Sanjay M Sisodiya

Publications of Sanjay M Sisodiya

• The idic(15) syndrome: Expanding the phenotype.

  Authors: Elizabeth Caruana Galizia, Rodger Palmer, Jonathan J Waters, Matthias J Koepp, Raoul C M Hennekam, Sanjay M Sisodiya

  American journal of medical genetics. Part A. 05/2012;

• Correlating 3T MRI and histopathology in patients undergoing epilepsy surgery.

  Authors: Georgia Lockwood-Estrin, Maria Thom, Niels K Focke, Mark R Symms, Lillian Martinian, Sanjay M Sisodiya, John S Duncan, Sofia H Eriksson

  Journal of neuroscience methods. 03/2012; 205(1):182-9.

  To investigate whether specific semi-quantitative 3T MRI parameters are associated with particular histological features in temporal lobe specimens in epilepsy surgery patients whose conventional MRITo investigate whether specific semi-quantitative 3T MRI parameters are associated with particular histological features in temporal lobe specimens in epilepsy surgery patients whose conventional MRI scan appeared normal. These MRI techniques have the potential to visualise subtle structural abnormalities currently undetected on conventional MRI; but correlation between pre-operative in vivo MRI and histopathology is needed to understand the basis of these MRI abnormalities. Predicting subtle histopathology with semi-quantitative MRI techniques could contribute to pre-surgical evaluation of epilepsy patients. MRI techniques: normalised FLAIR signal intensity (nFSI), grey matter probability and diffusion tensor imaging (DTI) were correlated with quantitative histopathological measures: NeuN (neuronal nuclear antigen); GFAP (glial fibrillary acidic protein) and MBP (myelin basic protein) field fractions and stereological neuronal densities obtained in grey and white matter regions in twenty-four patients who underwent anterior temporal lobe resections. There were no significant correlations between the histopathological measurements and MRI values in grey or white matter in macroscopically normal appearing tissue. Findings suggest that in macroscopically normal appearing tissue, the studied semiquantitative MRI measurements are not significantly related to the measures of gliosis, neuronal loss/gain and myelin used in the current study. Studies of macroscopically abnormal tissue as well as improvements to the MRI techniques may increase the sensitivity of future correlative studies to improve our understanding of the histopathological basis of MRI signal characteristics.

• Genome-wide mapping for clinically relevant predictors of lamotrigine- and phenytoin-induced hypersensitivity reactions.

  Authors: Mark McCormack, Thomas J Urban, Kevin V Shianna, Nicole Walley, Massimo Pandolfo, Chantal Depondt, Elijah Chaila, Gerard D O'Conner, Dalia Kasperavičiūtė, Rodney A Radtke, Erin L Heinzen, Sanjay M Sisodiya, Norman Delanty, Gianpiero L Cavalleri

  Pharmacogenomics. 03/2012; 13(4):399-405.

  An association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other commonAn association between carbamazepine-induced hypersensitivity and HLA-A*3101 has been reported in populations of both European and Asian descent. We aimed to investigate HLA-A*3101 and other common variants across the genome as markers for cutaneous adverse drug reactions (cADRs) attributed to lamotrigine and phenytoin. We recruited patients with lamotrigine-induced cADRs (n = 46) and patients with phenytoin-cADRs (n = 44) and the 1958 British birth cohort was used as a control (n = 1296). HLA-A*3101 was imputed from genome-wide association study data. We applied genome-wide association to study lamotrigine- and phenytoin-induced cADR, and total cADR cases combined. Neither HLA-A*3101 nor any other genetic marker significantly predicted lamotrigine- or phenytoin-induced cADRs. HLA-A*3101 does not appear to be a predictor for lamotrigine- and phenytoin-induced cADRs in Europeans. Our genome-wide association study results do not support the existence of a clinically relevant common variant for the development of lamotrigine- or phenytoin-induced cADRs. As a predictive marker, HLA-A*3101 appears to be specific for carbamazepine-induced cADRs.

