Immune-mediated Demyelinating Diseases Research Articles

Comprehensive analysis of ocrelizumab's efficacy across different forms of multiple sclerosis: a multi-dimensional approach

BackgroundMultiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system. MS usually affects individuals between the ages of 20 and 40 and is 3 times more common among women than among men. This disease presents with a vast range of neurological symptoms and, in some cases, cognitive impairment. Aim of the studyThe purpose of this review was to assess whether the anti-CD20 antibody ocrelizumab has proven effective in treating MS since its introduction.Material and methodsThe PubMed database was searched for original papers on the effects of ocrelizumab in the treatment of MS. The inclusion criterion was a comparison of the clinical or radiological effectiveness of ocrelizumab versus placebo or other MS therapies. For this purpose, the phrase "Ocrelizumab AND Multiple Sclerosis" was used, marking only studies such as "Randomised Clinical Trial" and "Clinical Trial". The cut-off point for publishing the work was 2016.Results43 works were found, of which 15 met the conditions for inclusion in the work. The analysed studies investigated the efficacy and safety of ocrelizumab in Relapsing Multiple Sclerosis, Primary Progressive Multiple SclerosisConclusionsThe effectiveness of ocrelizumab treatment shows that the use of newly developed targeted factors may significantly improve the clinical status of MS patients. Preliminary real-world data on the efficacy of ocrelizumab are promising and align with clinical trial findings. Although ocrelizumab is generally well tolerated, it is essential to monitor and assess its long-term safety.

Clinical characteristics and long-term follow-up outcomes of myelin oligodendrocyte glycoprotein antibody-associated disease in Han Chinese participants.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an immune-mediated inflammatory demyelinating disease of the central nervous system. This study aimed to delineate the clinical manifestations, imaging features, and long-term outcomes in Chinese patients with MOGAD and analyze the recurrence-associated factors. The phenotypic and neuroimaging characteristics of 15 Han Chinese patients with MOGAD were retrospectively analyzed. Demyelinating attacks, MOG antibodies in the cerebrospinal fluid/serum, response to immunotherapy, follow-up outcomes, and recurrence-associated factors were recorded. The median age at disease onset was 34 years (range, 4-65 years). The most common initial presentations included vision loss (10/15, 66.7%) and seizures (5/15, 33.3%). Serum MOG-Ab titers in 14/15 cases were higher than those in the cerebrospinal fluid and were detected in 3/6 relapsed patients. Brain magnetic resonance imaging during acute attacks showed lesions in 10/15 patients (66.7%), mostly in the cortex/subcortical white matter (5/15, 33.3%). Recurrence occurred in 6/15 patients (40.0%); in 4 patients, recurrence occurred shortly after immunotherapy discontinuation. Residual neurological deficits were present in 5/15 patients (33.3%), including visual impairment, incapacitation, cognitive impairment, and speech reduction. Optic neuritis was the most common clinical manifestation of MOGAD. magnetic resonance imaging findings were heterogeneous and the cerebral cortex/subcortical white matter was the most susceptible brain region. Although patients in the acute phase responded well to methylprednisolone pulse therapy, the long-term recurrence rate was high. Consistently detected serum MOG antibodies and inappropriate maintenance immunotherapy may be associated with recurrence, and residual neurological deficits should not be ignored.

ALCAM on human oligodendrocytes mediates CD4 T cell adhesion.

