Anthony G Marson

University of Liverpool, Liverpool, England, United Kingdom

Are you Anthony G Marson?

Claim your profile

Publications (116)777.67 Total impact

  • Cochrane database of systematic reviews (Online) 06/2015; · 5.70 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: This document provides guidance on the use of valproate in women and girls from a joint task force of the Commission of European Affairs of the International League Against Epilepsy (CEA-ILAE) and the European Academy of Neurology (EAN), following strengthened warnings from the Coordination Group for Mutual Recognition and Decentralised Procedures-Human (CMDh) of the European Medicines Agency (EMA), which highlight the risk of malformations and developmental problems in babies who are exposed to valproate in the womb. To produce these recommendations, the Task Force has considered teratogenic risks associated with use valproate and treatment alternatives, the importance of seizure control and of patient and foetal risks with seizures, and the effectiveness of valproate and treatment alternatives in the treatment of different epilepsies. The Task Force's recommendations include the following: Where possible, valproate should be avoided in women of childbearing potential. The choice of treatment for women of childbearing potential should be based on a shared decision between clinician and patient, and where appropriate the patient's representatives. Discussions should include a careful risk benefit assessment of reasonable treatment options for the patient's seizure or epilepsy type. For seizure (or epilepsy) types where valproate is the most effective treatment, the risks and benefits of valproate and other treatment alternatives should be discussed. Valproate should not be prescribed as a first-line treatment for focal epilepsy. Valproate may be offered as a first line treatment for epilepsy syndromes where it is the most effective treatment, including idiopathic (genetic) generalized syndromes associated with tonic clonic seizures. Valproate may be offered as a first-line treatment in situations where pregnancy is highly unlikely (e.g. significant intellectual or physical disability). Women and girls taking valproate require regular follow-up for ongoing consideration of the most appropriate treatment regimen. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Epilepsia 04/2015; DOI:10.1111/epi.13021 · 4.58 Impact Factor
  • Cochrane database of systematic reviews (Online) 04/2015; 4:CD002896. DOI:10.1002/14651858.CD002896.pub2 · 5.94 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Between 35% and 50% of patients with epilepsy are reported to be not fully adherent to their medication schedule. We aimed to conduct an economic evaluation of strategies for improving adherence to antiepileptic drugs. Based on the findings of a systematic review, we identified an implementation intention intervention (specifying when, where, and how to act) which was tested in a trial that closely resembled current clinical management of patients with epilepsy and which measured adherence with an objective and least biased method. Using patient-level data, trial patients were matched with those recruited for the Standard and New Antiepileptic Drugs trial according to their clinical characteristics and adherence. Generalized linear models were used to adjust cost and utility in order to estimate the incremental cost per quality-adjusted life-year (QALY) gained from the perspective of the National Health Service in the UK. The mean cost of the intervention group, £1340 (95% CI: £1132, £1688), was marginally lower than that of the control group representing standard care, £1352 (95% CI: £1132, £1727). Quality-adjusted life-year values in the intervention group were higher than those in the control group, i.e., 0.75 (95% CI: 0.70, 0.79) compared with 0.74 (95% CI: 0.68, 0.79), resulting in a cost saving of £12 (€15, US$19) and with the intervention being dominant. The probability that the intervention is cost-effective at a threshold of £20,000 per QALY is 94%. Our analysis lends support to the cost-effectiveness of a self-directed, implementation intention intervention for improving adherence to antiepileptic drugs. However, as with any modeling dependent on limited data on efficacy, there is considerable uncertainty surrounding the clinical effectiveness of the intervention which would require a substantive trial for a more definitive conclusion. Copyright © 2015 Elsevier Inc. All rights reserved.
    Epilepsy & Behavior 03/2015; DOI:10.1016/j.yebeh.2015.01.035 · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although temporal lobe surgery is an effective treatment for patients with intractable mesial temporal lobe epilepsy (mTLE), a third of patients will continue to experience seizures at 2 years after surgery. The reasons are unknown. One suggestion is that patients with abnormalities of the entorhinal cortex might have a subtype of mTLE that is resistant to surgery. We investigated the association between presurgical entorhinal cortex volume and postoperative outcome in patients with mTLE.
