Central Nervous System Demyelination Research Articles

Low sulfated heparan sulfate mimetic differentially affects repair in immune-mediated and toxin-induced experimental models of demyelination.

There is an urgent need for therapies that target the multicellular pathology of central nervous system (CNS) disease. Modified, nonanticoagulant heparins mimic the heparan sulfate glycan family and are known regulators of multiple cellular processes. In vitro studies have demonstrated that low sulfated modified heparin mimetics (LS-mHeps) drive repair after CNS demyelination. Herein, we test LS-mHep7 (an in vitro lead compound) in experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination. In EAE, LS-mHep7 treatment resulted in faster recovery and rapidly reduced inflammation which was accompanied by restoration of animal weight. LS-mHep7 treatment had no effect on remyelination or on OLIG2 positive oligodendrocyte numbers within the corpus callosum in the cuprizone model. Further in vitro investigation confirmed that LS-mHep7 likely mediates its pro-repair effect in the EAE model by sequestering inflammatory cytokines, such as CCL5 which are upregulated during immune-mediated inflammatory attacks. These data support the future clinical translation of this next generation modified heparin as a treatment for CNS diseases with active immune system involvement.

New Onset Multiple Sclerosis Post-COVID-19 Vaccination and Correlation With Possible Predictors in a Case-Control Study.

Various inflammatory diseases have been associated with the administration of various vaccines. Several reports have associated vaccine administration with the demyelinating diseases of the central nervous system (CNS). However, no clear or strong scientific evidence exists to support the association of vaccine administration with the onset of demyelinating diseases. Some CNS demyelination diseases such as acute disseminated encephalomyelitis (ADEM) and neuromyelitis optica spectrum disorders (NMOSD) were reported following the administration of COVID-19 vaccines. In this study, new onset multiple sclerosis (MS) following COVID-19 vaccine administration was reported. In this longitudinal observational case-control study, a total of 65 participants were studied, who were divided into two groups. Group A included 32 MS patients who were diagnosed post-COVID-19 vaccine administration and group B included 33 participants who received COVID-19 vaccines and did not develop MS. Group B was used as a control. The Chi-square test and logistic regression analysis were carried out using Statistical Product and Service Solutions (SPSS) (IBM SPSS Statistics for Windows, Armonk, NY)software. Univariate and multivariate logistic regression analysis was performed and a significant correlation between the risk factors and the development of MS post-COVID-19 vaccination was identified. The risk factors, identified in this study, can be used as significant independent predictors for developing MS post-COVID-19 vaccinations.

Silent findings: Examination of asymptomatic demyelination in a pediatric US cohort.

Limited data is available on children with evidence of silent central nervous system demyelination on MRI. We sought to characterize the population in a US cohort and identify predictors of clinical and radiologic outcomes. We identified 56 patients such patients who presented with incidental MRI findings suspect for demyelination, enrolled through our US Network of Pediatric Multiple Sclerosis Centers, and conducted a retrospective review of 38 patients with MR images, and examined risk factors for development of first clinical event or new MRI activity. MRI were rated based on published MS and radiologically isolated syndrome (RIS) imaging diagnostic criteria. One-third had a clinical attack and ¾ developed new MRI activity over a mean follow-up time of 3.7 years. Individuals in our cohort shared similar demographics to those with clinically definite pediatric-onset MS. We show that sex, presence of infratentorial lesions, T1 hypointense lesions, juxtacortical lesion count, and callosal lesions were predictors of disease progression. Interestingly, the presence of T1 hypointense and infratentorial lesions typically associated with worse outcomes were instead predictive of delayed disease progression on imaging in subgroup analysis. Additionally, currently utilized diagnostic criteria (both McDonald 2017 and RIS criteria) did not provide statistically significant benefit in risk stratification. Our findings underscore the need for further study to determine if criteria currently used for pediatric patients with purely radiographic evidence of demyelination are sufficient.

An Updated Evaluation of Intrathecal IgG Synthesis Markers in Relation to Oligoclonal Bands.

