Recent advances in the treatment of primary and secondary progressive Multiple Sclerosis.

BACKGROUND: The article highlights upcoming potential treatments, which target different phases of inflammation and offer remyelinating strategies as well as direct and indirect neuroprotective and oligodendrocyte protective effects, providing a hopeful outlook for patients with primary and secondary progressive multiple sclerosis (PPMS and SPMS). OBJECTIVES: The review aims to identify potential treatments and ongoing clinical trials for PPMS and SPMS, and compare their mechanisms of action, efficacy, and side effects with current treatments. METHODS: We reviewed ongoing clinical trials for PPMS and SPMS on the NIH website, as well as articles from PubMed, Embase, and clinicaltrails.gov since 2010. RESULTS: BTKIs like, tolebrutinib, and fenebrutinib are being explored as potential PMS treatments. Vidofludimus calcium, an orally available treatment, has shown a reduction of active and new MRI lesions. Other treatments like simvastatin, N-acetylcysteine (NAC), and alpha-lipoic acid are being explored for their antioxidant properties. AHSCT and mesenchymal stem cell therapy are experimental options for younger patients with high inflammatory activity. CONCLUSIONS: SPMS and PPMS are being studied for new treatments and future trials should consider combination therapies targeting inflammation, demyelination, and neuronal death, as the pathogenesis of PMS involves complex factors.

Cross-talk between B cells, microglia and macrophages, and implications to central nervous system compartmentalized inflammation and progressive multiple sclerosis.

BACKGROUND: B cells can be enriched within meningeal immune-cell aggregates of multiple sclerosis (MS) patients, adjacent to subpial cortical demyelinating lesions now recognized as important contributors to progressive disease. This subpial demyelination is notable for a 'surface-in' gradient of neuronal loss and microglial activation, potentially reflecting the effects of soluble factors secreted into the CSF. We previously demonstrated that MS B-cell secreted products are toxic to oligodendrocytes and neurons. The potential for B-cell-myeloid cell interactions to propagate progressive MS is of considerable interest. METHODS: Secreted products of MS-implicated pro-inflammatory effector B cells or IL-10-expressing B cells with regulatory potential were applied to human brain-derived microglia or monocyte-derived macrophages, with subsequent assessment of myeloid phenotype and function through measurement of their expression of pro-inflammatory, anti-inflammatory and homeostatic/quiescent molecules, and phagocytosis (using flow cytometry, ELISA and fluorescently-labeled myelin). Effects of secreted products of differentially activated microglia on B-cell survival and activation were further studied. FINDINGS: Secreted products of MS-implicated pro-inflammatory B cells (but not IL-10 expressing B cells) substantially induce pro-inflammatory cytokine (IL-12, IL-6, TNFα) expression by both human microglia and macrophage (in a GM-CSF dependent manner), while down-regulating their expression of IL-10 and of quiescence-associated molecules, and suppressing their myelin phagocytosis. In contrast, secreted products of IL-10 expressing B cells upregulate both human microglia and macrophage expression of quiescence-associated molecules and enhance their myelin phagocytosis. Secreted factors from pro-inflammatory microglia enhance B-cell activation. INTERPRETATION: Potential cross-talk between disease-relevant human B-cell subsets and both resident CNS microglia and infiltrating macrophages may propagate CNS-compartmentalized inflammation and injury associated with MS disease progression. These interaction represents an attractive therapeutic target for agents such as Bruton's tyrosine kinase inhibitors (BTKi) that modulate responses of both B cells and myeloid cells. FUNDING: Stated in Acknowledgments section of manuscript.

MOG Antibody-Associated Disease and Thymic Hyperplasia: From the National Multiple Sclerosis Society Case Conference Proceedings.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently described CNS inflammatory disorder that may manifest with optic neuritis, myelitis, seizures, and/or acute disseminated encephalomyelitis. While MOG-specific antibodies in patients with MOGAD are IgG1, a T-cell-dependent antibody isotype, immunologic mechanisms of this disease are not fully understood. Thymic hyperplasia can be associated with certain autoimmune diseases. In this report we describe a case of MOGAD associated with thymic hyperplasia in a young adult.

Multiple Sclerosis Followed by Neuromyelitis Optica Spectrum Disorder: From the National Multiple Sclerosis Society Case Conference Proceedings.

