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Advances in Pediatrics Aug 2023Guillain-Barre syndrome (GBS) is an immune-mediated disease of the peripheral nerves and cause of acute flaccid paralysis in children around the world. The most common... (Review)
Review
Guillain-Barre syndrome (GBS) is an immune-mediated disease of the peripheral nerves and cause of acute flaccid paralysis in children around the world. The most common type of GBS in North America targets myelin and leads to demyelinating neuropathy. Often there is a history of infection in the weeks preceding motor symptoms. GBS has been associated with different infections, including COVID. Children usually recover motor function, but autonomic instability and respiratory compromise can occur necessitating close observation and potentially intensive care unit admission.
Topics: Humans; Child; Adolescent; Guillain-Barre Syndrome; COVID-19; Myelitis
PubMed: 37422300
DOI: 10.1016/j.yapd.2023.04.001 -
Brain : a Journal of Neurology Aug 2023The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in...
The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.
Topics: Humans; Female; Adult; Middle Aged; Male; Disease Progression; Demyelinating Diseases; Multiple Sclerosis; Magnetic Resonance Imaging; Risk Factors
PubMed: 36864688
DOI: 10.1093/brain/awad073 -
Journal of Neurology Aug 2023New diagnostic criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have recently been proposed, distinguishing this syndrome from other... (Review)
Review
New diagnostic criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) have recently been proposed, distinguishing this syndrome from other inflammatory diseases of the central nervous system. Seropositivity status for MOG-IgG autoantibodies is important for diagnosing MOGAD, but only in the context of robust clinical characterization and cautious interpretation of neuroimaging. Over the last several years, access to cell-based assay (CBA) techniques has improved diagnostic accuracy, yet the positive predictive value of serum MOG-IgG values varies with the prevalence of MOGAD in any given patient population. For this reason, possible alternative diagnoses need to be considered, and low MOG-IgG titers need to be carefully weighted. In this review, cardinal clinical features of MOGAD are discussed. Key challenges to the current understanding of MOGAD are also highlighted, including uncertainty regarding the specificity and pathogenicity of MOG autoantibodies, the need to identify immunopathologic targets for future therapies, the quest to validate biomarkers that facilitate diagnosis and detect disease activity, and the importance of deciphering which patients with MOGAD require long-term immunotherapy.
Topics: Humans; Myelin-Oligodendrocyte Glycoprotein; Autoantibodies; Central Nervous System; Immunotherapy; Immunoglobulin G; Aquaporin 4; Neuromyelitis Optica
PubMed: 37154894
DOI: 10.1007/s00415-023-11737-8 -
The Lancet. Neurology Nov 2023Individuals can be deemed to have radiologically isolated syndrome (RIS) if they have incidental demyelinating-appearing lesions in their brain or spinal cord that are... (Review)
Review
Individuals can be deemed to have radiologically isolated syndrome (RIS) if they have incidental demyelinating-appearing lesions in their brain or spinal cord that are highly suggestive of multiple sclerosis but their clinical history does not include symptoms consistent with multiple sclerosis. Data from international longitudinal cohorts indicate that around half of people with RIS will develop relapsing or progressive symptoms of multiple sclerosis within 10 years, suggesting that in some individuals, RIS is a presymptomatic stage of multiple sclerosis. Risk factors for progression from RIS to clinical multiple sclerosis include younger age (ie, <35 years), male sex, CSF-restricted oligoclonal bands, spinal cord or infratentorial lesions, and gadolinium-enhancing lesions. Other imaging, biological, genetic, and digital biomarkers that might be of value in identifying individuals who are at the highest risk of developing multiple sclerosis need further investigation. Two 2-year randomised clinical trials showed the efficacy of approved multiple sclerosis immunomodulatory medications in preventing the clinical conversion to multiple sclerosis in some individuals with RIS. If substantiated in longer-term studies, these data have the potential to transform our approach to care for the people with RIS who are at the greatest risk of diagnosis with multiple sclerosis.
