Sporadic Seizures Research Articles

CAMP Response Element-Binding Protein-Mediated Gene Expression Increases the Intrinsic Excitability of CA1 Pyramidal Neurons

To investigate the role of CREB-mediated gene expression on the excitability of CA1 pyramidal neurons, we obtained intracellular recordings from pyramidal neurons of transgenic mice expressing a constitutively active form of CREB, VP16-CREB, in a regulated and restricted manner. We found that transgene expression increased the neuronal excitability and inhibited the slow and medium afterhyperpolarization currents. These changes may contribute to the reduced threshold for LTP observed in these mice. When strong transgene expression was turned on for prolonged period of time, these mice also showed a significant loss of hippocampal neurons and sporadic epileptic seizures. These deleterious effects were dose dependent and could be halted, but not reversed by turning off transgene expression. Our experiments reveal a new role for hippocampal CREB-mediated gene expression, identify the slow afterhyperpolarization as a primary target of CREB action, provide a new mouse model to investigate temporal lobe epilepsy and associated neurodegeneration, and illustrate the risks of cell death associated to a sustained manipulation of this pathway. As a result, our study has important implications for both the understanding of the cellular bases of learning and memory and the consideration of therapies targeted to the CREB pathway.

A pilot study transitioning children onto levetiracetam monotherapy to improve language dysfunction associated with benign rolandic epilepsy

Benign rolandic epilepsy (BRE) and Landau–Kleffner syndrome (LKS) are similar epilepsy syndromes with sleep-accentuated epileptiform activity, sporadic seizures, and language dysfunction. Levetiracetam has been associated with improved language function in LKS and seizure reduction in BRE. We hypothesized levetiracetam would improve language function in children with BRE. A pilot study was performed with six children (aged 6–12) with BRE and evidence of impaired auditory comprehension and verbal memory. Children were transitioned from their current anticonvulsant to 40 mg/kg/day levetiracetam over a 2-week period and retested at 6 months. At 6 months, three of four children with baseline auditory comprehension impairments performed normally ( P = 0.06), and five had improved auditory verbal memory ( P = 0.08). Seizures improved in five, decreasing from 2.7 to 1.0 seizure per 6 months ( P = 0.11). Results from this pilot study suggest that levetiracetam may have a beneficial effect on language in children with BRE.

Multicentre search for genetic susceptibility loci in sporadic epilepsy syndrome and seizure types: a case-control study

The Epilepsy Genetics (EPIGEN) Consortium was established to undertake genetic mapping analyses with augmented statistical power to detect variants that influence the development and treatment of common forms of epilepsy. We examined common variations across 279 prime candidate genes in 2717 case and 1118 control samples collected at four independent research centres (in the UK, Ireland, Finland, and Australia). Single nucleotide polymorphism (SNP) and combined set-association analyses were used to examine the contribution of genetic variation in the candidate genes to various forms of epilepsy. We did not identify clear, indisputable common genetic risk factors that contribute to selected epilepsy subphenotypes across multiple populations. Nor did we identify risk factors for the general all-epilepsy phenotype. However, set-association analysis on the most significant p values, assessed under permutation, suggested the contribution of numerous SNPs to disease predisposition in an apparent population-specific manner. Variations in the genes KCNAB1, GABRR2, KCNMB4, SYN2, and ALDH5A1 were most notable. The underlying genetic component to sporadic epilepsy is clearly complex. Results suggest that many SNPs contribute to disease predisposition in an apparently population-specific manner. However, subtle differences in phenotyping across cohorts, combined with a poor understanding of how the underlying genetic component to epilepsy aligns with current phenotypic classifications, might also account for apparent population-specific genetic risk factors. Variations across five genes warrant further study in independent cohorts to clarify the tentative association.