A woman presented at age 18 years with partial myelitis and diplopia and experienced multiple subsequent relapses. Her MRI demonstrated T2 abnormalities characteristic of multiple sclerosis (MS) (white matter ovoid lesions and Dawson fingers), and CSF demonstrated an elevated IgG index and oligoclonal bands restricted to the CSF. Diagnosed with clinically definite relapsing-remitting MS, she was treated with various MS disease-modifying therapies and eventually began experiencing secondary progression. At age 57 years, she developed an acute longitudinally extensive transverse myelitis and was found to have AQP4 antibodies by cell-based assay. Our analysis of the clinical course, radiographic findings, molecular diagnostic methods, and treatment response characteristics support the hypothesis that our patient most likely had 2 CNS inflammatory disorders: MS, which manifested as a teenager, and neuromyelitis optica spectrum disorder, which evolved in her sixth decade of life. This case emphasizes a key principle in neurology practice, which is to reconsider whether the original working diagnosis remains tenable, especially when confronted with evidence (clinical and/or paraclinical) that raises the possibility of a distinctively different disorder.

Are There Racial Differences in Inpatient Outcomes and Treatment Utilization following Hospitalization for Myasthenia Gravis Exacerbation?

INTRODUCTION: Little is known about racial differences in inpatient outcomes following hospitalizations for myasthenia gravis (MG). In this study, we used a claims-based database to assess racial differences in outcomes in hospitalized myasthenics. METHODS: The 2006-2014 National Inpatient Sample database was queried using the International Classification of Diseases 9th Edition diagnosis code (358.01) to identify adult patients (age >17 years) undergoing hospitalization for MG. Race was categorized into - white, black/African American (AA), Asian or Pacific Islander, Hispanic, Native American, and other. Complications assessed included urinary tract infections, acute renal failure, cardiac complications, systemic infection, deep venous thrombosis, and pulmonary embolism. Multivariate logistic regression analyses were used to assess whether race was associated with a difference in outcomes, after controlling for baseline demographics, hospital characteristics, and treatment factors. RESULTS: A total of 56,189 patient admissions, using a weighted sample, underwent hospitalization for MG between 2006 and 2014. Black/AA patients had significantly higher odds of experiencing systemic infections (odds ratio [OR] 1.35 [95% confidence intervals [CI] 1.16-1.58]; p < 0.001), deep venous thrombosis (OR 2.11 [95% CI 1.36-3.27]; p = 0.001), and renal failure (OR 1.19 [95% CI 1.05-1.35]; p = 0.005). Black/AA patients were more likely to be intubated (OR 1.09 [95% CI 1.01-1.19]; p = 0.028) and receive noninvasive mechanical ventilation (OR 1.62 [95% CI 1.46-1.79]; p < 0.001), however, were less likely to receive intravenous immunoglobulin (OR 0.77 [95% CI 0.73-0.82]; p < 0.001) and plasmapheresis (OR 0.77 [95% CI 0.72-0.82]; p < 0.001). Black/AA and Hispanic patients had lower mortality (OR 0.74 [95% CI 0.59-0.94; p = 0.012]. CONCLUSIONS: Significant racial differences exist in both treatment utilization and inpatient outcomes for patients hospitalized for MG.

Early versus delayed treatment with glatiramer acetate: Analysis of up to 27 years of continuous follow-up in a US open-label extension study.

BACKGROUND: Glatiramer acetate (GA) is US-approved for relapsing multiple sclerosis. OBJECTIVES: To describe GA long-term clinical profile. To compare effectiveness of early start (ES) versus delayed start (DS; up to 3 years) with GA. METHODS: Phase 3 trial participants entered a randomized placebo-controlled period then an open-label extension (OLE) with GA. RESULTS: Overall, 208 out of 251 (82.9%) randomized participants entered the OLE; 24 out of 101 (23.8%, ES) and 28 out of 107 (26.2%, DS) participants completed the OLE. Median GA treatment was 9.8 (0.1-26.3) years. Annualized change in Expanded Disability Status Scale (EDSS) score was lower with ES versus DS (p = 0.0858: full study; p = 0.002; Year 5). Participants with improved/stable EDSS was consistently higher with ES versus DS: 40.3% versus 31.6% (p = 0.1590; full study); 70.8% versus 55.6% (p = 0.015; Year 5). ES prolonged time-to-6-month confirmed disease worsening (CDW) versus DS (9.8 vs 6.7 years), time-to-12-month CDW (18.9 vs 11.6 years), and significantly reduced time-to-second-6-month CDW (p = 0.0441). No new safety concerns arose. CONCLUSION: GA long-term treatment maintained clinical benefit with a similar safety profile to phase 3 results; a key limitation was that only 25% of participants completed the OLE. Early initiation of GA had sustained benefits versus delayed treatment.

Progressive multifocal leukoencephalopathy and sphingosine 1-phosphate receptor modulators used in multiple sclerosis: an updated review of literature.

