Partial Seizures With Secondary Generalization While on Treatment With Clozapine and Sertraline

Abstract

Sir: Clozapine is known to cause generalized and myoclonic seizures. Here we report a neurologically normal individual who developed partial seizures with secondary generalization while receiving clozapine and sertraline. Case report. Mr. A, a 19-year-old man with paranoid schizophrenia whose psychotic symptoms had remitted with clozapine (300 mg/day), presented in 2007 with severe obsessive impulses to jump from heights. He had unremarkable birth and developmental history and had no past or family history of neurologic illness including epilepsy. He had never used psychoactive substances. His physical examination was normal. He was started on treatment with sertraline 50 mg/day, which was increased to 100 mg/day after 4 days; clozapine was continued at 300 mg/day. A week after the sertraline dose was increased to 100 mg/day, his mother noticed twitching of the angle of his mouth, which deviated toward the left with jerky movements of facial muscles. This was followed, within seconds, by a generalized tonic-clonic seizure lasting for about 2 minutes. He regained consciousness after about 5 minutes. He was treated with intravenous phenytoin and subsequently (the next day) prescribed oral phenytoin (300 mg/day) and quetiapine (200 mg/day); clozapine and sertraline were discontinued. Magnetic resonance imaging (MRI) of the brain revealed no lesion that could explain focal seizures. Electroencephalograms (EEGs) recorded immediately following seizure and after 2 days were normal. He reported that he had involuntary twitching movements of his face toward the left starting on the day after sertraline treatment was begun. These lasted for a few seconds and occurred about 7 to 8 times a day, but he had not reported it until he had a generalized seizure. Partial seizures decreased in frequency and stopped within a week; they did not recur while the patient was on treatment with quetiapine, which was built up to 800 mg/day over 2 weeks, along with phenytoin at 300 mg/day. Phenytoin was tapered and stopped after a 2-month seizure-free period. A diagnosis of seizure induced by combination of clozapine and sertraline was made. This case illustrates that clozapine may cause partial seizures in neurologically normal patients. History, examination, and MRI revealed no neurologic problems. Seizures had not occurred while the patient was taking only 300 mg/day of clozapine but occurred immediately after adding sertraline. Sertraline can increase plasma clozapine level.1,2 Since clozapine's epileptogenic property is dose dependent, this effect could induce seizures. Alternatively, sertraline could have independently put the patient at risk for development of seizures.3 About 10% of patients treated with any dose of clozapine develop seizures.4 However, partial seizures due to atypical antipsychotics either have been associated with brain lesions5–7 or have not been investigated for an association with such lesions.7 We investigated our patient for possible focal lesions but could find none. Hypotheses that attempt to explain the epileptogenic properties of clozapine mainly apply to the generalized seizures.7 One theory posits that clozapine increases rapid eye movement (REM) sleep and that a compensatory non-REM mechanism occurring during the wakeful state causes seizures. Another theory implicates mesolimbic selectivity of clozapine to explain its epileptogenic property.7 Neither theory explains generation of partial seizures. The seizure threshold–lowering property of clozapine could have activated some micro-epileptogenic focus not detected by EEG and MRI in our patient. At this stage, this explanation remains hypothetical. Systematic analysis of EEGs and clinical seizures of clozapine-treated patients that looks specifically for evidence of the focal nature of the seizures may clarify whether clozapine can cause partial seizures in the absence of focal lesions. Our patient did not complain of partial seizures until he developed a generalized seizure. It is possible that, in many patients, such partial seizures caused by clozapine could go unnoticed. It is tempting to hypothesize that partial seizures may be harbingers of generalized seizures in some patients, and if so, clinicians should have a high index of suspicion to look for partial seizures. Further research is needed to investigate this possible connection between partial and generalized seizures. Vivek H. Phutane, M.B.B.S. Channaveerachari Naveen Kumar, M.D., D.P.M. Jagadisha Thirthalli, M.D. Department of Psychiatry Seemendra Kumar Mahato, M.D. Department of Neuro Radiology Sanjib Sinha, M.D., D.M. Department of Neurology, National Institute of Mental Health and Neurosciences, Bangalore, India