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BACKGROUND: California sea lions have a large body burden of organochlorine pesticides, and over the last decade they have also been subject to domoic acid poisoning. Domoic acid poisoning, previously [...]

Several lines of evidence indicate that neurotrophic factors (NTFs) could be key causal mediators in the development of acquired epileptic syndromes. Yet the trophic properties of NTFs indicate that they might be used to treat epilepsy-associated damage. Accordingly, different NTFs, or even the same NTF, could produce functionally contrasting effects in the context of epilepsy. Recent experimental evidence begins to shed light on the mechanisms underlying these contrasting effects. Understanding these mechanisms will be instrumental for the development of effective therapies, which must be based on a careful consideration of the biological properties of NTFs. Here, we critically evaluate new information emerging in this area and discuss its implications for clinical treatment.

Epilepsies, once regarded as due to demoniacal possession, can have both genetic and acquired causes, with interaction of these factors in many cases. To date, nearly all the genes discovered to be involved in human epilepsies encode subunits of ion channels, both voltage-gated and ligand-gated. Established acquired causes include serious brain trauma, stroke, tumours and infective lesions. Thus, in terms of exploring the neurobiology of 'nature and nurture' in disease, the epilepsies are an excellent paradigm. Here, we review the evidence and discuss the possibility that ion channels are a common biological substrate for both genetic and acquired epilepsies. This review is part of the INMED/TINS special issue Nature and nurture in brain development and neurological disorders, based on presentations at the annual INMED/TINS symposium (http://inmednet.com/).

Absence epilepsy, a disease predominantly of childhood, has long been known to arise from an aberration of the interplay between two brain regions, the cortex and the thalamus. Pharmacological treatment of the disorder has advanced little during past decades, with ethosuximide and sodium valproate remaining the principle drugs of choice. Absence epilepsy is classified as a generalized seizure type and it has been widely assumed that the thalamus is the generator of this seizure activity. However, recent evidence has identified a specific site of seizure generation within the peri-oral region of the primary somatosensory cortex (S1po). Furthermore, ethosuximide has been shown to exert its inhibitory effect on absence seizure activity specifically at this focus, and not in other parts of the cortex or in the thalamus. A greater understanding of the molecular mechanisms within this cortical region might therefore give rise to newer, more effective treatments of absence epilepsy, and perhaps of other thalamocortical dysfunctions.

Epilepsy is the most common neurological disorder of young humans. Each year 150,000 children in the United States experience their first seizure. Antiepileptic drugs (AEDs), used to treat seizures in children, infants, and pregnant women, cause cognitive impairment, microcephaly, and birth defects. The cause of unwanted effects of therapy with AEDs is unknown. Here we reveal that phenytoin, phenobarbital, diazepam, clonazepam, vigabatrin, and valproate cause apoptotic neurodegeneration in the developing rat brain at plasma concentrations relevant for seizure control in humans. Neuronal death is associated with reduced expression of neurotrophins and decreased concentrations of survival-promoting proteins in the brain. [beta]-Estradiol, which stimulates pathways that are activated by neurotrophins, ameliorates AED-induced apoptotic neurodegeneration. Our findings present one possible mechanism to explain cognitive impairment and reduced brain mass associated with prenatal or postnatal exposure of humans to antiepileptic therapy. Survival | epilepsy | rat | neurotrophins

Byline: Danny Flanagan (1), Karabi Ghose (1) Keywords: Key words Aura; EEG; Epilepsy; Headache; Migraine; Seizures Abstract: Migraine and epilepsy are common neurological conditions that often co-exist. There are some common symptoms and in some patients there may be a diagnostic problem. The purpose of this study was to review the literature on the co-morbidity of migraine and epilepsy, and to differentiate their clinical characteristics. A search in Medline using the terms 'migraine and epilepsy' was conducted to identify articles published during the period 1963--1999. Articles describing co-morbidity of epilepsy and migraine have been reviewed. In the absence of convulsive episodes or a clearly migrainous profile (especially in children), confusion is most likely in patients affected by transient blindness, paroxysmal abdominal pain, unseen nocturnal events and 'basilar' symptoms. Electroencephalographic abnormalities and response to an anticonvulsant may not clarify diagnosis. Although clinicians generally have little difficulty, rarely more investigations may be required for some patients. An isolated, single electroencephalogram may not provide definitive data unless an event is captured during the recording. Clinicians, therefore, have to rely mainly on the interpretation of the patient's history and clinical presentation. Author Affiliation: (1) Department of Pharmacology, Faculty of Medicine, University of Otago, PO Box 913, Dunedin, New Zealand, e-mail: karabi.ghose@stonebow.otago.ac.nz, Tel.: +64-3-4797245, Fax: +64-3-4795743, NZ Article note: Received: 10 Juli 2000 / Accepted in revised form: 5 October 2000

There are many unresolved issues surrounding the rare genetic disorder of tuberous sclerosis, including its natural history and medical management, but it is possible to give some guidelines on these issues. The condition has physical manifestations, including typical skin lesions and cortical tubers and subependymal nodules in the brain. It has neuropsychiatric manifestations, including epilepsy. There are cognitive and developmental impairments, and 51% of sufferers are autistic. Hyperactivity is common. Researchers have found some evidence for a link between specific brain abnormalities and other manifestations.

