We have read with great interest the recently published guideline by Walbert et al on antiepileptic drug (AED) prophylaxis in brain tumor patients.1 We thank the authors for making the effort to update the more than 20-year-old American Academy of Neurology practice parameter, given the second- and third-generation AEDs with less pharmacokinetic interactions that have been introduced since then. While primary AED prophylaxis is still frequently administered in brain tumor patients without a history of seizures, particularly in those undergoing tumor surgery, the authors rightly address that there is still insufficient evidence to support this practice. Whereas the recommendations on the use of primary AED prophylaxis in brain tumor patients are supported by the identified studies, we have various concerns about the recommendations related to those clinical questions that go beyond the question of primary AED prophylaxis.
First, when providing an answer to clinical question 3 (ie, 3a in table 1), the authors conclude that AED treatment does not appear to increase progression-free survival or overall survival, but that the use of valproic acid is associated with adverse effects, such as thrombocytopenia and hepatotoxicity. In the context of a question related to the survival benefit of AEDs, this remark could be interpreted as a potential disadvantage of valproic acid that needs to be taken into account by the treating physician. However, other commonly prescribed second-generation AEDs such as levetiracetam may lead to other types of adverse effects including psychiatric symptoms that could be of similar or even more clinical relevance to the patient, potentially resulting in AED discontinuation. As the clinical implications of AED adverse effects on survival are far from elucidated, we would advise caution in highlighting adverse effects of a specific AED in this context.
Second, question 3a (ie, 3b in table 1) addresses the adverse effect profiles of non-enzyme-inducing AEDs compared to the older enzyme-inducing AEDs in brain tumor patients with and without a history of seizures. To substantiate that second-generation AEDs such as levetiracetam are preferred, the authors describe a selection of articles that are almost exclusively related to primary prophylactic AED use. However, quite a few comparative studies that have been published in the past two decades reporting on AED treatment failure due to adverse effects are lacking, while they are of direct relevance for the current guideline.2–6 We cannot avoid the impression that the initial search strategy was restricted to identify those studies related to primary AED prophylaxis in brain tumor patients only, leading to a selection of articles that are less representative to draw reliable conclusions about different types of AED adverse effects in brain tumor patients with active epilepsy.
Third, in the concluding paragraph, the authors state that newer generation AEDs are preferred for the treatment of epilepsy because of their favorable adverse effect profile whereas efficacy in preventing seizures seemed equivalent. A recent retrospective observational study among 1435 glioma patients with epilepsy suggested the opposite: levetiracetam had significantly better efficacy compared to valproic acid, while toxicity was similar.6 Although we agree that non-enzyme-inducing AEDs such as levetiracetam seem to be preferred in brain tumor patients, the underlying reasons may actually be different.
To summarize, we share the authors’ conclusion that AEDs should not be prescribed prophylactically to seizure-naïve brain tumor patients, but believe more precise substantiation is needed to support the recommendations related to AED treatment in patients with active epilepsy. Ongoing randomized trials, such as the Seizure Treatment IN Glioma (STING, NCT03048084) and Seizure PRophylaxis IN Glioma (SPRING) study will eventually contribute to the development of higher-level evidence for AED selection in brain tumor patients with and without epilepsy.
Conflict of interest statement. None of the authors declare a conflict of interest.
Authorship statement. All authors were involved in the writing of the letter, and have read and approved the final version.
Funding
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References
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