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PubMed1977

Pathophysiology of generalized penicillin epilepsy in the cat: the role of cortical and subcortical structures. I. Systemic application of penicillin.

The mechanism of precipitation of generalized epileptiform discharges in feline generalized penicillin epilepsy, a model of human generalized corticoreticular ('centrencephalic') epilepsy, was studied in acute and chronic experiments in cats with implanted skull and intracerebral electrodes. Single shock and low frequency repetitive stimulation of subcortical sites from which prior to penicillin administration spindle activity and recruiting responses could be elicited, readily triggered epileptiform discharges in the same animals after penicillin. These structures comprised the intralaminar and midline thalamic nuclei, the neostriatum, and some posterior thalamic association nuclei (Pulvinar and nucleus lateralis posterior). Subcortical and cortical structures which prior to penicillin elicited neither spindle activity nor recruiting responses were significantly less effective in triggering generalized epileptic bursts after penicillin injection. The probability with which such bursts were elicited from these structures was still, however, in many instances above chance level. It is concluded that the generalized epileptiform discharges in feline generalized penicillin epilepsy can be triggered from a large number of brain sites, but most reliably so from subcortical nuclei involved in spindle generation and recruiting responses. The experimental evidence presented still does not allow one to determine whether epileptic alteration of neuronal function in this form of epilepsy primarily resides in cortical or subcortical nerve cells or in both.

Animals↗
PubMed2002

[Characteristics and indications of topiramate].

AIM: To evaluate the efficiency of topiramate (TPM), an antiepileptic medication (AEM) which possesses multiple mechanisms of action and good pharmacokinetics, in the different types of childhood epilepsy and to make an appraisal of its value in migraines, bipolar disorder, eating disorders and neuropathic pain, according to studies that have been published. To do so, we have made use of an analysis of the literature, together with a multi centre study conducted in Spain and personal casuistry. METHOD: We consider the percentage of seizure free patients and of patients who responded (reduction of 50% or above in the frequency of the seizures) in childhood epilepsy, partial epilepsy, generalized tonic clonic seizures, absence seizures, tonic seizures, patients with diverse types of seizures, juvenile myoclonic epilepsy, Lennox Gastaut syndrome, falling sickness and GTCS, West s syndrome and Dravet s syndrome. With monotherapy, in partial epilepsy, between 39 and 54% of patients treated were seizure free. TPM has also proved to be efficient in experiments with animals, as a neuroprotector, and in clinical trials, in type I bipolar disorder, eating disorders, neuropathic pain and migraine. CONCLUSIONS: TPM is an AEM offering a wide therapeutic spectrum that has proved to be efficient in clinical trials, expansion phases and observational studies, as an associated drug in partial epilepsy, generalized epilepsy, Lennox Gastaut syndrome, West s syndrome and Dravet s syndrome. It has proved to be more efficient in monotherapy, in partial epilepsy, as a first line AEM. TPM has also proved to be useful in mood disorders, eating disorders, neuropathic pain and tremor in observational studies, although this efficiency has not been backed up by clinical trials. In migraine and in clinical trials TPM has shown its efficiency. Its neuroprotective effect opens up new therapeutic perspectives.

Animals↗
PubMed2001

First genetic evidence of GABA(A) receptor dysfunction in epilepsy: a mutation in the gamma2-subunit gene.

Major advances in the identification of genes implicated in idiopathic epilepsy have been made. Generalized epilepsy with febrile seizures plus (GEFS+), benign familial neonatal convulsions and nocturnal frontal lobe epilepsy, three autosomal dominant idiopathic epilepsies, result from mutations affecting voltage-gated sodium and potassium channels, and nicotinic acetylcholine receptors, respectively. Disruption of GABAergic neurotransmission mediated by gamma-aminobutyric acid (GABA) has been implicated in epilepsy for many decades. We now report a K289M mutation in the GABA(A) receptor gamma2-subunit gene (GABRG2) that segregates in a family with a phenotype closely related to GEFS+ (ref. 8), an autosomal dominant disorder associating febrile seizures and generalized epilepsy previously linked to mutations in sodium channel genes. The K289M mutation affects a highly conserved residue located in the extracellular loop between transmembrane segments M2 and M3. Analysis of the mutated and wild-type alleles in Xenopus laevis oocytes confirmed the predicted effect of the mutation, a decrease in the amplitude of GABA-activated currents. We thus provide the first genetic evidence that a GABA(A) receptor is directly involved in human idiopathic epilepsy.