Although seizures are recognized as a potential complication of acute stroke, the frequency of seizures in this condition is not well established. To estimate the frequency of seizures, 1,000 consecutive stroke patients were prospectively evaluated for seizures. In this study, seizures were observed only in strokes involving the cerebral cortex, a finding which contrasts with some previous observations. The total frequency of seizures was 4.4 percent; a greater percentage, 15.4, was observed for those patients with lobar or extensive hemorrhage. Of the 44 seizure patients, 35 survived for a follow-up period of seven months; 4 had recurring seizures during this period. It was also found that neither the overall survival nor the functional outcome of the seizure patients was any worse than for stroke patients in general. (Consumer Summary produced by Reliance Medical Information, Inc.)

Epilepsy is characterized by the sudden appearance of motor or sensory phenomena, or an alteration in the state of consciousness. The most common phenomenon is convulsive seizures. The origin of seizures is poorly understood, but they are generally considered to begin as abnormal electrical activity in some part, or parts, of the brain which then kindles a reaction that spreads to other brain regions. There is some controversy about whether epilepsy is always a primary disorder in humans or whether it may sometimes by a secondary consequence of some other abnormal physiological process. There is frequently an association between epilepsy and cerebral arteriovenous malformations (AVMs), abnormal structures in the blood vessels of the brain. While these AVMs often lead to intracranial hemorrhages and complications thereof, there is no indication that an AVM must bleed to cause epilepsy. It is estimated that from 17 to 40 percent of people with nonhemorrhagic AVMs are likely to have epileptic seizures. The authors present two cases that illustrate a curious relation between arteriovenous malformations and epilepsy. The two men, one 20 and one 30, had generalized seizures that began without a warning period or ''aura''. In one case, an arteriovenous malformation was revealed by CT scan; in the other, by angiography. In both cases, electroencephalography (EEG) revealed electrical activity consistent with epilepsy in the region of the cerebral cortex near the AVM, and in both cases both the AVM and the epileptic cortex were surgically removed. This resulted in complete freedom from generalized seizures in both patients. However, both patients subsequently developed partial seizures, which caused confusion and automatisms in one patient and hallucinatory smells in the other. Further EEG examination revealed a temporal lobe source for epileptic activity in both patients, an area distant from the original malformation. Second procedures were performed to extirpate these brain regions, which freed the patients from epileptic activity. The present cases are unique in that the surgical treatment of the AVMs resulted in the disappearance of generalized seizure activity, but apparently unmasked a second focus of epileptic activity causing partial seizures. (Consumer Summary produced by Reliance Medical Information, Inc.)

Research has been conducted on idiopatic epilepsy in dogs which is characterized by recurrent seizure activity. The authors describe their efforts to establish molecular linkage between the epileptic phenotype and the locus large effect, which have been achieved via genomic DNA screening from affected Belgian turvuren and sheepdogs possessing polymorphic canine microsatellite markers.

Background. Neuroimaging is generally considered a part of the evaluation of seizures and epilepsy. There is limited information about its current use in the initial evaluation of pediatric epilepsy and about its yield during the initial diagnosis of epilepsy. We describe the patterns in the use and yield of diagnostic imaging in children with newly diagnosed epilepsy in a community-based study. Methods. Children were recruited when first diagnosed with epilepsy by participating physicians in Connecticut (1993-1997). Definitions for etiology and underlying epilepsy syndromes are as published by the International League Against Epilepsy. Results. Of 613 children, 488 (79.6%) had imaging: 388 (63.3%) magnetic resonance imaging, 197 (32.1%) computed tomography scans, and 97 (15.8%) both. Half of children with idiopathic generalized epilepsy had imaging studies compared with 70% to 100% of children with other forms of epilepsy, depending on the specific type. Etiologically relevant abnormalities were found in 62 (12.7% of those imaged). Fourteen of these children had otherwise completely normal presentations and histories. Their abnormalities included tuberous sclerosis (N = 4), tumors (N = 2), an arteriovenous malformation later diagnosed as a tumor, a cavernous angioma, cerebral malformations (N = 3), and other abnormalities (N = 3). Thirteen of the 14 had partial seizures and 12 had focal electroencephalographic (EEG) findings. Only 1 had neither. Conclusions. In children with newly diagnosed epilepsy, neuroimaging reveals a small but significant number of serious abnormalities not previously suspected. Most of these children have partial seizures or focal EEG abnormalities. Neuroimaging should be considered during the evaluation of children with newly diagnosed epilepsy, especially for those with neurologic deficits or partial seizures or focal EEG abnormalities that are not part of an idiopathic localization-related epilepsy syndrome. Pediatrics 2000;106:527-532; neuroimaging, epilepsy, children, evaluation, MRI., ABBREVIATIONS. MRI, magnetic resonance imaging; CT, computed tomography (scan); EEG, electroencephalogram; IGE, idiopathic generalized epilepsies; GTCS, generalized tonic-clonic seizures; OR, odds ratio; CI, 95% confidence interval; DNET, dysembryoplastic neuroepithelial tumor; [...]

