Colin P. Doherty

Rare deletions at 16p13.11 predispose to a diverse spectrum of sporadic epilepsy syndromes.

Deletions at 16p13.11 are associated with schizophrenia, mental retardation, and most recently idiopathic generalized epilepsy. To evaluate the role of 16p13.11 deletions, as well as other structural variation, in epilepsy disorders, we used genome-wide screens to identify copy number variation in 3812 patients with a diverse spectrum of epilepsy syndromes and in 1299 neurologically-normal controls. Large deletions (> 100 kb) at 16p13.11 were observed in 23 patients, whereas no control had a deletion greater than 16 kb. Patients, even those with identically sized 16p13.11 deletions, presented with highly variable epilepsy phenotypes. For a subset of patients with a 16p13.11 deletion, we show a consistent reduction of expression for included genes, suggesting that haploinsufficiency might contribute to pathogenicity. We also investigated another possible mechanism of pathogenicity by using hybridization-based capture and next-generation sequencing of the homologous chromosome for ten 16p13.11-deletion patients to look for unmasked recessive mutations. Follow-up genotyping of suggestive polymorphisms failed to identify any convincing recessive-acting mutations in the homologous interval corresponding to the deletion. The observation that two of the 16p13.11 deletions were larger than 2 Mb in size led us to screen for other large deletions. We found 12 additional genomic regions harboring deletions > 2 Mb in epilepsy patients, and none in controls. Additional evaluation is needed to characterize the role of these exceedingly large, non-locus-specific deletions in epilepsy. Collectively, these data implicate 16p13.11 and possibly other large deletions as risk factors for a wide range of epilepsy disorders, and they appear to point toward haploinsufficiency as a contributor to the pathogenicity of deletions.

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

BACKGROUND 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. METHODS 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. FINDINGS 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. INTERPRETATION 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.

Diffusion‐weighted Imaging Abnormalities in the Splenium after Seizures

Summary:  Purpose: Transient increased T2 signal in the splenium of the corpus callosum after seizures has been reported and sometimes attributed to a postulated toxicity of anticonvulsant medications (AEDs).

A multicenter study of BRD2 as a risk factor for juvenile myoclonic epilepsy.

Summary:  Purpose: Although complex idiopathic generalized epilepsies (IGEs) are recognized to have a significant genetic component, as yet there are no known common susceptibility variants. It has recently been suggested that variation in the BRD2 gene confers increased risk of juvenile myoclonic epilepsy (JME), which accounts for around a quarter of all IGE. Here we examine the association between the candidate causal SNP (the promoter variant rs3918149) and JME in five independent cohorts comprising in total 531 JME cases and 1,390 healthy controls.

Multimodal longitudinal imaging of focal status epilepticus.

BACKGROUND Little is understood about the evolution of structural and functional brain changes during the course of uncontrolled focal status epilepticus in humans. METHODS We serially evaluated and treated a nine-year-old girl with refractory focal status epilepticus. Long-term EEG monitoring, MRI, MRA, SPECT, intraoperative visualization of affected cortex, and neuropathological examination of a biopsy specimen were conducted over a three year time span. Imaging changes were correlated with simultaneous treatment and EEG findings. RESULTS The EEG monitoring showed almost continuous spike discharges emanating initially from the right frontocentral area. These EEG abnormalities were intermittently suppressed by treatment with anesthetics. Over time, additional brain areas developed epileptiform EEG abnormalities. Serial MRI studies demonstrated an evolution of changes from normal, through increased regional T2 signal to generalized atrophy. An MRA demonstrated dilatation of the middle cerebral artery stem on the right compared to the left with a broad distribution of flow-related enhancement. An 18FDG-PET scan showed a dramatically abnormal metabolic profile in the same right frontocentral areas, which modulated in response to treatment during the course of the illness. A right frontotemporal craniotomy revealed a markedly hyperemic cortical focus including vascular shunting. A sample of resected cortex showed severe gliosis and neuronal death. CONCLUSIONS The co-registration of structural and functional imaging and its correlation with operative and pathological findings in this case illustrates the relentless progression of regional and generalized abnormalities in intractable focal status epilepticus that were only transiently modified by exhaustive therapeutic interventions. Increased flow through large vessels appeared to be shunted and did not translate into increased microvascular perfusion.

The Irish epilepsy surgery experience: Long-term follow-up

AIM To assess the long-term seizure outcome of Irish patients who underwent resective surgery for refractory epilepsy since 1975. We also wished to determine the impact of pathology and surgical technique (with particular reference to neocorticectomy) on seizure outcome. METHODS A retrospective review of medical notes, radiological and histopathological records, was undertaken between 1975 and 2005. Missing data was supplemented by telephone calls to patients. One hundred and ninety-nine patients suited the criteria for inclusion and had at least 1-year follow-up (1-24 years, mean 7.0 years). Engels criteria were used to classify seizure outcome at 1, 2, 5, 10, 15 and >15 years follow-up. RESULTS The percentage of patients seizure free at 2, 5, 10, 15 and >15 years were, 56.6%, 41.4%, 44%, 25% and 31.3%, respectively. Of patients with a pathologically confirmed diagnosis of mesial temporal sclerosis, 55.6% were seizure free at 10 years. Equivalent figures for tumour were 62.5%, for cortical dysplasia, 34.8%, for those without any demonstrable pathologic abnormality, 50%, for dual pathology, 50% and for all others, 33.3%. Of those with 10 years or greater follow-up only 20% of neocorticectomy patients were in Engel class 1, compared with an average of 58.5% for the other surgical techniques. CONCLUSION Seizure freedom rates for Irish Patients were comparable to other large retrospective studies. Patients who underwent selective procedures tended to do better than those undergoing lobar resections, in keeping with international trends. The surgical technique unique to the Irish cohort, temporal necocorticectomy, had the worst long-term outcome.