Topics: Humans; Male; Adult; Magnetic Resonance Imaging; Disease Progression; Demyelinating Diseases; Multiple Sclerosis; Spinal Cord
PubMed: 37839432
DOI: 10.1016/S1474-4422(23)00281-8 -
Muscle & Nerve Oct 2023Intravenous immune globulin (IVIG) is an immune-modulating biologic therapy that is increasingly being used in neuromuscular disorders despite the paucity of... (Review)
Review
Intravenous immune globulin (IVIG) is an immune-modulating biologic therapy that is increasingly being used in neuromuscular disorders despite the paucity of high-quality evidence for various specific diseases. To address this, the AANEM created the 2009 consensus statement to provide guidance on the use of IVIG in neuromuscular disorders. Since then, there have been several randomized controlled trials for IVIG, a new FDA-approved indication for dermatomyositis and a revised classification system for myositis, prompting the AANEM to convene an ad hoc panel to update the existing guidelines.New recommendations based on an updated systemic review of the literature were categorized as Class I-IV. Based on Class I evidence, IVIG is recommended in the treatment of chronic inflammatory demyelinating polyneuropathy, Guillain-Barré Syndrome (GBS) in adults, multifocal motor neuropathy, dermatomyositis, stiff-person syndrome and myasthenia gravis exacerbations but not stable disease. Based on Class II evidence, IVIG is also recommended for Lambert-Eaton myasthenic syndrome and pediatric GBS. In contrast, based on Class I evidence, IVIG is not recommended for inclusion body myositis, post-polio syndrome, IgM paraproteinemic neuropathy and small fiber neuropathy that is idiopathic or associated with tri-sulfated heparin disaccharide or fibroblast growth factor receptor-3 autoantibodies. Although only Class IV evidence exists for IVIG use in necrotizing autoimmune myopathy, it should be considered for anti-hydroxy-3-methyl-glutaryl-coenzyme A reductase myositis given the risk of long-term disability. Insufficient evidence exists for the use of IVIG in Miller-Fisher syndrome, IgG and IgA paraproteinemic neuropathy, autonomic neuropathy, chronic autoimmune neuropathy, polymyositis, idiopathic brachial plexopathy and diabetic lumbosacral radiculoplexopathy.
Topics: Humans; Child; Immunoglobulins, Intravenous; Dermatomyositis; Neuromuscular Diseases; Myasthenia Gravis; Guillain-Barre Syndrome; Myositis; Polyneuropathies; Myositis, Inclusion Body
PubMed: 37432872
DOI: 10.1002/mus.27922 -
JAMA Neurology Sep 2023Differential diagnosis of patients with seronegative demyelinating central nervous system (CNS) disease is challenging. In this regard, evidence suggests that...
IMPORTANCE
Differential diagnosis of patients with seronegative demyelinating central nervous system (CNS) disease is challenging. In this regard, evidence suggests that immunoglobulin (Ig) A plays a role in the pathogenesis of different autoimmune diseases. Yet little is known about the presence and clinical relevance of IgA antibodies against myelin oligodendrocyte glycoprotein (MOG) in CNS demyelination.
OBJECTIVE
To investigate the frequency of MOG-IgA and associated clinical features in patients with demyelinating CNS disease and healthy controls.
DESIGN, SETTING, AND PARTICIPANTS
This longitudinal study comprised 1 discovery and 1 confirmation cohort derived from 5 centers. Participants included patients with suspected or confirmed demyelinating diseases and healthy controls. MOG-IgA, MOG-IgG, and MOG-IgM were measured in serum samples and cerebrospinal fluid (CSF) of patients, who were assessed from September 2012 to April 2022.
MAIN OUTCOMES AND MEASURES
Frequency and clinical features of patients who were seropositive for MOG-IgA and double-seronegative for aquaporin 4 (AQP4) IgG and MOG-IgG.
RESULTS
After the exclusion of 5 participants with coexisting AQP4-IgG and MOG-IgA, MOG-IgG, and/or MOG-IgM, 1339 patients and 110 healthy controls were included; the median follow-up time was 39 months (range, 0-227 months). Of included patients with isolated MOG-IgA, 11 of 18 were female (61%), and the median age was 31.5 years (range, 3-76 years). Among patients double-seronegative for AQP4-IgG and MOG-IgG (1126/1339; 84%), isolated MOG-IgA was identified in 3 of 50 patients (6%) with neuromyelitis optica spectrum disorder, 5 of 228 patients (2%) with other CNS demyelinating diseases, and 10 of 848 patients (1%) with multiple sclerosis but in none of the healthy controls (0/110). The most common disease manifestation in patients seropositive for isolated MOG-IgA was myelitis (11/17 [65%]), followed by more frequent brainstem syndrome (7/16 [44%] vs 14/75 [19%], respectively; P = .048), and infrequent manifestation of optic neuritis (4/15 [27%] vs 46/73 [63%], respectively; P = .02) vs patients with MOG-IgG. Among patients fulfilling 2017 McDonald criteria for multiple sclerosis, MOG-IgA was associated with less frequent CSF-specific oligoclonal bands (4/9 [44%] vs 325/351 [93%], respectively; P < .001) vs patients with multiple sclerosis who were MOG-IgG/IgA seronegative. Further, most patients with isolated MOG-IgA presented clinical attacks after recent infection or vaccination (7/11 [64%]).
