Reassessing the adverse event profiles of levetiracetam and brivaracetam: a systematic review and meta-analysis.

Epilepsy affects approximately 65 million individuals worldwide, making it one of the most prevalent neurological disorders []. As such, it imposes a substantial global burden, particularly in terms of years lived with disability []. While antiseizure medications (ASMs) enable seizure control in up to 70% of patients [], treatment tolerability remains a significant concern, as adverse events (AEs) can compromise adherence and quality of life [, ]. AEs not only diminish patients' psychosocial well-being but may also lead to emergency consultations or treatment discontinuation [, ], ultimately compromising long-term seizure control. Among the widely used newer ASMs, levetiracetam (LEV) and brivaracetam (BRV) exemplify the tension between efficacy and tolerability. Given that many patients require lifelong therapy, tolerability issues are of major clinical relevance. LEV, a second-generation ASM, exerts its antiepileptic effects via binding to synaptic vesicle protein 2 (SV2A). It plays a pivotal role in the treatment of epilepsy, particularly as a first-line option for focal seizures, owing to its efficacy, minimal drug interactions, and favorable pharmacokinetics [, ]. However, LEV is associated with a distinct AE profile, which may lead to decreased adherence or discontinuation []. Psychiatric and behavioral AEs, such as irritability and mood disturbances, are particularly well recognized []. A meta-analysis on the AE profile also linked neurological and systemic AEs such as somnolence, dizziness, asthenia/fatigue, and nasopharyngitis to LEV use. Notably, these events may occur independently of dose []. BRV is a propyl analog of LEV with a 15–30-fold higher binding affinity for SV2A []. Across randomized controlled trials (RCTs), BRV demonstrated efficacy comparable to LEV in focal seizures, with consistent efficacy observed in special populations such as generalized epilepsy, post-stroke epilepsy, and elderly patients []. Since its approval in 2016, BRV has been included in international guidelines and is increasingly used as a second-line strategy for mono- or add-on therapy []. Regarding AEs, a meta-analysis reported an increased risk of dizziness and fatigue, but a reduced risk of back pain compared to placebo []. Overall, its safety profile resembles that of LEV, although BRV appears to carry a lower risk of psychiatric and behavioral AEs, yet a higher risk of dizziness [, , ].