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Anthony G Marson - One of the best experts on this subject based on the ideXlab platform.

  • lamotrigine add on for drug resistant Partial Epilepsy
    Cochrane Database of Systematic Reviews, 2016
    Co-Authors: Sridharan Ramaratnam, Mariangela Panebianco, Anthony G Marson
    Abstract:

    Background This is an updated version of the Cochrane review published in The Cochrane Library 2010, Issue 1. Epilepsy is a common neurological disorder, affecting almost 0.5% to 1% of the population. For nearly 30% of these people, their Epilepsy is refractory to currently available drugs. Pharmacological treatment remains the first choice to control Epilepsy. Lamotrigine is one of the newer antiepileptic drugs and is the topic of this review. Lamotrigine in combination with other antiepileptic drugs (add-on) can reduce seizures, but with some adverse effects. The aim of this systematic review was to overview the current evidence for the efficacy and tolerability of lamotrigine when used as an adjunctive treatment for people with refractory Partial Epilepsy. Objectives To determine the effects of lamotrigine on (1) seizures, (2) adverse effect profile, and (3) cognition and quality of life, compared to placebo controls, when used as an add-on treatment for people with refractory Partial Epilepsy. Search methods For the previous version of the review, the authors searched the Cochrane Epilepsy Group Specialized Register (January 2010), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2010, Issue 1), MEDLINE (1950 to January 2010), and reference lists of articles. For this update, we searched the Cochrane Epilepsy Group Specialized Register (28 May 2015), CENTRAL (The Cochrane Library 2015, Issue 4), MEDLINE (Ovid, 1946 to May 2015), and reference lists of articles. We also contacted the manufacturers of lamotrigine (GlaxoSmithKline). No language restrictions were imposed. Selection criteria Randomised placebo-controlled trials of people with drug-resistant Partial Epilepsy of any age, in which an adequate method of concealment of randomisation was used. The studies were double-, single- or unblinded. For cross-over studies, the first treatment period was treated as a parallel trial. Eligible participants were adults or children with drug-resistant Partial Epilepsy. Data collection and analysis For this update, two review authors independently assessed the trials for inclusion, and extracted data. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal (any reason), adverse effects, effects on cognition and quality of life. Primary analyses were by intention-to-treat. Sensitivity best and worse case analyses were undertaken to account for missing outcome data. Pooled Risk Ratios (RR) with 95% confidence intervals (95% Cl) were estimated for the primary outcomes of seizure frequency and treatment withdrawal. For adverse effects, pooled RRs and 99% Cls were calculated. Main results We did not identify any new studies for this update, therefore, the results are unchanged. For the previous version of the review, the authors found five parallel add-on studies and eight cross-over studies in adults or children with refractory focal Epilepsy, and one parallel add-on study with a responder-enriched design in infants. In total, these 14 studies included 1958 participants (38 infants, 199 children, and 1721 adults). Baseline phases ranged from 4 to 12 weeks; treatment phases from 8 to 36 weeks. Overall, eleven studies (n = 1243 participants) were rated as having a low risk of bias, and three (n = 715 participants) had un unclear risk of bias due to lack of reported information around study design. Effective blinding of studies was reported in three studies (n = 504 participants). The overall risk ratio (RR) for 50% or greater reduction in seizure frequency was 1.80 (95% CI 1.45 to 2.23; 12 RCTs) for twelve studies (n = 1322 participants, adults and children) indicating that lamotrigine was significantly more effective than placebo in reducing seizure frequency. The overall RR for treatment withdrawal (for any reason) was 1.11 (95% CI 0.90 to 1.36; 14 RCTs) for fourteen studies (n = 1958 participants). The adverse events significantly associated with lamotrigine were: ataxia, dizziness, diplopia, and nausea. The RR of these adverse effects were as follows: ataxia 3.34 (99% Cl 2.01 to 5.55; 12 RCTs; n = 1524); dizziness 2.00 (99% Cl 1.51 to 2.64;13 RCTs; n = 1767); diplopia 3.79 (99% Cl 2.15 to 6.68; 3 RCTs; n = 943); nausea 1.81 (99% Cl 1.22 to 2.68; 12 RCTs; n = 1486). The limited data available precluded any conclusions about effects on cognition and quality of life. No important heterogeneity between studies was found for any of the outcomes. Overall, we assessed the evidence as high to moderate quality, due to incomplete data for some outcomes. Authors' conclusions Lamotrigine as an add-on treatment for Partial seizures appears to be effective in reducing seizure frequency, and seems to be fairly well tolerated. However, the trials were of relatively short duration and provided no evidence for the long-term. Further trials are needed to assess the long-term effects of lamotrigine, and to compare it with other add-on drugs. Since we did not find any new studies, our conclusions remain unchanged.

