Dyskinesia-An to
Unusual Reaction
Ethosuximide
Gordon J. Kirschberg, MD, FRCP(C)
A 15-year-old girl was given two 250-mg doses of ethosuximide because of petit mal seizures. Within hours of taking the first pill she developed an acute reaction Involving dyskinetic movements of the face, arms, and legs. These were abruptly and completely relieved by an intravenous Injection of diphenhydramine hydrochloride. (Arch Neurol 32:137-138, 1975)
ince the introduction of ethosuximide (Zarontin) for the control of petit mal epilepsy in 1958,1 it has become acknowledged as the drug of choice for such seizures because of both its lack of serious side effects and its excellent therapeutic control. In their original study, Zimmerman and Burgemeister,' pointed out that side effects occurred in fewer than 9% of patients, appeared after administration of relatively high doses, and could be reduced or eliminated by reducing the amount of medication given. No neurological side effects were noted. Recently, in a patient who was given ethosuximide for petit mal epilepsy, I observed a very unusual reaction, to my knowledge b
Accepted for publication July 9, 1974. From St. Joseph's Hospital and the Department of Medicine, McMaster University Medical
School, Hamilton, Ontario, Canada. Reprint requests to Department of Medicine, McMaster University Medical School, Hamilton, Ontario, Canada (Dr. Kirschberg).
heretofore not described in the literature-namely, acute reversible dyskinesia. REPORT OF A CASE A 15-year-old, right-handed girl had episodes of stomach pains and sudden "spells" with eyes rolling backward lasting several minutes throughout the previous year. Just prior to my first seeing her, she had a major motor seizure. Results of the physical examination were within normal limits. All laboratory test findings were normal with the exception of the electroencephalogram, which revealed synchronous bilateral spike and wave and polyspike and slow wave discharges at 3 to 4 hertz lasting up to 12 seconds. The EEG was considered to be consistent with minor epileptic attacks, and no focal abnormality was noted. Because of the grand mal seizures, she was started on therapy with phenobarbital, 30 mg four times daily. About six months later she had a severe grand mal seizure and diphenylhydantoin (Dilantin), 100 mg three times daily, was added. Four months following this she developed true staring spells lasting 20 to 30 seconds without any other concomitant signs or symptoms; ethosuximide, 250 mg three times a day, was advocated. Results of physical examination before beginning the medication were normal except for some bilateral lateral nystagmus. She took her first pill that evening. On awakening the next morning, abnormal involuntary movements were noted. She took another ethosuximide pill because her parents thought that the movements were epi-
leptic in origin. However, when the movements continued for several hours, I was asked to see her. She had taken no other medications. When examined, the patient had continuous abnormal involuntary movements of a nonrepetitive, purposeless nature. They were quite rapid and choreiform. They involved orofacial movements including tongue protrusion, side-to-side movements, and lip smacking, as well as pronation, supination, and flailing of the arms and crossing and uncrossing of the legs with occasional dorsi and plantar flexion of the feet and toes. She could not stop the movements voluntarily nor could they be stopped by holding the affected part. She was conscious throughout, and there was no mental impairment evident. Diphenhydramine, 75 mg, was given intravenously and the movements stopped within minutes. The ethosuximide was discontinued. She has since been put on a regimen of 300 mg of trimethadione three times each day and has had no further staring spells nor any further abnormal involuntary movements in over one year of followup.
COMMENT
Abnormal dyskinetic movement has not been described previously with ethosuximide therapy.1-4 The article by Zimmerman and Burgemeister mentions only a few minor side effects including drowsiness, dizziness, nausea, and gastric distress. In a review by Fischer et al3 of ethosuximide treatment in 105 patients, the only side effects noted were transitory
Arch Neurol/Vol 32, Feb 1975
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Dyskinesia/Kirschberg 137
dyspepsia, restlessness, sleep disturbances, anxiety, headaches, fatigue, dizziness, and psychosis. Nowhere was any mention made of abnormal involuntary movements, and the "restlessness" was described as a mental problem and did not consist of restless movements of any body part. In the most recent edition of the standard pharmacologic textbooks,4 again no mention is made of the possibility of abnormal dyskinetic reactions to this drug.
This movement disorder, however, has been seen as an idiosyncratic reaction to some of the phenothiazines, particularly prochlorperazine.4 In these cases, movements often appear after only one or two pills and can be eliminated by intravenous injection of diphenhydramine (Benadryl). The fact that diphenhydramine relieved the dyskinesia in our patient so promptly would make one suspect a similar underlying mechanism for the abnormal involuntary movement.
There is little similarity between the chemical structure of ethosuximide and the phenothiazines well known to give such a reaction. The only possible association that comes to mind is that the piperazine side chain, commonly thought to be an important factor in producing abnormal involuntary movements,4 as found, for example, in prochlorperazine, does contain a ring structure with nitrogen in it as does the ring of the succinamides.
References 1. Zimmerman FT, Burgemeister BB: A new drug for petit mal epilepsy. Neurology 8:769-775, 1958. 2. Schwartz JF: Recent advances in treating
138
epileptic children. Postgrad Med 44:107-111,1968. 3. Fischer M, Korskjaer G, Pedersen E: Psychotic episodes in Zarondan treatment. Epilepsia 6:325-334, 1965.
4. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics, ed 4. Toronto, McMillan Co, 1970.
