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Background: The clinical implications of myelin oligodendrocyte glycoprotein autoantibodies (MOG-Abs) are increasing. Establishing MOG-Ab assays is essential for effectively treating patients with MOG-Abs. We established an in-house cell-based assay (CBA) to detect MOG-Abs to identify correlations with patients' clinical characteristics. Methods: We established the CBA using HEK 293 cells transiently overexpressing fulllength human MOG, tested it against 166 samples from a multicenter registry of central nervous system (CNS) inflammatory disorders, and compared the results with those of the Oxford MOG-Ab-based CBA and a commercial MOG-Ab CBA kit. We recruited additional patients with MOG-Abs and compared the clinical characteristics of MOG-Ab-associated disease (MOGAD) with those of neuromyelitis optica spectrum disorder (NMOSD). Results: Of 166 samples tested, 10 tested positive for MOG-Abs, with optic neuritis (ON) being the most common manifestation (4/15, 26.7%). The in-house and Oxford MOG-Ab CBAs agreed for 164/166 (98.8%) samples (?=0.883, P <0.001); two patients (2/166, 1.2%) were only positive in our in-house CBA, and the CBA scores of the two laboratories correlated well (r=0.663, P <0.001). The commercial MOG-Ab CBA kit showed one falsenegative and three false-positive results. The clinical presentation at disease onset differed between MOGAD and NMOSD; ON was the most frequent manifestation in MOGAD, and transverse myelitis was most frequent in NMOSD. Conclusions: The in-house CBA for MOG-Abs demonstrated reliable results and can potentially be used to evaluate CNS inflammatory disorders. A comprehensive, long-term study with a large patient population would clarify the clinical significance of MOG-Abs. [ABSTRACT FROM AUTHOR]

Myelin, the lipid-rich structure formed by oligodendrocytes (OLGs) in the central nervous system, is fundamental for normal motor, sensory, and cognitive functions. Myelin pathology in Huntington's disease (HD) appears early in the course of the disease and is progressive in nature, pointing to its possible contribution to neurological manifestations of the disease. Increasing evidence suggests that cell-intrinsic deficits in OLGs are the earliest cause of myelination abnormalities in HD, with several OLG-specific pathogenic mechanisms involved, including altered lipid metabolism, modifications in epigenetic signaling, and dysregulated activity of transcription factors. Understanding the mechanisms that underlie myelination deficits in HD can expand therapeutic options to include targeting oligodendroglial pathology as an additional treatment avenue. Oligodendrocytes (OLGs), highly specialized glial cells that wrap axons with myelin sheaths, are critical for brain development and function. There is new recognition of the role of OLGs in the pathogenesis of neurodegenerative diseases (NDDs), including Huntington's disease (HD), a prototypic NDD caused by a polyglutamine tract expansion in huntingtin (HTT), which results in gain- and loss-of-function effects. Clinically, HD is characterized by a constellation of motor, cognitive, and psychiatric disturbances. White matter (WM) structures, representing myelin-rich regions of the brain, are profoundly affected in HD, and recent findings reveal oligodendroglia dysfunction as an early pathological event. Here, we focus on mechanisms that underlie oligodendroglial deficits and dysmyelination in the progression of the disease, highlighting the pathogenic contributions of mutant HTT (mHTT). We also discuss potential therapeutic implications involving these molecular pathways. Oligodendrocytes (OLGs), highly specialized glial cells that wrap axons with myelin sheaths, are critical for brain development and function. There is new recognition of the role of OLGs in the pathogenesis of neurodegenerative diseases (NDDs), including Huntington's disease (HD), a prototypic NDD caused by a polyglutamine tract expansion in huntingtin (HTT), which results in gain- and loss-of-function effects. Clinically, HD is characterized by a constellation of motor, cognitive, and psychiatric disturbances. White matter structures, representing myelin-rich regions of the brain, are profoundly affected in HD, and recent findings reveal oligodendroglia dysfunction as an early pathological event. Here, we focus on mechanisms that underlie oligodendroglial deficits and dysmyelination in the progression of the disease, highlighting the pathogenic contributions of mutant HTT. We also discuss potential therapeutic implications involving these molecular pathways. [ABSTRACT FROM AUTHOR]

Background: Differentiating neuromyelitis optica spectrum disorder (NMOSD) from its mimics is crucial to avoid misdiagnosis, especially in the absence of aquaporin‐4‐IgG. While multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein‐IgG associated disease (MOGAD) represent major and well‐defined differential diagnoses, non‐demyelinating NMOSD mimics remain poorly characterized. Methods: We conducted a systematic review on PubMed/MEDLINE to identify reports of patients with non‐demyelinating disorders that mimicked or were misdiagnosed as NMOSD. Three novel cases seen at the authors' institutions were also included. The characteristics of NMOSD mimics were analyzed and red flags associated with misdiagnosis identified. Results: A total of 68 patients were included; 35 (52%) were female. Median age at symptoms onset was 44 (range, 1–78) years. Fifty‐six (82%) patients did not fulfil the 2015 NMOSD diagnostic criteria. The clinical syndromes misinterpreted for NMOSD were myelopathy (41%), myelopathy + optic neuropathy (41%), optic neuropathy (6%), or other (12%). Alternative etiologies included genetic/metabolic disorders, neoplasms, infections, vascular disorders, spondylosis, and other immune‐mediated disorders. Common red flags associated with misdiagnosis were lack of cerebrospinal fluid (CSF) pleocytosis (57%), lack of response to immunotherapy (55%), progressive disease course (54%), and lack of magnetic resonance imaging gadolinium enhancement (31%). Aquaporin‐4‐IgG positivity was detected in five patients by enzyme‐linked immunosorbent assay (n = 2), cell‐based assay (n = 2: serum, 1; CSF, 1), and non‐specified assay (n = 1). Conclusions: The spectrum of NMOSD mimics is broad. Misdiagnosis frequently results from incorrect application of diagnostic criteria, in patients with multiple identifiable red flags. False aquaporin‐4‐IgG positivity, generally from nonspecific testing assays, may rarely contribute to misdiagnosis. [ABSTRACT FROM AUTHOR]

Background and purpose: Defects in the mitochondrial respiratory chain (MRC) can lead to combined MRC dysfunctions (COXPDs) with heterogenous genotypes and clinical features. We report a patient carrying heterozygous variants in the TUFM gene who presented with clinical features compatible with COXPD4 and radiological findings mimicking multiple sclerosis (MS). Methods: A 37‐year‐old French Canadian woman was investigated for recent onset of gait and balance problems. Her previous medical history included recurrent episodes of hyperventilation associated with lactic acidosis during infections, asymptomatic Wolff–Parkinson–White syndrome, and nonprogressive sensorineural deafness. Results: Neurological examinations revealed fine bilateral nystagmus, facial weakness, hypertonia, hyperreflexia, dysdiadochokinesia, dysmetria, and ataxic gait. Brain magnetic resonance imaging (MRI) showed multifocal white matter abnormalities in cerebral white matter as well as cerebellar hemispheres, brainstem, and middle cerebellar peduncles, some of which mimicked MS. Analysis of native‐state oxidative phosphorylation showed a combined decrease in CI/CII, CIV/CII, and CVI/CII. Exome sequencing detected two heterozygous TUFM gene variants. Little clinical progression was noted over a 5‐year follow‐up. Brain MRI remained unchanged. Conclusions: Our report broadens the phenotypic and radiological spectrum of TUFM‐related disorders by adding milder, later onset forms to the previously known early onset, severe presentations. The presence of multifocal white matter abnormalities can be misinterpreted as due to acquired demyelinating diseases, and thus TUFM‐related disorders should be added to the list of mitochondrial MS mimickers. [ABSTRACT FROM AUTHOR]

Objective: To investigate the clinical manifestations, treatment and prognosis of COVID-19-associated central nervous system (CNS) complications. Methods: In this single-centre observation study, we recruited patients with COVID-19-associated CNS complications at the neurology inpatient department of the Eighth Affiliated Hospital, Sun Yat-Sen University (Futian, Shenzhen) from Dec 2022 to Feb 2023. Patients were analysed for demographics, clinical manifestations, cerebrospinal fluid properties, electroencephalographic features, neuroimaging characteristics, and treatment outcome. All patients were followed-up at 1 and 2 months after discharge until Apr 2023. Results: Of the 12 patients with COVID-19-associated CNS complications, the CNS symptoms occur between 0 days and 4 weeks after SARS-CoV-2 infection. The most common CNS symptoms were memory deficits (4/12, 33%), Unresponsiveness (4/12, 33%), mental and behavioural disorders (4/12, 33%). Seven of 12 cases can be categorized as probable SARS-CoV-2 encephalitis, and 5 cases can be described as brainstem encephalitis, acute disseminated encephalomyelitis, optic neuritis, multiple sclerosis or tremor probably associated with SARS-CoV-2 infection. Six patients received antiviral therapy, and 11 patients received glucocorticoid therapy, of which 3 patients received human immunoglobulin synchronously. Nine patients recovered well, two patients had residual neurological dysfunction, and one patient passed away from complications associated with tumor. Conclusion: In this observational study, we found that the inflammatory or immune-related complications were relatively common manifestations of COVID-19-associated CNS complications, including different phenotypes of encephalitis and CNS inflammatory demyelinating diseases. Most patients recovered well, but a few patients had significant neurological dysfunctions remaining. [ABSTRACT FROM AUTHOR]

In patients with inactive disease, especially in those older where MS inflammatory activity is likely low, MS should not be considered a contraindication for ICI treatment, particularly in patients with refractory malignancies and limited treatment options. In a recent study of 16 inactive MS patients, none experienced relapses or new MRI lesions following ICI treatment [[1]]. A review of 42,529 adverse events from ICI exposure through the United States Food and Drug Administration Adverse Event Reporting System (FAERS) database identified 13 patients with MS relapses after ICI, eight of whom had pre-existing MS diagnosis. Patient #3: Brain MRI T1 post-contrast images showing enhancing lesions 2 months (3a, 3b) and 7 months (3c, 3d) after ICI initiation We describe demyelinating disease activity after ICI in a series of patients in the MS disease continuum. [Extracted from the article]

