Faculty Bibliography

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.

INTRODUCTION/UNASSIGNED:Recent investigations have identified patients of African ancestry (AA) with Multiple Sclerosis (MS), who display more rapid B-cell repopulation after standard semi-annual infusions with an anti-CD20 monoclonal antibody for B cell depletion. In this study, we explored the immunologic and genetic factors, with, serum drug monitoring that may contribute to a faster rate of B-cell repletion that follows during recovery from treatment with anti-CD20 antibody. METHODS/UNASSIGNED:In AA MS patients treated with an anti-CD20 antibody that had early repopulation of peripheral blood B cells, we assessed for extrinsic factors, including the presence of anti-drug antibodies against ocrelizumab, which may contribute to early repletion. We also documented the associated serum drug levels. In addition, we examined for inheritance of intrinsic gene polymorphisms associated with B cell survival and immune function. RESULTS/UNASSIGNED:Our findings identified a subset of AA patients with early B cell repletion after anti-CD20 treatment associated with anti-drug antibodies and an absence of detectable drug. Furthermore, a separate set of AA patients with the early B cell repletion phenotype without anti-drug antibodies had significant over-representation of genetic polymorphisms that map to genes for the B cell survival factor, BAFF, to antibody-dependent cytotoxicity, and to pathways involved in inflammation, leukocyte activation and B cell differentiation. DISCUSSION/UNASSIGNED:In AA patients with MS, after anti-CD20 antibody treatment we found an unexpected high occurrence of early B cell replenishment. This was associated with the presence of anti-drug antibodies and/or specific genetic polymorphisms. Larger studies are now needed to determine whether these factors may lead to impaired therapeutic benefits of B cell targeted therapy and clinical progression, and these findings may be useful to guide future optimized personalized therapeutic strategies.

[This corrects the article DOI: 10.3389/fimmu.2025.1590165.].

BACKGROUND AND OBJECTIVES/OBJECTIVE:Immune checkpoint inhibitors (ICIs) are increasingly used against various cancers but are associated with immune-related adverse events (irAEs). Risk of irAEs may be higher in patients with certain preexisting autoimmune diseases, and these patients may also experience exacerbation of the underlying autoimmune disease following ICI initiation. People with multiple sclerosis (MS) have mostly been excluded from clinical trials of ICIs, so data on the safety of ICIs in MS are limited. This study aims to assess the rate of MS activity, as well as neurologic and nonneurologic irAEs in persons with MS treated with ICIs for cancer. METHODS:Participating sites were invited to this retrospective observational study through the Medical Partnership 4 MS+ listserv. Seven large academic centers participated in the study, each conducting a systematic search of their electronic medical record system for patients with MS and history of ICI treatment. The participating neurologist reviewed each chart individually to ensure the inclusion criteria were met. Demographics and data on MS and cancer history, treatments, and outcomes were abstracted from patient charts using a structured instrument. RESULTS:We identified 66 people with MS (median age 66 years, 73% female, 68% not on disease-modifying therapy for MS) who were treated with ICIs for lung cancer (35%), melanoma (21%), or another oncologic indication. During post-ICI follow-up (median: 11.7 months, range 0.2-106.3 months), 2 patients (3%) had relapse or MRI activity, 3 (5%) had neurologic irAEs, and 21 (32%) had nonneurologic irAEs. At the last follow-up, 25 (38%) participants had partial or complete remission of their cancer, while 35 (53%) were deceased. DISCUSSION/CONCLUSIONS:In this multi-institutional systematic retrospective study of predominantly older patients with MS, most of whom were not on disease-modifying therapy, MS activity and neurologic irAEs following ICI treatment were rare. These data suggest that preexisting MS should not preclude the use of ICIs for cancer in older patients, but the results may not be generalizable to younger patients with active MS. Prospective studies of ICI safety that enroll younger patients with MS are needed.

Background Patients with neuromyelitis optica spectrum disorder (NMOSD) are often seropositive for antibodies against aquaporin-4 (AQP4). The importance of MRI monitoring in this disease requires evaluation. Purpose To profile MRI features from a large international cohort with AQP4 immunoglobulin G (IgG)-seropositive NMOSD (from the Parallel MRI in NMOSD [PAMRINO] study) and to evaluate and confirm existing knowledge regarding the incidence, location, and longitudinal development of characteristic lesions in the central nervous system associated with AQP4-IgG-seropositive NMOSD. Materials and Methods In this retrospective study (from August 2016 to January 2019), MRI and clinical data were collected from 17 NMOSD expert sites in 11 countries across four continents. Clinical features and lesions identified at cross-sectional and longitudinal MRI were assessed. No formal statistical tests were used to compare observations; however, means, SDs, and 95% CIs are reported when evaluating lesion frequencies. Results Available T1-weighted and T2-weighted MRI scans in patients with AQP4-IgG-seropositive NMOSD (n = 525) were read. Among the 525 patients, 320 underwent cerebral MRI examinations with T2-weighted hyperintense cerebral (264 of 320; 82.5%), cerebellar (44 of 320; 13.8%), and brainstem (158 of 321 [49.2%], including one lesion observed at cervical spinal cord [SC] MRI) lesions. Lesions in the optic nerves, analyzed from 152 MRI examinations, were mainly found in the central (81 of 92; 88%) and posterior (79 of 92; 86%) sections (bilaterally in 39 of 92; 42%). Longitudinally extensive transverse myelitis was the predominant SC lesion pattern (upper compartment from 322 MRI examinations, 133 of 210 [63.3%]; and lower compartment from 301 MRI examinations, 149 of 212 [70.3%]). However, nonlongitudinal extensive transverse myelitis lesions were also observed frequently (105 of 210; 50.0%) in the cervical SC. Clinical data (n = 349; mean age, 44 years ± 14 [SD]; 202 female patients) and acute lesions at contrast-enhanced (CE) MRI (n = 58, performed within 30 days of the last attack) were evaluated. CE lesions were detected in the cerebrum (eight of 13; 62%), optic nerves (14 of 19; 74%), or chiasm (three of four; 75%) within 15 days of any relapse. In the upper SC (29 of 44; 66%), CE lesions were frequently observed up to 20 days after a clinical myelitis event. Conclusion A high incidence of abnormal brain MRI examinations and nonlongitudinal extensive SC lesions was found in patients in PAMRINO with AQP4-IgG-seropositive NMOSD. © RSNA, 2024 Supplemental material is available for this article.

OBJECTIVE:The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. METHODS:We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. RESULTS:The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). INTERPRETATION/CONCLUSIONS:CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024;96:34-45.