Members of the Src family of nonreceptor protein tyrosine kinases (PTKs) have been implicated in the regulation of cellular excitability and synaptic plasticity. We have investigated the role of these PTKs in in vitro models of epileptiform activity. Spontaneous epileptiform discharges were induced in vitro in the CA3 region of rat hippocampal slices by superfusion with the potassium channel blocker 4-aminopyridine in [Mg.sup.2+]-free medium. In hippocampal slices treated in this fashion, Src kinase activity was increased and the frequency of epileptiform discharges could be greatly reduced by inhibitor of the Src family of PTKs, 4-amino-5-(4-chlorophenyl)-7-(t-butyl) pyrazolo[3,4-d]pyrimidine (PP2), but not by the inactive structural analog 4-amino-7-phenylpyrazol[3,4-d]pyrimidine (PP3). 4-Amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine also reduced epileptiform activity induced by either 4-aminopyridine or [Mg.sup.2+]-free medium alone. These observations demonstrate a role for Src family PTKs in the pathophysiology of epilepsy and suggest potential therapeutic targets for antiepileptic therapy.

Epileptic syndromes have very diverse primary causes, which may be genetic, developmental or acquired. In rodent models, altering glutamate receptor or glutamate transporter expression by knockout or knockdown procedures can induce or suppress epileptic seizures. Regardless of the primary cause, synaptically released glutamate acting on ionotropic and metabotropic receptors appears to play a major role in the initiation and spread of seizure activity. In rodent models of acquired epilepsy and in human temporal lobe epilepsy, there is evidence for enhanced functional efficacy of ionotropic N-methyl-D-aspartate (NMDA) and metabotropic (Group I) receptors. In animal models of epilepsy, antagonists acting at NMDA receptors or at Group I metabotropic receptors have potent anticonvulsant actions. J. Nutr. 130: 1043S-1045S, 2000. KEY WORDS: * epilepsy * glutamate * N-methyl-D-aspartate * kindling * glutamate metabotropic receptors * antiepileptics

BETA2/NeuroD is a homologue of the Drosophila atonal gene that is widely expressed during development in the mammalian brain and pancreas. Although studies in Xenopus suggest that BETA2/ NeuroD is involved in cellular differentiation, its function in the mammalian nervous system is unclear. Here we show that mutant mice homozygous for a deletion at the BETA2/NeuroD locus fail to develop a granule cell layer within the dentate gyrus, one of the principal structures of the hippocampal formation. To understand the basis of this abnormality, we analyzed dentate gyrus development by using immunocytochemical markers in BETA2/NeuroD deficient mice. The early cell populations in the dentate gyrus, including Cajal-Retzius cells and radial glia, are present and appear normally organized. The migration of dentate precursor cells and newly born granule cells from the neuroepithelium to the dentate gyrus remains intact. However, there is a dramatic defect in the proliferation of precursor cells once they reach the dentate and a significant delay in the differentiation of granule cells. This leads to malformation of the dentate granule cell layer and excess cell death. BETA2/NeuroD null mice also exhibit spontaneous limbic seizures associated with electrophysiological evidence of seizure activity in the hippocampus and cortex. These findings thus establish a critical role of BETA2/NeuroD in the development of a specific class of neurons. Furthermore, failure to express BETA2/NeuroD leads to a stereotyped pattern of pathological excitability of the adult central nervous system.

Neuropeptide Y (NPY) is an inhibitory neuromodulator expressed abundantly in the central nervous system that is suspected of being an endogenous antiepileptic agent that can control propagation of limbic seizures. Electrophysiological and pharmacological data suggest that these actions of NPY are mediated by G protein-coupled NPY Y2 and NPY Y5 receptors. To determine whether the NPY Y5 receptor (Y5R) is required for normal control of limbic seizures, we examined hippocampal function and responsiveness to kainic acid-induced seizures in YSR-deficient ([Y5R.sup.-/-]) mice. We report that [Y5R.sup.-/-] mice do not exhibit spontaneous seizure-like activity; however, they are more sensitive to kainic acid-induced seizures. Electrophysiological examination of hippocampal slices from mutant mice revealed normal function, but the antiepileptic effects of exogenously applied NPY were absent. These data demonstrate that YSR has an important role in mediating NPY's inhibitory actions in the mouse hippocampus and suggest a role for Y5R in the control of limbic seizures.

Experts and researchers globally are calling for epilepsy to be recognized as a spectrum disorder, a mental illness with a host of cognitive, behavioral, psychiatric and other neurological disorders. The reasons that epilepsy is being called a spectrum disease include variations in seizures types, treatments, causes, disabilities and outcomes.