Thalamohippocampal atrophy in focal epilepsy of unknown cause at the time of diagnosis.

BACKGROUND AND PURPOSE: Patients with chronic focal epilepsy may have atrophy of brain structures important for the generation and maintenance of seizures. However, little research has been conducted in patients with newly diagnosed focal epilepsy (NDfE), despite it being a crucial point in time for understanding the underlying biology of the disorder. We aimed to determine whether patients with NDfE show evidence of volumetric abnormalities of subcortical structures. METHODS: Eighty-two patients with NDfE and 40 healthy controls underwent magnetic resonance imaging scanning using a standard clinical protocol. Volume estimation of the left and right hippocampus, thalamus, caudate nucleus, putamen and cerebral hemisphere was performed for all participants and normalised to whole brain volume. Volumes lower than two standard deviations below the control mean were considered abnormal. Volumes were analysed with respect to patient clinical characteristics, including treatment outcome 12 months after diagnosis. RESULTS: Volume of the left hippocampus (p(FDR-corr)  = 0.04) and left (p(FDR-corr)  = 0.002) and right (p(FDR-corr)  = 0.04) thalamus was significantly smaller in patients relative to controls. Relative to the normal volume limits in controls, 11% patients had left hippocampal atrophy, 17% had left thalamic atrophy and 9% had right thalamic atrophy. We did not find evidence of a relationship between volumes and future seizure control or with other clinical characteristics of epilepsy. CONCLUSIONS: Volumetric abnormalities of structures known to be important for the generation and maintenance of focal seizures are established at the time of epilepsy diagnosis and are not necessarily a result of the chronicity of the disorder.

Neuroradiological findings in patients with "non-lesional" focal epilepsy revealed by research protocol.

AIM: To evaluate whether a dedicated epilepsy research protocol with expert image re-evaluation can increase identification of patients with lesions and to attempt to ascertain the potential reasons why lesions were not identified previously on earlier clinical magnetic resonance imaging (MRI). MATERIALS AND METHODS: Forty-three patients (26 female) with focal refractory epilepsy who had failed at least two trials of anti-epileptic drug treatments were studied. Patients were recruited prospectively into the study if previous clinical MRI was deemed to be "non-lesional" by the clinicians involved in the initial assessment. Three-dimensional (3D) T1-weighted (T1W), T2-weighted (T2W), T2 fluid-attenuated inversion recovery (T2-FLAIR) sequences, and two-dimensional (2D) coronal T1-/T2W FLAIR were assessed by a neuroradiologist, including the previous clinical MRI of individual patients. RESULTS: Twenty-nine or 43 (67%) patients remained MRI-negative after scanning with the epilepsy-dedicated protocol and image reappraisal by expert consultant neuroradiologists; however, 14/43 (33%) patients were found to have potentially epileptogenic brain lesions. The lesion that most frequently escaped the attention of clinicians was hippocampal sclerosis (nine cases, of which two had an additional focal cortical dysplasia, FCD), followed by single FCDs (two cases), and others including gliosis, encephalocoele, and amygdala enlargement (one case each). Eleven of the 14 (79%) previously "non-lesional" patients had electroencephalogram (EEG) imaging-concordant localisation features, rendering them potential candidates for resective surgery. CONCLUSIONS: The primary factors explaining the newly identified lesions were the choice of MRI sequences, imaging parameters, data quality, lesion not reported (human factor), and loss of information through incomplete documentation. It is important for all clinicians to proceed meticulously in the detailed assessment of epilepsy-dedicated in-vivo MRI and discuss difficult patient cases in multidisciplinary team meetings.

A disease, disorder, illness or condition: How to label epilepsy?

The International League Against Epilepsy (ILAE) is an important source of guidance for health professionals when it comes to epilepsy. Their latest recommendation that epilepsy should no longer be called a "disorder," but a "disease" has though caused controversy. The ILAE contends the change will improve epilepsy's image. Some clinicians and other organizations fear the change may not though be accepted by patients as in common parlance "disease" can be associated with "contagiousness"/"infection." To allow practicing clinicians to make informed judgements about what language they use, we completed the first study to assess the preferences of those with epilepsy and significant others and explore if any of their characteristics were associated with preference. Via epilepsy interest groups and associations in England, Wales, Scotland and the Republic of Ireland, 971 patients and significant others were surveyed. Participants identified which of four labels for epilepsy ("disorder," "illness," "disease," "condition") they favoured and rated each using a Likert-scale. Patients' median age was 39; 69% had experienced seizures in the prior year. "Condition" was favoured by most patients (74.3%) and significant others (71.2%). Only 2.2% of patients and 1.2% of significant others chose "disease"; it received a median Likert-rating indicating "strongly dislike." Multinomial logistic regression found it was not possible to reliably distinguish between participants favouring the different terms on the basis of demographics. The ILAE's position is at odds with what most patients and carers want and we discuss the implications of this.

