Epileptogenic Property Research Articles

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

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

Topographic electroencephalogram in children during mask induction of anaesthesia with sevoflurane

Epileptiform patterns, spikes, polyspikes and periodic epileptiform discharges (PED) have been reported in electroencephalograms (EEGs) during anaesthesia induction with sevoflurane in healthy adults and children. Published recordings have been performed with a limited number of channels, and therefore the topographic distributions of these patterns are not known. Twenty ASA I children aged 4-10 years undergoing routine operations were anaesthetized with 8% sevoflurane in 50%/50% oxygen and nitrous oxide using mask induction with controlled normoventilation. An EEG was recorded with a full 10-20 electrode system including orbitofrontal and ear electrodes, and a recording band of 0.016-70 Hz. Beat-to-beat heart rate (HR) was calculated off-line. Nineteen out of 20 children developed multifocal spikes and polyspikes with a maximum over the frontal lobes. Four patients developed suppression, which was almost continuous and lasted several minutes, and thereafter a continuous EEG resumed, a few spikes were seen and then a nonepileptiform pattern. In three children a couple of PED waves were seen at the onset of a continuous EEG. HR increased maximally before the onset of spikes. No motor phenomena were seen. These recordings confirm the epileptogenic property of sevoflurane in mask induction. The spikes and polyspikes had frontal multifocal maxima and may be missed in recordings from frontopolar electrodes used by depth-of-anaesthesia monitors. PED and burst suppression were synchronous over the whole cortex. Epileptiform activity was indiscernible from epileptiform waveforms without anaesthesia, such as the patterns seen in status epilepticus.

Tardive Seizure and Antibiotics

Tardive seizure is a serious adverse reaction of electroconvulsive therapy (ECT). However, it was rarely reported in ECT sessions for psychiatric patients who needed concurrent antibiotic treatments. We present 2 cases of patients with schizophrenia who manifested a catatonic syndrome and were indicated for ECT, along with antibiotic therapies for infectious diseases with piperacillin and cefotiam, respectively. The beta-lactam antibiotics are reported to induce convulsions caused by the suppression of inhibitory GABAergic functions. In addition, there is a report on prolonged ECT seizure related to ciprofloxacin, which has an epileptogenic property with a similar action to beta-lactam antibiotics. Thus, tardive seizures in our cases are thought to be related to piperacillin and cefotiam.

The Epileptogenic Property of Sevoflurane and in Patients Without Epilepsy

The Epileptogenic Property of Sevoflurane and in Patients Without Epilepsy

Mechanism responsible for epileptogenic activity by first-generation H1-antagonists in rats

In the present study, we have demonstrated that multiple first-generation H1-antagonists caused behavioral and EEG seizures in rats. The epileptogenic property of pyrilamine was more potent than either chlorpheniramine or diphenhydramine. In contrast, the second-generation H1-antagonists, loratadine and ebastine did not induce detectable epileptogenic activity. Intraperitoneal injection of histidine inhibited the EEG seizures induced by pyrilamine, diphenhydramine or chlorpheniramine; however no antagonism was observed with physostigmine. These results clearly suggest that the epileptogenic activity of first-generation H1-antagonists is dependent upon a centrally acting histaminergic mechanism.

P–689 - Comparative study of carbapenem antibiotics including biapenem on epileptogenic property.

P–689 - Comparative study of carbapenem antibiotics including biapenem on epileptogenic property.

Surgical treatment of epilepsy: our experiences with 34 children

Surgical treatment of medically intractable epileptic fits in children is highly specialized, owing to the specific etiology of epilepsies in this age group and the epileptogenic property of the brain in childhood. In our series of 340 patients operated on for medically intractable epileptic seizures, there were 34 (10%) patients up to 15 years of age (the youngest was 2 years old; mean age was 11 years). This group of patients comprises four subgroups: 9 patients with temporal foci, 6 patients with extratemporal foci, 16 patients with infantile hemiplegia and epilepsy, and 3 patients with epilepsia partialis continua (Kozhevnikov's disease). Preoperatively, detectable brain lesions were present in 30 (88%) cases, a much higher frequency than in adult surgical series. Postoperative follow-up so far is 1-14 years (mean, 4 years). Surgical outcome in this group of 34 patients is as follows: 21 (62%) are seizure-free, 8 (23%) have improved, and 5 (15%) have shown no improvement.

Comparative Study of Certain Antibiotics on Epileptogenic Property, Including (1Rpi, 5S, 6S)-2-((6,7-Dihydro-5H-pyrazolo(1,2-a)(1,2,4)triazolium-6-yl)thio-6-((R)-1-hydroxyethyl)-1-methyl-carbapenem-3-carboxylate (LJC10627), a Carbapenem Antibiotic with Broad Antimicrobial Spectrum.

The epileptogenic effects of (1R, 5S, 6S)-2-[(6,7-dihydro-5H-pyrazolo[1,2-a][1,2,4]triazolium-6- yl)]thio-6-[(R)-1-hydroxyethyl]-1-methyl-carbapenem-3-carboxylate (LJC10627), a new derivative of carbapenem were studied in comparison with those of imipenem (imipenem/cilastatin), cefazolin and penicillin G. In intraventricular injection in rats, LJC10627 caused no epileptogenic activity at a dose of 32 micrograms. In contrast, imipenem, cefazolin and penicillin G showed dose-related seizure signs, continuous rhythmic spikes or high voltage spike-wave complexes and convulsive behaviors at doses higher than 10 micrograms. After intravenous injection of LJC10627, no epileptogenic signs on the electroencephalogram (EEGs) or in behavioral symptoms were observed, even at a dose of 500 mg/kg in rats and 300 mg/kg in rabbits, respectively. By contrast, imipenem/cilastatin provoked severe seizure patterns characterized by high voltage spikes-wave complex and convulsive behavior, both in rats and rabbits, using the same doses of LJC10627. Cefazolin and penicillin G also induced obvious epileptogenic signs in both rats and rabbits after intravenous injection. From these results, it was concluded that LJC10627, unlike imipenem (imipenem/cilastatin) and cefazolin, dose not elicit epileptogenic activity, and may therefore be safely used for clinical purpose.

