topiramate and Seizures--Febrile

The present study aimed at exploring a potentially neuroprotective effect of topiramate (TPM), one of the most commonly used newer-generation, broad-spectrum, antiepileptic drugs against ultrastructural damage of hippocampal synaptic endings in the experimental model of febrile seizures (FS). The study used male young Wistar rats aged 22-30 days, divided into three experimental groups and the control group. Brain maturity in such animals corresponds to that of 1- or 2-year-old children. Hyperthermic stress was evoked by placing animals in a 45°C water bath for four consecutive days. TPM at a dose of 80 mg/kg b.m. was administered with an intragastric tube before and immediately after FS. Specimens (1 mm3) collected from the hippocampal CA1 and CA3 sectors, fixed via transcardial perfusion with a solution of paraformaldehyde and glutaraldehyde, were routinely processed for transmission-electron microscopic analysis. Advanced ultrastructural changes induced by hyperthermic stress were manifested by distinct swelling of hippocampal pre- and post-synaptic axodendritic and axospinal endings, including their vacuolization and disintegration. The axoplasm of the presynaptic boutons contained a markedly decreased number of synaptic vesicles and their abnormal accumulation in the active synaptic region. The synaptic junctions showed a dilated synaptic cleft and a decreased synaptic active zone. TPM used directly after FS was ineffective in the prevention of hyperthermia-induced injury of synaptic endings in hippocampal CA1 and CA3 sectors. However, "prophylactic" administration of TPM, prior to FS induction, demonstrated a neuroprotective effect against synaptic damage in approximately 25% of the synaptic endings in the hippocampal sectors, more frequently located in perivascular zones. It was manifested by smaller oedema of both presynaptic and postsynaptic parts, containing well-preserved mitochondria, increased number and regular distribution of synaptic vesicles within the axoplasm, and increased synaptic active zone. Our current and previous findings suggest that TPM administered "prophylactically", before FS, could exert a favourable effect on some synapses, indirectly, via the vascular factor, i.e. protecting blood-brain barrier components and through better blood supply of the hippocampal CA1 and CA3 sectors, which may have practical implications.

Topics: Animals; Anticonvulsants; CA1 Region, Hippocampal; CA3 Region, Hippocampal; Disease Models, Animal; Male; Microscopy, Electron, Transmission; Neuroprotective Agents; Presynaptic Terminals; Rats; Rats, Wistar; Seizures, Febrile; Topiramate

We investigated the effects of topiramate (TPM), a novel broad spectrum anticonvulsant, on seizure severity, survival rate and blood-brain barrier (BBB) integrity during hyperthermic seizures in rats with cortical dysplasia (CD). Offsprings of irradiated mothers were used in this study. To show the functional and morphological alterations in BBB integrity, quantitative analysis of Evans blue (EB) extravasation, immunohistochemistry and electron microscopic assessment of horseradish peroxidase (HRP) permeability were performed. Rats with CD exposed to hyperthermia exhibited seizures with mean Racine's scores of 3.92 ± 1.2. Among the rats with CD pretreated with TPM, 21 of 24 rats showed no sign of seizure activity upon exposure to hyperthermia (p<0.01). The immunoreactivity of occludin, a tight junction protein, remained essentially unaltered in capillaries of hippocampus in all groups. In animals with CD exposed to hyperthermia, the significantly increased p-glycoprotein immunoreactivity in hippocampus (p<0.01) was slightly decreased by TPM pretreatment. Hyperthermic seizures increased BBB permeability to EB in animals with CD, but TPM pretreatment decreased the penetration of the tracer into the brain in these animals (p<0.01). Ultrastructurally frequent vesicles containing HRP reaction products were observed in capillary endothelial cells in cerebral cortex and hippocampus of rats with CD subjected to hyperthermia-induced seizures, and TPM pretreatment prevented the development of HRP reaction products in these animals. The results of this study suggest that TPM inhibits seizure activity and maintains BBB integrity in the course of febrile seizures in the setting of CD.

