Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder: Onset Following Acute COVID-19 Infection, a Case Series.

BACKGROUND AND OBJECTIVES: Acute COVID-19 infection has been associated with neurological involvement. We report a case series of newly diagnosed patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) developed in a short period of time after acute COVID-19 infection. METHODS: New MS patients developing initial symptoms shortly after an acute COVID-19 infection were diagnosed based on the 2017 McDonald Criteria [Garcia-Ramos et al. in Cells, 2021]. The patients diagnosed with NMOSD met the 2015 International Panel criteria for the diagnosis of NMOSD (IPDN) [Thompson et al. in Lancet Neurol 17:162-173, 2018]. RESULTS FROM THE MS PATIENT GROUP: Ten patients were included who had developed initial MS symptoms after COVID-19 infection. Gender distribution was equal (50% male). The mean age was 28 (range 17-39) years. Average time to neurological presentation was between 2 and 6 weeks following acute COVID-19 infection. Partial transverse myelitis was the initial presentation in 40% of the cases, and 60% of patients had spinal cord lesions present at the moment of diagnosis. All patients showed enhancing lesions on brain magnetic resonance imaging (MRI). The presence of cerebrospinal fluid (CSF) oligoclonal bands was found in all six tested cases. The majority of patients (80%) were unvaccinated for COVID-19. The two vaccinated patients had received two doses of the monovalent COVID-19 messenger ribonucleic acid (mRNA) (Pfizer Biotech) vaccine and no booster, a year prior to contracting COVID-19. RESULTS FROM THE NMOSD GROUP: Two patients with NMOSD were included. Positive aquoporin-4 protein antibody (AQP-4 Ab) was detected in serum in both cases [one Enzyme Linked immunosorbent assay (ELISA) and one cell based]. Both patients had mild COVID-19 infection prior to presentation, initial neurologic symptoms presented between 3 and 6 weeks after COVID-19 infection. Neither patients were vaccinated. Both responded partially to steroids, one developed a relapse 40 days after diagnosis. CONCLUSION: COVID-19 infection has been linked to several neurological and immune-driven conditions. This study suggests that in susceptible individuals, acute COVID-19 infection may act as a trigger for developing MS and NMOSD.

Evaluation of Urea-Based Inhibitors of the Dopamine Transporter Using the Experimental Autoimmune Encephalomyelitis Model of Multiple Sclerosis.

The dopaminergic system is involved in the regulation of immune responses in various homeostatic and disease conditions. For conditions such as Parkinson's disease and multiple sclerosis (MS), pharmacological modulation of dopamine (DA) system activity is thought to have therapeutic relevance, providing the basis for using dopaminergic agents as a treatment of relevant states. In particular, it was proposed that restoration of DA levels may inhibit neuroinflammation. We have recently reported a new class of dopamine transporter (DAT) inhibitors with high selectivity to the DAT over other G-protein coupled receptors tested. Here, we continue their evaluation as monoamine transporter inhibitors. Furthermore, we show that the urea-like DAT inhibitor (compound 5) has statistically significant anti-inflammatory effects and attenuates motor deficits and pain behaviors in the experimental autoimmune encephalomyelitis model mimicking clinical signs of MS. To the best of our knowledge, this is the first study reporting the beneficial effects of DAT inhibitor-based treatment in animals with induced autoimmune encephalomyelitis, and the observed results provide additional support to the model of DA-related neuroinflammation.

Meta-analysis of effectiveness of steroid-sparing attack prevention in MOG-IgG-associated disorder.

