Tony Marson

HLA-A*3101 and Carbamazepine-Induced Hypersensitivity Reactions in Europeans

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

Clinical Administration of New Antiepileptic Drugs: An Overview of Safety and Efficacy

Summary: Gabapentin, lamotrigine, tiagabine, topira‐mate, vigabatrin, and zonisamide are all administered as add‐on therapy for treatment of patients with refractory epilepsy. To date, no comparative randomized trials have been performed that could potentially allow an evidence‐based choice to be made between these antiepileptic drugs (AEDs). We report a series of meta‐analyses of placebo‐controlled, randomized add‐on trials in patients with partial epilepsy. Results of these meta‐analyses are compared, thus giving broad estimates of the comparative efficacy and tolerability of these AEDs. The efficacy out come is the odds ratio for the number of patients with a ≥50% reduction in seizure frequency. Reported side ef fects are also used as tolerability outcomes, and study withdrawal is used as a global outcome measure. Results are summarized as odds ratios with 95% confidence in tervals (CIs). When each outcome is compared among drugs, the 95% CIS overlap. Therefore, no conclusive ev idence of a difference in efficacy or tolerability between these AEDs was derived, even though the apparently most effective agent (topiramate) may be twice as effec tive as the apparently least effective agent (lamotrigine). Comparative randomized studies are needed to further evaluate these drugs.

The development of a QALY measure for epilepsy: NEWQOL-6D

Cost-utility analysis is used to inform the allocation of healthcare resources, using the quality-adjusted life year (QALY) as the outcome measure. We report the development of an epilepsy-specific QALY measure (NEWQOL-6D) derived from the NEWQOL measure of health-related quality of life. Firstly, psychometric and Rasch analyses established the dimension structure of NEWQOL and generated a reduced health state classification system including one item per dimension. Secondly, health states generated by the classification system were valued using Time Trade Off, and the results were modeled to generate a utility score for every health state. A classification system with 6 dimensions (worry about attacks; depression; memory; concentration; stigma; control) was produced, and generalized least squares regression was used to generate utility scores for every health state. This study is the first attempt to derive an epilepsy-specific QALY measure, and the utility values can be used in the economic evaluation of emerging technologies for epilepsy.

Choosing a First Drug Treatment for Epilepsy after SANAD: Randomized Controlled Trials, Systematic Reviews, Guidelines and Treating Patients.

Summary:  The ILAE treatment guidelines for initial monotherapy emphasise the poor quality of information available to inform everyday clinical practice. Industry sponsored studies comparing antiepileptic drugs answer restricted licensing questions, rather than those relevant to the clinical community (patients, health professionals and funders of health care). The SANAD study, a pragmatic randomized clinical trial, offers a methodology to address some of these questions. It identifies lamotrigine as a cost‐effective alternative to carbamazepine for the treatment of focal epilepsies, but confirms valproate as the most effective drug for the treatment of generalized or unclassified epilepsy.

Valuations of epilepsy-specific health states: a comparison of patients with epilepsy and the general population

AIMS Utility values that can be used in the economic evaluation of treatments for epilepsy can be elicited from the general population and the patient population, but it is unclear how the health state values differ. The aim of this study is to compare the preferences of the general population and a sample of people with epilepsy for health states described by the NEWQOL-6D QALY measure. METHODS The Time Trade Off preference elicitation technique was used to value eight NEWQOL-6D health states. The general population sample was recruited and interviewed in their homes, and the sample with epilepsy was recruited and interviewed in an epilepsy service in North West England. Descriptive analysis and regression modeling were used to compare health state values across the populations. RESULTS A sample of 70 people with epilepsy and a sample of 60 members of the general population were included. The populations differed across a range of background characteristics, but there were limited differences between the health state values. Patients provided significantly higher (better) values for the most severe health state described by the NEWQOL-6D (p<0.01) and nonsignificant higher values for states with intermediate severity. The general population health state value was only higher for the best health state described by the NEWQOL-6D. CONCLUSIONS The similarities in the patient and general population values for NEWQOL-6D health states suggest that the use of the general population utility weights for the estimation of QALYs in the economic evaluation of epilepsy interventions is appropriate and largely representative of patient preferences.

