Yoshimi Sogawa

Long-term effects of neonatal seizures: a behavioral, electrophysiological, and histological study

Previous studies have demonstrated that recurrent seizures during the neonatal period lead to permanent changes in seizure threshold and learning and memory. The pathophysiological mechanisms for these changes are not clear. To determine if neonatal seizures cause changes in hippocampal excitability or inhibition, we subjected rats to 50 flurothyl-induced seizures during the first 10 days of life (five seizures per day). When the rats were adults, we examined seizure threshold using flurothyl inhalation, and learning and memory in the water maze. In separate groups of animals, we evaluated in vivo paired-pulse facilitation and inhibition in either CA1 with stimulation of the Schaffer collaterals or dentate gyrus with stimulation of the perforant path. Following these studies, the animals were sacrificed and the brains evaluated for mossy fiber sprouting with the Timm stain. Compared to control animals, rats with 50 flurothyl seizures had a reduced seizure threshold, impaired learning and memory in the water maze, and sprouting of mossy fibers in the CA3 pyramidal cell layer and molecular layer of the dentate gyrus. No significant differences in impaired paired-pulse inhibition was noted between the flurothyl-treated and control rats. This study demonstrates that recurrent neonatal seizures result in changes of neuronal connectivity and alterations in seizure susceptibility, learning and memory. However, the degree of impairment following 50 seizures was modest, demonstrating that the immature brain is remarkably resilient to seizure-induced damage.

Long-term Effects of Status Epilepticus in the Immature Brain Are Specific for Age and Model

Summary:  Purpose: Status epilepticus (SE) is more common in children than adults and has a high mortality and morbidity rate. SE in adult rats results in long‐term disturbances in learning and memory, as well as an enhanced seizure susceptibility to further seizures. In contrast, a number of studies suggest that the immature brain is less vulnerable to the morphologic and physiologic alterations after SE. The goal of this study was to determine whether the long‐term consequences of SE during development on hippocampal plasticity and cognitive function are age and model specific.

The expression of Fos following kainic acid‐induced seizures is age‐dependent

The expression of limbic seizures following kainic acid (KA) administration starts at approximately postnatal day (P) 19 in rats. In this study we investigated whether the expression of Fos‐like immunoreactivity (Fos‐IR) in limbic regions occurs concomitantly with the behavioural expression of limbic seizures. Immunohistochemistry for c‐Fos protein was examined 1, 2, 4, 12 and 24 h following seizure onset (KA‐treated rats) or saline injections (controls) in immature and adult rats at P7, P13, P20 and P60. The expression of Fos‐IR in limbic structures following KA‐induced seizures is age‐dependent. There is a strong and selective induction of Fos‐IR in the CA3 region of the hippocampus following KA‐induced seizures in rats at P7. However, the expression of Fos‐IR in KA‐treated rats at P13, P20 and P60 involved other hippocampal structures in addition to CA3. Abundant induction of Fos‐IR was found in the CA1, CA3 and dentate gyrus (DG) in KA‐treated rats at P13, P20 and P60. While immature rats at P7 and P13 showed very few or no Fos‐IR neurons in most amygdala nuclei, rat pups at P20 showed strong induction of Fos‐IR in the amygdala. Our results demonstrated that the induction of Fos‐IR in most amygdala nuclei and the full expression of behavioural limbic seizures occur at the same developmental age, which is consistent with the idea that the amygdala may play a role in the modulation of limbic seizures.

When It’s Not Just a Febrile Seizure: Epileptic Encephalopathy

The contribution of genetics is increasingly recognized in the field of pediatric epilepsy. Dravet syndrome is associated with difficult-to-control epilepsy and developmental, cognitive, and behavioral impairments. Identification of the genetic mutation has shed light on mechanisms that cause seizures as well as cause motor abnormalities associated with developmental regression. Recognition of this phenotype is important as it may initially present as febrile seizures, a benign pediatric condition which then progresses to a severe epileptic encephalopathy and uncontrolled epilepsy. Frequent seizures and multiple seizure medications contribute to neuropsychiatric symptoms. Understanding the mechanism of this particular condition can inform treatment and serve as a neurobiological model for other genetically mediated epilepsies.

