Faculty Bibliography

BACKGROUND AND OBJECTIVES/OBJECTIVE:Double seronegative NMOSD (DS-NMOSD) lacks approved disease-modifying treatments, and limited data exist on optimal relapse-prevention strategies. In this multicenter, international, retrospective cohort study, we sought to compare the real-world effectiveness of anti-CD20 agents vs nonspecific immunosuppressants as disease-modifying strategies for relapse prevention in DS-NMOSD. METHODS:A retrospective cohort database was constructed using standardized data collection from medical records across collaborating centers in the United States, Brazil, the United Kingdom, Thailand, Turkiye, and China. Patients meeting IPND-2015 NMOSD criteria with negative serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibody testing via cell-based assays and at least 12 months of follow-up were reviewed. The primary outcome was the incidence rate ratio (IRR) of relapses; secondary outcomes included the annualized relapse rate (ARR) and time to relapse. RESULTS:A total of 103 patients with DS-NMOSD met study criteria, with a median follow-up of 6 years. Anti-CD20 therapy was associated with a significantly lower IRR (0.02, 95% CI 0.01-0.04) and ARR (0.17, 95% CI 0.07-0.40) compared with nonspecific immunosuppressants (0.76, 95% CI 0.40-1.43) after adjusting for covariates. Survival analysis demonstrated a prolonged relapse-free interval with anti-CD20 agents. DISCUSSION/CONCLUSIONS:Our findings support the use of B-cell depletion as a potentially superior relapse-prevention strategy in DS-NMOSD, highlighting its potential as a first-line therapy. CLASSIFICATION OF EVIDENCE/METHODS:This study provides Class IV evidence that, in patients with DS-NMOSD, treatment with a DMT reduces relapse incidence rate ratio compared with no treatment and anti-CD20 DMTs are associated with a lower relapse incidence rate ratio compared with nonspecific immunosuppressants.

BACKGROUND:Multiple sclerosis (MS) and neurosarcoidosis (NS) can present as similar neuro-radiologic syndromes. Neither disease has pathognomonic clinical or laboratory findings and differentiating between them may be challenging. We hypothesized that cerebrospinal fluid (CSF) immune cell profiles, including CD4/CD8 cell ratio and proportion of B cells, might help to distinguish NS from MS. METHODS:Patients with probable or definite NS who were evaluated at the NYU MS Comprehensive Care Center (New York) and had CSF flow cytometry done as part of diagnostic workup were matched by age, sex, and race/ethnicity to MS patients with available CSF flow cytometry. All patients who received immunomodulatory therapy within 3 months of lumbar puncture were excluded. Flow cytometry was performed using BD FACSCanto™ and FACSCanto™ II Cell Analyzers (BDBiosciences, San Jose, CA) and manually verified by a hematopathologist. Group comparisons were made with an unpaired two-tailed Student's t-test, Chi-square test, or Wilcoxon rank sum test, as appropriate; p < 0.05 was considered significant. RESULTS:, p < 0.0001) and protein levels (101.2 ± 88.9 mg/dL vs. 35.7 ± 19.6, p = 0.003), while MS patients had more CSF-restricted oligoclonal bands (7.7 ± 5.3 vs. 1.7 ± 2.4, p < 0.00042). No differences were found in CSF glucose concentrations or IgG indices. Proportions of all immune cells in CSF were similar in NS and MS, including the CD4/CD8 ratio and percentages of B cells. CONCLUSION/CONCLUSIONS:Clinically available CSF flow cytometry immune profiles do not offer added discriminatory value for differentiating NS from MS. More granular immunophenotyping may be needed to improve diagnostic precision.

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).