    The Lancet 02/2015; 385. DOI:10.1016/S0140-6736(15)60349-X · 39.21 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective Carbamazepine causes severe cutaneous adverse drug reactions that may be predicted by the presence of the HLA-A*31:01 allele in northern European populations. There is uncertainty as to whether routine testing of patients with epilepsy is cost-effective. We conducted an economic evaluation of HLA-A*31:01 testing from the perspective of the National Health Service (NHS) in the United Kingdom.MethodsA short-term, decision analytic model was developed to estimate the outcomes and costs associated with a policy of routine testing (with lamotrigine prescribed for patients who test positive) versus the current standard of care, which is carbamazepine prescribed without testing. A Markov model was used to estimate total costs and quality-adjusted life-years (QALYs) over a lifetime to account for differences in drug effectiveness and the long-term consequences of adverse drug reactions.ResultsTesting reduced the expected rate of cutaneous adverse drug reactions from 780 to 700 per 10,000 patients. The incremental cost-effectiveness ratio for pharmacogenetic testing versus standard care was £12,808 per QALY gained. The probability of testing being cost-effective at a threshold of £20,000 per QALY was 0.80, but the results were sensitive to estimated remission rates for alternative antiepileptic drugs (AEDs).SignificanceRoutine testing for HLA-A*31:01 in order to reduce the incidence of cutaneous adverse drug reactions in patients being prescribed carbamazepine for epilepsy is likely to represent a cost-effective use of health care resources.
    Epilepsia 02/2015; DOI:10.1111/epi.12937 · 4.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To compare quality-of-life (QoL) outcomes over 2 years following initiation of treatment with a standard or newer antiepileptic drug (AED) in adults with new-onset epilepsy. To examine the impact of seizure remission and failure of initial treatment on QoL outcomes measured over 2 years. We conducted a pragmatic, randomized, unblinded, multicenter, parallel-group clinical trial (the Standard and New Antiepileptic Drugs [SANAD] trial) comparing clinical and cost effectiveness of initiating treatment with carbamazepine versus lamotrigine, gabapentin, oxcarbazepine and topiramate, and valproate versus lamotrigine and topiramate. QoL data were collected by mail at baseline, 3 months, and at 1 and 2 years using validated measures. These data were analyzed using longitudinal data models. Continuous QoL measures, time to 12-month remission and time to treatment withdrawal were explored using joint models. Baseline questionnaires were returned by 1,575 adults; 1,439 returned the 3-month questionnaire, 1,274 returned the 1-year questionnaire, and 1,121 returned the 2-year questionnaire. There were few statistically significant differences between drugs over 2 years in QoL outcomes. Significant association was identified between QoL scores over the 2-year time frame and the risk of experiencing a 12-month remission or treatment withdrawal over that period. The choice of initial treatment had no significant effect on QoL by 2-year follow-up. However, overall QoL was reduced with continued seizures, adverse events, and failure of the initial treatment. Wiley Periodicals, Inc. © 2015 International League Against Epilepsy.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective There are competing explanations for persistent postoperative seizures after temporal lobe surgery. One is that 1 or more particular subtypes of mesial temporal lobe epilepsy (mTLE) exist that are particularly resistant to surgery. We sought to identify a common brain structural and connectivity alteration in patients with persistent postoperative seizures using preoperative quantitative magnetic resonance imaging and diffusion tensor imaging (DTI).Methods We performed a series of studies in 87 patients with mTLE (47 subsequently rendered seizure free, 40 who continued to experience postoperative seizures) and 80 healthy controls. We investigated the relationship between imaging variables and postoperative seizure outcome. All patients had unilateral temporal lobe seizure onset, had ipsilateral hippocampal sclerosis as the only brain lesion, and underwent amygdalohippocampectomy.ResultsQuantitative imaging factors found not to be significantly associated with persistent seizures were volumes of ipsilateral and contralateral mesial temporal lobe structures, generalized brain atrophy, and extent of resection. There were nonsignificant trends for larger amygdala and entorhinal resections to be associated with improved outcome. However, patients with persistent seizures had significant atrophy of bilateral dorsomedial and pulvinar thalamic regions, and significant alterations of DTI-derived thalamotemporal probabilistic paths bilaterally relative to those patients rendered seizure free and controls, even when corrected for extent of mesial temporal lobe resection.InterpretationPatients with bihemispheric alterations of thalamotemporal structural networks may represent a subtype of mTLE that is resistant to temporal lobe surgery. Increasingly sensitive multimodal imaging techniques should endeavor to transform these group-based findings to individualize prediction of patient outcomes. Ann Neurol 2015;77:760–774
