Faculty Bibliography

Acute symptomatic seizures are a well recognized symptom of myelin oligodendrocyte antibody-associated disease (MOGAD), but long-term seizure outcomes and risk of epilepsy are understudied. In a retrospective cohort of 135 consecutive patients meeting consensus criteria for MOGAD without a prior diagnosis of epilepsy or concurrent NMDA-R Ab positivity, 19 developed seizures after MOGAD onset (16 %). Of these 19 patients, 7 patients (37 % of those with seizures, and 5 % of the total cohort). experienced one or more seizure recurrence during MOGAD remission (i.e. outside of an acute attack). Five of the 7 patients with recurrent seizures remained on antiseizure medication (ASM) (four on monotherapy and one on two ASMs) at last follow-up (median duration of follow up: 92 months). We discuss phenotypes of recurrent seizures in patients with MOGAD in the context of the conceptual framework of acute symptomatic seizures versus autoimmune encephalitis associated epilepsy (AEAE).

OBJECTIVE:This study aims to better characterize the long-term neurological quality of life (QOL) outcomes (using the Neuro-QOL scale) in survivors of new onset refractory status epilepticus (NORSE), including its subtype febrile infection-related epilepsy syndrome (FIRES), and provide guidance for psychological and social support strategies. METHODS:Utilizing data from a multicenter prospective study of NORSE/FIRES led by Yale University, we enrolled patients who completed the validated, patient-reported Neuro-QOL scale at least once at 3-6 months (n = 37), 12 months (n = 29), 24 months (n = 23), or ≥36 months (n = 9) following discharge. The Neuro-QOL scale assesses physical, mental, and social health in patients with neurological disorders. QOL impairment (QOL-I) scores were calculated, with higher scores indicating greater impairment. T-scores enabled comparisons with reference populations. RESULTS:In adults, median QOL-I improved from 44.1% at 3-6 months to 37.6% at 36+ months. Paired analysis showed significant improvement in QOL-I between 3-6 and 24 months (p = .016), with specific improvements in communication, satisfaction with social roles, fatigue, and mobility. Greater improvement was also observed for participation in social roles (5.5-point T-score gain) compared to the reference population, suggesting meaningful change. A gradual improvement in overall QOL-I scores was also observed in pediatric participants, despite a modest sample size (n = 5 with data at 3-6 and 12 months). Measures of fatigue and anxiety persisted in adults, and cognitive difficulties persisted in both adults and children. In adults, longer status epilepticus duration and intensive care unit stay were associated with poorer QOL. Additionally, a higher number of antiseizure medications was associated with more depression, cognitive impairments, and perceived stigma. SIGNIFICANCE/CONCLUSIONS:These findings highlight the potential for recovery following an acute episode of NORSE, although many patients continue to face challenges requiring ongoing support, and the clinical meaning of the reported QOL improvement remains unclear. Furthermore, the findings underscore the importance of strategic multidisciplinary support systems in the years following discharge.

OBJECTIVE:Encephalitis is brain parenchyma inflammation, frequently resulting in seizures which worsens outcomes. Early anti-seizure medication could improve outcomes but requires identifying patients at greatest risk of acute seizures. The SEIZURE (SEIZUre Risk in Encephalitis) score was developed in UK cohorts to stratify patients by acute seizure risk. A 'basic score' used Glasgow Coma Scale (GCS), fever and age; the 'advanced score' added aetiology. This study aimed to evaluate the score internationally to determine its global applicability. DESIGN/METHODS:Patients were retrospectively analysed regionally, and by country, in this international evaluation study. Univariate analysis was conducted between patients who did and did not have inpatient seizures, followed by multivariable logistic regression, hierarchical clustering and analysis of the area under the receiver operating curves (AUROC) with 95% CIs. PARTICIPANTS AND SETTING/METHODS:2032 patients across 13 countries were identified, among whom 1324 were included in SEIZURE score calculations and 970 were included in regression modelling. The involved countries comprised 19 organisations spanning all WHO regions. OUTCOME MEASURES/METHODS:The primary outcome was measuring inpatient seizure rates. RESULTS:Autoantibody-associated encephalitis, low GCS and presenting with a seizure were frequently associated with inpatient seizures; fever showed no association. Globally, the score had limited discriminatory ability (basic AUROC 0.58 (95% CI 0.55 to 0.62), advanced AUROC 0.63 (95% CI 0.60 to 0.66)). The scoring system performed acceptably in western Europe, excluding Spain, with the best performance in Portugal (basic AUROC 0.82 (95% CI 0.69 to 0.94), advanced AUROC 0.83 (95% CI 0.72 to 0.95)). CONCLUSIONS:The SEIZURE score performed best in several countries in Western Europe but performed poorly elsewhere, partly due to differing and unknown aetiologies. In most regions, the score did not reach a threshold to be clinically useful. The Western European results could aid in designing clinical trials assessing primary anti-seizure prophylaxis in encephalitis following further prospective trials. Beyond Western Europe, there is a need for tailored, localised scoring systems and future large-scale prospective studies with optimised aetiological testing to accurately identify high-risk patients.

