Anthony G Marson

University of Liverpool, Liverpool, England, United Kingdom

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Publications (199)1246.24 Total impact

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    ABSTRACT: Cognitive dysfunction is a common comorbidity in people with epilepsy, but its causes remain unclear. It may be related to the etiology of the disorder, the consequences of seizures, or the effects of antiepileptic drug treatment. Genetics may also play a contributory role. We investigated the influence of variants in the genes encoding neuron-restrictive silencer factor (NRSF) and brain-derived neurotrophic factor (BDNF), proteins previously associated with cognition and epilepsy, on cognitive function in people with newly diagnosed epilepsy. A total of 82 patients who had previously undergone detailed neuropsychological assessment were genotyped for single nucleotide polymorphisms (SNPs) across the NRSF and BDNF genes. Putatively functional SNPs were included in a genetic association analysis with specific cognitive domains, including memory, psychomotor speed, and information processing. Cross-sectional and longitudinal designs were used to explore genetic influences on baseline cognition at diagnosis and change from baseline over the first year since diagnosis, respectively. We found a statistically significant association between genotypic variation and memory function at both baseline (NRSF: rs1105434, rs2227902 and BDNF: rs1491850, rs2030324, rs11030094) and in our longitudinal analysis (NRSF: rs2227902 and BDNF: rs12273363). Psychomotor speed was also associated with genotype (NRSF rs3796529) in the longitudinal assessment. In line with our previous work on general cognitive function in the healthy aging population, we observed an additive interaction between risk alleles for the NRSF rs2227902 (G) and BDNF rs6265 (A) polymorphisms which was again consistent with a significantly greater decline in delayed recall over the first year since diagnosis. These findings support a role for the NRSF-BDNF pathway in the modulation of cognitive function in patients with newly diagnosed epilepsy.
    Full-text · Article · Dec 2016 · Epilepsy & Behavior
  • J Singh · Melissa J Maguire · AG Marson
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    ABSTRACT: Epilepsy is defined as the occurrence of one seizure with high probability of recurrence as newly defined by the International League Against Epilepsy. Psychosis is a psychiatric illness characterized by the presence of delusions, hallucinations and thought disorder with loss of perception of reality. Epidemiological studies suggest that epilepsy is more common in those with psychosis and vice versa. The exact reason for this is unclear but may relate to similar pathophysiology, genetic predisposition or iatrogenic interplay between anti-epileptic drugs and anti-psychotic drugs used to treat the conditions. In comparison to other psychotic disorders, psychosis of epilepsy can be classified according to the temporal relationship with seizures i.e. ictal, postictal and interictal psychosis. Each sub-classification has its own clinical features, the commonest of which is interictal psychosis with a prevalence rate of between 2 and 10%, which may resemble schizophrenia in its presentation. The management of psychosis of epilepsy and conversely management of epilepsy in schizophrenia can be a challenging. There is a perceived risk of exacerbating seizures with some anti-psychotics. Similarly, some anti-epileptic drugs may cause or increase the risk of psychosis. Current uncertainty as to the best management policy means that some patients may not be receiving appropriate care. In this review we summarize the available evidence on; linked pathophysiology, clinical features and how to distinguish between primary psychotic disorders and epilepsy associated psychosis, current evidence on risk of psychosis with available AEDs and the evidence base on risk of seizures with anti-psychotic drugs.
