Effectiveness of immunotherapies in relapsing myelin oligodendrocyte glycoprotein antibody-associated disease.

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) can cause optic neuritis, transverse myelitis, or acute disseminated encephalomyelitis (ADEM). Immunotherapy is often used for relapsing disease, but there is variability in treatment decisions. OBJECTIVE: The objective was to determine the annualized relapse rates (ARRs) and incidence rate ratios (IRRs) compared to pre-treatment and relapse-freedom probabilities among patients receiving steroids, B-cell depletion (BCD), intravenous immunoglobulin (IVIG), and mycophenolate mofetil (MMF). METHODS: Retrospective cohort study of patients with relapsing MOGAD treated at Mass General Brigham. ARRs and IRRs compared to pre-treatment, and relapse-freedom probability and odds ratio for relapse-freedom compared to prednisone were calculated. RESULTS: A total of 88 patients met the inclusion criteria. The ARR on IVIG was 0.13 (95% confidence interval (CI) = 0.06-0.27) and the relapse-freedom probability after at least 6 months of therapy was 72%. The ARR on BCD was 0.51 (95% CI = 0.34-0.77), and the relapse-freedom probability was 33%. The ARR on MMF was 0.32 (95% CI = 0.19-0.53) and the relapse-freedom probability was 49%. In pediatric-onset disease, MMF had the lowest ARRs (0.15, 95% CI = 0.07-0.33). CONCLUSION: IVIG had the lowest ARRs and IRRs compared to pre-treatment and the highest relapse-freedom odds ratio compared to prednisone, while BCD had the lowest. In pediatric-onset MOGAD, MMF had the lowest ARRs.

Anti-SARS-CoV-2 monoclonal antibodies for the treatment of active COVID-19 in multiple sclerosis: An observational study.

Monoclonal antibodies (mAbs) against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) received emergency use authorization for the acute treatment of COVID-19. We are not aware of published data on their use in immunosuppressed people with multiple sclerosis (pwMS). We report 23 pwMS (mean age = 49 years, ocrelizumab (n = 19), fingolimod (n = 2), vaccinated with at least an initial series (n = 19)) who received mAb for acute COVID-19. Following mAb receipt, approximately half recovered in <7 days (48%). There were no adverse events or deaths. Use of mAb for pwMS treated with fingolimod or ocrelizumab was not observed to be harmful and is likely helpful for treatment of acute COVID-19.

Telehealth for Comprehensive Care of Acute Neurologic Disorders.

A teleneurology hospitalist model aims to address the demand for high-quality neurologic acute care and the shortage of neurologists. Here, we review concepts and models of teleneurology services to address access and care gaps in neurology beyond telestroke models. The goal of these emergent teleservices is to empower community hospitals to deliver the highest quality care, while also reducing unnecessary patient transfers to tertiary care hospitals. We highlight the clinical models, patient populations, and innovative approaches of different tele-neurohospitalist services. This includes challenges related to clinical limitations, legal issues, and reimbursement. We highlight specific areas of research that can further clarify and refine the appropriate use, cost-effectiveness, and clinical outcomes of these telemedicine-based care models.

Autoimmune encephalitis: proposed recommendations for symptomatic and long-term management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. The most popular bridging therapy was oral prednisone taper chosen by 38% of responders while rituximab was the most popular maintenance therapy chosen by 46%. Most responders considered maintenance immunosuppression after a second relapse in patients with neuronal surface antibodies (70%) or seronegative autoimmune encephalitis (61%) as opposed to those with onconeuronal antibodies (29%). Most responders opted to cancer screening for 4 years in patients with neuronal surface antibodies (49%) or limbic encephalitis (46%) as opposed to non-limbic seronegative autoimmune encephalitis (36%). Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Autoimmune encephalitis: proposed best practice recommendations for diagnosis and acute management.

The objective of this paper is to evaluate available evidence for each step in autoimmune encephalitis management and provide expert opinion when evidence is lacking. The paper approaches autoimmune encephalitis as a broad category rather than focusing on individual antibody syndromes. Core authors from the Autoimmune Encephalitis Alliance Clinicians Network reviewed literature and developed the first draft. Where evidence was lacking or controversial, an electronic survey was distributed to all members to solicit individual responses. Sixty-eight members from 17 countries answered the survey. Corticosteroids alone or combined with other agents (intravenous IG or plasmapheresis) were selected as a first-line therapy by 84% of responders for patients with a general presentation, 74% for patients presenting with faciobrachial dystonic seizures, 63% for NMDAR-IgG encephalitis and 48.5% for classical paraneoplastic encephalitis. Half the responders indicated they would add a second-line agent only if there was no response to more than one first-line agent, 32% indicated adding a second-line agent if there was no response to one first-line agent, while only 15% indicated using a second-line agent in all patients. As for the preferred second-line agent, 80% of responders chose rituximab while only 10% chose cyclophosphamide in a clinical scenario with unknown antibodies. Detailed survey results are presented in the manuscript and a summary of the diagnostic and therapeutic recommendations is presented at the conclusion.