OBJECTIVE: To estimate the efficacy of the commonly used long-term immunotherapies in myelin oligodendrocyte glycoprotein IgG associated disorder (MOGAD) METHOD: A comprehensive search of the databases including PubMed/MEDLINE, EMBASE, and Cochrane database was performed for all studies that assessed the efficacy of azathioprine (AZA), mycophenolate mofetil (MMF), rituximab (RTX), and maintenance intravenous immunoglobulin (mIVIG) in MOGAD. The random-effect model is used to estimate the standard mean difference (SMD) of annualized relapse rate (ARR) and expanded disability status scale (EDSS), mean ARR, probabilities of relapse and worsening EDSS during treatment. RESULTS: The initial search identified 714 articles, and 21 satisfied eligibility criteria. All immunotherapies significantly reduced ARR in both pediatric and adult populations. Relapse probabilities and pooled mean ARR (SE: standard error) during therapies were as follow: AZA 53.1% [95%CI 37.4% to 68.2%; ARR 0.291 (0.134)], MMF 38.5% [95%CI 19.4% to 62.0%; ARR 0.836 (0.176)], RTX 48.9% [95%CI 37.8% to 60.2%; ARR 0.629(0.162)], and mIVIG 25.3% [95%CI 14.0% to 41.3%; ARR 0.081 (0.058)]. Only RTX significantly improved EDSS, SMD -0.499 (95%CI -0.996 to -0.003). The proportion of worsening EDSS with immunotherapies were 20.7% (95%CI 8.8% to 41.6%), 8.1% (95%CI 1.1% to 41.2%), and 10.8% (95%CI 3.8% to 26.8%) for AZA, MMF, and RTX, respectively. CONCLUSION: These commonly used immunotherapies significantly reduced ARR in MOGAD. Only RTX had a significant benefit in EDSS improvement. However, a substantial portion of patients continued to relapse with treatment. Randomized controlled studies are needed to verify these findings and perform head-to-head comparisons among these treatment options.

Geographic heterogeneity in the association of varicella-zoster virus seropositivity and multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Although there has long been a suspected association between varicella-zoster virus (VZV) and multiple sclerosis (MS), the connection has remained unclear. In this study, we performed a meta-analysis in an attempt to assess the association between VZV IgG serostatus and MS. METHODS: A literature search was performed using three databases: MEDLINE, EMBASE, and Cochrane. Eligible results included observational studies investigating the seroprevalence of VZV immunoglobulin G (IgG) in adults with MS versus non-MS controls. Two authors performed a screen of the search results, evaluating them for quality and relevant outcomes. Using a random-effect model, we estimated pooled odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: The literature search yielded 1,268 articles, 8 of which (2,266 MS patients and 1,818 controls) were eligible for inclusion in the meta-analysis. Evaluation of all included studies together showed no significant association between VZV IgG seropositivity and MS (OR 1.439; 95%CI, 0.503-4.118; p 0.497). However, when analyzed in subgroups based on geographical area, studies performed in Asian countries showed VZV IgG seropositivity was more common in MS patients than in controls (OR 4.470; 95%CI 1.959-10.203; p < 0.001). No significant association was found in European countries. CONCLUSIONS: This study found evidence of an association between VZV IgG seropositivity and MS in Asian countries. Additional studies are warranted to ascertain factors impacting this association.

The effect of tonsillectomy on John Cunningham virus serological status in multiple sclerosis patients: A retrospective case-control study.

Tonsils are believed to be the initial site of the John Cunningham virus (JCV) infection. The long-term effect of childhood tonsillectomy on JCV status in multiple sclerosis (MS) patients has not been investigated. In this retrospective case-control study, we analyzed data of 144 JCV seropositive cases and 82 JCV seronegative controls from three outpatient MS clinics in the United States. Early tonsillectomy (before the age of 8) was reported among 8 (5.56%) JCV seropositive subjects and 19 (23.17%) controls. Early tonsillectomy was associated with JCV negative status (adjusted odds ratio = 5.39, 95% confidence interval = 2.13-13.62, p < 0.001) independent of age and gender.

Adult Langerhans cell histiocytosis of the central nervous system.

Langerhans cell histiocytosis (LCH), a disorder characterized by aberrant function and proliferation of mononuclear phagocytic cells called Langerhans cells, usually occurs in those <15 years of age. Adult-onset LCH is extremely rare. We present a case of a 35-year-old woman who presented with multiple episodes of confusion, rapidly progressive cognitive decline, and multiple endocrinopathies, including diabetes insipidus. Brain imaging showed a hypothalamic lesion, and biopsy results confirmed the diagnosis of LCH. Given the wide variety of presentations and the multiple differential diagnoses of hypothalamic lesions, it is essential to be aware of this uncommon condition, especially in adults, where it may be underdiagnosed.

Disease-Modifying Therapies During the COVID-19 Outbreak: A Narrative Review of International and National Recommendations.

BACKGROUND: Managing multiple sclerosis (MS) during the novel coronavirus disease 2019 (COVID-19) pandemic is a challenge due to the lack of evidence from clinical studies. Disease-modifying therapies (DMTs) may affect the immune response and subsequently alter the risk of COVID-19 infections. METHODS: A literature search was conducted on the MEDLINE, Embase, and Cochrane databases. A focused Google search was also performed. Recommendations regarding the use of DMTs during the COVID-19 outbreak from national and international MS/neurology societies were identified and reviewed. RESULTS: The review included 16 recommendations from international and national MS organizations. All recommendations are based on expert opinions. The recommendations regarding DMT initiation and management during this outbreak are summarized. Moreover, the experts' views about the risk of COVID-19 infection with each DMT are discussed. CONCLUSIONS: There is significant agreement among most experts' recommendations from a variety of sources based on collective clinical experience. However, the recommendations will likely evolve because sufficient clinical data are limited. Several ongoing registries will help provide information for future recommendations.