    Annals of Neurology 01/2015; 77(5). DOI:10.1002/ana.24376 · 11.91 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: About 100 000 people present to hospitals each year in England with an epileptic seizure. How they are managed is unknown; thus, the National Audit of Seizure management in Hospitals (NASH) set out to assess prior care, management of the acute event and follow-up of these patients. This paper describes the data from the second audit conducted in 2013. 154 emergency departments (EDs) across the UK. Data from 4544 attendances (median age of 45 years, 57% men) showed that 61% had a prior diagnosis of epilepsy, 12% other neurological problems and 22% were first seizure cases. Each ED identified 30 consecutive adult cases presenting due to a seizure. Details were recorded of the patient's prior care, management at hospital and onward referral to neurological specialists onto an online database. Descriptive results are reported at national level. Of those with epilepsy, 498 (18%) were on no antiepileptic drug therapy and 1330 (48%) were on monotherapy. Assessments were often incomplete and witness histories were sought in only 759 (75%) of first seizure patients, 58% were seen by a senior doctor and 57% were admitted. For first seizure patients, advice on further seizure management was given to 264 (27%) and only 55% were referred to a neurologist or epilepsy specialist. For each variable, there was wide variability among sites that was not explicable. For the sites who partook in both audits, there was a trend towards better care in 2013, but this was small and dwarfed by the intersite variability. These results have parallels with the Sentinel Audit of Stroke performed a decade earlier. There is wide intersite variability in care covering the entire care pathway, and a need for better organised and accessible care for these patients. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
    BMJ Open 01/2015; 5(3):e007325. DOI:10.1136/bmjopen-2014-007325 · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The objectives are as follows: To review the time to withdrawal, remission and first seizure of 10 antiepileptic drugs (carbamazepine, phenytoin, valproate, phenobarbitone, oxcarbazepine, lamotrigine, gabapentin, topiramate, levetiracetam, zonisamide) currently used as monotherapy in children and adults with partial onset seizures or generalised tonic-clonic seizures with or without other generalised seizure types.
    Cohrane Database of Systematic Reviews 12/2014; DOI:10.1002/14651858.CD011412.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background Depressive disorders are the most common psychiatric comorbidity in patients with epilepsy, affecting around one-third, with a significant negative impact on quality of life. There is concern that patients may not be receiving appropriate treatment for their depression because of uncertainty regarding which antidepressant or class works best and the perceived risk of exacerbating seizures. This review aims to address these issues and inform clinical practice and future research. Objectives We aimed to review and synthesise evidence from randomised controlled trials of antidepressants and prospective non-randomised studies of antidepressants used for treating depression in patients with epilepsy. The primary objectives were to evaluate the efficacy and safety of antidepressants in treating depressive symptoms and the effect on seizure recurrence. Search methods We conducted a search of the following databases: the Cochrane Epilepsy Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL 2014, Issue 5), MEDLINE (Ovid), SCOPUS, PsycINFO, www.clinicaltrials.gov and conference proceedings, including studies published up to 31 May 2014. There were no language restrictions. Selection criteria We included randomised controlled trials (RCTs) and prospective non-randomised cohort controlled and uncontrolled studies investigating children or adults with epilepsy treated with an antidepressant for depressive symptoms. The intervention group consisted of patients receiving an antidepressant drug in addition to an existing antiepileptic drug regimen. The control group(s) consisted of patients receiving a placebo, comparative antidepressant, psychotherapy or no treatment in addition to an existing antiepileptic drug regimen. Data collection and analysis We extracted data on trial design factors, patient demographics and outcomes for each study. The primary outcomes were changes in depression scores (proportion with a greater than 50% improvement or mean difference) and change in seizure frequency (mean difference or proportion with a seizure recurrence or episode of status epilepticus, or both). Secondary outcomes included the number of patients withdrawing from the study and reasons for withdrawal, as well as any adverse events. Two authors undertook data extraction separately for each included study. We then cross-checked the data extraction. We assessed risk of bias using a version of the extended Cochrane Collaboration tool for assessing risk of bias in both randomised and non-randomised studies. We presented binary outcomes as risk ratios (RRs) with 