Terence J. O'brien

Description:Background: Selection of antiseizure medications (ASMs) for newly diagnosed epilepsy remains largely a trial-and-error process. We have developed a machine learning (ML) model using retrospective data collected from five international cohorts that predicts response to different ASMs as the initial treatment for individual adults with new-onset epilepsy. This study aims to prospectively evaluate this model in Australia using a randomised controlled trial design. Methods: At least 234 adult patients with newly diagnosed epilepsy will be recruited from 14 centres in Australia. Patients will be randomised 1:1 to the ML group or usual care group. The ML group will receive the ASM recommended by the model unless it is considered contraindicated by the neurologist. The usual care group will receive the ASM selected by the neurologist alone. Both the patient and neurologists conducting the follow-up will be blinded to the group assignment. Both groups will be followed up for 52 weeks to assess treatment outcomes. Additional information on adverse events, quality of life, mood and use of healthcare services and productivity will be collected using validated questionnaires. Acceptability of the model will also be assessed.The primary outcome will be the proportion of participants who achieve seizure-freedom (defined as no seizures during the 12-month follow-up period) while taking the initially prescribed ASM. Secondary outcomes include time to treatment failure, time to first seizure after randomisation, changes in mood assessment score and quality of life score, direct healthcare costs, and loss of productivity during the treatment period.This trial will provide class I evidence for the effectiveness of a ML model as a decision support tool for neurologists to select the first ASM for adults with newly diagnosed epilepsy. Background: This study is approved by the Alfred Health Human Research Ethics Committee (Project 130/23). Findings will be presented in academic conferences and submitted to peer-reviewed journals for publication. Background: ACTRN12623000209695.

Description:Objective: There is a clear need in epilepsy clinical trials and practice for a measure that captures the trade-off between seizure and treatment-related adverse effects, which is reliable over time and across different treatment regimens. We aimed to create and validate the Seizure-Related Impact Assessment Scale (SERIAS) to fill this need. Methods: This was a prospective longitudinal study of adults with epilepsy recruited from an Australian comprehensive epilepsy center. Participants completed SERIAS at baseline and 3 and 6 months later. SERIAS has 6 self-report items. Five items record the number of days per month that seizures or treatment-related adverse effects partially or fully affect work/home/school and family/social/nonwork activities. The final item is an epilepsy disability visual analog scale. SERIAS is scored by adding the days per month of disability, with scores ranging from 0 to 150 (higher scores indicate more disability). SERIAS was completed alongside 7 validated instruments measuring seizure-related and treatment-related adverse effects (Work and Social Adjustment Scale [WSAS], Liverpool Adverse Events Profile [LAEP]), mood disorders (Neurological Disorders Depression Inventory for Epilepsy [NDDI-E], Generalized Anxiety Disorder [GAD-7]), somatic symptoms (Somatic Symptom Scale [SSS-8]), and quality of life (Quality of Life in Epilepsy Inventory [QOLIE]-31, EuroQol 5 Dimensions [EQ-5D]). General linear mixed models were used to investigate the relationship between the SERIAS and other relevant clinical and psychometric data. Standardized model coefficients β are presented with 95% confidence intervals. Results: A total of 90 patients (64.4% female, mean age 43.1 years) completed baseline SERIAS. Most patients reported at least 1 day of disability (62%, median SERIAS score = 3, interquartile range = 18.3). Greater disability was negatively correlated with QOLIE-31 total score (β = -0.17, 95% CI -0.27 to -0.07) and positively correlated with scores on 5-level EQ-5D (β = 0.15, 95% CI 0.04-0.25), NDDI-E (β = 0.22, 95% CI 0.13-0.31), GAD-7 (β = 0.21, 95% CI 0.09-0.32), SSS8 (β = 0.29, 95% CI 0.17-0.41), LAEP (β = 0.29, 95% CI 0.20-0.39), WSAS seizure-related adverse events (β = 0.23, 95% CI 0.14-0.33), and WSAS treatment-related adverse events (β = 0.36, 95% CI 0.26-0.46). Higher seizure frequency was associated with higher SERIAS score (β = 0.07, 95% CI 0.03-0.11). Psychometric reliability for the SERIAS was acceptable (all coefficients >0.70) as was test-retest reliability (n = 35 patients, intraclass correlation coefficient = 0.72, 95% CI 0.51-0.85). Conclusions: SERIAS shows good psychometric reliability and strong test-retest stability. These findings suggest that SERIAS is a valid scale to measure epilepsy-related disability.