Epilepsy and adverse quality of life in surgically resected meningioma.

OBJECTIVES: Meningiomas are common intracranial tumors, and despite surgery or therapy with anti-epileptic drugs (AEDs), many patients suffer from seizures. Epilepsy has a significant impact on quality of life (QoL) in non-tumor populations, but the impact of epilepsy on QoL in patients with meningioma is unknown. Our aim was to evaluate the impact of epilepsy on QoL in patients that have undergone resection of a benign meningioma. MATERIALS AND METHODS: We recruited meningioma patients without epilepsy (n=109), meningioma patients with epilepsy (n=56), and epilepsy patients without meningioma (n=64). QoL was measured with the Short Form 36 version 2 (SF-36), the Functional Assessment of Cancer Therapy (FACT-BR), and the Liverpool Adverse Events Profile (LAEP). Regression analyses identified significant determinants of QoL. RESULTS: Patients with meningioma and epilepsy had poorer QoL scores than meningioma patients without epilepsy in all measures. In FACT-BR, this difference was significant. Multiple regression analyses demonstrated that current AED use had a greater impact on QoL scores than recent seizures. Other variables associated with impaired QoL included depression, unemployment, and meningioma attributed symptoms. CONCLUSIONS: Epilepsy has a negative impact on quality of life in patients with benign meningioma. AED use is correlated with impaired QoL and raised LAEP scores, suggesting that AEDs and adverse effects may have led to impaired QoL in our meningioma patients with epilepsy. The severity of epilepsy in our meningioma population was comparatively mild; therefore, a more conservative approach to AED therapy may be indicated in an attempt to minimize adverse effects.

Which outcomes should we measure in adult epilepsy trials? The views of people with epilepsy and informal carers.

OBJECTIVE: So that informed treatment decisions can be made, clinical trials need to evaluate treatments against domains that are important to people with epilepsy (PWE), their carers, and clinicians. Health professionals have identified domains of importance to them via the International League Against Epilepsy's Commission on Outcome Measurement (COME). However, patients and carers have not been systematically asked. METHODS: Via the membership of the British Epilepsy Association, we recruited and surveyed 352 PWE and 263 of their informal carers. They were presented with 10 outcome domains (including the 5 identified by COME) and asked to rate their importance using a 9-point Likert scale. They were also asked to identify any additional domains of importance. RESULTS: The patients' mean age was 49years, the median number of years since diagnosis was 20, and 65% had experienced seizures in the prior 12months. Most carers were the spouse or parent. Patients' and carers' mean ratings indicated that their outcome priorities were similar, as were those of patients who had and had not experienced recent seizures. There was consensus among patients that 6 domains were of critical importance. These included the 5 identified by COME (namely, and in order of importance, the effects of the treatment on "Seizure severity", "Seizure frequency", "Quality of life", "Cognitive function", and "Adverse events"), as well as one additional domain ("Independence/need for support"). There was consensus among carers that the 5 COME domains were also critically important. They, however, identified 3 further domains as critically important. These were the effects of the treatment on patient "Depression", "Anxiety", and "Independence/need for support". CONCLUSIONS: Our study found some overlap between the priorities of PWE, carers, and health professionals. They, however, highlight additional areas of importance to patients and carers. Our results could inform a core outcome set for epilepsy that represents the domains that should be reported as a minimum by all trials. This could promote trials which produce meaningful results and consistency in measurement and reporting.

Personalized medicine approaches in epilepsy.

