Date/Time: Tuesday, September 12, 2023 - 11:00 AM – 12:30 PM
Track: Special Interest Group (SIG) Session
Room: Franklin Hall 1 (4th Floor)
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Description:

Session Evaluation Form: https://myana.org/form/ana2023-session-evaluation-autoi

Chair: Gregory Day, MD, MSc, MSCI, FAAN

Co-Chair: Amanda Piquet, MD

This session will discuss emergent and established measures of meaningful outcomes in patients with autoimmune encephalitis and multiple sclerosis. Topics will highlight recent publications and developing research on patient- and care-giver specified quality of life measures, associated symptoms/signs in recovering patients (e.g., depression, apathy, fatigue, pseudobulbar affect, cognitive impairment, sleep dysfunction), and objective neuroimaging biomarker measures of disease activity. Active screening and documentation of meaningful outcomes is critical to quantify the burden of disease in recovering patients, identify and target treatable symptoms that compromise function, and optimize long-term outcomes in patients with neurological autoimmune disease.

Learning Objectives:

• Knowledge: Learners need to recognize common sequelae of autoimmune neurological diseases and the impact of persistent symptoms / signs / syndromes on meaningful recovery. 
• Performance: Learners need to actively assess / measure meaningful outcomes in patients with autoimmune neurological disease. 
• Performance: Learners need to leverage available on-label therapies to manage common sequelae of autoimmune neurological diseases to optimize long-term outcomes.

Measuring Disease Activity in Multiple Sclerosis: Beyond New Lesions

Speaker: Matthew Brier, MD, PhD

Radiological assessment of inflammatory disease activity in multiple sclerosis (MS) has historically focused on the formation of new T2-hyperintense white matter lesions (WMLs). These new lesions closely correlate with inflammatory activity and clinical relapses but fail to predict clinical disability or closely track neurodegeneration associated with progressive disease courses. Furthermore, pathology outside of discrete lesions is increasingly recognized as a driver of MS-related disability. New MRI and PET tools allow for a more detailed assessment of this pathology in patients with MS. This talk will review the increasingly recognized imaging heterogeneity of WMLs including paramagnetic rim lesions and slowly expanding lesions. Similarly, new understanding of non-lesional pathology has been obtained by leveraging quantitative MRI as well as novel radiotracers targeted at specific components of the MS disease process. Together, this more comprehensive radiologic assessment of MS pathology may improve understanding of how progressive degeneration emerges and stubbornly resists treatment despite seemingly well-treated relapsing MS.

Cognitive & Psychological Outcomes in Patients with Anti-NMDAR Encephalitis

Speaker: Mar Guasp, MD, PhD

Anti-NMDA receptor (NMDAR) encephalitis is associated with a post-acute stage that is not well known. We aimed to describe in a prospective cohort study the clinical features of this stage, similarities with schizophrenia spectrum disorders, and the factors that predict cognitive–psychiatric outcomes and could serve as prognostic biomarkers. Between Jan 1, 2017, and Sept 30, 2020, 82 participants were recruited, 28 (34%) with anti-NMDAR encephalitis, 27 (33%) age-matched individuals with stable symptoms of schizophrenia spectrum disorders, and 27 (33%) age- and sex-matched healthy participants. All participants underwent extensive neuropsychiatric evaluations at three follow-up visits over a 1-year period (at study entry -V1-, at 6 months -V2-, and at 12 months -V3). We found that the cognitive–psychiatric symptoms of anti-NMDAR encephalitis in the post-acute stage resembled those of stabilised schizophrenia, but only those in participants with anti-NMDAR encephalitis progressively improved, predominantly during V1–V2. Moreover, two features of the acute stage of anti-NMDAR encephalitis (ie, decreased level of consciousness and no improvement within the first 4 weeks of treatment), as well as a visuospatial task (ie, serial biases) at study entry, predicted cognitive outcomes. Finally, some patients with anti-NMDAR encephalitis would have met the current diagnostic criteria of schizophrenia if CSF antibody findings had not been investigated or anti-NMDAR encephalitis not included in the differential diagnosis. These findings are important for clinical trials on anti-NMDAR encephalitis and suggest that prompt cognitive–psychosocial rehabilitation might be a valuable intervention.