Description:Objective: Few studies have evaluated acute immunotherapy and relapse prevention strategies in patients with anti-leucine-rich glioma-inactivated 1 (LGI1) antibody (Ab)-mediated encephalitis. The objective of this study was to analyze the outcomes of acute and long-term immunotherapy strategies in this population. Methods: We undertook a multicenter cohort study of 55 patients with anti-LGI1 Ab-mediated encephalitis, either recruited prospectively or identified retrospectively from 10 Australian hospitals as part of the Australian Autoimmune Encephalitis Consortium. Clinical data were collected, including treatment durations of all relevant immunotherapies. Clinical outcomes that we examined included (1) time to first clinical relapse, (2) improvement on modified Rankin Scale (mRS), and (3) favorable binary composite clinical-functional outcome at 12 months. A favorable outcome was defined as fulfilling all three of mRS less than 3, a score of 1 or less in the memory dysfunction component of the Clinical Assessment Scale in Autoimmune Encephalitis, and absence of drug-resistant epilepsy. Results: Rituximab, adjusted for concomitant use of other immunotherapies, was associated with increased time to first relapse (hazard ratio 0.10; 95% CI 0.001-0.85; p = 0.03). Intravenous pulsed methylprednisolone was associated with an improvement in mRS (OR 4.48; 95% CI 1.03-21.3; p = 0.048) and a favorable composite clinical-functional outcome (OR 4.96; 95% CI 1.07-27.2; p = 0.049) at 12 months. Conclusions: Rituximab may be effective at preventing relapses in patients with anti-LGI1 Ab-mediated encephalitis. Acute methylprednisolone treatment may be associated with favorable outcomes at 12 months. Methods: This study provides Class IV evidence that for patients with anti-LGI1 Ab-mediated encephalitis, rituximab prevents relapses and acute methylprednisolone is associated with favorable outcomes at 12 months.

Description:Objective: Rituximab is an anti-CD20 monoclonal antibody used in patients with anti-NMDAR antibody (Ab)-mediated encephalitis as both an acute escalation therapy and a longer term relapse risk-reduction treatment. The potential long-term benefit of a single course administered during the acute disease phase on future relapse risk is uncertain. Moreover, the optimal dosing duration to reduce relapse risk is unknown. The aim of this study was to evaluate the effect of a single course of rituximab on relapse incidence. We also studied the duration of effect of a course of rituximab in adult patients with anti-NMDAR Ab-mediated encephalitis. Methods: We recruited 67 patients with anti-NMDAR Ab-mediated encephalitis from 10 Australian hospitals. Rituximab exposure was quantified as a time-varying covariate in Cox proportional hazard models. Results: A single course of rituximab was associated with longer time to first relapse (hazard ratio [HR] 0.11, 95% CI 0.02-0.70, p = 0.02). For patients in whom redosing is considered, rituximab was associated with longer time to first relapse at 6 months after the last infusion, after adjusting for concurrent immunotherapies and the presence of ovarian teratoma at disease onset (HR 0.05, 95% CI 0.00-0.48, p = 0.005). The treatment effect did not persist out to 12 months after a given course (HR 0.60, 95% CI 0.15-2.44, p = 0.47). Conclusions: A single course of rituximab reduces the risk of relapse of anti-NMDAR antibody-mediated encephalitis. In select patients for whom redosing of rituximab is considered, administration at 6 months delays relapses. Methods: This study provides Class IV evidence that rituximab delays relapses in patients with anti-NMDAR antibody-mediated encephalitis.

Description:Background: Stereoelectroencephalography (SEEG) has been used to localise the epileptogenic zone in focal epilepsy for several decades. Our centre's current method of implantation with a CRW Precision Arc system will soon be no longer supported in our region, necessitating alternative devices in SEEG procedures. In this study we compared accuracy, efficiency and safety of the CRW frame with the Autoguide robotic system. Methods: A retrospective review of a prospectively maintained database was performed of all patients in a single Australian institution who underwent SEEG between August 2019 and July 2024. Pre- and post-operative stereotactic image-based analysis was performed, with target accuracy and error measurements, operation time logs, and inpatient notes reviewed. Results: 50 patients with a total of 629 electrodes were identified who had undergone SEEG electrode implantation with the CRW frame and 8 patients with a total of 119 electrodes with the assistance of the Medtronic Autoguide robot. The electrode target point error was significantly lower in the CRW group (1.85 mm [1.23-2.58]) compared to the Autoguide assisted group (2.97 mm [1.81--4.22], p = 0.01). The difference was also significant in the individual parameters of depth error (0.57 vs.1.33 mm, p = 0.01) and the radial error (1.56 vs. 2.25 mm, p = 0.01). Bone entry point error was lower in the CRW group (1.04 vs. 2.32 mm, p < 000.1). However, the Autoguide assisted cases demonstrated a significant reduction in pre-implantation time (104.9 Vs. 129.0 min, p = 0.01) and time per electrode (13.9 vs 17.3 min, p = 0.005) compared to the CRW frame. Neither group recorded any significant adverse events nor required re-implantation due to electrode inaccuracy. Conclusions: Our experience demonstrates that the Medtronic Autoguide robot can safely be used for SEEG electrode implantation, and has improved the pre-implantation and implantation time per electrode for SEEG cases. However, accuracy in our initial cohort was reduced compared to the CRW frame.