The Best Rodent for the Job: NTP Workshop Compares Models

Vol. 115, No. 9 EnvironewsOpen AccessThe Best Rodent for the Job: NTP Workshop Compares Models Julia R. Barrett Julia R. Barrett Search for more papers by this author Published:1 September 2007https://doi.org/10.1289/ehp.115-a460bAboutSectionsPDF ToolsDownload CitationsTrack Citations ShareShare onFacebookTwitterLinked InReddit Researchers have long used rats and mice to understand the potential links between environmental exposures and incidences of breast, ovarian, testicular, and prostate tumors. Concern exists, however, that rodent models are not optimal for detecting carcinogens that act through the hormone system. To address this concern, the National Toxicology Program (NTP) organized a workshop in May 2006 to evaluate the utility of current two-year rodent bioassays to adequately evaluate these hormon ally mediated tumors and the relevance of the findings to humans [EHP 115:1351–1356; Thayer and Foster].The workshop, part of a series of events aimed at evaluating and refining the NTP’s testing program, included representatives from academia, industry, government, and nonprofit groups, as well as a panel of invited experts in endocrinology, cancer biology, reproductive toxicology, statistics, and other fields. Workshop participants were concerned that many hormonally mediated tumors, such as those in the testes and breasts, are initiated in fetal or early neonatal life, yet these periods of exposure are not covered in the NTP’s standard cancer bioassay. In response to this concern, the NTP has committed to routinely include perinatal exposures in these studies unless there is a specific justification not to do so.Furthermore, some rat and mouse strains used in testing either do not develop certain tumors or have a high incidence of spontaneous tumors. For example, the F344/N rat typically used by the NTP has high background incidences of testicular Leydig cell tumors and mononuclear cell leukemia, along with unresolved issues about declining fertility, sporadic seizures, and chylothorax (accumulation of lymphatic fluid in the pleural cavity, which can result from lymphoma). By press time, in response to this and other workshop findings, the NTP had selected the Wistar Han as its standard rat strain cancer and noncancer end points, although other strains will be used when appropriate.Although rodent models are considered to have certain deficiencies and can be improved, they are considered valuable nonetheless. Rodent models for prostate and ovarian tumors are the most problematic for understanding human disease because of significant interspecies differences in anatomy and tumor prevalence. Participants in the workshop recommended using alternative models, such as genetically engineered models and in vitro systems, to address some of these deficiencies. They also recommended more in-depth investigation of how noncancerous changes observed in rodents might be relevant to human diseases.FiguresReferencesRelatedDetails Vol. 115, No. 9 September 2007Metrics About Article Metrics Publication History Originally published1 September 2007Published in print1 September 2007 Financial disclosuresPDF download License information EHP is an open-access journal published with support from the National Institute of Environmental Health Sciences, National Institutes of Health. All content is public domain unless otherwise noted. Note to readers with disabilities EHP strives to ensure that all journal content is accessible to all readers. However, some figures and Supplemental Material published in EHP articles may not conform to 508 standards due to the complexity of the information being presented. If you need assistance accessing journal content, please contact [email protected]. Our staff will work with you to assess and meet your accessibility needs within 3 working days.

Deletions or duplications in KCNQ2 can cause benign familial neonatal seizures

Background:Benign familial neonatal seizures are most often caused by mutations in the voltage-gated potassium channel subunit gene KCNQ2. More than 60 mutations have been described in BFNS families, approximately half...

