Epilepsia, 42(12):1611–1613, 2001
Blackwell Science, Inc.
© International League Against Epilepsy
Levetiracetam Psychosis in Children with Epilepsy
Eric H. Kossoff, Gregory K. Bergey, John M. Freeman, and Eileen P. G. Vining
Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, Maryland, U.S.A.
Summary: Purpose: Levetiracetam is a new anticonvulsant
(AED) with a novel mechanism of action. Although it is gen-
erally well tolerated with a good cognitive profile, irritability
and hostility have been reported in some adults taking leveti-
racetam. Observations in children are limited; levetiracetam is
not yet approved by the Food and Drug Administration for use
in children.
Methods: In four young patients, acute psychosis developed
within days to months of initiation of levetiracetam for sei-
zures.
Results: A 5-year-old girl began having visual hallucinations
of spiders in her room 14 days after starting levetiracetam. A
13-year-old boy began having auditory hallucinations, insom-
nia, and screaming behavior 3 months after initiation of leve-
tiracetam. A 16-year-old girl became acutely agitated,
Levetiracetam, an S-enantiomer pyrrolidone deriva-
tive, is a new anticonvulsant similar in chemical structure
to piracetam (1). The mechanism of action may entail
blockade of zinc and ␤-carbolines from interrupting
chloride influx in the ␥-aminobutyric acid (GABA) and
glycine receptors (2). Levetiracetam reduces kindling in
mice, potentially indicating antiepileptogenic benefits
(3). Although it has been available in the United States
since 2000, with ∼75,000 patient exposures, the full side-
effect profile is still being determined. This is especially
true in the pediatric population younger than 16 years;
Food and Drug Administration (FDA) approval is lim-
ited to adults. Treatment-emergent side effects in initial
trials in adults included asthenia, dizziness, increased
upper respiratory infections, headache, and somnolence
(4). More recent studies indicated a higher prevalence of
neuropsychiatric symptoms such as irritability, hostility,
sedation, and headache than reported previously (5,6).
The occurrence of these neurobehavioral side effects
may be reduced by slow titration (6). Five of ∼700 pa-
tients in initial trials of levetiracetam had reversible psy-
Revision accepted October 30, 2001.
Address correspondence and reprint requests to Dr. E.H. Kossoff at
Meyer 2-147, Department of Pediatric Epilepsy, The Johns Hopkins
Hospital, 600 North Wolfe Street, Baltimore, MD 21287-7247, U.S.A.
E-mail: ekossoff@jhmi.edu
1611
hyperreligious, and had persecutory delusions within 7 days of
starting levetiracetam. A 17-year-old girl had auditory halluci-
nations telling her to sing and yell after 30 days of taking the
drug. All four children had dramatic improvement within days
of either discontinuing or decreasing the dose of levetiracetam.
The three adolescents had historical findings consistent with
mild behavioral problems before initiating levetiracetam, and
all four patients had prior cognitive deficits.
Conclusions: Reversible treatment-emergent psychosis asso-
ciated with levetiracetam therapy was observed in four children
and adolescents. Whether rapid initiation or prior neurobehav-
ioral problems predispose to this side effect is not established.
Key Words: Levetiracetam—Psychosis—Epilepsy—Chil-
dren—Behavioral.
chosis (7). We report the occurrence of acute, reversible
psychosis in four children and adolescents with seizures.
METHODS
Four children with the acute onset of psychosis (delu-
sions or auditory/visual hallucinations) within 2 days to
3 months after initiation of levetiracetam for resistant
epilepsy are reported (Table 1). Ages ranged from 5 to 17
years, with three girls and one boy. All four patients were
treated and levetiracetam started by physicians in the
Johns Hopkins Hospital Department of Neurology.
Doses started were ∼15–25 mg/kg/day, administered
twice a day, and plans were to increase the dose in 2
weeks. No child had previously manifested psychosis.
All four children had prior cognitive deficits (learning
disability), and the three adolescent patients had mild
behavioral issues before initiating levetiracetam.
RESULTS
Case 1
A 5-year-old girl with multifocal epilepsy was started
on levetiracetam at a dose of 250 mg twice a day (25
mg/kg/day) for seizure control. She had a history of mild
mental retardation and was receiving special education.
Her only other treatment at the time, the ketogenic diet,
1612
TABLE 1. Description of the four cases discussed
Case no. Age (yr) Gender Seizure focus
1 5 Female None
2 13 Male Left temporal
3 16 Female Right temporal
4 17 Female Left temporal
was continued unaltered while levetiracetam was initi-
ated. Two weeks after starting levetiracetam, she began
having visual hallucinations of spiders on the floor, on
her body, and in the air. She subsequently became agi-
tated, bit relatives, and was unable to sleep. She was
seizure free with levetiracetam over the prior 2-week
period, and the family had not noticed any recent sei-
zures during her acute symptoms. Oral diazepam (DZP)
caused sedation, but her hallucinations persisted. After
levetiracetam was abruptly discontinued, her symptoms
resolved within 24 h and did not recur.