Epilepsy affects 50 million persons worldwide, a third of whom continue to experience debilitating seizures despite optimum anti-epileptic drug (AED) treatment. Twelve-month remission from seizures is less likely in female patients, individuals aged 11-36 years and those with neurological insults and shorter time between first seizure and starting treatment. It has been found that the presence of multiple seizures prior to diagnosis is a risk factor for pharmacoresistance and is correlated with epilepsy type as well as intrinsic severity. The key role of neuroinflammation in the pathophysiology of resistant epilepsy is becoming clear. Our work in this area suggests that high-mobility group box 1 isoforms may be candidate biomarkers for treatment stratification and novel drug targets in epilepsy. Furthermore, transporter polymorphisms contributing to the intrinsic severity of epilepsy are providing robust neurobiological evidence on an emerging theory of drug resistance, which may also provide new insights into disease stratification. Some of the rare genetic epilepsies enable treatment stratification through testing for the causal mutation, for example SCN1A mutations in patients with Dravet's syndrome. Up to 50% of patients develop adverse reactions to AEDs which in turn affects tolerability and compliance. Immune-mediated hypersensitivity reactions to AED therapy, such as toxic epidermal necrolysis, are the most serious adverse reactions and have been associated with polymorphisms in the human leucocyte antigen (HLA) complex. Pharmacogenetic screening for HLA-B*15:02 in Asian populations can prevent carbamazepine-induced Stevens-Johnson syndrome. We have identified HLA-A*31:01 as a potential risk marker for all phenotypes of carbamazepine-induced hypersensitivity with applicability in European and other populations. In this review, we explore the currently available key stratification approaches to address the therapeutic challenges in epilepsy.

A comprehensive functional and clinical analysis of ABCC2 and its impact on treatment response to carbamazepine.

At the blood-brain barrier, overexpression of the drug efflux transporter ABCC2 (also known as MRP2) has been proposed as a mechanism for impaired carbamazepine (CBZ) treatment response in epilepsy. However, investigation of the impact of ABCC2 polymorphisms on CBZ treatment efficacy has produced conflicting and inconclusive results. A series of in vitro cell efflux and plasma membrane vesicle uptake assays were undertaken to investigate whether CBZ was an ABCC2 substrate. In addition, the effect of three common ABCC2 polymorphisms, -24C>T, c.1249G>A and c.3972C>T, on the efficacy of CBZ in epilepsy (assessed using the clinical end points time to first seizure and time to 12-month remission from the SANAD (Standard and New Antiepileptic Drugs) trial) was determined. CBZ was found not to be a substrate for human ABCC2 in vitro. Clinically, no significant association was observed for the ABCC2 genetic variants and CBZ treatment outcomes. This comprehensive analysis does not support a role for ABCC2 in CBZ treatment efficacy.

Using routinely recorded data in a UK RCT: a comparison to standard prospective data collection methods.

BACKGROUND: Routinely recorded data held in electronic health records can be used to inform the conduct of randomised controlled trials (RCTs). However, limitations with access and accuracy have been identified. OBJECTIVE: Using epilepsy as an exemplar condition, we assessed the attributes and agreement of routinely recorded data compared to data collected using case report forms in a UK RCT assessing antiepileptic drug treatments for individuals newly diagnosed with epilepsy. METHODS: The case study RCT is the Standard and New Antiepileptic Drugs II (SANAD II) trial, a pragmatic, UK multicentre RCT assessing the clinical and cost-effectiveness of antiepileptic drugs as treatments for epilepsy. Ninety-eight of 470 eligible participants provided consent for access to routinely recorded secondary care data that were retrieved from NHS Digital Hospital Episode Statistics (N=71) and primary and secondary care data from The Secure Anonymised Information Linkage Databank (N=27). We assessed data items relevant to the identification of individuals eligible for inclusion in SANAD II, baseline and follow-up visits. The attributes of routinely recorded data were assessed including the degree of missing data. The agreement between routinely recorded data and data collected on case report forms in SANAD II was assessed using calculation of Cohen's kappa for categorical data and construction of Bland-Altman plots for continuous data. RESULTS: There was a significant degree of missing data in the routine record for 15 of the 20 variables assessed, including all clinical variables. Agreement was poor for the majority of comparisons, including the assessments of seizure occurrence and adverse events. For example, only 23/62 (37%) participants had a date of first-ever seizure identified in routine datasets. Agreement was satisfactory for the date of prescription of antiepileptic drugs and episodes of healthcare resource use. CONCLUSIONS: There are currently significant limitations preventing the use of routinely recorded data for participant identification and assessment of clinical outcomes in epilepsy, and potentially other chronic conditions. Further research is urgently required to assess the attributes, agreement, additional benefits, cost-effectiveness and 'optimal mix' of routinely recorded data compared to data collected using standard methods such as case report forms at clinic visits for people with epilepsy. TRIAL REGISTRATION: Standard and New Antiepileptic Drugs II (SANAD II (EudraCT No: 2012-001884-64, registered 05/09/2012; ISRCTN Number: ISRCTN30294119 , registered 03/07/2012)).