• Array comparative genomic hybridization: Results from an adult population with drug-resistant epilepsy and co-morbidities.

  Authors: Elizabeth C Galizia, Maithili Srikantha, Rodger Palmer, Jonathan J Waters, Nicholas Lench, Caroline Mackie Ogilvie, Dalia Kasperavičiūtė, Lina Nashef, Sanjay M Sisodiya

  European journal of medical genetics. 01/2012;

  BACKGROUND: The emergence of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated recognition of microdeletions and microduplications as riskBACKGROUND: The emergence of array comparative genomic hybridization (array CGH) as a diagnostic tool in molecular genetics has facilitated recognition of microdeletions and microduplications as risk factors for both generalised and focal epilepsies. Furthermore, there is evidence that some microdeletions/duplications, such as the 15q13.3 deletion predispose to a range of neuropsychiatric disorders, including intellectual disability (ID), autism, schizophrenia and epilepsy. We hypothesised that array CGH would reveal relevant findings in an adult patient group with epilepsy and complex phenotypes. METHODS: 82 patients (54 from the National Hospital for Neurology and Neurosurgery and 28 from King's College Hospital) with drug-resistant epilepsy and co-morbidities had array CGH. Separate clinicians ordered array CGH and separate platforms were used at the two sites. RESULTS: In the two independent groups we identified copy number variants judged to be of pathogenic significance in 13.5% (7/52) and 20% (5/25) respectively, noting that slightly different selection criteria were used, giving an overall yield of 15.6%. Sixty-nine variants of unknown significance were also identified in the group from the National Hospital for Neurology and Neurosurgery and 5 from the King's College Hospital patient group. CONCLUSION: We conclude that array CGH be considered an important investigation in adults with complicated epilepsy and, at least at present for selected patients, should join the diagnostic repertoire of clinical history and examination, neuroimaging, electroencephalography and other indicated investigations in generating a more complete formulation of an individual's epilepsy.

• Another cause of vaccine encephalopathy: A case of Angelman syndrome.

  Authors: Jan Novy, Claudia B Catarino, Krishna Chinthapalli, Shelagh M Smith, Jill Clayton-Smith, Raoul C M Hennekam, Peter Hammond, Sanjay M Sisodiya

  European journal of medical genetics. 01/2012;

  Dravet syndrome has been found recently as an important underlying condition in cases of alleged vaccine encephalopathy after pertussis vaccination, where vaccination seemed to have precipitated theDravet syndrome has been found recently as an important underlying condition in cases of alleged vaccine encephalopathy after pertussis vaccination, where vaccination seemed to have precipitated the occurrence of the disease without modifying the long-term course. We report on a patient diagnosed with Angelman syndrome in her fifth decade, in whom the intellectual disability and epilepsy had been assumed to be caused by a vaccine encephalopathy following smallpox vaccination. Clinical features of Angelman syndrome had faded away. The history of the present patient suggests that genetic conditions other than Dravet syndrome can be associated with an alleged vaccine encephalopathy. A history of vaccine encephalopathy is rare among patients with learning disability and refractory epilepsy (1.4% in our cohort), but it should lead to consideration of a comprehensive genetic work-up if Dravet syndrome is excluded. The early history of the patient, when available, should guide the investigations. Medico-legal aspects are also discussed.

• Neuropathology of 16p13.11 deletion in epilepsy.

  Authors: Joan Y W Liu, Dalia Kasperavičiūtė, Lillian Martinian, Maria Thom, Sanjay M Sisodiya

  PloS one. 01/2012; 7(4):e34813.