Background: Multiple sclerosis is a neuro-inflammatory disease that affects adults and children and causes somatic and cognitive symptoms. Diagnosis after the first clinical symptoms is challenging, involves laboratory and magnetic resonance imaging work-up and is often inconclusive unless subsequent clinical attacks occur. Neurofilament light chains are structural proteins within neurons. Levels of this marker in cerebrospinal fluid, plasma and serum are consistently higher in patients with an initial clinical demyelinating attack that later go on to develop multiple sclerosis. Evidence concerning serum levels of this biomarker in children with multiple sclerosis is scarce. Our aim is to review and analyze the evidence available for patients with multiple sclerosis, under the age of 18. Methods: We conducted a systematic search of PubMed/Medline, Embase, Cochrane Database, and ProQuest. Human studies that provided data on serum levels of Neurofilament light chains in pediatric patients with MS, measured at the time of the first demyelinating attack and before treatment were included in meta-analysis. Results: Three studies satisfied the inclusion criteria. 157 pediatric patients with multiple sclerosis and 270 hospital-based controls that did not present with this condition were included in the analysis. A fixed effects meta-analysis showed that the standardized mean difference between patients and controls is 1.82, with a 95% confidence interval of [1.56–2.08]. Conclusion: Pediatric patients with multiple sclerosis show higher levels of serum neurofilament light chains at their first clinical demyelinating attack compared to pediatric hospital-based controls. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an immune-mediated disease of the central nervous system, characterized by chronic, inflammatory, demyelinating, and neurodegenerative processes. MS management relies on disease-modifying drugs that suppress/modulate the immune system. Cladribine tablets (CladT) have been approved by different health authorities for patients with various forms of relapsing MS. The drug has been demonstrated to deplete CD4+ and CD8+ T-cells, with a higher effect described in the former, and to decrease total CD19+, CD20+, and naive B-cell counts. COVID-19 is expected to become endemic, suggesting its potential infection risk for immuno-compromised patients, including MS patients treated with disease-modifying drugs. We report here the available data on disease-modifying drug-treated-MS patients and COVID-19 infection and vaccination, with a focus on CladT. MS patients treated with CladT are not at higher risk of developing severe COVID-19. While anti-SARS-CoV-2 vaccination is recommended in all MS patients with guidelines addressing vaccination timing according to the different disease-modifying drugs, no vaccination timing restrictions seem to be necessary for cladribine, based on its mechanism of action and available evidence. Published data suggest that CladT treatment does not impact the production of anti-SARS-CoV-2 antibodies after COVID-19 vaccination, possibly due to its relative sparing effect on naïve B-cells and the rapid B-cell reconstitution following treatment. Slightly lower specific T-cell responses are likely not impacting the risk of breakthrough COVID-19. It could be stated that cladribine's transient effect on innate immune cells likely contributes to maintaining an adequate first line of defense against the SARS-CoV-2 virus. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease involving demyelination and axonal damage in the central nervous system (CNS). In this study, we investigated pathological changes in the lumbar spinal cord of C57BL/6 mice induced with progressive experimental autoimmune encephalomyelitis (EAE) disease using 9.4‐T magnetic resonance imaging (MRI). Multiparametric MRI measurements including MR spectroscopy, diffusion tensor imaging (DTI) and volumetric analyses were applied to detect metabolic changes in the CNS of EAE mice. Compared with healthy mice, EAE mice showed a significant reduction in N‐acetyl aspartate and increases in choline, glycine, taurine and lactate. DTI revealed a significant reduction in fractional anisotropy and axial diffusivity and an increase in radial diffusivity in the lumbar spinal cord white matter (WM), while in the grey matter (GM), fractional anisotropy increased. High‐resolution structural imaging also revealed lumbar spinal cord WM hypertrophy and GM atrophy. Importantly, these MRI changes were strongly correlated with EAE disease scoring and pathological changes in the lumbar (L2–L6), particularly WM demyelination lesions and aggregation of immune cells (microglia/macrophages and astrocytes) in this region. This study identified changes in MRI biomarker signatures that can be useful for evaluating the efficacy of novel drugs using EAE models in vivo. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) is an inflammatory and demyelinating disorder of central nervous system that can be diagnosed in pediatric age (<18 years) in 3-5% of the cases. This early onset is associated with higher relapse rates and earlier progression to neurological disability. By using NEDA-3 (No Evidence of Disease Activity-3) criteria, we aimed to identify clinical predictors associated with absence of disease activity and control of disease progression 12 months after the diagnosis, in a cohort of pediatric-onset MS (POMS) patients regularly followed-up in our center. Methods: We analyzed demographic, clinical, laboratorial and imaging variables of patients with POMS identified in our center, between 2010 and 2021, in two moments: at the diagnosis and 12 months after it. Statistical tests were applied to compare the distribution of those variables between groups defined by NEDA-3 status and by each one of its three variable components. Results: We included 27 patients in the study (18 female), with a mean age of 14.8years (± 2.8), being all diagnosed with relapsing-remitting MS and with a median score of 1.5 at the Expanded Disability Status Scale (EDSS). The use of natalizumab (p = 0.017) and the negativity for anti-EBV IgG antibodies (p = 0.018) at diagnosis were associated with a higher achievement of NEDA-3 status 12months after, in our cohort. Prescribed treatment was also associated with statistically significant differences in the "absence of MRI activity" component of NEDA-3 (p = 0.006): patients under treatment with natalizumab had a higher probability of achieving this status, and the opposite was observed in glatiramer acetate-treated children. Discussion and conclusion: Our exploratory results underline the pivotal importance that an early and more effective therapeutical approach may have in the control of disease activity, in POMS. Additionally, they also seem to suggest that the presence of anti-EBV antibodies is not innocent, as it can be related to a less favorable evolution of the disease, even at a very early stage. Further studies are needed to confirm the applicability of these variables as prognostic and personalized tools in this clinical setting. [ABSTRACT FROM AUTHOR]

Background: Myelin oligodendrocyte glycoprotein antibody-associated autoimmune disease (MOGAD) is a rare monophasic or relapsing inflammatory demyelinating disease of the central nervous system (CNS) and can mimic multiple sclerosis (MS). The variable availability of live cell-based MOG-antibody assays and difficulties in interpreting low-positive antibody titers can complicate diagnosis. Literature on cerebrospinal fluid (CSF) profiles in MOGAD versus MS, one of the most common differential diagnoses, is scarce. We here analyzed the value of basic CSF parameters to i) distinguish different clinical MOGAD manifestations and ii) differentiate MOGAD from MS. Methods: This is retrospective, single-center analysis of clinical and laboratory data of 30 adult MOGAD patients and 189 adult patients with relapsing-remitting multiple sclerosis. Basic CSF parameters included CSF white cell count (WCC) and differentiation, CSF/serum albumin ratio (QAlb), intrathecal production of immunoglobulins, CSF-restricted oligoclonal bands (OCB) and MRZ reaction, defined as intrathecal production of IgG reactive against at least 2 of the 3 viruses measles (M), rubella (R) and varicella zoster virus (Z). Results: MOGAD patients with myelitis were more likely to have a pleocytosis, a QAlb elevation and a higher WCC than those with optic neuritis, and, after review and combined analysis of our and published cases, they also showed a higher frequency of intrathecal IgM synthesis. Compared to MS, MOGAD patients had significantly more frequently neutrophils in CSF and WCC>30/µl, QAlb>10x10-3, as well as higher mean QAlb values, but significantly less frequently CSF plasma cells and CSF-restricted OCB. A positive MRZ reaction was present in 35.4% of MS patients but absent in all MOGAD patients. Despite these associations, the only CSF parameters with relevant positive likelihood ratios (PLR) indicating MOGAD were QAlb>10x10-3 (PLR 12.60) and absence of CSF-restricted OCB (PLR 14.32), whereas the only relevant negative likelihood ratio (NLR) was absence of positive MRZ reaction (NLR 0.00). Conclusion: Basic CSF parameters vary considerably in different clinical phenotypes of MOGAD, but QAlb>10x10-3 and absence of CSF-restricted OCB are highly useful to differentiate MOGAD from MS. A positive MRZ reaction is confirmed as the strongest CSF rule-out parameter in MOGAD and could be useful to complement the recently proposed diagnostic criteria. [ABSTRACT FROM AUTHOR]

Background: In the demyelinating disease multiple sclerosis (MS), chronic-active brain inflammation, remyelination failure and neurodegeneration remain major issues despite immunotherapy. While B cell depletion and blockade/sequestration of T and B cells potently reduces episodic relapses, they act peripherally to allow persistence of chronic-active brain inflammation and progressive neurological dysfunction. N-acetyglucosamine (GlcNAc) is a triple modulator of inflammation, myelination and neurodegeneration. GlcNAc promotes biosynthesis of Asn (N)-linked-glycans, which interact with galectins to co-regulate the clustering/signaling/endocytosis of multiple glycoproteins simultaneously. In mice, GlcNAc crosses the blood brain barrier to raise N-glycan branching, suppress inflammatory demyelination by T and B cells and trigger stem/progenitor cell mediated myelin repair. MS clinical severity, demyelination lesion size and neurodegeneration inversely associate with a marker of endogenous GlcNAc, while in healthy humans, age-associated increases in endogenous GlcNAc promote T cell senescence. Objectives and methods: An open label dose-escalation mechanistic trial of oral GlcNAc at 6 g (n = 18) and 12 g (n = 16) for 4 weeks was performed in MS patients on glatiramer acetate and not in relapse from March 2016 to December 2019 to assess changes in serum GlcNAc, lymphocyte N-glycosylation and inflammatory markers. Post-hoc analysis examined changes in serum neurofilament light chain (sNfL) as well as neurological disability via the Expanded Disability Status Scale (EDSS). Results: Prior to GlcNAc therapy, high serum levels of the inflammatory cytokines IFNγ, IL-17 and IL-6 associated with reduced baseline levels of a marker of endogenous serum GlcNAc. Oral GlcNAc therapy was safe, raised serum levels and modulated N-glycan branching in lymphocytes. Glatiramer acetate reduces TH1, TH17 and B cell activity as well as sNfL, yet the addition of oral GlcNAc dose-dependently lowered serum IFNγ, IL-17, IL-6 and NfL. Oral GlcANc also dose-dependently reduced serum levels of the anti-inflammatory cytokine IL-10, which is increased in the brain of MS patients. 30% of treated patients displayed confirmed improvement in neurological disability, with an average EDSS score decrease of 0.52 points. Conclusions: Oral GlcNAc inhibits inflammation and neurodegeneration markers in MS patients despite concurrent immunomodulation by glatiramer acetate. Blinded studies are required to investigate GlcNAc's potential to control residual brain inflammation, myelin repair and neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

