Anti-seizure medications and efficacy against focal to bilateral tonic-clonic seizures: A systematic review with relevance for SUDEP prevention

We conducted a systematic review of anti-seizure medications (ASMs) and their efficacy for the control of focal to bilateral tonic-clonic seizures (FBTCS). FBTCS, especially when nocturnal, are recognized as one of the major risk factors for Sudden Unexpected Death in Epilepsy (SUDEP). We searched different online databases for all the randomized, double-blinded, and placebo-controlled clinical trials of ASMs that were FDA-approved after 1990 and that reported specifically on the reduction in FBTCS; when possible, this was compared to reduction in focal impaired awareness (FIA) seizures. The ASMs that yielded the most data (3 or more studies) were topiramate (TPM), followed by tiagabine (TGB), brivaracetam (BRV), and lamotrigine (LTG). TPM trials showed a reduction in FBTCS of 44.8% to 100% (4.5–99% over placebo); TGB 21.8% to 46.7% (21.8–61% over placebo); BRV 33.9% to 82.1% (11.6–57.4% over placebo); and LTG 55.2% (20.3–52% over placebo). Promising results, but with data from only one or two studies, were seen with cenobamate (18–59% efficacy above placebo), lacosamide (45.1–78.7%), levetiracetam (40.1–60.3%), oxcarbazepine (58.5–81.5%), and gabapentin (50–53.8%). Higher responses were often seen at higher doses, including at doses above those currently approved by the FDA. Results specific to nocturnal FBTCS were never reported for any ASM. Moreover, complete freedom from FBTCS specifically was very rarely reported, despite its relevance for SUDEP prevention. In conclusion, there are few data specifically comparing the efficacy of ASMs for prevention of FBTCS despite the known strong association of BTCS with SUDEP. This review was our attempt at filling a gap in the literature and calling for universal reporting of data specific to BTC seizure reduction in all future studies, preferably including specific reporting on nocturnal BTCS. This will help enable rational ASM selection to minimize BTC seizures and thereby decrease the risk of SUDEP.