Aggressive behavior of epilepsy patients in the course of levetiracetam add-on therapy: report of 33 mild to severe cases
Introduction
Levetiracetam (LEV) was approved in the United States in November 1999 as add-on therapy for the treatment of partial-onset seizures in adults and was introduced in the Clinic for Epileptology Bonn in the year 2000. Its mode of action is still unknown and cannot be explained by mere interaction with the benzodiazepine receptor [1], [2]. LEV is not metabolized via the liver, displays very low protein binding [3], and has therefore only little interaction with other antiepileptic drugs (AEDs). LEV medication can be rapidly raised and its starting dose is effective [for review see 4].
A favorable safety profile has been demonstrated in placebo-controlled clinical trials [[5], [6], [7], [8], [9]; for review on tolerability see [10], [11]]. Treatment-emergent adverse effects were confined mainly to the central nervous system and included somnolence/asthenia, dizziness, and coordination difficulties (ataxia, abnormal gait). In particular, unwanted behavioral effects were observed in 13.3% of the cases (vs 6.2% in the placebo group). The latter comprised agitation and hostility as well as anxiety, apathy, emotional instability, depersonalization, and depression. Psychotic symptoms occurred in 0.7% of the patients treated with LEV as compared with 0.2% of the placebo group [9].
Concerning behavioral changes seen in clinical practice, the literature on LEV is still rather limited. Both favorable and unfavorable effects have been reported. A potential to provoke psychosis was indicated in a case report of four children developing psychotic symptoms under LEV medication [12]. Also in the pediatric field, a positive effect on the behavior of autistic children has been observed [13]. Aggressiveness in these children was improved if they had no medication prior to LEV. Yet, if risperidone, desipramine, or carbamazepine (CBZ) was reduced simultaneously with the introduction of LEV there was a tendency toward worsened aggressiveness under LEV. A case study suggested that LEV may be efficacious in the treatment of acute mania [14]. Cramer et al. [15] showed a general improvement of epilepsy-related quality of life. The study pointed out the positive cognitive profile of LEV. An increase in aggressiveness has so far only been evoked in the context of general tolerability in clinical trials [9], [16]. A growing interest in scrutinizing LEV and specific behavioral effects was recently revealed in the American Epilepsy Society annual meetings in 2001 and 2002 [for abstracts see [17], [18], [19], [20]].
In general, irritability and aggression are not uncommon in epileptic patients. Undirected, poorly controlled violent acts often take place peri-ictally, i.e., within hours before and after a seizure [21], [22], and may be associated with psychotic symptoms [23]. Interictal aggression may result from the use of antiepileptic drugs [24] but also from subclinical interictal epileptic activity, structural lesions, psychiatric comorbidity, mental retardation, and low socioeconomic status [22], [25], [26], [27], [28], [29], [30], [31]. Therefore, care must be taken when differentiating between drug related effects and the impact of the medical, psychiatric, and social context of epileptic disease.
Here we intend to share our clinical experience with treatment-emergent adverse effects of LEV. We present a chart review of 33 patients who developed mild to severe symptoms of irritability and aggression under LEV.
Section snippets
Selection of patients
In this report of 33 cases of aggressive behavior, patients were selected according to a computer-based library of medical records. We used a search engine that selected all records containing both levetiracetam/Keppra and aggressive/aggression or irritable/irritability. All patients except one were known to the clinic for at least one consultation prior to the administration of LEV; most of them already had multiple consultations in our clinic. Pediatric patients were not included in this
Efficacy of LEV treatment
The 33 patients presented in this study had longstanding histories of refractory epilepsy (3–45 years), with drug resistance defined as the unsuccessful trial of at least two different AEDs. Thirty patients had simple and/or complex partial seizures, 25 of these with secondary generalization. Two of the latter had become seizure-free after epileptic surgery. The remaining three patients had primary generalized epilepsy.
After LEV was increased to efficacious levels, one or two previously
Discussion
In this study, we have presented 33 patients who developed mild to severe aggressiveness in the course of LEV treatment. The incidence of this adverse effect amounts to approximately 3.5%. As to the efficacy of LEV, a major benefit was observed in 10 of these 33 patients. The largest group of patients presented here (n=14) displayed only moderate symptoms of irritability and continued LEV treatment because of satisfying seizure control. In an additional 10 cases, LEV was reduced or discontinued
Acknowledgments
We thank A. Flender for his work on the patients’ statistics.
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