    No preview · Article · Feb 2016 · Practical Neurology
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    Melissa Maguire · Cerian Jackson · Anthony Marson · Sarah Nolan

    Full-text · Article · Feb 2016 · Cochrane database of systematic reviews (Online)
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    ABSTRACT: Purpose: Semi-quantitative analysis of hippocampal internal architecture (HIA) on MRI has been shown to be a reliable predictor of the side of seizure onset in patients with temporal lobe epilepsy (TLE). In the present study, we investigated the relationship between postoperative seizure outcome and preoperative semi-quantitative measures of HIA. Methods: We determined HIA on high in-plane resolution preoperative T2 short tau inversion recovery MR images in 79 patients with presumed unilateral mesial TLE (mTLE) due to hippocampal sclerosis (HS) who underwent amygdalohippocampectomy and postoperative follow up. HIA was investigated with respect to postoperative seizure freedom, neuronal density determined from resected hippocampal specimens, and conventionally acquired hippocampal volume. Results: HIA ratings were significantly related to some neuropathological features of the resected hippocampus (e.g. neuronal density of selective CA regions, Wyler grades), and bilaterally with preoperative hippocampal volume. However, there were no significant differences in HIA ratings of the to-be-resected or contralateral hippocampus between patients rendered seizure free (ILAE 1) compared to those continuing to experience seizures (ILAE 2-5). Conclusions: This work indicates that semi-quantitative assessment of HIA on high-resolution MRI provides a surrogate marker of underlying histopathology, but cannot prospectively distinguish between patients who will continue to experience postoperative seizures and those who will be rendered seizure free. The predictive power of HIA for postoperative seizure outcome in non-lesional patients with TLE should be explored.
    Full-text · Article · Jan 2016 · Seizure
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    ABSTRACT: Objectives To identify emergency seizure admissions to hospital and their subsequent access to specialist outpatient services. Design Algorithmic analysis of anonymised routine hospital data over 7 years using specialist follow-up by 3 months as the target outcome. Population All adults resident in Merseyside and Cheshire, England. Main Outcomes Whether, and when, access to the specialist advice that might prevent further admissions was offered. Results 1.4% of all emergency medical admissions are as a result of seizure. In the following 12 months 35% were readmitted and experienced a mean of 2.3 emergency department visits. Only 27% (48% of those already known to specialists and 13% of those not known) were offered appointments. Subsequent attendance at a specialist clinic is more likely if already known to a clinic, if aged <35 years, if female, or required a longer spell in hospital. Extrapolation from other work suggests 100 000 bed days per annum could be saved. Conclusions Most seizure admissions are not being referred for the help that could prevent future admissions. The majority of those that are referred are not seen within an appropriate time frame. Our service structures are not providing an optimum service for people with epilepsy.
    Preview · Article · Jan 2016 · BMJ Open
  • Chapter: Valproate
    Anthony G. Marson · Graeme J. Sills
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    ABSTRACT: Valproic acid, or valproate, has been in clinical use for the treatment of epilepsy for more than 40 years. In addition to its place in the treatment of epilepsy, valproic acid has gained acceptance in the treatment of conditions that are not included in this chapter, such as affective disorders in psychiatry and the prophylaxis of migraine headaches. Valproic acid differs from all other known antiepileptic drugs (AEDs). It has shown efficacy in an impressively wide range of experimental models, including maximal electroshock-induced seizures, seizures induced chemically by pentylenetetrazole, bicuculline, glutamic acid, kainic acid, strychnine, ouabain, nicotine and intramuscular penicillin, seizures induced by kindling, and spontaneously occurring seizures in genetic models of generalized epilepsy such as the Genetic Absence Epileptic Rat of Strasbourg (GAERS) rat. It is a valuable antiepileptic drug, particularly in the management of generalized epilepsies, but should be used with caution in females of childbearing potential.
