Ayush Agarwal, DM

Jones FJS, Sanches PR, Smith JR, Zafar SF, Hernandez-Diaz S, Blacker D, Hsu J, Schwamm LH, Westover MB, Moura LMVR. Anticonvulsant Primary and Secondary Prophylaxis for Acute Ischemic Stroke Patients: A Decision Analysis. Stroke. 2021.

Poststroke seizures are classified into early seizures and late seizures based on the time of occurrence with regards to the stroke. Seizures occurring within the first 7 days are classified as early seizures. Guidelines for the management of poststroke seizures are unclear due to the lack of adequate randomized clinical trials. Therefore, management mostly remains uncertain and “expert opinion” based. The newer generation of antiseizure drugs (ASD) with their comparatively better safety and adverse effect profiles tempt physicians to prescribe them as primary preventive therapy on the premise that they are relatively low-risk. Secondary prophylaxis for early seizures is also debated, with some advocating for not treating early seizure since they were likely to fall into the acute symptomatic seizure category. Late seizures are thought to arise from an anatomical substrate and are always treated with ASDs. However, the duration of treatment with ASDs for secondary prophylaxis is also contentious, with some advocating for a short treatment duration compared to lifelong therapy.

In this decision analysis study, adult patients with an index ischemic stroke were categorized into one of three treatment strategies: (a) long-term primary prophylaxis (ASDs lifelong); (b) short-term secondary prophylaxis following early seizures (for one week after the stroke event), with lifelong treatment if late seizures occurred; and (c) long-term secondary prophylaxis following early seizures (ASDs lifelong). The main outcome of the study was quality-adjusted life-years (QALY).

A model was used to make up multiple scenarios based on a combination of the cumulative risk of poststroke late seizures (low, low-intermediate and high) and adverse effects from ASDs (very low, low and high). The late seizure risk was calculated from the SeLECT score (late seizure prediction score), and the 5-year risk was considered as the lifetime cumulative risk. All of these variables eventually were given a utility variable based on which the QALY was calculated.

Results showed that secondary prophylaxis was superior to primary prophylaxis in all scenarios. The results between the two types of secondary prophylaxis (b and c mentioned previously) were nearly similar, with short duration therapy following early seizures, surprisingly, being the most promising. Proponents of the same claim potential benefits of not only preventing avoidable neuronal injury from recurrent seizures, but also long-term adverse effects of ASDs when they might not be needed. This decreases cost of therapy, side effects as well as potential drug interactions with antithrombotic drugs that the patient is on.

The study, although impactful, has some limitations. The inclusion criteria involved patients presenting with index stroke events. However, some included individuals might have had silent strokes in the past, predisposing to seizures. Radiologically proven index ischemic strokes might have prevented this. The lifetime cumulative poststroke seizure risk was considered to be the same as 5 years post stroke, which is likely to be an under-representation. ASD efficacy was based on the general ASD efficacy data since little is known about their efficacy following a seizure after an acute ischemic stroke. The long-term side effects of ASDs may also have been undermined since most of them are based on studies with a study duration <=6 months. Some studies have also raised the concern of traditional ASDs like phenytoin, phenobarbitone and benzodiazepines hampering motor recovery after stroke.  What happens to the seizure risk and how does management change if a patient develops a recurrent stroke is also not described. Finally, since this study is a decision analysis, a randomized controlled trial is needed to confirm its findings.

To conclude, the study reaffirmed that primary prophylaxis has no role for poststroke seizures, and ASDs should only be prescribed following a post-stroke seizure. Short duration therapy is preferable. A Cochrane review on poststroke seizure management echoed these sentiments against primary prophylaxis. European guidelines recommend against primary prophylaxis, whereas American guidelines state a lack of data supporting the same.

One wonders whether early poststroke seizures should be treated on the same lines as traumatic brain injury with a short duration of ASDs. A high-quality randomized controlled trial will probably give us the answer.