Locus Coeruleus and Neuronal Plasticity in a Model of Focal Limbic Epilepsy

A lesion of the noradrenergic nucleus Locus Coeruleus (LC) converts sporadic seizures evoked by microinfusion of bicuculline into the anterior piriform cortex (APC) of rats into limbic status epilepticus (SE). The purpose of this study was to evaluate the chronic effects of this new model of SE on the onset of secondary epileptogenesis. We further related the loss of noradrenaline (NE) with hippocampal mossy fiber sprouting. Male Sprague Dawley rats were treated with systemic saline or DSP-4 (a neurotoxin selective for noradrenergic terminals originating from the LC), microinfused with bicuculline into the APC three days later, and sacrificed after 45 days. Naïve and DSP-4 pretreated sham-operated rats served as respective controls. The following evaluations were performed: (a) monitoring of acute seizures and delayed occurrence of spontaneous recurrent seizures (SRS); (b) NE levels in the hippocampus, frontal and olfactory cortex; (c) occurrence of mossy fiber sprouting into the inner molecular layer of the dentate gyrus of the dorsal hippocampus. In 30% of rats lacking noradrenergic terminals, SE evoked from the APC was followed by SRS. Conversely, seizures evoked in intact rats did not result in chronic epileptogenesis. Seizures/SE did not modify NE levels as compared with baseline levels both in naïve and DSP-4-pretreated rats. Rats undergoing SE following DSP-4 + bicuculline developed SRS which were accompanied by hippocampal mossy fiber sprouting. Noradrenergic loss converts focally induced sporadic seizures into an epileptogenic SE, which is accompanied by mossy fiber sprouting within the dentate gyrus.

Ketogenic diet in patients with myoclonic‐astatic epilepsy

ABSTRACT For more than 80 years, the ketogenic diet has been used as an alternative to antiepileptic drugs for patients with refractory epilepsy. Myoclonic‐astatic epilepsy in early childhood is one of the malignant epilepsy syndromes that often proves refractory to antiepileptic drugs treatment. Objective In this prospective study we assess the efficacy and tolerability of the ketogenic diet in patients with myoclonic‐astatic epilepsy. Material and methods Between March 1, 1990 and August 31, 2004, 30 patients who met diagnostic criteria of myoclonic‐astatic epilepsy were seen at our department. Eleven of them were placed on the ketogenic diet using the Hopkins protocol and were followed for a minimum of 18 months. Results The children had previously received a mean of 5.2 different antiepileptic drugs and were on a mean of 2.2 antiepileptic drugs when the diet was started. Eighteen months after initiating the diet, six of the patients (54.5%) remained on the diet. Two patients (18%) were seizure‐free, two (18%) had a 75‐99% decrease in seizures, and the remaining two children (18%) had a 50% to 74% decrease in seizures. The first two patients were tapered off the diet after remaining seizure‐free, without antiepileptic drugs for several years. In the two patients who had sporadic seizures, antiepileptic drugs were reduced to one, and in the last two the seizure frequency was significantly reduced. No differences in seizure control were found when compared for age, sex, or seizure type. Five of our patients discontinued the ketogenic diet in less than 3 months (four because of lack of effectiveness and one because of persistent vomiting). Conclusion The ketogenic diet is a promising therapy for patients with myoclonic‐astatic epilepsy, with over half the children showing a > 50% reduction in seizures, and seizure‐freedom in 18%. In drug resistant cases of myoclonic‐astatic epilepsy, the diet should be considered early in the course of this syndrome and not as a last resort.

Cerebral cavernomas and seizures: a retrospective study on 163 patients who underwent pure lesionectomy

The objective was to evaluate the outcome of microsurgical "pure" lesionectomy in patients with supratentorial cavernous angiomas presenting with seizures. For this retrospective study 163 patients with cavernoma-related epileptic seizures were selected. They all underwent surgery in a single institution between 1988 and 2003. A microsurgical frame/frameless guided minimally invasive transulcal "pure" lesionectomy was performed. The haemosiderin stained gliotic brain parenchyma that was usually found surrounding the lesion was not removed. Among the 99 patients with epilepsy and longer clinical history, 68 (68.7%) were found completely to be seizure-free, 10 (10.1%) presented sporadic and less frequent seizures and 17 (17.1%) remained unchanged. Sixty-three out of 64 (98.4%) patients who experienced only single or sporadic seizures were found to be completely seizure-free after surgery. Five patients were lost at follow-up (mean 48 months, range 0.5-14 years). Long-term morbidity was 1.8%. Mortality was null. No haemorrhagic episodes were observed during follow-up. Pure lesionectomy prevents bleeding and development of epilepsy in patients that receive early surgery after the epileptic onset. In most of the epileptic patients with a good concordance between the electroclinical data and the location of the angioma, good results can be achieved by this kind of surgery so that more invasive and costly studies to find and remove the epileptogenic cerebral parenchyma seem justified only after lesionectomy fails.