Patients with Neuromyelitis Optica Spectrum Disorders (NMOSD) have a well-recognized predilection to autoimmune comorbidities, of which systemic lupus erythematosus (SLE), Sjögren's syndrome (SjS), and autoimmune thyroid diseases are the most common. The question of whether some autoimmune diseases, such as inflammatory bowel disease (IBD), may not be overrepresented (or may even be underrepresented) in NMOSD has not received much attention. Here, we retrospectively reviewed the electronic medical records of all patients diagnosed with NMOSD in our two large referral centers (NYU and MGB), as well as patients with two neuroinflammatory disorders as comparator groups (myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and MS), and calculated the rates of IBD, SLE, SjS, autoimmune thyroid disorders, and myasthenia gravis (MG) in these groups. We found that 1 out of 347 NMOSD patients had a diagnosis of IBD (0.3%), and this patient was seronegative for anti-AQP4 autoantibodies, while 4/271 patients in the MS group (1.5%), 2 of whom were exposed to anti-CD20 therapy, had IBD, and 2/366 MOGAD patients (0.8%), neither of whom was exposed to anti-CD20 therapy, had IBD. In contrast, the rate of the other four autoimmune conditions was significantly higher in NMOSD (24%) than in MOGAD (8.5%, p < 0.0001) or MS (5.2%, p < 0.0001). Thus, IBD was not diagnosed in any of our 317 seropositive NMOSD patients, despite the fact that this group had a higher use of B-cell depletion than patients with MS and MOGAD. We discuss the various hypotheses that may explain this observation.

The formation of a stable antigenic peptide-HLA II (p-HLA class II) complex is a critical early step in the adaptive immune response. In this work, we identify the residue-residue contacts that 'anchor' the peptide between the alpha and beta chains of HLA II and examine whether the anchoring residue-residue contacts are shared among different p-HLA II complexes. We hypothesize that there are similarities between the contact map of the alpha and beta chains of HLA II with CLIP (the fragment of the invariant gamma chain that binds to newly synthesized HLA II molecules) and the contact maps between the different alpha and beta chains of HLA II molecules with various antigenic peptides. To test the hypothesis, 81 diverse peptide-HLA II DR and DQ complexes, including CLIP-HLA II complex, were selected from the PDB database, and 'Unified Residue Numbering' was introduced for all complexes. The Unified Residue Numbering enables us to compare residue contacts across complexes for each position, e.g., to identify the position in peptides occupied by residues with the highest number of contacts with HLA II similar to CLIP position with the highest number of contacts in all structures, and to define characteristics of residues for each position. We also identified all 'similar contacts' in the analyzed structures. 'Similar contacts' are defined as contacts between same-numbered residues in the peptide and HLA II and CLIP with HLA II structure independent of physicochemical properties of residues involved in the contact. We found that in the 81 analyzed structures, 90% of contacts between peptide and the alpha chains were 'similar contacts', as were 80% of contacts between peptides and the beta chains. Thus, our approach to sequence alignment, which is based on alignment of similar contacts rather than similar residues, allows one to define the common network of residues that underlies the interactions between peptide and HLA II. We also consider several criteria for the specificity of antigen peptide loading into HLA II based on the structural and physicochemical characteristics of the residues involved in the 'anchoring' contacts. These data may be useful for refining existing computational algorithms that predict peptide interactions with HLA II complexes.

BACKGROUND:Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described inflammatory disorder of the central nervous system. Unlike other demyelinating disorders of the central nervous system, the impact of pregnancy and the postpartum period on MOGAD disease activity remains uncertain. A better understanding of pregnancy-related relapse risk in MOGAD is essential to inform management. METHODS:We conducted a retrospective chart review of all patients followed in two large referral centers in the Northeastern United States with a confirmed diagnosis of MOGAD and at least one post-MOGAD onset pregnancy carried to the third trimester. Demographic, neurological, obstetric, and treatment-related data were extracted from electronic medical records, centered around the 12-month pre-pregnancy, pregnancy, and 12-month post-pregnancy periods, for each of which the annualized relapse rates (ARRs) were calculated. RESULTS:We identified 15 women diagnosed with MOGAD who had 22 post-MOGAD onset pregnancies. No relapses were observed during any of the 22 pregnancies, but 2 relapses were observed in the postpartum period in a single patient with a steroid-dependent relapsing course. The mean ARR was 0.26 ± 0.86 during the 12-month pre-pregnancy period, 0 during pregnancy, and 0.09 ± 0.42 in the 12-month postpartum period. Twelve of 22 pregnancies (55 %) were exposed to disease-modifying therapy (DMT) at conception, and 59 % were continued on DMT into the postpartum period. Obstetric complications were recorded in 5 of 22 pregnancies (22 %). CONCLUSIONS:The two main findings of our retrospective study are: 1) the relapse risk is very low during pregnancy in women with MOGAD, and 2) postpartum relapse risk does not appear to be elevated in patients with a low pre-pregnancy relapse rate. Approximately half of the women in our series were receiving disease-modifying therapies during the postpartum period, which may have decreased relapse rates. Larger prospective studies are needed to validate our observations.