The aim was to evaluate the performance of the latest quantitative marker for intrathecal IgG synthesis and to compare it with other established markers used for the same purpose. We retrospectively applied Auer's and Reiber's intrathecal IgG synthesis formulae in a cohort of 372 patients under investigation for central nervous system demyelination who had undergone lumbar puncture and oligoclonal bands (OCBs) detection for demonstrating intrathecal IgG synthesis. A ROC analysis revealed Auer's formula had lower sensitivity (68%) compared to Reiber's formula (83%) and IgG index (89%), in our cohort of patients that exhibited normal to mildly elevated albumin quotients (4.48 ± 3.93). By excluding possible sources of errors, we assume that Auer's formula is less sensitive than other established tools for the "prediction" of the detection of OCBs in routine cerebrospinal fluid (CSF) analyses due to the mathematical model used. Given the ability of Reiber's hyperbolic formula to describe the blood-CSF IgG distribution across a wide range of blood-brain barrier functionality, its use and the use of similar formulae are recommended for the discrimination between CNS-derived and blood-derived molecules in clinical laboratories.

Berberine promotes immunological outcomes and decreases neuroinflammation in the experimental model of multiple sclerosis through the expansion of Treg and Th2 cells.

Among the most frequent demyelinating autoimmune disorders of the central nervous system (CNS) is multiple sclerosis. Experimental autoimmune encephalomyelitis (EAE) is used as an animal model of multiple sclerosis. Berberine is an alkaloid found in some medicinal plants with anti-inflammatory effects. C57BL/6 female mice were used and divided into three groups: (1) The control group received PBS, (2) the low-dose treatment group received 10 mg/kg of berberine, and (3) The high-dose treatment group received 30 mg/kg of berberine. Myelin Oligodendrocyte Glycoprotein and complete Freund's adjuvant were subcutaneously administered to induce EAE. Mice were given intraperitoneal injections of pertussis toxin on the day of immunization and 2 days later. Histological studies showed low lymphocyte infiltration and demyelination of CNS in the treated groups. The clinical scores of the treatment group with low-dose berberine (T1: 2 ± 0.13) and high-dose berberine (T2: 1.5 ± 0.14) were significantly (p < .001) lower than the control group (CTRL: 4.5 ± 0.13). Treatment groups decreased pro-inflammatory cytokines (IFN-γ, TNF-α, interleukin [IL]-17) (p < .001) as well as increased anti-inflammatory cytokine expression (IL-4, IL-10, IL-27, IL-33, IL-35, TGF-β) (p < .01) when compared to the CTRL group. Treatment groups with berberine reduced expression of the Th1 and Th17 cytokines and transcription factors (p < .001) and increased expression of transcription factors and Th2 and Treg cytokines (p < .01) in contrast to CTRL group. Berberine appears to have a protective effect on disease development and alleviating disease status in EAE, which appears to be due to the cell expansion and function of Treg and Th2 cells in addition to berberine's anti-inflammatory properties.

Sjögren syndrome in childhood mimicking pediatric multiple sclerosis

Abstract The differential diagnosis of pediatric multiple sclerosis (MS) presents a wide spectrum of diseases. Sjögren syndrome (SS) is also a rare cause of this disease. Neurological involvement in SS ranges from peripheral neuropathies to the central nervous system (CNS). We report the case of a 5-year-old boy with a possible diagnosis with SS based on positive minor salivary gland biopsy findings and positive anti-smooth muscle antibodies, also fulfilling the 2017 McDonald criteria. If a patient is younger and meets the MS criteria clinically and radiologically, it is suggested to carefully examine the CNS demyelination in a patient for autoimmune diseases, particularly SS.

