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Valproate is the most effective treatment for idiopathic generalized epilepsy. Current guidance precludes its use in females of childbearing potential, unless other treatments are ineffective or not tolerated, because of high teratogenicity. This risk was recently extended to males. New guidance will limit use both in males and females aged <55 years, resulting in withdrawal of valproate from males already taking it, as occurs for females. Whether there are risks of personal harm (including injury or death) associated with valproate withdrawal has not yet been quantified for males or females ON valproate, meaning clinicians cannot reliably counsel either sex when discussing valproate withdrawal with them, despite that this concern may be at the forefront of patients' and clinicians' minds. We assessed whether there are any morbidity or mortality risks associated with valproate withdrawal in young males and females. We performed a retrospective cohort study of internationally derived electronic health data within the TriNetX Global Collaborative Network. Included were males and females aged 16–54 years with ≥1 epilepsy disease or symptom code between 1 December 2017 and 1 December 2018, and ≥2 valproate prescriptions over the preceding 2 years (1 January 2015–30 November 2017). Five-year propensity-matched risks of mortality and a range of morbidity outcomes were compared between those remaining ON versus withdrawn from valproate during the 1 December 2017–1 December 2018 recruitment period, regardless of whether switched to another antiseizure medication. Survival analysis was undertaken using Cox-proportional hazard models, generating hazard ratios (HRs) with 95% confidence intervals (CIs). In total, 8991 males and 5243 females taking valproate were recruited. Twenty-eight per cent of males and 36% of females were subsequently withdrawn from valproate. Valproate withdrawal was associated with significantly increased risks of emergency department attendance [HRs overall: 1.236 (CI 1.159–1.319), males: 1.181 (CI 1.083–1.288), females: 1.242 (CI 1.125–1.371)], hospital admission [HRs overall: 1.160 (CI 1.081–1.246), males: 1.132 (CI 1.027–1.249), females: 1.147 (CI 1.033–1.274)], falls [HRs overall: 1.179 (CI 1.041–1.336), males: 1.298 (CI 1.090–1.546)], injuries [HRs overall: 1.095 (CI 1.021–1.174), males: 1.129 (CI 1.029–1.239)], burns [HRs overall: 1.592 (CI 1.084–2.337)] and new-onset depression [HRs overall 1.323 (CI 1.119–1.565), females: 1.359 (CI 1.074–1.720)]. The risk of these outcomes occurring was 1%–7% higher in those withdrawn from valproate than in those remaining ON valproate. Overall, valproate withdrawal was not associated with increased mortality. These results may help patients and clinicians have a more informed discussion about personal safety when considering valproate withdrawal. [ABSTRACT FROM AUTHOR]

This study aimed to develop a risk prediction model for epilepsy-related death in adults. In this age- and sex-matched case-control study, we compared adults (aged ≥16 years) who had epilepsy-related death between 2009 and 2016 to living adults with epilepsy in Scotland. Cases were identified from validated administrative national datasets linked to mortality records. ICD-10 cause-of-death coding was used to define epilepsy-related death. Controls were recruited from a research database and epilepsy clinics. Clinical data from medical records were abstracted and used to undertake univariable and multivariable conditional logistic regression to develop a risk prediction model consisting of four variables chosen a priori. A weighted sum of the factors present was taken to create a risk index—the Scottish Epilepsy Deaths Study Score. Odds ratios were estimated with 95% confidence intervals (CIs). Here, 224 deceased cases (mean age 48 years, 114 male) and 224 matched living controls were compared. In univariable analysis, predictors of epilepsy-related death were recent epilepsy-related accident and emergency attendance (odds ratio 5.1, 95% CI 3.2–8.3), living in deprived areas (odds ratio 2.5, 95% CI 1.6–4.0), developmental epilepsy (odds ratio 3.1, 95% CI 1.7–5.7), raised Charlson Comorbidity Index score (odds ratio 2.5, 95% CI 1.2–5.2), alcohol abuse (odds ratio 4.4, 95% CI 2.2–9.2), absent recent neurology review (odds ratio 3.8, 95% CI 2.4–6.1) and generalized epilepsy (odds ratio 1.9, 95% CI 1.2–3.0). Scottish Epilepsy Deaths Study Score model variables were derived from the first four listed before, with Charlson Comorbidity Index ≥2 given 1 point, living in the two most deprived areas given 2 points, having an inherited or congenital aetiology or risk factor for developing epilepsy given 2 points and recent epilepsy-related accident and emergency attendance given 3 points. Compared to having a Scottish Epilepsy Deaths Study Score of 0, those with a Scottish Epilepsy Deaths Study Score of 1 remained low risk, with odds ratio 1.6 (95% CI 0.5–4.8). Those with a Scottish Epilepsy Deaths Study Score of 2–3 had moderate risk, with odds ratio 2.8 (95% CI 1.3–6.2). Those with a Scottish Epilepsy Deaths Study Score of 4–5 and 6–8 were high risk, with odds ratio 14.4 (95% CI 5.9–35.2) and 24.0 (95% CI 8.1–71.2), respectively. The Scottish Epilepsy Deaths Study Score may be a helpful tool for identifying adults at high risk of epilepsy-related death and requires external validation. [ABSTRACT FROM AUTHOR]