Cigdem I. Akman

Beneficial effects of enriched environment following status epilepticus in immature rats

Background: There is increasing evidence that enriching the environment can improve cognitive and motor deficits following a variety of brain injuries. Whether environmental enrichment can improve cognitive impairment following status epilepticus (SE) is not known. Objective: To determine whether the environment in which animals are raised influences cognitive function in normal rats and rats subjected to SE. Methods: Rats (n = 100) underwent lithium-pilocarpine–induced SE at postnatal (P) day 20 and were then placed in either an enriched environment consisting of a large play area with toys, climbing objects, and music, or in standard vivarium cages for 30 days. Control rats (n = 32) were handled similarly to the SE rats but received saline injections instead of lithium-pilocarpine. Rats were then tested in the water maze, a measure of visual–spatial memory. A subset of the rats were killed during exposure to the enriched or nonenriched environment and the brains examined for dentate granule cell neurogenesis using bromodeoxyuridine (BrdU) and phosphorylated cyclic AMP response element binding protein (pCREB) immunostaining, a brain transcription factor important in long-term memory. Results: Both control and SE rats exposed to the enriched environment performed significantly better than the nonenriched group in the water maze. There was a significant increase in neurogenesis and pCREB immunostaining in the dentate gyrus in both control and SE animals exposed to the enriched environment compared to the nonenriched groups. Environmental enrichment resulted in no change in SE-induced histologic damage. Conclusions: Exposure to an enriched environment in weanling rats significantly improves visual–spatial learning. Even following SE, an enriched environment enhances cognitive function. An increase in neurogenesis and activation of transcription factors may contribute to this enhanced visual–spatial memory.

Nonconvulsive Status Epilepticus in Children: Clinical and EEG Characteristics

Summary:  Background: Nonconvulsive status epilepticus (NCSE) is a highly heterogeneous clinical condition that is understudied in the pediatric population.

Autosomal Dominant Inheritance of Centrotemporal Sharp Waves in Rolandic Epilepsy Families

Purpose: Centrotemporal sharp (CTS) waves, the electroencephalogram (EEG) hallmark of rolandic epilepsy, are found in approximately 4% of the childhood population. The inheritance of CTS is presumed autosomal dominant but this is controversial. Previous studies have varied considerably in methodology, especially in the control of bias and confounding. We aimed to test the hypothesis of autosomal dominant inheritance of CTS in a well‐designed family segregation analysis study.

Limbic encephalitis associated with anti‐GAD antibody and common variable immune deficiency

A variety of autoantibodies have been identified with complex neurological disorders including limbic encephalitis. The underlying trigger for the immune‐mediated process and the role of autoantibodies in the pathogenesis of limbic encephalitis remain to be clarified. Here, we report a 16‐year‐old female who was diagnosed with acute‐onset non‐neoplastic limbic encephalitis. The initial treatment with pulse doses of i.v. methylprednisolone improved the neurological symptoms. During the next 12 months, progressive decline was reported in her academic functioning and seizure control. Additional diagnostic evaluation revealed no evidence of malignancy or central nervous system infection but circulating anti‐GAD antibodies were present in the serum and cerebrospinal fluid. Intravenous gammaglobulin infusion was initiated and continued monthly. Intravenous and oral steroids were added to the intravenous immunoglobulin treatment because of the worsening course and seizures, despite treatment with antiepileptic medications. Screening for quantitative immunoglobulins demonstrated hypogammaglobulinaemia with low immunoglobulin M and G in addition to low immunoglobulin A levels. There was a lack of protective pneumococcal antibody titers before and after immunization. Therefore, common variable immunodeficiency was suspected despite there being no history of recurrent infections. To our knowledge, this is the first report describing a possible link between immune‐mediated limbic encephalitis and immune deficiency.

