ARTICLE
Auteur(s) : Roberto H Caraballo,
Ricardo Cersósimo, Cecilia De los Santos
Hospital de Pediatría “Prof. Dr. Juan P. Garrahan”, Buenos
Aires, Argentina
Article reçu le 20 Juillet 2009, accepté le 18 Mars 2010
Levetiracetam (LEV) is chemically unrelated to any of the other
current antiepileptic drugs (AEDs). LEV is a new AED approved as
monotherapy for new-onset focal epilepsy in patients older than
16 years of age (Brodie et al., 2007) and as adjuntive
treatment for focal epilepsy in adults and children (Glauser
et al., 2006). LEV has also been approved for myoclonic
seizures in patients with juvenile myoclonic epilepsy and for
generalised tonic-clonic seizures in patients with idiopathic
generalised epilepsy (Berkovic et al., 2007).
Worsening of seizures by AEDs is a well-documented phenomenon,
although there are few reported systematic studies.
A paradoxical effect of LEV was previously reported in both
children and adults with epilepsy (Nakken et al., 2003).
Here, we present two patients, one with cryptogenic focal
epilepsy and another with Dravet syndrome, who experienced negative
myoclonus and increased seizure frequency associated with
continuous spike-waves during slow-sleep (CSWSS), induced by
LEV.
Case report 1
The patient was a 10-year-old girl whose parents were
non-consanguineous and in good health. There was no family history
of epilepsy. Pregnancy and delivery were normal, but the child had
a mild developmental delay. At age 13 months, she
apparently had a generalised tonic-clonic seizure. Carbamazepine
20 mg/kg/day was prescribed. Between the ages of two and five
years, the child presented with right motor focal seizures with or
without secondary generalisation every two months. Interictal awake
and sleep EEG showed occasional bilateral spikes with left
predominance. Carbamazepine was discontinued. The patient was
administered phenobarbital and sodium valproate, but control of
seizures was incomplete. Neurological examination showed moderate
mental retardation. Physical and fundus examination were normal and
no focal neurological signs were found. Routine laboratory
investigations and brain CT scan were also normal. When the patient
was seven years old, the number of focal seizures increased. Other
AEDs, such as oxcarbazepine and lamotrigine were tried, but without
a good response. MRI, metabolic investigations, and karyotype were
normal.
At eight years of age, seizures continued to be frequent and the
EEG recording did not show CSWSS. Oxcarbazepine was withdrawn and
two months later LEV 1,500 mg/day was added to the lamotrigine
treatment. The number of focal seizures with secondary
generalisation increased and the patient developed gait
instability. The interictal EEG showed frequent bilateral spikes
predominating in anterior regions during wakefulness and increasing
during sleep. The patient became unable to walk and developed
behavioural disturbances. At that time, her weight was 35 kg.
Serum LEV levels were not monitored.
The girl had frequent, discontinuous seizures compatible with
negative myoclonus, but we were unable to perform a polygraphic EEG
recording to document this particular type of seizure. Negative
myoclonus involved the neck muscles and trunk. The involvement of
these parts of the body provoked head drops and gait
instability. This encephalopathic state lasted for four
months. The EEG showed CSWSS (figure 1A, B). The
spike-and-wave index was more than 85%, calculated during all
nap/sleep EEG recording.
At 8.5 years of age, LEV was discontinued and the patient slowly
recovered her gait and the CSWSS disappeared within approximately
two months. The interictal EEG recording during sleep showed
bilateral spikes predominantly in the left hemisphere (figure 2).
At her last examination at the age of 10 years, she had
motor focal seizures occurring every four months with normal gait
and moderate mental retardation. Her last EEG recording showed
occasional bilateral spikes predominantly confined to the anterior
left regions.
Case report 2
The patient was a 9.5-year-old boy without significant personal or
familial antecedents whose parents were non-consanguineous. At the
age of five months, he presented with a generalised tonic-clonic
seizure (GTCS) during a febrile illness. From then on he had
monthly moderate and prolonged GTCS and, less frequently,
hemiclonic and focal motor seizures associated with febrile events
that lasted during the first two years of life. In the same period
he also experienced generalised tonic-clonic and hemiclonic status
epilepticus associated with febrile events, and admission to an
intensive care unit was necessary on three occasions. He
initially received phenobarbital and subsequently valproic acid was
introduced, but the latter drug was discontinued after he developed
thrombocytopenia. The interictal EEG recordings were normal.