Tissue-resident immune cells in the pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) in which genetic and environmental factors contribute to disease progression. Both innate and adaptive immune cells, including T cells, B cells, activated macrophages and microglia, have been identified to be involved in the pathogenesis of MS, leading to the CNS inflammation, neurodegeneration and demyelination. In recent years, there has been considerable progress in understanding the contribution of tissue-resident immune cells in the pathogenesis of MS. We performed a keyword-based search in PubMed database. We combined "multiple sclerosis" with keywords, such as tissue-resident memory T cells, microglia to search for relevant literatures in PubMed. In this review, we comprehensively describe the characteristics of tissue-resident memory T cells and microglia, summarize their role in the pathogenesis of MS, and discuss their interaction with other immune cells in the CNS.

Acute Central Nervous System Demyelination Following COVID-19 Vaccination

Objective To describe features of central nervous system (CNS) demyelinating events following vaccination against coronavirus disease 19 (COVID-19). Background Several reports suggest a potential association between COVID-19 vaccines and acute CNS inflammation. Design/Methods A case series was performed at the BARLO MS Centre in Toronto, Ontario, Canada. Clinicians reported patients who experienced an acute CNS demyelinating event within 60 days after receiving at least one COVID-19 vaccination from March 2021 to January 2022. Clinical characteristics were evaluated. Results Twenty patients were identified (median age 39 years (range 25-82); 13 (65.0%) female). Two had pre-existing multiple sclerosis (MS). Individuals received the Pfizer (n = 14), Moderna (n = 5) or Astrazeneca (n = 1) COVID-19 vaccines. Within 1-53 days (median 12) of the first (n = 8) or second (n = 12) vaccine dose, patients developed transverse myelitis (TM) (n = 15), optic neuritis (n = 4) or brain demyelination (n = 4). Diagnoses at last follow up (median 114 days (range 39-255)) were relapsing remitting MS (n = 8), post-vaccine TM (n = 5), clinically isolated syndrome (n = 3), myelin oligodendrocyte glycoprotein antibody disease (n = 2), MS relapse (n = 1) and neuromyelitis optica spectrum disorder (n = 1). Thirteen patients received pulse corticosteroids, and of these, 4 received plasma exchange. Seven did not receive acute treatment. 20.0% returned to baseline (n = 4), 75.0% partially recovered (n = 15) and 5.0% worsened (n = 1). At last follow up, 11 were on disease modifying therapy and 9 were not. Nine patients received a subsequent COVID-19 vaccine. Of these, one experienced symptom recrudescence without radiologic evidence of a new demyelinating attack. Conclusions To our knowledge, this is the largest series to date describing acute CNS demyelination after vaccination against COVID-19. The rate of vaccination in the eligible general population was high during the time of the cases and we could not determine whether the number of demyelinating events was higher than expected. Repeat vaccination was not associated with recurrent adverse events in this small observational series.

Multiple sclerosis and mitral stenosis: is there an association? A dilemma

Mitral stenosis is a valvular heart disease defined by narrowing of the mitral valve orifice and is characterized as the most common valvular involvement in developing countries. Although, the most common manifestations of mitral stenosis (MS) include heart failure, stroke, failure to thrive, pulmonary hypertension, and endocarditis, unusual associations occur too. Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory demyelinating disease of the Central Nervous System (CNS) with relapsing-remitting phases due to recurrent episodes of inflammation and demyelination of Central Nervous System (CNS). Some studies found multiple sclerosis patients have a higher prevalence of cardiovascular disease that could be described by coexistence of some common risk factors and etiologies. incidence and prevalence of cardiac valvular disease in these patients were reported 0.7% over a 30 years follow up and 0-2.3% at the time of multiple sclerosis diagnosis, too .There is no proven association between cardiac MS (mitral stenosis) and demyelinating CNS MS (multiple sclerosis), but there have been hypotheses according to case reports and case series. We encountered three cases of mitral stenosis coexistent with multiple sclerosis who underwent appropriate treatment with good outcome and in our facility, we report one of them who had been previously diagnosed with CNS MS and admitted to our hospital with pulmonary edema due to cardiac MS. she underwent Percutaneous transvenous mitral commissurotomy (PTMC), her mitral valve area and systolic pulmonary artery pressure were improved. She is in good condition in both terms of mitral stenosis and multiple sclerosis during follow up. Mitral stenosis and multiple sclerosis, although rare, may occur together. Awareness of it for acceptable diagnosis and treatment and more evaluation in this issue should be noticed.