Ketogenic Diet in Patients with Dravet Syndrome

The ketogenic diet (KD) has been used as a therapeutic alternative to antiepileptic drugs (AEDs) for refractory epilepsy. Severe myoclonic epilepsy in infants or Dravet syndrome (DS) is one of the most malignant epileptic syndromes. In this retrospective study, we evaluated the efficacy and tolerability of the KD in patients with diagnostic criteria of DS. Between March 1, 1990, and August 31, 2004, 52 patients who met diagnostic criteria for DS were enrolled in a study at our department. Twenty of them were placed on the KD with the Hopkins protocol and followed up for a minimum of 1 year. Three of the 20 original children stayed on the diet for 12 months, four children for 2 years, four children for 3 years, and two children for 4 years. One year after initiating the diet, 13 (65%) of the initial patients remained on the diet. Two (15%) patients were seizure free, eight (61.7%) children had a 75-99% decrease in seizures, and the remaining three (23%) children had a 50-74% decrease in seizures. Thus 1 year after starting the diet, 10 (77%) children had achieved a >75% decrease in their seizures. Four patients have been off the diet for >2 years; one of them is seizure free, two have sporadic seizures, and one, who abandoned the diet after 2 years of adhering to it, relapsed. No differences in seizure control when compared with age, sex, or seizure type were found. Considering the severity and intractability of seizures in patients with DS, the fact that 10 of the 13 children who remained on the diet had a significant reduction in number of seizures shows that the KD is at present an interesting therapeutic alternative. Even in patients in whom seizure reduction was not dramatic, quality of life improved, and in all of them, the number of AEDs was reduced to one or two. We consider that children with DS should be offered the KD immediately after three adequate trials of AEDs have failed.

A damage to locus coeruleus neurons converts sporadic seizures into self‐sustaining limbic status epilepticus

Various studies demonstrated that the neurotransmitter norepinephrine (NE) plays a relevant role in modulating seizures; in particular, a powerful effect consists in delaying the kindling of limbic areas such as the amygdala and hippocampus. Given the rich NE innervation of limbic regions, we selected a sensitive trigger area, the anterior piriform cortex, to test whether previous loss of noradrenergic terminals modifies sporadic seizures in rats. The damage to locus coeruleus terminals was produced by using the selective neurotoxin N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4, 60 mg/kg i.p.). In intact rats, bicuculline (a GABA-A antagonist, 118 pmol) microinfused into this area produced sporadic seizures, while in rats previously injected with DSP-4, bicuculline determined long-lasting self-sustaining status epilepticus. In intact rats, sporadic seizures were accompanied by a marked increase in norepinephrine release in the contralateral piriform cortex, while in locus coeruleus-lesioned rats this phenomenon was attenuated. While bicuculline-induced sporadic seizures were prevented by the focal infusion of amino-7-phosphonoheptanoic acid (AP-7, a selective NMDA antagonist), or 1,2,3,4-tetrahydro-6-nitro-2,3-dioxo-benzo[f]quinoxaline-7-sulphonamide (NBQX, a selective non-NMDA antagonist), status epilepticus obtained in norepinephrine-lesioned rats was insensitive to AP-7 but was still inhibited by NBQX. By using fluorescent staining for damaged (Fluoro-Jade B) and intact (DAPI) neurons, as well as cresyl violet, we found that rats undergoing status epilepticus developed neuronal loss in various limbic regions. This study demonstrates a powerful effect of noradrenergic terminals in regulating the onset of limbic status epilepticus and its sensitivity to specific glutamate antagonists.