  • lacosamide add on therapy for Partial Epilepsy
    Cochrane Database of Systematic Reviews, 2015
    Co-Authors: Jennifer Weston, Arif Shukralla, Andrew Mckay, Anthony G Marson
    Abstract:

    Background Around half of people with Epilepsy will not achieve seizure freedom on their first antiepileptic drug; many will require add-on treatment with another drug. Sometimes multiple treatment combinations are tried to achieve maximum seizure control, although around a third of people do not achieve complete seizure control. Lacosamide is an antiepileptic drug that has been licensed as an add-on treatment for Partial Epilepsy. Objectives To evaluate the efficacy and tolerability of lacosamide when used as an add-on treatment for patients with drug-resistant Partial Epilepsy. Search methods We searched the Cochrane Epilepsy Group's Specialized Register (21 May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL , The Cochrane Library Issue 4, April 2015), MEDLINE (Ovid, 1946 to 21 May 2015), Scopus (1823 to 13 November 2014), ClinicalTrials.gov (21 May 2015) and the WHO International Clinical Trials Registry Platform (ICTRP, 21 May 2015). We imposed no language restrictions. We contacted UCB (sponsors of lacosamide) and experts in the field. Selection criteria Randomised controlled trials of add-on lacosamide in people with drug-resistant Partial Epilepsy. Data collection and analysis Two review authors independently assessed trials for inclusion and extracted the relevant data. We assessed the following outcomes: (1) 50% or greater reduction in seizure frequency; (2) seizure freedom; (3) treatment withdrawal for any reason; and (4) adverse events. Primary analyses were intention-to-treat. Summary risk ratios were estimated for each outcome. Main results We included three trials in our review (1311 participants), which were classified as having low risk of bias. All trials were placebo-controlled and assessed doses ranging from 200 mg to 600 mg per day. Trial duration ranged from 24 to 26 weeks. All trials used adequate methods of randomisation and were double-blind. Overall the quality of the evidence was rated as moderate to high. The overall risk ratio for a 50% or greater reduction in seizure frequency for all doses of lacosamide compared with placebo was 1.70 (95% confidence interval (CI) 1.38 to 2.10); for seizure freedom for all doses of lacosamide compared with placebo was 2.50 (95% CI 0.85 to 7.34); and for treatment withdrawal for all doses of lacosamide compared with placebo was 1.88 (95% CI 1.40 to 2.52). Adverse effects significantly associated with lacosamide were abnormal co-ordination (risk ratio (RR) 6.12, 99% CI 1.35 to 27.77), diplopia (RR 5.29, 99% CI 1.97 to 14.23), dizziness (RR 3.53, 99% CI 2.20 to 5.68), nausea (RR 2.37, 99% CI 1.23 to 4.58) and vomiting (RR 3.49, 99% CI 1.43 to 8.54). Adverse effects that were not statistically significant were headache (RR 1.34, 99% CI 0.83 to 2.18), fatigue (RR 2.11, 99% CI 0.92 to 4.85), nystagmus (RR 1.47, 99% CI 0.61 to 3.52) and somnolence (RR 1.44, 99% CI 0.67 to 3.09). Authors' conclusions This review has shown lacosamide to be effective and fairly well tolerated in the short term when used as add-on treatment for drug-resistant Partial Epilepsy in adults. Higher doses of lacosamide may be more associated with adverse effects and withdrawal of the drug than lower doses. Additional evidence on children is needed, and longer-term efficacy is unknown.