Chronic graft-versus-host disease (cGVHD) represents a serious complication of allogeneic haematopoietic stem cell transplant that occurs in 20%-80% of patients. A leading hypothesis posits that chronic CNS-GHVD onset stems from sequential CNS infiltration of donor CD8 SP + sp T cells, donor CD4 SP + sp T cells and donor bone marrow-derived macrophages (BMDMs). 4 Polchlopek Blasiak K, Simonetta F, Vargas MI, Chalandon Y. Central nervous system graft-versus-host disease (CNS-GvHD) after allogeneic haematopoietic stem cell transplantation. [Extracted from the article]

The central vein sign (CVS) on brain magnetic resonance imaging (MRI) is a promising diagnostic marker for distinguishing adult multiple sclerosis (MS) from other demyelinating conditions, but its prevalence is not well-established in pediatric-onset multiple sclerosis (POMS) versus myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). MOGAD can mimic MS radiologically. This study seeks to determine the utility of CVS, together with other radiological findings, in distinguishing POMS from MOGAD in children. Children with POMS or MOGAD were identified in a pediatric demyelinating database. Two reviewers, blinded to diagnosis, fused fluid-attenuated inversion recovery sequences and susceptibility-weighted imaging from clinical imaging to identify CVS. Agreement in CVS number was reported using intraclass correlation coefficients (ICC). We performed topographic analyses as well as characterization of the clinical information and lesions on brain, spinal cord, and orbital MRI when available. Twenty children, 10 with POMS and 10 with MOGAD, were assessed. The median lesion percentage of CVS was higher in POMS versus MOGAD for both raters (rater 1: 80% vs 9.8%; rater 2: 22.7% vs 7.5%). Inter-rater reliability for identifying total white matter lesions was strong (ICC 0.94 [95% confidence interval [CI] 0.84, 0.97]); however, it was poor for detecting CVS lesions (ICC −0.17 [95% CI: −0.37, 0.58]). The CVS can be a useful diagnostic tool for differentiating POMS from MOGAD. However, advanced clinical imaging tools that can better detect CVS are needed to increase inter-rater reliability before clinical application. [ABSTRACT FROM AUTHOR]

Background: Race and ancestry influence the course of multiple sclerosis (MS). Objectives: Explore clinical characteristics of MS and neuromyelitis optica spectrum disorder (NMOSD) in Asian American patients. Methods: Chart review was performed for 282 adults with demyelinating disease who self-identified as Asian at a single North American MS center. Demographics and clinical characteristics were compared to non-Asian MS patients and by region of Asian ancestry. Results: Region of ancestry was known for 181 patients. Most (94.7%) preferred English, but fewer East Asian patients did (80%, p = 0.0001). South Asian patients had higher neighborhood household income (p = 0.002). Diagnoses included MS (76.2%) and NMOSD (13.8%). More patients with NMOSD than MS were East and Southeast Asian (p = 0.004). For MS patients, optic nerve and spinal cord involvement were similar across regions of ancestry. Asian MS patients were younger at symptom onset and diagnosis than non-Asian MS patients. MS Severity Scale scores were similar to non-Asian MS patients but worse among Southeast Asians (p = 0.006). Conclusions: MS severity was similar between Asian American patients and non-Asian patients. Region of ancestry was associated with differences in sociodemographics and MS severity. Further research is needed to uncover genetic, socioeconomic, or environmental factors causing these differences. [ABSTRACT FROM AUTHOR]

The widespread use of magnetic resonance imaging (MRI) has led to an increase in incidental findings in the central nervous system. Radiologically isolated syndrome (RIS) is a condition where imaging reveals lesions suggestive of demyelinating disease without any clinical episodes consistent with multiple sclerosis (MS). The prognosis for RIS patients is uncertain, with some remaining asymptomatic while others progress to MS. Several risk factors for disease progression have been identified, including male sex, younger age at diagnosis, and spinal cord lesions. This article reviews two promising biomarkers, the central vein sign (CVS) and the paramagnetic rim sign (PRS), and their potential role in the diagnosis and prognosis of MS and RIS. Both CVS and PRS have been shown to be accurate diagnostic markers in MS, with high sensitivity and specificity, and have been useful in distinguishing MS from other disorders. Further research is needed to validate these findings and determine the clinical utility of these biomarkers in routine practice. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor-alpha inhibitors and immune-checkpoint inhibitors are the most frequently reported agents, but recently, the number of cases reporting iatrogenic central nerve demyelination with tyrosine kinase inhibitors has increased. Tumor necrosis factor-alpha inhibitors and immune-checkpoint inhibitors are the most frequently reported agents in iatrogenic central nervous system demyelination cases [[1]]. As treatment options for cancer and autoimmune diseases are developing each day, iatrogenic central demyelination case reports are increasing in number. [Extracted from the article]

Background: Multiple sclerosis (MS) is an autoimmune neurodegenerative disease of central nervous system characterized by inflammation, demyelination, as well as neuro-degeneration. The aim of the study is to detect factors affecting the degree of disability in multiple sclerosis patients for early identification and prognosis estimation. Methods: Ninety relapsing remitting multiple sclerosis (RRMS) patients (36 males and 54 females) were included in this retrospective cohort study in the period from February 2020 to October 2022 in Zagazig University hospital and outpatient MS clinic. Full general and neurological assessments were done to all patients. Severity was evaluated by expanded disability status scale (EDSS). Physical and psychological MS impact scales were also done. Magnetic resonance imaging (MRI) for brain and spine were done with gadolinium enhancement; visual evoked potential was done for the patients. Results: Among 90 patients with RRMS, 52 (57.8 %) patients had EDSS ≤3 (group A), while 38 patients (42.2%) had EDSS >3 (group B). Multilogistic regression analysis showed that black holes, total cholesterol (TC) and disease modifying therapy (DMT) use were the independent factors affecting disability in RRMS patients. There was significant positive correlation between EDSS and Visual evoked potential (VEP) latency of RT eye and there was a negative correlation between EDSS and VEP amplitude of the RT eye. Conclusions: Black holes, TC and DMT use were independent factors affecting prognosis of RRMS that help early estimation and intervention. [ABSTRACT FROM AUTHOR]

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Introduction: Multiple sclerosis is an inflammatory and demyelinating disease caused by a pathogenic immune response against the myelin sheath surfaces of oligodendrocytes. The demyelination has been classically associated with pathogenic B cells residing in the central nervous system that release autoreactive antibodies against myelin. The aim of the present study was to investigate whether extracellular vesicles (EVs) mediate delivery of myelin autoreactive antibodies from peripheral B cells against oligodendrocytes in multiple sclerosis (MS) and to analyze whether these EVs could mediate demyelination in vitro. We also studied the role of these EV-derived myelin antibodies as a diagnostic biomarker in MS. Methods: This is a prospective, observational, and single-center study that includes patients with MS and two control groups: patients with non-immune white matter lesions and healthy controls. We isolated B-cell-derived EVs from the blood and cerebrospinal fluid (CSF) and analyzed their myelin antibody content. We also studied whether antibody-loaded EVs reach oligodendrocytes in patients with MS and the effect on demyelination of Bcell- derived EVs containing antibodies in vitro. Results: This study enrolled 136 MS patients, 23 white matter lesions controls, and 39 healthy controls. We found autoreactive myelin antibodies in EVs that were released by peripheral B cells, but not by populations of B cells resident in CSF. We also identified a cut-off of 3.95 ng/mL of myelin basic protein autoantibodies in EVs from peripheral B cells, with 95.2% sensitivity and 88.2% specificity, which allows us to differentiate MS patients from healthy controls. EVderived myelin antibodies were also detected in the oligodendrocytes of MS patients. Myelin antibody-loaded EVs from B cells induced myelin markers decrease of oligodendrocytes in vitro. Discussion: Peripheral reactive immune cells could contribute remotely to MS pathogenesis by delivering myelin antibodies to oligodendrocytes. EV-derived myelin antibodies could play a role as diagnostic biomarker in MS. [ABSTRACT FROM AUTHOR]

Introduction: Multiple Sclerosis (MS) is a chronic inflammatory demyelinating disease of the CNS with an autoimmune pathogenesis. Over the years, numerous disease-modifying therapies (DMTs) have proven effective in disease control; to date, there is a need to identify a personalized treatment effective in ensuring disease-free status or no evidence of disease activity (NEDA). Objective: identify clinical, demographic and treatment approach characteristics that affect the maintenance of NEDA-3 and the occurrence of clinical relapses during a 6-years follow-up. Materials and method: a retrospective study was conducted on a cohort of MS patients followed up with six-year period. All participants were treated with first- or second-line MS drugs. Clinical relapse, NEDA-3 at 6 years and sustained EDSS were assessed as disease activity outcomes. Patients with follow-up of less than 6 years and insufficient clinical and radiological data were excluded from the study. Results: Two-hundred-eighty naive patients (mean age was 49.8 years, SD ± 11.35 years, 23-76, F/M 182/98), with MS were followed up for 6 years. The mean age at diagnosis was 34.3 years (SD ±11.5, 14-62 years), the mean EDSS score at the onset was 1.9 (±1.3), 76.8% of patients had an EDSS below or equal to 2.5 at diagnosis. In the cohort 37 (13.2%) directly received second-line treatment, 243 (86.8%) received first-line drugs. The analysis showed that second-line treatment from beginning had a protective effect for the achievement of NEDA-3 (p = 0.029), on the prevention of clinical relapse (p = 0.018) and on number of relapses (p = 0.010); this finding was confirmed by logistic regression analysis (p = 0.04) and Kaplan-Meier analysis (p = 0.034). Conclusion: The results of this study demonstrate the efficacy of targeted and early intervention so as to act in the right time window, ensuring a favorable outcome in both clinical and radiological terms; this could be decisive in reducing clinical relapse, disease progression and related disability. Therefore, prescribing highly effective drug in the early stages of the disease represents a leading strategy with the most favorable cost-benefit ratio. [ABSTRACT FROM AUTHOR]