CONCLUSION AND RELEVANCE
In this study, MOG-specific IgA was identified in a subgroup of patients who were double-seronegative for AQP4-/MOG-IgG, suggesting that MOG-IgA may be a novel diagnostic biomarker for patients with CNS demyelination.
Topics: Humans; Female; Male; Myelin-Oligodendrocyte Glycoprotein; Longitudinal Studies; Neuromyelitis Optica; Aquaporin 4; Brain Stem; Multiple Sclerosis; Autoantibodies; Immunoglobulin G; Immunoglobulin A; Immunoglobulin M
PubMed: 37548987
DOI: 10.1001/jamaneurol.2023.2523 -
Cell May 2024Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are...
Remyelination failure in diseases like multiple sclerosis (MS) was thought to involve suppressed maturation of oligodendrocyte precursors; however, oligodendrocytes are present in MS lesions yet lack myelin production. We found that oligodendrocytes in the lesions are epigenetically silenced. Developing a transgenic reporter labeling differentiated oligodendrocytes for phenotypic screening, we identified a small-molecule epigenetic-silencing-inhibitor (ESI1) that enhances myelin production and ensheathment. ESI1 promotes remyelination in animal models of demyelination and enables de novo myelinogenesis on regenerated CNS axons. ESI1 treatment lengthened myelin sheaths in human iPSC-derived organoids and augmented (re)myelination in aged mice while reversing age-related cognitive decline. Multi-omics revealed that ESI1 induces an active chromatin landscape that activates myelinogenic pathways and reprograms metabolism. Notably, ESI1 triggered nuclear condensate formation of master lipid-metabolic regulators SREBP1/2, concentrating transcriptional co-activators to drive lipid/cholesterol biosynthesis. Our study highlights the potential of targeting epigenetic silencing to enable CNS myelin regeneration in demyelinating diseases and aging.
Topics: Animals; Myelin Sheath; Humans; Epigenesis, Genetic; Mice; Remyelination; Oligodendroglia; Central Nervous System; Mice, Inbred C57BL; Rejuvenation; Induced Pluripotent Stem Cells; Sterol Regulatory Element Binding Protein 1; Organoids; Demyelinating Diseases; Cell Differentiation; Small Molecule Libraries; Male; Regeneration; Multiple Sclerosis
PubMed: 38701782
DOI: 10.1016/j.cell.2024.04.005 -
JAMA Neurology Oct 2023Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance... (Randomized Controlled Trial)
Randomized Controlled Trial
IMPORTANCE
Radiologically isolated syndrome (RIS) represents the earliest detectable preclinical phase of multiple sclerosis (MS) punctuated by incidental magnetic resonance imaging (MRI) white matter anomalies within the central nervous system.
OBJECTIVE
To determine the time to onset of symptoms consistent with MS.
DESIGN, SETTING, AND PARTICIPANTS
From September 2017 to October 2022, this multicenter, double-blind, phase 3, randomized clinical trial investigated the efficacy of teriflunomide in delaying MS in individuals with RIS, with a 3-year follow-up. The setting included referral centers in France, Switzerland, and Turkey. Participants older than 18 years meeting 2009 RIS criteria were randomly assigned (1:1) to oral teriflunomide, 14 mg daily, or placebo up to week 96 or, optionally, to week 144.
INTERVENTIONS
Clinical, MRI, and patient-reported outcomes (PROs) were collected at baseline and yearly until week 96, with an optional third year in the allocated arm if no symptoms have occurred.
MAIN OUTCOMES
Primary analysis was performed in the intention-to-treat population, and safety was assessed accordingly. Secondary end points included MRI outcomes and PROs.