  16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse16p13.11 genomic copy number variants are implicated in several neuropsychiatric disorders, such as schizophrenia, autism, mental retardation, ADHD and epilepsy. The mechanisms leading to the diverse clinical manifestations of deletions and duplications at this locus are unknown. Most studies favour NDE1 as the leading disease-causing candidate gene at 16p13.11. In epilepsy at least, the deletion does not appear to unmask recessive-acting mutations in NDE1, with haploinsufficiency and genetic modifiers being prime candidate disease mechanisms. NDE1 encodes a protein critical to cell positioning during cortical development. As a first step, it is important to determine whether 16p13.11 copy number change translates to detectable brain structural alteration. We undertook detailed neuropathology on surgically resected brain tissue of two patients with intractable mesial temporal lobe epilepsy (MTLE), who had the same heterozygous NDE1-containing 800 kb 16p13.11 deletion, using routine histological stains and immunohistochemical markers against a range of layer-specific, white matter, neural precursor and migratory cell proteins, and NDE1 itself. Surgical temporal lobectomy samples from a MTLE case known not to have a deletion in NDE1 and three non-epilepsy cases were included as disease controls. We found that apart from a 3 mm hamartia in the temporal cortex of one MTLE case with NDE1 deletion and known hippocampal sclerosis in the other case, cortical lamination and cytoarchitecture were normal, with no differences between cases with deletion and disease controls. How 16p13.11 copy changes lead to a variety of brain diseases remains unclear, but at least in epilepsy, it would not seem to be through structural abnormality or dyslamination as judged by microscopy or immunohistochemistry. The need to integrate additional data with genetic findings to determine their significance will become more pressing as genetic technologies generate increasingly rich datasets. Detailed examination of brain tissue, where available, will be an important part of this process in neurogenetic disease specifically.

• The ketogenic and related diets in adolescents and adults--a review.

  Authors: Natasha E Payne, J Helen Cross, Josemir W Sander, Sanjay M Sisodiya

  Epilepsia. 11/2011; 52(11):1941-8.

  The ketogenic diet (KD) has been used to treat children with epilepsy who are resistant to antiepileptic drugs (AEDs) since the 1920s, and has undergone a resurgence in popularity over the last 15The ketogenic diet (KD) has been used to treat children with epilepsy who are resistant to antiepileptic drugs (AEDs) since the 1920s, and has undergone a resurgence in popularity over the last 15 years Its use in adolescents and adults has been more restrained. During the past few decades, more liberal regimens have emerged that may seem more attractive to older people while still proving effective, often independent of ketone levels. The KD and its variants may lead to similar reductions in seizure frequency in adolescents and adults as seen in children, although studies are limited and of poor quality. A total of only 122 adults and 82 adolescents have been included in open-label studies on the KD, and only 56 adults and 10 adolescents on the Modified Atkins Diet. Side effects appear similar to those encountered in children. Noncompliance may be higher in adolescents and adults than in children, but the main reason for discontinuation is lack of efficacy. A better understanding of the mechanisms underlying the effects of the KD might allow the same treatment effects to be achieved using novel, better-tolerated, nondietary approaches.

• Reply.

  Authors: Lisa M Clayton, James Acheson, Sanjay M Sisodiya

  Annals of neurology. 10/2011; 70(4):672-3.

• One hundred and one dysembryoplastic neuroepithelial tumors: an adult epilepsy series with immunohistochemical, molecular genetic, and clinical correlations and a review of the literature.

  Authors: Maria Thom, Ahmed Toma, Shu An, Lillian Martinian, George Hadjivassiliou, Bernardo Ratilal, Andrew Dean, Andrew McEvoy, Sanjay M Sisodiya, Sebastian Brandner

  Journal of neuropathology and experimental neurology. 10/2011; 70(10):859-78.