    No preview · Chapter · Nov 2015
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    ABSTRACT: Introduction It is unknown why over one-third of patients with mesial temporal lobe epilepsy (mTLE) and hippocampal sclerosis (HS) continue to experience seizures despite temporal lobe surgery. We investigated the relationship between hippocampal internal architecture (HIA) on preoperative MRI, and postoperative seizure outcome in patients with refractory mTLE and HS. Methods HIA was assessed on preoperative T2-STIR MR images using a published scoring system1 for 79 patients undergoing evaluation at University Hospital Bonn, Germany. Patients underwent amygdalohippocampectomy and received postoperative outcome assessment using the International League Against Epilepsy (ILAE) classification. Hippocampal volumes were obtained using 3D T1-weighted images. Quantitative histopathological assessment was performed on resected hippocampal specimens. Results No significant differences in ipsilateral or contralateral HIA ratings, or HIA score asymmetry, were found between patients rendered seizure free (ILAE I) compared to those continuing to experience postoperative seizures (ILAE II-VI). HIA significantly correlated with neuronal density in CA3 and CA4 in the pathologic hippocampus, and hippocampal volumes bilaterally. There was no significant correlation between HIA and clinical variables. Conclusion Although valuable in determining seizure laterality, HIA does not predict postoperative outcome. Acknowledgements This work was supported by a UK MRC grant awarded to SSK (Grant Number: MR/K023152/1). References:1Ver Hoef 2013
    Preview · Article · Nov 2015 · Journal of Neurology Neurosurgery & Psychiatry
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    ABSTRACT: Objective Topiramate (TPM) is an antiepileptic drug that is also used for other indications (e.g., migraine). Adverse event (AE) data from epilepsy trials could be supplemented by data from trials in other indications. Combining data across trials and indications is a novel method for evaluating AEs. We conducted a multiple-indications review by systematically reviewing randomized placebo-controlled trials of TPM, to compare the nervous system AEs of TPM in epilepsy with those in other indications.Methods Randomized placebo-controlled trials of TPM including patients with any indication were included. We searched Cochrane Central Register of Controlled Trials (Issue 2, 2012) and MEDLINE (1966–February 2012). Two authors assessed eligibility and risk of bias, and extracted data. For each reported nervous system AE, we extracted event rates, applied random-effects inverse-variance meta-analysis (pooling within-indications then across-indications), and assessed within- and across-indication heterogeneity.ResultsNinety trials, including 16 epilepsy trials, were included. A difference was detected between TPM and placebo for three events (i.e., drooling, dysgeusia, and hypoesthesia) that were not reported in epilepsy trials but were reported by other trials. A difference between TPM and placebo was detected for speech disorder using epilepsy trials but not when combining all trials. For two events (i.e., cognitive disorder and “language problems”), no difference was detected between TPM and placebo when using epilepsy trials alone, but a difference was identified using all trials. A difference was detected between TPM and placebo for six events (i.e., ataxia, disturbance in attention, dizziness, memory impairment, paraesthesia, and somnolence) when using epilepsy trials alone, and using all trials.SignificanceIncluding trials of any indication enabled detection of differences that would have been missed using epilepsy trials alone. Multiple-indications reviews can improve the synthesis of AEs for antiepileptic drugs.
    No preview · Article · Oct 2015 · Epilepsia
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    Cerian F Jackson · Selina M Makin · Anthony G Marson · Michael Kerr
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    ABSTRACT: Background: Approximately 30% of patients with epilepsy remain refractory to drug treatment and continue to experience seizures whilst taking one or more antiepileptic drugs (AEDs). Several non-pharmacological interventions that may be used in conjunction with or as an alternative to AEDs are available for refractory patients. In view of the fact that seizures in people with intellectual disabilities are often complex and refractory to pharmacological interventions, it is evident that good quality randomised controlled trials (RCTs) are needed to assess the efficacy of alternatives or adjuncts to pharmacological interventions.This is an updated version of the original Cochrane review (Beavis 2007) published in The Cochrane Library (2007, Issue 4). Objectives: To assess data derived from randomised controlled trials of non-pharmacological interventions for people with epilepsy and intellectual disabilities.Non-pharmacological interventions include, but are not limited to, the following.• Surgical procedures.• Specialised diets, for example, the ketogenic diet, or vitamin and folic acid supplementation.• Psychological interventions for patients or for patients and carers/parents, for example, cognitive-behavioural therapy (CBT), electroencephalographic (EEG) biofeedback and educational intervention.• Yoga.• Acupuncture.• Relaxation therapy (e.g. music therapy). Search methods: For the latest update of this review, we searched the Cochrane Epilepsy Group Specialised Register (19 August 2014), the Cochrane Central Register of Controlled Trials (CENTRAL) via CRSO (19 August 2014), MEDLINE (Ovid, 1946 to 19 August 2014) and PsycINFO (EBSCOhost, 1887 to 19 August 2014). Selection criteria: Randomised controlled trials of non-pharmacological interventions for people with epilepsy and intellectual disabilities. Data collection and analysis: Two review authors independently applied the inclusion criteria and extracted study data. Main results: One study is included in this review. When two surgical procedures were compared, results indicated that corpus callosotomy with anterior temporal lobectomy was more effective than anterior temporal lobectomy alone in improving quality of life and performance on IQ tests among people with epilepsy and intellectual disabilities. No evidence was found to support superior benefit in seizure control for either intervention. This is the only study of its kind and was rated as having an overall unclear risk of bias. The previous update (December 2010) identified one RCT in progress. The study authors have confirmed that they are aiming to publish by the end of 2015; therefore this study (Bjurulf 2008) has not been included in the current review. Authors' conclusions: This review highlights the need for well-designed randomised controlled trials conducted to assess the effects of non-pharmacological interventions on seizure and behavioural outcomes in people with intellectual disabilities and epilepsy.