RESULTS
Among 124 individuals assessed for eligibility, 35 were excluded for declining to participate, not meeting inclusion criteria, or loss of follow-up. Eighty-nine participants (mean [SD] age, 37.8 [12.1] years; 63 female [70.8%]) were enrolled (placebo, 45 [50.6%]; teriflunomide, 44 [49.4%]). Eighteen participants (placebo, 9 [50.0%]; teriflunomide, 9 [50.0%]) discontinued the study, resulting in a dropout rate of 20% for adverse events (3 [16.7%]), consent withdrawal (4 [22.2%]), loss to follow-up (5 [27.8%]), voluntary withdrawal (4 [22.2%]), pregnancy (1 [5.6%]), and study termination (1 [5.6%]). The time to the first clinical event was significantly extended in the teriflunomide arm compared with placebo, in both the unadjusted (hazard ratio [HR], 0.37; 95% CI, 0.16-0.84; P = .02) and adjusted (HR, 0.28; 95% CI, 0.11-0.71; P = .007) analysis. Secondary imaging end point outcomes including the comparison of the cumulative number of new or newly enlarging T2 lesions (rate ratio [RR], 0.57; 95% CI, 0.27-1.20; P = .14), new gadolinium-enhancing lesions (RR, 0.33; 95% CI, 0.09-1.17; P = .09), and the proportion of participants with new lesions (odds ratio, 0.72; 95% CI, 0.25-2.06; P = .54) were not significant.
CONCLUSION AND RELEVANCE
Treatment with teriflunomide resulted in an unadjusted risk reduction of 63% and an adjusted risk reduction of 72%, relative to placebo, in preventing a first clinical demyelinating event. These data suggest a benefit to early treatment in the MS disease spectrum.
TRIAL REGISTRATION
ClinicalTrials.gov Identifier: NCT03122652.
Topics: Humans; Female; Adult; Multiple Sclerosis; Crotonates; Toluidines; Hydroxybutyrates; Demyelinating Diseases; Double-Blind Method
PubMed: 37603328
DOI: 10.1001/jamaneurol.2023.2815 -
The Medical Clinics of North America Jan 2024Acquired demyelinating syndromes (ADS) are a heterogenous group of inflammatory demyelinating conditions that include presentations of optic neuritis, transverse... (Review)
Review
Acquired demyelinating syndromes (ADS) are a heterogenous group of inflammatory demyelinating conditions that include presentations of optic neuritis, transverse myelitis, and acute demyelinating encephalomyelitis. They can be monophasic or can develop into relapsing episodes of the initial demyelinating event or evolve to include other types of demyelination. Significant progress has been made in differentiating subtypes of ADS that differ in their tendency to relapse and in which anti-inflammatory therapies are effective. Differentiating between these subtypes is important for the optimal management of these patients. Clinical features, labs (especially autoantibodies), and MRI findings can help to differentiate between the different ADS.
Topics: Humans; Magnetic Resonance Imaging; Demyelinating Diseases; Diagnosis, Differential
PubMed: 37951658
DOI: 10.1016/j.mcna.2023.05.017 -
Cells Oct 2023Inflammatory neuromuscular disorders encompass a diverse group of immune-mediated diseases with varying clinical manifestations and treatment responses. The... (Review)
Review
Inflammatory neuromuscular disorders encompass a diverse group of immune-mediated diseases with varying clinical manifestations and treatment responses. The identification of specific biomarkers has the potential to provide valuable insights into disease pathogenesis, aid in accurate diagnosis, predict disease course, and monitor treatment efficacy. However, the rarity and heterogeneity of these disorders pose significant challenges in the identification and implementation of reliable biomarkers. Here, we aim to provide a comprehensive review of biomarkers currently established in Guillain-Barré syndrome (GBS), chronic inflammatory demyelinating polyneuropathy (CIDP), myasthenia gravis (MG), and idiopathic inflammatory myopathy (IIM). It highlights the existing biomarkers in these disorders, including diagnostic, prognostic, predictive and monitoring biomarkers, while emphasizing the unmet need for additional specific biomarkers. The limitations and challenges associated with the current biomarkers are discussed, and the potential implications for disease management and personalized treatment strategies are explored. Collectively, biomarkers have the potential to improve the management of inflammatory neuromuscular disorders. However, novel strategies and further research are needed to establish clinically meaningful biomarkers.
Topics: Humans; Neuromuscular Diseases; Guillain-Barre Syndrome; Myasthenia Gravis; Polyradiculoneuropathy, Chronic Inflammatory Demyelinating; Immune System Diseases; Biomarkers
PubMed: 37887300
DOI: 10.3390/cells12202456