(1) Background: Multiple sclerosis (MS) is an auto-immune, chronic, neuroinflammatory, demyelinating disease that affects mainly young patients. This progressive inflammatory process causes the chronic loss of brain tissue and results in a deterioration in quality of life. To monitor neuroinflammatory process activity and predict the further development of disease, it is necessary to find a suitable biomarker that could easily be used. In this research, we verify the usability of choroid plexus (CP) volume, a new MS biomarker, in the monitoring of the progression of multiple sclerosis disease. (2) Methods: A single-center, prospective study with three groups of patients was conducted based on the following groups: MS patients who received experimental cellular therapy (Treg), treatment-naïve MS patients and healthy controls. (3) Results: This study concludes that there is a correlation between the CPV/TIV (choroid plexus/total intracranial volume) ratio and the progress of multiple sclerosis disease—patients with MS (MS + Treg) had larger volumes of choroid plexuses. CPV/TIV ratios in MS groups were constantly and significantly growing. In the Treg group, patients with relapses had larger plexuses in comparison to the group with no relapses of MS. A similar correlation was observed for the GD+ group (patients with postcontrast enhancing plaques) compared against the non-GD group (patients without postcontrast enhancing plaques). (4) Conclusion: Choroid plexus volume, due to its immunological function, correlates with the inflammatory process in the central nervous system. We consider it to become a valuable radiological biomarker of MS activity. [ABSTRACT FROM AUTHOR]

Background: Distinguishing between central nervous system lymphoma (CNSL) and CNS infectious and/or demyelinating diseases, although clinically important, is sometimes difficult even using imaging strategies and conventional cerebrospinal fluid (CSF) analyses. To determine whether detection of genetic mutations enables differentiation between these diseases and the early detection of CNSL, we performed mutational analysis using CSF liquid biopsy technique. Methods: In this study, we extracted cell‐free DNA from the CSF (CSF‐cfDNA) of CNSL (N = 10), CNS infectious disease (N = 10), and demyelinating disease (N = 10) patients, and performed quantitative mutational analysis by droplet‐digital PCR. Conventional analyses were also performed using peripheral blood and CSF to confirm the characteristics of each disease. Results: Blood hemoglobin and albumin levels were significantly lower in CNSL than CNS infectious and demyelinating diseases, CSF cell counts were significantly higher in infectious diseases than CNSL and demyelinating diseases, and CSF‐cfDNA concentrations were significantly higher in infectious diseases than CNSL and demyelinating diseases. Mutation analysis using CSF‐cfDNA detected MYD88L265P and CD79Y196 mutations in 60% of CNSLs each, with either mutation detected in 80% of cases. Mutual existence of both mutations was identified in 40% of cases. These mutations were not detected in either infectious or demyelinating diseases, and the sensitivity and specificity of detecting either MYD88/CD79B mutations in CNSL were 80% and 100%, respectively. In the four cases biopsied, the median time from collecting CSF with the detected mutations to definitive diagnosis by conventional methods was 22.5 days (range, 18–93 days). Conclusions: These results suggest that mutation analysis using CSF‐cfDNA might be useful for differentiating CNSL from CNS infectious/demyelinating diseases and for early detection of CNSL, even in cases where brain biopsy is difficult to perform. [ABSTRACT FROM AUTHOR]

Introduction: Multiple sclerosis (MS) is a chronic autoimmune-mediated demyelinating disease of the central nervous system (CNS). A clinical presentation of the disease is highly differentiated even from the earliest stages of the disease. The application of stratifying tests in clinical practice would allow for improving clinical decision-making including a proper assessment of treatment benefit/risk balance. Methods: This prospective study included patients with MS diagnosed up to 1 year before recruitment. We analyzed serumbiomarkers such as CXCL13, CHI3L1, OPN, IL-6, and GFAP and neurofilament light chains (NfLs); brain MRI parameters of linear atrophy such as bicaudate ratio (BCR), third ventricle width (TVW); and information processing speed were measured using the Symbol Digit Modalities Test (SDMT) during the 2 years follow-up. Results: The study included a total of 50 patients recruited shortly after the diagnosis of MS diagnosis (median 0 months; range 0-11 months), and the mean time of observation was 28 months (SD = 4.75). We observed a statistically significant increase in the EDSS score (Wilcoxon test: Z = 3.06, p = 0.002), BCR (Wilcoxon test: Z = 4.66, p < 0.001), and TVW (Wilcoxon test: Z = 2.84, p = 0.005) after 2 years of disease. Patients who had a significantly higher baseline level of NfL suffered fromamore severe disease course as per the EDSS score (Mann-Whitney U-test: U = 107, Z = -2,74, p = 0.006) and presence of relapse (Mann-Whitney U-test: U = 188, Z = -2.01, p = 0.044). In the logistic regression model, none of the parameters was a significant predictor for the achieving of no evidence of disease activity status (NEDA). In the model considering all assessed parameters, only the level of NfL had a significant impact on disease progression, measured as the increase in EDSS (logistic regression: β = 0.002, p = 0.017). Conclusion: We confirmed that NfL levels in serum are associated with more active disease. Moreover, we found that TVW at the time of diagnosis was associated with an impairment in cognitive function measured by information processing speed at the end of the 2-year observation. The inclusion of serum NfL and TVW assessment early in the disease may be a good predictor of disease progression independent of NEDA. [ABSTRACT FROM AUTHOR]

Myelin oligodendrocyte glycoprotein (MOG) is expressed on the outermost layer of the myelin sheath in the central nervous system. Recently, the clinical concept of MOG antibody-associated disease (MOGAD) was established based on the results of human MOG-transfected cell-based assays which can detect conformation-sensitive antibodies against MOG. In this review, we summarized the pathological findings of MOGAD and discussed the issues that remain unresolved. MOGAD pathology is principally inflammatory demyelination without astrocyte destruction, characterized by perivenous demyelination previously reported in acute disseminated encephalomyelitis and by its fusion pattern localized in both the white and gray matter, but not by radially expanding confluent demyelination typically seen in multiple sclerosis (MS). Some of demyelinating lesions in MOGAD show severe loss of MOG staining compared with those of other myelin proteins, suggesting a MOG-targeted pathology in the disease. Perivascular cuffings mainly consist of macrophages and T cells with CD4-dominancy, which is also different from CD8+ T-cell-dominant inflammation in MS. Compared to aquaporin 4 (AQP4) antibody-positive neuromyelitis optica spectrum disorders (NMOSD), perivenous complement deposition is less common, but can be seen on myelinated fibers and on myelin degradation products within macrophages, resembling MS Pattern II pathology. Thus, the pathogenetic contribution of complements in MOGAD is still debatable. Together, these pathological features in MOGAD are clearly different from those of MS and AQP4 antibody-positive NMOSD, suggesting that MOGAD is an independent autoimmune demyelinating disease entity. Further research is needed to clarify the exact pathomechanisms of demyelination and how the pathophysiology relates to the clinical phenotype and symptoms leading to disability in MOGAD patients. [ABSTRACT FROM AUTHOR]

Nervous system disorders may be accompanied by gastrointestinal (GI) dysfunction. Brain lesions may be responsible for GI problems such as decreased peristalsis (e.g., lesions in the basal ganglia, pontine defecation center/Barrington's nucleus), decreased abdominal strain (e.g., lesions in the parabrachial nucleus), hiccupping and vomiting (e.g., lesions in the area postrema), and appetite loss (e.g., lesions in the hypothalamus). Decreased peristalsis also may be caused by lesions of the spinal long tracts or the intermediolateral nucleus projecting to the myenteric plexus. This review addresses GI dysfunction caused by multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein-associated disorder. Neuro-associated GI dysfunction may develop concurrently with brain or spinal cord dysfunction or may predate it. Collaboration between gastroenterologists and neurologists is highly desirable when caring for patients with GI dysfunction related to nervous system disorders, particularly since patients with these symptoms may visit a gastroenterologist prior to the establishment of a neurological diagnosis. [ABSTRACT FROM AUTHOR]

• Although there is no drug treatment available for CMT, great advances are being made. • Promising approaches are under investigation and clinical trials ongoing/planned. • Different approaches are under study for CMT1A including PMP22 gene silencing. • Gene therapy and several compounds for different pathways are being evaluated. • Active trials include PXT3003 in CMT1A, aldose reductase inhibitor for defective SORD. There is still no effective drug treatment available for Charcot-Marie-Tooth disease (CMT). Current management relies on rehabilitation therapy, surgery for skeletal deformities, and symptomatic treatment. The challenge is to find disease-modifying therapies. Several approaches, including gene silencing (by means of ASO, siRNA, shRNA, miRNA, CRISPR-Cas9 editing), to counteract the PMP22 gene overexpression in the most frequent CMT1A type are under investigation. PXT3003 is the compound in the most advanced phase for CMT1A, as a second phase-III trial is ongoing. Gene therapy to substitute defective genes (particularly in recessive forms associated with loss-of-function mutations) or insert novel ones (e.g., NT3 gene) are being developed and tested in animal models and in still exceptional cases have reached the clinical trial phase in humans. Novel treatment approaches are also aimed at developing compounds acting on pathways important for different CMT types. Modulation of the neuregulin pathway determining myelin thickness is promising for both hypo-demyelinating and hypermyelinating neuropathies; intervention on Unfolded Protein Response seems effective for rescuing misfolded myelin proteins such as MPZ in CMT1B. HDAC6 inhibitors improved axonal transport and ameliorated phenotypes in different CMT models. Other potential therapeutic strategies include targeting macrophages, lipid metabolism, and Nav1.8 sodium channel in demyelinating CMT and the P2×7 receptor, which regulates calcium influx into Schwann cells, in CMT1A. Further approaches are aimed at correcting metabolic abnormalities, including the accumulation of sorbitol caused by biallelic mutations in the sorbitol dehydrogenase (SORD) gene and of neurotoxic glycosphingolipids in HSN1. [ABSTRACT FROM AUTHOR]