A pharmacogenetic exploration of vigabatrin-induced visual field constriction

INTRODUCTION Use of the antiepileptic drug (AED) vigabatrin is severely limited by irreversible visual field constriction, an adverse reaction to the drug reported in approximately 40% of patients. Given the evidence suggesting an idiosyncratic drug response, we set out to detect genetic variation of strong, clinically relevant effect that might guide clinicians in the safe, controlled prescribing of this otherwise usefuldrug. METHODS Patients with a history of at least 1-year exposure to vigabatrin were enrolled at two independent referral centers. Using Goldmann perimetry, visual fields and the extent of constriction were calculated for each patient. We examined the correlation between the extent of vigabatrin induced visual field constriction and genetic variation across six candidate genes (SLC6A1, SLC6A13, SCL6A11, ABAT, GABRR1 and GABRR2). We availed of HapMap data and used a tagging SNP technique in an effort to efficiently capture all common variation within these genes. We attempted to replicate any positive associations before drawing conclusions from our results. RESULTS The degree of visual field constriction correlated with three SNPs and one haplotype in a cohort of 73 patients. However we were unable to replicate these findings in a second independent cohort consisting of 58 patients, suggesting the initial results were possibly false positives, or variants of weak effect. CONCLUSION Common variants of strong, clinically relevant effect do not appear to reside in the candidate genes studied here. This does not rule out the presence of genetic variants of weak effect in these genes, nor of variants of strong effect in other genes.

No major role of common SV2A variation for predisposition or levetiracetam response in epilepsy

Levetiracetam (LEV), a newer antiepileptic drug (AED) useful for several epilepsy syndromes, binds to SV2A. Identifying genetic variants that influence response to LEV may allow more tailored use of LEV. Obvious candidate genes are SV2A, SV2B and SV2C, which encode the only known binding site, synaptic vesicle protein 2 (SV2), with LEV binding to the SV2A isoform. SV2A is an essential protein as homozygous SV2A knockout mice appear normal at birth but fail to grow, experience severe seizures and die by 3 weeks. We addressed characterising AED response issues in pharmacogenetics and whether variation in these genes associates with response to LEV in two independent cohorts with epilepsy. We also investigated whether variation in these three genes associated with epilepsy predisposition in two larger cohorts of patients with various epilepsy phenotypes. Common genetic variation in SV2A, encoding the actual binding site of LEV, was fully represented in this study whereas SV2B and SV2C were not fully covered. None of the polymorphisms tested in SV2A, SV2B or SV2C influence LEV response or predisposition to epilepsy. We found no association between genetic variation in SV2A, SV2B or SV2C and response to LEV or epilepsy predisposition. We suggest this study design may be used in future pharmacogenetic work examining AED or LEV efficacy. However, different study designs would be needed to examine common variation with minor effect sizes, or rare variation, influencing AED or LEV response or epilepsy predisposition.

Discrimination of prosody and music by normal children

Prosody or the melody of speech is the process used to alter the meaning (linguistic prosody) or emotional force (affective prosody) of a sentence. The components of prosody are rhythm, pitch, tone and stress and they are articulated by modulation of the acoustic correlates of prosody; frequency, duration and amplitude. Little is known about the development of prosody in normal children other than that it appears to be a precursor to the further acquisition of normal language. In order to examine the development of the perception of prosody in normal children, a group of 40 neurologically normal children aged between 5 and 9 years were subjected to a number of prosodic recognition tasks. The objective was to modify a number of existing tasks and to devise a number of new ones to test both linguistic and affective prosody and the appreciation of affective cues in music. The results indicate a step‐wise improvement in perceptual contours up to 8.5 years old. However the perception of emotion in music appears highly developed early on in development. This study provides normative data and is the first report of a comparison between the development of prosodic and musical appreciation in this age group of normal children.

Rapid stereological quantitation of temporal neocortex in TLE

To determine the extent of neocortical atrophy in the temporal lobe using rapid stereological analysis of magnetic resonance slices in patients with temporal lobe epilepsy and to compare the findings to those obtained by visual analysis of high-resolution magnetic resonance images. 25 patients with temporal lobe epilepsy, along with 25 age-matched controls were scanned using a 1.5 Tesla magnetic resonance imaging machine (GE signa systems Paris). Visual analysis was performed on standard high-resolution images. Volumetric analysis of hippocampus and temporal neocortex was performed using computer-aided stereology (MEASURE program, Patrick Barta, Johns Hopkins, Baltimore, USA). Stereological volumetric analysis demonstrated isolated hippocampal atrophy in only nine (36%) cases including three (12%) with bilateral disease. However, eight (32%) cases had combined hippocampal and neocortical atrophy and three (12%) had isolated neocortical atrophy. All volumetric measurements took less than 10 min. On the other hand, visual analysis suggested that 17 (68%) had hippocampal atrophy alone with only two (8%) having combined neocortical atrophy and a further two (8%) having isolated neocortical atrophy. Nearly half of the patients had temporal neocortical atrophy with or without hippocampal atrophy. This rapid, accurate and non-biased quantitative technique has wide clinical utility and is significantly more valuable in detecting neocortical atrophy than visual analysis alone. The results support the notion that abnormalities may be overlooked by current standards of routine magnetic resonance imaging.