SUDEP and mortality in developmental and epileptic encephalopathies: A meta-analysis of randomized clinical trials...

Developmental and epileptic encephalopathies (DEEs) are associated with high premature mortality and increased risk of sudden unexpected death in epilepsy (SUDEP). However, epidemiological data remain limited, particularly for specific syndromes such as Dravet syndrome (DS), Lennox-Gastaut syndrome (LGS), and infantile epileptic spasms syndrome (IESS). To address this gap, we conducted a Bayesian meta-analysis of randomized controlled trials (RCTs) and corresponding long-term open-label extension (OLE) studies.

All-cause mortality and SUDEP incidence rates were estimated using hierarchical Bayesian models with moderately informative priors derived from the literature. A negative binomial likelihood was used for all-cause mortality, whereas a Poisson likelihood was used for SUDEP. Subgroup analysis were conducted for DS, LGS, and IESS.

Thirty-seven RCTs and 15 OLE studies were included, comprising 3757 patients with DEEs (2221 LGS, 998 DS, 369 IESS, and 169 other DEEs). Across pooled data, 37 deaths occurred, including 2 definite, 12 probable, and 1 possible SUDEP. In the overall DEE population, the Bayesian posterior median estimated mortality rate was 8.76 per 1000 person-years (PY; 95% credible interval [CrI], 5.50-13.89), and SUDEP rate was 4.32 per 1000 PY (95% CrI, 2.66-6.64). In LGS, mortality was 7.05 per 1000 PY and SUDEP was 3.4 per 1000 PY. In DS, mortality was 8.0 per 1000 PY, with a SUDEP rate of 7.59 per 1000 PY. In IESS, mortality was 9.41 per 1000 PY and SUDEP was 2.79 per 1000 PY.

SUDEP accounted for approximately half of deaths in the overall DEE population and in LGS, with a proportionally greater contribution in DS. Potential trial-related underestimation should be considered when interpreting these findings, as features of trial-based datasets could have contributed to lower observed mortality and SUDEP estimates. Prospective population-based studies are needed to more accurately define the real-world incidence of SUDEP in DEEs.