Case 2
A 13-year-old boy with a 3-year history of drug-
resistant complex partial seizures and left temporal lobe
sharp waves on EEG was switched to levetiracetam
monotherapy. After a 2-week titration, he was main-
tained on a dose of 500 mg twice a day (16 mg/kg/day).
He had a history of learning disability and oppositional
behavior toward authority figures. Magnetic resonance
imaging (MRI) was normal. Approximately 3 months
later, he had the acute onset of auditory and visual hal-
lucinations of a female person in his room. In addition,
he began having insomnia, screaming episodes, and de-
pressed mood. Levetiracetam was abruptly discontinued
with complete resolution of his psychosis.
Case 3
A 16-year-old girl with a right temporoparietal lobe
dysembryoplastic neuroepithelial tumor (DNET) was
first seen in our institution with carbamazepine (CBZ)
monotherapy for surgical evaluation. She had a previous
history of periodic anger outbursts to her family and had
borderline intelligence (Weschler full-scale IQ of 76).
Levetiracetam was started at 500 mg twice a day (15
mg/kg/day) to help control her complex partial epilepsy
while her presurgical evaluation was completed. Two
days later, she became acutely agitated with pressured
speech and attempted to run away from home. Local law
enforcement found her suicidal and homicidal, with per-
secutory delusions. In addition, she became hyperreli-
gious and quoted scripture. Electroencephalogram
revealed right temporal lobe slowing, but no epileptiform
discharges. Psychiatry was consulted and agreed that this
was drug-induced psychosis. One day after levetiracetam
was discontinued, she was apologetic, and 3 days later
was near baseline. Follow-up neuropsychological testing
Epilepsia, Vol. 42, No. 12, 2001
E. H. KOSSOFF ET AL.
Previous Time of dose escalation Dose Time of first
behavioral issues to maximum (days) (mg/kg/day) symptoms (days)
No 0 25 14
Yes 14 16 90
Yes 0 15 2
Yes 14 33 30
6 months later identified continued occasional paranoid
thoughts, but no clear delusions as seen previously.
Case 4
A 17-year-old girl with mild cognitive impairment,
depression, and left temporal lobe epilepsy was started
on levetiracetam, and titrated over a 2-week period to a
dose of 1,000 mg twice a day (33 mg/kg/day). Her symp-
toms were attributable to a head injury 10 years previ-
ously, but her MRI was normal. Levetiracetam was an
adjunct to CBZ, which was maintained at a dose of 800
mg, 3 times a day. Approximately 30 days after initia-
tion, she began having headaches, lethargy, and auditory
hallucinations. The hallucinations were of a voice out-
side her bedroom telling her to sing and dance. Leveti-
racetam was abruptly discontinued with resolution of
symptoms. One month later, medication was restarted at
a lower dose of 500 mg twice a day because of severe
breakthrough seizures, without any recurrence of psy-
chotic symptoms.
DISCUSSION
With the rapid introduction of new antiepileptic drugs
(AEDs) onto the market, large population information
regarding benefits and side effects are often unavailable.
Many agents are marketed with only a limited sense
of potential adverse reactions. This emergence of side
effects not seen in trials has been a problem with many
new AEDs such as vigabatrin (VGB; irreversible retinal
field deficits) and felbamate (FBM; aplastic anemia, he-
patic failure) (8,9). Almost all new agents have reported
neurobehavioral side effects in children (10).
Levetiracetam has been beneficial against myoclonus
and myoclonic epilepsy types that had not been identi-
fied in the preclinical trials (11). The benefit/side-effect
ratio seems favorable, with one recent study of 1,422
patients describing 60% 1-year retention rate, and 38.6%
of patients having a ⱖ50% reduction in seizure fre-
quency (12). Newly recognized neurobehavioral side ef-
fects, including acute psychosis, may be more common
than previously realized.
In these four children and adolescents, psychosis was
reversible within days. It is unclear whether a rapid ini-
tiation of dose, as was seen in three of four patients that
had symptoms within 30 days, or a high total dose was
responsible for the symptoms. Young age also may be a
 LEVETIRACETAM PSYCHOSIS IN CHILDREN
possible link to psychosis. In addition, all children had
cognitive or behavioral abnormalities before starting le-
vetiracetam, which may have predisposed them to its
neuropsychiatric side effects. These risk factors should
be prospectively studied, but we advocate careful, slow
initiation (10 mg/kg/day, increasing over a 4-week pe-
riod to 20 mg/kg/day) when starting levetiracetam in
children with epilepsy, especially in those with comorbid
neurobehavioral abnormalities. When necessary, discon-
tinuation of levetiracetam produced prompt resolution.
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Epilepsia, Vol. 42, No. 12, 2001