UK epilepsy audit shows major deficiencies in care: who should respond and how?

There have been very few national audits of the care provided to patients with epilepsy. The confidential enquiry into maternal deaths in epilepsy and the Clinical Standards Advisory Group report identified deficiencies in the care of people with epilepsy in the UK. However, the Department of Healths response was lukewarm and additional investment earmarked for services was not forthcoming. Neither epilepsy nor neurological conditions moved up the list of priorities for commissioning. Similarly, the National Services Framework for longer term conditions did not come with ring-fenced resources. So, will the National Audit of Seizure Management in Hospitals (NASH)1 receive a similar response? This is possible, but we should take encouragement from the success of other national audits, such as those for stroke or chronic obstructive pulmonary disease, since they played a major role in driving up standards and moving these conditions up the commissioning agenda. Seizures account for 2–3% of emergency …

Comparing Drug Treatments in Epilepsy

The great majority of randomised controlled trials (RCTs) that compare antiepileptic drugs are industry sponsored and have the objective of obtaining a monotherapy license for a drug. Such trials do not inform everyday clinical practice as they tend to be too short and to depart from clinical practice by restricting clinicians in their choice of actions. The data that exists provides evidence that drugs with actions on voltage-gated sodium channels provide best seizure control for localised onset seizures and epilepsy syndromes, while valproate provides best seizure control for generalised epilepsy and unclassified syndromes. Drugs do, however, vary in their tolerability over the short term and in their risk for rare serious idiosyncratic adverse events, chronic toxicity and teratogenicity; issues that cannot be examined within the scope of RCTs.

Measuring patient experience: a systematic review to evaluate psychometric properties of patient reported experience measures (PREMs) for emergency care service provision

Abstract Purpose Knowledge about patient experience within emergency departments (EDs) allows services to develop and improve in line with patient needs. There is no standardized instrument to measure patient experience. The aim of this study is to identify patient reported experience measures (PREMs) for EDs, examine the rigour by which they were developed and their psychometric properties when judged against standard criteria. Data sources Medline, Scopus, CINAHL, PsycINFO, PubMed and Web of Science were searched from inception to May 2015. Study selection Studies were identified using specific search terms and inclusion criteria. A total of eight articles, reporting on four PREMs, were included. Data extraction Data on the development and performance of the four PREMs were extracted from the articles. The measures were critiqued according to quality criteria previously described by Pesudovs K, Burr JM, Harley C, et al. (The development, assessment, and selection of questionnaires. Optom Vis Sci 2007;84:663–74.). Results There was significant variation in the quality of development and reporting of psychometric properties. For all four PREMs, initial development work included the ascertainment of patient experiences using qualitative interviews. However, instrument performance was poorly assessed. Validity and reliability were measured in some studies; however responsiveness, an important aspect on survey development, was not measured in any of the included studies. Conclusion PREMS currently available for use in the ED have uncertain validity, reliability and responsiveness. Further validation work is required to assess their acceptability to patients and their usefulness in clinical practice.

New advice on switching antiepileptic drugs might be a false economy

Advice from the Medicines and Healthcare Products Regulatory Agency (MRHA) on switching between different manufacturers’ products for a particular antiepileptic drug may have unintended consequences.1 2 In a move to allay concerns about the potential loss of seizure control when switching products, the MHRA’s classification of these drugs according to their pharmacokinetic and pharmacodynamics properties may encourage switching—for cost …

Simulation study - handling missing covariates in the context of external validation

Objectives Before a predictive or prognostic model, often developed using data from clinical trials, can be introduced into general practice, it needs to be externally validated to ensure that it performs satisfactorily in data sets that are fully independent of the development data. Various methods exist to handle covariates with missing data and many of these are regularly employed in the analysis of data from a single trial. We propose that several of these strategies may be adapted to handle covariates with every entry missing in the context of external validation.