Regional differences in the association of cytomegalovirus seropositivity and multiple sclerosis: A systematic review and meta-analysis.

BACKGROUND: Despite of a few decades of investigations, the association and role of cytomegalovirus (CMV) and multiple sclerosis (MS) remain inconclusive. Herein, we performed a meta-analysis to investigate the association between CMV IgG serostatus and MS. METHODS: A literature search was conducted on MEDLINE, EMBASE, and Cochrane databases. Eligibility criteria included observational studies assessing the seroprevalence of CMV immunoglobulin G (IgG) in adults with MS and non-MS control. Two authors screened all resulting studies and evaluated the quality of the included studies. Pooled odd ratios (ORs) and 95% confidence intervals (CIs) were estimated using a random-effect model. RESULTS: The search identified 771 unique citations, and 15 (3,591 MS patients and 4,241 controls) satisfied eligibility criteria. The meta-analysis of all included studies showed no significant association between CMV IgG seropositivity and MS with a substantial heterogeneity (OR 1.190; 95%CI 0.780-1.813; I2 32.7%). Subgroup analysis, stratified by geographic area, showed different associations and less heterogeneity in each geographical area. In Europe, CMV IgG seroprevalence was lower among people with MS than controls (OR 0.750; 95%CI 0.599-0.940; I213.9%). In contrast, CMV IgG seropositivity was more common among MS patients compared to controls in the Middle East region (OR 5.089; 95%CI 01.067-24.263; I2 5.6%). There was no significant association in North America. CONCLUSIONS: There is evidence of the regional differences in the association between CMV IgG seropositivity and MS. Further biological and epidemiological studies are needed to identify the genetic or environmental factors which are potentially the effect modifiers of this association.

The Role of Sex Hormones in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelination disorder with an immune-mediated pathophysiology that affects the central nervous system (CNS). Like other autoimmune conditions, it has a predilection for female gender. This suggests a gender bias and a possible hormonal association. Inflammation and demyelination are hallmarks of MS. Oligodendrocytes are the myelinating cells of the CNS and these continue to be generated by oligodendrocyte precursor cells (OPCs). The process of remyelination represents a major form of plasticity in the developing adult CNS. Remyelination does occur in MS, but the process is largely inadequate and/or incomplete. Current treatment strategies primarily focus on reducing inflammation or immunosuppression, but there is a need for more extensive research on re-myelination as a possible mechanism of treatment. Previous studies have shown that pregnancy leads to an increase in OPC proliferation, oligodendrocyte generation and the number of myelinated axons in the maternal CNS. Studies have also suggested that this remyelination is possibly mediated by estriol. Sex hormones in particular have been shown to have an immuno-protective effect in TH1-driven autoimmunity diseases. The aim of our article is to review the available research on sex hormone-specific immune modulatory effects, assess its remyelination potential in MS, and suggest a future path for more extensive research on sex hormone as a target for therapeutics in MS.

The role of postpartum intravenous corticosteroids in the prevention of relapses in multiple sclerosis.

Multiple sclerosis (MS) is most prevalent in women of childbearing age. It is well established that the relapse rate decreases during pregnancy but increases significantly during the first postpartum trimester. The objective of this retrospective study was to evaluate the effectiveness of the administration of 1 g of intravenous methylprednisolone (IVMP) after delivery in the prevention of MS relapses. The study involved 47 women with one or more documented pregnancies; each pregnancy was treated as a separate case. There were 50 cases with relapsing-remitting MS and 2 with secondary progressive MS. The cases were divided into two groups: the IVMP group (those who received 1 g of IVMP after delivery) and the no-IVMP group (those who did not receive IVMP after delivery). There were 39 cases in the IVMP group and 13 in the no-IVMP group. During the first postpartum trimester, relapses occurred in 17.9% of the IVMP group, compared with 46.2% of the no-IVMP group (P = .0448). The difference in relapse percentage between the two groups during the second and third postpartum trimesters was not statistically significant. Our study shows a statistically significant benefit of postpartum IVMP administration in reducing MS relapses.