  Simple and complex forms of dysembryoplastic neuroepithelial tumors (DNTs) are readily recognizable but forms with diffuse growth pattern, and hybrid tumors, that is, mixed DNT and gangliogliomaSimple and complex forms of dysembryoplastic neuroepithelial tumors (DNTs) are readily recognizable but forms with diffuse growth pattern, and hybrid tumors, that is, mixed DNT and ganglioglioma (DNT/GG), are more contentious entities. Rare DNTs have shown aggressive behavior. We reviewed cortical growth patterns, immunophenotype (including CD34, nestin and calbindin), genetic profile, and outcome in 101 DNT in adults. Simple (n = 18), complex (n = 31), diffuse (n = 35) DNT, and mixed DNT/GG (n = 17) showed no difference in age of onset, associated seizure type, or outcome (67.5% free from seizure; mean follow-up, 6 years). CD34 was seen in 61%, calbindin in 57%, and nestin in 86% of all DNT types; these markers were less common in simple DNT. Peritumoral cortical changes (Layer I hypercellularity [61%], satellite nodules [51.6%]) were frequent, but dyslamination (cortical dysplasia) was not identified. Molecular genetic abnormalities identified in 17 cases were IDH1 mutation (n = 3), 1p/19q loss (n = 10), isolated loss 9q (n = 2), and PTEN loss (n = 3), which were not associated with tumor type or location, higher cell proliferation, or distinguishing clinical features (mean age of epilepsy onset, 9 years; age at surgery = 31 years; 69% free from seizure); none had progression on magnetic resonance imaging (mean follow-up, 6 years). No single feature was predictive of seizure-free outcome, but there was a trend for better outcome in CD34-positive tumors (p = 0.07). One case has shown transformation to a higher grade. This study supports the existence of a range of subtypes of DNT some with overlapping features with ganglioglioma; molecular genetic abnormalities were not predictive of atypical behavior.

• Neurofibrillary tangle pathology and Braak staging in chronic epilepsy in relation to traumatic brain injury and hippocampal sclerosis: a post-mortem study.

  Authors: Maria Thom, Joan Y W Liu, Pam Thompson, Rahul Phadke, Marta Narkiewicz, Lillian Martinian, Derek Marsdon, Matthias Koepp, Luis Caboclo, Claudia B Catarino, Sanjay M Sisodiya

  Brain : a journal of neurology. 09/2011; 134(Pt 10):2969-81.

  The long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients andThe long-term pathological effects of chronic epilepsy on normal brain ageing are unknown. Previous clinical and epidemiological studies show progressive cognitive decline in subsets of patients and an increased prevalence of Alzheimer's disease in epilepsy. In a post-mortem series of 138 patients with long-term, mainly drug-resistant epilepsy, we carried out Braak staging for Alzheimer's disease neurofibrillary pathology using tau protein immunohistochemistry. The stages were compared with clinicopathological factors, including seizure history and presence of old traumatic brain injury. Overall, 31% of cases were Braak Stage 0, 36% Stage I/II, 31% Stage III/IV and 2% Stage V/VI. The mean age at death was 56.5 years and correlated with Braak stage (P < 0.001). Analysis of Braak stages within age groups showed a significant increase in mid-Braak stages (III/IV), in middle age (40-65 years) compared with data from an ageing non-epilepsy series (P < 0.01). There was no clear relationship between seizure type (generalized or complex partial), seizure frequency, age of onset and duration of epilepsy with Braak stage although higher Braak stages were noted with focal more than with generalized epilepsy syndromes (P < 0.01). In 30% of patients, there was pathological evidence of traumatic brain injury that was significantly associated with higher Braak stages (P < 0.001). Cerebrovascular disease present in 40.3% and cortical malformations in 11.3% were not significantly associated with Braak stage. Astrocytic-tau protein correlated with the presence of both traumatic brain injury (P < 0.01) and high Braak stage (P < 0.001). Hippocampal sclerosis, identified in 40% (bilateral in 48%), was not associated with higher Braak stages, but asymmetrical patterns of tau protein accumulation within the sclerotic hippocampus were noted. In over half of patients with cognitive decline, the Braak stage was low indicating causes other than Alzheimer's disease pathology. In summary, there is evidence of accelerated brain ageing in severe chronic epilepsy although progression to high Braak stages was infrequent. Traumatic brain injury, but not seizures, was associated with tau protein accumulation in this series. It is likely that Alzheimer's disease pathology is not the sole explanation for cognitive decline associated with epilepsy.

• Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy.

  Authors: Francesca I Arrigoni, Mar Matarin, Pamela J Thompson, Michel Michaelides, Michelle E McClements, Elizabeth Redmond, Lindsey Clarke, Elizabeth Ellins, Saifullah Mohamed, Ian Pavord, Nigel Klein, David M Hunt, Anthony T Moore, Julian Halcox, Sanjay M Sisodiya

  European journal of human genetics : EJHG. 09/2011; 19(9):1018.

• Dravet syndrome as epileptic encephalopathy: evidence from long-term course and neuropathology.

  Authors: Claudia B Catarino, Joan Y W Liu, Ioannis Liagkouras, Vaneesha S Gibbons, Robyn W Labrum, Rachael Ellis, Cathy Woodward, Mary B Davis, Shelagh J Smith, J Helen Cross [......] Simone C Yendle, Jacinta M McMahon, Susannah T Bellows, Thomas S Jacques, Sameer M Zuberi, Matthias J Koepp, Lillian Martinian, Ingrid E Scheffer, Maria Thom, Sanjay M Sisodiya

  Brain : a journal of neurology. 06/2011; 134(Pt 10):2982-3010.

  Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. WeDravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20-66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy.

• Epilepsy causing pupillary hippus: an unusual semiology.

  Authors: Maria Centeno, Maria Feldmann, Neil A Harrison, Fergus J Rugg-Gunn, Umair Chaudhary, Carles Falcon, Louis Lemieux, Maria Thom, Shelagh J M Smith, Sanjay M Sisodiya

  Epilepsia. 06/2011; 52(8):e93-6.

  Altered pupillary behavior is commonly present during and following epileptic seizures, but symptomatic pupillary hippus as the main feature of a seizure has not been reported in the modernAltered pupillary behavior is commonly present during and following epileptic seizures, but symptomatic pupillary hippus as the main feature of a seizure has not been reported in the modern literature. We present the case of a woman with epileptic seizures consisting of sustained fluctuation of perception of brightness. Bilateral pupillary hippus is the main semiologic feature.This autonomic phenomenon is selective for the pupils and does not involve other autonomic-mediated responses. An ictal video illustrates this phenomenon. The epileptogenic region, determined by ictal scalp and intracranial electroencephalography (EEG), is localized in the right posterior parietooccipital areas. Pupillary reflexes can be overridden by cortical input; here authors review the literature and discus the physiologic mechanisms underlying this autonomic phenomenon. Fluctuation in perceptual brightness during epileptic seizures may have a basis in ictal pupillary hippus.

• Genomic microdeletions associated with epilepsy: not a contraindication to resective surgery.

  Authors: Claudia B Catarino, Dalia Kasperavičiūtė, Maria Thom, Gianpiero L Cavalleri, Lillian Martinian, Erin L Heinzen, Thomas Dorn, Thomas Grunwald, Elijah Chaila, Chantal Depondt, Günter Krämer, Norman Delanty, David B Goldstein, Sanjay M Sisodiya

  Epilepsia. 06/2011; 52(8):1388-92.