At the age of three years, the boy started with myoclonias,
absences, and non-febrile focal and generalised motor seizures. At
the same time, he also developed behavioural and language
disturbances. The interictal EEG recordings showed frequent
generalised polyspikes and slow waves and occasional focal spikes
in anterior regions. Physical and fundus examinations were normal.
Routine laboratory investigations, CT scan, and MRI were normal.
The electroclinical picture and evolution were compatible with the
so called “Dravet spectrum”.
At 4.5 years of age, the seizures were refractory to classic and
new antiepileptic drugs. The EEG recording showed occasional
polyspikes and slow waves while awake and during sleep.
Neurometabolic investigations and karyotype were normal. The
patient was not tested for the SCNIA gene. LEV 1,000 mg/day was
added to clobazam and topiramate, and one month later the boy
presented with negative myoclonus and the number of generalised
motor seizures increased. The EEG recording showed bilateral spikes
and polyspikes and waves while awake and continuous spikes and
waves during sleep (figure 3). The
spike-and-wave index was more than 85%, calculated during all
nap/sleep EEG recording. The encephalopathic state, from the onset
of negative myoclonus and CSWSS until LEV was discontinued, lasted
3.5 months. After LEV was discontinued the patient improved
significantly, the negative myoclonus disappeared, the frequency of
the other seizures diminished, and even the EEG abnormalities
improved over a period of one and a half months. The EEG recording
showed isolated bilateral polyspikes and waves. Between the ages of
five and nine years, the patient presented once- or twice-monthly
non-febrile and, less frequently, febrile seizures.
At his last examination, at age the age of nine years, he
experienced two-monthly GTCS, hyperkinetic behaviour, language
disturbances, and moderate mental retardation. He was refractory to
the ketogenic diet. His last EEG recording showed occasional
bilateral spikes and polyspikes and waves while awake and during
sleep.
Discussion
The two patients presented here, the first with electroclinical
features of cryptogenic focal epilepsy and seizures associated with
a probable frontal lobe origin and the second with Dravet syndrome,
developed a peculiar clinical evolution characterized by increased
seizure frequency, negative myoclonus, and behavioural disturbances
associated with CSWSS. These characteristics were induced by LEV
which, to our knowledge, has not been described previously. In
our opinion, two mandatory requirements were met to confirm
the hypothesis of a strict correlation between LEV use and
occurrence of adverse events. The first was the appearance of
clinical symptoms when the AED was introduced, and the second,
their disappearance soon after AED was discontinued.
In some cases, a paradoxical increase in seizure frequency may
be observed as a consequence of drug intoxication, however, this is
not the explanation for our patients. In other settings, seizure
exacerbation seems to be the result of an adverse interaction
between the mode of action of the drug and the pathogenetic
mechanisms underlying specific seizure types or syndromes. Some
cases are even more intriguing, because exacerbation of seizures
occurs at therapeutic dosages and in patients with types of
epilepsy which normally respond favourably to the offending drug.
In our patients, the latter mechanism may be involved.
LEV is an effective AED when used as adjunctive treatment to
control focal seizures in children (Glauser et al., 2006).
Moreover, a reduction of EEG abnormalities and improvement in
cognition or behaviour and even complete recovery in children with
CSWSS have been described (Capovilla et al., 2004; Aeby
et al., 2005).
There is evidence that classic AEDs, particularly carbamazepine,
may induce aggravation of EEG and clinical symptoms in patients
with focal epilepsies especially in idiopathic forms (Caraballo
et al., 1989; Guerrini et al., 1995; Prats et al.,
1998). In two cases with benign focal epilepsy with centrotemporal
spikes, negative myoclonus associated with CSWSS was induced by
carbamazepine (Caraballo et al., 1989). The negative myoclonus
was documented by polygraphic recording and in one of these cases,
CSWSS disappeared after discontinuation of carbamazepine and
reappeared on reintroduction of that AED (Caraballo et al.,
1989). Among the new AEDs, oxcarbazepine, lamotrigine, and
topiramate were also reported as involved in inducing CSWSS
(Montenegro and Guerreiro, 2002; Grosso et al., 2003;
Cerminara et al., 2004).
Conclusion
To the best of our knowledge, these are the first reported patients
who, in spite of having very different epilepsy syndromes,
experienced seizure aggravation associated with CSWSS induced by
LEV. This particular electroclinical picture should be
corroborated.
Disclosure
All co-authors have had a significant role in designing, executing,
and/or analyzing data from the study, and/or in writing the
manuscript, and they have seen and approved the final version of
the paper and accept responsibility for the data presented.
None of the authors has any conflict of interest to
disclose.
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