EFHC1 variants in juvenile myoclonic epilepsy: reanalysis according to NHGRI and ACMG guidelines for assigning disease causality.

PURPOSE: EFHC1 variants are the most common mutations in inherited myoclonic and grand mal clonic-tonic-clonic (CTC) convulsions of juvenile myoclonic epilepsy (JME). We reanalyzed 54 EFHC1 variants associated with epilepsy from 17 cohorts based on National Human Genome Research Institute (NHGRI) and American College of Medical Genetics and Genomics (ACMG) guidelines for interpretation of sequence variants. METHODS: We calculated Bayesian LOD scores for variants in coinheritance, unconditional exact tests and odds ratios (OR) in case-control associations, allele frequencies in genome databases, and predictions for conservation/pathogenicity. We reviewed whether variants damage EFHC1 functions, whether efhc1-/- KO mice recapitulate CTC convulsions and "microdysgenesis" neuropathology, and whether supernumerary synaptic and dendritic phenotypes can be rescued in the fly model when EFHC1 is overexpressed. We rated strengths of evidence and applied ACMG combinatorial criteria for classifying variants. RESULTS: Nine variants were classified as "pathogenic," 14 as "likely pathogenic," 9 as "benign," and 2 as "likely benign." Twenty variants of unknown significance had an insufficient number of ancestry-matched controls, but ORs exceeded 5 when compared with racial/ethnic-matched Exome Aggregation Consortium (ExAC) controls. CONCLUSIONS: NHGRI gene-level evidence and variant-level evidence establish EFHC1 as the first non-ion channel microtubule-associated protein whose mutations disturb R-type VDCC and TRPM2 calcium currents in overgrown synapses and dendrites within abnormally migrated dislocated neurons, thus explaining CTC convulsions and "microdysgenesis" neuropathology of JME.Genet Med 19 2, 144-156.

Granule cell dispersion is not a predictor of surgical outcome in temporal lobe epilepsy with mesial temporal sclerosis.

The aim of this retrospective study of a series of patients with mesial temporal lobe epilepsy (MTLE) and mesial temporal sclerosis (MTS) was to analyze the association of granule cell dispersion (GCD) with surgical prognosis, patterns of MTS and clinical data. Hippocampal specimens from 66 patients with MTLE and unilateral MTS and from 13 controls were studied. Quantitative neuropathological evaluation was performed on NeuN-stained hippocampal sections. Patients' clinical data, types of MTS and surgical outcome were reviewed. GCD occurred in 45.5% of cases and was not correlated with clinical variable. More severe neuronal loss was observed in patients with GCD. Except for MTS Type 2 - observed only in four no- GCD patients - groups did not differ with respect to the types of MTS. Surgical outcome was similar in both groups. In conclusion, GCD was associated with the degree of hippocampal cell loss, but was not a predictor of surgical outcome.

Case report: Successful anterior temporal lobectomy in drug-resistant temporal lobe epilepsy associated with Sotos syndrome.

The Sotos syndrome is an autosomal dominant disorder characterized by haploinsufficiency of NSD1 gene, with some individuals affected by epilepsy and, rarely, drug-resistant seizures. A 47-years-old female patient with Sotos syndrome was diagnosed with focal-onset seizures in left temporal lobe, left-side hippocampal atrophy, and neuropsychological testing with decreased performance in several cognitive domains. Patient was treated with left-side temporal lobe resection and developed complete awake seizure control in 3-years of follow-up, with marked improvement in quality-of-life. In selected, clinically concordant patients, resective surgeries may play a significant role in improving patient's quality of life and seizure control.

Characterising subtypes of hippocampal sclerosis and reorganization: correlation with pre and postoperative memory deficit.

Neuropathological subtypes of hippocampal sclerosis (HS) in temporal lobe epilepsy (The 2013 International League Against Epilepsy classification) are based on the qualitative assessment of patterns of neuronal loss with NeuN. In practice, some cases appear indeterminate between type 1 (CA1 and CA4 loss) and type 2 HS (CA1 loss) and we predicted that MAP2 would enable a more stringent classification. HS subtypes, as well as the accompanying alteration of axonal networks, regenerative capacity and neurodegeneration have been previously correlated with outcome and memory deficits and may provide prognostic clinical information. We selected 92 cases: 52 type 1 HS, 15 type 2 HS, 18 indeterminate-HS and 7 no-HS. Quantitative analysis was carried out on NeuN and MAP2 stained sections and a labeling index (LI) calculated for six hippocampal subfields. We also evaluated hippocampal regenerative activity (MCM2, nestin, olig2, calbindin), degeneration (AT8/phosphorylated tau) and mossy-fiber pathway re-organization (ZnT3). Pathology measures were correlated with clinical epilepsy history, memory and naming test scores and postoperative outcomes, at 1 year following surgery. MAP2 LI in indeterminate-HS was statistically similar to type 2 HS but this clustering was not shown with NeuN. Moderate verbal and visual memory deficits were noted in all HS types, including 54% and 69% of type 2 HS. Memory deficits correlated with several pathology factors including lower NeuN or MAP2 LI in CA4, CA1, dentate gyrus (DG) and subiculum and poor preservation of the mossy fiber pathway. Decline in memory at 1 year associated with AT8 labeling in the subiculum and DG but not HS type. We conclude that MAP2 is a helpful addition in the classification of HS in some cases. Classification of HS subtype, however, did not significantly correlate with outcome or pre- or postoperative memory dysfunction, which was associated with multiple pathology factors including hippocampal axonal pathways, regenerative capacity and degenerative changes.

