James Broadley

Description:Background and Objectives: Autoimmune encephalitis (AE) is an inflammatory disease of the central nervous system which can result in long-term seizures and cognitive dysfunction despite treatment with immunotherapy. The role of the innate immune system in AE is not well established. To investigate the contribution of innate immunity to AE and its long-term outcomes we evaluated peripheral monocytes and serum cytokines in the periphery of patients with AE. Methods and Results: We recruited 40 patients with previously diagnosed AE and 28 healthy volunteers to our cross-sectional observation study and evaluated their peripheral blood monocytes via flow cytometry and serum cytokines (CCL-2, CCL-17, G-CSF, GM-CSF, IFNγ, IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-17, TNFα) via ELISA.Compared with controls the AE cohort had expansion of the 'pro-inflammatory' CD14+CD16+ monocyte sub-population (7.13% vs 5.46%, p < 0.01) with higher levels of serum IL-6 (2.34 pg/mL vs 0.54 pg/mL, p < 0.001). These changes were most significant in anti-LGI-1 antibody mediated AE, an AE subtype with poor long-term cognitive outcomes. Conclusion: Expansion of the peripheral CD14+CD16+ monocyte population and increased serum IL-6 in AE is reflective of changes seen in other systemic inflammatory and neurodegenerative conditions. These changes may indicate a persistent pro-inflammatory state in AE and may contribute to poor long-term outcomes.

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:Objective: To identify factors predictive of a favourable modified Rankin score (mRS) at 12 months in patients with autoimmune encephalitis (AE). To evaluate predictors of a binary composite clinical-functional outcome measure, encompassing mRS, drug-resistant epilepsy (DRE) and memory impairment, at 12 months. Methods: Univariable and multivariable logistic regression analyses for predictors of a favourable mRS (i.e. mRS ≤ 2) and a composite clinical-functional outcome at 12 months were used. Results: A total of 231 patients with AE were recruited. Multivariable logistic regression identified factors predictive of reduced odds of favourable mRS at 12 months were older age (OR 0.97; 95% CI 0.95, 0.98; p < 0.001), T2/FLAIR hyperintensity on initial MRI (OR 0.27; 95% CI 0.13, 0.56; p < 0.001), RSE (OR 0.17; 95% CI 0.06, 0.52; p = 0.002) and first-line immunotherapy failure (OR 0.18; 95% CI 0.09, 0.37; p < 0.001). Anti-LGI1 antibody-mediated encephalitis relative to other subtypes (OR 4.46; 95% CI 1.55, 12.80; p = 0.006) was associated with a better 12-month mRS. We found concordant associations for a composite outcome at 12 months, with the addition of a diagnosis of definite autoimmune limbic encephalitis (AILE) predicting a poor outcome. Conclusions: Older age, MRI T2/FLAIR hyperintensity, RSE and first-line immunotherapy failure predicted worse mRS and composite clinical-functional outcome at 12 months, while a diagnosis of anti-LGI1 antibody-mediated encephalitis was associated with favourable outcomes. Our data highlight acute clinical factors predictive of a more severe clinical and functional course at 12 months.

Description:Objective: To examine the utility of neuroimaging characteristics as biomarkers of prognosis in seropositive autoimmune encephalitis (AE). Methods: In this multi-center study, we retrospectively analyzed 66 cases of seropositive AE. The MRI and PET imaging was assessed by independent visual inspection. Whole brain and regional volumes were imputed by IcoMetrix, an automated volumetric assessment package. The modified Rankin Scale (mRS) was utilized to assess the patients' follow-up disability. Other outcomes were mortality, first line treatment failure, medial temporal lobe (MTL) atrophy, and clinical relapse. Univariate and multivariable regression analysis was performed. Results: Abnormalities on MRI were detected in 35.1% of patients, while PET was abnormal in 46.4%. Initial median whole brain and hippocampal volumes were below the 5th and 20th percentile respectively compared to an age-matched healthy database. After a median follow-up of 715 days, 85.2% had good functional outcome (mRS ≤ 2). Nine patients developed MTL atrophy during follow-up. On multivariable analysis, inflammatory MTL changes were associated with development of MTL atrophy (HR 19.6, p = 0.007) and initial hippocampal volume had an inverse relationship with mortality (HR 0.04, p = 0.011). Patients who developed MTL atrophy had a reduced chance of good final mRS (HR 0.16, p = 0.015). Conclusions: Neuroimaging on initial hospital admission may be provide important diagnostic and prognostic information. This study demonstrates that structural and inflammatory changes of the MTL may have importance in clinical and radiological prognosis in seropositive AE.