Background and purpose: There is an absence of data from large population‐based cohort studies on the incidence of radiologically isolated syndrome (RIS). The incidence of RIS and the subsequent risk for multiple sclerosis (MS) were investigated. Methods: A population‐based, retrospective cohort study was conducted using a data‐lake‐based analysis of digitalized radiology reports. All brain and spinal cord magnetic resonance imaging (MRI) in people aged 16–70 during the years 2005–2010 (n = 102,224) were screened using optimized search terms to detect cases with RIS. The subjects with RIS were followed up until January 2022. Results: The cumulative incidence of RIS was 0.03% when all MRI modalities were included and 0.06% when only brain MRI was included according to MAGNIMS 2018 recommendation criteria. With the Okuda 2009 criteria, the respective figures were 0.03% and 0.05% (86% concordance). The overall risk for MS after RIS was similar, 32% by using the MAGNIMS and 32% by using the Okuda definition of RIS. Individuals aged <35.5 years exhibited the most significant predisposition to MS (80%), whilst those >35.5 years had less than 10% risk of MS. MS diagnosed after RIS constituted 0.8% of the incident MS cases in the population during 2005–2010. Conclusions: A population‐wide context was provided for the incidence of RIS and its relationship to MS. MAGNIMS recommendations were only slightly more sensitive to detect RIS compared to the Okuda criteria. RIS has a subtle effect on the overall incidence of MS, yet the risk for MS in individuals under the age of 35.5 years is substantial. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a chronic progressive demyelinating disease of the central nervous system (CNS), which also affects the autonomic nervous system (ANS). Manifestations of MS in the ANS include urological, sexual, gastrointestinal, cardiovascular, and thermoregulatory disorders as well as increased fatigue. These problems are common yet are often underestimated due to the non-specificity of the symptoms and the limited evaluation of the ANS in the usual clinical practice. Most of these symptoms seem to be related to localized lesions in the CNS. However, the mechanisms by which these disorders are caused in MS have not been fully investigated, thus preventing any focused etiological treatment. The most common disorders of the ANS in MS represent a challenge for clinicians due to the variability of the clinical picture and our minimal data on their diagnosis and treatment. Early diagnosis and initiation of individualized treatment regimens, often in need of multiple approaches, seem to yield the best results in managing ANS dysfunction in MS patients. [ABSTRACT FROM AUTHOR]

Aim: We reviewed the clinical features of a sample of pediatric acquired demyelinating syndromes with the purpose of determining the appropriate protocol for follow-up after the first episode. Methods: A multicenter retrospective observational study was conducted on a cohort of 40 children diagnosed with a first episode of acquired demyelinating syndrome over the period 2012-2021. Patients were evaluated with clinical and neuroradiologic assessment after 3, 6, and 12 months, with a median follow-up of 4.0 years. Results: At the first acquired demyelinating syndrome episode, 18 patients (45%) were diagnosed with acute disseminated encephalomyelitis, 18 (45%) with clinical isolated syndrome, and 4 (10%) with multiple sclerosis. By month 12, 12 patients (30%) had progressed from an initial diagnosis of acute disseminated encephalomyelitis (2) or clinical isolated syndrome (10) to multiple sclerosis. Of these, 6 had clinical relapse and 6 radiologic relapse only. The first relapse occurred after a median of 3 months. Among the patients who had evolved toward multiple sclerosis, there was a prevalence of females (P =.014), higher oligoclonal bands positivity (P =.009), and older median age (P <.001) as compared with those who had remained stable. Interpretation: Both clinical and radiologic follow-up of children with acquired demyelinating syndromes is crucial, especially during the first year after acute onset, for early identification of multiple sclerosis and prompt initiation of disease-modifying treatment to delay axonal damage and to limit disability. [ABSTRACT FROM AUTHOR]

Introduction: Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is a rare progressive or relapsing inflammatory disease. Intravenous immunoglobulin (IVIG) is recommended as a first-line therapy. The aim of this study was to describe real-world treatment patterns and outcomes of patients with CIDP in the Define initiating IVIG treatment. Methods: This cohort study used health insurance claims data from the Merative MarketScan Research Databases (2008–2018). Adult patients (≥ 18 years old) with CIDP without prior immunoglobulin treatment were identified using International Statistical Classification of Diseases and Related Health Problems (ICD) codes, and patients subsequently initiating IVIG were included in the analysis. Real-world IVIG treatment patterns and treatment and safety outcomes (assessed via ICD codes) were described. Results: In total, 3975 patients (median age 58 years) with CIDP who initiated IVIG were identified. After the initial IVIG loading period, patients received IVIG at a median dosing interval of 21 days (quartile [Q]1, Q3: 7, 28), and continued treatment for a median of 129 days (Q1, Q3: 85, 271). After the 2-year follow-up period, 55% of patients had discontinued all IVIG treatment; more than one-half of these discontinuations occurred within 4 months. Diagnoses of impaired functional status were evident in more than 30% of patients at baseline, but at lower rates during follow-up. Rates of new-onset safety outcomes after IVIG treatment were low. Conclusion: This real-world analysis of IVIG treatment patterns and treatment and safety outcomes of patients with CIDP who initiated IVIG highlights the unmet need for improved long-term management. Further research is needed to evaluate the use of functional status measures as endpoints for immunoglobulin treatment effectiveness. Plain Language Summary: Chronic inflammatory demyelinating polyradiculoneuropathy, also called CIDP, is a rare disease that causes the body's immune system to attack its nerves. Treatments for CIDP include antibodies, which are also called immunoglobulins. Immunoglobulins may be given intravenously, meaning they are administered into a vein. Intravenous immunoglobulin, also called IVIG, is recommended as one of the first treatments that patients with CIDP receive in their therapy and involves giving antibodies through a drip into a vein. This study aimed to gather information on the day-to-day use of IVIG by patients with CIDP. Information from 2008 to 2018 was collected from a large health insurance database in the USA. Information was taken from the records of patients aged 18 years or older who had received IVIG during the information collection period. In total, records from 3975 patients with an average age of 58 years were included in the study. On average, patients received IVIG every 21 days for 129 days. By 2 years, 55% of patients had stopped receiving IVIG; most of those patients had stopped within 4 months of first receiving the treatment. In the 6 months before receiving IVIG, over 30% of patients experienced limitations owing to their CIDP that affected their daily lives, although this percentage became smaller once patients started to receive IVIG. In addition, a low number of patients experienced side effects because of their IVIG treatment. This study highlights that improved long-term care for patients with CIDP is needed. Further research into ways of measuring the impact of CIDP on patients' daily lives is required, which may help doctors to work out how effective IVIG is at treating CIDP. [ABSTRACT FROM AUTHOR]

Introduction: Intravenous immunoglobulin (IVIG) is recommended as first-line therapy for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), an immune-mediated neuropathy. The clinical profile of patients with CIDP newly initiating IVIG is poorly characterized. This claims-based cohort study describes characteristics of US patients with CIDP initiating IVIG treatment. Methods: Adult immunoglobulin (IG)-naïve patients with CIDP diagnosed between 2008 and 2018 and a subgroup of patients subsequently initiating IVIG were identified in the Merative MarketScan Research Databases. Demographics, clinical characteristics, and diagnostic procedures were described for patients initiating IVIG. Results: Of 32,090 patients with CIDP identified, 3975 (mean age 57 years) subsequently initiated IVIG. In the 6 months prior to IVIG initiation, diagnoses of comorbidities including neuropathy (75%), hypertension (62%), and diabetes (33%) were frequent, as were CIDP features/symptoms/markers of functional status including chronic pain (80%), difficulty walking (30%), and weakness (30%). CIDP-related laboratory/diagnostic procedures were performed in approximately 20– > 40% of patients in the 3 months prior to IVIG initiation (63.7% underwent electrodiagnostic/nerve conduction testing in the 6 months prior to IVIG initiation). Patient characteristics by initial IVIG product differed only in IVIG initiation year, US geographic region, and insurance type. Comorbidities, CIDP severity or functional status markers, and other clinical variables were generally well balanced across initial IVIG product groups. Conclusion: A heavy burden of symptoms, comorbidities, and diagnostic testing exists in patients with CIDP initiating IVIG. Characteristics of patients with CIDP initiating different IVIG products are well balanced, suggesting an absence of clinical or demographic determinants underlying IVIG selection. Plain Language Summary: Intravenous immunoglobulin, also called IVIG, involves giving antibodies through a drip into a vein. IVIG is recommended as one of the first treatments that patients receive if they have chronic inflammatory demyelinating polyradiculoneuropathy, also called CIDP, which is a rare disease that causes the body's immune system to attack its nerves. Our study described the characteristics of patients with CIDP who received IVIG in the USA. Information was collected from a large health insurance database and included records of patients aged ≥ 18 years who were diagnosed with CIDP between 2008 and 2018. Overall, 3975 patients with CIDP who received IVIG were included in the study. In the 6 months before starting IVIG, patients frequently had diagnoses of other diseases in addition to their CIDP; these included neuropathy (75% of patients), hypertension (62%), and diabetes (33%). CIDP features and symptoms that affected patients' daily lives were also frequently reported in these 6 months, including long-lasting pain (80%), difficulty walking (30%), and weakness (30%). In the 3 months before starting IVIG treatment, 20% to > 40% of patients underwent diagnostic procedures related to their CIDP. Different IVIG products were used similarly, but the year of IVIG initiation, geographic region, and insurance type all differed by IVIG product. In conclusion, patients with CIDP who receive IVIG experience a heavy burden caused by their symptoms, other diseases, and CIDP-related procedures. Patient characteristics were generally similar between patients receiving different IVIG products, suggesting that no specific characteristics are factored in when doctors select an IVIG product. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is an inflammatory demyelinating central nervous system disease with diverse clinical manifestations. The present study aimed to compare the psychiatric outcomes of MS patients with full ambulatory versus impaired ambulatory function and identify the potential risk factors for disability in MS. Seventy MS patients were classified into two groups based on their Expanded Disability Status Scale (EDSS) scores, Group A: full ambulatory (EDSS ≤ 4.5) (N = 48), Group B: impaired ambulatory (EDSS ≥ 5) (N = 22). All participants were evaluated by the Socioeconomic Scale, Hamilton Anxiety Scale, Hamilton Depression Scale, Brief Psychiatric Rating Scale, and The Pittsburgh Sleep Quality Index. Results: In the total cohort (N = 70), females represented (77.1%). The mean age was 31.16 ± 6.46, the mean age of onset was 26 ± 6.083, and the mean disease duration was 5.33 ± 3.653 years which was less in Group A than in Group B. Relapsing–remitting multiple sclerosis (RRMS) was the most common presentation (80%), representing 93.6% of Group A. Group A reported more severe depression and anxiety, while Group B had more poor sleep quality. Correlation analysis showed increased relapses, progressive-relapsing multiple sclerosis (PRMS), cervical or dorsal plaques, sensory or motor manifestations, and precipitancy increased disability, while RRMS type decreased disability. Conclusions: Full ambulatory MS patients had high anxiety and depression, while impaired ambulatory MS patients had poor sleep quality. Associated factors for disability were frequent relapses, plaque location, MS subtype, sphincter, and sensory symptoms. Trial registration clinicaltrials.gov, NCT05029830. Registered: September 01, 2021, https://clinicaltrials.gov/ct2/show/NCT05029830 [ABSTRACT FROM AUTHOR]