Multiple sclerosis is a chronic neuroinflammatory disorder characterized by demyelination, oligodendrocyte damage/loss and neuroaxonal injury in the context of immune cell infiltration in the CNS. No neuroprotective therapy is available to promote the survival of oligodendrocytes and protect their myelin processes in immune-mediated demyelinating diseases. Pro-inflammatory CD4 Th17 cells can interact with oligodendrocytes in multiple sclerosis and its animal model, causing injury to myelinating processes and cell death through direct contact. However, the molecular mechanisms underlying the close contact and subsequent detrimental interaction of Th17 cells with oligodendrocytes remain unclear. In this study we used single cell RNA sequencing, flow cytometry and immunofluorescence studies on CNS tissue from multiple sclerosis subjects, its animal model and controls to characterize the expression of cell adhesion molecules by mature oligodendrocytes. We found that a significant proportion of human and murine mature oligodendrocytes express melanoma cell adhesion molecule (MCAM) and activated leukocyte cell adhesion molecule (ALCAM) in multiple sclerosis, in experimental autoimmune encephalomyelitis and in controls, although their regulation differs between human and mouse. We observed that exposure to pro-inflammatory cytokines or to human activated T cells are associated with a marked downregulation of the expression of MCAM but not of ALCAM at the surface of human primary oligodendrocytes. Furthermore, we used in vitro live imaging, immunofluorescence and flow cytometry to determine the contribution of these molecules to Th17-polarized cell adhesion and cytotoxicity towards human oligodendrocytes. Silencing and blocking ALCAM but not MCAM limited prolonged interactions between human primary oligodendrocytes and Th17-polarized cells, resulting in decreased adhesion of Th17-polarized cells to oligodendrocytes and conferring significant protection of oligodendrocytic processes. In conclusion, we showed that human oligodendrocytes express MCAM and ALCAM, which are differently modulated by inflammation and T cell contact. We found that ALCAM is a ligand for Th17-polarized cells, contributing to their capacity to adhere and induce damage to human oligodendrocytes, and therefore could represent a relevant target for neuroprotection in multiple sclerosis.

Vitamin D Level in Children with Acute and Relapsing Demyelinating Disorders of the Nervous System

Background Vitamin D has recently gained increased attention owing to its immunomodulatory role. Epidemiological evidence demonstrates that deficiency of Vitamin D is a relevant risk for acute acquired immune-mediated inflammatory demyelinating diseases in childhood, such as Multiple sclerosis (MS). Exact mechanism remains widely unexplored. Aim to measure the serum level vitamin D-25(OH) in pediatric patients diagnosed with acquired central and peripheral demyelinating diseases, and to compare these to levels found in healthy age and gender matched controls. Patients and Methods Twenty children (patients’ group) diagnosed with acute demyelinating diseases (Acute Disseminated Encephalomyelitis (ADEM, n = 7), Acute Necrotizing Encephalopathy of Childhood (ANEC, n = 3), Autoimmune Encephalitis (AE, n = 3), Transverse Myelitis (TM, n = 3), Guillain-Barre syndrome (GBS, n = 4)) and 40 healthy age and gender matched children (control group), were enrolled in the study. All patients were subject to full history, examination and measurement of serum levels of 25 (OH) vitamin D3 in both cases and control group. Results The mean level of vitamin D in cases was 4.4 ± 11.14 ng/ml, and it was deficient in 75% of the cases and insufficient in 15% of cases. The mean vitamin d level in cases was significantly lower than that in controls (27.18 ± 7.8 ng/ml). Conclusion Serum levels of 25 (OH) Vitamin D3 in pediatric acute acquired demyelinating diseases of the nervous system are significantly lower than levels in healthy controls, raising a possibility that vitamin D deficiency may be a risk factor for the development of various autoimmune neurological diseases.

Assessment of Multiple Sclerosis Patients' Knowledge and Behavioral Practice Regarding COVID-19 in Saudi Arabia.