Quality of Life (patient and caregiver) and other factors influencing recovery following autoimmune encephalitis

Speaker: Sophie N. M. Binks, BMBS, MRCP, PhD

Long-term outcomes in LGI1-antibody encephalitis (LGI1-Ab-E), a treatable cause of seizures and cognitive decline in predominantly middle aged and older men, are often considered favourable if judged by traditional measures used in the field such as the Mini Mental State Examination (MMSE). However, our in-depth cognitive, neuropsychiatric and quality-of-life (QoL) profiling of 60 LGI1-Ab-E patients has identified 85% (51/60) are impaired on at least one assessed domain, whereas only 3/56 (5%) showed MMSE deficits. Fatigue was the most prevalent long-term challenge, present in >50% of our study participants. These deficits associated with impaired function as only 15% (4/27) could return to employment. 

This session will present detailed data from our LGI1-Ab-E cohort, including factors influencing QoL post-acute illness, and a state-of-the-art review of current evidence on QoL in LGI1-Ab-E and other forms of autoimmune encephalitis.

The Innate Immune Regulator Nlrx1 Limits Inflammatory Neurodegeneration in the Visual Pathway in Experimental Autoimmune Encephalomyelitis

Oral Abstract Presenter: Alexander Gill, MD, PhD

Smoldering low-level inflammation within the central nervous system (CNS) due to reactive glia is one potential source of chronic demyelination and neurodegeneration in progressive multiple sclerosis (MS). There is a critical need for the identification of novel adjunctive therapeutic strategies that target these inflammatory glia and prevent downstream neurodegeneration in MS. Nucleotide-binding, leucine-rich repeat containing X1 (NLRX1) is an innate immune sensor that negatively regulates several pro-inflammatory signaling cascades including nuclear factor-κB. We have recently shown that neurotoxic astrocytes and microglia are prevalent in the optic nerve and retina and are associated with retinal ganglion cell (RGC) loss in mice with experimental autoimmune encephalomyelitis (EAE), a model of inflammatory demyelination. In the current study, we used several EAE models to determine the ability of NLRX1 to limit visual pathway inflammation and neurodegeneration. In active EAE induced by myelin oligodendrocyte glycoprotein (MOG)35-55-immunization, Nlrx1-/- mice had similar EAE clinical scores but more severe loss of retinal Brn3a+ RGCs at day 42 post-immunization (42 PID) compared to wild-type EAE mice (1699 vs. 2097 RGC/mm2, p = 0.02). A similar enhanced loss of RGCs was observed in Nlrx1-/- opticospinal encephalomyelitis (OSE) mice, a spontaneous EAE model in which mice have both CD4+ T-lymphocytes expressing a transgenic T-cell receptor recognizing MOG35-55 peptide (“2D2”) and B-lymphocytes that produce antibodies with MOG-specific heavy-chains. To assess the role of NLRX1 in the innate immune compartment in EAE visual pathway inflammation, we adoptively transferred T-cells from 2D2 mice into Rag-/- and Nlrx1-/-Rag-/- mice. We found atypical EAE cerebellar symptoms and more severe optic neuritis associated with increased optic nerve infiltration by T-cells and myeloid cells in Nlrx1-/-Rag-/- mice compared to Rag-/- mice. A novel CNS-penetrant NLRX1 activating compound, LABP-66, has recently been developed. To assess whether activation of NLRX1 could ameliorate RGC loss in EAE, we treated wild-type MOG35-55-immunized mice after EAE symptom onset with oral LABP-66. Compared to vehicle-treated mice, LABP-66 treated mice had significantly higher RGC density at 42 PID (2418 vs. 1997 RGCs/mm2, p =.02). These findings suggest that loss of NLRX1 within the innate immune compartment exacerbates inflammation and neurodegeneration within the visual pathway in multiple models of CNS autoimmunity. Moreover LABP-66 limited RGC loss even when initiated after the development of EAE clinical symptoms, suggesting pharmacologic NLRX1 activators have the potential to limit inflammatory neurodegeneration in chronic CNS inflammatory diseases including MS.

