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Seizure 1996; 5:153-156

CASE REPORT

Tiagabine and non-convulsive

GRAHAM SCHAPEL & DAVID CHADWICK

Department of Neurological Science, The Walton Centre for Neurology and Neurosurgery, Liverpool, UK

Correspondence to: Professor David Chadwick, Department of Neurological Science, The Walton Centre for Neurology and Neurosurgery, Rice Lane, Liverpool L9 1AE, UK

Three patients who developed clinical evidence of non-convulsive status epilepticus while on high doses of the investigational antiepileptic drug, tiagabine are reported. This apparently paradoxical phenomenon developed when the tiagabine dose was increased to 48 mg/day in one patient, and to 60 mg/day in two other patients, in combination with other antiepileptic drugs. control improved following reduction in tiagabine dose in one patient and discontinuation of tiagabine in the two others. The observation raises the possibility of a clinically relevant paradoxical epileptogenic effect of GABA-ergic drugs such as tiagabine.

INTRODUCTION continuation phase of a parallel arm design, double-blind, -controlled, multicentre Non-convulsive status epilepticus comprises 25% trial of tiagabine in 15 patients with refractory of all cases of status 1, with complex partial status, . often regarded as a rare condition, being the most common in adults 2"3. Paradoxical exacerbation of by conventional antiepileptic drugs has Case 1 been reported sporadically for at least the last 30 years4. Tiagabine, a analogue, is an This 46-year-old man had experienced complex investigational antiepileptic drug which inhibits partial seizures from the age of 21 years. gamma amino (GABA) neuronal Electroencephalography showed bilateral an- and glial re-uptake. It is effective in patients with terior sharp wave activity, mostly over the left partial seizures, with or without secondarily temporal region, and foramen ovale recordings generalized seizures and has only mild adverse indicated lateralization of the left medial temp- effects on the central nervous system 5. There have oral lobe and secondary generalization. Tiagabine been no reports of paradoxical aggravation of was added to the pre-existing combination of seizure control by tiagabine, either in the 400mg b.i.d., and published literature or in reports to the phar- 200 mg b.i.d, when he was averaging five complex maceutical company. In this report we describe partial seizures a month. Subsequently, the non-convulsive status epilepticus in three patients patient's carbamazepine dose was reduced to treated with tiagabine, in doses of 48 to 400 mg daily when tiagabine was increased to 60 mg/day, for refractory complex partial seizures 14 mg t.i.d, and lamotrigine continued in a dose of in combination with two other antiepileptic drugs. 400 mg daily. Carbamazepine was then progres- sively withdrawn, while tiagabine was increased to 16 mg t.i.d, in an attempt to limit lassitude. CASE REPORTS Three days later the patient was admitted to hospital when he became progressively confused The three patients reported here comprised three and unresponsive, exhibiting aggressive be- of the six patients who entered the open haviour, repeated chewing activity and yawning,

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as well as repeated falls. He was unaware of his 60mg per day. The patient subsequently ex- surroundings for at least 3 hours on the day of perienced three to four episodes of blank staring, admission. When admitted to hospital he exhib- with impaired awareness lasting up to 30 minutes, ited stereotyped movements, was aggressive and appearing to be in a world of his own, and there uncooperative, using expletives. Following in- was a cluster of 3 secondarily generalized travenous administration of 10 mg of tonic-clonic seizures over the 3-4 weeks leading there was an instantaneous change, the patient up to his admission to hospital, with twitching of becoming fully orientated in time, person and the right side of his face and shaking of the right place, with cessation of involuntary movements arm, held in a flexed position close to his chest. and return of normal responsiveness. Subsequent One week later the patient was admitted through physical and neurological examination was nor- the casualty department of a local hospital mal. The patient remembered that he could not because of prolonged seizure activity for 4 hours find the right words prior to admission when in his during which he continued to stare into space for confused state, but the day after admission his a few minutes followed by rigidity of his shoulder, speech was completely normal, although he did holding his arms flexed in front of his chest and experience one secondarily generalized tonic- shaking. He appeared to respond to his wife at clonic seizure 20 hours after admission. He made times, but at others was unresponsive and an uneventful recovery and has remained well, aphasic. His pupils were both dilated. This experiencing his previous level of seizure fre- episode lasted two and a quarter hours until he quency, continuing to take a lower dose of was given diazepam 5 mg intravenously, following tiagabine, 14mg t.i.d., in combination with which he became normally responsive but com- lamotrigine, 200mg b.i.d., and carbamazepine plained of tiredness with no memory of the 200 mg b.i.d. preceding event. Tiagabine was progressively withdrawn over the ensuing week while the patient remained seizure-free in hospital and Case 2 experienced only two partial seizures during the 3 weeks after leaving hospital. He continued to This 49-year-old man had a 41 year history of take 350 mg daily and carbamazepine localization-related epilepsy, poorly controlled on 400 mg t.i.d, and has remained well. previous antiepileptic drug therapy, most recently taking carbamazepine 400 mg t.i.d, and phenytoin 350 mg daily. His seizures were characterized by Case 3 an aura described as 'giving way' as well as by secondarily generalized convulsive seizures with This 19-year-old moderately retarded man had a deterioration in seizure control in the 3 months ventricular haemorrhage in the perinatal period prior to his entering the open continuation phase with subsequent hydrocephalus, requiring a of the tiagabine trial. The patient had a long ventriculo-peritoneal shunt. He had experienced standing left lower motor neurone facial weak- generalized tonic-clonic seizures without any ness. The EEG recorded a left temporal slow warning, at a frequency of approximately one per wave abnormality and CT head scan showed month all his life, with clusters of complex partial cerebral and cerebellar atrophy. Tiagabine 10 mg seizures occurring at weekly intervals. He was t.i.d, was added to carbamazepine 400 mg t.i.d. being treated with a combination of and phenytoin 350 mg daily when his monthly and lamotrigine when he entered a trial of the seizure frequency ranged from two to six complex investigational drug, tiagabine. The patient was partial and secondarily generalized tonic-clonic subsequently continued on open-label tiagabine, seizures. The dose of tiagabine was subsequently 12mg three times daily, in combination with increased in steps to 12 mg t.i.d., 16 mg t.i.d, and lamotrigine, 200 mg twice daily, and vigabatrin then to a total daily dose of 54 mg at which time 1500mg twice a day, at which time he was his monthly seizure frequency was four. It was averaging 25 complex partial seizures per month. then further increased to 20 mg t.i.d, in combina- He experienced an episode of twilight state in tion with carbamazepine 400mg t.i.d, and May 1993, when he tookan accidental overdose phenytoin 350 mg per day. Two weeks later the of tigabine from which he made an uneventful patient's wife noticed that he was unresponsive, recovery. Following an increase in tiagabine, with periods of staring blankly for up to one hour from 48 mg/day to 60 mg daily, he experienced 12 and recurrent episodes of disturbed balance and episodes of a trance-like state, lasting from 1 to 2 vision, following the increase in tiagabine dose to hours during a 4 week period, commencing in Tiagabine and non-convulsive status epilepticus 155