Granular cell dispersion and bilamination: two distinct histopathological patterns in epileptic hippocampi?

Cytoarchitectural modifications of the dentate gyrus are among the most obvious abnormalities observed in the hippocampal sclerosis associated with refractory epilepsy. Here, we examined the morphological changes of granular cells (dispersion, bilamination and cell loss) in sclerotic hippocampi from nine TLE patients, comparing abnormal and preserved areas. A total of 2,577 granular cells were analyzed with respect to four different histopathological patterns: areas with bilamination (n = 936), areas with dispersion (n = 905), areas with neuronal loss (n = 279), and preserved areas (n = 457). Quantitative parameters included somatic perimeter (P), area (A) and form factor (ff). Although different patterns were often observed in the same patient, highly significant differences were observed (p < 0.0001) when patterns were compared to one another. Since granular cell dispersion and bilamination have different morphological aspects in sclerotic hippocampi from TLE patients, we suggest that these patterns should be considered separately. Future studies are needed to determine the frequency with which these patterns occur in the general population and whether each one can interfere with seizure susceptibility.

Dysmorphic neurons in patients with temporal lobe epilepsy.

We studied morphologic characteristics of dysmorphic neurons in the hippocampus of seven patients with medically intractable TLE and compare histological, clinical, and imaging features with ten TLE patients with classical hippocampal sclerosis without abnormal cells. Such dysmorphic neurons were observed in the hilus of the dentate gyrus and were characterized by giant or misshapen cells with abnormal cytoskeletal structure and atypical dendritic processes that resembled the dysmorphic neurons from cortical dysplasias. Specimens with dysmorphic cells also contained other cytoarchitectural abnormalities including bilamination of the dentate granular cell layer (four out seven cases), and the presence of Cajal-Retzius cells in the dentate gyrus or Ammon's horn (five out seven cases). There were no statistically significant differences regarding the age at onset, duration of epilepsy, and hippocampal asymmetry ratio between patients with or without dysmorphic cells. Nevertheless, it is interesting to note that a higher proportion of patients with dysmorphic neurons continued to present auras after surgery, when compared with patients without those cells.

The Portuguese version of the Epilepsy Surgery Inventory (ESI-55): cross-cultural adaptation and evaluation of psychometric properties.

The purpose of this study was to develop a Portuguese version of the Epilepsy Surgery Inventory (ESI-55) and to assess its psychometric properties. Sixty patients with temporal lobe epilepsy related to unilateral mesial temporal sclerosis who underwent presurgical evaluation at the Universidade Federal de São Paulo (UNIFESP) formed the sample for this study. The psychometric properties of the ESI-55 included: reliability, validity, and responsiveness. Internal consistency was high in all domains (Cronbach's alpha ranging from 0.76 for Social Function to 0.88 for Physical Function) except Overall Quality of Life (alpha=0.45). Test-retest reliability after 1 week was good, with the intraclass correlation coefficient ranging from 0.79 (Energy/Fatigue) to 0.92 (Role Limitations due to Emotional Problems). Interrater reliability ranged from 0.84 (Cognitive Function) to 0.94 (Role Limitations due to Physical Problems). For construct validity, we verified a high correlation between the ESI-55 and Health Assessment Questionnaire-8 for the Physical Function domain (Pearson linear correlation=-0.84), and a moderate correlation for the Pain domain (P=-0.58), but for the other subscales no correlation was detected. Beck Depression Inventory and ESI-55 domains were highly statistically correlated (ANOVA: P<0.005), but there was no association of the Cognitive Function and Role Limitations due to Memory Problems subscales with neuropsychological evaluation (Pearson coefficient: P>0.05). With respect to demographic characteristics, a statistically significant correlation was observed for the variable educational level (Student t, P<0.005) and ESI-55 scores. There was a high correlation between seizure frequency and ESI-55 domains for clinical variables (ANOVA, P<0.005). Surgical treatment in this series improved health-related quality of life in the seizure-free group in three domains--Health Perception (1.24), Emotional Well-Being (1.32), and Energy/Fatigue (1.48)-as reflected by the standard response mean and the effect size of the sample. Our results support the psychometric properties of the Portuguese version of the ESI-55 as a measure of health-related quality of life.