Investigations of Synaptic Signaling Targets of Human Anti-NMDAR Antibodies

Oral Abstract Presenter: David Benavides, MD, PhD

The most common form of autoimmune encephalitis is associated with antibodies that target N-methyl-D-aspartic acid (NMDA) receptors. NMDARs are glutamate receptors that govern cellular mechanisms of learning and memory, including synaptic long-term potentiation (LTP), through induction of post-synaptic signaling cascades and regulation of synaptic protein synthesis. In anti-NMDAR encephalitis, antibody binding to the obligate GluN1 subunit of NMDARs leads to crosslinking and internalization of NMDARs. The molecular mechanisms that lead to the diverse neuropsychiatric symptoms associated with anti-NMDAR encephalitis remain incompletely defined but are hypothesized to involve synaptic dysfunction. We previously demonstrated that human GluN1 monoclonal antibodies (GluN1 hMAbs) rapidly localize to and regulate synaptic NMDAR function at native synapses of primary neurons. Here, we sought to explore signaling targets of GluN1 hMAbs in primary neurons using biochemistry and subcellular fractionation. We utilized unbiased quantitative phosphoproteomics to evaluate signaling pathways in membrane fractions from primary cortical neurons. GluN1 hMAbs altered global membrane protein phosphorylation states associated with numerous biological processes relevant to neuronal structure and function. These data suggest that NMDAR antibodies alter neuronal signaling networks. In separate experiments, we defined activity-dependent regulation of local RNA content in the postsynaptic density (PSD) fractions of primary neurons. Pharmacological manipulation of autophagy resulted in local synaptic RNA regulation. Thus, autophagy may contribute to synaptic plasticity via regulation of local RNA metabolism. These results raise the question of whether the effects of GluN1 hMAbs impact synaptic protein homeostasis involving autophagy and local RNA metabolism at the PSD. Future studies will investigate the regulation of autophagy and RNA metabolism in the underlying pathophysiology of anti-NMDAR encephalitis. These studies may contribute to the identification of potential therapeutic targets for novel therapies for patients with anti-NMDAR encephalitis and disorders involving antibodies targeting cell surface antigens.

The Racial and Ethnic Disparities in Clinical Outcomes in Patients with Encephalitis

Oral Abstract Presenter: Sienna Wu, BSA

Introduction: Encephalitis is estimated to occur in around 5-10 per 100,000 U.S. persons each year [1] with a mortality rate of 5.6% [2,3]. Encephalitis can generally be classified into infectious or autoimmune etiology. The influence of racial disparities on clinical outcomes has been studied in some autoimmune diseases, such as multiple sclerosis[4-6] but there is no literature on encephalitis including autoimmune encephalitis. Objective: The aim was to determine if there are significant differences in clinical outcomes among encephalitis patients of different racial backgrounds. Method: We conducted an IRB-approved, retrospective chart review of patients between 2005 and 2022, diagnosed with encephalitis at a large tertiary care academic center in Houston. We included 336 patients with an identified race and dichotomized race into Non-Hispanic Whites and ethnic minorities (African American, Hispanic, and Asian). Descriptive statistics were used to analyze the data being investigated, including mean with standard deviation and range for continuous variables, and proportions or percentages for categorical variables. Pearson correlation was used to estimate the correlation between continuous variables. Result: As expected, 63% of our patients were of an ethnic minority (n=213) while 37% were Non-Hispanic White (n=123) given the racial makeup of Houston. The Non-Hispanic White population had significantly more patients over the age of 60 (p = .013, 38%, n=47) compared to our ethnic minority patient population (25%, n=54). Significant findings include the data regarding encephalitis etiology and seizure incidence. 80% of patients with a definite autoimmune etiology were of an ethnic minority (p = .012, n=28). Ethnic minority patients also had a higher incidence of seizures (p = .046, 37%, n=78) than Non-Hispanic White patients (26%, n=32). Meanwhile, Non-Hispanic White patients had a significantly greater number of encephalitis cases due to viral causes (p = .028, 43%, n=53), and HSV/VZV encephalitis was twice as common in these patients than in patients of an ethnic minority (p = .005, 26% vs 13%). Discussion: Our analysis demonstrates that race and ethnicity may play a role in the etiology and clinical outcome of encephalitis and highlights that racial disparities may factor specifically into autoimmune etiology and the incidence of seizures in our cohort of encephalitis patients. References: 1. Graus, Francesc. The Lancet. Neurology. 2016. 2. George, Benjamin P. PloS one. 2014. 3. Vora, Neil M. Neurology. 2014. 4. Amezcua, Lilyana. Multiple sclerosis (Houndmills, Basingstoke, England). 2020. 5. Dobson, Ruth. Nature Reviews Neurology. 2022. 6. Onuorah, Helen-Margaret. Neurology. 2022.

Speaker(s):

• Sophie N M Binks, BMBS, MRCP, PhD
• Matthew Brier, MD, PhD
• Mar Guasp, MD, PhD