Faculty Bibliography

In response to the evolving treatment landscape for new-onset refractory status epilepticus (NORSE) and the publication of consensus recommendations in 2022, we conducted a comparative analysis of NORSE management over time. Seventy-seven patients were enrolled by 32 centers, from July 2016 to August 2023, in the NORSE/FIRES biorepository at Yale. Immunotherapy was administered to 88% of patients after a median of 3 days, with 52% receiving second-line immunotherapy after a median of 12 days (anakinra 29%, rituximab 25%, and tocilizumab 19%). There was an increase in the use of second-line immunotherapies (odds ratio [OR] = 1.4, 95% CI = 1.1-1.8) and ketogenic diet (OR = 1.8, 95% CI = 1.3-2.6) over time. Specifically, patients from 2022 to 2023 more frequently received second-line immunotherapy (69% vs 40%; OR = 3.3; 95% CI = 1.3-8.9)-particularly anakinra (50% vs 13%; OR = 6.5; 95% CI = 2.3-21.0), and the ketogenic diet (OR = 6.8; 95% CI = 2.5-20.1)-than those before 2022. Among the 27 patients who received anakinra and/or tocilizumab, earlier administration after status epilepticus onset correlated with a shorter duration of status epilepticus (ρ = .519, p = .005). Our findings indicate an evolution in NORSE management, emphasizing the increasing use of second-line immunotherapies and the ketogenic diet. Future research will clarify the impact of these treatments and their timing on patient outcomes.

With the discovery of an expanding number of neural autoantibodies, autoimmune etiologies of seizures have been increasingly recognized. Clinical phenotypes have been identified in association with specific underlying antibodies, allowing an earlier diagnosis. These phenotypes include faciobrachial dystonic seizures with LGI1 encephalitis, neuropsychiatric presentations associated with movement disorders and seizures in NMDA-receptor encephalitis, and chronic temporal lobe epilepsy in GAD65 neurologic autoimmunity. Prompt recognition of these disorders is important, as some of them are highly responsive to immunotherapy. The response to immunotherapy is highest in patients with encephalitis secondary to antibodies targeting cell surface synaptic antigens. However, the response is less effective in conditions involving antibodies binding intracellular antigens or in Rasmussen syndrome, which are predominantly mediated by cytotoxic T-cell processes that are associated with irreversible cellular destruction. Autoimmune encephalitides also may have a paraneoplastic etiology, further emphasizing the importance of recognizing these disorders. Finally, autoimmune processes and responses to novel immunotherapies have been reported in new-onset refractory status epilepticus (NORSE) and febrile infection-related epilepsy syndrome (FIRES), warranting their inclusion in any current review of autoimmune-associated seizure disorders.

BACKGROUND AND OBJECTIVES/OBJECTIVE:R). We hypothesized that after a seizure-free period of 3 months, patients with AIE have a seizure recurrence risk of <20% during the subsequent 12 months. This would render them eligible for noncommercial driving according to driving regulations in several countries. METHODS:R-AIE, who had been seizure-free for ≥3 months. We used Kaplan-Meier (KM) estimates for the seizure recurrence risk at 12 months for each antibody group and tested for the effects of potential covariates with regression models. RESULTS:R. DISCUSSION/CONCLUSIONS:Taking a <20% recurrence risk within 12 months as sufficient, patients with NMDAR-AIE and LGI1-AIE could be considered eligible for noncommercial driving after having been seizure-free for 3 months.

