Faculty Bibliography

BACKGROUND:Isolated psychiatric symptoms can be the initial symptom of pediatric anti-N-methyl-d-aspartate (NMDA) receptor autoimmune encephalitis (pNMDARE). Here we report on the prevalence of isolated psychiatric symptoms in pNMDARE. We also assess whether initial neurodiagnostic tests (brain magnetic resonance imaging [MRI], electroencephalography [EEG], and/or cerebrospinal fluid [CSF] white blood cell count) are abnormal in children with isolated psychiatric symptoms and pNMDARE. METHODS:This multicenter retrospective cohort study from CONNECT (Conquering Neuroinflammation and Epilepsies Consortium) from 14 institutions included children under age 18 years who were diagnosed with pNMDARE. Descriptive statistics using means, medians, and comparisons for continuous versus discrete data was performed. RESULTS:Of 249 children included, 12 (5%) had only psychiatric symptoms without other typical clinical features of autoimmune encephalitis at presentation. All but one (11 of 12 = 92%) had at least one abnormal finding on initial ancillary testing: eight of 12 (67%) had an abnormal EEG, six of 12 (50%) had an abnormal MRI, and five of 12 (42%) demonstrated CSF pleocytosis. The single patient with a normal MRI, EEG, and CSF profile had low positive CSF NMDA antibody (titer of 1:1), and symptoms improved without immunotherapy. CONCLUSIONS:Isolated first-episode psychiatric symptoms in pNMDARE are uncommon, and the majority of children will exhibit additional neurodiagnostic abnormalities. Delaying immunotherapy in a child with isolated psychiatric symptoms and normal neurodiagnostic testing may be warranted while awaiting confirmatory antibody testing.

PURPOSE/OBJECTIVE:Rasmussen syndrome (RS) is marked by progressive unihemispheric atrophy, resulting in hemiparesis, refractory epilepsy, and cognitive/language decline. Detailed diagnostic and treatment algorithms are currently lacking. We aimed to survey medical providers on their current practices in the diagnosis and treatment of RS. METHODS:A steering committee was formed to create the survey, which was disseminated to the international medical community. One hundred twelve surveys were completed. Descriptive statistics, as well as comparisons by level of experience, patient age group cared for, and geographic region using Fisher's exact test, were conducted. RESULTS:Analysis of cerebrospinal fluid (82 %) and serum (78 %) for autoimmune encephalitis (AE) are completed by most, while approximately one-third obtain genetic and metabolic studies in all patients (36 % and 38 %, respectively). Providers in US and Europe more readily pursue serum AE antibody panels (85 % and 85 %, respectively, versus 67 %, p = 0.019) and genetic testing (56 % and 47 %, respectively, versus 14 %, p < 0.001) than the rest of the world. Thirty-six percent proceed to biopsy in patients otherwise meeting diagnostic criteria, and US providers are more likely to suggest this than others (73 % versus 14-41 %, p < 0.001). Opinions differed on the prioritization of hemispherectomy/hemispherotomy versus immunotherapy in 14 clinical scenarios with various neurologic deficit severity provided. Preferred immunotherapy regimens also varied, with US providers more often choosing IVIG as first-line (67 %) compared to others (28 %-32 %, p = 0.030). Surgical standard of care was identified as functional hemispherectomy or hemispherotomy by 90 %. CONCLUSION/CONCLUSIONS:The survey highlights trends but also significant variations in clinical practice that can serve as targets for future research and expert consensus guidelines.

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.