Background Coronavirus disease 2019 (COVID-19) is caused by a coronavirus subtype called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is crucial to control the spread of coronavirus by understanding the disease and practicing the measures adopted during the COVID-19 pandemic. Multiple sclerosis (MS) is a central nervous system immune-mediated inflammatory demyelinating disease. COVID-19 infection may exacerbate the MS disease and its relapses. Therefore, MS patients are more susceptible to infection because of their immunosuppressive or immunomodulatory medications. Objective We aimed to evaluate the knowledge, attitude, and behaviors of patients with MS in Saudi Arabia regarding the COVID-19 pandemic. Method A quantitative observational cross-sectional study was conducted. MS patients in Saudi Arabia were included in the study population. Data were collected via an online self-reported questionnaire from 214 participants from November 2020 to June 2021. Results A total of 214 MS patients participated in this study. The gender distribution showed that the male participants represented 38.3% (n = 82), while female participants accounted for 61.7% (n = 132).Most MS patients understood the COVID-19 preventive measures. The mean knowledge score was 15.7 (SD = 2.34, range: 1-20), showing an appropriate level of knowledge. While the mean behaviors score was 6.1 (SD = 1.2, range: 2-9), showing good behaviors. The mean score for attitude was 5.4 (SD = 1.77, range: 1-8), showing optimistic attitudes. However, a closer analysis of the participants' answers showed that 74.3% of the patients agreed that the treatment plan should be discussed with their doctors during the pandemic. In addition, almost half of the participants (49.1%) agreed that being an MS patient means they are at higher risk of getting infected by the virus. Data also showed that 17% of patients continued to attend social events involving many people. Also, 28.0% of the patients reported being in crowded places. Conclusion MS patients' risk of COVID-19 might be linked to their knowledge, attitude, and behaviors. Our results suggest that although MS patients have a high knowledge and good attitude and behaviors, it is still essential to have health education programs among MS patients to reduce the risk of SARS-CoV-2 infection and the impact of the COVID-19 pandemic on MS patients' care. Knowledge, attitude, and behaviors toward the COVID-19 pandemic can highlight the importance of education programs and translate the findings into action to minimize the disease risk.

Magnolol prevented brain injury through the modulation of Nrf2-dependent oxidative stress and apoptosis in PLP-induced mouse model of multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated chronic inflammatory demyelinating disease of the central nervous system (CNS). The aim of the current study was to investigate the effects of magnolol in an experimental autoimmune encephalomyelitis (EAE) model of MS in female mice. Magnolol (0.1, 1, and 10 mg/kg) was administered once daily for 21 days after immunization of mice. Magnolol post-immunization treatment significantly reversed clinical scoring, EAE-associated pain parameters, and motor dysfunction in a dose-dependent manner. Magnolol treatment significantly inhibited oxidative stress by reducing malondialdehyde (MDA), nitric oxide (NO) production, and myeloperoxidase (MPO) activity while enhancing the level of antioxidants such as reduced glutathione (GSH), glutathione-S-transferase (GST), catalase, and superoxide dismutase (SOD) in the brain and spinal cord. It reduced cytokine levels in the brain and spinal cord. It suppressed CD8+ T cells frequency in the spleen tissue. Magnolol remarkably reversed the EAE-associated histopathology of the brain and spinal cord tissue. Magnolol significantly intensifies the antioxidant defense system by enhancing the expression level of nuclear factor erythroid 2-related factor (Nrf2) while decreasing the expression of inducible nitric oxide synthase (iNOS) and cleaved-caspase-3 in the brain. Molecular docking results showed that magnolol possesses a better binding affinity for Nrf2, iNOS, and caspase-3 proteins. Taken together, the present study demonstrated that magnolol has significant neuroprotective properties in EAE via inhibition of oxidative stress.

Acute disseminated encephalomyelitis with bilateral optic neuritis following ChAdOx1 COVID-19 vaccination

BackgroundAcute disseminated encephalomyelitis (ADEM) is a rare immune-mediated inflammatory demyelinating disease of the central nervous system. We report a case of ADEM presenting with bilateral optic neuritis temporally associated with the ChAdOx1 vaccine against SARS-COVID19 virus.Case presentationA 36-year-old female presented with bilateral optic neuritis following her first dose of the ChAdOx1 vaccine. Initial MRI Brain showed evidence of demyelination within the subcortical white matter, with no radiological involvement of the optic nerves. Visual evoked potentials were consistent with bilateral optic neuritis which was confirmed radiologically on follow up MRI. She was treated with intravenous steroids with improvement both in symptoms and radiological appearance. A pseudo-relapse occurred which was treated with a further course of intravenous steroids followed by an oral taper. The clinical, radiological and serological results were most consistent with diagnosis of ADEM.ConclusionsADEM is an exceedingly rare complication of ChAdOx1 vaccine despite millions of doses. While it is imperative clinicians remain aware of neurological complications of vaccines, the importance of vaccination to control a pandemic should not be undermined.

