Epilepsia, 36(11):1l58-1160, 1995. Lippincott-Raven Publishers, Philadelphia 0 International League Against Epilepsy

Brief Communication

Oculogyric Crisis Induced by Carbamazepine

Mark Gorman and Gregory L. Barkley

Department of Neurology, Henry Ford Hospital and Health Sciences Center, Detroit, Michigan, U.S.A.

Summary: A 32-year-old man with mental retardation and uncontrolled complex partial epilepsy receiving car- bamazepine (CBZ) and divalproex sodium (VPA), devel- oped frequent episodes of forced upward gaze after in- crease in the daily VPA dosage. CBZ dosage was de- creased, with prompt resolution of symptoms. The

upward gaze problem recurred several months later. CBZ dosage was decreased further with subsequent resolution of symptoms. Therefore, the oculogyric crisis (OGC) ap- peared to be induced by CBZ. Key Words: Anticonvul- sants-Adverse events-Oculogyric crisis-carbamaze- pine-Valproate.

Oculogyric crisis (OGC) is a rarely reported com- plication of carbamazepine (CBZ) therapy. OGC is an involuntary, slow, conjugate deviation of the eyes, generally in the upward direction, which may last minutes or longer. It can be overcome by using the oculocephalic reflex, but the tonic deviation then returns. OGC is a cardinal sign of postenceph- alitic parkinsonism, and a basal ganglia lesion has been postulated, but to our knowledge, never con- firmed. OGC has been well documented to occur in therapy with phenothiazines and other neuroleptics agents (1,2). OGC was also reported in a case of unilateral striatocapsular infarction (3). Review of the English literature indicates only four case re- ports of CBZ-induced OGC, all involving young fe- males receiving multiple antiepileptic drug (AED) therapy (43). We report a further case.

CASE REPORT Early records were unavailable for a 32-year-old

man with moderate mental retardation and epilepsy (presumed complex partial epilepsy) since child- hood. He was institutionalized at a very young age until his transfer to an adult foster care (AFC) home, at which time we examined him. Family members were unavailable, and his early back- ground was largely unknown to the AFC home staff. His condition had not changed significantly in

Received January 1994; revision accepted March 1995. Address correspondence and reprint requests to Dr. M.

Gorman at Department of Neurology, Henry Ford Hospital, 2799 W. Grand Blvd., Detroit, MI 48202, U.S.A.

many years. Physical examinations including neu- rological examination were normal other than the mental retardation. He generally had fair seizure control.

In November 1988, during a routine clinic visit, AEDs were divalproex sodium (VPA) 2,500 mg daily (1,000 500-1,000 mg) and CBZ 1,200 mg daily (400 mg three times daily, t.i.d.). He complained of vertex headaches and one to two seizures a month. VPA dosage was increased to 3,000 mgtday (1,000 mg t.i.d.). In December 1988, seizure frequency in- creased slightly, but AEDs were not changed. In March 1989, the patient was unhappy and not eat- ing; he had a 14-pound weight loss, nausea, and vomiting. He complained of headaches and often touched the top of his head, and the AFC staff noted that he looked up frequently. This was con- sidered to be OGC possibly secondary to CBZ tox- icity, and the dosage was decreased to 1,000 mg/day (400-200-400 mg). Two weeks later, there was mild improvement, but he was still staring up occasion- ally. In September 1989, caretakers related that he had poor appetite, nausea, vomiting, and more ag- gressive behavior. Examination showed an episode of forced upward conjugate gaze deviation with nor- mal lateral gaze. During the episode, which was ob- served for several minutes, he had repeated brief, rapid conjugate upward eye excursions, sometimes associated with neck extension. The eyes would sustain the forced upgaze for a few seconds, and then would slowly return to primary position. The neck extension would simultaneously return to mid-

1158

OCULOGYRIC CRISIS INDUCED BY CBZ 1159

3 o L 2 0 -

10

position with return of k11.t: tii primary position. Each episode lasted 5 to 10 s and recurred 5 to 15 times a minute. During the episode, he complained that his head hurt. This condition was again inter- preted as OGC, and the dosage was decreased to 900 mg daily (300 mg t.i.d.). In October 1989, the

eye rolling ceased promptly after the September medication change. Appetite improved. In Febru- ary 1990, the patient had multiple brief seizures, headaches and, occasionally, upward eye rolling, but of decreased frequency. CBZ was decreased to 600 mg/day (200 mg t.i.d.). From March 1990 to the

- , I I I I I I I I I

Oculogyric Crisisl- - -1

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BLOOD 8 - LEVEL 7 MEG/ML 6

5 - 4 -

3 - 2 -

1 -

150

;: 120

-

- -

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50 7 40

VALPROATE LEVELS

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1000

io/w iilw 121.98 1/89 2/89 3/89 4/89 5/89 6/89 7/89 8/89 9/89 ioi89 11/89 12/89 1/90 2/90 3/90 4/90

:: 1 11

CARBAMAZEW LEVELS

I I I I I I I I I I I 1 I I

10188 11188 12/88 1189 2/89 3189 4/89 5/89 6/89 7/89 8/89 9/89 10189 11189 12/89 1/90 2/90 3/90 4/90

TME (MONTHS)

FIG. 1. Plasma drug concentrations (heavy lines). Periods of observed intermittent oculogyric crises (broken lines).