95% confidence intervals (CIs). We presented continuous outcomes as standardised mean differences (SMDs) with 95% CIs, and mean differences (MDs) with 95% CIs. If possible we intended to use meta-regression techniques to investigate possible sources of heterogeneity however this was not possible due to lack of data. Main results We included in the review eight studies (three RCTs and five prospective cohort studies) including 471 patients with epilepsy treated with an antidepressant. The RCTs were all single-centre studies comparing an antidepressant versus active control, placebo or no treatment. The five non-randomised prospective cohort studies reported on outcomes mainly in patients with partial epilepsy treated for depression with a selective serotonin reuptake inhibitor (SSRI). We rated all the RCTs and one prospective cohort study as having unclear risk of bias. We rated the four other prospective cohort studies as having high risk of bias. We were unable to perform any meta-analysis for the proportionwith a greater than 50% improvement in depression scores because the studies reported on different treatment comparisons. The results are presented descriptively and show a varied responder rate of between 24% and 97%, depending on the antidepressant given. For the mean difference in depression score we were able to perform a limited meta-analysis of two prospective cohort studies of citalopram, including a total of 88 patients. This gave low quality evidence for the effect estimate of 1.17 (95% CI 0.96 to 1.38) in depression scores. Seizure frequency data were not reported in any RCTs and we were unable to perform any meta-analysis for prospective cohort studies due to the different treatment comparisons. The results are presented descriptively and show that treatment in three studies with a selective serotonin reuptake inhibitor did not significantly increase seizure frequency. Patients given an antidepressant were more likely to withdraw due to adverse events than inefficacy. Reported adverse events for SSRIs included nausea, dizziness, sedation, gastrointestinal disturbance and sexual dysfunction. Across three comparisons we rated the evidence as moderate quality due to the small sizes of the contributing studies and only one study each contributing to the comparisons. We rated the evidence for the final comparison as low quality as there was concern over the study methods in the two contributing studies. Authors' conclusions Existing evidence on the effectiveness of antidepressants in treating depressive symptoms associated with epilepsy is very limited. Only one small RCT demonstrated a statistically significant effect of venlafaxine on depressive symptoms. We have no high quality evidence to inform the choice of antidepressant drug or class of drug in treating depression in people with epilepsy. This review provides low quality evidence of safety in terms of seizure exacerbation with SSRIs, but there are no available comparative data on antidepressant classes and safety in relation to seizures. There are currently no comparative data on antidepressants and psychotherapy in treating depression in epilepsy, although psychotherapy could be considered in patients unwilling to take antidepressants or where there are unacceptable side effects. Further comparative clinical trials of antidepressants and psychotherapy in large cohorts of patients with epilepsy and depression are required to better inform treatment policy in the future.
    Cochrane database of systematic reviews (Online) 12/2014; 12(12):CD010682. DOI:10.1002/14651858.CD010682.pub2 · 5.70 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Emerging evidence indicates that epileptic encephalopathies are genetically highly heterogeneous, underscoring the need for large cohorts of well-characterized individuals to further define the genetic landscape. Through a collaboration between two consortia (EuroEPINOMICS and Epi4K/EPGP), we analyzed exome-sequencing data of 356 trios with the “classical” epileptic encephalopathies, infantile spasms and Lennox Gastaut syndrome, including 264 trios previously analyzed by the Epi4K/EPGP consortium. In this expanded cohort, we find 429 de novo mutations, including de novo mutations in DNM1 in five individuals and de novo mutations in GABBR2, FASN, and RYR3 in two individuals each. Unlike previous studies, this cohort is sufficiently large to show a significant excess of de novo mutations in epileptic encephalopathy probands compared to the general population using a likelihood analysis (p = 8.2 × 10−4), supporting a prominent role for de novo mutations in epileptic encephalopathies. We bring statistical evidence that mutations in DNM1 cause epileptic encephalopathy, find suggestive evidence for a role of three additional genes, and show that at least 12% of analyzed individuals have an identifiable causal de novo mutation. Strikingly, 75% of mutations in these probands are predicted to disrupt a protein involved in regulating synaptic transmission, and there is a significant enrichment of de novo mutations in genes in this pathway in the entire cohort as well. These findings emphasize an important role for synaptic dysregulation in epileptic encephalopathies, above and beyond that caused by ion channel dysfunction.