Amino Acid Sequence↗
PubMed1997

Managing epilepsy in general practice: the dissemination and uptake of a free audit package, and collated results from 12 practices in England and Wales.

This study aimed to assess the uptake and use by general practitioners of a free epilepsy audit protocol, and describe the care provided by practices which returned completed audits. A protocol for epilepsy audit in general practice was designed and described in the medical press. Practices were invited to reply. Responders were provided with the protocol. A total of 215 practices responded to the articles in the press. Questionnaires asking how they had used the audit protocol were sent to them 18 months later. One hundred and seventy (79%) of the 215 responding practices returned the questionnaires. Forty-seven (28%) had collected some or all of the data. Twenty-two (13%) submitted data of which 12 (7%) matched the original protocol. Aggregated list sizes for these 12 practices was 75689 and 502 (0.66%) patients were being treated. Of these, 60% were seizure free and 11% were having more than one seizure per month. Seventy-one were receiving monotherapy and only two patients were taking more than three drugs. Eighty-eight per cent of patients still having seizures had been seen by their GP for their epilepsy in the last 12 months. In 18% of cases, information on epilepsy lifestyle issues had been given and noted. Offering a free epilepsy audit package can stimulate interest amongst practices in the topic and resulted in 13% collecting and submitting their data for analysis. Practices reported a higher prevalence for epilepsy (0.66%) than in previous studies. The majority of patients with active epilepsy (88%) had been seen by a general practitioner in the last 12 months. Most (71%) were receiving monotherapy, but recording of seizure frequency and provision of information about epilepsy was low.

Anticonvulsants↗
PubMed2006

Efficacy and safety of zonisamide monotherapy in a cohort of children with epilepsy.

The aim of this study was to evaluate the efficacy and safety of zonisamide monotherapy in a cohort of children and adolescents with various types of epilepsy. Retrospective review of charts of our institution from 2001 through 2004 identified 69 children (19 males and 50 females, mean age 13.2 years) with epilepsy on zonisamide monotherapy. Seizure count and side effect profile were maintained during therapy. Sixty-one percent had idiopathic generalized epilepsy, 4% symptomatic generalized epilepsy, and 35% partial-onset epilepsy. Zonisamide was the first-line and second-line monotherapy for 32% and 68% of patients, respectively. The mean duration of follow-up on treatment was 22 months (range 3-48 months). The overall efficacy of zonisamide was 75.4% (> or = 50% seizure frequency reduction: good responders). Sixty-seven percent of good responders became seizure-free. Seventy-nine percent of patients with partial epilepsy and 71% with generalized epilepsy were good responders, of whom 79% and 63% were free of seizure, respectively. Eighteen (26%) patients developed side effects: weight loss (9), cognitive impairment (3), sleepiness (3), dizziness (2), and decreased appetite (1). In seven patients (10%), zonisamide had to be discontinued: four due to side effects and three because of poor seizure control. Zonisamide was demonstrated to be effective as monotherapy in children with epilepsy.

Adolescent↗
PubMed1995

A diagnostic practice study using international classification of epilepsies and epileptic syndromes in 302 cases.

We attempted to classify, according to the International Classification of Epilepsies and Epileptic Syndromes (1989), 302 patients at a tertiary epilepsy referral center. Proportion in categories as defined by the International League Against Epilepsy (ILAE) were as follows: localization-related epilepsies: 62.9%, generalized epilepsies: 22.2%, epilepsies undetermined whether focal or generalized: 14.2%, special syndromes: 0.7%. Only 26.8% cases were definitely classified in single diagnostic ILAE categories based on ictal CCTV/EEG recordings. The distribution of epileptic syndromes was different from the previous reports due to various methods of case ascertainment and inclusion criteria. Use of specific criteria for the reliability study of international classification has been proposed.

Adolescent↗
PubMed2006

A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy.

OBJECTIVE: To detect mutations in GABRA1 in idiopathic generalized epilepsy. METHODS: GABRA1 was sequenced in 98 unrelated idiopathic generalized epilepsy patients. Patch clamping and confocal imaging was performed in transfected mammalian cells. RESULTS: We identified the first GABRA1 mutation in a patient with childhood absence epilepsy. Functional studies showed no detectable GABA-evoked currents for the mutant, truncated receptor, which was not integrated into the surface membrane. INTERPRETATION: We conclude that this de novo mutation can contribute to the cause of "sporadic" childhood absence epilepsy by a loss of function and haploinsufficiency of the GABA(A) receptor alpha(1)-subunit, and that GABRA1 mutations rarely are associated with idiopathic generalized epilepsy.