Epilepsia, Vol. 36, No. 11, 1995

1160 M . GORMAN AND G. L . BARKLEY

present, he has had intermittent seizures, with res- olution of headaches and OGCs. CBZ was de- creased to 500 mg per day (200-100-200 mg).

Throughout this period the patient received only AEDs and no phenothiazines. Unfortunately, none of the episodes were captured on split-screen video- EEG. Episodes observed by 1 of the authors and by AFC staff were different than his seizures, and he was fully responsive during the episode observed in the office.

DISCUSSION

Although CBZ serum levels (Fig. 1) did not cor- relate with the observed OGCs, during each of the episodes the patient did exhibit other symptoms of CBZ toxicity (anorexia, nausea, vomiting, and be- havioral deterioration). As CBZ dosages were de- creased, these symptoms improved, concomitant with resolution of the OGCs. The patient’s repeti- tive touching of the top of his head during some of these episodes also may have represented an invol- untary movement similar to OGC. It is noteworthy that the symptoms had onset several months after an increase in VPA dosage.

CBZ is biotransformed through the epoxide path- way (inducible P450 isoenzyme) in the liver to 10,ll epoxycarbamazepine (CBZ-E) (6). Although not generally measured clinically, the active metabolite CBZ-E accounts for some of CBZ’s effectiveness and toxicity (7). VPA decreases protein binding of CBZ and CBZ-E and inhibits the enzyme epoxide hydrolase, thereby decreasing clearance of CBZ-E (8). The combination of VPA and CBZ may result in marked increase in CBZ-E levels with attendant CBZ toxicity, even with “normal” plasma CBZ lev- els (8). We believe this is the most likely explana- tion for the precipitation of the OGCs by VPA.

Of the five reported cases of OGC in association with CBZ therapy, including ours, 4 of 5 patients have been females, 4 of 5 have been mentally re- tarded, and all received combination AED therapy at the time of the dystonic reaction (43). In our case, all measured CBZ blood levels were within the usual “therapeutic range.” Prompt resolution or at least improvement of the symptoms followed reduction of the CBZ dosage each time. The reason for susceptibility of mentally retarded people and females is uncertain, but such susceptibility has

been reported in other CBZ-related dystonias (9). In our case, successive CBZ and VPA serum concen- trations showed no clear relationship to the periods of OGC. We speculate that large VPA-induced in- creases in unmeasured CBZ-E levels resulted in the oculogyric response.

Generally considered a specific type of orofacial dyskinesia, OGC has frequently been noted, but its pathophysiology has not been fully elucidated. A frequently postulated mechanism is a dopamine an- tagonist action, possibly superimposed on an under- lying predisposition to this particular type of dyski- nesia. CBZ has been suggested to have dopamine antagonist activity (9) and to increase central cholinergic activity (10). Either of these mecha- nisms, by disrupting the delicate balance between these neurotransmitter systems in the basal ganglia, might explain the rare ability of CBZ to produce OGCs (1 1) as well as some of the other more widely recognized dystonic reactions.

REFERENCES

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2. Schumock GT, Martinez E. Acute oculogyric crisis after administration of prochlorperazine. South Med J 1991 $4: 407-8.

3. Liu GT, Carrazana EJ, Macklis JD, Mikati MA. Delayed oculogyric crises associated with striatocapsular infarction. J Clin Neuro Ophthalmol 1991;11:198-201.

4. Arnstein E. Oculogyric crisis: a distinct toxic effect of car- bamazepine. J Child Neurol 1986;1:289-90.

5 . Berchou RC, Rodin EA. Carbamazepine-induced oculogyric crisis [Letter]. Arch Neurol 1979;36:522-3.

6. Faigle JW, Feldmann KF. Carbamazepine. Biotransforma- tion. In: Levy R, Mattson R, Meldrum B, Penry JK, Dre- ifuss FE, eds. Antiepileptic drugs, 3rd ed . New York: Raven Press, 1989:491-504.

7. Kerr BM, Levy RH. Carbamazepine. Carbamazepine ep- oxide. In: Levy R, Mattson R, Meldrum B, Penry JK, Dre- ifuss FE, eds. Antiepileptic drugs, 3rd ed. New York: Raven Press, 1989505-20.

8. Pitlick WH, Levy RH. Carbamazepine. Interactions with other drugs. In: Levy R, Mattson R, Meldrum B, Penry JK, Dreifuss FE, eds. Antiepileptic drugs, 3rd ed. New York: Raven Press, 1989521-31.

9. Crosley CJ, Swender PT. Dystonia associated with carba- mazepine administration: experience in brain-damaged chil- dren. Pediatrics 1979;63:612-5.

10. Consolo S, Bianchi S, Ladinsky H. Effect of carbamazepine on cholinergic parameters in rat brain areas. Neuropharma- cology 1976; 15:653-7.

11. Leigh RJ, Foley JM, Remler BF, Civil RH. Oculogyric cri- sis: a syndrome of thought disorder and ocular deviation. Ann Neurol 1987;22: 13-7.

Epilepsia, Vol. 36, No. 11, 1995