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Epileptic Disorders

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Acute psychosis associated with levetiracetam Volume 5, numéro 2, June 2003

Auteur(s) : Sotiris Youroukos, Despina Lazopoulou, Danae Michelakou, Joanna Karagianni

First Department of Paediatrics, Athens University Medical School, "St. Sophia" Children’s Hospital, Athens, Greece

Correspondence: S. Youroukos, First Department of Paediatrics, Athens University Medical School, "St. Sophia" Children’s Hospital, 115 27 Athens, Greece Tel.:  + 30.201 746 70 00 Fax:  + 30.201 7 79 76 49 E-mail: sotelhol.gr

Received November 8, 2002; Accepted February 4, 2003

Introduction

No pharmacotherapeutic agent is free of side effects and of course this is also the case with antiepileptic drugs. The fact that these drugs are given for long periods of time, may partly explain the fact that side effects are recognized more often than in drugs given only for brief periods [1]. It is well established that it may take several years and large number of patients before a side effect becomes obvious. During the last years, several new antiepileptic drugs have become available. Obviously, the knowledge of possible side effects of these drugs is in most cases limited. The identification of unknown side effects lies in careful clinical observation.

We report on a 13 year-old girl that developed acute psychosis after the administration of Levetiracetam.

Case report

A 12 year-old female was admitted because of poorly controlled epileptic seizures. She was the second of three children of healthy, unrelated parents. Family history, pregnancy and delivery by caesarean section were all unremarkable. Her birth weight was 2.9 kg. Her motor and mental development were normal. She attended normal school but her school performance was below average. She had always been a very shy and timid girl and until admission she had presented no evidence of behavioural disturbances.

She started having seizures at the age of three. Her seizures were partial, with or without secondary generalization. Most episodes at that age were nocturnal and involved the left or the right side. Routine biochemical investigations were normal. Brain imaging with CT at the age of three, and MRI at the age of five, were normal. Sleep EEGs were either normal or demonstrated occasional spikes from the parietal and temporal areas. Her seizures were well controlled with carbamazepine for long periods lasting six to 18 months. At the age of nine, and after a two and half-year seizure-free period, a slow withdrawal of carbamazepine was attempted. Her seizures recurred but the reintroduction of carbamazepine failed to control the attacks. A trial of oxcarbazepine was also unsuccessful. In November 2001, she was admitted to the Department because of frequent partial seizures with secondary generalization. The patient was on oxcarbazepine 1 200 mg (35 mg/kg). Clinical examination was normal and her EEGs, both while asleep and awake, were normal. A new brain MRI scan was also normal. Oxcarbazepine was replaced with sodium valproate, reaching a dosage of 1 000 mg (33 mg/kg) daily. She continued to have, almost daily, partial seizures with generalization both during sleep and alertness. In early December 2001, levetiracetam was added to the valproate. Initially she was given 500 mg (15 mg/ kg) daily, then the dosage was increased to 2 000 mg (60 mg/kg) daily within a period of ten days. When the patient was on 1 000 mg of levetiracetam, no significant change in seizure frequency was observed. However, when the dosage was increased to 2 000 mg daily, she became seizure-free for the first time in several months. Unfortunately, significant changes in her behaviour were noticed. The patient gradually became confused and developed withdrawal, and poor response to social contact. Her behaviour was characterized by long periods of silence and episodes of terror. The patient was frightened and could not recognize her own parents. On a few occasions, she developed brief episodes of agitation and self-harming behaviour that were difficult to control. She also presented visual hallucinations. She was convinced that "an angel was standing next to her hospital bed". She was also convinced that "herself, her parents and the hospital staff were all dead but did not know about it". No antipsychotic medication was used but levetiracetam was stopped over a period of eight days. Her behavior became entirely normal again one week after the discontinuation of levetiracetam. Unfortunately, her seizures relapsed and were only partially controlled with a combination of valproate and carbamazepine. During the following months she presented no evidence of psychotic behaviour.

Discussion

Antiepileptic drugs may cause nonspecific, dose-related responses, unique effects specific to a given drug, or rare, but potentially dangerous idiosyncratic reactions [1]. As far as new antiepileptic drugs are concerned, it is reasonable to expect that side effects that were missed in the early studies will be identified when large number of patients will receive the drug. The experience of vigabatrin and felbamate is characteristic.
Psychiatric disorders after the administration of antiepileptic drugs have been reported in the past. Acute psychosis was reported after the administration of ethosuximide. This type of disorder was attributed to a process of rapid "forced normalization" of the EEG. However, the fact that other drugs achieve rapid normalization of the EEG with no such side effect, makes this hypothesis rather less tenable [2]. Severe changes in behaviour, with agitation and hallucinations, have been reported after the administration of vigabatrin. These side effects were thought to be dose-related [3]. Patients on vigabatrin were found to have a higher incidence of depression and psychosis. This behaviour was actually observed during the first three months of drug administration. Depression was usually mild and the psychosis responded to reduction or discontinuation of vigabatrin [4]. The mechanism that could explain why some anticonvulsants produce psychosis remains unclear. However, it is possible that the patients who develop such a side effect, may, in fact, have a pre-existing psychotic disorder that is not clinically evident. In such cases the administration of the antiepileptic drug may act as trigger mechanism.
Side effects of levetiracetam include dizziness, fatigue, headache, upper respiratory tract infection and somnolence. It was reported that the incidence of CNS-related adverse events was not influenced by the speed of titration [5]. It is well known that levetiracetam can influence behaviour. Although there is evidence that the drug may trigger behavioural disorders, there are reports that it may reduce hyperactivity, impulsivity, mood instability and aggression in autistic children [6]. Four patients who developed acute psychosis after the administration of levetiracetam were reported last year [7]. All patients however, had cognitive and behavioral abnormalities before starting the drug. In the patient reported here, there was no evidence of any pre-existing psychiatric disorder. However, a high dosage of levetiracetam (2 000 mg, 60 mg/kg) was used, and the rate of titration was rapid due to persistent seizures. It is possible that these two factors may have played a significant role in the development of psychosis.
There is no doubt that several antiepileptic drugs may provoke the development of psychosis. At present there is no evidence to suggest that levetiracetam produces psychosis at significantly higher rates than other antiepileptic drugs. The fact that the discontinuation of levetiracetam produced a rapid return to normal behaviour, is reassuring. However, it may be reasonable to avoid the use of levetiracetam in patients with pre-existing psychotic disorders. o