    Full-text · Article · Sep 2015 · Cochrane database of systematic reviews (Online)
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    ABSTRACT: Introduction: People with chronic epilepsy (PWE) often make costly but clinically unnecessary emergency department (ED) visits. Offering them and their carers a self-management intervention that improves confidence and ability to manage seizures may lead to fewer visits. As no such intervention currently exists, we describe a project to develop and pilot one. Methods and analysis: To develop the intervention, an existing group-based seizure management course that has been offered by the Epilepsy Society within the voluntary sector to a broader audience will be adapted. Feedback from PWE, carers and representatives from the main groups caring for PWE will help refine the course so that it addresses the needs of ED attendees. Its behaviour change potential will also be optimised. A pilot randomised controlled trial will then be completed. 80 PWE aged ≥16 who have visited the ED in the prior 12 months on ≥2 occasions, along with one of their family members or friends, will be recruited from three NHS EDs. Dyads will be randomised to receive the intervention or treatment as usual alone. The proposed primary outcome is ED use in the 12 months following randomisation. For the pilot, this will be measured using routine hospital data. Secondary outcomes will be measured by patients and carers completing questionnaires 3, 6 and 12 months postrandomisation. Rates of recruitment, retention and unblinding will be calculated, along with the ED event rate in the control group and an estimate of the intervention's effect on the outcome measures. Ethics and dissemination: Ethical approval: NRES Committee North West-Liverpool East (Reference number 15/NW/0225). The project's findings will provide robust evidence on the acceptability of seizure management training and on the optimal design of a future definitive trial. The findings will be published in peer-reviewed journals and presented at conferences. Trial registration number: ISRCTN13 871 327.
    Full-text · Article · Jul 2015 · BMJ Open
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    Full-text · Article · Jul 2015 · Cochrane database of systematic reviews (Online)
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    ABSTRACT: Background: This is an updated version of the original Cochrane review published in Issue 2, 2002 and its subsequent update in 2010.Epilepsy is a common neurological condition in which recurrent, unprovoked seizures are caused by abnormal electrical discharges from the brain. It is believed that with effective drug treatment, up to 70% of individuals with active epilepsy have the potential to become seizure-free and go into long-term remission shortly after starting drug therapy with a single antiepileptic drug in monotherapy.Worldwide, carbamazepine and phenytoin are commonly used broad spectrum antiepileptic drugs, suitable for most epileptic seizure types. Carbamazepine is a current first line treatment for partial onset seizures in the USA and Europe. Phenytoin is no longer considered a first line treatment due to concerns over adverse events associated with its use, however the drug is still commonly used in low- to middle-income countries due to it's low cost. No consistent differences in efficacy have been found between carbamazepine and phenytoin in individual trials, however the confidence intervals generated by these studies are wide. Therefore, differences in efficacy may be shown by synthesising the data of the individual trials. Objectives: To review the time to withdrawal, six- and 12-month remission, and first seizure of carbamazepine compared to phenytoin when used as monotherapy in people with partial onset seizures (simple partial, complex partial, or secondarily generalised tonic-clonic seizures) or generalised tonic-clonic seizures, with or without other generalised seizure types. Search methods: We searched the Cochrane Epilepsy Group's Specialised Register (16 September 2014), the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 