Differential diagnosis of multiple sclerosis in children

At the onset, multiple sclerosis (MS) in children is characterized by a phase of active inflammation with extensive demyelination of the white matter of the CNS, which often mimics this nosology with a whole spectrum of inflammatory demyelinating diseases such as ADEM, anti-MOG encephalitis, ONMSD. In order to formalize the diagnostic process, the International Pediatric Multiple Sclerosis Study Group (IPMSSG) proposed diagnostic criteria for the main immune-mediated demyelinating diseases of the CNS in children, which, in theory, should simplify the diagnostic search. However, in practice, the range of nosologies in the course of differential diagnosis is much wider and often it is not possible to establish an unambiguous diagnosis in the early stages. The authors analyze their own clinical observations based on a sample of 100 pediatric patients with a referral diagnosis of «MS?» and describe a clinical case of the onset of highly active MS with an assessment of the dynamics of the clinical and paraclinical course of the disease.

Long Non-Coding RNA- Associated Competing Endogenous RNA Axes in T-Cells in Multiple Sclerosis.

Multiple sclerosis (MS) is an immune-mediated demyelinating and degenerative disease with unknown etiology. Inappropriate response of T-cells to myelin antigens has an essential role in the pathophysiology of MS. The clinical and pathophysiological complications of MS necessitate identification of potential molecular targets to understand the pathogenic events of MS. Since the functions and regulatory mechanisms of long non-coding RNAs (lncRNAs) acting as competing endogenous RNAs (ceRNAs) in MS are yet uncertain, we conducted a bioinformatics analysis to explain the lncRNA-associated ceRNA axes to clarify molecular regulatory mechanisms involved in T-cells responses in MS. Two microarray datasets of peripheral blood T-cell from subjects with relapsing-remitting MS and matched controls containing data about miRNAs (GSE43590), mRNAs and lncRNAs (GSE43591) were downloaded from the Gene Expression Omnibus database. Differentially expressed miRNAs (DEmiRNAs), mRNAs (DEmRNAs), and lncRNAs (DElncRNAs) were identified by the limma package of the R software. Protein-protein interaction (PPI) network and module were developed using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) and the Molecular Complex Detection (MCODE) Cytoscape plugin, respectively. Using DIANA-LncBase and miRTarBase, the lncRNA-associated ceRNA axes was constructed. We conducted a Pearson correlation analysis and selected the positive correlations among the lncRNAs and mRNAs in the ceRNA axes. Lastly, DEmRNAs pathway enrichment was conducted by the Enrichr tool. A ceRNA regulatory relationship among Small nucleolar RNA host gene 1 (SNHG1), hsa-miR-197-3p, YOD1 deubiquitinase (YOD1) and zinc finger protein 101 (ZNF101) and downstream connected genes was identified. Pathway enrichment analysis showed that DEmRNAs were enriched in “Protein processing in endoplasmic reticulum” and “Herpes simplex virus 1 infection” pathways. To our knowledge, this would be the first report of a possible role of SNHG1/hsa-miR-197-3p/YOD1/ZNF101 axes in the pathogenesis of MS. This research remarks on the significance of ceRNAs and prepares new perceptions for discovering the molecular mechanism of MS.