Meta-regression with partial information on summary trial or patient characteristics.

We present a model for meta-regression in the presence of missing information on some of the study level covariates, obtaining inferences using Bayesian methods. In practice, when confronted with missing covariate data in a meta-regression, it is common to carry out a complete case or available case analysis. We propose to use the full observed data, modelling the joint density as a factorization of a meta-regression model and a conditional factorization of the density for the covariates. With the inclusion of several covariates, inter-relations between these covariates are modelled. Under this joint likelihood-based approach, it is shown that the lesser assumption of the covariates being Missing At Random is imposed, instead of the more usual Missing Completely At Random (MCAR) assumption. The model is easily programmable in WinBUGS, and we examine, through the analysis of two real data sets, sensitivity and robustness of results to the MCAR assumption.

Interpreting regulatory trials in epilepsy.

PURPOSE OF REVIEW: This review discusses the interpretation of regulatory randomized controlled trials of antiepileptic drugs. An ever increasing number of drugs have been licensed, more so for add-on treatment than for monotherapy. Regulatory trials constitute the main body of evidence to inform clinical decisions about their use. Designs of regulatory trials for monotherapy are the most controversial as regulators take different views as to the type of designs that are required, which has implications for interpretation and for the risks to which patients are exposed. FINDINGS: From the perspective of the regulator, the interpretation of placebo controlled add-on trials is straightforward as they have the capacity to show efficacy compared with placebo. These designs do not, however, inform clinical decisions where a choice among drugs is required. For monotherapy the European Medicines Agency will accept head-to-head trials designed to show noninferiority for licensing. The Food and Drug Administration in the USA will not, and requires trials that show superiority. The resulting 'pseudoplacebo' trials expose patients allocated to pseudoplacebo to risks that may be unacceptable. SUMMARY: Regulatory trials continue to have major limitations for informing clinical decisions and this should be addressed.

Consensus guidelines into the management of epilepsy in adults with an intellectual disability.

BACKGROUND: Epilepsy has a pervasive impact on the lives of people with intellectual disability and their carers. The delivery of high-quality care is impacted on by the complexity and diversity of epilepsy in this population. This article presents the results of a consensus clinical guideline process. RESULTS: A Delphi process identified a list of priority areas for the development of evidence-based guidelines. All guidelines were graded and consensus on scoring was achieved across the guideline group. CONCLUSION: There is a dearth of high-quality evidence from well-constructed studies on which to base guidance. However, the development of internationally derived consensus guidelines may further support the management of epilepsy in adults with an intellectual disability.

Compression stockings to prevent post-thrombotic syndrome in adults, a Bayesian meta-analysis.

BACKGROUND: Prescription of compression stockings to prevent post-thrombotic syndrome (PTS) in adults is controversial. We sought to estimate the efficacy of compression stockings vs. placebo/no intervention (control) in preventing PTS, and to estimate the probability of observing a benefit when prescribing compression stockings to prevent PTS. METHODS: We conducted a systematic review of the literature in MEDLINE, EMBASE, and the Cochrane Central Register of Randomized Trials, searching for randomized controlled trials that compared compression stockings, applied in the acute setting of deep vein thrombosis, vs. control to prevent PTS. We used a Bayesian approach for data analysis. RESULTS: Four studies met our inclusion criteria. When comparing intervention vs. control, the estimated odds ratio (OR) was 0.57 (95% Credible Interval (CrI): 0.21 to 1.20) for PTS vs. no PTS and 0.79 (95% CrI 0.31 to 1.67) for severe vs. no/mild/moderate PTS. The probabilities of observing treatment benefits in the population if prescribing compression stockings ranged between 47% (large benefit, OR < 0.50) and 95% (small benefit, OR < 1.00) for any PTS and between 16% and 82% (from large to small benefit) for severe PTS. The probabilities of observing benefit of compression stockings in a future study ranged 44%-76% and 25%-72% (from large to small benefit) for any PTS and severe PTS, respectively. CONCLUSION: Despite heterogeneity, data show that it is still probable to observe some degree of treatment benefit when prescribing compression stockings and to observe some degree of treatment benefit in a future study.