8), MEDLINE (1946 to 16 September 2014), SCOPUS (1823 to 16 September 2014), (16 September 2014), and the World Health Organization (WHO) International Clinical Trials Registry Platform ICTRP (18 September 2014). We handsearched relevant journals, contacted pharmaceutical companies, original trial investigators and experts in the field. Selection criteria: Randomised controlled trials (RCTs) in children or adults with partial onset seizures or generalised onset tonic-clonic seizures with a comparison of carbamazepine monotherapy versus phenytoin monotherapy. Data collection and analysis: This was an individual participant data (IPD) review. Our primary outcome was time to withdrawal of allocated treatment, and our secondary outcomes were time to 12-month remission, time to six-month remission and time to first seizure post-randomisation. We used Cox proportional hazards regression models to obtain study-specific estimates of hazard ratios (HRs) with 95% confidence intervals (CIs) and the generic inverse variance method to obtain the overall pooled HR and 95% CI. Main results: IPD were available for 595 participants out of 1192 eligible individuals, from four out of 12 trials (i.e. 50% of the potential data). For remission outcomes, HR > 1 indicates an advantage for phenytoin; and for first seizure and withdrawal outcomes, HR > 1 indicates an advantage for carbamazepine. Methodological quality of the four studies providing IPD was generally good and we rated it at low risk of bias overall in the analyses.The main overall results (pooled HR adjusted for seizure type) were time to withdrawal of allocated treatment: 1.04 (95% CI 0.78 to 1.39); time to 12-month remission: 1.01 (95% CI 0.78 to 1.31); time to six-month remission: 1.11 (95% CI 0.81 to 1.37); and time to first seizure: 0.85 (95% CI 0.70 to 1.04). The results suggest no overall statistically significant difference between the drugs for these outcomes. There is some evidence of an advantage for phenytoin for individuals with generalised onset seizures for our primary outcome (time to withdrawal of allocated treatment): pooled HR 0.42 (95% CI 0.18 to 0.96); and a statistical interaction between treatment effect and epilepsy type (partial versus generalised) for this outcome (P = 0.02), however misclassification of seizure type for up to 48 individuals (32% of those with generalised epilepsy) may have confounded the results of this review. Despite concerns over side effects leading to the withdrawal of phenytoin as first line treatment in the USA and Europe, we found no evidence that phenytoin is more likely to be associated with serious side effects than carbamazepine; 26 individuals withdrew from 290 randomised (9%) to carbamazepine due to adverse effects compared to 12 out of 299 (4%) randomised to phenytoin from four studies conducted in the USA and Europe (risk ratio (RR) 1.42, 95% CI 1.13 to 1.80, P = 0.014). We rated the quality of the evidence as low - moderate according to GRADE criteria, due to imprecision and potential misclassification of seizure type. Authors' conclusions: We have not found evidence that a statistically significant difference exists between carbamazepine and phenytoin for the efficacy outcomes examined in this review, however, CIs are wide and the possibility of important differences existing has not been excluded. There is no evidence in this review that phenytoin is more strongly associated with serious adverse events than carbamazepine. There is some evidence that participants with generalised seizures may be less likely to withdraw early from phenytoin than carbamazepine, but misclassification of seizure type may have impacted upon the results of this review. We recommend caution when interpreting the results of this review, and do not recommend that the results of this review alone should be used in choosing between carbamazepine and phenytoin. We recommend that future trials should be designed to the highest quality possible with considerations on allocation concealment and masking, choice of population, choice of outcomes and analysis, and presentation of results.