Clinical Risk Factors and Prognostic Model for Idiopathic Inflammatory Demyelinating Diseases after Haploidentical Hematopoietic Stem Cell Transplantation in Patients with Hematological Malignancies

IntroductionAs a neurological complication following haploidentical haematopoietic stem cell transplantation (haplo-HSCT), immune-mediated demyelinating diseases (IIDDs) of the central nervous system (CNS) are rare, but they seriously affect a patient's quality of life (J Neurooncol, 2012). Although several reports have demonstrated that IIDDs have a high mortality rate and a poor prognosis (J Neurooncol, 2012; Neurology 2013), a method to predict the outcome of CNS IIDDs after haplo-HSCT is not currently available. Here, we reported the largest research on CNS IIDDs post haplo-HSCT, and we developed and validated a prognostic model for predicting the outcome of CNS IIDDs after haplo-HSCT.MethodsWe retrospectively evaluated 184 consecutive CNS IIDD patients who had undergone haplo-HSCT at a single center between 2008 and 2019. The derivation cohort included 124 patients receiving haplo-HSCT from 2014 to 2019, and the validation cohort included 60 patients receiving haplo-HSCT from 2008 to 2013. The diagnosis of CNS IIDDs was based on the clinical manifestations and exclusion of other aetiologies, including infection, neurotoxicity, metabolic encephalopathy, ischaemic demyelinating disorders, and tumor infiltration. The final prognostic model selection was performed by backward stepwise logistic regression using the Akaike information criterion. The final model was internally and externally validated using the bootstrap method with 1000 repetitions. We assessed the prognostic model performance by evaluating the discrimination [area under the curve (AUC)], calibration (calibration plot), and net benefit [decision curve analysis (DCA)].ResultsIn total, 184 of 4532 patients (4.1%) were diagnosed with CNS IIDDs after transplantation. Among them, 120 patients had MS, 53 patients had NMO, 7 patients had ADEM, 3 patients had Schilder's disease, and 1 patient had Marburg disease. Grades II to IV acute graft-versus-host disease (aGVHD) (p<0.001) and chronic GVHD (cGVHD) (p<0.001) were identified as risk factors for developing IIDDs after haplo-HSCT. We also tested immune reconstitution by measuring the following parameters 30, 60, and 90 days after haplo-HSCT: proportions of CD19+ B cells, CD3+ T cells and CD4+ T cells; counts of lymphocytes and monocytes; and levels of immunoglobulins A, G, and M. These parameters showed no significant differences between patients with and without IIDD.CNS IIDDs were significantly associated with higher mortality and a poor prognosis (p＜0.001). In a/the multivariate logistic analysis of the derivation cohort, four candidate predictors were entered into the final prognostic model: cytomegalovirus (CMV) infection, Epstein-Barr virus (EBV) infection, the cerebrospinal fluid (CSF) IgG synthesis index (IgG-Syn), and spinal cord lesions. The value assignment was completed according to the regression coefficient of each identified independent prognostic factor for CNS IIDDs in the derivation cohort to establish the CELS risk score model. According to the regression coefficient, point values were given to each factor based on the log scale, and 1 point was awarded for each variable. These 4 factors determined the total risk score, ranging from 0 to 4. There was a higher risk of death in IIDD patients with higher CELS scores and we, therefore, defined three levels of risk of death in IIDD patients: a low-risk group for patients with a score of 0, a medium-risk group for patients with a total score of 1 or 2, and a high-risk group for patients with a total score of 3 or 4. The prognostic model had an area under the curve of 0.864 (95% CI: 0.803-0.925) in the internal validation cohort and 0.871 (95% CI: 0.806-0.931) in the external validation cohort. The calibration plots showed a high agreement between the predicted and observed outcomes. Decision curve analysis indicated that IIDD patients could benefit from the clinical application of the prognostic model.ConclusionsWe identified the risk factors for IIDD onset after haplo-HSCT, and we also developed and validated a reliable prediction model, namely, the CELS, to accurately assess the outcome of IIDD patients after haplo-HSCT. Identifying IIDD patients who are at a high risk of death can help physicians treat them in advance, which will improve patient survival and prognosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical experience of plasmapheresis for neuromyelitis optica patients in Mexico