Visual agnosia in a child with non-lesional occipito-temporal CSWS

In this paper we describe a case of severe visual agnosia in a child with an electrophysiological pattern of continuous spike–wave discharges in slow sleep (CSWS) in the occipito-temporal regions. The neuropsychological spectrum related to this phenomenon is discussed. Published paediatric reports associate visual agnosia (i.e. an inability to recognize objects without impairment of visual acuity) mainly with symptomatic occipito-temporal aetiology (e.g. cortical dysplasia, vascular insults) and other neurological symptoms (e.g. autism). We describe a detailed 2 year electrophysiological and neuropsychological follow-up of an 8-year-old boy with sporadic seizures, occipito-temporal CSWS and visual agnosia. The growth and neurological development of the child had been considered as normal, neurological examination did not reveal any focal signs, visual acuity was intact and MRI was normal. First EEG and six consecutive 24 h video EEG recordings during the follow-up of 22 months showed continuous spike-and-wave activity covering over 85% of the non-REM sleep. According to structured neuropsychological tests (Wechsler Intelligence Scale for Children – Third Edition, A Developmental Neuropsychological Assessment (NEPSY), Test of Visual-Perceptual Skills, Corsi block, Hooper Visual Organization Test) the boy had normal verbal intelligence but major deficits in visual perception, especially in object recognition, impaired shape discrimination and detection, and poor copying skills. Attention and executive functions were intact. There were no difficulties in short- or long-term memory. Verbal cues and naming the objects improved visual memory. Tracing the objects with a finger or by moving the head improved object recognition. Currently the boy attends a special school with a rehabilitation plan including neuropsychological and occupational therapies. This case adds a new facet to the spectrum of neuropsychological deficits in children with CSWS. Sleep EEG should be included in the etiological studies of children with specific neuropsychological problems and detailed neuropsychological assessment is needed for diagnostic and rehabilitation purposes.

Relevance of residual histologic and electrocorticographic abnormalities for surgical outcome in frontal lobe epilepsy.

To estimate the significance of residual electrocorticographic and neuropathologic abnormalities on seizure control after surgery for frontal lobe epilepsy with the purpose of determining their relevance in deciding the extent of the surgical procedure. The presence of epileptiform discharges in intraoperative electrocorticograms (ECoGs) and the nature and extent of neuropathologic abnormalities were reviewed for 35 patients who underwent frontal lobe resections for the treatment of epilepsy at our institution. The relations between surgical outcome and presence of the following features were studied: (a) presence of abnormal tissue at the limits of the resection; (b) presence of sporadic spikes and seizure patterns in the preresection ECoG; (c) their abolition in the postresection ECoG; and (d) the topography of residual discharges with respect to the margins of the resection. On neuropathologic examination, 18 patients showed focal cortical dysplasia (CD), and 17 showed other abnormalities (non-CD). Ten CD patients and 11 non-CD patients experienced a favourable outcome. Seizure patterns were significantly more common in patients with focal cortical dysplasia than in those without, with a sensitivity of 94% and a specificity of 75%. Abolition of seizure patterns was associated with a favourable surgical outcome (p = 0.031). Abolition of sporadic spikes or their presence in the postresection ECoG did not influence outcome. There was no clear relation between outcome and location of residual sporadic discharges. Seizure patterns persisted in the postresection ECoG in three CD patients, were located at the margins of the resection in all three, and these patients had a poor outcome. Incomplete removal of abnormal tissue was not associated with a poorer outcome in either patient group or in the complete sample. Seizure patterns were significantly more common in patients with cortical dysplasia, and their abolition on postresection ECoG recordings was associated with a favourable surgical outcome. Persistence of sporadic ECoG spikes and incomplete removal of histologic abnormalities did not affect outcome significantly.