Topics: Animals; Anticonvulsants; ATP Binding Cassette Transporter, Subfamily B, Member 1; Blood-Brain Barrier; Capillary Permeability; Disease Models, Animal; Female; Fever; Fructose; Male; Malformations of Cortical Development; Random Allocation; Rats; Rats, Wistar; Seizures, Febrile; Topiramate

The objective of the current ultrastructural study was to explore the potentiality of the neuroprotective effect of TPM against damage of pyramidal neurons in the hippocampal CA1 and CA3 sectors in an experimental model of febrile seizures (FS) in rats. The FS group exhibited variously pronounced submicroscopic lesions of the neuronal perikarya, including total cell disintegration. Advanced changes induced by hyperthermic stress were manifested by marked degenerative abnormalities, such as substantial swelling of the mitochondria, dilation, degranulation and disintegration of the granular endoplasmic reticulum, and vacuolar changes in the Golgi complex. The most substantially damaged pyramidal neurons showed features of aponecrosis (so-called "dark neurons"), resulting in a marked neuronal loss in the explored areas of the hippocampal cortex. The neurodegenerative changes were accompanied by distinct damage to the blood-brain barrier components. The administration of topiramate at a dose of 80/kg b.m. prior to the induction of hyperthermic stress (as prevention against febrile seizures) caused a substantial neuroprotective action - the drug efficiently lightened the neuronal damage, basically reduced cell aponecrosis and enhanced cell viability. However, TPM applied directly after FS induction did not exert any distinct neuroprotective effect on the perikarya of pyramidal neurons in the hippocampal cortex.

Topics: Animals; Anticonvulsants; Disease Models, Animal; Fructose; Male; Microscopy, Electron, Transmission; Neuroprotective Agents; Pyramidal Cells; Rats; Rats, Wistar; Seizures, Febrile; Topiramate

The objective of the current study was ultrastructural assessment of astroglia in specimens of the hippocampal cortex and neocortex of the temporal lobe in our own experimental model of febrile seizures (FS) in rats, as well as the analysis of the influence of a structurally novel broad spectrum anticonvulsant, topiramate (TPM), upon these cells in the CNS regions studied. The current study was inspired by some interesting literature reports on the in vitro investigation into the biological effects of TPM in primary cultures of rat cortical astrocytes and by the lack of data concerning astroglial morphology in vivo in an experimental model with this antiepileptic. In the FS group, the most pronounced changes in the study cell population referred to protoplasmic astroglia and were observed in approximately 3/4 of these cells. The abnormalities were similarly expressed in the two CNS regions studied, in terms of both quantity and quality. They were characterized by considerable swelling and degenerative changes, both in astrocytic perikarya and their processes. Changes were visible in the elements of the granular endoplasmic reticulum and mitochondria, which had a condensed configuration. In the group receiving topiramate directly after the induction of FS, submicroscopic changes in protoplasmic astrocytes were similarly expressed as in the FS group. However, in the group receiving the drug prior to the induction of FS its protective action was observed on the morphology of approximately 1/3 of the population of the protoplasmic astroglial cells. The remaining protoplasmic astrocytes still showed features of considerable or moderately pronounced injury. The beneficial effect of TPM on the ultrastructure of part of the population of the protoplasmic astroglia in the group in which the drug was applied prior to the induction of FS can be explained, among others, by a protective effect of the blood-brain barrier enhanced by the drug administration, as indicated by our earlier findings.

Topics: Animals; Anticonvulsants; Astrocytes; Brain; Disease Models, Animal; Fructose; Male; Microscopy, Electron, Transmission; Rats; Rats, Wistar; Seizures, Febrile; Topiramate

The ultrastructure of the blood-brain barrier (BBB) of the gyrus hippocampal cortex in an experimental model of febrile seizures in rats and the effect of a new generation antiepileptic drug, topiramate, on the morphological status of this barrier were investigated. Advanced changes indicating a substantial increase in BBB permeability were observed in the animals with induced febrile seizures (FS), with approximately 2/3 of capillaries and perivascular astroglial processes being affected. Almost total occlusion of the capillary lumen was frequently seen, caused by damaged endothelial lining and by external pressure from markedly swollen perivascular astrocytic processes. Mitochondrial changes predominated among the abnormalities found in endoplasmic organelles of endothelial cells. Lesions in the BBB coexisted with damage to pyramidal neurons, mainly with features of aponecrosis ("dark neurons"). The study on topiramate seems to demonstrate its protective action on the BBB components of the ammonal cortex in the group receiving the drug as prevention, i.e. against febrile seizures. It was found to prevent marked BBB damage in over half of the capillaries. However, the application of topiramate directly after FS induction had no distinct beneficial effect on the structural BBB components.