BackgroundNeuromyelitis optica spectrum disorders (NMOSDs) are a group of chronic immune-mediated demyelinating diseases of the central nervous system. Their pathophysiology dependent on humoral mediated responses caused by autoreactive IgG antibodies against aquaporin-4 water channels (AQP4-IgG) or myelin oligodendrocyte glycoprotein (MOG-IgG). Plasma exchange (PLEX) has proved to be a beneficial therapy in patients with severe relapses. We present the largest series of Latin American patients treated with PLEX for acute NMOSDs relapses. MethodsA retrospective study was conducted. Selection included patients diagnosed with NMOSDs who received PLEX between 2010-2019, irrespective of their AQP4-IgG serostatus. All patients received 5 grams of IV methylprednisolone. PLEX therapy could be initiated simultaneously or after IV steroids. Baseline and post-PLEX therapy Expanded Disability Status Scale (EDSS) was measured to identify acute response to therapy. Comparison between responders and non-responders was also conducted. Subgroup analysis stratified response by serostatus, type of clinical relapse and time to PLEX. ResultsA total of 89 patients were included. Mean age at onset was 38 ± 12.97 years. 49 (55.1%) patients were AQP4-IgG seropositive. Most patients had unilateral optic neuritis (34.8%) or longitudinally extensive transverse myelitis (33.7%). Mean time from onset to PLEX initiation was 20.9 ± 18.1 days. Response rate was 39.3% and mean decline in EDSS was 0.7 ± 0.9 (p <0.001). Decline in EDSS and response rate were independent of serostatus, type of clinical relapse or time to PLEX initiation. ConclusionPLEX appears to be an effective therapy for NMOSDs relapses even in limited resources setting where treatment initiation may be delayed. The benefit seems to be independent of the type of clinical relapse and AQP4 IgG serostatus.

Relapsing-Remitting Multiple Sclerosis

Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system. There are neither diagnostic tests nor markers for MS. Other causes must be excluded thoroughly before an MS diagnosis is considered definitive. The relapsing-remitting type is a major clinical course in MS. Most disease-modifying drugs (DMDs) target this clinical type. Many clinical studies have demonstrated that early intervention with DMDs may prevent disease progression and transition from relapsing-remitting MS to the secondary progressive type. There are windows of opportunity for DMDs. An adequate DMD should be used for the appropriate patient at the optimal time.

Neuropsychiatric symptoms of multiple sclerosis: A case report

IntroductionMultiple Sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system. Concomitant psychiatric diseases are frequent in MS, with depression and anxiety disorders constituting the majority. The presence of psychotic disorders with MS is rare. Several studies have reported that psychotic symptoms usually develop after the neurological signs of MS and they are mostly linked to the side effects of treatment with interferon or with corticosteroids.ObjectivesThe authors report here the case of patient with MS without psychiatric history that developed psychotic symptoms.MethodsBeside the medical record of the patient a non-systematic search of the literature was carried out in the databases Pubmed and Google Scholar with the terms “Multiple Sclerosis”, “Multiple Sclerosis treatment ”and“ Neuropsychiatric symptoms ”.ResultsA 38 years old woman with MS, with no psychiatry history developed paranoid and reference delusions, several months after starting interferon beta-1a therapy. The inferferon therapy was stopped and the patient was started Risperidone 3 mg id with a rapid but only partial remission of the psychotic symptoms. The patient presented high blood levels of prolactine and the MRI showed a pituitary microadenome. The Risperidone was switched to Aripiprazol 15 mg also with partial remission of the psychtic symptons.ConclusionsIt is not possible to attribute our patient’s psychotic symptoms entirely to his Interferon therapy or to MS lesion load, but the occurrence during treatment, no psychiatric history and the rapid but parcial resolution with discontinuing suggest that Interferon therapy was at least contributory to the clinical picture.

