Genetics of epilepsy: epilepsy research foundation workshop report.

The Sixth Epilepsy Research Foundation workshop, held in Oxford in March 2006, brought together basic scientists, geneticists, epidemiologists, statisticians, pharmacologists and clinicians to consider progress, issues and strategies for harnessing genetics to improve the understanding and treatment of the epilepsies. General principles were considered, including the fundamental importance of clear study design, adequate patient numbers, defi ned phenotypes, robust statistical data handling, and follow-up of genetic discoveries. Topics where some progress had been made were considered including chromosomal abnormalities, neurodevelopment, hippocampal sclerosis, juvenile myoclonic epilepsy, focal cortical dysplasia and pharmacogenetics. The ethical aspects of epilepsy genetics were reviewed. Principles and limitations of collaboration were discussed. Presentations and their matched discussions are produced here. There was optimism that further genetic research in epilepsy was not only feasible, but might lead to improvements in the lives of people with epilepsy.     

Management of postcardiotomy hypertension by microcomputer-controlled administration of sodium nitroprusside

Manual administration of sodium nitroprusside in patients who have undergone cardiac operations can be associated with wide swings in mean systemic arterial pressure. Moreover, it is necessary for constant attention to be paid in order to minimize these potentially catastrophic arterial pressure changes. A microcomputer-based controller was constructed in the belief that it might improve the accuracy of systemic arterial pressure control as well as relieve the clinical staff of a time-consuming task. Comparison was made of the effectiveness of manual control versus computer control of sodium nitroprusside infusion in two groups of patients with similar clinical characteristics. In the manual control group the mean systemic arterial pressure could be maintained within 5 mm Hg of the target pressure only half (52%) of the time. In the computer-controlled group the mean systemic arterial pressure was maintained within 5 mm Hg of the target pressure 94% of the time (p less than 0.005). Thus, computerized control of sodium nitroprusside infusion eliminated the need for an intensive care unit nurse to be "locked into" the task of making frequent adjustments of infusion rate. Of even greater importance, control of mean systemic arterial pressure was more precise.     

Calretinin-immunoreactive terminals make synapses on calbindin D28k-immunoreactive neurons in the lateral nucleus of the human amygdala

A double-labeling immunohistochemical procedure and correlated light and electron microscopy were used to examine if calretinin-immunoreactive terminals make synapses on calbindin D28k-positive cells. In the lateral nucleus of the human amygdala, calretinin terminals make symmetric-like synapses on the somata and proximal dendrites of calbindin D28k-labeled cells. Our data provide the first evidence that neurons which contain two different calcium-binding proteins form synaptic contacts with each other in the human amygdala.     

Specificity of Vigabatrin for the GABAergic System in Human Epilepsy

Summary: The therapeutic action of vigabatrin (gamma vinyl GABA, GVG) has been reported to be mediated by GABAergic neurotransmission. In the present study, we evaluated different neurotransmitter systems in the cerebrospinal fluid (CSF) of patients with complex partial epilepsy, before and during GVG treatment. The markers of the GABAergic system (free GABA, total GABA, homocarnosine) showed a two- to threefold elevation. There was also an increase in glycine during the 6 months of GVG treatment. In contrast, we did not find any constant CSF changes in either excitatory amino acids or in markers of the cholinergic (acetylcholinesterase), dopaminergic (homovanillic acid), serotonergic (5-hydroxyin-doleacetic acid), or peptidergic (somatostatin, prolactin, β-endorphin) systems. This finding (except an elevation in glycine) was in agreement with previous studies which suggest a specific action of GVG on the GABAergic system. The role of glycine in antiepileptic efficacy of GVG needs further evaluation.     

Cystatin C expression is increased in the hippocampus following photothrombotic stroke in rat

Stroke is a major cause of epilepsy, but the molecular mechanisms underlying post-stroke epileptogenesis are unknown. The expression of cystatin C, a cysteine protease inhibitor, is increased in the hippocampus during status epilepticus (SE)-induced epileptogenesis, and regulates both cell death and birth. To test the hypothesis that increased cystatin C expression represents a common molecular alteration induced by epileptogenic brain insults, we investigated the time course, cellular localization, and association of cystatin C expression with neuronal damage during post-stroke epileptogenesis. Stroke was induced with photothrombosis, which leads to epilepsy in approximately 20-30% of rats. Cystatin C expression was increased in the CA1 area of the hippocampus 4 days after photothrombosis, when the diameter of the lesion was the largest. Double-labeling and confocal analysis indicated that cystatin C was expressed in astrocytes and microglia. Unlike after SE, cystatin C expression did not change in the dentate gyrus. Also, increased cystatin C expression was not associated with neurodegeneration, which was demonstrated as an absence of Fluoro Jade B-positive cells in adjacent sections. The present study provides evidence that cystatin C may be involved in cellular alterations that occur after an epileptogenic insult, not only after SE but also after photothrombotic stroke.     