Creutzfeldt-Jakob disease in a man with COVID-19: SARS-CoV-2-accelerated neurodegeneration?

We describe a man whose first manifestations of Creutzfeldt-Jakob disease occurred in tandem with symptomatic onset of coronavirus disease 2019 (COVID-19). Drawing from recent data on prion disease pathogenesis and immune responses to SARS-CoV-2, we hypothesize that the cascade of systemic inflammatory mediators in response to the virus accelerated the pathogenesis of our patient's prion disease. This hypothesis introduces the potential relationship between immune responses to the novel coronavirus and the hastening of preclinical or manifest neurodegenerative disorders. The global prevalence of both COVID-19 and neurodegenerative disorders adds urgency to the study of this potential relationship.

Teleneurology Consultations for Prognostication and Brain Death Diagnosis.

The diagnosis of brain death and the determination of neurologic prognosis following cardiac arrest are important reasons for neurology consultation in the intensive care unit. In hospitals without access to neurology consultation, it may be challenging to address these important questions with high reliability in a timely manner. The American Academy of Neurology has established consensus criteria for diagnosis of brain death, which include (i) comatose state; (ii) presence of apnea; and (iii) absence of brainstem reflexes in the setting of a diagnosis of underlying brain injury compatible with brain death. It has recently been shown that virtual assessment of coma using standardized scales is feasible with good inter-rater reliability. The supervision of apnea testing and the neurologic examination of the brainstem by a remote neurologist are possible if conducted in conjunction with a well-trained and experienced bedside team. In this communication, we explore the essential clinical and legal framework that can support using virtual teleconsultations to address this complex topic.

Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum.

OBJECTIVE: Neuromyelitis optica (NMO) and its spectrum disorders (NMOSD) are inflammatory demyelinating diseases (IDDs) with a specific biomarker, aquaporin-4-immunoglobulin G (AQP4-IgG). Prior NMO/NMOSD epidemiological studies have been limited by lack of AQP4-IgG seroprevalence assessment, absence of population-based USA studies, and under-representation of blacks. To overcome these limitations, we sought to compare NMO/NMOSD seroepidemiology across 2 ethnically divergent populations. METHODS: We performed a population-based comparative study of the incidence (2003-2011) and prevalence (on December 31, 2011) of NMO/NMOSD and AQP4-IgG seroincidence and seroprevalence (sera collected in 80-84% of IDD cases) among patients with IDD diagnosis in Olmsted County, Minnesota (82% white [Caucasian]) and Martinique (90% black [Afro-Caribbean]). AQP4-IgG was measured by M1 isoform fluorescence-activated cell-sorting assays. RESULTS: The age- and sex-adjusted incidence (7.3 vs 0.7/1,000,000 person-years [p < 0.01]) and prevalence (10 vs 3.9/100,000 [p = 0.01]) in Martinique exceeded that in Olmsted County. The AQP4-IgG age- and sex-adjusted seroincidence (6.5 vs 0.7/1,000,000 person-years [p < 0.01]) and seroprevalence (7.9 vs 3.3/100,000 [p = 0.04]) were also higher in Martinique than Olmsted County. The ethnicity-specific prevalence was similar in Martinique and Olmsted County: 11.5 and 13/100,000 in blacks, and 6.1 and 4.0/100,000 in whites, respectively. NMO/NMOSD represented a higher proportion of IDD cases in Martinique than Olmsted County (16% vs 1.4%; p < 0.01). The onset age (median = 35-37 years) and female:male distribution (5-9:1) were similar across both populations; 60% of prevalent cases were either blind in 1 eye, dependent on a gait aid, or both. INTERPRETATION: This study reports the highest prevalence of NMO/NMOSD in any population (10/100,000 in Martinique), estimates it affects 16,000 to 17,000 in the USA (higher than previous predictions), and demonstrates it disproportionately affects blacks. Ann Neurol 2016;79:775-783.

Treatment of neuromyelitis optica.