C-ANCA-associated vasculitis with predominant CNS demyelination after COVID-19

COVID-19 infection may trigger the presentation or exacerbation of autoimmune diseases. c-Antineutrophil cytoplasmic antibody (c-ANCA)-associated vasculitis after COVID-19 mainly involves the kidneys and lungs, and is rarely reported. We describe the case of a 13-year-old girl with a history of chronic immunologic thrombocytopenic purpura who presented with transverse myelitis and central nervous system demyelination, and was subsequently diagnosed with c-ANCA-associated vasculitis following COVID-19. The patient's condition improved after pulse therapy with methylprednisolone and rituximab. To our knowledge, this is the first reported pediatric case of ANCA-associated vasculitis with predominant central nervous system involvement after COVID-19 infection.

Combined central and peripheral demyelination: a case report

Overlapping central nervous system (CNS) and peripheral nervous system (PNS) demyelination is a rare clinical entity, more frequently seen in patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and multiple sclerosis (MS). This case report showcases a patient with atypical CIDP and CNS demyelination lesions. Demographic data, disease course, treatment responsiveness, neurological examination, laboratory tests, nerve conduction studies (NCS), and brain and spinal cord MRI were registered. The case highlights the difficulty of diagnosis establishment and treatment selection, given the atypical course of the disease and limited answers to the indicated therapies. The data from our report suggest that specific and widely available immunological targets are necessary for diagnosing combined central and peripheral demyelination cases appropriately. The association of different immunotherapeutic agents may be necessary to induce and maintain disease remission.

Treatment with an antigen-specific dual microparticle system reverses advanced multiple sclerosis in mice

Antigen-specific therapies hold promise for treating autoimmune diseases such as multiple sclerosis while avoiding the deleterious side effects of systemic immune suppression due to delivering the disease-specific antigen as part of the treatment. In this study, an antigen-specific dual-sized microparticle (dMP) treatment reversed hind limb paralysis when administered in mice with advanced experimental autoimmune encephalomyelitis (EAE). Treatment reduced central nervous system (CNS) immune cell infiltration, demyelination, and inflammatory cytokine levels. Mechanistic insights using single-cell RNA sequencing showed that treatment impacted the MHC II antigen presentation pathway in dendritic cells, macrophages, B cells, and microglia, not only in the draining lymph nodes but also strikingly in the spinal cord. CD74 and cathepsin S were among the common genes down-regulated in most antigen presenting cell (APC) clusters, with B cells also having numerous MHC II genes reduced. Efficacy of the treatment diminished when B cells were absent, suggesting their impact in this therapy, in concert with other immune populations. Activation and inflammation were reduced in both APCs and T cells. This promising antigen-specific therapeutic approach advantageously engaged essential components of both innate and adaptive autoimmune responses and capably reversed paralysis in advanced EAE without the use of a broad immunosuppressant.

Vanishing White Matter Disease- Report of two Cases

Vanishing white matter (VWM) disease is a chronic progressive childhood onset leukodystrophy that result in central nervous system demyelination, often precipitated by some stressful events. There is wide phenotypic variation buy typical MRI findings are diagnostic in most of the patients. Here we report two cases of vanishing white matter disease with typical MRI findings. J Bangladesh Coll Phys Surg 2022; 40: 314-317