Seizure detection using digital trend analysis: Factors affecting utility

BACKGROUND EEG monitoring is important for the early detection of seizures during the course of critical illness. However, the logistics of real time EEG interpretation is challenging for the neurophysiology and critical care medicine teams. This study evaluated factors affecting the utility of digital trend analysis (DTA) for rapid seizure identification in children. METHODS digital EEG files of seizures in critically ill children were retrieved for DTA. The envelop trend (ET) and compressed spectral array (CSA) were applied to the raw EEG data and presented to an experienced and inexperienced user for interpretation who were blinded to conventional EEG findings. The EEG findings with and without presence of seizures and features of seizures were analyzed. RESULTS we found that a number of factors affected accurate seizure detection including factors related to interpreters experiences, display size and type of DTA methods used for analysis in addition to baseline EEG findings. ET was more dependent on user experience, furthermore, display size and multimodal DTA application (CSA and ET combined) increased the sensitivity of seizure detection for the experienced user compared to inexperience users. The artifacts were reported as seizures regardless of experience without presence of conventional EEG recording. The maximum spike amplitude, seizure duration, and seizure frequency were other important determinants for accuracy. Electrographic seizures with shorter duration were better detected by ET, and the maximum spike amplitude was important for both the ET and CSA. Repetitive seizures are readily detected by both digital trending methods. Artifacts may be reported as seizures regardless of experience if conventional EEG recording is not available for the interpretation. CONCLUSION DTA applied to the raw EEG data does produce a graphic display that facilitates identification of seizures. The actual characteristics of the electrographic seizure may predict which DTA method is better and the overall accuracy of seizure detection may increase when multimodal trending is used simultaneously. Application of DTA alone with display of conventional EEG is beneficial for rapid interpretation of EEG findings regardless of experience.

Epilepsy duration impacts on brain glucose metabolism in temporal lobe epilepsy: Results of voxel-based mapping

OBJECTIVE [(18)F]Fluorodeoxyglucose positron emission tomography ([(18)F]FDG-PET) is a valuable method for detecting focal brain dysfunction associated with epilepsy. Evidence suggests that a progressive decrease in [(18)F]FDG uptake occurs in the epileptogenic cortex with an increase in the duration of epilepsy. In this study, our aim was to use statistical parametric mapping (SPM) to test the validity of this relationship in a retrospective study of patients with temporal lobe epilepsy (TLE). METHODS [(18)F]FDG-PET scans of 46 adult patients with pharmacoresistant unilateral TLE (25 RTLE and 21 LTLE) were subjected to SPM analysis. RESULTS Forty-six patients were diagnosed with nonlesional TLE, 16 of whom had hippocampal sclerosis (HS). The average duration of epilepsy was 17.4 +/- 12.3 years (3-46 years), <5 years in 10 patients and >or=10 years in 30 patients. Visual analysis of [(18)F]FDG-PET scans revealed hypometabolism in the epileptogenic temporal cortex in 31 (67%) patients. After SPM analysis of all [(18)F]FDG-PET images, hypometabolism was unilateral and reported in lateral and mesial structures of the epileptogenic temporal cortex in addition to the ipsilateral fusiform and middle occipital gyrus. Subsequent analysis revealed that temporal lobe hypometabolism was present only in patients with longer epilepsy duration (>or=10 years) in parahippocampal gyrus, uncus, and middle and superior temporal gyrus (P < 0.05 corrected). Epilepsy duration was inversely correlated with decreased glucose uptake in the inferior temporal gyrus, hippocampus, and parahippocampal gyrus of the epileptogenic temporal cortex (P < 0.05). Age at seizure onset did not affect the correlation between epilepsy duration and glucose uptake except in the inferior temporal gyrus (P < 0.05). CONCLUSION Voxel-based mapping supports the assertion that glucose hypometabolism of the epileptogenic temporal lobe cortex and other neighboring cortical regions increases with longer epilepsy duration in TLE.

