Prognostic Factors for Treatment Outcomes in Focal Epilepsy: A Scoping Review to Inform the Design of a Sequential Multiple Assignment Randomised Trial (SMART)

Background and Rationale Focal epilepsy accounts for approximately 60% of all epilepsy diagnoses and is managed sequentially through anti-seizure medication (ASM) trials. Approximately 50–60% of patients with newly diagnosed epilepsy (NDE) achieve seizure freedom on their first ASM. For those who fail, clinical decision-making about the second treatment is complex and consequential — the trajectory from NDE to either seizure freedom or drug-resistant epilepsy (DRE) is largely determined within the first two treatment attempts. Prognostic factors — patient characteristics associated with treatment outcomes — are fundamental to both clinical decision-making and adaptive trial design. Within the PROGRESS framework, prognostic factor research (PROGRESS 2) provides the evidence base for stratified medicine (PROGRESS 4). In the context of designing a Sequential Multiple Assignment Randomised Trial (SMART) for focal epilepsy, prognostic factor evidence is needed to inform stratification at randomisation, definition of treatment response criteria, selection of second-stage interventions, sample size estimation, and pre-specified moderator analyses. Despite a substantial body of existing prognostic research in epilepsy, no review has synthesised this evidence with the specific aim of informing adaptive trial design. Existing reviews have not focused specifically on focal epilepsy, and none have distinguished prognostic factors assessed at the point of diagnosis from those assessed at the clinically critical but evidence-sparse timepoint of first ASM treatment failure. Aim This scoping review maps and critically synthesises available evidence on prognostic factors for treatment outcomes in focal epilepsy at two clinical timepoints — (i) newly diagnosed epilepsy at first ASM initiation, and (ii) focal epilepsy at the point of first ASM treatment failure — and translates this evidence into design considerations for a SMART for focal epilepsy. Objectives (i) To identify and summarise prognostic factors for treatment outcomes in focal epilepsy reported in existing systematic reviews and primary prognostic studies, focusing on factors identified through multivariable analysis. (ii) To assess the consistency, direction, and strength of evidence for each identified prognostic factor across sources. (iii) To distinguish between prognostic factors at the point of diagnosis (informing SMART Stage 1 — first ASM selection) and prognostic factors at the point of first treatment failure (informing the tailoring variable and SMART Stage 2 — second treatment decision). (iv) To develop a translational mapping framework linking identified prognostic factors to specific SMART trial design elements, from design through analysis to implementation. (v) To identify gaps in the current prognostic evidence base for focal epilepsy relevant to the design and conduct of a SMART. Methods This scoping review follows the Joanna Briggs Institute (JBI) methodology for scoping reviews and is reported according to the PRISMA extension for Scoping Reviews (PRISMA-ScR). Eligibility criteria are defined using the Population, Concept, and Context (PCC) framework. The population includes adults and children with focal epilepsy at two timepoints: NDE and at first ASM failure. The concept of interest is any prognostic factor (demographic, clinical, electrophysiological, neuroimaging, treatment-related, or comorbidity variable) examined in relation to treatment outcomes through multivariable analysis. Treatment outcomes include seizure freedom/remission, treatment failure, time to seizure recurrence, early treatment response, and DRE. Any clinical setting and geographic region is included, with no publication year restriction. A two-stage search strategy was employed: Stage 1 draws on eight existing systematic reviews and key primary prognostic studies known to have comprehensively searched the literature (Abimbola et al., Bonnett et al. 2012 and 2014, Janmohamed et al., Mohanraj and Brodie, Ratcliffe et al., Spain et al., Wang et al.), supplemented by additional database searches (OVID MEDLINE, Cochrane register). Stage 2 involves backward and forward citation searching of included sources. Screening, data extraction, and evidence synthesis were performed by a single reviewer. Data are synthesised narratively with structured tabulation by clinical timepoint and prognostic factor domain. No meta-analysis is performed. A translational mapping framework links identified factors to SMART design elements across the trial lifecycle. Expected Outcomes This review is expected to produce: (1) a structured evidence map of prognostic factors at NDE and at first ASM failure in focal epilepsy; (2) a domain-based synthesis identifying the most consistently supported factors and the direction of their effects; (3) a translational framework mapping prognostic evidence to SMART design parameters; and (4) a clear articulation of evidence gaps with implications for the proposed focal epilepsy SMART. Note: This registration is retrospective. The scoping review was conducted as a chapter within a PhD thesis. Protocol registration was not completed prior to data extraction.