PURPOSE OF REVIEW: Neuromyelitis optica (NMO) is an antibody-mediated inflammatory disease of the central nervous system with a predilection for the optic nerves, spinal cord and certain brain regions. It has a distinct pathogenesis relating to aquaporin-4 autoimmunity and complement-mediated injury. This knowledge has translated into targeted efforts to develop novel, disease-specific treatments. In this review, we discuss evidence supporting the use of currently available treatments for acute exacerbations and for long-term disease modification. We also discuss the risks and benefits of available and emerging immunotherapies. RECENT FINDINGS: Early, accurate diagnosis of NMO with appropriate acute and long-term immunosuppressive treatment is of prime importance for the prevention of disability associated with this disease. Standard measures for the management of acute exacerbations include intravenous methylprednisolone and plasmapheresis. First-line, long-term immunotherapies for NMO include azathioprine, mycophenolate mofetil and rituximab. Three randomized controlled treatment trials evaluating these agents are currently being conducted. In addition, there are numerous emerging therapies that are based upon current understanding of the disease immunopathogenesis. SUMMARY: NMO is an autoimmune disease that is separate from multiple sclerosis. Better understanding of its antibody and complement-dependent pathophysiology has proven to be critical for the formulation of current and future treatment strategies.

Predictors of relapsing disease course following index event in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD).

BACKGROUND: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune disease that can present as a monophasic or relapsing disease course. Here, we investigate the predictors of developing relapsing disease with a focus on the index event. METHODS: MOGAD patients followed at Massachusetts General Hospital and Brigham and Women's Hospital were included. Data on demographic, clinical, and laboratory features were collected. Time-to-event survival analysis was performed using a Cox proportional hazards model. Univariate and multivariate regression analyses were performed. RESULTS: We included 124 patients with a diagnosis of MOGAD of which 62.1% (n = 77) were female. The median (IQR) onset age and follow-up time were 31 (16, 45), and 4.08 (2.2, 7.9) years respectively. In total, 40.3% (n = 50) of patients remained monophasic and, 59.7% (n = 74) developed a relapsing course. The median (IQR) time between the index event and the second attack was 3(2, 13.7) months. Starting maintenance therapy following the index event was associated with decreased risk of relapsing disease (HR:0.26; 95%CI: 0.12, 0.54; P < 0.001). Maintenance therapy with intravenous immunoglobulin (HR:0.1; 95% CI:0.01, 0.78, P = 0.02), rituximab (HR: 0.21; 95%CI: 0.08, 0.55; P = 0.001), and mycophenolate mofetil (HR: 0.27; 95%CI: 0.09, 0.77; P = 0.01) was associated with a decreased risk of relapsing disease course. A polyphasic first attack (HR:2.4; 95%CI:1.31, 4.4; P = 0.004) and high CSF protein (HR:2.06; 95%CI: 1.01, 4.16; P = 0.04) were associated with a relapsing course. CONCLUSIONS: In MOGAD patients, starting maintenance therapy following the index event reduces the risk of relapsing disease regardless of age, sex, and onset phenotype, while polyphasic first attack, and elevated CSF protein predict relapsing disease course.

Assessment of international MOGAD diagnostic criteria in patients with overlapping MOG-associated disease and multiple sclerosis phenotypes.

BACKGROUND: The clinical spectrum and diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has evolved in the setting of an optimized anti-MOG-IgG cell-based assay and expert consensus. The McDonald criteria for MS have been revised multiple times to improve the accuracy and specificity of diagnosis on a framework based on clinical presentation, MRI findings, and CSF results. While the uses of MS and MOGAD diagnostic criteria are helpful for typical cases, such utility for patients with overlapping clinical, laboratorial, and imaging features is unknown, posing diagnostic and management uncertainties. OBJECTIVES: To report a multicenter cohort of patients with overlapping phenotypic features of MOGAD and MS and evaluate the application of new MOGAD diagnostic criteria. METHODS: A collaborative retrospective cohort study was performed to identify patients with both positive serum anti-MOG-IgG and fulfillment of the MS revised 2017 McDonald criteria. Clinical and radiographic features of patients fulfilling inclusion criteria were reviewed longitudinally, including relapses, repeated MRI, and MOG-IgG testing in detail to allow the panel of expert opinion to assign to each case. The International MOGAD Panel proposed criteria were applied at onset and last follow-up to each case and compared to the expert author diagnosis assignment based on presentation, clinical and imaging features, and response to treatment. RESULTS: Ten of 225 (4%) MOG-IgG seropositive cases met study inclusion criteria [seven of 10 were female; age at initial event: eight adults (mean age 26.8 years), two adolescents (mean age 14.5 years)]. AQP4-IgG was negative for all. Apart from serum titers of MOG-IgG, distinguishing clinical and radiographic features [i.e., clinical severity of the initial demyelinating event, radiographic features (optic nerve/spine/brain), and presence/absence of lesion normalization on serial scans] led to consensus of three separate classifications differing by degrees of shared features of MOGAD and MS. Patients were classified by expert panel into (1) Classic MOGAD even with MS-like, well-defined brain lesions, when severe events and most T2 lesions normalized (n = 5; MOG-IgG titers 1:100, 1:20, 1:160, 1:40, 1:200); (2) Classic RRMS included cases thought to have likely false positive or clinically irrelevant MOG-IgG, due to mild clinical events and no radiographic normalization of well-defined MS-like lesions (n = 3; MOG titers 1:20, 1:100, 1:40); (3) MOGAD and MS overlapping phenotype was defined by those with a combination of mild and severe clinical events, partial T2 lesion normalization, both well- and ill-defined lesions (n = 2; MOG titers 1:20, 1:100). The application of the International MOGAD Panel criteria categorized five patients (50%) in agreement with expert assignment. One additional patient was classified in agreement to assignment when MOGAD criteria were applied after serial MOG-IgG titers testing. DISCUSSION: While the International MOGAD Panel diagnostic criteria have helped with accuracy for the diagnosis of this condition, in a group of patients seropositive for MOG-IgG with overlapping clinical and imaging features of RRMS criteria review may lead to increased accuracy. Serial serologies, repeated imaging, close attention to clinical course, and response to therapy are possible variables to consider for further refinement of MOGAD diagnostic criteria.