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (AEM) is an immune-mediated inflammatory demyelinating disease of the central nervous system (CNS), usually single-phase. In WREM, multiple lesions of the central nervous system of an inflammatory-demyelinating nature accompanied by extremely polymorphic neurological disorders develop acutely or subacutely. The review considers the issues of epidemiology, trigger factors of the inflammatory process, clinical manifestations, differential and molecular diagnostics of WECM, and outlines the ways for further study of this pathology.Острый рассеянный энцефаломиелит (ОРЭМ) — иммуноопосредованное воспалительное демиелинизирующее заболевание центральной нервной системы (ЦНС), как правило, однофазное. При ОРЭМ остро или подостро развивается множественное поражение ЦНС воспалительно-демиелинизирующего характера, сопровождающееся крайне полиморфными неврологическими нарушениями. В обзоре рассмотрены вопросы эпидемиологии, триггерные факторы воспалительного процесса, клинические проявления, дифференциальная и молекулярная диагностика ОРЭМ, намечены пути дальнейшего изучения данной патологии.

New progress in the treatment of neuromyelitis optica spectrum disorder with monoclonal antibodies (Review).

Neuromyelitis optica spectrum disorder (NMOSD) is a group of immune-mediated inflammatory demyelinating diseases mainly affecting the central nervous system. It is characterized by high risk of relapse and progression to disability. The frequent recurrences of neuromyelitis optica spectrum disorder often exacerbate the neurological dysfunction and severely affect the patient's quality of life. Conventional treatments for neuromyelitis optica spectrum disorder, including acute treatment and sequential therapy, aim to decrease the degree of disability and recurrences. In recent years, new monoclonal antibodies have yielded encouraging results. The present review discusses the research status and recent progress in the treatment of NMOSD with monoclonal antibodies.

Infection and Activation of B Cells by Theiler's Murine Encephalomyelitis Virus (TMEV) Leads to Autoantibody Production in an Infectious Model of Multiple Sclerosis.

Theiler’s murine encephalomyelitis virus (TMEV) induces immune-mediated inflammatory demyelinating disease in susceptible mice that is similar to human multiple sclerosis (MS). In light of anti-CD20 therapies for MS, the susceptibility of B cells to TMEV infection is particularly important. In our study, direct viral exposure to macrophages and lymphocytes resulted in viral replication and cellular stimulation in the order of DCs, macrophages, B cells, and T cells. Notably, B cells produced viral proteins and expressed elevated levels of CD69, an activation marker. Similarly, the expression of major histocompatibility complex class II and costimulatory molecules in B cells was upregulated. Moreover, TMEV-infected B cells showed elevated levels of antigen-presenting function and antibody production. TMEV infection appeared to polyclonally activate B cells to produce autoantibodies and further T cell stimulation. Thus, the viral infection might potentially affect the outcome of autoimmune diseases, and/or the development of other chronic infections, including the protection and/or pathogenesis of TMEV-induced demyelinating disease.

Systemic lupus erythematosus with the development of neuromyelitis optica (Devic's syndrome) is a rare combination of autoimmune diseases

Neuromyelitis optica ((NMO), Devic's syndrome) is an immune-mediated inflammatory demyelinating disease characterized by transverse myelitis and optic neuritis. Determination of the level of antibodies to aquaporin 4 (NMO-IgG) is presently one of the key methods for the diagnosis and assessment of the activity of ONM, which allows this disease to be differentiated from multiple sclerosis and other demyelinating CNS lesions. ONM can occur not only as an independent disease, but also as a syndrome in different systemic diseases, such as: systemic lupus erythematosus (SLE), antineutrophilic cytoplasmic antibody-associated vasculitides, Sjögren's disease, etc. (up to 50–70%). In such situations, the clinician is always confronted with a question as whether the patient can have two rare autoimmune diseases or develop ONM as a systemic manifestation of rheumatic disease.The paper describes a clinical case of a young female patient with SLE concurrent with a CNS lesion, the manifestations of which corresponded to ONM. The patient had focal changes in the substance of the brain and spinal cord, as evidenced by magnetic resonance imaging, as well as high NMO-IgG titers. The development of ONM worsens SLE prognosis and requires active immunosuppressive therapy. The patient received three plasmapheresis sessions, ultrahigh-dose glucocorticoid and cyclophosphamide therapy, followed by replacement with azathioprine, causing a stable clinical and laboratory disease remission to be achieved.