Background and purpose: Myelin oligodendrocyte glycoprotein antibodyassociated disease (MOGAD) has gained recognition in recent years as an immune-mediated inflammatory demyelinating disease of the central nervous system. The clinical features and prognosis of MOGAD adult cerebral cortical encephalitis (adult CCE) have not been fully elucidated. This study aims to further characterize the clinical symptoms, magnetic resonance imaging (MRI) findings, and prognosis of CCE with anti-MOG antibody. Methods: We present two adult cases of CCE with anti-MOG antibody and summarize the clinical symptoms, magnetic resonance imaging (MRI) findings, and prognosis of this phenotype as per a completed systematic review of the literature. Results: We found a total of 39 cases of MOGAD adult CCE (36% females; average age of onset of 29 years). Among them, 85% had seizure, 82% had headache, 64% had cortical symptoms, 64% had fever, 54% had changes of consciousness, and 38% had ocular symptoms. All cases demonstrated cerebral cortical T2 fluid-attenuated inversion recovery (FLAIR) lesions on MRI. Of the 25 patients (with seizure or not) who had EEG reports, 76% of patients showed abnormal EEG. Cerebrospinal fluid (CSF) white blood cell count of 90% of patients and CSF total protein of 67% of patients were elevated. In 16 patients with available CSF cytology data, 11 (69%) had abnormal cytology findings with monocytic predominance. In the 15 cases for which MOG antibody IgG was tested in both serum and CSF, 14 (93%) demonstrated a higher positive MOG IgG titer in serum than CSF. The majority of patients were treated with immunosuppressive therapy (97% corticosteroids, 15% mycophenolate mofetil, 13% IVIg, 5% azathioprine, and 5% other). The majority of patients had a favorable prognosis after treatment, as exemplified by improved clinical symptoms and imaging. Two patients relapsed. Conclusions: The clinical presentation and prognosis of adult CCE remain less understood in comparison to more common MOGAD phenotypes. It is important to consider MOGAD as an underlying etiology for adult CCE, as early detection and immunotherapy may improve outcomes. [ABSTRACT FROM AUTHOR]

With a rapidly aging global population and improvement of outcomes with newer multiple sclerosis (MS)-specific disease-modifying therapies (DMTs), the epidemiology of MS has shifted to an older than previously described population, with a peak prevalence of the disease seen in the 55-65 years age group. Changes in the pathophysiology of MS appear to be age-dependent. Several studies have identified a consistent phase of disability worsening around the fifth decade of life. The latter appears to be independent of prior disease duration and inflammatory activity and concomitant to pathological changes from acute focal active demyelination to chronic smoldering plaques, slow-expanding lesions, and compartmentalized inflammation within the central nervous system (CNS). On the other hand, decreased CNS tissue reserve and poorer remyelinating capacity with aging lead to loss of relapse recovery potential. Aging with MS may imply longer exposure to DMTs, although treatment efficacy in patients >55 years has not been evaluated in pivotal randomized controlled trials and appears to decrease with age. Older individuals are more prone to adverse effects of DMTs, an important aspect of treatment individualization. Aging with MS also implies a higher global burden of comorbid illnesses that contribute to overall impairments and represent a crucial confounder in interpreting clinical worsening. Discontinuation of DMTs after age 55, when no evidence of clinical or radiological activity is detected, is currently under the spotlight. In this review, we will discuss the impact of aging on MS pathobiology, the effect of comorbidities and other confounders on clinical worsening, and focus on current therapeutic considerations in this age group. [ABSTRACT FROM AUTHOR]

Background: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a newly defined autoimmune inflammatory demyelinating central nervous system (CNS) disease characterized by antibodies against MOG. Leptomeningeal enhancement (LME) on contrast-enhanced fluid-attenuated inversion recovery (CE-FLAIR) images has been reported in patients with other diseases and interpreted as a biomarker of inflammation. This study retrospectively analyzed the prevalence and distribution of LME on CE-FLAIR images in children with MOG antibody-associated encephalitis (MOG-E). The corresponding magnetic resonance imaging (MRI) features and clinical manifestations are also presented. Methods: The brain MRI images (native and CE-FLAIR) and clinical manifestations of 78 children with MOG-E between January 2018 and December 2021 were analyzed. Secondary analyses evaluated the relationship between LME, clinical manifestations, and other MRI measures. Results: Forty-four children were included, and the median age at the first onset was 70.5 months. The prodromal symptoms were fever, headache, emesis, and blurred vision, which could be progressively accompanied by convulsions, decreased level of consciousness, and dyskinesia. MOG-E showed multiple and asymmetric lesions in the brain by MRI, with varying sizes and blurred edges. These lesions were hyperintense on the T2-weighted and FLAIR images and slightly hypointense or hypointense on the T1-weighted images. The most common sites involved were juxtacortical white matter (81.8%) and cortical gray matter (59.1%). Periventricular/juxtaventricular white matter lesions (18.2%) were relatively rare. On CE-FLAIR images, 24 (54.5%) children showed LME located on the cerebral surface. LME was an early feature of MOG-E (P = 0.002), and cases without LME were more likely to involve the brainstem (P = 0.041). Conclusion: LME on CE-FLAIR images may be a novel early marker among patients with MOG-E. The inclusion of CE-FLAIR images in MRI protocols for children with suspected MOG-E at an early stage may be useful for the diagnosis of this disease. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a chronic autoimmune and neuroinflammatory disease of the central nervous system characterized by peripheral activation of immune-inflammatory pathways which culminate in neurotoxicity causing demyelination of central neurons. Nonetheless, the pathophysiology of relapsing-remitting MS (RRMS)-related chronic fatigue, depression, anxiety, cognitive impairments, and autonomic disturbances is not well understood. Objectives: The current study aims to delineate whether the remitted phase of RRMS is accompanied by activated immune-inflammatory pathways and if the latter, coupled with erythron variables, explain the chronic fatigue and mood symptoms due to RRMS. Material and Methods: We recruited 63 MS patients, 55 in the remitted phase of RRMS and 8 with secondary progressive MS, and 30 healthy controls and assessed erythron variables, and used a bio-plex assay to measure 27 serum cytokines. Results: A significant proportion of the MS patients (46%) displayed activation of the immune-inflammatory response (IRS) and compensatory immune response (CIRS) systems, and T helper (Th)1 and Th17 cytokine profiles. Remitted RRMS patients showed increased chronic fatigue, depression, anxiety, physiosomatic, autonomic, and insomnia scores, which could partly be explained by M1 macrophage, Th1, Th-17, growth factor, and CIRS activation, as well as aberrations in the erythron including lowered hematocrit and hemoglobin levels. Conclusions: Around 50% of remitted RRMS patients show activation of immune-inflammatory pathways in association with mood and chronic-fatigue-like symptoms. IRS and CIRS activation as well as the aberrations in the erythron are new drug targets to treat chronic fatigue and affective symptoms due to MS. [ABSTRACT FROM AUTHOR]

Background: A pro-inflammatory diet has been posited to induce chronic inflammation within the central nervous system (CNS), and multiple sclerosis (MS) is an inflammatory disease of the CNS. Objective: We examined whether Dietary Inflammatory Index (DII®)) scores are associated with measures of MS progression and inflammatory activity. Methods: A cohort with a first clinical diagnosis of CNS demyelination was followed annually (10 years, n = 223). At baseline, 5- and 10-year reviews, DII and energy-adjusted DII (E-DIITM) scores were calculated (food frequency questionnaire) and assessed as predictors of relapses, annualised change in disability (Expanded Disability Status Scale) and two magnetic resonance imaging measures; fluid-attenuated inversion recovery (FLAIR) lesion volume and black hole lesion volume. Results: A more pro-inflammatory diet was associated with a higher relapse risk (highest vs. lowest E-DII quartile: hazard ratio = 2.24, 95% confidence interval (CI) = −1.16, 4.33, p = 0.02). When we limited analyses to those assessed on the same manufacturer of scanner and those with a first demyelinating event at study entry (to reduce error and disease heterogeneity), an association between E-DII score and FLAIR lesion volume was evident (β = 0.38, 95% CI = 0.04, 0.72, p = 0.03). Conclusion: There is a longitudinal association between a higher DII and a worsening in relapse rate and periventricular FLAIR lesion volume in people with MS. [ABSTRACT FROM AUTHOR]