    Full-text · Article · Jul 2015 · Cochrane database of systematic reviews (Online)
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    ABSTRACT: Pharmacogenetic studies have identified the presence of the HLA-A*31:01 allele as a predictor of cutaneous adverse drugs reactions (ADRs) to carbamazepine. This study aimed to ascertain the preferences of patients and clinicians to inform carbamazepine pharmacogenetic testing services. Attributes of importance to people with epilepsy and neurologists were identified through interviews and from published sources. Discrete choice experiments (DCEs) were conducted in 82 people with epilepsy and 83 neurologists. Random-effects logit regression models were used to determine the importance of the attributes and direction of effect. In the patient DCE, all attributes (seizure remission, reduction in seizure frequency, memory problems, skin rash and rare, severe ADRs) were significant. The estimated utility of testing was greater, at 0.52 (95% CI, 0.19 to 1.00) than not testing at 0.33 (95% CI, -0.07 to 0.81). In the physician DCE, cost, inclusion in the British National Formulary, coverage, negative predictive value (NPV), and positive predictive value (PPV) were significant. Marginal rates of substitution indicated that neurologists were willing to pay £5.87 for a 1 percentage point increase in NPV and £3.99 for a 1 percentage point increase in PPV. The inclusion of both patients' and clinicians' perspectives represents an important contribution to the understanding of preferences towards pharmacogenetic testing prior to initiating carbamazepine. Both groups identified different attributes but had generally consistent preferences. Patients' acceptance of a decrease in treatment benefit for a reduced chance of severe ADRs adds support for the implementation of HLA-A*31:01 testing in routine practice. This article is protected by copyright. All rights reserved.
    No preview · Article · Jul 2015 · British Journal of Clinical Pharmacology
  • Jennifer Weston · Arif Shukralla · Andrew J McKay · Anthony G Marson
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    ABSTRACT: 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. To evaluate the efficacy and tolerability of lacosamide when used as an add-on treatment for patients with drug-resistant partial epilepsy. 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), (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. Randomised controlled trials of add-on lacosamide in people with drug-resistant partial epilepsy. 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. 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). 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.
    No preview · Article · Jun 2015 · Cochrane database of systematic reviews (Online)
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    Melissa Jane Maguire · Cerian Jackson · Anthony G Marson
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    ABSTRACT: Background Sudden Unexpected Death in Epilepsy (SUDEP) is defined as sudden, unexpected, witnessed or unwitnessed, non-traumatic or non-drowning death of patients with epilepsy, with or without evidence of a seizure, excluding documented status epilepticus and in whom postmortem examination does not reveal a structural or toxicological cause for death. SUDEP has a reported incidence of 1-2 per 1000 patient years and represents the most common epilepsy-related cause of death. The presence and frequency of generalised tonic clonic seizures (GTCS), male sex, early age of seizure onset, duration of epilepsy and polytherapy are all predictors of risk of SUDEP. Currently, the exact pathophysiology of SUDEP is unknown although GTCS-induced cardiac, respiratory and brainstem dysfunction appears likely. Appropriately chosen anti-epileptic drug treatment can render around 70% of patients free of all seizures. However, around one-third will remain drug refractory despite polytherapy. Continuing seizures place patients at risk of SUDEP, depression and reduce quality of life. Preventative strategies for SUDEP include reducing the occurrence of GTCS by timely referral for presurgical evaluation in patients with lesional epilepsy and advice on lifestyle measures; detecting cardiorespiratory distress through clinical observation and seizure, respiratory and heart rate monitoring