Topics: Animals; Anticonvulsants; Blood-Brain Barrier; Fructose; Hippocampus; Male; Microscopy, Electron, Transmission; Rats; Rats, Wistar; Seizures, Febrile; Topiramate

To investigate the hypothesis that some patients with epilepsy are generally prone to develop psychiatric adverse events (PAEs) during antiepileptic drug (AED) therapy irrespective of the mechanism of action of the drugs.. From a large case registry of patients prescribed topiramate (TPM) and levetiracetam (LEV), data of patients who had a trial with both drugs were analyzed. Demographic and clinical variables of those who developed PAEs with both drugs (group 1) were compared with those who did not (group 2). Subsequently, from the whole case registry, psychopathological features, demographic, and clinical variables of patients developing PAEs with TPM were compared with those of patients developing PAEs with LEV.. The case registry included over 800 patients. Among 108 patients having a trial with both drugs, we identified 9 patients in group 1 and 71 in group 2. Previous psychiatric history, family psychiatric history and history of febrile convulsions showed to be significant clinical correlates. Comparing patients who developed PAEs with LEV with those who developed PAEs with TPM, there were no differences in epilepsy related variables. Well-defined DSM-IV disorders were more frequent with TPM than with LEV. Seizure freedom was associated with psychosis.. This study suggests that a subgroup of patients is generally prone to develop PAEs during AED therapy, despite different pharmacological properties of the AEDs. A particular clinical profile and relevant variables have been identified.

Topics: Adult; Anticonvulsants; Comorbidity; Diagnostic and Statistical Manual of Mental Disorders; Epilepsy; Female; Fructose; Humans; Levetiracetam; Male; Mental Disorders; Netherlands; Piracetam; Psychiatric Status Rating Scales; Psychoses, Substance-Induced; Registries; Retrospective Studies; Seizures, Febrile; Topiramate

The aim of the study wad to estimate a potentially neuroprotective effect of topiramate (TPM) in the experimental model of FS.. 24 young male rats divided in 4 groups were involved in the study. Febrile seizures were induced by placing the animals in 45 degrees C warm water bath for four consecutive days. TPM at the dose 80 mg/kg b.m. was administered: before the FS and immediately after the FS. FS group and control rats received only normal saline. Thereafter hippocampal slices were prepared to performing histological and morphometric examination.. Morphometric investigations revealed that FS caused death of 60% of the neurons in sector CA1 and a half of them in sector CA3. Histological examinations of hippocampal slices showed that TPM at a dose of 80 mg/kg b.m., administered before the seizures, considerably improved CA1 and CA3 pyramidal cell survival. Similar neuroprotective effect, but in a markedly lesser degree was observed when TPM was administrated after the FS.. Our findings seem to confirm that FS exert a strong destructive effect on the sensitive hippocampal neurons and on the neuroprotective properties of TPM in this process, which may have practical implications. It can be assumed that in children with recurrent and prolonged FS, prophylactic drug administration could prevent hippocampal sclerosis and development of symptomatic epilepsy.

Topics: Animals; Disease Models, Animal; Fructose; Hippocampus; Male; Neurons; Neuroprotective Agents; Rats; Seizures, Febrile; Topiramate

The purpose of this study was to assess the effectiveness and tolerability of topiramate (TPM) as add-on therapy in children with Dravet syndrome and considered unsatisfactorily controlled using stiripentol. All the 36 patients having been treated with TPM in our centre in 2001 were retrospectively evaluated. Seventy percent of them still received stiripentol when TPM was introduced. The association of both drugs did not need any particular adaptation of dosages. The mean TPM follow-up was 13.3 months (4-25 months) and the mean optimal TPM dose was 3.2 mg/kg/d (0.6-9.2 mg/kg/d). Twenty eight children (78 %) showed more than 50 % reduction in the frequency of generalized tonic-clonic seizures and status epilepticus (SE), whereas 8 % had more than 50 % increase. Six patients (17 %) remained seizure-free for at least 4 months. The most frequently reported side-effects were gastrointestinal and behavioural disturbances. TPM had to be stopped in 17 % of patients, because of poor tolerability and/or lack of efficacy. Topiramate seems therefore to be helpful in Dravet syndrome, even in patients not satisfactorily controlled by stiripentol. Both drugs can be easily and safely associated.

Topics: Anticonvulsants; Dioxolanes; Drug Therapy, Combination; Electroencephalography; Epilepsies, Myoclonic; Epilepsy, Tonic-Clonic; Female; Follow-Up Studies; Fructose; Humans; Infant; Male; Retrospective Studies; Seizures, Febrile; Status Epilepticus; Topiramate; Treatment Outcome