Abnormal Morphological and Functional Organization of the Hippocampus in a p35 Mutant Model of Cortical Dysplasia Associated with Spontaneous Seizures

Cortical dysplasia is a major cause of intractable epilepsy in children. However, the precise mechanisms linking cortical malformations to epileptogenesis remain elusive. The neuronal-specific activator of cyclin-dependent kinase 5, p35, has been recognized as a key factor in proper neuronal migration in the neocortex. Deletion of p35 leads to severe neocortical lamination defects associated with sporadic lethality and seizures. Here we demonstrate that p35-deficient mice also exhibit dysplasia/ heterotopia of principal neurons in the hippocampal formation, as well as spontaneous behavioral and electrographic seizures. Morphological analyses using immunocytochemistry, electron microscopy, and intracellular labeling reveal a high degree of abnormality in dentate granule cells, including heterotopic localization of granule cells in the molecular layer and hilus, aberrant dendritic orientation, occurrence of basal dendrites, and abnormal axon origination sites. Dentate granule cells of p35-deficient mice also demonstrate aberrant mossy fiber sprouting. Field potential laminar analysis through the dentate molecular layer reflects the dispersion of granule cells and the structural reorganization of this region. Similar patterns of cortical disorganization have been linked to epileptogenesis in animal models of chronic seizures and in human temporal lobe epilepsy. The p35-deficient mouse may therefore offer an experimental system in which we can dissect out the key morphological features that are causally related to epileptogenesis.

Treatment of central pontine myelinolysis with therapeutic plasmapheresis

Central pontine myelinolysis (CPM) is a demyelinating disease of the brainstem but rarely found in other cerebral regions. Signs of pseudobulbar palsy with dysphagia and dysarthria, paraparesis or quadriparesis are first symptoms, which usually appear within 2–6 days after correction of hyponatraemia. CPM is also associated with chronic alcohol abuse or liver transplantation. Magnetic resonance imaging confirms the diagnosis of CPM. The disease has a poor prognosis and no effective treatment is established. The lesions are characterised by a loss of oligodendrocytes and myelin with preserved neuronal cell bodies and axons. The histological similarity of CPM lesions with lesions from other demyelinating disorders, like multiple sclerosis, may lead to the assumption that these lesions have the same pathogenetic pathway. However, the background remains unclear. In three cases with CPM we did extensive therapeutic plasmapheresis immediately after confirmation by magnetic resonance imaging (figure). A 29-year-old female patient with chronic alcohol abuse was admitted to hospital with nausea and diarrhoea. Hyponatraemia (107 mmol/L) was rapidly corrected with isotonic saline. 3 days later she had pseudoflabby tetraparesis, absent deep-tendon reflexes in the extremities, and abnormal bulbar movements. Plasmapheresis started with daily sessions over 4 days changing to twice a week for a further 3 weeks. In total 24 700 mL plasma was exchanged with albumin and cristalloid solutions. Tetraplegia resolved within 2 months. Silent signs of ataxia remained after 1 year. In a second case a 20-year-old female patient with anorexia nervosa (21 kg) was admitted to the hospital with diarrhoea and a sporadic seizure. Hyponatraemia (106 mmol/L) was slowly adjusted over 5 days to normal values. She then became somnolent and a complete spastic tetraparesis occurred together with dysarthria, dysphagia, and bulbar movement disorders. 5243 mL plasma was withdrawn in five plasmapheresis sessions. Equal amounts of albumin and cristalloid solutions were infused. One month later she was able to walk with assistance. The mental status test showed an impaired intermediate-term memory. In the third case a 30-year-old female patient with pneumonia and a history of chronic alcoholic abuse was referred to our hospital. After 2 weeks of treatment with cephalasporine mild hyponatraemia was corrected slowly over 5 days. At the third day of infusion therapy the patient became lethargic and the extremities were flaccid, with reduced deep-tendon reflexes. The neurological examination showed a pseudobulbar palsy with persistent nystagmus, dysphagia, dysarthria and tetraparesis. Therapeutic plasmapheresis was done over 7 weeks. 18 270 mL plasma was exchanged with albumin and cristalloids. Mild ataxia improved to total remission after 12 months. The pontine lesions appeared unchanged in the magnetic resonance imaging even 6 months after treatment in all patients. We suppose that osmotic stress may release myelinotoxic compounds, which then cause the irreversible demyelination. Therapeutic plasmapheresis may reduce high-molecular myelinotoxic substances and therefore lead to clinical improvement. However, immediate therapeutic plasmaheresis should be considered as a safe and effective method to improve the clinical outcome of patients with CPM.