    The American Journal of Human Genetics 09/2014; · 10.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A multigenic classifier based on five single nucleotide polymorphisms (SNPs) was previously reported to predict treatment response in an Australian newly-diagnosed epilepsy cohort using a k-Nearest Neighbour (kNN) algorithm. We assessed the validity of this classifier in predicting response to initial antiepileptic drug (AED) treatment in two UK cohorts of newly-diagnosed epilepsy and investigated the utility of these five SNPs in predicting seizure control in general. The original Australian cohort constituted the training set for the classifier and was used to predict response to the first well-tolerated AED monotherapy in independently recruited UK cohorts (Glasgow, n = 281; SANAD, n = 491). A “leave-one-out” cross-validation was also employed, with training sets derived internally from the UK datasets. The multigenic classifier using the Australian cohort as the training set was unable to predict treatment response in either UK cohort. In the “leave-one-out” analysis, the five SNPs collectively predicted treatment response in both Glasgow and SANAD patients prescribed either carbamazepine or valproate (Glasgow OR = 3.1, 95% CI = 1.4-6.6, p = 0.018; SANAD OR = 2.8, 95% CI = 1.3-6.1, p = 0.048), but not those receiving lamotrigine (Glasgow OR = 1.3, 95% CI = 0.6-2.8, p = 1.0; SANAD OR = 2.2, 95% CI = 0.9-5.4, p = 0.36) or other AEDs (Glasgow OR = 0.6, 95% CI = 0.2-2.0, p = 1.0; SANAD OR = 1.9, 95% CI = 0.9-4.2, p = 0.36). The Australian-based multigenic kNN model is not predictive of initial treatment response in UK cohorts of newly-diagnosed epilepsy. However, the five SNPs identified in the original Australian study appear to collectively have a predictive influence in UK patients prescribed either carbamazepine or valproate.
    Epilepsy Research 09/2014; 108(10). DOI:10.1016/j.eplepsyres.2014.08.022 · 2.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective To investigate the length of time taken to open UK research sites in multicentre clinical trials and to identify reasons for any delays. Design A case study, recording key milestone dates from the time a site receives ethical approval through to opening to recruitment. Delay reasons were prospectively logged by trial staff at a minimum of fortnightly periods using a coding system. Setting SANADII, a phase IV pragmatic trial, managed by the Clinical Trials Research Centre, Liverpool. The trial seeks to work with over 100 National Health Service (NHS) sites to meet its recruitment target of 1510 patients. Outcomes and analysis The primary outcome was time from Multicentre Regional Ethics Committee (MREC) approval to site opening using survival analysis. Where sites took over a specified time to reach milestones (>3 months from MREC to Site Specific Information (SSI) submission, >30 days from SSI validation to local R&D approval, or >30 days from local Research and Development (R&D) approval to opening to recruitment), the longest continuous delay during that milestone was identified. Results The median opening time for participating sites was 9.7 months (IQR 6.2 to Not Reached). SSI submission took 7 months (IQR 4.1–12.3) from ethics approval, R&D approval took 16 days (IQR 5.0–32.0) from SSI validation and site opening took 15 days (IQR 8.5–40.0) following R&D approval. The longest delays before SSI submission resulted from negotiating excess treatment costs, finalising logistics, collecting CVs and ongoing participation discussions. Conclusions While recently imposed targets are reducing the time taken for R&D departments to approve valid applications, the time taken to open UK research sites remains excessive and must be reduced. At present significant public funds are being used inefficiently in order to navigate NHS systems, challenging the resolve of trial teams and the competitiveness of the UK.
    BMJ Open 09/2014; 4(9):e005874. DOI:10.1136/bmjopen-2014-005874 · 2.06 Impact Factor
  • Source
    Tom B. Mole, Richard Appleton, Anthony Marson
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose Although sodium valproate (VPA) remains the most effective antiepileptic for generalised and unclassified epilepsies, clinicians may be failing to discuss this treatment option because of guideline misinterpretation. Current guidelines recommend caution regarding teratogenic risks but do not advocate absolute avoidance. Methods We assessed VPA prescribing in young people attending a transition epilepsy clinic. We present six patients with idiopathic generalised epilepsy (IGE) in whom VPA had been initially avoided. Results Overall, the results were consistent with VPA's superior antiepileptic efficacy and ability to reduce harmful seizure-related complications. Young people denied of VPA showed prolonged periods of poor seizure control with medical, social and psychological complications. Following contraceptive counselling and VPA introduction, all six patients showed improved seizure control including seizure-freedom during follow-up of up to twenty-four months. There was also evidence of reduced seizure-related morbidity and improved educational and occupational functioning. Prior to referral, documentation revealed no discussion of VPA treatment options. Conclusion Failure to prescribe valproate for IGE, particularly when another first-line treatment has failed, may not be in a young woman's best interests particularly when they are most vulnerable to sequelae from uncontrolled seizures. Indiscriminate avoidance of valproate needs to be recognised as a misinterpretation of current epilepsy guidelines as it may harm young people. Although the use of valproate demands careful consideration, there remains a strong case to always discuss this medication because of its efficacy and potential to reduce seizure-related harm. Patients must be allowed to make their own informed decisions about effective epilepsy treatments.