Manifestaciones neurológicas asociadas a la vacuna contra COVID-19

IntroductionCoronavirus disease 2019 (COVID-19) has spread rapidly, giving rise to a pandemic, causing significant morbidity and mortality. In this context, many vaccines have emerged to try to deal with this disease. ObjectiveTo review the reported cases of neurological manifestations after the application of COVID-19 vaccines, describing clinical, analytical and neuroimaging findings and health outcomes. MethodsWe carried out a review through bibliographic searches in PubMed. ResultsWe found 86 articles, including 13,809 patients with a wide spectrum of neurological manifestations temporally associated with COVID-19 vaccination. Most occurred in women (63.89%), with a median age of 50 years. The most frequently reported adverse events were Bell's palsy 4936/13809 (35.7%), headache (4067/13809), cerebrovascular events 2412/13809 (17.47%), Guillain-Barré syndrome 868/13809 (6.28%), central nervous system demyelination 258/13809 (1.86%) and functional neurological disorder 398/13809 (2.88%). Most of the published cases occurred in temporal association with the Pfizer vaccine (BNT162b2), followed by the AstraZeneca vaccine (ChAdOX1 nCoV-19). ConclusionsIt is not possible to establish a causal relationship between these adverse events and COVID-19 vaccines with the currently existing data, nor to calculate the frequency of appearance of these disorders. However, it is necessary for health professionals to be familiar with these events, facilitating their early diagnosis and treatment. Large controlled epidemiological studies are necessary to establish a possible causal relationship between vaccination against COVID-19 and neurological adverse events.

Neurological manifestations associated with COVID-19 vaccine

IntroductionCoronavirus disease 2019 (COVID-19) has spread rapidly, giving rise to a pandemic, causing significant morbidity and mortality. In this context, many vaccines have emerged to try to deal with this disease. ObjectiveTo review the reported cases of neurological manifestations after the application of COVID-19 vaccines, describing clinical, analytical and neuroimaging findings and health outcomes. MethodsWe carried out a review through bibliographic searches in PubMed. ResultsWe found 86 articles, including 13 809 patients with a wide spectrum of neurological manifestations temporally associated with COVID-19 vaccination. Most occurred in women (63.89%), with a median age of 50 years. The most frequently reported adverse events were Bell’s palsy 4936/13 809 (35.7%), headache (4067/13 809), cerebrovascular events 2412/13 809 (17.47%), Guillain-Barré syndrome 868/13 809 (6.28%), central nervous system demyelination 258/13 809 (1.86%) and functional neurological disorder 398/13 809 (2.88%). Most of the published cases occurred in temporal association with the Pfizer vaccine (BNT162b2), followed by the AstraZeneca vaccine (ChAdOX1-S). ConclusionsIt is not possible to establish a causal relationship between these adverse events and COVID-19 vaccines with the currently existing data, nor to calculate the frequency of appearance of these disorders. However, it is necessary for health professionals to be familiar with these events, facilitating their early diagnosis and treatment. Large controlled epidemiological studies are necessary to establish a possible causal relationship between vaccination against COVID-19 and neurological adverse events.

An anti-inflammatory transcriptional cascade conserved from flies to humans.

Innate immunity is an ancestral process that can induce pro- and anti-inflammatory states. A major challenge is to characterize transcriptional cascades that modulate the response to inflammation. Since the Drosophila glial cells missing (Gcm) transcription factor has an anti-inflammatory role, we explored its regulation and evolutionary conservation. Here, we show that the murine Gcm2 (mGcm2) gene is expressed in a subpopulation of aged microglia (chronic inflammation) and upon lysophosphatidylcholine (LPC)-induced central nervous system (CNS) demyelination (acute inflammation). Moreover, mGcm2 conditional knockout mice show an increased inflammatory phenotype upon aging or LPC injection, and hGCM2 is expressed in active demyelinating lesions of patients with multiple sclerosis. Finally, Drosophila Gcm expression is induced upon aging and acute challenge, and its overexpression decreases the inflammatory phenotype. Altogether, these data indicate that the inducible Gcm cascade is conserved from flies to humans and represents a potential therapeutic target in the control of the inflammatory response.