Arch Neurol/Vol 32, Feb 1975
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/09/2015
Dyskinesia/ Kirschberg
Unusual Reaction
Ethosuximide
Gordon J. Kirschberg, MD, FRCP(C)
A 15-year-old girl was given two 250-mg doses of ethosuximide because of petit mal seizures. Within hours of taking the first pill she developed an acute reaction Involving dyskinetic movements of the face, arms, and legs. These were abruptly and completely relieved by an intravenous Injection of diphenhydramine hydrochloride. (Arch Neurol 32:137-138, 1975)
ince the introduction of ethosuximide (Zarontin) for the control of petit mal epilepsy in 1958,1 it has become acknowledged as the drug of choice for such seizures because of both its lack of serious side effects and its excellent therapeutic control. In their original study, Zimmerman and Burgemeister,' pointed out that side effects occurred in fewer than 9% of patients, appeared after administration of relatively high doses, and could be reduced or eliminated by reducing the amount of medication given. No neurological side effects were noted. Recently, in a patient who was given ethosuximide for petit mal epilepsy, I observed a very unusual reaction, to my knowledge b
Accepted for publication July 9, 1974. From St. Joseph's Hospital and the Department of Medicine, McMaster University Medical
School, Hamilton, Ontario, Canada. Reprint requests to Department of Medicine, McMaster University Medical School, Hamilton, Ontario, Canada (Dr. Kirschberg).
heretofore not described in the literature-namely, acute reversible dyskinesia. REPORT OF A CASE A 15-year-old, right-handed girl had episodes of stomach pains and sudden "spells" with eyes rolling backward lasting several minutes throughout the previous year. Just prior to my first seeing her, she had a major motor seizure. Results of the physical examination were within normal limits. All laboratory test findings were normal with the exception of the electroencephalogram, which revealed synchronous bilateral spike and wave and polyspike and slow wave discharges at 3 to 4 hertz lasting up to 12 seconds. The EEG was considered to be consistent with minor epileptic attacks, and no focal abnormality was noted. Because of the grand mal seizures, she was started on therapy with phenobarbital, 30 mg four times daily. About six months later she had a severe grand mal seizure and diphenylhydantoin (Dilantin), 100 mg three times daily, was added. Four months following this she developed true staring spells lasting 20 to 30 seconds without any other concomitant signs or symptoms; ethosuximide, 250 mg three times a day, was advocated. Results of physical examination before beginning the medication were normal except for some bilateral lateral nystagmus. She took her first pill that evening. On awakening the next morning, abnormal involuntary movements were noted. She took another ethosuximide pill because her parents thought that the movements were epi-
leptic in origin. However, when the movements continued for several hours, I was asked to see her. She had taken no other medications. When examined, the patient had continuous abnormal involuntary movements of a nonrepetitive, purposeless nature. They were quite rapid and choreiform. They involved orofacial movements including tongue protrusion, side-to-side movements, and lip smacking, as well as pronation, supination, and flailing of the arms and crossing and uncrossing of the legs with occasional dorsi and plantar flexion of the feet and toes. She could not stop the movements voluntarily nor could they be stopped by holding the affected part. She was conscious throughout, and there was no mental impairment evident. Diphenhydramine, 75 mg, was given intravenously and the movements stopped within minutes. The ethosuximide was discontinued. She has since been put on a regimen of 300 mg of trimethadione three times each day and has had no further staring spells nor any further abnormal involuntary movements in over one year of followup.
COMMENT
Abnormal dyskinetic movement has not been described previously with ethosuximide therapy.1-4 The article by Zimmerman and Burgemeister mentions only a few minor side effects including drowsiness, dizziness, nausea, and gastric distress. In a review by Fischer et al3 of ethosuximide treatment in 105 patients, the only side effects noted were transitory
Arch Neurol/Vol 32, Feb 1975
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/09/2015
Dyskinesia/Kirschberg 137
dyspepsia, restlessness, sleep disturbances, anxiety, headaches, fatigue, dizziness, and psychosis. Nowhere was any mention made of abnormal involuntary movements, and the "restlessness" was described as a mental problem and did not consist of restless movements of any body part. In the most recent edition of the standard pharmacologic textbooks,4 again no mention is made of the possibility of abnormal dyskinetic reactions to this drug.
This movement disorder, however, has been seen as an idiosyncratic reaction to some of the phenothiazines, particularly prochlorperazine.4 In these cases, movements often appear after only one or two pills and can be eliminated by intravenous injection of diphenhydramine (Benadryl). The fact that diphenhydramine relieved the dyskinesia in our patient so promptly would make one suspect a similar underlying mechanism for the abnormal involuntary movement.
There is little similarity between the chemical structure of ethosuximide and the phenothiazines well known to give such a reaction. The only possible association that comes to mind is that the piperazine side chain, commonly thought to be an important factor in producing abnormal involuntary movements,4 as found, for example, in prochlorperazine, does contain a ring structure with nitrogen in it as does the ring of the succinamides.
References 1. Zimmerman FT, Burgemeister BB: A new drug for petit mal epilepsy. Neurology 8:769-775, 1958. 2. Schwartz JF: Recent advances in treating
138
epileptic children. Postgrad Med 44:107-111,1968. 3. Fischer M, Korskjaer G, Pedersen E: Psychotic episodes in Zarondan treatment. Epilepsia 6:325-334, 1965.
4. Goodman LS, Gilman A: The Pharmacological Basis of Therapeutics, ed 4. Toronto, McMillan Co, 1970.
Arch Neurol/Vol 32, Feb 1975
Downloaded From: http://archneur.jamanetwork.com/ by a University of California - San Diego User on 06/09/2015
Dyskinesia/ Kirschberg
