Melissa J. Maguire

Prevalence of visual field loss following exposure to vigabatrin therapy: A systematic review

Purpose:  Vigabatrin is an efficacious antiepileptic drug licensed as add‐on therapy in refractory epilepsy and used in infantile spasms. Eight years after licensing, there emerged a strong and possibly causative association with bilateral visual field loss. We report a systematic review ascertaining the magnitude of risk of vigabatrin associated visual field loss (VAVFL) and any clinical predictors of risk.

Music and epilepsy: A critical review

The effect of music on patients with epileptic seizures is complex and at present poorly understood. Clinical studies suggest that the processing of music within the human brain involves numerous cortical areas, extending beyond Heschl’s gyrus and working within connected networks. These networks could be recruited during a seizure manifesting as musical phenomena. Similarly, if certain areas within the network are hyperexcitable, then there is a potential that particular sounds or certain music could act as epileptogenic triggers. This occurs in the case of musicogenic epilepsy, whereby seizures are triggered by music. Although it appears that this condition is rare, the exact prevalence is unknown, as often patients do not implicate music as an epileptogenic trigger and routine electroencephalography does not use sound in seizure provocation. Music therapy for refractory epilepsy remains controversial, and further research is needed to explore the potential anticonvulsant role of music. Dopaminergic system modulation and the ambivalent action of cognitive and sensory input in ictogenesis may provide possible theories for the dichotomous proconvulsant and anticonvulsant role of music in epilepsy. The effect of antiepileptic drugs and surgery on musicality should not be underestimated. Altered pitch perception in relation to carbamazepine is rare, but health care professionals should discuss this risk or consider alternative medication particularly if the patient is a professional musician or native‐born Japanese. Studies observing the effect of epilepsy surgery on musicality suggest a risk with right temporal lobectomy, although the extent of this risk and correlation to size and area of resection need further delineation. This potential risk may bring into question whether tests on musical perception and memory should form part of the preoperative neuropsychological workup for patients embarking on surgery, particularly that of the right temporal lobe.

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.

Open label extension studies and patient selection biases.

RATIONALE Long-term observational studies are essential in assessing the effect of interventions for chronic diseases on long-term safety and tolerability, as well as informing on efficacy in a non-clinical trial setting. Concerns over the scientific validity of open label extension studies to randomized controlled trials have recently been raised. Patients experiencing adverse events will be withdrawn before the follow-on period of the study, and those experiencing milder side-effects will be less likely to opt to continue into the open label extension. METHODS The usual method of analysis of the open label extension study, which ignores any patients not continuing into the follow-on period of the study, is outlined. It is shown that ignoring patients who exit the trial is equivalent to assuming the outcome data are missing completely at random. Where this assumption is not met, treatment effect estimates will be biased. An alternative method of analysis is proposed, which does not rely on the often unjustifiable assumption of outcomes being missing completely at random. RESULTS In an example open label extension study, with reported responder rate 43%, we show how an analysis allowing for patient selection biases produces a responder rate of just 28%. CONCLUSIONS The method of analysis proposed here, minimizes the effect of patient selection biases. Future reporting ideals for open label extension studies are recommended to minimize future biases. For studies which have not reported results in detail we suggest a sensitivity based on the worst case scenario, as a minimum treatment effect estimator.

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.

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.

Efficacy of carbamazepine and valproate as monotherapy for early epilepsy and single seizures

In the Multi-Centre Study of Early Epilepsy and Single Seizures (MESS), patients were randomly allocated to immediate or delayed antiepileptic drug treatment. For time to first seizure recurrence, MESS provides strong evidence of an effect for carbamazepine as monotherapy but mixed evidence of an effect for valproate.

Music and its association with epileptic disorders

The association between music and epileptic seizures is complex and intriguing. Musical processing within the human brain recruits a network which involves many cortical areas that could activate as part of a temporal lobe seizure or become hyperexcitable on musical exposure as in the case of musicogenic epilepsy. The dichotomous effect of music on seizures may be explained by modification of dopaminergic circuitry or counteractive cognitive and sensory input in ictogenesis. Research has explored the utility of music as a therapy in epilepsy and while limited studies show some evidence of an effect on seizure activity; further work is required to ascertain its clinical potential. Sodium channel-blocking antiepileptic drugs, e.g., carbamazepine and oxcarbazepine, appear to effect pitch perception particularly in native-born Japanese, a rare but important adverse effect, particularly if a professional musician. Temporal lobe surgery for right lateralizing epilepsy has the capacity to effect all facets of musical processing, although risk and correlation to resection area need further research. There is a need for the development of investigative tools of musical processing that could be utilized along the surgical pathway. Similarly, work is also required in devising a musical paradigm as part of electroencephalography to improve surveillance of musicogenic seizures. These clinical applications could aid the management of epilepsy and preservation of musical ability.

Epilepsy and psychosis: a practical approach

The psychoses of epilepsy can be classified according to their temporal relationship with seizures, namely as ictal, postictal and interictal psychosis. Interictal psychosis is the most common and may resemble schizophrenia. They can be challenging to diagnose and to manage, especially given the perception that some antipsychotic drugs may exacerbate seizures, while some antiepileptic medications may worsen psychosis. The current uncertainty around their best management means that some patients may not receive appropriate care. We propose a practical stepwise approach to managing psychosis in patients with epilepsy, summarising the key clinical features. We provide a framework for diagnosis, investigation and management of psychosis in the acute and long term. We also summarise the available evidence on the risk of psychosis with current antiepileptic drugs and the risk of seizures with antipsychotic drugs.