Neuroinflammation involving glial cell activation and BBB dysfunction has increasingly been recognized as a key feature of neuropsychiatric disorders. In vivo imaging methods, particularly translocator protein positron emission tomography (TSPO-PET) and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), have advanced our understanding of glial activation and BBB permeability in conditions such as Alzheimer's disease, Parkinson's disease, epilepsy, multiple sclerosis, Huntington's disease, schizophrenia, and depression. We present key findings from the clinical application of these imaging modalities and highlight critical methodological challenges-including variability in study protocols, tracer selection, input function derivation, and parameter estimation-that currently limit cross-study comparability and clinical translation. TSPO-PET and DCE-MRI provide valuable clinical insights on the inflammatory mechanisms contributing to CNS disease at various disease stages. Future methodological standardization, co-localization studies, and longitudinal multi-modal applications will be crucial for using these tools as markers of disease in the context of immune interventions in at-risk populations.

OBJECTIVE:New-onset refractory status epilepticus (NORSE) occurs in people without pre-existing epilepsy or a rapidly identified structural, toxic, metabolic, or other cause. NORSE is a rare disorder with high morbidity and mortality rates and limited evidence for effective therapies. We aimed to assess whether the gut microbiome of NORSE and status epilepticus (SE) differs from that of chronic epilepsy, whether NORSE differs from SE at different disease time points, and to examine the correlations between specific gut microbiota and cytokines in NORSE and SE. METHODS:This longitudinal cohort study observed patients with NORSE (n = 15), SE (n = 17), and chronic epilepsy who were not in SE (n = 12). NORSE patients were recruited through the NORSE Consortium. Patients with NORSE and SE underwent longitudinal serial biospecimen collection. Fecal samples were subjected to whole-community shotgun metagenomics to characterize microbiome features. Cohorts were evaluated for prokaryotic, eukaryotic, and functional diversity. Correlations between blood inflammatory cytokine levels and microbiome features and covariate analysis with critical illness and clinical treatments were examined for NORSE and SE patients during and after SE resolution. RESULTS:During SE, NORSE and SE patients had significantly different prokaryotic, eukaryotic, and functional microbiome levels compared to chronic epilepsy patients without SE. Limited microbiome differences were observed within and between NORSE and SE, although these groups displayed differing correlation patterns between microbial species and cytokines. Patients who later died or were tube-fed harbored significantly different microbiomes than those who survived or were orally fed. SIGNIFICANCE/CONCLUSIONS:NORSE and SE patients present with a more variable and dramatically different fecal microbiome than chronic epilepsy patients, which may indicate gut dysbiosis that may be reciprocally linked to inflammatory responses. Although NORSE and SE patients had similar microbiome structures, fungal and bacterial correlates with inflammatory cytokines differed between NORSE and SE, with confounding factors influencing microbiome structure. Our data suggest a microbiome-specific response to NORSE and SE, with implications for future treatment strategies.

PURPOSE/OBJECTIVE:To compare the performance of different measures of long-term psychiatric outcomes in patients with post-acute autoimmune encephalitis (AE) who may require comprehensive psychiatric evaluation. METHODS:The sensitivity of three self-reported measures of mood and anxiety symptoms (Patient Health Questionnaire [PHQ-9]; Profiles of Mood States-2 [POMS-2]; Generalized Anxiety Disorder 7-item [GAD7]) was compared with a structured clinician-administered tool (Mini Neuropsychiatric Inventory 7.0.2 [MINI 7.0.2]). New cutoff scores that optimized accuracy were then identified by Youden Index Method. RESULTS:Thirty-five patients with post-acute AE completed testing a median of 3 years after symptomatic onset (range = 1-22 years). The median PHQ9 score was 5 (range = 0-18), median POMS2 Total Mood Disturbance T-Score was 52 (range = 37-93), and median GAD7 score was 3 (range = 0-17). Twenty-five patients (71 %) met criteria for a psychiatric diagnosis on the MINI. When compared with the MINI, the sensitivity and specificity of the self-reported psychiatric symptom tools using standard cutoffs were 25 % and 80 % for the PHQ9, 50 % and 87 % for the POMS-2, 23 % and 91 % for the GAD7. Accuracy was improved when cutoffs of ≥5 for the PHQ9, ≥50 for the POMS2, and ≥ 3 for the GAD7 were used, at the cost of lower specificity. CONCLUSIONS:Patients with post-acute AE with psychiatric sequalae may be underrecognized if self-reported measures of psychiatric symptoms are used instead of clinician-administered structured interviews. If self-reported measures are used in AE, consideration should be given into using tools with higher validity in this patient population, such as the POMS-2.