Adolescent↗
PubMed1979

Medicosocial aspect of people with epilepsy in Japan--a survey from standpoint of epilepsy center.

Medicosocial aspects of 2,000 patients with epilepsy were outlined on the basis of international classification of epilepsies and epileptic seizures. 1. The incidence of secondary generalized epilepsy was higher compared with that reported previously. It was possible that we have been dealing with rather intractable epilepsy. Non-convulsive epileptic seizures should be treated as intensively as convulsive attacks. 2. Contrary to primary generalized epilepsy, secondary generalized epilepsy and partial epilepsy, a part of which was complex partial seizures, were more prone to be associated with psychological difficulties. 3. The rate of normal mentality was apparently proportional to the actual ease of employment among adult patients. Fortunately, the general attitude of education toward younger people with epilepsy was seemingly generous. However, the marital status of both sexes was far from satisfactory. The stigma might have been felt more by adult patients than younger ones. 4. It appeared to be conceivable that two-thirds of the people with epilepsy are treatable to a certain extent by adequate regimens while one-tenth are obliged to stay in residential centers for a lengthy period of time. Thus, various rehabilitation activities are indicated for one-fourth of the patient population. Actual strategy for rehabilitation of epileptics should be individually designed in accordance with the natural history of each epilepsy.

Adolescent↗
PubMed2002

Near reflex accommodation spasm: unusual presentation of generalized photosensitive epilepsy.

We report on a 9 year old girl admitted with prolonged and recurrent episodes of near reflex accommodation spasm (NRAS), which was the sole clinical manifestation of primary generalized photosensitive epilepsy. Four days prior to admission, the patient started to experience intermittent episodes of adduction of both eyes and miosis, namely near reflex accommodation spasm, which apparently became fixed three hours prior to admission, with no other perturbations. On examination she was fully alert showing a fixed NRAS, but otherwise unremarkable neurological examination. Time locked with NRAS, the EEG demonstrated generalized spike/wave discharges, also induced with photic stimuli, compatible with generalized photosensitive epilepsy. Assuming an epileptic etiology for the diagnosed NRAS, she was started on a small dose of valproate and became asymptomatic within the first day of treatment, along with EEG normalization. She remained asymptomatic within seven months when the valproic acid was erroneously discontinued. After a few days she began experiencing short lived episodes of NRAS, which could also be induced by photic stimulation and a concurrent EEG again demonstrated generalized epileptiform discharges. Searching the literature, this is the first report associating generalized photosensitive epilepsy with NRAS, and hence complete resolution of NRAS in response to antiepileptic therapy along with normalization of the EEG. An epileptic disorder should be therefore taken into account in any patient with new onset NRAS, especially when other epileptic phenomena are absent.

Accommodation, Ocular↗
PubMed1982

Antiepileptic effects of clobazam in children.

Many benzodiazepines used as anticonvulsants have nitrogen radicals in positions 1 and 4. Clobazam has nitrogen radicals in positions 1 and 5. We studied the antiepileptic effect of clobazam in 36 patients with intractable epilepsies in childhood. Their ages were 1 year 1 month to 16 years 5 months (mean 8 years). The mean initial dose was 0.33 mg/kg of daily doses and increased up to 0.71 mg/kg. Nine cases (primary generalized epilepsy 2/2, secondary generalized epilepsy 7/29) were completely free from seizures, and another 9 (secondary generalized epilepsy 8/29, partial epilepsy 1/5) experienced a decrease of 50% or more in seizure frequency. Seizure frequency did not change in 16, and increased in the other 2 (secondary generalized epilepsy 2/29). The antiepileptic effects were observed on the first day to 10th day after clobazam treatment. There were recurrences of seizures in 4 out of 9 patients with complete control of seizures, 1 month alter in 3 and 10 months later in one. Mean serum clobazam level of 7 improved cases was 73 ng/ml and that of 3 cases with no response was 94 ng/ml. Although mild clinical side effects such as drowsiness were observed transiently in 17 cases, no abnormality was found in laboratory investigations performed.

Adolescent↗
PubMed2005

Efficacy and safety of topiramate in infants according to epilepsy syndromes.