Subacute Brachial Plexopathy due to Intraneural Epithelioid Hemangioma: A Case Report.

Brachial plexopathy is a common consideration in the differential diagnosis of upper extremity sensory and motor deficits, and neoplasms signify one possible etiology of brachial plexopathy. Of the neoplastic brachial plexopathies, hemangiomas involving the brachial plexus are rare. Most reported cases describe extraneural brachial plexus hemangiomas that present as a palpable, tender neck mass associated with pain and sensory disturbance, with minimal motor deficits. Here we share the case of a 48 year-old man with intraneural epithelioid hemangioma of the brachial plexus who presented with prominent motor weakness and no palpable mass. The patient presented with subacute onset of left arm pain, numbness and progressive weakness. Neurologic exam revealed lower motor neuron signs and weakness spanning multiple nerve root and peripheral nerve distributions. Dedicated brachial plexus MRI showed two mass lesions involving the cords of the brachial plexus, with corresponding FDG-avidity on PET/CT. Biopsy revealed intraneural atypical epithelioid hemangioma. After nerve transfer surgery, he had moderate improvement in left arm strength. This case serves to: emphasize the importance of both clinical localization and dedicated brachial plexus imaging in the evaluation of brachial plexopathy; introduce to the literature a new clinical presentation of brachial plexus hemangiomas; encourage consideration of neoplastic brachial plexopathy even when faced with an illness script resembling Parsonage-Turner Syndrome, to avoid delays in diagnosis and treatment.

Safety and Feasibility of an Emergency Department-to-Outpatient Pathway for Patients With TIA and Nondisabling Stroke.

Background and Objectives: Evaluation of transient ischemic attack/nondisabling ischemic strokes (TIA/NDS) in the emergency department (ED) contributes to capacity issues and increasing health care expenditures, especially high-cost duplicative imaging. Methods: As an institutional quality improvement project, we developed a novel pathway to evaluate patients with TIA/NDS in the ED using a core set of laboratory tests and CT-based neuroimaging. Patients identified as 'low risk' through a safety checklist were discharged and scheduled for prompt outpatient tests and stroke clinic follow-up. In this prespecified analysis designed to assess feasibility and safety, we abstracted data from patients consecutively enrolled in the first 6 months. Results: We compared data from 106 patients with TIA/NDS enrolled in the new pathway from April through September 2020 (age 67.9 years, 45% female), against 55 unmatched historical controls with TIA encountered from April 2016 through March 2017 (age 68.3 years, 47% female). Both groups had similar median NIHSS scores (pathway and control 0) and ABCD2 scores (pathway and control 3). Pathway-enrolled patients had a 44% decrease in mean ED length of stay (pathway 13.7 hours, control 24.4 hours, p < 0.001) and decreased utilization of ED MRI-based imaging (pathway 63%, control 91%, p < 0.001) and duplicative ED CT plus MRI-based brain and/or vascular imaging (pathway 35%, control 53%, p = 0.04). Among pathway-enrolled patients, 89% were evaluated in our stroke clinic within a median of 5 business days; only 5.5% were lost to follow-up. Both groups had similar 90-day rates of ED revisits (pathway 21%, control 18%, p = 0.84) and recurrent TIA/ischemic stroke (pathway 1%, control 2%, p = 1.0). Recurrent ischemic events among pathway-enrolled patients were attributed to errors in following the safety checklist before discharge. Discussion: Our TIA/NDS pathway, implemented during the initial outbreak of COVID-19, seems feasible and safe, with significant positive impact on ED throughput and ED-based high-cost duplicative imaging. The safety checklist and option of virtual telehealth follow-up are novel features. Broader adoption of such pathways has important implications for value-based health care.