The evaluation of vesicoureteral reflux among children using contrast-enhanced ultrasound: a literature review.

INTRODUCTION: Voiding cystourethrogram (VCUG) with fluoroscopy remains the gold standard for detection and evaluation of vesicoureteral reflux (VUR) among children. However, the ionizing radiation exposure remains a concern for this diagnostic modality. Recent studies have proposed using contrast-enhanced ultrasound as an alternative option for VUR screening and follow-up in children. The aim of the study was to review the literature of comparative studies that assessed the diagnostic accuracy of contrast-enhanced ultrasound compared with VCUG. METHODOLOGY: A systematic literature search was performed on electronic medical literature databases in July 2017. Literature identification, screening, and assessment of eligibility were performed by five reviewers with a pediatric radiologist. Literature was summarized for the study population, contrast used, and ultrasound mode as well as the timing of comparative reference study being performed. The studies were clustered according to the kind of contrast used. Reported diagnostic accuracy was extracted from individual studies and summarized across the included studies using descriptive statistics of median and interquartile range (IQR). RESULT: A total of 45 comparative studies were identified as eligible for the summary of the literature. Two generations of ultrasound contrast were identified in the available studies (first generation, Levovist and second generation, SonoVue). For the ultrasound studies using the first-generation contrast, the median sensitivity, regardless of the ultrasound mode, was 90.25 (IQR 83.25-97), and the median specificity was 93 (IQR 91.3-95.25). Among studies using the second-generation contrast, the median sensitivity was 86.26 (IQR 81.13-97), and the median specificity was 90.99 (IQR 84-98). No serious adverse events were reported in any of the studies. CONCLUSION: Overall, this review highlights the application of contrast-enhanced ultrasound for its advantage of no exposure to ionizing radiation and diagnostic accuracy relatively comparable to VCUG in the evaluation of VUR. In addition to the functional evaluation of the VUR, it also provides an anatomic evaluation of the kidneys and bladder with ultrasound imaging. However, one should also note that this alternate procedure is highly operator dependent where diagnostic accuracy is excellent when the expertise is available.

Reporting and analysis of open-label extension studies of anti-epileptic drugs.

PURPOSE: Open-label extension studies, or follow-on randomised controlled trials (FORCTs) are widely believed to be prone to patient selection biases which may inflate effect estimates. This study investigates the reporting and analysis of efficacy outcomes in FORCTs and critically evaluates the associated underlying assumptions. We propose an alternative method of analysis, in line with that recommended in the analysis of RCTs, the intention to treat (ITT) approach, in which it is assumed that all patients who discontinue treatment are non-responders. METHODS: A systematic review of FORCTs and randomised controlled trials (RCT) of topiramate, levetiracetam and gabapentin as adjuvant therapy in refractory adult epilepsy was conducted. Sample sizes and numbers of responders, along with reported outcomes were extracted. To evaluate the feasibility of the assumptions underlying the various methods of analysis, the most common causes of discontinuation were evaluated. For each FORCT, we compared the reported outcome to the proposed ITT analysis. RESULTS: The 10 FORCT reports identified all excluded from the analysis patients who dropped out of the RCT. Adverse events or inefficacy were the main reasons for treatment discontinuation. Analysis based on the ITT method, led to smaller effect estimates than those reported. For example, a FORCT of levetiracetam reported a responder rate of 43%, which reduced to 28% under an ITT analysis, comparable to an ITT analysis outcome of 26% for the parent RCT. CONCLUSIONS: FORCTs can provide important information about long-term efficacy and tolerability of newer therapies. However, current reporting methods are likely to be misleading as outcomes are reported for the subset of patients continuing with treatment at the end of the FORCT. Since the majority of patients who discontinue treatment do so for reasons associated with inefficacy, an analysis based on the ITT approach more closely reflects the outcomes of the patients.

