Real-world effectiveness and tolerability of highly purified cannabidiol in patients with monogenic developmental and epileptic encephalopathies with highly active epilepsy

Abstract

Developmental and epileptic encephalopathies (DEEs) represent a group of disorders characterized by developmental slowing or regression together with seizures, that are often drug-resistant.1 . The cumulative incidence of DEEs has been recently estimated at approximately 169 per 100,000 children, with infantile epileptic spasms syndrome, epilepsy with myoclonic–atonic seizures, Lennox–Gastaut syndrome (LGS), and Dravet syndrome (DS) among the most common syndromes.2 Given the substantial burden of disability associated with these syndromes, efforts by the scientific community and pharmaceutical companies in recent years have focused on developing new antiseizure medications (ASMs) for these patients. With this objective, the European Medicines Agency (EMA) and the U.S. Food and Drug Administration (FDA) recently approved highly purified cannabidiol (CBD) for DS, LGS, and tuberous sclerosis complex (TSC)-related epilepsy. Following the randomized controlled trials that led to CBD approval,3–5 numerous real-world studies have increasingly suggested effectiveness in other DEEs, particularly those of genetic origin.6–8 However, most data combine patients with a wide range of seizure frequencies, and it is unclear whether individuals with very high seizure burden benefit to a similar extent as those with less active epilepsy. In patients with DEEs, seizures are typically pleomorphic and occur at high frequency, with many individuals continuing to experience daily seizures even in the long term.9 Persistent frequent seizures remain a major challenge in the management of DEEs and, depending on the developmental stage and underlying aetiology, can be associated with disruption of developmental trajectories, stagnation or loss of previously acquired skills. These effects extend to caregivers, contributing to substantial psychological distress.10,11 High seizure burden further contributes to morbidity and mortality, including a heightened risk of sudden unexpected death in epilepsy (SUDEP).12,13 Previous studies have identified a threshold of ≥ 20 seizures per month as a marker of poorer prognosis and less favorable treatment outcome.14,15. These considerations underscore the need for therapies that can substantially reduce seizure burden in this population, particularly in patients with highly active epilepsy. With this background, we investigated the effectiveness and tolerability of highly purified CBD in a cohort of monogenic DEEs, focusing on patients with highly active epilepsy.