Studies of the efficacy of topiramate (TPM) in infants and young children are few. Here we report an open, prospective, and pragmatic study of effectiveness of TPM in terms of epilepsy syndromes, in children aged less than 2 years. The median follow-up period was 11 months. We enrolled 59 children in the study: 22 affected by localization-related epilepsy (LRE), 23 by generalized epilepsy, six by Dravet's syndrome, and eight with unclassifiable epilepsy. TPM was effective (responders showed a decrease of more than 50% in seizure frequency) in 47% of patients, including 13% who were seizure-free at the last visit. TPM was more effective in localization-related epilepsy (48% of responders) than in generalized epilepsy (32% of responders). In the latter group, 19 patients suffered from infantile spasms. Four of six patients with cryptogenic infantile spasms became seizure-free. Of the 13 patients with symptomatic infantile spasms, only one was seizure-free. Results were poor for patients with Dravet's syndrome. In general, TPM was well tolerated. The most frequently reported adverse effects were drowsiness, irritability, hyperthermia, and anorexia. The present study concludes that TPM is effective for a broad range of seizures in infants and young children and represents a valid therapeutic option in this population.

Anorexia↗
PubMed2004

Two cases of generalized seizures and the Velocardiofacial syndrome -- a clinically significant association?

BACKGROUND: Velocardiofacial syndrome (VCFS) is caused by a micro deletion of chromosome 22q11 and associated with multiple system abnormalities. There is an increasing recognition of associations with psychiatric disorders. Neurological and brain abnormalities have been reported but to date no association with generalized epilepsy has been reported in literature. METHODS: We report two cases of adults with VCFS and primary generalized epilepsy. The details on their background, psychiatric history and history of epilepsy including results of investigations will be discussed. RESULTS: Case 1 is an adult male with mild learning disability (LD), VCFS, paranoid schizophrenia and primary generalized epilepsy. Case 2 is an adult female with mild LD, VCFS, schizoaffective disorder and primary generalized epilepsy. The diagnosis of epilepsy in both cases was based on clinical and EEG findings of primary generalized abnormalities. CONCLUSION: As there is an evidence of association between VCFS and psychiatric disorders, this raises the possibility of an association with generalized epilepsy.

Abnormalities, Multiple↗
PubMed2000

Autoantibodies to glutamic acid decarboxylase in patients with therapy-resistant epilepsy.

BACKGROUND: Autoantibodies to glutamic acid decarboxylase (GAD-A) are present in type 1 diabetes and stiff man syndrome (SMS), and have also been reported in cerebellar ataxia. Epilepsy was present in 4 of 19 patients with SMS and GAD-A, implying that epilepsy sometimes is associated with anti-GAD autoimmunity. METHODS: The authors investigated the prevalence of GAD-A in patients with therapy-resistant localization-related epilepsy (n = 51) and generalized epilepsy (n = 49) by a radiobinding assay. The positive samples were confirmed by immunohistochemistry and immunoblotting of recombinant human GAD65. RESULTS: GAD-A were found in eight patients with localization-related epilepsy, whereas none of the patients with generalized epilepsy, other neurologic disorders (n = 38), or the control subjects (n = 48) had GAD-A. Two patients had high levels of GAD-A, similar to SMS, whereas six patients had significantly lower titers, characteristic of type 1 diabetes. The two patients with high levels of GAD-A had GAD-A both in serum and CSF by immunohistochemistry and immunoblotting. Both of them had longstanding therapy-resistant temporal lobe epilepsy but did not have diabetes. One had a history of autoimmune disease, whereas the other had serologic evidence of multiple autoantibodies without any clinical signs of autoimmune disease. CONCLUSIONS: GAD autoimmunity may be associated with refractory localization-related epilepsy.

Adolescent↗
PubMed2003

[Epilepsy and genetics].

Our knowledge in the field of epilepsy has evolved since the discovery of new specific inherited epilepsy syndromes. Causal mutations have been identified for some of these syndromes. They involve various ionic channels: Na+ channels in the generalized epilepsy with febrile seizures plus (GEFS+) among the idiopathic generalized epilepsies, nicotinic receptors in autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE), K+ channels in benign familial neonatal convulsions, and GABAA receptors in some forms of generalized epilepsy. The major challenge that lies ahead is to solve the genetics of the common forms of epilepsy following complex inheritance. It is likely that a number of genes coding for one or more ion channels may interact to produce specific epilepsy syndromes. A number of classical idiopathic generalized epilepsies have been mapped but no genes identified to date. It remains to be seen whether the molecular insights gained from the monogenic epilepsies will be directly relevant to the common epilepsies.