Overwhelming heterogeneity in systematic reviews of observational anti-epileptic studies.

PURPOSE: Observational studies may provide important information on the long-term effects of treatments for epilepsy, but systematic reviews of observational studies may be more prone to heterogeneity and biases. These issues were investigated in a systematic review of non-randomised add-on anti-epileptic drug studies. METHODS: Searches of MEDLINE (1966-2006), EMBASE (1974-2006), CINAHL (1982-2006), the Cochrane database of systematic reviews, the Cochrane Controlled Trials register, the DARE database and hand-searching congress proceedings were conducted. Randomised controlled trials, follow-on randomised controlled trials and prospective and retrospective cohort studies of gabapentin, topiramate, or levetiracetam as add-on therapy in adults (>12 years old) were identified. Outcomes were 50% responders and proportion seizure free. RESULTS: Thirty-eight non-randomised gabapentin studies, 82 topiramate and 84 levetiracetam studies were identified. There was marked heterogeneity of effect estimates from observational studies which prohibited the pooling of estimates in random effects models. Median effect estimates were larger and more varied for observational studies than randomised placebo-controlled trials (RCTs). For example, the median value (10th and 90th percentile) for 50% responders for gabapentin was 36% (15 and 71%) compared to 23% (19 and 38%) for gabapentin RCTs. Patient and study covariates in meta-regression models could not explain the vast heterogeneity. Publication bias was evident and a sensitivity analysis, allowing for the effects of publication bias, showed that effect estimates could increase by up to 6% for seizure freedom rates. DISCUSSION: Reports of observational anti-epileptic studies give limited information on patient selection and characteristics. Systematic reviews of observational studies are prone to significant heterogeneity and bias which cannot adequately be explained by reported study characteristics. Reporting standards for observational studies of anti-epileptic drugs could be improved by following guidelines for reporting non-randomised studies of interventions.

Pregabalin add-on for drug-resistant partial epilepsy.

BACKGROUND: Epilepsy is a common chronic neurological disease with an estimated prevalence of 1% in the United Kingdom. Approximately a third of these people continue to have seizures despite drug treatment. In order to try to improve outcomes a number of new antiepileptic drugs have been developed and pregabalin is one of these. OBJECTIVES: To summarize evidence from randomized, controlled trials regarding the efficacy and tolerability of pregabalin when used as an add-on antiepileptic drug in treatment-resistant partial epilepsy. SEARCH STRATEGY: We searched the Cochrane Epilepsy Group Specialized Register (July 2007), The Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2007), Medline (1966 to March 2007) and contacted Pfizer Inc (the manufacturers of pregabalin) to identify published, unpublished, and ongoing trials. SELECTION CRITERIA: We included randomized controlled double-blind trials comparing pregabalin with placebo for people with drug-refractory partial epilepsy. Outcomes included 50% or greater reduction in seizure frequency, treatment withdrawal for any reason, treatment withdrawal for adverse events, and nature of adverse events. DATA COLLECTION AND ANALYSIS: Two review authors (DL and AGM) independently selected and assessed suitable trials and extracted data. Primary analyses were by intention-to-treat (ITT). Results are presented as relative risks (RR) with 95% confidence intervals (CI). MAIN RESULTS: Four suitable trials (1397 participants) were identified and included in the analysis. Trials tested doses of pregabalin ranging from 50 mg to 600 mg per day. For the primary outcome, 50% or higher seizure reduction was significantly more likely in patients randomized to pregabalin than to placebo (RR 3.56, 95% CI 2.60 to 4.87). A dose response analysis suggested increasing effect with increasing dose. Pregabalin was not significantly associated with seizure freedom (RR 2.73, 95% CI 0.72 to 10.33). Patients were significantly more likely to have pregabalin withdrawn for any reason (RR 1.43, 95% CI 1.11 to 1.85) or for adverse effects (RR 2.47, 95% CI 1.80 to 4.17). Ataxia, dizziness, somnolence and weight gain were significantly associated with pregabalin. AUTHORS' CONCLUSIONS: Pregabalin, when used as an add-on drug for treatment-resistant partial epilepsy, is significantly more effective than placebo at achieving a 50% or greater seizure reduction. Results demonstrate efficacy for doses from 150 mg to 600 mg per day, with no evidence for plateauing of effect at the doses tested. The trials included in this review were of short duration and longer term trials are needed to better inform clinical decision making.