OBJECTIVE:To report a novel anatomical pattern of autoimmune encephalitis characterized by strictly unilateral cortical inflammation and a clinical picture overlapping with late-onset Rasmussen's encephalitis. METHODS:We retrospectively gathered data of patients identified at two tertiary referral academic centers who met inclusion criteria. RESULTS:We identified twelve cases (average age 65, +/- 19.8 years, 58% female). All patients had unilateral cortical inflammation manifesting with focal seizures, cognitive decline, hemicortical deficits, and unilateral MRI and/or EEG changes. Six cases were idiopathic, two paraneoplastic, two iatrogenic (in the setting of immune checkpoint inhibitors), and two post-COVID-19. Serologically, ten patients were seronegative, one had high titer anti-GAD65, and one had anti-NMDAR. Five patients met Rasmussen's encephalitis criteria, and six did not fully meet the criteria but had symptoms significantly overlapping with the condition. Most patients had significant improvement with immunotherapy. DISCUSSION/CONCLUSIONS:Unilateral cortical AE seems to be more prevalent in the elderly and more frequently idiopathic and seronegative. Patients with this anatomical variant of autoimmune encephalitis have overlapping features with late-onset Rasmussen's encephalitis but are more responsive to immunotherapy. In cases refractory to immunotherapy, interventions used in refractory Rasmussen's encephalitis may be considered, such as functional hemispherectomy.

Febrile infection-related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status epilepticus. It is unclear whether FIRES and non-FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non-FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non-FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non-infection-related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein-1 alpha (MIP-1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non-FIRES NORSE are very similar conditions.

OBJECTIVES:How brain MRI lesions associate with outcomes in pediatric anti-NMDA receptor encephalitis (pNMDARE) is unknown. In this study, we correlate T2-hyperintense MRI brain lesions with clinical outcomes in pNMDARE. METHODS:This was a multicenter retrospective cohort study from 11 institutions. Children younger than 18 years with pNMDARE were included. One-year outcomes were assessed by the modified Rankin Score (mRS) with good (mRS ≤2) and poor (mRS ≥3) outcomes. RESULTS:A total of 175 pNMDARE subjects were included, with 1-year mRS available in 142/175 (81%) and 60/175 (34%) had abnormal brain MRIs. The most common T2-hyperintense lesion locations were frontal, temporal, and parietal. MRI features that predicted poor 1-year outcomes included abnormal MRI, particularly T2 lesions in the frontal and occipital lobes. After adjusting for treatment within 4 weeks of onset, improvement within 4 weeks, and intensive care unit admission, MRI features were no longer associated with poor outcomes, but after multiple imputation for missing data, T2 frontal and occipital lesions associated with poor outcomes. DISCUSSION:Abnormal frontal and occipital lesions on MRI may associate with 1-year mRS in pNMDARE. MRI of the brain may be a helpful prognostication tool that should be examined in future studies.

OBJECTIVE:Autoimmune encephalitis can be followed by treatment-resistant epilepsy. Understanding its predictors and mechanisms are crucial to future studies to improve autoimmune encephalitis outcomes. Our objective was to determine the clinical and imaging predictors of postencephalitic treatment-resistant epilepsy. METHODS:We performed a retrospective cohort study (2012-2017) of adults with autoimmune encephalitis, both antibody positive and seronegative but clinically definite or probable. We examined clinical and imaging (as defined by morphometric analysis) predictors of seizure freedom at long term follow-up. RESULTS:Of 37 subjects with adequate follow-up data (mean 4.3 yrs, SD 2.5), 21 (57 %) achieved seizure freedom after a mean time of 1 year (SD 2.3), and one third (13/37, 35 %) discontinued ASMs. Presence of mesial temporal hyperintensities on the initial MRI was the only independent predictor of ongoing seizures at last follow-up (OR 27.3, 95 %CI 2.48-299.5). Morphometric analysis of follow-up MRI scans (n = 20) did not reveal any statistically significant differences in hippocampal, opercular, and total brain volumes between patients with postencephalitic treatment-resistant epilepsy and those without. SIGNIFICANCE/CONCLUSIONS:Postencephalitic treatment-resistant epilepsy is a common complication of autoimmune encephalitis and is more likely to occur in those with mesial temporal hyperintensities on acute MRI. Volume loss in the hippocampal, opercular, and overall brain on follow-up MRI does not predict postencephalitic treatment-resistant epilepsy, so additional factors beyond structural changes may account for its development.