OBJECTIVE: Progressive multifocal leukoencephalopathy (PML) is a serious viral infection associated with disease-modifying therapies (DMT) for multiple sclerosis (MS) including sphingosine 1-phosphate receptor (S1PR) modulators. The objective of this review was to investigate the characteristics of PML in MS patients associated with drugs of the S1PR modulator. METHODS: We conducted a literature review and analysis of 24 patients from 12 publications in PubMed, SCOPUS and EMBASE. This is a descriptive analysis and study of characteristics of PML associated fingolimod and related S1PR modulator group of DMT. RESULTS: A total of 24 cases of PML in MS patients treated with fingolimod were identified. Of these, 21 cases contained data regarding changes in the expanded disability status scale (EDSS). One case of PML in association with ozanimod treatment in a clinical trial was also identified. In PML cases associated with fingolimod, the mean age at the time of PML diagnosis was 50.91 ± 11.5 years. All patients were treated with fingolimod for more than 24 months. Compared to patients who improved or were stable, in terms of EDSS, after symptomatic management of PML, the non-improved groups were significantly older. There were no fatalities in either group during the reported follow-up period. CONCLUSION: The incidence of PML appears to be extremely low in MS patients treated with S1PR modulators. Risk of PML increases with increase in duration of treatment with S1PR modulators like fingolimod, and increased age at the time of PML diagnosis is associated with worse prognosis.

Acetylcholine receptor antibodies in a patient with sensory neuropathy.

Antibodies to acetylcholine receptor (AChR) are detected in the vast majority of patients with generalized myasthenia gravis (MG) and are rarely detected in significant titer in other autoimmune diseases. We report a patient with an axonal predominately sensory neuropathy for over 12 years with persistent binding and modulating AChR antibodies as well as striational muscle antibodies with no evidence of MG or any neoplastic disease.

Review of the COVID-19 Risk in Multiple Sclerosis.

The ongoing pandemic of the novel coronavirus of 2019 (COVID-19) has resulted in over 1 million deaths, primarily affecting older patients with chronic ailments. Multiple sclerosis (MS) patients have been deemed particularly vulnerable given their high rates of disability and increased susceptibility to infections. There have also been concerns regarding disease-modifying therapy (DMT) during the pandemic as many DMTs may increase the risk of infection due to some of their immunosuppressive properties. Furthermore, due to MS-related chronic inflammatory damage within the central nervous system, there have been concerns for worsening neurological injury by COVID-19. This has resulted in an alarmingly high level of anxiety and stress among the MS community leading to a lack of compliance with medications and routine check-ups, and even failure to obtain treatment for relapse. However, there is currently substantial evidence that MS and most DMT usage is not associated with increased COVID-19 severity. MS patients who suffer worse outcomes were more likely to be older and suffer from significant disabilities and comorbid conditions, which would also be expected from those in the general population. Likewise, there is little if any evidence demonstrating an increased susceptibility of MS patients to COVID-19-related neurological complications. Therefore, we aim to summarize the most recent findings related to COVID-19 and MS demonstrating that MS and most DMTs do not appear as risk factors for severe COVID-19.

COVID-19 and neuroinflammation: a literature review of relevant neuroimaging and CSF markers in central nervous system inflammatory disorders from SARS-COV2.

BACKGROUND: The literature on neurological manifestations in COVID-19 patients has been rapidly increasing with the pandemic. However, data on CNS inflammatory disorders in COVID-19 are still evolving. We performed a literature review of CNS inflammatory disorders associated with coronavirus disease-2019 (COVID-19). METHODS: We screened all articles resulting from a search of PubMed, Google Scholar and Scopus, using the keywords; "SARS-CoV-2 and neurological complication", "SARS-CoV-2 and CNS Complication" looking for reports of transverse myelitis, longitudinally extensive transverse myelitis, neuromyelitis optica, myelitis, Myelin Oligodendrocyte Glycoprotein Antibody Disorder (MOGAD), Acute Disseminated Encephalomyelitis (ADEM), Acute Hemorrhagic Necrotizing Encephalitis/Acute Hemorrhagic Leukoencephalitis (AHNE/AHLE), Cytotoxic lesion of the Corpus Callosum/Mild Encephalopathy Reversible Splenium Lesion(CLOCC/MERS) and Optic neuritis published between December 01, 2019 and March 15, 2021. RESULTS: Our literature search revealed 43 patients meeting the diagnosis of myelitis, including Transverse Myelitis, ADEM, AHNE/AHLE or CLOCC/MERS and Optic neuritis. Acute myelitis was most commonly associated with non-severe COVID-19 and all reported cases of AHNE/AHLE had severe COVID-19 infection. Based on IDSA/ATS criteria of either requiring vasopressor for septic shock or mechanical ventilation, 49% (n = 18) patients were considered to have a severe COVID infection. There were 7 (n = 19%) fatalities. CONCLUSION: To our knowledge, this is among the first reviews that includes the clinical features, neuroimaging, CSF findings and outcomes in COVID-19-associated CNS inflammatory disorders. Our observational review study reveals that although rare, myelitis, ADEM, AHNE and CLOCC can be associated with COVID-19 infection. Further studies using MRI imaging and CSF analysis in early diagnosis and intervention of these disorders are warranted.