BACKGROUND AND OBJECTIVES/OBJECTIVE:The aim of this study was to identify distinct inflammatory response subtypes in patients with c-NORSE by analyzing their cytokine profiles. Insights into underlying mechanisms were sought to understand the pathophysiology and guide personalized therapies to improve patient outcomes. METHODS:Sixty-two patients with c-NORSE were included. A comprehensive panel of 96 cytokines was analyzed in serum samples. Patients were clustered based on their cytokine profiles using the Louvain algorithm, an unsupervised graph-based clustering method. The identified clusters of patients were compared regarding cytokine levels and clinical features. Protein pathway analysis was used to explore the biological relevance of the inflammatory markers within each cluster. Patients with c-NORSE were compared with control patients (n = 18) and patients with other forms of refractory SE (n = 45). RESULTS:Compared with controls, patients with c-NORSE exhibited significant differences in 33 cytokines. Pathway analysis revealed dysregulations in chemotaxis and neutrophil recruitment and migration, highlighting the importance of innate immunity in patients with c-NORSE. Within the c-NORSE cohort, 3 clusters of patients emerged: cluster A, lacking specific inflammatory markers; cluster B, with a much stronger innate-immunity cytokine-driven inflammatory response compared with clusters A and C; and cluster C, defined by dysregulated autoimmune processes. Notably, patients in cluster B showed a statistically significant elevation of innate immune-related proinflammatory cytokines associated with leukocyte recruitment and degranulation. By contrast, those in cluster C showed activation of Janus kinase signal transducer and activator of transcription (JAK-STAT) pathways, suggesting autoimmune mechanisms. Patients in clusters B and C demonstrated varied responses to immunotherapies, with cluster C patients showing favorable outcomes after multiple immunotherapies. DISCUSSION/CONCLUSIONS:The identification of distinct inflammatory subgroups in c-NORSE suggests that variations in the underlying immune mechanisms contribute to differential treatment responses. These findings underscore the importance of personalized therapeutic strategies, potentially targeting specific inflammatory pathways, to optimize clinical outcomes in this challenging condition.

Autoimmune encephalitis (AE), defined by clinical criteria and its frequent association with neural autoantibodies, often manifests with seizures, which usually stop with immunotherapy. However, a subset of encephalitic conditions present with recurrent seizures that are resistant to immunotherapy. Three primary neurological constellations that fall within this subset are discussed in this Perspective: temporal lobe epilepsy with antibodies against glutamic acid decarboxylase, epilepsy in the context of high-risk paraneoplastic antibodies, and epilepsy following adequately treated surface antibody-mediated AE. These entities all share a common mechanism of structural injury and potentially epileptogenic focal neural loss, often induced by cytotoxic T cells. Recently, we have proposed conceptualizing these conditions under the term autoimmune encephalitis-associated epilepsy (AEAE). Here, we discuss the new concept of AEAE as an emerging field of study. We consider the clinical characteristics of patients who should be investigated for AEAE and highlight the need for judicious use of traditional epilepsy therapeutics alongside immunotherapeutic considerations that are of uncertain and incomplete efficacy for this group of disorders. Last, we discuss future efforts needed to diagnose individuals before structural epileptogenesis has superseded inflammation and to develop improved therapeutics that target the specific immunological or functional disturbances in this entity.

OBJECTIVE/UNASSIGNED:The authors aimed to characterize the long-term psychiatric outcomes and their predictors among survivors of autoimmune encephalitis (AE). METHODS/UNASSIGNED:In this retrospective cohort study, patients diagnosed as having AE between 2008 and 2023 at two academic medical centers (in New York City and Toronto) completed the Mini International Neuropsychiatric Interview 7.0.2 (MINI) and Profile of Mood States (POMS-2) to assess long-term psychiatric outcomes. Clinical characteristics were assessed for potential predictors of psychiatric outcomes. Bivariate analyses and univariate logistic regressions were conducted to assess the relationship between the predictors and the primary outcome. RESULTS/UNASSIGNED:-methyl-d-aspartate (33%), anti-leucine-rich-glioma-inactivated 1 (24%), anti-glutamic acid decarboxylase 65 (14%), and antibody-negative encephalitis (29%). In total, 71% of participants who completed the MINI met criteria for a DSM-5 diagnosis, and 56% were diagnosed as having a mood disorder. Thirteen participants (31%) reported above-average total mood disturbance on the POMS-2. Mann-Whitney U tests revealed that participants diagnosed as having a mood disorder self-reported significantly higher levels of confusion and bewilderment (z=-2.04, p=0.04) and depression and dejection (z=-2.24, p=0.03) and lower levels of vigor and activity (z=-2.62, p=0.01). CONCLUSIONS/UNASSIGNED:AE survivors have a high prevalence of psychiatric comorbid conditions, with most being diagnosed as having a mood disorder and a significant proportion endorsing ongoing mood disturbance. Patients with a psychiatric history may benefit from closer psychiatric follow-up.