    Seizure 08/2014; 24. DOI:10.1016/j.seizure.2014.08.006 · 2.06 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Background: The epilepsies are a clinically heterogeneous group of neurological disorders. Despite strong evidence for heritability, genome-wide association studies have had little success in identification of risk loci associated with epilepsy, probably because of relatively small sample sizes and insufficient power. We aimed to identify risk loci through meta-analyses of genome-wide association studies for all epilepsy and the two largest clinical subtypes (genetic generalised epilepsy and focal epilepsy). Methods: We combined genome-wide association data from 12 cohorts of individuals with epilepsy and controls from population-based datasets. Controls were ethnically matched with cases. We phenotyped individuals with epilepsy into categories of genetic generalised epilepsy, focal epilepsy, or unclassified epilepsy. After standardised filtering for quality control and imputation to account for different genotyping platforms across sites, investigators at each site conducted a linear mixed-model association analysis for each dataset. Combining summary statistics, we conducted fixed-effects meta-analyses of all epilepsy, focal epilepsy, and genetic generalised epilepsy. We set the genome-wide significance threshold at p<1·66 × 10–8. Findings: We included 8696 cases and 26 157 controls in our analysis. Meta-analysis of the all-epilepsy cohort identified loci at 2q24.3 (p=8·71 × 10–10), implicating SCN1A, and at 4p15.1 (p=5·44 × 10–9), harbouring PCDH7, which encodes a protocadherin molecule not previously implicated in epilepsy. For the cohort of genetic generalised epilepsy, we noted a single signal at 2p16.1 (p=9·99 × 10–9), implicating VRK2 or FANCL. No single nucleotide polymorphism achieved genome-wide significance for focal epilepsy. Interpretation: This meta-analysis describes a new locus not previously implicated in epilepsy and provides further evidence about the genetic architecture of these disorders, with the ultimate aim of assisting in disease classification and prognosis. The data suggest that specific loci can act pleiotropically raising risk for epilepsy broadly, or can have effects limited to a specific epilepsy subtype. Future genetic analyses might benefit from both lumping (ie, grouping of epilepsy types together) or splitting (ie, analysis of specific clinical subtypes).
    The Lancet Neurology 07/2014; · 21.82 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Epilepsy is a disease with substantial missing heritability; despite its high genetic component, genetic association studies have had limited success detecting common variants which influence susceptibility. In this paper, we reassess the role of common variants on epilepsy using extensions of heritability analysis. Our data set consists of 1258 UK patients with epilepsy, of which 958 have focal epilepsy, and 5129 population control subjects, with genotypes recorded for over 4 million common single nucleotide polymorphisms. Firstly, we show that on the liability scale, common variants collectively explain at least 26% (standard deviation 5%) of phenotypic variation for all epilepsy and 27% (standard deviation 5%) for focal epilepsy. Secondly we provide a new method for estimating the number of causal variants for complex traits; when applied to epilepsy, our most optimistic estimate suggests that at least 400 variants influence disease susceptibility, with potentially many thousands. Thirdly, we use bivariate analysis to assess how similar the genetic architecture of focal epilepsy is to that of non-focal epilepsy; we demonstrate both significant differences (P = 0.004) and significant similarities (P = 0.01) between the two subtypes, indicating that although the clinical definition of focal epilepsy does identify a genetically distinct epilepsy subtype, there is also scope to improve the classification of epilepsy by incorporating genotypic information. Lastly, we investigate the potential value in using genetic data to diagnose epilepsy following a single epileptic seizure; we find that a prediction model explaining 10% of phenotypic variation could have clinical utility for deciding which single-seizure individuals are likely to benefit from immediate anti-epileptic drug therapy.