November 1993, whilst taking tiagabine, 20mg epilepticus 1-3. All the episodes of twilight state in three times daily, in combination with lamotrigine these three patients occurred in the context of 200 mg twice a day and vigabatrin, 1500 mg twice well documented epilepsy, implying that they daily. The patient's parents considered that they were examples of complex partial status which is resembled the period following the accidental now being recognized with increasing overdose of tiagabine several months previously. frequency~e. There was no previous history of His parents noted that he returned to normal episodes of complex partial status in any of the between the episodes and interictally the patient three. was found to have a normal general physical Paradoxical exacerbation of epilepsy by other examination and normal neurological antiepileptic drugs has been reported sporadically examination. for at least the last 30 years4. Increased seizure frequency and precipitation of status epilepticus has been reported for phenytoin6-8. Exacerbation DISCUSSION by carbamazepine has also been reported, par- ticularly in association with acute intoxication2, These three patients originally formed part of a and in children with recognized brain damage9-1~. multicentre parallel arm, placebo-controlled, Characteristically, the seizures involved were double-blind trial of tiagabine versus placebo in mainly 'atypical' absences and minor motor 15 patients, six of whom continued on the drug as seizures which increased in frequeficy a few days part of an open dose-ranging trial. They had after carbamazepine was started and subsided certain clinical features in common. They were all following its discontinuation4. male with a long history of refractory localization- Tiagabine, a nipecotic acid analogue, is an related epilepsy, taking other antiepileptic drugs investigational antiepileptic drug which inhibits in combination with tiagabine. All three patients gamma amino butyric acid (GABA) re-uptake. experienced prolonged episodes of unresponsive- Its clearance is via hepatic , without ness, a type of twilight state, during step-dose production of active metabolites, with an elimi- increases of tiagabine to maximum doses ranging nation half-life of 5-8 hours and plasma protein between 48mg/day and 60mg daily. In two binding of 96%. Tiagabine does not induce patients the seizure symptomatology was im- hepatic activity, but its metabolism is mediately terminated by parenteral ben- enhanced by other enzyme-inducing drugs, re- zodiazepine therapy and it did not recur in the ducing its elimination half-life to approximately third following progressive withdrawal of tiaga- 2-4 hours. Sodium displaces tiagabine bine. One patient has continued on tiagabine from sites, but tiagabine without any further twilight state episodes, but at does not affect the kinetics of other antiepileptic a lower dose. In case 1, carbamazepine discon- drugs 5. Interactions with other antiepileptic drugs tinuation, despite its cautious rate of withdrawal, would not seem to explain our observations. could have lead to the increase in seizure Tiagabine is effective in patients with partial frequency, associated with lack of adequate seizures, including secondarily generalized se- antiepileptic efficacy of the continuing drugs, izures and only mildly adverse effects on the namely tiagabine and lamotrigine, despite their central nervous system have been recognized5. To continuation in doses that would be expected to date, there have been no reports of paradoxical have antielpileptic efficacy. aggravation of seizure control, either in the The following criteria have been recommended published literature or reported to Novo Nordisk for the diagnosis of non-convulsive status epilep- by Lassen (pers. comm.). ticus, namely, impaired consciousness or respon- In summary, we have reported three patients siveness, without convulsions, for at least 60 who developed prolonged episodes of twilight minutes, and concomitant seizure activity in the state, clinically consistent with non-convulsive EEG entirely different from the interictal EEG status epilepticus, following progressive increase pattern ~ and recurrent clinical seizures and in tiagabine dose to between 48 and 60 mg/day. continuous altered behaviour2. No EEG was The aim of this report is to draw the attention of performed in these cases because the episodes clinicians involved in treating patients with resulted in out of hours admission. However, the refractory epilepsy to the possibility that anti- clinical picture and response to intravenous epileptic drugs may produce paradoxical epilep- diazepam in two of them, and the history from togenic effects, particularly in patients with reliable eye witnesses in the third, were consistent certain types of refractory partial epilepsy, who with the diagnosis of non-convulsive status are prone to seizure clustering. 156 G. Schapel & D. Chadwick

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