Sudden sensorineural hearing loss as an initial presentation in multiple sclerosis

Figure. Multiple sclerosis (MS) is a neuroinflammatory disorder characterized by central nervous system demyelination. Acute sensorineural hearing loss (SNHL) is a rare, but recognized MS-associated symptom [1]. Here we present a 33yo female with acute-onset right-sided SNHL that resolved within 1 month. Neurologic examination, including Rinne’s and Webber’s, was normal. An MRI revealed a demyelinating lesion in the right VIII entry root zone (A), as well as juxtacortical, periventricular, and infratentorial demyelinating lesions (B-D) characteristic of MS.

Altered Immune Response to the Epstein-Barr Virus as a Prerequisite for Multiple Sclerosis.

Strong epidemiologic evidence links Epstein–Barr virus (EBV) infection and its altered immune control to multiple sclerosis (MS) development. Clinical MS onset occurs years after primary EBV infection and the mechanisms linking them remain largely unclear. This review summarizes the epidemiological evidence for this association and how the EBV specific immune control is altered in MS patients. The two main possibilities of mechanisms for this association are further discussed. Firstly, immune responses that are induced during a symptomatic primary EBV infection, namely infectious mononucleosis, might be amplified during the following years to finally cause central nervous system (CNS) inflammation and demyelination. Secondly, genetic predisposition and environmental factors might not allow for an efficient immune control of the EBV-infected B cells that might drive autoimmune T cell stimulation or CNS inflammation. These two main hypotheses for explaining the association of the EBV with MS would implicate opposite therapeutic interventions, namely either dampening CNS inflammatory EBV-reactive immune responses or strengthening them to eliminate the autoimmunity stimulating EBV-infected B cell compartment. Nevertheless, recent findings suggest that EBV is an important puzzle piece in the pathogenesis of MS, and understanding its contribution could open new treatment possibilities for this autoimmune disease.

Machine learning classification of multiple sclerosis in children using optical coherence tomography

Background: In children, multiple sclerosis (MS) is the ultimate diagnosis in only 1/5 to 1/3 of cases after a first episode of central nervous system (CNS) demyelination. As the visual pathway is frequently affected in MS and other CNS demyelinating disorders (DDs), structural retinal imaging such as optical coherence tomography (OCT) can be used to differentiate MS. Objective: This study aimed to investigate the utility of machine learning (ML) based on OCT features to identify distinct structural retinal features in children with DDs. Methods: This study included 512 eyes from 187 (neyes = 374) children with demyelinating diseases and 69 (neyes = 138) controls. Input features of the analysis comprised of 24 auto-segmented OCT features. Results: Random Forest classifier with recursive feature elimination yielded the highest predictive values and identified DDs with 75% and MS with 80% accuracy, while multiclass distinction between MS and monophasic DD was performed with 64% accuracy. A set of eight retinal features were identified as the most important features in this classification. Conclusion: This study demonstrates that ML based on OCT features can be used to support a diagnosis of MS in children.

Interdependency of NINJ2 gene expression and polymorphism with susceptibility and response to interferon beta in patients with multiple sclerosis

Objective Multiple sclerosis (MS) is a multifactorial inflammatory and autoimmune condition that lead to chronic neurodegeneration and central nervous system (CNS) demyelination that mainly affects young adults. The incidence and prevalence rate of MS considerably vary in ethnicities and geographic regions and affecting women more than men. Interferon-β (IFN-β) is the first-line disease management for MS, while the majority of affected members does not respond to the IFN-β. Numerous recent studies shown a significant relationship between genetic variations and responsiveness to the IFN-β. Therefore, determining the genetic differences in the drug response could help determine precise treatment strategies. Methods The genotyping of the rs7298096 polymorphism (SNP) and NINJ2 gene expression were assessed in 99 responders and 106 non-responder patients with IFN-β treated RRMS. Results The distribution of rs7298096 SNP was significantly different in the responders and non-responder patients and the NINJ2 gene expression considerably increased in the non-responder patients compare to the responders. The NINJ2 gene expression level in the AA genotype of the non-responder group was higher than to the other genotypes of both groups. Conclusion Our results showed that the NINJ2 gene expression level and rs7298096 genotype possibly affect the response to the IFN-β in patients with RRMS.