    Brain 07/2014; 137. DOI:10.1093/brain/awu206 · 10.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objectives: We assessed the likelihood of 12-month seizure remission and treatment failure after failure of a first antiepileptic drug, and identified factors influencing these outcomes. Methods: SANAD (Standard and New Antiepileptic Drug) was a randomized controlled trial comparing monotherapy with standard and new antiepileptic drugs. Patients were followed up to study completion, even if they were switched from their randomized treatment. After a first treatment failure, we assessed the probability of 12-month seizure remission and treatment failure. Prognostic modeling identified predictors of these outcomes. Results: Forty-four percent of patients in the SANAD trial had a first treatment failure. Seventy-five percent of these subsequently achieved 12-month remission by 6 years of follow-up. Significant prognostic factors included sex, age at treatment failure, time on randomized treatment at treatment failure, neurologic insult, total number of tonic-clonic seizures at treatment failure, reason for treatment failure, seizure type, and CT/MRI scan result. After a first treatment failure, young patients without tonic-clonic seizures, with a normal CT/MRI scan and failing their treatment because of unacceptable adverse events, had the highest likelihood of 12-month remission. Approximately 50% of patients who failed a first treatment also failed their second. Significant prognostic factors included total number of tonic-clonic seizures at first treatment failure, reason for first treatment failure, and CT/MRI scan result. Patients with tonic-clonic seizures and failing because of inadequate seizure control had the highest risk of a second treatment failure. Conclusions: A high proportion of patients will achieve 12-month remission after a first treatment failure. Clinical factors can stratify patients according to likely outcome.
    Neurology 07/2014; 83(6). DOI:10.1212/WNL.0000000000000673 · 8.30 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The study of juvenile myoclonic epilepsy is important in that: it is common and heterogeneous; the etiology is unknown; and patients report broad cognitive problems. We utilized a broad battery of neuropsychometric tests to assess the following: intellectual function, memory, language and naming, executive function, the impact of epilepsy, and antiepilepsy drug side effects. Sixty people with drug-refractory JME were interviewed, and performance was profoundly impaired across the range of tests. Impairments included the following: full-scale IQ (89, p < 0.001); processing speed (86, p < 0.001); visual memory (immediate and delayed) more affected than verbal memory; verbal fluency and inhibition (p < 0.001); and self-reported drug side effects (p < 0.001). Eighty-three percent of patients exhibited frank executive dysfunction, which was moderate to severe in 66%. Regression modeling confirmed that an early age at onset and the need for polytherapy were associated with poorer cognitive outcomes. This study confirms previous reports of executive dysfunction in a larger cohort and with greater statistical rigor. We also identified a high prevalence of neurotoxicity symptoms such as fatigue and poorer functioning across intellectual and memory tests than had previously been reported.
    Epilepsy & Behavior 07/2014; 36:124–129. DOI:10.1016/j.yebeh.2014.04.027 · 2.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Despite optimal medical treatment, including epilepsy surgery, many epilepsy patients have uncontrolled seizures. In the last decades, interest has grown in invasive intracranial neurostimulation as a treatment for these patients. Intracranial stimulation includes both deep brain stimulation (DBS) (stimulation through depth electrodes) and cortical stimulation (subdural electrodes).
    Cochrane database of systematic reviews (Online) 06/2014; 6(6):CD008497. DOI:10.1002/14651858.CD008497.pub2 · 5.70 Impact Factor

Publication Stats

2k Citations
777.67 Total Impact Points

Institutions

  • 2000–2015
    • University of Liverpool
      • • Department of Molecular and Clinical Pharmacology
      • • Department of Psychological Sciences
      Liverpool, England, United Kingdom
  • 2012
    • Paracelsus Medical University Salzburg
      Salzburg, Salzburg, Austria
  • 2010–2011
    • The Newcastle upon Tyne Hospitals NHS Foundation Trust
      Newcastle-on-Tyne, England, United Kingdom
  • 1998–2011
    • The Walton Centre NHS Foundation Trust
      Liverpool, England, United Kingdom
  • 2008
    • Imperial College London
      Londinium, England, United Kingdom
  • 2005
    • Newcastle University Medicine Malaysia
      Bharu, Johor, Malaysia