Clobazam as an add-on in the management of refractory epilepsy.

BACKGROUND: Epilepsy effects approximately 1% of the population, with up to 30% of patients continuing to have seizures despite antiepileptic drug treatment. OBJECTIVES: To assess the efficacy and tolerability of clobazam when used as an add-on therapy for patients with refractory partial onset or generalised onset seizures. SEARCH STRATEGY: We searched the following on 22nd March 2007: (a) The Cochrane Epilepsy Group Specialised Register; (b) The Cochrane Central Register of Controlled Trials (CENTRAL); (c) MEDLINE; (d) EMBASE; (e) Database of Abstracts of Reviews of Effectiveness (DARE); (f) American College of Physicians Journals; (g) BIOSIS. SELECTION CRITERIA: Randomised trials of add-on clobazam, with adequate methods of allocation concealment, recruiting patients with drug refractory partial or generalised onset seizures, with a minimum treatment period of eight weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion and extracted relevant data. The following outcomes were assessed: 50% or greater reduction in seizures; seizure freedom; treatment withdrawal and adverse effects. MAIN RESULTS: Four cross-over studies, representing 196 participants, were included. However, due to significant methodological heterogeneity and differences in outcome measures it was not possible to summarise data in a meta-analysis. Only two of the studies reported a 50% or greater seizure reduction compared to placebo; 57.7% and 52.4%. Side effects were only described in two of the studies, reportedly present in 36% and 85% of patients. AUTHORS' CONCLUSIONS: Clobazam as an add-on treatment may reduce seizure frequency and may be most effective in partial onset seizures. However, it is not clear who will best benefit and over what time-frame. A large scale, randomised controlled trial conducted over a greater period of time, incorporating subgroups with differing seizure types, is required to inform clinical practice.

A randomised controlled trial examining the longer-term outcomes of standard versus new antiepileptic drugs. The SANAD trial.

OBJECTIVES: To compare clinicians' choice of one of the standard epilepsy drug treatments (carbamazepine or valproate) versus appropriate comparator new drugs. DESIGN: A clinical trial comprising two arms, one comparing new drugs in carbamazepine and the other with valproate. SETTING: A multicentre study recruiting patients with epilepsy from hospital outpatient clinics. PARTICIPANTS: Patients with an adequately documented history of two or more clinically definite unprovoked epileptic seizures within the last year for whom treatment with a single antiepileptic drug represented the best therapeutic option. INTERVENTIONS: Arm A was carbamazepine (CBZ) versus gabapentin (GBP) versus lamotrigine (LTG) versus oxcarbazepine (OXC) versus topiramate (TPM). Arm B valproate (VPS) versus LTG versus TPM. MAIN OUTCOME MEASURES: Time to treatment failure (withdrawal of the randomised drug for reasons of unacceptable adverse events or inadequate seizure control or a combination of the two) and time to achieve a 12-month remission of seizures. Time from randomisation to first seizure, 24-month remission of seizures, incidence of clinically important adverse events, quality of life (QoL) outcomes and health economic outcomes were also considered. RESULTS: Arm A recruited 1721 patients (88% with symptomatic or cryptogenic partial epilepsy and 10% with unclassified epilepsy). Arm B recruited 716 patients (63% with idiopathic generalised epilepsy and 25% with unclassified epilepsy). In Arm A LTG had the lowest incidence of treatment failure and was statistically superior to all drugs for this outcome with the exception of OXC. Some 12% and 8% fewer patients experienced treatment failure on LTG than CBZ, the standard drug, at 1 and 2 years after randomisation, respectively. The superiority of LTG over CBZ was due to its better tolerability but there is satisfactory evidence indicating that LTG is not clinically inferior to CBZ for measures of its efficacy. No consistent differences in QoL outcomes were found between treatment groups. Health economic analysis supported LTG being preferred to CBZ for both cost per seizure avoided and cost per quality-adjusted life-year gained. In Arm B for time to treatment failure, VPS, the standard drug, was preferred to both TPM and LTG, as it was the drug least likely to be associated with treatment failure for inadequate seizure control and was the preferred drug for time to achieving a 12-month remission. QoL assessments did not show any between-treatment differences. The health economic assessment supported the conclusion that VPS should remain the drug of first choice for idiopathic generalised or unclassified epilepsy, although there is a suggestion that TPM is a cost-effective alternative to VPS. CONCLUSIONS: The evidence suggests that LTG may be a clinical and cost-effective alternative to the existing standard drug treatment, CBZ, for patients diagnosed as having partial seizures. For patients with idiopathic generalised epilepsy or difficult to classify epilepsy, VPS remains the clinically most effective drug, although TPM may be a cost-effective alternative for some patients. Three new antiepileptic drugs have recently been licensed in the UK for the treatment of epilepsy (levetiracetam, zonisamide and pregabalin), therefore these drugs should be compared in a similarly designed trial.