Guillain Barré Syndrome and its variants as a manifestation of COVID-19: A systematic review of case reports and case series.

BACKGROUND: The COVID-19 pandemic caused by SARS-COV-2 began in Wuhan, China in December 2019. Reports of COVID-19 with central (CNS) and peripheral nervous (PNS) system manifestations are emerging. In this systematic review, we compared and summarized the demographics, clinical features, Brighton criteria, immunological and laboratory findings with a focus on modified Erasmus GBS Outcome Score (mEGOS) in SARS-CoV-2 patients with GBS and its variants. METHODS: Based on PRISMA guidelines, we searched three databases (PubMed, Scopus, and Google Scholar) for studies on COVID-19 and GBS between December 1, 2019 to July 15, 2020. For descriptive analysis, we studied two groups with: 1) acute inflammatory demyelinating polyradiculoneuropathy (AIDP) variant, and 2) Non-AIDP/Other variants. We compared mEGOS scores for patients in both groups along with other key clinical features. RESULTS: Of the 50 GBS cases identified from 37 studies, 33 (66%) had acute inflammatory demyelinating polyradiculopolyneuropathy (AIDP) while 17 (34%) were of other (non-AIDP) variants. There mEGOS scores did not differ between AIDP patients and AMAN/AMSAN patients. Majority of the AIDP (66.7%) and AMAN/AMSAN (57.2%) patients belonged to Brighton level 1 indicating maximum diagnostic certainty. CONCLUSION: To our knowledge, this is among the first reviews that includes GBS variants and the clinical prediction tool mEGOS for prognostication in COVID-19 patients. Further research is needed to assess whether IVIG is preferable over plasmapheresis in this population of GBS patients. It would also be crucial to follow these patients over time to identify the long-term disability as well as treatment outcomes.

Clinical features of LRP4/agrin-antibody-positive myasthenia gravis: A multicenter study.

INTRODUCTION: Our aim in this study was to identify the prevalence and clinical characteristics of LRP4/agrin-antibody-positive double-seronegative myasthenia gravis (DNMG). METHODS: DNMG patients at 16 sites in the United States were tested for LRP4 and agrin antibodies, and the clinical data were collected. RESULTS: Of 181 DNMG patients, 27 (14.9%) were positive for either low-density lipoprotein receptor-related protein 4 (LRP4) or agrin antibodies. Twenty-three DNMG patients (12.7%) were positive for both antibodies. More antibody-positive patients presented with generalized symptoms (69%) compared with antibody-negative patients (43%) (P ≤ .02). Antibody-positive patients' maximum classification on the Myasthenia Gravis Foundation of America (MGFA) scale was significantly higher than that for antibody-negative patients (P ≤ .005). Seventy percent of antibody-positive patients were classified as MGFA class III, IV, or V compared with 39% of antibody-negative patients. Most LRP4- and agrin-antibody-positive patients (24 of 27, 89%) developed generalized myathenia gravis (MG), but with standard MG treatment 81.5% (22 of 27) improved to MGFA class I or II during a mean follow-up of 11 years. DISCUSSION: Antibody-positive patients had more severe clinical disease than antibody-negative patients. Most DNMG patients responded to standard therapy regardless of antibody status.

Sigma-1 receptor agonists as potential protective therapies in multiple sclerosis.

The sigma-1 receptor (σ-1R) is an endoplasmic reticulum (ER) chaperone upregulated during ER stress, and regulates calcium homeostasis. Agonists of σ-1R are neuroprotective. ANAVEX2-73, a new σ-1R agonist, is undergoing several clinical trials. We show that ANAVEX2-73 protects oligodendroglia (OL) and oligodendroglial precursors (OPC) from apoptosis, excitotoxicity, reactive oxygen species (ROS) and quinolinic acid (QA), associated with inflammation. ANAVEX2-73 stimulates OPC proliferation, but does not alter early maturation to OL. We previously reported that dextromethorphan (DM), another σ-1R agonist with a different structure, had similar effects. We now show that both DM and ANAVEX2-73 protect neurons from the four cytotoxic agents.