Tiagabine Overdose Can Induce Convulsive Status Epilepticus

Tiagabine (Gabitril, TGB) is the first γ-aminobutyric acid (GABA) uptake inhibitor introduced as adjunctive therapy for refractory partial seizures (1). The effective dose range is 32–56 mg daily, and the dose range as monotherapy is likely to be lower. Therapeutic monitoring of plasma concentration of TGB is not recommended. TGB is considered to be an effective anticonvulsant medication (AED) and appears to lack serious adverse reactions. However, as of September 1996, 13 patients in a total of 2,531 in the literature, who received the medication had mental-status changes and EEG findings suggestive of nonconvulsive status epilepticus (NCSE) (2–8). The TGB dose in these reports was within the therapeutic range, but blood levels were not obtained. Review of data confirmed the diagnosis of NCSE in three of 13 patients (8). In the remainder, clinical and EEG findings were attributed to TGB intolerance secondary to high dose (8). When the TGB dose was reduced clinical symptoms resolved. We describe the first case of convulsive status epilepticus (CSE) induced by TGB overdose. A 39-year-old right-handed man was followed up for 2 years in our epilepsy clinic for intractable seizures that began at age 30 years. His seizures consisted of staring episodes daily and infrequent generalized tonic–clonic seizures once per year. He had no history of status epilepticus (SE). His past medical history was significant for traumatic head injury, but loss of consciousness was not confirmed. The patient was evaluated with routine 21-channel referential and bipolar EEG with temporal leads and brain magnetic resonance imaging (MRI) with and without gadolinium. Both studies were unremarkable. From the ages 30 to 37, he had received carbamazepine (CBZ), valproate (VPA), or phenytoin (PHT) monotherapy, but he had discontinued the medication 2 years before his visit. During his evaluation in our clinic, TGB was introduced as monotherapy at 4 mg/day and increased by increments of 4 mg/week, ≤16 mg twice per day. While taking TGB monotherapy and after being seizure free for 2 years, recurrent generalized tonic–clonic seizures developed, lasting for 40 min without recovery of consciousness between the seizures. He was initially evaluated and treated with intravenous administration of 8 mg of lorazepam (LZP) and intravenous infusion of fosphenytoin (FOS; 20 mg/kg). Despite treatment, seizure activity evolved into myoclonic jerks in the extremities and facial myoclonus. The patient was subsequently started on midazolam (MDL) drip at a rate of 7 mg/h, intubated, and transferred to Froedtert Memorial Lutheran Hospital (FMLH) for further management. On his admission, he had facial myoclonus and nystagmus to the right. Neurologic examination was otherwise unremarkable. Extensive laboratory workup including liver function, biochemistry, and blood counts did not reveal any metabolic disturbances or concomitant infection. Urine toxic screen also was negative. A plasma TGB level was sent for measurement in an outside facility. Prolonged video-EEG monitoring demonstrated sustained myoclonic jerks and continuous generalized bursts of spike-and-wave activity. Brain computed tomography (CT) and MRI were unremarkable. Barbiturate coma was induced till generalized slowing with no epileptiform abnormalities was achieved. In 24 h, the patient weaned from phenobarbital (PB) and extubated. His mental status returned to normal, and there was no seizure activity during the remaining few days of hospitalization. A TGB level was not available before his discharge, and the diagnosis of SE due to subtherapeutic TGB levels, presumably due to noncompliance, was made. TGB monotherapy at dose of 20 mg twice per day was recommended. One week later, the patient was readmitted with recurrent CSE, and similar diagnostic and therapeutic interventions were performed. The patient's family reported that the supply of TGB filled 1 week before was empty. The amount of ingested TGB was estimated to be ∼1 gr. The patient admitted to having attempted suicide. During this admission, the TGB level from the previous admission was available, and it was 1,870 ng/ml. During this hospital stay, plasma TGB level was 2,620 ng/ml. After his recovery, he was transferred to psychiatric care. To the best of our knowledge, this is the first report of generalized tonic–clonic SE due to TGB overdose. Plasma TGB level (1,870–2,620 ng/ml) was 10–13 times higher than the measured TGB concentrations in clinical trials (1–234 ng/ml). It has been shown, based on data from clinical trials, that TGB toxicity may precipitate spike-and-wave discharges (SWDs), in particular if there is evidence of SWDs on prior EEGs (8). In a few cases, SWDs were associated with NCSE, especially after increases in TGB doses (8). However, CSE has not been reported with TGB, even in patients with a history of SE or SWDs on prior EEGs (8). In one case, deliberate overdose of 320 mg TGB with 400 mg of phenytoin (PHT) led to coma without clinical convulsive activity and rapid recovery without any therapeutic intervention (7). The authors hypothesized that induction of TGB metabolism by PHT might have contributed to the patient's rapid recovery (7). The mechanism of TGB-induced SE in not known. γ-aminobutyric acid (GABA)ergic drugs including vigabatrin (VGB) and baclofen have been associated with absence SE (9). It has been suggested that stimulation of GABAB receptors in the thalamus may be the underlying mechanism (10). The presence of SE in an epilepsy patient taking AEDs most likely reflects insufficient drug concentrations, often attributed to noncompliance. In our case, the absence of a readily available TGB concentration led to erroneous diagnosis of SE due to low TGB dose. Levels of other AEDs associated with seizure exacerbation, such as PHT, CBZ, or VPA, are easily obtainable, and intoxication can be identified promptly. This limitation for TGB therapy should be taken into consideration if a patient has SE. TGB is a safe, effective, and well-tolerated medication for refractory epilepsy. There is no doubt that our patient had a great benefit from TGB monotherapy. We believe that TGB overdose-induced SE is a strictly dose-dependent phenomenon and can be easily avoided. Physicians should be aware of this potential complication and be able to rule out the diagnosis of CSE due to TGB overdose by obtaining a TGB plasma level early in the course of treatment.