  Several recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of suchSeveral recent reports of genomic microdeletions in epilepsy will generate further research; discovery of more microdeletions and other important classes of variants may follow. Detection of such genetic abnormalities in patients being evaluated for surgical treatment might raise concern that a genetic defect, possibly widely expressed in the brain, will affect surgical outcome. A reevaluation was undertaken of clinical presurgical data, histopathology of surgical specimen, and postsurgical outcome in patients with mesial temporal lobe epilepsy (MTLE) who have had surgical treatment for their drug-resistant seizures, and who have been found to have particular genomic microdeletions. Three thousand eight hundred twelve patients with epilepsy were genotyped and had a genome-wide screen to identify copy number variation. Ten patients with MTLE, who had resective epilepsy surgery, were found to have 16p13.11 microdeletions or other microdeletions >1 Mb. On histopathology, eight had classical hippocampal sclerosis (HS), one had nonspecific findings, and one had a hamartoma. Median postsurgical follow-up time was 48 months (range 10-156 months). All patients with HS were seizure-free after surgery, International League Against Epilepsy (ILAE) outcome class 1, at last follow-up; the patient with nonspecific pathology had recurrence of infrequent seizures after 7 years of seizure freedom. The patient with a hamartoma never became seizure-free.   Large microdeletions can be found in patients with "typical" MTLE. In this small series, patients with MTLE who meet criteria for resective surgery and harbor large microdeletions, at least those we have detected, can have a good postsurgical outcome. Our findings add to the spectrum of causal heterogeneity of MTLE + HS.

• Neuroimaging and neuropathology of Dravet syndrome.

  Authors: Renzo Guerrini, Pasquale Striano, Claudia Catarino, Sanjay M Sisodiya

  Epilepsia. 04/2011; 52 Suppl 2:30-4.

  Brain magnetic resonance imaging (MRI) studies in patients with Dravet syndrome and SCN1A mutations have shown abnormal findings in a small minority of patients. The origin of the structuralBrain magnetic resonance imaging (MRI) studies in patients with Dravet syndrome and SCN1A mutations have shown abnormal findings in a small minority of patients. The origin of the structural abnormalities--such focal brain atrophy, cortical dysplasia, and hippocampal sclerosis--observed in some children remains unclear. There seems to be no correlation between the presence of MRI abnormalities and duration of epilepsy, age at seizure onset, or the frequency of episodes of status epilepticus having occurred early in life. Recent descriptions of Rasmussen syndrome and of the hemiconvulsion-hemiplegia syndrome in isolated patients with SCN1A mutations are of uncertain meaning but might indicate that co-occurring immunomediated or seizure-induced structural changes can, in turn, become a substrate for the severe epileptic encephalopathy. The few available neuropathologic studies of Dravet syndrome have provided inconsistent findings, including evidence of subtle brain malformation. However, the underlying dysfunction of the SCN1A gene might confer to the brain a unique profile of vulnerability whose consequences are not easily disclosed by neuropathology and require specific experimental settings to be fully appreciated. There would seem to be value in studies in animal models of these aspects, as well as prospective studies in humans, with a particular view to establishing if earlier diagnosis and efforts at seizure control may influence the development of any clinical, imaging, or pathologic deterioration.

• HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.

  Authors: Mark McCormack, Ana Alfirevic, Stephane Bourgeois, John J Farrell, Dalia Kasperavičiūtė, Mary Carrington, Graeme J Sills, Tony Marson, Xiaoming Jia, Paul I W de Bakker [......] Massimo Pandolfo, Werner Pichler, B Kevin Park, Chantal Depondt, Sanjay M Sisodiya, David B Goldstein, Panos Deloukas, Norman Delanty, Gianpiero L Cavalleri, Munir Pirmohamed

  The New England journal of medicine. 03/2011; 364(12):1134-43.

  Carbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlatedCarbamazepine causes various forms of hypersensitivity reactions, ranging from maculopapular exanthema to severe blistering reactions. The HLA-B*1502 allele has been shown to be strongly correlated with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS-TEN) in the Han Chinese and other Asian populations but not in European populations. We performed a genomewide association study of samples obtained from 22 subjects with carbamazepine-induced hypersensitivity syndrome, 43 subjects with carbamazepine-induced maculopapular exanthema, and 3987 control subjects, all of European descent. We tested for an association between disease and HLA alleles through proxy single-nucleotide polymorphisms and imputation, confirming associations by high-resolution sequence-based HLA typing. We replicated the associations in samples from 145 subjects with carbamazepine-induced hypersensitivity reactions. The HLA-A*3101 allele, which has a prevalence of 2 to 5% in Northern European populations, was significantly associated with the hypersensitivity syndrome (P=3.5×10(-8)). An independent genomewide association study of samples from subjects with maculopapular exanthema also showed an association with the HLA-A*3101 allele (P=1.1×10(-6)). Follow-up genotyping confirmed the variant as a risk factor for the hypersensitivity syndrome (odds ratio, 12.41; 95% confidence interval [CI], 1.27 to 121.03), maculopapular exanthema (odds ratio, 8.33; 95% CI, 3.59 to 19.36), and SJS-TEN (odds ratio, 25.93; 95% CI, 4.93 to 116.18). The presence of the HLA-A*3101 allele was associated with carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry. The presence of the allele increased the risk from 5.0% to 26.0%, whereas its absence reduced the risk from 5.0% to 3.8%. (Funded by the U.K. Department of Health and others.).

• Extended extraocular phenotype of PROM1 mutation in kindreds with known autosomal dominant macular dystrophy.

  Authors: Francesca I Arrigoni, Mar Matarin, Pamela J Thompson, Michel Michaelides, Michelle E McClements, Elizabeth Redmond, Lindsey Clarke, Elizabeth Ellins, Saifullah Mohamed, Ian Pavord, Nigel Klein, David M Hunt, Anthony T Moore, Julian Halcox, Sanjay M Sisodiya

  European journal of human genetics : EJHG. 02/2011; 19(2):131-7.

  Mutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, weMutations in prominin 1 (PROM1) have been shown to result in retinitis pigmentosa, macular degeneration and cone-rod dystrophy. Because of the putative role of PROM1 in hippocampal neurogenesis, we examined two kindreds with the same R373C PROM1 missense mutation using our established paradigm to study brain structure and function. As the protein encoded by PROM1, known as CD133, is used to identify stem/progenitor cells that can be found in peripheral blood and reflect endothelial reparatory mechanisms, other parameters were subsequently examined that included measures of vascular function, endothelial function and angiogenic capacity. We found that aspects of endothelial function assayed ex vivo were abnormal in patients with the R373C PROM1 mutation, with impaired adhesion capacity and higher levels of cellular damage. We also noted renal infections, haematuria and recurrent miscarriages possibly reflecting consequences of abnormal tubular modelling. Further studies are needed to confirm these findings.

• Investigation of widespread neocortical pathology associated with hippocampal sclerosis in epilepsy: a postmortem study.

  Authors: Francine Blanc, Lillian Martinian, Ioannis Liagkouras, Claudia Catarino, Sanjay M Sisodiya, Maria Thom

  Epilepsia. 01/2011; 52(1):10-21.

  One possible cause for surgical failure following temporal lobectomy for the treatment of epilepsy due to classical hippocampal sclerosis (CHS) is the presence of more widespread cortical changes.One possible cause for surgical failure following temporal lobectomy for the treatment of epilepsy due to classical hippocampal sclerosis (CHS) is the presence of more widespread cortical changes. Neocortical changes in CHS shown by quantitative neuroimaging studies may involve hippocampal projection pathways. Our aim was to quantitate neocortical pathology using a postmortem series of brains from patients with epilepsy and CHS. Sections from 13 cortical regions from both left and right hemispheres, including hippocampal projection pathways, were examined from nine epilepsy patients with unilateral CHS (4), bilateral CHS (2), non-CHS (3), and non-epilepsy controls (4). Using GFAP, CD68, and NPY immunohistochemistry as markers of acquired neocortical pathology, quantitative analysis of the staining fractions in the cortex and white matter was carried out. Higher staining fractions were observed for all markers in both cortex and white matter in CHS patients, which was significantly different for CD68 and NPY compared to controls (p < 0.05) but not to non-CHS epilepsy cases. There was no significant difference between staining fractions in left and right hemispheres for unilateral CHS cases. Regional analysis showed preferential gliosis and microgliosis of temporal poles, frontal poles, and orbitofrontal cortex in epilepsy cases. This study supports acquired neocortical pathology in epilepsy patients both with and without CHS. Cortical pathology does not show lateralization to the side of CHS. Preferential involvement of the temporal and frontal poles may relate to other factors, such as cortical injury associated with seizures, rather than involvement through hippocampal pathways.