The effect of vagus nerve stimulator in controlling status epilepticus in children

PURPOSE This study explores the effect of Vagus Nerve Stimulator (VNS) on Status Epilepticus (SE) in children with medically intractable epilepsy. METHODS Retrospective review was conducted in children with a history of at least two SE, who had VNS implantation and had at least one year follow up after the procedure. RESULTS Sixteen patients met inclusion/exclusion criteria. The median age of seizure onset and surgery was 1.3 years and 9.0 years, respectively. Prior to VNS implantation, 81% (13/16) of patients had ≥one seizure per month when all seizure types were combined. 75% (12/16) of patients experienced  ≥one generalized convulsive seizure per month. The median number of SE prior to VNS was three (2-9), and 63% (10/16) had at least one SE during a year prior to implantation. The proportion of patients who did not have any SE one year after VNS implantation increased compared to the year prior (75% vs. 37%, p = 0.07). The seizure frequency decreased in a minority of patients when all seizure types were combined (20% at one year, p = 1.00, 44% at the last follow up, p = 0.55), but generalized convulsive seizure decreased in 69% of patients at one year (p = 0.01) and 75% of patients at last follow up (p = 0.01). CONCLUSION VNS appears to have favorable impact on SE and generalized convulsive seizures in children with medically intractable epilepsy.

Use of Vagus Nerve Stimulator on Children With Primary Generalized Epilepsy

Objective: To describe the response to vagus nerve stimulator (VNS) in otherwise neurotypical children with medically intractable primary generalized epilepsy. Methods: Retrospective chart review of patients who underwent vagus nerve stimulator surgery between January 2011 and December 2015. Results: Eleven patients were identified. Median follow-up duration was 2.5 years (1.2-8.4 years). Prior to vagus nerve stimulator surgery, all patients had at least 1 seizure per week, and 7/11 (64%) had daily seizures. At 1-year follow-up after vagus nerve stimulator, 7/11 (64%) reported improved seizure frequency and 6/11 (55%) reported fewer than 1 seizure per month. Three patients (27%) reported complications related to vagus nerve stimulator surgery, and no patients required device removal. Significance: In children with medically intractable primary generalized epilepsy, vagus nerve stimulator is well tolerated and appears to lead to improvement in seizure frequency. Improvement was not attributable to epilepsy classification, age at vagus nerve stimulator implantation, output current, duty cycle, or follow-up duration.

The phenotypic spectrum of WWOX - related disorders: 20 additional cases of WOREE syndrome and review of the literature

AbstractPurposeGermline WWOX pathogenic variants have been associated with disorder of sex differentiation (DSD), spinocerebellar ataxia (SCA), and WWOX-related epileptic encephalopathy (WOREE syndrome). We review clinical and molecular data on WWOX-related disorders, further describing WOREE syndrome and phenotype/genotype correlations.MethodsWe report clinical and molecular findings in 20 additional patients from 18 unrelated families with WOREE syndrome and biallelic pathogenic variants in the WWOX gene. Different molecular screening approaches were used (quantitative polymerase chain reaction/multiplex ligation-dependent probe amplification [qPCR/MLPA], array comparative genomic hybridization [array-CGH], Sanger sequencing, epilepsy gene panel, exome sequencing), genome sequencing.ResultsTwo copy-number variations (CNVs) or two single-nucleotide variations (SNVs) were found respectively in four and nine families, with compound heterozygosity for one SNV and one CNV in five families. Eight novel missense pathogenic variants have been described. By aggregating our patients with all cases reported in the literature, 37 patients from 27 families with WOREE syndrome are known. This review suggests WOREE syndrome is a very severe epileptic encephalopathy characterized by absence of language development and acquisition of walking, early-onset drug-resistant seizures, ophthalmological involvement, and a high likelihood of premature death. The most severe clinical presentation seems to be associated with null genotypes.ConclusionGermline pathogenic variants in WWOX are clearly associated with a severe early-onset epileptic encephalopathy. We report here the largest cohort of individuals with WOREE syndrome.

A Newborn With Hyperlactatemia and Epileptic Encephalopathy

The etiology of hyperlactatemia in newborns could be a challenging diagnosis. In this article we are discussing a diagnostic paradigm using the clinical history, laboratory results, and brain imaging that could be helpful in directing the work up.