Knockout Corner: Neurobehavioural consequences of a serotonin 5-HT(2C) receptor gene mutation.

Studies employing nonselective serotonin 5-HT(2C) receptor agonists and antagonists have implicated this receptor subtype in many of the actions of serotonin. To further examine the function of this receptor, 5-HT(2C) receptor mutant mice were generated; studies of these animals reveal pleiotropic neurobehavioural effects of the mutation. Three examples are described: (1) Mutants exhibit chronically elevated food intake and the development of an obesity syndrome during the 'middle-age' portion of their lifespan. Their potential utility as a model of human obesity is further indicated by their enhanced sensitivity to high-fat feeding, leading to the development of type 2 diabetes. (2) 5-HT(2C) receptor mutants also display infrequent and sporadic spontaneous seizures. Further studies suggested the presence of globally enhanced neuronal network excitability in these mice. These findings raise the possibility that 5-HT(2C) receptors mediate a role for serotonin in the suppression of seizure activity. (3) Behavioural analysis of mutant mice revealed abnormal performance in a spatial learning task and altered exploratory behaviour, associated with perturbed long-term potentiation restricted to the dentate gyrus perforant path synapse. Taken together, the above findings implicate 5-HT(2C) receptors in the serotonergic regulation of feeding, neuronal network excitability, and hippocampal function.

Evolución de las crisis epilépticas en el síndrome de Rett

Seventeen girls diagnosed as Rett syndrome (RS) patients suffer or have suffered epileptic fits; we have analyzed the evolution of these seizures. The RS diagnosis is based on criteria established by the Rett Syndrome Diagnostic Criteria Working Group in 1988. All girls have had clinical, biochemical, electroneurophysiological neuroimaging and cytogenetic studies done on them. Periodic EEG were carried out while the girls were awake; all had night-time EEGs done. The females are aged between 7 y 5 m, and 22 y 7 m (medium 14 years, 8 months). The age at first seizure was between 18 m and 7 y 8 m (median 4 years 5 months). The clinic semiology is in decreasing order: tonic, generalized clonic, partial, absence and myoclonic seizures; eight patients have had more than one type of seizures. The frequency is variable: one or more continuous seizures in 6 cases, sporadic seizures in 3 cases, series of seizures in 4 cases, and subnitrant seizures in 4 cases. The evolution is variable: 6 cases have presented only the first fit, and 11 cases recurrent seizures which in 5 have ceased between 8 and 9 years, and 1 case at 13 years. The study shows that the epileptic seizures in RS present three evolution profiles: 1. One or more non recurrent seizures (35.3%); 2. Recurrent seizures until 8-9 years (35.3%); 3. Recurrent seizures in subnitrant form which continued after puberty (29.4%).

Global increases in seizure susceptibility in mice lacking 5-HT2C receptors: a behavioral analysis.

Previous studies have shown that mice bearing a targeted disruption of the 5-HT2C receptor gene exhibit an epilepsy syndrome associated with sporadic spontaneous seizures that occasionally result in death. In this study, we have defined the seizure susceptibility profiles of these 5-HT2C receptor mutant mice backcrossed onto a C57BL/6 background. Wild-type and mutant animals were either electrically kindled from the olfactory bulb, exposed to corneal electroshock, or tested with the chemoconvulsant, flurothyl. In all paradigms, mice lacking the 5-HT2C receptor were significantly more seizure susceptible than wild-type controls. Results indicate that mutants have lower focal seizure thresholds, increased focal seizure excitability, and facilitated propagation within the forebrain seizure system. Mutants also exhibit lower generalized seizure thresholds for the expression of both generalized clonic and generalized tonic seizures. Importantly, the 5-HT receptor antagonist, mesulergine (2 or 4 mg/kg), administered prior to electroshock testing, recapitulated the mutant phenotype in wild-type mice. Together, these data strongly implicate a role for serotonin and 5-HT2C receptors in the modulation of neuronal network excitability and seizure propagation globally, throughout the CNS.