Metabolic activation of intercortical and corticothalamic pathways during enflurane anesthesia in rats.

The purpose of this study was to examine the effects of enflurane on local cerebral glucose utilization (LCGU), and to provide further insight into the mechanism of the epileptogenic properties of enflurane. Twenty-four male Wistar rats were divided into four groups; three groups with intact cortex received 0.5, 2, or 4% enflurane, and one group with unilateral cortex excised received 4% enflurane. LCGU was measured at each anesthetic concentration using the autoradiographic 2-[14C]deoxyglucose method. LCGU in ten of 33 structures examined during 2% enflurane decreased by 19-33%, and LCGU in 22 structures during 4% enflurane decreased by 19-65%, when compared with that during 0.5% enflurane. While LCGU, in most structures, decreased in a dose-related manner, LCGU in the corpus callosum, thalamic ventrobasal complex, and hippocampal CA3 field during 4% enflurane increased by 31-70%, compared with that during 0.5% and/or 2% enflurane. With unilateral cortical excision during 4% enflurane, the increase in LCGU in the ventrobasal complex was obliterated in the excision side, and the increase in the corpus callosum was attenuated. High LCGU in the hippocampal CA3 field and contralateral ventrobasal complex was not affected with cortical excision. These results indicate that intercortical and corticothalamic pathways are metabolically activated during deep enflurane anesthesia, suggesting that the epileptogenic property of enflurane is related to activation of these pathways.

Neuronal effects of water-soluble contrast agents.

The in vitro rat hippocampus slice preparation has been utilized to examine the direct neurotoxicity of water-soluble contrast agents. Intraneuronal recordings were obtained from pyramidal cells in the CA1 field of rat hippocampus slices. Synaptic activity was evoked by Schaffer's collateral stimulation. The effects of Na-diatrizoate and metrizamide were studied. Test solutions were 300 to 345 mOsm and had iodine concentrations of 22.5 to 30 mg I/ml which are probably near clinical concentrations. The two effects of the contrast agents are apparent within 10 minutes and reversible within 30 to 45 minutes. The first is an epileptogenic property reflected by repetitive action potentials arising from an early prolonged depolarization. The second effect is a depression of electrical activity characterized by hyperpolarization of the resting membrane potential. Na-diatrizoate predominantly produced the first effect. Metrizamide principally produced the second effect. These results indicate that contrast agent seizure activity is not due to hyperosmolarity but a more direct chemical effect. The depression, however, may be related to a hyperosmolar effect. The differences between the dominant effects of the ionic vs. nonionic agents observed in these experiments seem to correlate with clinical experience and may indicate the etiology of central nervous system neurotoxicity of these drugs.

EFFECTS OF NITROUS OXIDE ON THE EPILEPTOGENIC PROPERTY OF ENFLURANE IN CATS

A method was developed to standardize the induction of seizure activity during enflurane anaesthesia in cats. The effects of nitrous oxide on the epileptogenic property of enflurane were investigated. A potent anticonvulsant action of nitrous oxide was noted, but partial tolerance to this effect rapidly developed. Some evidence of withdrawal hyperexcitability was also detected. The changes induced by nitrous oxide, despite existing enflurane anaesthesia, suggest that these two anaesthetic agents have different sites or mechanisms of actions.

Neurotoxic Effects of Water-Soluble Contrast Agents on Rat Hippocampus Extracellular Recordings

Synaptically evoked extracellular field potentials were obtained from the pyramidal cell layer of the Cal field of rat hippocampus slices. Synaptic activity was evoked by Schaffer's collateral stimulation. The effects of the water-soluble contrast agents Na-diatrizoate and metrizamide, as well as control solutions of NaCl and sucrose, were studied. Test solutions were 300-345 mOsm and had iodine concentrations of 3-30 mg I/ml. The effects of test solutions are apparent within 10 minutes and reversible within 30-45 minutes. Control recordings have a small positive potential, followed by a large negative spike and a final slow positive wave. Contrast agents have two effects. The first is an epileptogenic property characterized by repetitive negative spikes arising from an extended slow positive field. The second effect is a depression characterized by a reduction in the amplitude of the synaptically evoked fields, particularly the negative spikes. Na-diatrizoate predominately produces the first effect, while metrizamide principally produces the second. Hyperosmolar solutions only produce depression. These results correlate well with the clinical setting where Na-diatrizoate is a potent convulsant, while metrizamide produces symptoms compatible with neuronal depression. These results indicate that contrast agent seizure activity is not due to hyperosmolarity but to a more direct chemical effect. The depression, however, may be related to a hyperosmolar effect.

Hippocampal epilepsy produced by ouabain. Studies of cerebral circulation and ionic metabolism.

The epileptogenic property of ouabain was studied in cats including 17 chronic and 13 acute animals. In chronic experiments, infusion of ouabain into the septum by means of an indwelling cannula induc