  • topiramate add on for drug resistant Partial Epilepsy
    Cochrane Database of Systematic Reviews, 2014
    Co-Authors: Jennifer Pulman, Karla Hemming, Jane L Hutton, Nathalie Jette, Jonathan Dykeman, Anthony G Marson
    Abstract:

    Background: The majority of people with Epilepsy have a good prognosis and their seizures are controlled by a single antiepileptic drug. However, up to 20% of patients from population-based studies and up to 30% from clinical series ( not population-based) develop drug-resistant Epilepsy, especially those with Partial onset seizures. In this review we summarize the current evidence regarding a new antiepileptic drug, topiramate, when used as an add-on treatment for drug-resistant Partial Epilepsy. Objectives: To evaluate the efficacy and safety of topiramate when used as an add-on treatment for drug-resistant Partial Epilepsy. Search strategy: We searched he Cochrane Epilepsy Group Specialized Register ( 10 May 2007); the Cochrane Central Register of Controlled Trials ( CENTRAL) ( T h e Cochrane Library Issue 3, 2007). No language restrictions were imposed. We also contacted the manufacturers of topiramate and researchers in the field to see any ongoing or published studies. Selection criteria: Randomized placebo controlled add-on trials of topiramate recruiting people with drug-resistant Partial Epilepsy. Data collection and analysis: Two review authors independently selected trials for inclusion and extracted the relevant data. The following outcomes were assessed: ( a) 50% or greater reduction in seizure frequency; (b) treatment withdrawal ( any reason); ( c) side effects. Primary analyses were intention-to-treat. Summary relative risks (RR) with 95% confidence intervals ( 95% CI) are presented. Dose response was evaluated in regression models. Main results: Ten trials were included representing 1312 randomized participants. Baseline phases ranged from 4-12 weeks and double-blind phases from 11-19 weeks. The RR for a 50% or greater reduction in seizure frequency compared to placebo was 2.85 ( 95% CI 2.27 to 3.59). Dose regression analysis shows increasing effect with increasing dose, but found no advantage for doses over 300 or 400 mg per day. The RR for treatment withdrawal compared to placebo was 2.26 ( 95% CI 1.55 to 3.31). The RR for the following side effects indicate that they are significantly associated with topiramate: ataxia 1.95 ( 99% CI 1.04 to 3.65); dizziness 1.55 ( 99% CI 1.08 to 2.22); fatigue 2.19 ( 99% CI 1.43 to 3.35); nausea 2.35 ( 99% CI 1.28 to 4.29); somnolence 2.18 ( 99% CI 1.47 to 3.21) and 'thinking abnormally' 5.77 ( 99% CI 2.50 to 13.35).

  • vigabatrin for refractory Partial Epilepsy
    Cochrane Database of Systematic Reviews, 2013
    Co-Authors: Karla Hemming, Melissa J Maguire, Jane L Hutton, Anthony G Marson
    Abstract:

    Background Epilepsy is a common neurological condition which affects between 0.5% and 1% of the population. Approximately 30% of people with Epilepsy do not respond to treatment with currently available drugs, and the majority of these people have Partial Epilepsy. Vigabatrin is an antiepileptic drug licensed for use in the treatment of refractory Epilepsy. No major side effects associated with the use of vigabatrin were detected by initial randomised controlled trials of the drug. However, longer term observational studies have subsequently identified that its use is associated with asymptomatic visual field constriction. Objectives The objective of this review is to synthesise evidence from short-term, randomised, placebo-controlled trials of vigabatrin. We summarise the effects of vigabatrin on seizures and short-term side effects when used as an add-on treatment for people with drug-resistant Partial Epilepsy. A review of longer term observational studies and estimates of proportions of patients developing visual field constrictions is currently being undertaken and results will be cited here in due course. Search strategy We searched the Cochrane Epilepsy Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (T h e Cochrane Library Issue 1, 2008), MEDLINE (1950-March 2008), and reference lists of articles. We also contacted the manufacturers of vigabatrin (Hoechst Marion Roussel). Selection criteria We included randomised, double-blind, placebo-controlled, fully published trials of vigabatrin, in people with drug-resistant Partial Epilepsy. Data collection and analysis Two review authors assessed trials for inclusion and extracted data. Primary analysis was by intention-to-treat (ITT). Outcomes evaluated included 50% or greater reduction in seizure frequency, treatment withdrawal and side effects observable in the short term. Results are presented on the relative risk (RR) scale with 95 or 99% confidence intervals (CI). Main results Eleven suitable trials, testing doses between 1000 mg and 6000 mg, were identified and included in the analysis. There were 982 observations on 747 patients in the primary ITT analysis of treatment efficacy. Patients treated with vigabatrin were significantly more likely to obtain a 50% or greater reduction in seizure frequency compared with those treated with placebo (RR 2.58 (95% CI 1.87 to 3.57)). Those treated with vigabatrin were also significantly more likely to have treatment withdrawn (RR 2.49 (95% CI 1.05 to 5.88)), and more likely to experience a number of side effects, significantly so for fatigue or drowsiness. There was some evidence of small study effect bias, with smaller studies tending to report greater estimates of RR than larger studies. It is possible that the actual relative risk of obtaining 50% reduction in seizure frequency may therefore be less than that obtained by a meta-analysis of fully published studies. Authors' conclusions This review of randomised controlled trials shows that vigabatrin can reduce seizure frequency in people with drug-resistant Partial Epilepsy. Short-term follow up of patients shows some side effects are associated with its use. Further analysis of longer term observational studies is required to evaluate how likely patients are to develop visual field defects, and whether such side effects are associated with dose and duration of drug use.

Miriam H Meisler - One of the best experts on this subject based on the ideXlab platform.

  • mutation of sodium channel scn3a in a patient with cryptogenic pediatric Partial Epilepsy
    Neuroscience Letters, 2008
    Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H Meisler
    Abstract:

    Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for Epilepsy. We screened a consecutive cohort of 18 children with cryptogenic Partial Epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q alters an evolutionarily conserved amino acid in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood Epilepsy.

  • mutation of sodium channel scn3a in a patient with cryptogenic pediatric Partial Epilepsy
    Neuroscience Letters, 2008
    Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H Meisler
    Abstract:

    Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for Epilepsy. We screened a consecutive cohort of 18 children with cryptogenic Partial Epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q substitutes glutamine for an evolutionarily conserved lysine residue in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood Epilepsy.

Luigi Giorgi - One of the best experts on this subject based on the ideXlab platform.

  • adjunctive zonisamide therapy in the long term treatment of children with Partial Epilepsy results of an open label extension study of a phase iii randomized double blind placebo controlled trial
    Epilepsia, 2014
    Co-Authors: Renzo Guerrini, Anna Rosati, Kate Bradshaw, Luigi Giorgi
    Abstract:

    Summary Objective To investigate the safety/tolerability and efficacy of long-term adjunctive zonisamide and its impact on growth and development in children (6–18 years) with Partial Epilepsy. Methods Open-label extension of a phase III, placebo-controlled trial. Started with double-blind transition period (2–11 weeks), during which patients on zonisamide continued at the same dose and those on placebo switched to zonisamide 1 mg/kg/day, up-titrated to 8 mg/kg/day (maximum 500 mg/day). During the subsequent open-label period (45–57 weeks), zonisamide dosing could be adjusted according to tolerability/response. Safety assessments included treatment-emergent adverse events (TEAEs), clinical laboratory parameters, and vital signs. Efficacy assessments included responder rate (primary assessment) and seizure freedom rate during the open-label period. Growth and development assessments comprised Tanner stages, hand x-rays, Child Behavior Checklist (CBCL 6/18), School Performance questionnaire, Physician and Parent/Guardian Global Impression of Change, and Controlled Oral Word Association Test (COWAT). Results One hundred forty-four children entered the study; 99 (68.8%) of 144 children completed it, and 108 (75.0%) of 144 received zonisamide for ≥1 year. TEAEs occurred in 39 (27.1%) of 144 patients. There were low incidences of serious TEAEs (2.1%) and TEAEs leading to discontinuation (2.8%). Bicarbonate level decreases >3.5 mm occurred in 64 patients (44.4%), and 24 patients (16.7%) had a weight decrease of ≥10% from baseline. During the open-label period, 81 (56.3%) of 144 patients were responders and 16 (11.1%) of 144 achieved seizure freedom. Tanner staging and skeletal development were as expected for the study population. Changes were minimal for CBCL 6/18 and School Performance scores. Most patients were “much improved”/“very much improved” on Physician (73.8%) and Parent/Guardian (75.4%) Global Impressions of Change. Median changes in COWAT Category and Letter Fluency scores were 2.0 and 0.5, respectively. Significance Adjunctive zonisamide was well tolerated and efficacious over a period of at least 1 year in children with Partial Epilepsy, with no unexpected safety concerns and no consistent detrimental effects on growth and development. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

  • a randomized phase iii trial of adjunctive zonisamide in pediatric patients with Partial Epilepsy
    Epilepsia, 2013
    Co-Authors: Renzo Guerrini, Anna Rosati, Joanna Segieth, Simona Pellacani, Kate Bradshaw, Luigi Giorgi
    Abstract:

    Summary Purpose To assess the efficacy and safety/tolerability of adjunctive zonisamide treatment in pediatric patients with Partial Epilepsy. Methods In this phase III, double-blind, randomized, placebo-controlled, multicenter trial, 207 patients (age 6–17 years) with Partial Epilepsy, receiving one or two antiepileptic drugs, were randomized to receive adjunctive zonisamide or placebo. Zonisamide was initiated at 1 mg/kg/day, titrated to a target dose of 8 mg/kg/day over 8 weeks (one down-titration permitted), and maintained for 12 weeks. The primary efficacy end point was the proportion of responders (≥50% seizure frequency reduction from baseline) during the 12-week maintenance period. Safety/tolerability assessments included the incidence of treatment-emergent adverse events (TEAEs). Key Findings In total, 93 (86.9%) of 107 patients randomized to zonisamide and 90 (90.0%) of 100 patients randomized to placebo completed the trial. Responder rates were 50% for zonisamide versus 31% for placebo (p = 0.0044; intention-to-treat population, last observation carried forward). The overall incidence of TEAEs was similar for zonisamide (55.1%) versus placebo (50.0%), with low rates of serious TEAEs with zonisamide and placebo (3.7% vs. 2.0%) and TEAEs leading to withdrawal (0.9% vs. 3.0%). TEAEs reported more frequently with zonisamide versus placebo were decreased appetite (6.5% vs. 4.0%), decreased weight (4.7% vs. 3.0%), somnolence (4.7% vs. 2.0%), vomiting (3.7% vs. 2.0%), and diarrhea (3.7% vs. 1.0%). Significance Adjunctive zonisamide treatment was shown to be effective and well tolerated in pediatric patients with Partial Epilepsy. No new or unexpected safety findings emerged.

  • efficacy and tolerability of zonisamide versus controlled release carbamazepine for newly diagnosed Partial Epilepsy a phase 3 randomised double blind non inferiority trial
    Lancet Neurology, 2012
    Co-Authors: Michel Baulac, Joanna Segieth, Anna Patten, Martin J Brodie, Luigi Giorgi
    Abstract:

    Summary Background Additional options are needed for monotherapy treatment of adults newly diagnosed with Partial Epilepsy. This trial compares the efficacy and tolerability of once-daily zonisamide with twice-daily controlled-release carbamazepine monotherapy for such patients. Methods In this phase 3, randomised, double-blind, parallel-group, non-inferiority trial, adults from 120 centres in Asia, Australia, and Europe, aged 18–75 years and newly diagnosed with Partial Epilepsy, were randomly assigned (in a 1:1 ratio, done with a computer-generated pseudorandom code) to receive zonisamide or carbamazepine. Patients, investigators, and sponsor personnel giving drugs, analysing outcomes, and interpreting data were masked to treatment allocation. After treatment initiation (zonisamide 100 mg/day vs carbamazepine 200 mg/day [given in two doses]) and up-titration (to 300 mg/day vs 600 mg/day), patients entered a 26–78 weeks flexible-dosing period (200–500 mg/day vs 400–1200 mg/day, according to response and tolerance). Once patients were seizure-free for 26 weeks they entered a 26-week maintenance phase. The primary endpoint was the proportion of patients who achieved seizure freedom for 26 weeks or more in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT00477295. Findings 583 patients were randomly assigned to treatment groups (282 zonisamide, 301 carbamazepine), of whom 456 were analysed for the primary endpoint (per-protocol population: 223 zonisamide, 233 carbamazepine). 177 of 223 (79·4%) patients in the zonisamide group and 195 of 233 (83·7%) patients in the carbamazepine group were seizure-free for 26 weeks or more (adjusted absolute treatment difference −4·5%, 95% CI −12·2 to 3·1). The incidence of treatment-emergent adverse events was 170 (60%) in the zonisamide group versus 185 (62%) in the carbamazepine group, of which 15 (5%) versus 17 (6%) were serious and 31 (11%) versus 35 (12%) led to withdrawal. Interpretation Zonisamide was non-inferior to controlled-release carbamazepine—according to International League Against Epilepsy guidelines—and could be useful as an initial monotherapy for patients newly diagnosed with Partial Epilepsy. Funding Eisai Ltd.

Ruth Ottman - One of the best experts on this subject based on the ideXlab platform.

  • altered language processing in autosomal dominant Partial Epilepsy with auditory features
    Neurology, 2008
    Co-Authors: Ruth Ottman, L Rosenberger, Anto Bagic, K Kamberakis, Eva K Ritzl, A M Wohlschlager, Sadat Shamim, Susumu Sato, Clarissa J Liew
    Abstract:

    Background: Autosomal dominant Partial Epilepsy with auditory features (ADPEAF) is an idiopathic focal Epilepsy syndrome with auditory symptoms or receptive aphasia as major ictal manifestations, frequently associated with mutations in the leucine-rich, glioma inactivated 1 ( LGI1 ) gene. Although affected subjects do not have structural abnormalities detected on routine MRI, a lateral temporal malformation was identified through high resolution MRI in one family. We attempted to replicate this finding and to assess auditory and language processing in ADPEAF using fMRI and magnetoencephalography (MEG). Methods: We studied 17 subjects (10 affected mutation carriers, 3 unaffected carriers, 4 noncarriers) in 7 ADPEAF families, each of which had a different LGI1 mutation. Subjects underwent high-resolution structural MRI, fMRI with an auditory description decision task (ADDT) and a tone discrimination task, and MEG. A control group comprising 26 volunteers was also included. Results: We found no evidence of structural abnormalities in any of the 17 subjects. On fMRI with ADDT, subjects with Epilepsy had significantly less activation than controls. On MEG with auditory stimuli, peak 2 auditory evoked field latency was significantly delayed in affected individuals compared to controls. Conclusions: These findings do not support the previous report of a lateral temporal malformation in autosomal dominant Partial Epilepsy with auditory features (ADPEAF). However, our fMRI and magnetoencephalography data suggest that individuals with ADPEAF have functional impairment in language processing.