devices; preventing airway obstruction through nocturnal supervision and safety pillows; reducing central hypoventilation through physical stimulation and enhancing serotonergic mechanisms of respiratory regulation using selective serotonin reuptake inhibitors (SSRIs); reducing adenosine and endogenous opioid-induced brain and brainstem depression. Objectives We aimed to assess the effectiveness of interventions in preventing SUDEP in people with epilepsy by synthesising evidence from randomised controlled trials of interventions and cohort and case-control non-randomised studies. Search methods We searched the following databases:Cochrane Epilepsy Group Specialized Register; Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO); MEDLINE (Ovid, 1946 onwards); SCOPUS (1823 onwards);PsycINFO (EBSCOhost, 1887 onwards); CINAHL Plus (EBSCOhost, 1937 onwards);; World Health Organisation (WHO) International Clinical Trials Registry Platform (ICTRP). There were no language restrictions. We checked the reference lists of retrieved studies for additional reports of relevant studies. We also contacted lead study authors for any relevant unpublished material. Duplicate studies were identified by screening reports according to title, authors names, location and medical institute. We omitted any duplicated studies. Regarding grey literature studies, we identified any published in the last five years by searching: ZETOC database; ISI Proceedings; International Bureau for Epilepsy (IBE) congress proceedings database; ILAE congress proceedings database; Abstract books of symposia and congresses, meeting abstracts and research reports. Selection criteria We aimed to include Randomised controlled trials (RCTs), quasi-RCTs and cluster-RCTs; Prospective non-randomised cohort controlled and uncontrolled studies and case-control studies of adults and children with epilepy recieving an intervention for the prevention of SUDEP. Types of interventions included: Early versus delayed pre-surgical evaluation for lesional epilepsy; Educational programmes; Seizure monitoring devices; Safety pillows; Nocturnal supervision; Selective Serotonin Reuptake Inhibitors (SSRIs); Opiate antagonists; Adenosine antagonists. Data collection and analysis We aimed to collect data on study design factors and patient demographics for included studies. The primary outcome of interest was the number of deaths from SUDEP. Secondary outcomes included; Number of other deaths (unrelated to SUDEP); Change in mean depression and anxiety scores (as defined within the study); Clinically important change in quality of life: Any change in quality of life score (average and endpoint) according to validated quality of life scales; Number of hospital attendances for seizures. Main results We identified 582 records from the databases and search strategies. We found 10 further records by searching other resources (handsearching). We removed 201 duplicate records and screened 381 records (title and abstract) for inclusion in the review.We excluded 365 records based on the title and abstract and assessed 16 full text articles for inclusion in the review. We excluded 14 studies from the review: seven studies did not assess interventions to prevent SUDEP; five studies measured sensitivity of devices to detect generalised tonic clonic seizures but did not directly measure SUDEP; and two studies assessed risk factors for SUDEP but not interventions for preventing SUDEP. One listed study is awaiting classification. One case-control study with moderate risk of bias was included within a qualitative analysis in this review. This study of 154 cases of SUDEP and 616 controls ascertained a protective effect for the presence of nocturnal supervision (OR; 0.4, 95%CI:0.2 to 0.8) and when a supervising person shared the same bedroom or when special precautions, for example a listening device were used (OR; 0.1, 95% CI: 0.0 to 0.3). This effect was independant of seizure control. Authors' conclusions There is low quality evidence of a significant preventative effect for nocturnal supervision against SUDEP. Further research is required to identify the effectiveness of other current interventions, for example seizure detection devices, safety pillows, SSRIs, early surgical evaluation, educational programmes and opiate and adenosine antagonists in preventing SUDEP in people with epilepsy.