Epilepsies, Partial↗
PubMed1980

The role of the corpus callosum in bilateral interhemispheric synchrony of spike and wave discharge in feline generalized penicillin epilepsy.

In this study on interhemispheric synchrony of spike and wave discharges in feline generalized penicillin epilepsy, four groups of cats were treated in the following manner: Group A underwent complete section of the corpus callosum and anterior commissure; group B underwent division of the massa intermedia alone; group C underwent partial section of the corpus callosum; and in group D, a slab of the cortex on one side, comprising the middle parts of the lateral and suprasylvian gyri, was severed from all its subcortical inputs, without disturbing its connections with the opposite hemisphere through the corpus callosum. Two weeks after surgery or later the cats received an i.m. injection of penicillin. Bilateral synchrony of the epileptic discharges was abolished in group A, but not in group B. In group C, bilateral synchrony of the epileptic bursts was impaired, but not abolished. In group D, epileptic bursts synchronous with those occurring in the intact hemisphere continued to occur in the slab, but at lower amplitude. It is concluded that the corpus callosum is the main, if not the exclusive, pathway ensuring bilateral synchrony of the epileptic discharges of feline generalized penicillin epilepsy.

Animals↗
PubMed2004

Dysfunction of the brain calcium channel CaV2.1 in absence epilepsy and episodic ataxia.

The molecular basis of idiopathic generalized epilepsy remains poorly understood. Absence epilepsy with 3 Hz spike-wave EEG is one of the most common human epilepsies, and is associated with significant morbidity. Several spontaneously occurring genetic mouse models of absence epilepsy are caused by dysfunction of the P/Q-type voltage-gated calcium channel CaV2.1. Such mice exhibit a primary generalized spike-wave EEG, with frequencies in the range of 5-7 Hz, often associated with ataxia, evidence of cerebellar degeneration and abnormal posturing. Previously, we identified a single case of severe primary generalized epilepsy with ataxia associated with CaV2.1 dysfunction, suggesting a possible link between this channel and human absence epilepsy. We now report a family in which absence epilepsy segregates in an autosomal dominant fashion through three generations. Five members exhibit a combination of absence epilepsy (with 3 Hz spike-wave) and cerebellar ataxia. In patients with the absence epilepsy/ataxia phenotype, genetic marker analysis was consistent with linkage to the CACNA1A gene on chromosome 19, which encodes the main pore-forming alpha1A subunit of CaV2.1 channels (CaV2.1alpha1). DNA sequence analysis identified a novel point mutation resulting in a radical amino acid substitution (E147K) in CaV2.1alpha1, which segregated with the epilepsy/ataxia phenotype. Functional expression studies using human CACNA1A cDNA demonstrated that the E147K mutation results in impairment of calcium channel function. Impaired function of the brain calcium channel CaV2.1 may have a central role in the pathogenesis of certain cases of primary generalized epilepsy, particularly when associated with ataxia, which may be wrongly ascribed to anticonvulsant medication.

Adult↗
PubMed2006

Role of genetics in the diagnosis and treatment of epilepsy.

Epilepsy is a heterogeneous group of multifactorial diseases, the vast majority determined by interactions between many genes and environmental factors; however, there are rare epilepsy syndromes that can be caused by a single gene mutation and are inherited according to classical mendelian genetic principles. Finding disease-causing genetic mutations in epilepsy has provided new opportunities for aiding diagnosis and developing therapies. Thus, the discovery of KCNQ2 mutations in benign familial neonatal convulsions, SCN1A mutations in severe myoclonic epilepsy of infancy and in generalized epilepsy with febrile seizures plus, and CHRA4 and CHRB2 mutations in autosomal-dominant nocturnal frontal lobe epilepsy, has led to the establishment of epilepsy as a disorder of ion channel function and, furthermore, has led to the introduction of genetic tests that are available clinically to aid in diagnosis and treatment. At the present time, clinical use of genetic testing in epilepsy is greatest in suspected cases of severe myoclonic epilepsy of infancy, generalized epilepsy with febrile seizures plus, atypical cases of benign familial neonatal convulsions and 'occult' cases of autosomal-dominant nocturnal frontal lobe epilepsy without a family history. Overall, clinical use is limited by the low number of documented disease-associated mutations and the uncertain clinical significance of many test results. Further elucidation of the relationship between gene mutations and channel function will add value to genetic testing in the future, as will better characterization of the association between gene mutations and clinical phenotypes.

Biomarkers↗