Positive Predictive Value of MOG-IgG for Clinically Defined MOG-AD Within a Real-World Cohort.

Myelin oligodendrocyte glycoprotein antibody associated disease (MOG-AD) is a CNS demyelinating disease, typically presenting with optic neuritis, transverse myelitis, and/or ADEM-like syndromes. The positive predictive value (PPV) of MOG-IgG testing by live cell-based assay was reported to be 72% in a study performed at the Mayo Clinic using a cut-off of 1:20. PPV may vary depending upon the tested population, thus supporting further investigation of MOG-IgG testing at other centers. In this real-world institutional cohort study, we determined the PPV of serum MOG-IgG for clinically defined MOG-AD in our patient population. The Massachusetts General Brigham Research Patient Data Registry database was queried for patients with positive serum MOG-IgG detection, at least once, between January 1, 2017 and March 25, 2021. All were tested via the MOG-IgG1 fluorescence-activated cell sorting assay (Mayo Laboratories, Rochester, MN). MOG-IgG positive cases were reviewed for fulfillment of typical MOG-AD clinical features, determined by treating neurologists and study authors. Of 1,877 patients tested, 78 (4.2%) patients tested positive for MOG-IgG with titer ≥1:20, and of these, 67 had validated MOG-AD yielding a PPV of 85.9%. Using a ≥1:40 titer cutoff, 65 (3.5%) tested positive and PPV was 93.8%. Three MOG positive cases had a prototypical multiple sclerosis diagnosis (RRMS n = 2, titers 1:20 and 1:40; PPMS n = 1; 1:100). The treating diagnosis for one RRMS patient with a 1:40 titer was subsequently modified to MOG-AD by treating neurologists. Validated diagnoses of the remaining positive patients without MOG-AD included: migraine (n = 2, titers 1:20, 1:100), inclusion body myositis (n = 1, titer 1:100), autoimmune encephalitis (n = 2, titers 1:20, 1:20), hypoxic ischemic brain injury (n = 1, titer 1:20), IgG4-related disease (n = 1, titer 1:20), and idiopathic hypertrophic pachymeningitis (n = 1, titer 1:20). In our cohort, the PPV for MOG-IgG improved utilizing a titer cut-off of ≥1:40. The presence of positive cases with and without demyelinating features, emphasizes a need for testing in the appropriate clinical context, analysis of titer value and clinical interpretation.

Extended B-cell depletion beyond 6-months in patients receiving ocrelizumab or rituximab for CNS demyelinating disease.

OBJECTIVES: To investigate the duration of B-cell depletion in a cohort of patients receiving ocrelizumab or rituximab for multiple sclerosis (MS) or neuromyelitis optica spectrum disorders (NMOSD). METHODS: We retrospectively searched our database for patients diagnosed with MS or NMOSD, who were receiving ocrelizumab or rituximab and had available CD19 measurements. We collected demographic data, infusion doses, infusion dates, CD19 absolute counts and percentages, and their collection dates. We paired each infusion with the subsequent CD19 measurements recorded before the next infusion, discarding measurements done during a washout period of 30 days after each infusion. We applied three definitions for B-cell depletion, the most stringent of which was an absolute B-cell count ≤20 cells/uL. RESULTS: From 695 patients with demyelinating diseases in our database, over the period of January 1st 2010 to March 1st 2020, we identified 188 patients (178 with MS and 10 with NMOSD), who had received ocrelizumab or rituximab and had available CD19 measurements. 1054 CD19 measurements were captured. B-cell depletion, as defined above, was recorded as far out as 22.8 months after an ocrelizumab infusion, and 22.3 months after a rituximab infusion. Out of 90 B-cell measurements done ≥8 months (>210 days) after ocrelizumab infusion, 45(50%) measurements showed B-cell depletion. Similarly for rituximab, out of 113 measurements, 49(43%) showed B-cell depletion. CONCLUSIONS: This study demonstrates that B-cell depletion after ocrelizumab and rituximab continues beyond the traditional 6-month re-infusion interval in many patients. Our report provides data that can support clinical trials testing increasing the interval of re-infusion with ocrelizumab and rituximab beyond 6-months guided by B-cell measurements.