Can the predictive value of epileptiform electroencephalography abnormalities be assessed by a meta‐analysis?

In this issue of the journal Bouma et al. [1] report a meta-analysis on the diagnostic value of routine electroencephalography (EEG) to predict seizure recurrence after a first unprovoked seizure. The authors performed a systematic review of prospective or retrospective cohort studies of subjects with a first unprovoked seizure and followed for a seizure recurrence. Using likelihood ratios, they predict that an adult with an epileptiform abnormality has a 77% probability of a seizure recurrence and a child with an epileptiform abnormality has a 66% chance of recurrence. The paper presents a methodologically rigorous meta-analysis, following the Cochrane guidelines for systematic review of diagnostic studies. A modified QUADA-2 tool was used to assess risk of bias and applicability in each included study [2]. The goal of this meta-analysis was to assess the sensitivity and specificity of epileptiform EEGs for predicting seizure recurrence. This approach is best applied to closed populations, not to dynamic prospective populations. Most studies cited are prospective and used Kaplan Meier analysis to estimate seizure recurrence and, if multivariable analysis was performed, Cox regression was used. In the metaanalysis, only total sample size and number of recurrences could be used. This leads to an underestimate of recurrence and loses temporal characteristics of the influence of epileptiform activity on recurrence. Considerable heterogeneity in the study populations complicates the analysis. Some studies included primarily adults, some only children, and some a combination of the two. The analyses provided results for adults and for children separately but it is not clear how studies including both age groups were handled. Some included studies analyzed only genetic cases, others all cases of unknown cause, and other studies all cases, including those with an antecedent insult (e.g. stroke or traumatic brain injury). In the metaanalysis, for some studies, but not all, an attempt to restrict to cases of unknown cause was undertaken, explaining discrepancies in numbers of cases cited in the original papers compared to numbers provided by the authors. There is substantial collinearity between etiology and EEG on seizure recurrence risk, justifying an attempt to exclude symptomatic cases. It is not clear whether this can be done without primary data. In the majority of studies, the primary aim was not to assess the usefulness of EEG alone but to determine recurrence risk for seizures after a first unprovoked seizure and to identify an array of potential factors associated with recurrence. Therefore there is limited information in most studies on how EEGs were performed and inconsistent reporting of the nature of the abnormalities. In only one study was the primary focus on EEG characteristics. This study provides detailed information on methods (i.e. duration of recording, time of EEG after seizure occurrence, use of activation techniques) and on the definition used for abnormal or epileptiform results [3]. In the study by Cleland et al. [4] for example ‘abnormal EEG’ included non-specific abnormalities, focal and generalized slowing as well as epileptiform activity. The authors could not investigate the effect of other covariates that could affect EEG findings, such as anti-epileptic drug (AED) treatment. Excluded from the meta-analysis was a study that segregated people on and off AED treatment [5]. None of the other studies took AED treatment into account in terms of the predictive value of epileptiform abnormalities on seizure recurrence. The time between the first seizure and the EEG was not reported in several studies and, when specified, timing ranged from <48 h to several months. Epileptiform abnormalities are more likely to be identified when the EEG is performed in close proximity to the seizure. The lack of EEG as a primary outcome also leads to a reporting bias. In the study by Hauser et al. [6], arrays of epileptiform and non-epileptiform abnormalities were separately considered. Only individuals with a generalized spike and wave pattern had a significantly increased risk for seizure recurrence and this was the only pattern reported in the paper. Focal epileptiform discharges did not increase recurrence risk, but in the meta-analysis these cases were grouped with those with a normal EEG thus overestimating risk associated with an epileptiform EEG. In another