Epileptic Disorders
MENUAcute 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.grReceived 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