Exosomal Circular RNA as a Biomarker Platform for the Early Diagnosis of Immune-Mediated Demyelinating Disease.

Exosomes can pass through the blood-brain barrier and are present in the cerebrospinal fluid (CSF). The components in exosomes, such as DNA, RNA, protein, and lipids, change greatly and are closely related to disease progression. Circular RNA (circRNA) is stable in structure and has a long half-life in exosomes without degradation. Therefore, circRNA is considered an ideal biomarker and can be used to monitor a variety of central nervous system diseases. This study aimed to investigate the expression profiles of exosomal circRNA (exo-circRNA) in CSF from patients with immune-mediated demyelinating diseases to identify suitable biomarkers for the early diagnosis of immune-mediated demyelinating diseases. circRNA expression levels in exosomes obtained from five CSF samples from immune-mediated demyelinating disease patients and five paired CSF control samples were analyzed using a hybridization array. Hierarchical clustering analysis showed that 5,095 exo-circRNAs were differentially expressed between patients with immune-mediated demyelinating diseases and paired control samples. Of these exo-circRNAs, 26 were identified as significantly differentially expressed in CSF exosomes from patients with immune-mediated demyelinating diseases (FC ≥1.5 and p ≤ 0.05). Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis indicated that the upregulation or activation of protein tyrosine phosphatase receptor type F (PTPRF) and RAD23 homolog B, nucleotide excision repair protein (RAD23B) may be associated with the occurrence and development of immune-mediated demyelinating diseases. Then, a competing endogenous RNA network was constructed and centered on the most upregulated/downregulated exo-circRNAs to predict their function in immune-mediated demyelinating diseases. In addition, reverse transcription quantitative polymerase chain reaction results stating that hsa_circ_0087862 and hsa_circ_0012077 were validated in an independent cohort of subjects. Canonical correlation analysis results indicated a potential connection between exosomal hsa_circ_0012077 expression level and immunoglobulin G levels in CSF. Finally, the receiver operating characteristic (ROC) curve showed that when hsa_circ_0087862 or hsa_circ_0012077 was employed alone for diagnosing immune-mediated demyelinating diseases, the diagnostic accuracy was 100%. In conclusion, based on this study, exosomal hsa_circ_0087862 and hsa_circ_0012077 in CSF could be used as suitable biomarkers for the diagnosis of immune-mediated demyelinating disease based on their expression levels. Moreover, the upregulation or activation of PTPRF and RAD23B was potentially associated with the occurrence and development of immune-mediated demyelinating diseases.

Conversion Disorder (Functional Neurological Symptom Disorder) Masquerading as Multiple Sclerosis: A Case Report

Conversion disorder, also referred to as functional neurological symptom disorder, is a DSM-5 identified somatic disorder that presents with one or more neurological symptoms that does not clinically correlate with recognized neurological or medical conditions brought on by intense stress, emotions, or an associated psychiatric disorder. Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system and usually presents in young adults with clinical manifestations that range from cognitive abnormalities, eye movement problems, motor and sensory impairments such as weakness and numbness, bowel/bladder dysfunction, fatigue, and/or pain. This case report presents a patient with functional neurological symptom disorder presenting with clinical signs associated with MS.

The conceptual introduction of the "demyelinating Schwann cell" in peripheral demyelinating neuropathies.

Myelinating Schwann cells undergo irreversible demyelination in many demyelinating neuropathies that show complete demyelination of the internode. Dedifferentiation, reprogramming, and myelin clearance processes-which are specifically discussed in this article-appear to be shared by various demyelinating peripheral conditions, such as Wallerian degeneration, immune-mediated, and toxic demyelinating diseases. We propose to introduce the concept of the "demyelinating Schwann cell (DSC)" as a novel cell phenotype, which has specific properties required for myelin sheath clearance. We anticipate that the introduction of the DSC concept will provide a significant advance in understanding the pathophysiological mechanisms of demyelinating peripheral neuropathies.