  • lgi1 mutations in autosomal dominant Partial Epilepsy with auditory features
    Neurology, 2004
    Co-Authors: Ruth Ottman, Timothy A. Pedley, Melodie R Winawer, Sergey Kalachikov, Christie Barkercummings, T C Gilliam, W A Hauser
    Abstract:

    Objectives: Mutations in LGI1 cause autosomal dominant Partial Epilepsy with auditory features (ADPEAF), a form of familial temporal lobe Epilepsy with auditory ictal manifestations. The authors aimed to determine what proportion of ADPEAF families carries a mutation, to estimate the penetrance of identified mutations, and to identify clinical features that distinguish families with and without mutations. Methods: The authors sequenced LGI1 in 10 newly described ADPEAF families and analyzed clinical features in these families and others with mutations reported previously. Results: Three of the families had missense mutations in LGI1 (C42R, I298T, and A110D). Penetrance was 54% in eight families with LGI1 mutations the authors have identified so far (five reported previously and three reported here). Excluding the original linkage family, the authors have found mutations in 50% (7/14) of tested families. Families with and without mutations had similar clinical features, but those with mutations contained significantly more subjects with auditory symptoms and significantly fewer with autonomic symptoms. In families with mutations, the most common auditory symptom type was simple, unformed sounds (e.g., buzzing and ringing). In two of the newly identified families with mutations, some subjects with mutations had idiopathic generalized epilepsies. Conclusions: LGI1 mutations are a common cause of autosomal dominant Partial Epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant Partial Epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized Epilepsy or an effect of co-occurring idiopathic generalized Epilepsy-specific genes in these families.

  • Localization of a gene for Partial Epilepsy to chromosome 10q
    Nature genetics, 1995
    Co-Authors: Ruth Ottman, Neil Risch, W. Allen Hauser, Timothy A. Pedley, Joseph H. Lee, Christie Barker-cummings, Anita Lustenberger, Keith J. Nagle, Kyusang S. Lee, Mark L. Scheuer
    Abstract:

    There is strong evidence for a genetic contribution to Epilepsy, but it is commonly assumed that this genetic contribution is limited to 'generalized' epilepsies, and that most forms of 'Partial' Epilepsy are nongenetic. In a linkage analysis of a single family containing 11 affected individuals, we obtained strong evidence for localization of a gene for Partial Epilepsy. This susceptibility gene maps to chromosome 10q, with a maximum two-point lod score for D10S192 of 3.99 at theta = 0.0. All affected individuals share a single haplotype for seven tightly linked contiguous markers; the maximum lod score for this haplotype is 4.83 at theta = 0.0. Key recombinants place the susceptibility locus within a 10 centimorgan interval.

Katherine D Holland - One of the best experts on this subject based on the ideXlab platform.

  • mutation of sodium channel scn3a in a patient with cryptogenic pediatric Partial Epilepsy
    Neuroscience Letters, 2008
    Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H Meisler
    Abstract:

    Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for Epilepsy. We screened a consecutive cohort of 18 children with cryptogenic Partial Epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q alters an evolutionarily conserved amino acid in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood Epilepsy.

  • mutation of sodium channel scn3a in a patient with cryptogenic pediatric Partial Epilepsy
    Neuroscience Letters, 2008
    Co-Authors: Katherine D Holland, Gerri Buck, John R Blankston, Ian W Glaaser, Robert S Kass, Mehdi Keddache, Tracy A Glauser, Jennifer A Kearney, Miriam H Meisler
    Abstract:

    Mutations in the sodium channel genes SCN1A and SCN2A have been identified in monogenic childhood epilepsies, but SCN3A has not previously been investigated as a candidate gene for Epilepsy. We screened a consecutive cohort of 18 children with cryptogenic Partial Epilepsy that was classified as pharmacoresistant because of nonresponse to carbamazepine or oxcarbazepine, antiepileptic drugs that bind sodium channels. The novel coding variant SCN3A-K354Q was identified in one patient and was not present in 295 neurological normal controls. Twelve novel SNPs were also detected. K354Q substitutes glutamine for an evolutionarily conserved lysine residue in the pore domain of SCN3A. Functional analysis of this mutation in the backbone of the closely related gene SCN5A demonstrated an increase in persistent current that is similar in magnitude to epileptogenic mutations of SCN1A and SCN2A. This observation of a potentially pathogenic mutation of SCN3A (Nav1.3) indicates that this gene should be further evaluated for its contribution to childhood Epilepsy.