Recurrent Distal 7q11.23 Deletion Including HIP1 and YWHAG Identified in Patients with Intellectual Disabilities, Epilepsy, and Neurobehavioral Problems

We report 26 individuals from ten unrelated families who exhibit variable expression and/or incomplete penetrance of epilepsy, learning difficulties, intellectual disabilities, and/or neurobehavioral abnormalities as a result of a heterozygous microdeletion distally adjacent to the Williams-Beuren syndrome region on chromosome 7q11.23. In six families with a common recurrent ∼1.2 Mb deletion that includes the Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein gamma (YWHAG) genes and that is flanked by large complex low-copy repeats, we identified sites for nonallelic homologous recombination in two patients. There were no cases of this ∼1.2 Mb distal 7q11.23 deletion copy number variant identified in over 20,000 control samples surveyed. Three individuals with smaller, nonrecurrent deletions (∼180-500 kb) that include HIP1 but not YWHAG suggest that deletion of HIP1 is sufficient to cause neurological disease. Mice with targeted mutation in the Hip1 gene (Hip1⁻(/)⁻) develop a neurological phenotype characterized by failure to thrive, tremor, and gait ataxia. Overall, our data characterize a neurodevelopmental and epilepsy syndrome that is likely caused by recurrent and nonrecurrent deletions, including HIP1. These data do not exclude the possibility that YWHAG loss of function is also sufficient to cause neurological phenotypes. Based on the current knowledge of Hip1 protein function and its proposed role in AMPA and NMDA ionotropic glutamate receptor trafficking, we believe that HIP1 haploinsufficiency in humans will be amenable to rational drug design for improved seizure control and cognitive and behavioral function.

Long-Term Clinical Course of Glut1 Deficiency Syndrome

Our objective is to characterize the long-term course of Glut1 deficiency syndrome. Longitudinal outcome measures, including Columbia Neurological Scores, neuropsychological tests, and adaptive behavior reports, were collected for 13 participants with Glut1 deficiency syndrome who had been followed for an average of 14.2 (range = 8.9-23.6) years. A parent questionnaire assessed manifestations throughout development. The 6-Minute Walk Test captured gait disturbances and triggered paroxysmal exertional dyskinesia. All longitudinal outcomes remained stable over time. Epilepsy dominated infancy and improved during childhood. Dystonia emerged during childhood or adolescence. Earlier introduction of the ketogenic diet correlated with better long-term outcomes on some measures. Percent-predicted 6-Minute Walk Test distance correlated significantly with Columbia Neurological Scores. We conclude that Glut1 deficiency syndrome is a chronic condition, dominated by epilepsy in infancy and by movement disorders thereafter. Dietary treatment in the first postnatal months may effect improved outcomes, emphasizing the importance of early diagnosis and treatment.

Tiagabine-induced nonconvulsive status epilepticus in an adolescent without epilepsy

Tiagabine (TGB) is a γ-aminobutyric acid (GABA) reuptake inhibitor approved as adjunctive therapy for partial seizures in patients over age 12. It has been used off-label to treat depression, anxiety, bipolar disorder, neuropathic pain, headache, and spasticity. A recent epidemiologic study found that TGB adjunctive therapy does not increase the risk of status epilepticus (SE).1 However, there are now more than a dozen reports of precipitation of nonconvulsive status epilepticus (NCSE) in patients predisposed to seizures, including children,2 or in patients without epilepsy treated chronically with TGB.3 In February 2005, Cephalon, the manufacturer of TGB, issued a warning of the possibility of seizures in patients without epilepsy. We report a case of NCSE after TGB overdose in a 14-year-old girl who neither had epilepsy nor was taking the medication chronically. The present description clarifies some inaccuracies in an earlier report by others of our clinical and EEG findings in this case.4 The patient was a 14-year-old right-handed girl in good health except for mild asthma. On the day of admission, she was found at home obtunded after having ingested an estimated …

Acute hyperglycemia produces transient improvement in glucose transporter type 1 deficiency

Glucose transporter type 1 deficiency syndrome (Glut1‐DS) is characterized clinically by acquired microcephaly, infantile‐onset seizures, psychomotor retardation, choreoathetosis, dystonia, and ataxia. The laboratory signature is hypoglycorrhachia. The 5‐hour oral glucose tolerance test (OGTT) was performed to assess cerebral function and systemic carbohydrate homeostasis during acute hyperglycemia, in the knowledge that GLUT1 is constitutively expressed ubiquitously and upregulated in the brain.