Status epilepticus in 12-day-old rats leads to temporal lobe neurodegeneration and volume reduction: a histologic and MRI study

PURPOSE: Whether status epilepticus (SE) in early infancy, rather than the underlying illness, leads to temporal lobe neurodegeneration and volume reduction remains controversial. METHODS: SE was induced with LiCl-pilocarpine in P12 rats. To assess acute neuronal damage, brains (five controls, five with SE) were investigated at 8 h after SE by using silver and Fluoro-Jade B staining. Some brains from the early phase were processed for electron microscopy. To assess chronic changes, brains from nine controls and 13 rats with SE at P12 were analyzed after 3 months by using histology and magnetic resonance imaging (MRI). RESULTS: MRI analysis of the temporal lobe of adult animals with SE at P12 indicated that 23% of the rats had hippocampal, 15% had amygdaloid, and 31% had perirhinal volume reduction. Histologic analysis of sections from the MR-imaged brains correlated with the MRI data. Analysis of neurodegeneration 8 h after SE by using both silver and Fluoro-Jade B staining revealed degenerating neurons located in the same temporal lobe regions as the volume reduction in chronic samples. Electron microscopic analysis revealed irreversible ultrastructural alterations. As with the chronic histologic and MRI findings, interanimal variability was seen in the distribution and severity of acute damage. CONCLUSIONS: Our data indicate that SE at P12 can cause acute neurodegeneration in the hippocampus as well as in the adjacent temporal lobe. It is likely that acute neuronal death contributes to volume reduction in temporal lobe regions that is detected with MRI in a subpopulation of animals in adulthood.     

Epidemiology of domestic chemical burns in Saudi Arabia

The authors reviewed the domestic chemical injury experience in two major government hospitals in Saudi Arabia to determine the most common causative agents and the circumstances of the injury in order to give recommendations for their prevention and reduction of their morbidity. A total of 59 cases were included. The mean age was 25 years and the male to female ratio was 3:1. Alkali drain cleaners were the major cause of chemical burns in the series and this was seen in 75% of the total study population. The remaining 25% of cases resulted from concentrated sulfuric acid, car battery acid and topical application of medical herbs by non-professionals. Unfortunately, immediate water lavage was not done in the majority of alkali and acid burns and hence skin grafting was required in most patients. It was concluded that efforts for prevention of chemical burns in Saudi Arabia should be directed towards education of the population regarding the proper use of alkali cleaners for clogged drains. These cleaners and battery acid containers should also be kept in a safe place away from the reach of children. Furthermore, a warning to the public regarding the non-professional use of medical herbs should be given. Finally, increased awareness among the Saudi population as to the need for prompt water irrigation of chemical burns should help reduce the morbidity from these injuries.     

Finding a better drug for epilepsy: Antiepileptogenesis targets

For several decades, both in vitro and in vivo models of seizures and epilepsy have been employed to unravel the molecular and cellular mechanisms underlying the occurrence of spontaneous recurrent seizures (SRS)—the defining hallmark of the epileptic brain. However, despite great advances in our understanding of seizure genesis, investigators have yet to develop reliable biomarkers and surrogate markers of the epileptogenic process. Sadly, the pathogenic mechanisms that produce the epileptic condition, especially after precipitating events such as head trauma, inflammation, or prolonged febrile convulsions, are poorly understood. A major challenge has been the inherent complexity and heterogeneity of known epileptic syndromes and the differential genetic susceptibilities exhibited by patients at risk. Therefore, it is unlikely that there is only one fundamental pathophysiologic mechanism shared by all the epilepsies. Identification of antiepileptogenesis targets has been an overarching goal over the last decade, as current anticonvulsant medications appear to influence only the acute process of ictogenesis. Clearly, there is an urgent need to develop novel therapeutic interventions that are disease modifying—therapies that either completely or partially prevent the emergence of SRS. An important secondary goal is to develop new treatments that can also lessen the burden of epilepsy comorbidities (e.g., cognitive impairment, mood disorders) by preventing or reducing the deleterious changes during the epileptogenic process. This review summarizes novel antiepileptogenesis targets that were critically discussed at the XIth Workshop on the Neurobiology of Epilepsy (WONOEP XI) meeting in Grottaferrata, Italy. Further, emerging neurometabolic links among several target mechanisms and highlights of the panel discussion are presented.     

Distribution of calretinin-immunoreactivity in the rat entorhinal cortex: Coexistence with GABA

Inhibitory neurons in the entorhinal cortex control information flow between the cortical areas and the hippocampus. We characterized the inhibitory circuits in the rat entorhinal cortex by analyzing the distribution of calretinin-immunoreactivity and its colocalization with glutamate decarboxylase (GAD) and gamma-aminobutyric acid (GABA). The location of calretinin-immunoreactive (IR) neurons and terminals varies between the different layers and subfields of the entorhinal cortex. The immunopositive neurons can be divided into two major morphological classes: bipolar and multipolar, which have two or more long, aspiny or sparsely spiny dendrites that extend through several layers. In addition, there are unclassified immunopositive neurons that have large lightly stained somata. They are located primarily in layer V. Colocalization analyses with GAD and GABA revealed that approximately 40% (657 out of 1,777) of all calretinin-IR cells within the entorhinal cortex contain GAD or GABA. In layers I–III, over 90% of the calretinin-IR neurons contain GAD or GABA. In layers V–VI, however, most of the calretinin-IR neurons do not colocalize with either GAD or GABA. The distribution patterns of calretinin-immunoreactivity in the entorhinal cortex is consistent with the partitioning of the rat entorhinal cortex into six subfields. Furthermore, calretinin is expressed in a morphologically heterogeneous population of cells in the rat entorhinal cortex which includes both GABAergic and non-GABAergic neurons. J. Comp. Neurol. 378:363–378, 1997. © 1997 Wiley-Liss, Inc.