Pharmacological interventions for epilepsy in people with intellectual disabilities.

BACKGROUND: The development of epilepsy in a person with intellectual disabilities is a common occurrence. In view of the fact that seizures in intellectually disabled people are often complex and refractory to treatment and that antiepileptic medication may have a profound effect upon behaviour in this patient group, it is evident that good quality randomised controlled trials are needed in this population. OBJECTIVES: The aim of our study was to assess the data available from randomised controlled trials of antiepileptic drug interventions in people with epilepsy and intellectual disabilities. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2006, Issue 4), MEDLINE OVID (1966 to October 2006), PsychInfo OVID (1806 to October 2006) and EMBASE OVID (1980 to April 2005). SELECTION CRITERIA: Randomised controlled trials (RCTs) of pharmacological interventions for people with epilepsy and a learning disability. RCTs where inadequate methods of allocation concealment had been used were also included. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Outcome measures included the following.(1) Retention on treatment.(2) Seizure freedom.(3) Reduction in seizure frequency.(4) Seizure severity scales.(5) Global rating scales.(6) Behavioural outcomes.(7) Cognitive outcomes.(8) Adverse effects.(9) Quality of life. MAIN RESULTS: Data were heterogenous and a descriptive analysis is presented. This review confirms that in the majority of cases where antiepileptic drugs (AEDs) were trialled in this population, moderate reduction in seizure frequency and occasional seizure freedom were obtained. In general it seems reasonable to say that AEDs proven effective in the general epilepsy population are also effective in refractory epilepsy in people with intellectual disability. It is not possible to comment on relative efficacy between medications making clinical choice decisions difficult. Clinical decision is also likely to be guided by concern over side effects. The quality of the studies does not aid clinicians greatly to this respect. In general it seems that in trial settings patients continue on treatment, in the majority of cases, and placebo groups often experience less in the way of side effects. Where side effects are experienced they appear similar to those seen in non-intellectual disability studies. One area of key concern is that of behavioural exacerbation. The majority of studies are unhelpful due to lack of or non-reliable measures in this area. However, where measured, little obvious impact on behaviour is seen in terms of behaviour disorder. AUTHORS' CONCLUSIONS: In summary this review broadly supports the use of AEDs to reduce seizure frequency in people with refractory epilepsy and intellectual disability. The evidence suggests that side effects are similar to those in the general population and that behavioural side effects leading to discontinuation are rare but that other effects are under researched.

Non-pharmacological interventions for epilepsy in people with intellectual disabilities.

BACKGROUND: Approximately 30% of epilepsy patients remain refractory to drug treatment and continue to experience seizures whilst taking one or more antiepileptic drugs. There are a number of non-pharmacological interventions available to refractory patients which may be used in conjunction with or as an alternative to antiepileptic medication. In view of the fact that seizures in intellectually disabled people are often complex and refractory to pharmacological interventions it is evident that good quality randomised controlled trials (RCTs) assessing the efficacy of alternatives or adjuncts to pharmacological interventions are needed in this population. OBJECTIVES: The aim of our study was to assess the data available from randomised controlled trials of non-pharmacological interventions in patients with epilepsy and intellectual disabilities. SEARCH STRATEGY: We searched The Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 4, 2006), MEDLINE OVID (1966 to October 2006) and PsychInfo OVID (1806 to October 2006). 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 inclusion criteria and extracted data. MAIN RESULTS: No RCTs were found for this study population. AUTHORS' CONCLUSIONS: This review has highlighted the need for well-designed randomised controlled trials to assess the effect of non-pharmacological interventions on seizure and behavioural outcomes in an intellectually disabled epilepsy population.