    Full-text · Article · Jun 2015 · Cochrane database of systematic reviews (Online)
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    ABSTRACT: Numerous diverse biological pathways are dysregulated in the epileptic focus. Which of these pathways are most critical in producing the biological abnormalities that lead to epilepsy? Answering this question is key to identifying the primary causes of epilepsy and for discovering new therapeutic strategies with greater efficacy than currently available antiepileptics (AEDs). We have performed the largest genome-wide transcriptomic analysis to date comparing epileptic with normal human hippocampi. We have identified 118 differentially expressed and, for the first time, differentially connected pathways in the epileptic focus. Using network mapping techniques, we have shown that these dysregulated pathways, though seemingly disparate, form a coherent interconnected central network. Using closeness centrality analysis, we have identified that the most influential hub pathways in this network are signalling through G protein-coupled receptors, in particular opioid receptors, and their downstream effectors PKA/CREB and DAG/IP3. Next, we have objectively demonstrated that genetic-association of gene-sets in independent genome-wide association studies (GWAS) can be used to identify causally-relevant gene-sets: we show that proven causal epilepsy genes, which cause familial Mendelian epilepsy syndromes, are associated in published sporadic epilepsy GWAS results. Using the same technique, we have shown that central pathways identified (opioid receptor and PKA/CREB and DAG/IP3 signalling pathways) are genetically-associated with focal epilepsy and, hence, likely causal. Published functional studies in animal models provide evidence of a role for these pathways in epilepsy. Our work shows that these pathways play a central role in human focal epilepsy, and that they are important currently unexploited antiepileptic drug targets. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Full-text · Article · May 2015 · Human Molecular Genetics
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    ABSTRACT: Treatment decisions should be informed by high quality evidence of both the potential benefit and harms of treatment alternatives. Randomised controlled trials (RCTs) provide the best evidence regarding benefits; however information relating to serious, rare and long-term harms is usually available only from non-randomised studies (NRSs). The aim of this study was to use a checklist based on the CONSORT (Consolidating Standards for Reporting Trials) extension for harms recommendations to assess the quality of reporting of harms data in both NRSs and RCTs of antiepileptic drugs, using studies of topiramate as an example. Seventy-eight studies were included from an online search of seven databases. Harms data was extracted from each study using a 25-point checklist. The mean number of items met was 11.5 (SD 2.96) per study. Commercially funded studies met on average 12.7 items and non-commercially funded studies met 10.08 (p value<0.001). RCTs met on average 13.0 items and NRSs met 10.8 (p=0.001). Multi-centre studies and commercially funded studies met significantly more items than single centre and non-commercially funded studies respectively. There was no significant difference in the mean number of items met by studies that had included adult vs. child participants, or studies published pre- vs. post-CONSORT extension for harms in 2004. Reporting of harms is significantly better in RCTs than in NRSs of TPM, but is suboptimal overall and has not improved since the publication of CONSORT extension for harms in 2004. There is a need to improve the reporting of harms in order to better inform treatment decisions. Copyright © 2015 Elsevier B.V. All rights reserved.
    No preview · Article · May 2015 · Epilepsy Research
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    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.
    Full-text · Article · Apr 2015 · Epilepsia
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    ABSTRACT: BACKGROUND: Vagus nerve stimulation (VNS) is a neuromodulatory treatment that is used as an adjunctive therapy for treating people with medically refractory epilepsy. VNS consists of chronic intermittent electrical stimulation of the vagus nerve, delivered by a programmable pulse generator. The majority of people given a diagnosis of epilepsy have a good prognosis, and their seizures will be controlled by treatment with a single antiepileptic drug (AED), but up to 20%-30% of patients will develop drug-resistant epilepsy, often requiring treatment with combinations of AEDs. The aim of this systematic review was to overview the current evidence for the efficacy and tolerability of vagus nerve stimulation when used as an adjunctive treatment for people with drug-resistant partial epilepsy. This is an updated version of a Cochrane review published in Issue 7, 2010.
    No preview · Article · Apr 2015 · Cochrane database of systematic reviews (Online)
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    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.
    Full-text · Article · Mar 2015 · Epilepsy & Behavior

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  • 1996-2016
    • University of Liverpool
      • • Department of Molecular and Clinical Pharmacology
      • • Department of Psychological Sciences
      • • Department of Mathematical Sciences
      Liverpool, England, United Kingdom
  • 1998-2013
    • The Walton Centre NHS Foundation Trust
      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
    • Aintree University Hospital NHS Foundation Trust
      Liverpool, England, United Kingdom
  • 2009
    • The University of Warwick
      Coventry, England, United Kingdom
  • 2008
    • King's College London
      Londinium, England, United Kingdom
    • The University of Calgary
      • Department of Clinical Neurosciences
      Calgary, Alberta, Canada
  • 2007
    • Cardiff University
      Cardiff, Wales, United Kingdom
  • 2002
    • The Ottawa Hospital
      Ottawa, Ontario, Canada
  • 2001
    • Apollo Hospitals
      Chennai, Tamil Nadu, India
    • Mahidol University
      Krung Thep, Bangkok, Thailand