PURPOSE OF REVIEW/OBJECTIVE:To outline a practical and comprehensive approach to evaluating transient neurologic dysfunction (TND) in adults. RECENT FINDINGS/RESULTS:TNDs are a common reason for neurologic consultation. Diagnosis relies largely on history, as neurologic examination is usually normal in the post-ictal stage. The differential of TNDs is extensive, and testing should be targeted to the more likely etiologies and ones that may portend permanent loss of neurologic function. In addition to the more common causes - transient ischemic attack (TIA), seizures, migraine auras, drug-induced adverse events, hypoglycemia, blood pressure fluctuations, hyperventilation, panic attacks, and paroxysmal vestibular disorders, there are some distinctive TND presentations and special circumstances that may point to the less common etiologies. The article outlines the key features of the common presentations and presents a comprehensive differential diagnosis that includes many rare causes of TNDs in adults and adolescents. The proposed approach relies on carefully elucidating the nature, timeline, and circumstances of the symptoms, gathering examination clues, and seeking to determine whether the event is likely due to neuro-vascular, non-vascular neurologic (paroxysmal or chronic), non-neurologic, or rare neurologic etiologies. Specific diagnoses are listed for each of these categories.

BACKGROUND AND OBJECTIVES/UNASSIGNED:Neurosarcoidosis poses a diagnostic and management challenge due to its rarity, phenotypic variability, and lack of randomized controlled studies to guide treatment selection. Recommendations for management based on expert opinion are useful in clinical practice and provide a framework for designing prospective studies. METHODS/UNASSIGNED:In this Delphi survey study, specialists with experience in managing patients with neurosarcoidosis were invited to anonymously complete 2 surveys about key elements of evaluation, diagnosis, treatment, monitoring, and long-term management of neurosarcoidosis. Expert consensus recommendations were adopted if >80% threshold of agreement was reached. RESULTS/UNASSIGNED:Of the 41 invited expert clinicians across the United States, 32 (78%) participated in the study. All round 1 respondents self-identified as neuroimmunologists (except for 1 pulmonologist). Consensus was reached regarding the need to consider neurosarcoidosis phenotype and severity to guide the choice of initial immunosuppression in both the acute (relapse) and maintenance phases. Experts endorsed the use of TNF-α inhibitors as first-line agents in selected phenotypes with poor prognosis. Neuroimaging was recommended to complement clinical surveillance for treatment response. DISCUSSION/UNASSIGNED:There was agreement on several key issues, most importantly on the need to consider neurosarcoidosis phenotype and severity when deciding initial treatment. No consensus was achieved on the dosing and duration of specific immunosuppressants, nor regarding the management of the peripheral nervous system manifestation of neurosarcoidosis. These topics warrant further investigation.

BACKGROUND/UNASSIGNED:In the DISCOMS (DISCOntinuation of disease-modifying therapies (DMTs) in multiple sclerosis (MS)) randomized clinical trial, we could not demonstrate that discontinuing MS DMTs in older, stable adults was not inferior to continuing DMTs. Relapses were rare in both groups, and most new disease activity was one to two new brain magnetic resonance imaging (MRI) lesions unassociated with clinical changes. OBJECTIVE/AIMS/UNASSIGNED:Describe results of the DISCOMS extension study. METHODS/UNASSIGNED:Among 10/19 of the original sites, we enrolled patients who completed DISCOMS; did not reach the primary endpoint during the original trial; and retained original randomized assignment. Participants completed one study visit and brain MRI at least 30 months after original enrollment in DISCOMS. Primary endpoint was time from entry into the primary study to relapse or new brain MRI activity. RESULTS/UNASSIGNED:= 0.043 from log-rank test). CONCLUSIONS/UNASSIGNED:From entry into DISCOMS extension study, time to new MS activity remained shorter in discontinuers, but relapses were absent and new brain MRI lesions were rare.