• Retinal nerve fiber layer thickness in vigabatrin-exposed patients.

  Authors: Lisa M Clayton, Marita Dévilé, Trusjen Punte, Constantinos Kallis, Gerrit-Jan de Haan, Josemir W Sander, James Acheson, Sanjay M Sisodiya

  Annals of neurology. 01/2011; 69(5):845-54.

  Vigabatrin-associated visual field loss (VAVFL) occurs in 25 to 50% of exposed patients and is routinely monitored using perimetry, which has inherent limitations. Using optical coherence tomographyVigabatrin-associated visual field loss (VAVFL) occurs in 25 to 50% of exposed patients and is routinely monitored using perimetry, which has inherent limitations. Using optical coherence tomography (OCT), retinal nerve fiber layer (RNFL) thinning has been described in a small number of vigabatrin-exposed patients. We explored the relationship between RNFL thickness and visual field size, to determine whether OCT is a suitable tool to use in patients exposed to vigabatrin. Two hundred one vigabatrin-exposed subjects with epilepsy, divided into 2 groups, and 90 healthy controls participated. Visual fields were obtained using Goldmann kinetic perimetry and quantified using mean radial degrees (MRD). RNFL imaging was performed using either spectral-domain (Group 1) or time-domain (Group 2) OCT. Thirty-nine of 201 (19.4%) patients were unable to perform perimetry. Thirteen (6.5%) patients were unable to perform OCT. A total of 51.6% of patients showed VAVFL. Average RNFL thickness was significantly thinner in patients (77.9 μm) compared to healthy controls (93.6 μm) (p < 0.001). There was a strong correlation between MRD and average RNFL thickness for Group 1 (r = 0.768, p < 0.001) and Group 2 (r = 0.814, p < 0.001). OCT RNFL imaging showed high repeatability. OCT provides a useful tool to assess people exposed to vigabatrin, and can provide an accurate estimate of the extent of visual field loss in the absence of a reliable direct measure of the visual field. The strong linear relationship found between RNFL thickness and visual field size provides some evidence that irreversible VAVFL may be related to loss of retinal ganglion cell axons.

• Genetic contribution to common epilepsies.

  Authors: Sanjay M Sisodiya, Heather C Mefford

  Current opinion in neurology. 01/2011; 24(2):140-5.

  We review key findings over the past year in the genetics of the common epilepsies and consider their impact on the field. There have been important discoveries across two major aspects of geneticsWe review key findings over the past year in the genetics of the common epilepsies and consider their impact on the field. There have been important discoveries across two major aspects of genetics of the common epilepsies. Firstly, the first genome-wide association study in epilepsy has been published, for the focal epilepsies. With reasonable power to detect even modest effect sizes, the absence of genome-wide significant association demands refinement of further single-nucleotide polymorphism (SNP)-based genome-wide approaches, with a focus on more homogeneous phenotypes. Secondly, several putatively causal variants of a different type, copy number variants (CNVs), have been discovered. Several recurrent epilepsy-associated CNVs have been identified, including microdeletions at 15q13.3 and 16p13.11. CNVs constitute the commonest known genetic cause of the epilepsies. How CNVs cause disease, and why the same CNV can cause different diseases is unexplained. Nevertheless, CNVs will accelerate discovery of 'epilepsy genes', focussing attention on specific genomic regions. With the published genome-wide SNP study, CNVs are redirecting research efforts to a search for rare variants underlying common epilepsies. CNVs have also highlighted the challenges ahead in genotype-phenotype correlation. Major discoveries are reshaping the genetics of the common epilepsies and prefiguring whole exome/whole genome resequencing efforts.