cardiovascular University of California School of Medicine Davis, California 95616

HEART

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November, 1980, Vol. 100, No. 5