Long-term prognosis of juvenile myoclonic epilepsy: A systematic review searching for sex differences

Purpose: Juvenile myoclonic epilepsy (JME), like other forms of idiopathic generalized epilepsy, shows a marked female predominance. However, few studies have specifically addressed the role of sex in its long-term prognosis. We performed a systematic review of the literature relevant to JME prognosis, focusing on sex-based differences in prognostic factors and outcome. Methods: A comprehensive literature search of the PubMed and Scopus databases was performed, considering all articles up to April 2020 in which long-term prognosis in JME had been explored and sex differences in outcome or prognostic factors were specified. Results: We included 25 articles published between 1984 and 2020. Sex differences in epilepsy outcome were explored by 21 of the 25 studies, but only three reported different outcomes in male vs female patients. All three found female sex to be associated with a later response to antiseizure medications, worse seizure control, and a higher risk of relapse in their entire study samples, which included JME patients. Eight studies found sex-based differences in possible predictors of long-term outcome: prolonged epileptiform EEG runs and the presence of eye closure sensitivity, both more frequent in women, were factors possibly linked to a poorer prognosis, as were praxis induction and generalized EEG asymmetric changes, which instead were more common in men. Valproate use, more frequent in men, was associated with a better outcome. Conclusion: Most studies do not highlight sex differences in JME prognosis. However, some sex specificities do emerge, especially with regard to particular reflex traits and EEG abnormalities. Finally, sex may condition therapeutic choices, and thus have a possible impact on long-term outcome

Alternatives to valproate in girls and women of childbearing potential with Idiopathic Generalized Epilepsies: state of the art and guidance for the clinician proposed by the Epilepsy and Gender Commission of the Italian League Against Epilepsy (LICE)

Following recent European Medication Agency restrictions on valproate (VPA) use in girls and women of childbearing potential (WOCP), the Commission on Epilepsy and Gender of the Italian League against Epilepsy integrated current literature and legislative data in order to provide clinicians with guidance on antiseizure medication (ASM) prescription for Idiopathic Generalized Epilepsies (IGEs) in this population, avoiding VPA. We reviewed the updated literature on ASMs and examined the teratogenicity of those showing efficacy in IGEs. For all relevant ASMs, we considered the indications for use and the pregnancy and contraception-related recommendations given in the Italian Summary of Product Characteristics (SmPC) and on the websites of the European Medicines Agency (EMA) and other European Union (EU) countries’ regulatory agencies. With the exception of absence seizures, the literature lacks high quality studies on ASMs in IGEs. In girls and WOCP, levetiracetam and lamotrigine should be considered the first-choice drugs in Generalized Tonic-Clonic Seizures Alone and in Juvenile Myoclonic Epilepsy, lamotrigine in Juvenile Absence Epilepsy, and ethosuximide in Childhood Absence Epilepsy. Although supported by the literature, several ASMs are off label, contraindicated or burdened by special warnings in pregnancy. Some discrepancies emerged between the various SmPC warnings for different brands of the same active principle. We provided a therapeutic algorithm for each IGE syndrome and highlighted the need for revised prescription rules, consistent with the latest literature data, uniformity of SmPC warnings for the same active principle, and more data on the efficacy of new ASMs in IGEs and their safety in pregnancy

Genome-wide meta-analysis of over 29,000 people with epilepsy reveals 26 loci and subtype-specific genetic architecture

AbstractEpilepsy is a highly heritable disorder affecting over 50 million people worldwide, of which about one-third are resistant to current treatments. Here, we report a trans-ethnic GWAS including 29,944 cases, stratified into three broad- and seven sub-types of epilepsy, and 52,538 controls. We identify 26 genome-wide significant loci, 19 of which are specific to genetic generalized epilepsy (GGE). We implicate 29 likely causal genes underlying these 26 loci. SNP-based heritability analyses show that common variants substantially close the missing heritability gap for GGE. Subtype analysis revealed markedly different genetic architectures between focal and generalized epilepsies. Gene-set analysis of GGE signals implicate synaptic processes in both excitatory and inhibitory neurons in the brain. Prioritized candidate genes overlap with monogenic epilepsy genes and with targets of current anti-seizure medications. Finally, we leverage our results to identify alternate drugs with predicted efficacy if repurposed for epilepsy treatment