Anticonvulsive and neuroprotective actions of a potent agonist (DCG-IV) for Group II metabotropic glutamate receptors against intraventricular kainate in the rat

Anticonvulsive and neuroprotective effects of (2 S,1′ R,2′ R,3′ R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), a potent agonist for Group II metabotropic glutamate receptors, were examined in vivo against the excitotoxicity of kainic acid in the rat. Intraventricular injection of kainic acid (2 nmol) induced circling behavior and wet-dog shakes soon after injection, followed by episodes of limbic motor seizures at intervals of several minutes (sporadic limbic motor seizures). The frequency of sporadic limbic motor seizures gradually increased until seizures occurred incessantly (continuous limbic motor seizures). Intraventricular kainic acid also caused severe selective neuron damage in the hippocampal CA3 region, limbic lobe and medial geniculate body. Prolonged intraventricular infusion of DCG-IV (24–240 pmol/h) for 17 h before and 7 h after the application of kainic acid decreased the incidence of the continuous limbic motor seizures and the degree of neuronal damage in circumscribed brain areas. However, the behavioral changes observed immediately after the administration of kainic acid were unaffected by prolonged intraventricular infusion with DCG-IV (8–2400 pmol/h). Similarly, the occurrence of sporadic limbic motor seizures was only slightly reduced by the administration of DCG-IV (8–800 pmol/h). High doses of DCG-IV, greater than 800 pmol/h, afforded no protection against kainate-induced lesions; rather, the degradation of hippocampal CA1 pyramidal neurons was increased under such conditions. Single injections of DCG-IV (10–300 pmol/rat) in the lateral ventricle did not affect kainate neurotoxicity. Thus, prolonged infusion of DCG-IV showed a bell-shaped dose–response relationship with regard to protection against kainate-induced neurotoxicity.

Mice Lacking p35, a Neuronal Specific Activator of Cdk5, Display Cortical Lamination Defects, Seizures, and Adult Lethality

The adult mammalian cortex is characterized by a distinct laminar structure generated through a well- defined pattern of neuronal migration. Successively generated neurons are layered in an “inside-out” manner to produce six cortical laminae. We demonstrate here that p35, the neuronal-specific activator of cyclin-dependent kinase 5, plays a key role in proper neuronal migration. Mice lacking p35, and thus p35/cdk5 kinase activity, display severe cortical lamination defects and suffer from sporadic adult lethality and seizures. Histological examination reveals that the mutant mice lack the characteristic laminated structure of the cortex. Neuronal birth-dating experiments indicate a reversed packing order of cortical neurons such that earlier born neurons reside in superficial layers and later generated neurons occupy deep layers. The phenotype of p35 mutant mice thus demonstrates that the formation of cortical laminar structure depends on the action of the p35/cdk5 kinase.

Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene.

The bmi-1 proto-oncogene has been implicated in B-cell lymphomagenesis in E mu-myc transgenic mice. Distinct domains of the Bmi-1 protein are highly conserved within the Drosophila protein Posterior Sex Combs, a member of the Polycomb group involved in maintaining stable repression of homeotic genes during development. We have inactivated the bmi-1 gene in the germ line of mice by homologous recombination in ES cells. Null mutant mice display three phenotypic alterations: (1) a progressive decrease in the number of hematopoietic cells and an impaired proliferative response of these cells to mitogens; (2) neurological abnormalities manifested by an ataxic gait and sporadic seizures; and (3) posterior transformation, in most cases along the complete anteroposterior axis of the skeleton. The observations indicate that Mbi-1 plays an important role in morphogenesis during embryonic development and in hematopoiesis throughout pre- and postnatal life. Furthermore, these data provide the first evidence of functional conservation of a mammalian Polycomb group homolog.