Objective: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that leads to severe disability. A large proportion of NMOSD patients are seropositive for aquaporin‐4 autoantibodies (AQP4‐IgG, named as NMO‐IgG) targeting AQP4, which is selectively expressed on astrocytes in the central nervous system. This study tests the hypothesis that in response to NMO‐IgG, the pathogenic astrocyte‐derived exosomes are released and injure the neighboring cells. Methods: IgG purified from serum of either NMOSD patients or healthy controls was used to generate astrocyte‐derived exosomes (AST‐ExosNMO vs AST‐ExosCON) in cultured rat astrocytes. The exosomes were respectively delivered to cultured rat oligodendrocytes in vitro, tissue culture of rat optic nerve ex vivo, and rat optic nerve in vivo to evaluate the pathogenic roles of AST‐ExosNMO. The microRNA (miRNA) sequencing of AST‐Exos and verification were performed to identify the key pathogenic miRNA. The custom‐designed adeno‐associated virus (AAV) antagonizing the key miRNA was evaluated for its therapeutic effects in vivo. Moreover, the serum levels of the key exosomal miRNA were measured between NMOSD patients and healthy controls. Results: AST‐ExosNMO led to notable demyelination in both cultured oligodendrocytes and optic nerve tissue. Exosomal miR‐129‐2‐3p was identified as the key miRNA mediating the demyelinating pathogenesis via downstream target gene SMAD3. AAV antagonizing miR‐129‐2‐3p protected against demyelination in an NMOSD rodent model. The serum exosomal miR‐129‐2‐3p level was significantly elevated in NMOSD patients and correlated with disease severity. Interpretation: Astrocytes targeted by NMO‐IgG release pathogenic exosomes that could potentially be used as therapeutic targets or disease monitoring biomarkers in NMOSD. ANN NEUROL 2023;94:163–181 [ABSTRACT FROM AUTHOR]

Background and Objectives: Ultrasound (US) is a non-invasive tool for the in vivo detection of peripheral nerve alterations. Materials and Methods: In this study, we applied nerve US to assist the discrimination between the spectrum of amyotrophic lateral sclerosis (ALS, n = 11), chronic inflammatory demyelinating polyradiculoneuropathy (CIDP, n = 5), and genetically confirmed Charcot–Marie–Tooth disease (CMT, n = 5). All participants and n = 15 controls without neurological diseases underwent high-resolution US of the bilateral tibial nerve. The nerve cross-sectional area (CSA) and nerve microvascular blood flow were compared between the groups and related to cerebrospinal fluid (CSF) measures, clinical symptoms, and nerve conduction studies. The analyses are part of a larger multimodal study on the comparison between US and 7 Tesla (7T) magnetic resonance neurography (MRN). Results: The patients and controls were matched with respect to their demographical data. CMT had the longest disease duration, followed by CIDP and ALS. CSA was related to age, weight, and disease duration. CSA was larger in CMT and CIDP compared to ALS and controls. The blood flow was greatest in CIDP, and higher than in CMT, ALS, and controls. In ALS, greater CSA was correlated with greater CSF total protein and higher albumin quotient. The US measures did not correlate with clinical scores or nerve conduction studies in any of the subgroups. Conclusion: Our results point towards the feasibility of CSA and blood flow to discriminate between ALS, CIDP, and CMT, even in groups of small sample size. In ALS, larger CSA could indicate an inflammatory disease subtype characterized by reduced blood–nerve barrier integrity. Our upcoming analysis will focus on the additive value of 7T MRN in combination with US to disentangle the spectrum between more inflammatory or more degenerative disease variants among the disease groups. [ABSTRACT FROM AUTHOR]

Background: Helicobacter pylori (Hp) persists after colonizing the gut in childhood, and potentially regulates host immune system through this process. Earlier studies have shown that Hp infection in childhood, may protect against MS in later life. Such an association was not seen with AQP4-IgG positive NMOSD, while the association with MOGAD is unclear. Objective: To evaluate frequency of Hp IgG among patients with MOGAD, MS, NMOSD and matched controls and its effect on disease course. To ascertain whether childhood socio economic factors were linked to prevalence of Hp infection. Methods: In all, 99 patients diagnosed to have MOGAD, 99 AQP4 IgG+ NMOSD, 254MS and 243 matched controls were included. Patient demographics, diagnosis, age at disease onset, duration and the last recorded expanded disability status scale (EDSS) were obtained from our records. Socioeconomic and educational status was queried using a previously validated questionnaire. Serum HpIgG was detected using ELISA kits (Vircell, Spain). Result: Frequency of Hp IgG was significantly lower among MOGAD (28.3% vs 44%, p-0.007) and MS (21.2% vs 44%, p-0.0001) but not AQP4-IgG+ NMOSD patients (42.4% vs 44%, p-0.78) when compared to controls. Frequency of Hp IgG in MOGAD & MS patients combined (MOGAD-MS) was significantly lower than those with NMOSD (23.2% vs 42.4%, p-0.0001). Seropositive patients with MOGAD-MS were older (p-0.001. OR -1.04, 95% CI- 1.01- 1.06) and had longer disease duration (p- 0.04, OR- 1.04, 95% CI- 1.002- 1.08) at time of testing. Educational status was lower among parents/caregivers of this study cohort (p- 0.001, OR -2.34, 95% CI- 1.48-3.69) who were Hp IgG+. Conclusions: In developing countries Hp infection may be a significant environmental factor related to autoimmune demyelinating CNS disease. Our preliminary data suggests that Hp may exert a differential influence - a largely protective role for MS-MOGAD but not NMOSD and may influence disease onset and course. This differential response maybe related to immuno-pathological similarities between MOGAD and MS in contrast to NMOSD. Our study further underscores the role of Hp as a surrogate marker for poor gut hygiene in childhood and its association with later onset of autoimmune diseases. [ABSTRACT FROM AUTHOR]

Theiler's murine encephalomyelitis virus (TMEV) is the causative agent of TMEVinduced demyelinating disease (TMEV-IDD); a well-established animal model for the chronic progressive form of human multiple sclerosis (MS). In susceptible mice with an inadequate immune response, TMEV-IDD is triggered by virus persistence and maintained by a T cell mediated immunopathology. OT-mice are bred on a TMEV-resistant C57BL/6 background and own predominantly chicken ovalbumin (OVA)-specific populations of CD8+ T cells (OT-I) or CD4+ T cells (OT-II), respectively. It is hypothesized that the lack of antigen specific T cell populations increases susceptibility for a TMEV-infection in OT-mice on a TMEVresistant C57BL/6 background. OT-I, OT-II, and C57BL/6 control mice were infected intracerebrally with the TMEV-BeAn strain. Mice were scored weekly for clinical disease and after necropsy, histological and immunohistochemical evaluation was performed. OT-I mice started to develop progressive motor dysfunction between 7 and 21 days post infection (dpi), leading up to hind limb paresis and critical weight loss, which resulted in euthanasia for humane reasons between 14 and 35 dpi. OT-I mice displayed a high cerebral virus load, an almost complete absence of CD8+ T cells from the central nervous system (CNS) and a significantly diminished CD4+ T cell response. Contrarily, only 60% (12 of 20) of infected OT-II mice developed clinical disease characterized by mild ataxia. 25% of clinically affected OT-II mice (3 of 12) made a full recovery. 5 of 12 OT-II mice with clinical disease developed severe motor dysfunction similar to OT-I mice and were euthanized for humane reasons between 13 and 37 dpi. OT-II mice displayed only low virus-immunoreactivity, but clinical disease correlated well with severely reduced infiltration of CD8+ T cells and the increased presence of CD4+ T cells in the brains of OT-II mice. Though further studies are needed to reveal the underlying pathomechanisms following TMEV infection in OT mice, findings indicate an immunopathological process as a main contributor to clinical disease in OT-II mice, while a direct virus-associated pathology may be the main contributor to clinical disease in TMEV-infected OT-I mice. [ABSTRACT FROM AUTHOR]

Myelination by oligodendrocytes is crucial for neuronal survival and function, and defects in myelination or failure in myelin repair can lead to axonal degeneration and various neurological diseases. At present, the factors that promote myelination and overcome the remyelination block in demyelinating diseases are poorly defined. Although the roles of protein-coding genes in oligodendrocyte differentiation have been extensively studied, the majority of the mammalian genome is transcribed into noncoding RNAs, and the functions of these molecules in myelination are poorly characterized. Long noncoding RNAs (lncRNAs) regulate transcription at multiple levels, providing spatiotemporal control and robustness for cell type–specific gene expression and physiological functions. lncRNAs have been shown to regulate neural cell–type specification, differentiation, and maintenance of cell identity, and dysregulation of lncRNA function has been shown to contribute to neurological diseases. In this review, we discuss recent advances in our understanding of the functions of lncRNAs in oligodendrocyte development and myelination as well their roles in neurological diseases and brain tumorigenesis. A more systematic characterization of lncRNA functional networks will be instrumental for a better understanding of CNS myelination, myelin disorders, and myelin repair. [ABSTRACT FROM AUTHOR]

The neutrophil-to-lymphocyte ratio (NLR) and monocyte-to-lymphocyte ratio (MLR) are inflammatory biomarkers that may predict disease course in neuroinflammatory diseases. We examine whether NLR or MLR at the time of the first attack predicts longitudinal disease outcomes in pediatric neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Clinical data were collected retrospectively at a single institution. NLR (ratio of percent neutrophils to percent lymphocytes) and MLR (ratio of percent monocytes to percent lymphocytes) were calculated in the complete blood cell count at the time of presentation before treatments. Expanded Disability Status Scale (EDSS) score and time to next relapse were used as the outcome assessments. Twenty-eight patients with MS and eight patients with aquaporin-4-positive NMOSD were included. For NMOSD, NLR at presentation associated with EDSS at six months (P = 0.003) and one year (P = 0.032) even when adjusting for age at presentation. MLR associated with EDSS at six months (P = 0.0203) and EDSS at one year (P = 0.0079). However, NLR and MLR did not predict EDSS scores in MS. MLR and NLR did not predict time to next relapse or did not associate with magnetic resonance imaging activity in MS and NMOSD. Changes in MLR and NLR were observed with disease-modifying therapies but did not predict disease activity. NLR and MLR associated with six-month and one-year EDSS in children with NMOSD but not in MS. Future studies should explore whether changes in NLR and MLR could predict disease activity or treatment efficacy. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating, immune-mediated disease of the central nervous system. It is still unestablished whether heredity correlates with the disease's progression and severity. Methods: This study includes the patients with MS seen in the MS clinic of Kashani Hospital, affiliated with Isfahan University of Medical Sciences, from January 2019 to January 2020. We gathered data regarding the demographic and clinical characteristics, such as type of disease and family history of MS. Patients were grouped based on having relatives with MS. We compared demographic and clinical characteristics between those with a family history of MS (familial MS: FMS) and those without a family history of MS (sporadic MS: SMS). Results: We included 2,929 MS patients, 523 (17.2%) with FMS and 2,406 (82.8%) with SMS. Patients with FMS were found to have active lesions in the thoracic spine more frequently than those with SMS (P = 0.022). We also found differences in the distribution of gender (P = 0.036) and the frequency of having active brain lesions (P = .024) among patients with FMS and SMS. No difference was found between the demographic/clinical characteristics and the number of affected relatives in the family. Conclusions: Significant differences were found among different groups of patients in terms of demographical and clinical characteristics. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a chronic demyelinating autoimmune disorder which may cause long-term disability. MicroRNA (miRNA) are stable, non-coding molecules that have been identified in our Comprehensive Longitudinal Investigation of Multiple Sclerosis at the Brigham and Women's Hospital (CLIMB)-cohort, as well as other international cohorts, as potential disease biomarkers in MS. However, few studies have evaluated the association of miRNA expression early in the MS disease course with long-term outcomes. Therefore, we aimed to evaluate the potential role of three candidate serum miRNAs previously correlated with MS disability in patients with MS, miR-320b, miR-25-3p and miRNA 486-5p, as early biomarkers of MS disability at 10-year follow-up. Main body: We included 144 patients with serum obtained within three years of MS onset. miRNA expression was measured by RNA extraction followed by RT-PCR. Demographic, clinical, brain MRI and other biomarkers were collected. The primary outcome was the association between early miRNA expression and retaining benign MS, defined as EDSS ≤ 2 at 10-year follow-up. Among the 144 patients, 104 were benign and 40 were not benign at 10-year follow-up. 89 (62%) were women, with mean age at onset 37.7 (SD: 9.6) years. Patients who retained benign MS had lower values of miR-25-3p (p = 0.047) and higher miR-320b (p = 0.025) values. Development of SPMS was associated with higher miR-320b (p = 0.002) levels. Brain parenchymal fraction at year 10 was negatively correlated with miR-25-3p (p = 0.0004) and positively correlated with miR-320b (p = 0.006). No association was found between miR-486-5p and any outcome, and 10-year T2-lesion volume was not associated with any miRNA. Conclusions: Our results show that miR-320b and miR-25-3p expression are early biomarkers associated with MS severity and brain atrophy. This study provides class III evidence of that miR-320b and miR-25-3p are associated with long-term MS disability which may be a potential tool to risk-stratify patients with MS for early treatment decisions. [ABSTRACT FROM AUTHOR]

Background and purpose: Elevated plasma concentrations of neural cell adhesion molecule 1 (NCAM1) and p75 neurotrophin receptor (p75) in patients with peripheral neuropathy have been reported. This study aimed to determine the specificity of plasma concentration elevation of either NCAM1 or p75 in a subtype of Charcot–Marie–Tooth disease (CMT) and its correlation with pathologic nerve status and disease severity. Methods: Blood samples were collected from 138 patients with inherited peripheral neuropathy and 51 healthy controls. Disease severity was measured using Charcot–Marie–Tooth Neuropathy Score version 2 (CMTNSv2), and plasma concentrations of NCAM1 and p75 were analyzed by enzyme‐linked immunosorbent assay. Eight sural nerves from CMT patients were examined to determine the relation of histopathology and plasma NCAM1 levels. Results: Plasma concentration of NCAM1, but not p75, was specifically increased in demyelinating subtypes of CMT (median = 7100 pg/mL, p < 0.001), including CMT1A, but not in axonal subtype (5964 pg/mL, p > 0.05), compared to the control (3859 pg/mL). CMT1A patients with mild or moderate severity (CMTNSv2 < 20) showed higher levels of plasma NCAM1 than healthy controls. Immunofluorescent NCAM1 staining for the sural nerves of CMT patients showed that NCAM1‐positive onion bulb cells and possible demyelinating Schwann cells might be associated with the specific increase of plasma NCAM1 in demyelinating CMT. Conclusions: The plasma NCAM1 levels in demyelinating CMT might be a surrogate biomarker reflecting pathological Schwann cell status and disease progression. [ABSTRACT FROM AUTHOR]

In multiple sclerosis, while remarkable progress has been accomplished to control the inflammatory component of the disease, repair of demyelinated lesions is still an unmet need. Despite encouraging results generated in experimental models, several candidates favouring or promoting remyelination have not reached the expected outcomes in clinical trials. One possible reason for these failures is that, in most cases, during preclinical testing, efficacy was evaluated on histology only, while functional recovery had not been assessed. We have generated a Xenopus laevis transgenic model Tg(mbp:GFP-NTR) of conditional demyelination in which spontaneous remyelination can be accelerated using candidate molecules. Xenopus laevis is a classic model for in vivo studies of myelination because tadpoles are translucent. We reasoned that demyelination should translate into loss of sensorimotor functions followed by behavioural recovery upon remyelination. To this end, we measured the swimming speed and distance travelled before and after demyelination and during the ongoing spontaneous remyelination and have developed a functional assay based on the visual avoidance of a virtual collision. Here we show that alteration of these functional and clinical performances correlated well with the level of demyelination and that histological remyelination, assayed by counting in vivo the number of myelinating oligodendrocytes in the optic nerve, translated in clinical–functional recovery. This method was further validated in tadpoles treated with pro-remyelinating agents (clemastine, siponimod) showing that increased remyelination in the optic nerve was associated with functional improvement. Our data illustrate the potential interest of correlating histopathological parameters and functional–clinical parameters to screen molecules promoting remyelination in a simple in vivo model of conditional demyelination. [ABSTRACT FROM AUTHOR]

Genetic leukoencephalopathies (gLEs) are a highly heterogeneous group of rare genetic disorders. The spectrum of gLEs varies among patients of different ages. Distinct from the relatively more abundant studies of gLEs in children, only a few studies that explore the spectrum of adult gLEs have been published, and it should be noted that the majority of these excluded certain gLEs. Thus, to date, no large study has been designed and conducted to characterize the genetic and phenotypic spectra of gLEs in adult patients. We recruited a consecutive series of 309 adult patients clinically suspected of gLEs from Beijing Tiantan Hospital between January 2014 and December 2021. Whole exome sequencing, mitochondrial DNA sequencing, and repeat analysis of NOTCH2NLC, FMR1, DMPK and ZNF9 were performed for patients. We describe the genetic and phenotypic spectra of the set of patients with a genetically confirmed diagnosis and summarize their clinical and radiological characteristics. A total of 201 patients (65%) were genetically diagnosed, while 108 patients (35%) remained undiagnosed. The most frequent diseases were NOTCH3 (25%), NOTCH2NLC (19%), ABCD1 (9%), CSF1R (7%), and HTRA1 (5%)-related leukoencephalopathies. Based on a previously proposed pathological classification, the gLEs in our cohort were divided into leukovasculopathies (35%), leuko-axonopathies (31%), myelin disorders (21%), microgliopathies (7%), and astrocytopathies (6%). Patients with NOTCH3 mutations accounted for 70% of the leukovasculopathies, followed by HTRA1 (13%) and COL4A1/2 (9%). The leuko-axonopathies contained the richest variety of associated genes, of which NOTCH2NLC comprised 62%. Among myelin disorders, demyelinating leukoencephalopathies (61%)-mainly adrenoleukodystrophy and Krabbe disease-accounted for the majority, while hypomyelinating leukoencephalopathies (2%) were rare. CSF1R was the only mutated gene detected in microgliopathy patients. Leukoencephalopathy with vanishing white matter disease due to mutations in EIF2B2-5 accounted for half of the astrocytopathies. We characterized the genetic and phenotypic spectra of adult gLEs in a large Chinese cohort. The most frequently mutated genes were NOTCH3, NOTCH2NLC, ABCD1, CSF1R, and HTRA1. [ABSTRACT FROM AUTHOR]

Introduction: Vaccination against the coronavirus disease 2019 (COVID-19) is recommended for patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, vaccine safety in these patients taking immunotherapeutic agents is unclear as they were not included in the vaccine trials. Objectives: To evaluate the safety of COVID-19 vaccines in patients with MS, NMOSD, and MOGAD. Methods: We reviewed the medical records of MS, NMOSD, and MOGAD patients at the Keimyung University Dongsan Hospital. Information regarding vaccination schedules and adverse events was collected. Results: A total of 56 patients (19, 22, and 15 patients with MS, NMOSD, and MOGAD, respectively) with a median age of 48.18 ± 15.72 years (range, 16–81 years) were included. Of them, 42 (75.0%) were female. In total, 76.8% (43/56) of all patients were vaccinated, and the vaccination rate was the highest for NMOSD patients (81.8%) and the lowest for MS patients (68.4%). All vaccinated patients were administered mRNA vaccines at least once in single or multiple vaccination doses. Only 3 of 43 (7.0%) vaccinated patients experienced clinical relapse following vaccination. Facial sensory changes with a brainstem lesion developed in an MS patient taking dimethyl fumarate, while myelitis occurred in a MOGAD patient receiving azathioprine maintenance therapy. The first episode of optic neuritis occurred in a patient who was later diagnosed with MOGAD. Conclusions: Our study demonstrated a favorable safety profile with no serious adverse events associated with COVID-19 vaccines in patients with MS, NMOSD, and MOGAD. [ABSTRACT FROM AUTHOR]