Factors Associated With Relapse and Treatment of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease in the United Kingdom.

Importance: Longer-term outcomes and risk factors associated with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are not well established. Objective: To investigate longer-term risk of relapse and factors associated with this risk among patients with MOGAD. Design, Setting, and Participants: This large, single-nation, prospective cohort study was conducted among 276 patients with MOGAD at 5 health care centers in the UK. Data from January 1973 to March 2020 were collected from 146 patients at Oxford and its outreach sites, 65 patients at Liverpool, 32 patients at a children's hospital in Birmingham, 22 patients at a children's hospital in London, and 11 patients at Cardiff, Wales. Data were analyzed from April through July 2020. Main Outcomes and Measures: Risk of relapse and annualized relapse rate were evaluated according to different baseline features, including onset age, onset phenotype, and incident vs nonincident group, with the incident group defined as patients diagnosed with antibodies against myelin oligodendrocyte glycoprotein before a second attack. Time to next relapse among patients experiencing relapse was measured and compared between the maintenance therapy subgroup and each first-line treatment group. The no-treatment group was defined as the off-treatment phase among patients who were relapsing, which could occur between any attack or between the last attack and last follow-up. Results: Among 276 patients with MOGAD, 183 patients were identified as being part of the incident group. There were no differences in mean (SD) onset age between total and incident groups (26.4 [17.6] years vs 28.2 [18.1] years), and female patients were predominant in both groups (166 [60.1%] female patients vs 106 [57.9%] female patients). The most common presentation overall was optic neuritis (ON) (119 patients among 275 patients with presentation data [43.3%]), while acute disseminated encephalomyelitis (ADEM), brain, or brainstem onset was predominant among 69 patients aged younger than 12 years (47 patients [68.1%]), including 41 patients with ADEM (59.4%). In the incident group, the 8-year risk of relapse was 36.3% (95% CI, 27.1%-47.5%). ON at onset was associated with increased risk of relapse compared with transverse myelitis at onset (hazard ratio [HR], 2.66; 95% CI, 1.01-6.98; P = .047), but there was no statistically significant difference with adjustment for a follow-on course of corticosteroids. Any TM at onset (ie, alone or in combination with other presentations [ie, ON or ADEM, brain, or brain stem]) was associated with decreased risk of relapse compared with no TM (HR, 0.41; 95% CI, 0.20-0.88; P = .01). Young adult age (ie, ages >18-40 years) was associated with increased risk of relapse compared with older adult age (ie, ages >40 years) (HR, 2.71; 95% CI, 1.18-6.19; P = .02). First-line maintenance therapy was associated with decreased risk of relapse when adjusted for covariates (prednisolone: HR, 0.33; 95% CI, 0.12-0.92; P = .03; prednisolone, nonsteroidal immunosuppressant, or combined: HR, 0.51; 95% CI, 0.28-0.92; P = .03) compared with the no-treatment group. Conclusions and Relevance: The findings of this cohort study suggest that onset age and onset phenotype should be considered when assessing subsequent relapse risk and that among patients experiencing relapse, prednisolone, first-line immunosuppression, or a combination of those treatments may be associated with decreased risk of future relapse by approximately 2-fold. These results may contribute to individualized treatment decisions.

Exosomes derived from bone marrow mesenchymal stromal cells promote remyelination and reduce neuroinflammation in the demyelinating central nervous system.

Injury of oligodendrocytes (OLs) induces demyelination, and patients with neurodegenerative diseases exhibit demyelination concomitantly with neurological deficit and cognitive impairment. Oligodendrocyte progenitor cells (OPCs) are present in the adult central nervous system (CNS), and they can proliferate, differentiate, and remyelinate axons after damage. However, remyelination therapies are not in clinical use. Multiple sclerosis (MS) is a major demyelinating disease in the CNS. Mesenchymal stromal cells (MSCs) have demonstrated therapeutic promise in animal models and in clinical trials of MS. Exosomes are nanoparticles generated by nearly all cells and they mediate cell-cell communication by transferring cargo biomaterials. Here, we hypothesize that exosomes harvested from MSCs have a similar therapeutic effect on enhancement of remyelination as that of MSCs. In the present study we employed exosomes derived from rhesus monkey MSCs (MSC-Exo). Two mouse models of demyelination were employed: 1) experimental autoimmune encephalomyelitis (EAE), an animal model of MS; and 2) cuprizone (CPZ) diet model, a toxic demyelination model. MSC-Exo or PBS were intravenously injected twice a week for 4 weeks, starting on day 10 post immunization in EAE mice, or once a week for 2 weeks starting on the day of CPZ diet withdrawal. Neurological and cognitive function were tested, OPC differentiation and remyelination, neuroinflammation and the potential underlying mechanisms were investigated using immunofluorescent staining, transmission electron microscopy and Western blot. Data generated from the EAE model revealed that MSC-Exo cross the blood brain barrier (BBB) and target neural cells. Compared with the controls (p < 0.05), treatment with MSC-Exo: 1) significantly improved neurological outcome; 2) significantly increased the numbers of newly generated OLs (BrdU+/APC+) and mature OLs (APC+), and the level of myelin basic protein (MBP); 3) decreased amyloid-ß precursor protein (APP)+ density; 4) decreased neuroinflammation by increasing the M2 phenotype and decreasing the M1 phenotype of microglia, as well as their related cytokines; 5) inhibited the TLR2/IRAK1/NFκB pathway. Furthermore, we confirmed that the MSC-Exo treatment significantly improved cognitive function, promoted remyelination, increased polarization of M2 phenotype and blocked TLR2 signaling in the CPZ model. Collectively, MSC-Exo treatment promotes remyelination by both directly acting on OPCs and indirectly by acting on microglia in the demyelinating CNS. This study provides the cellular and molecular basis for this cell-free exosome therapy on remyelination and modulation of neuroinflammation in the CNS, with great potential for treatment of demyelinating and neurodegenerative disorders.

Myelin-oligodendrocyte glycoprotein antibody-associated disease.

Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a recently identified autoimmune disorder that presents in both adults and children as CNS demyelination. Although there are clinical phenotypic overlaps between MOGAD, multiple sclerosis, and aquaporin-4 antibody-associated neuromyelitis optica spectrum disorder (NMOSD) cumulative biological, clinical, and pathological evidence discriminates between these conditions. Patients should not be diagnosed with multiple sclerosis or NMOSD if they have anti-MOG antibodies in their serum. However, many questions related to the clinical characterisation of MOGAD and pathogenetic role of MOG antibodies are still unanswered. Furthermore, therapy is mainly based on standard protocols for aquaporin-4 antibody-associated NMOSD and multiple sclerosis, and more evidence is needed regarding how and when to treat patients with MOGAD.

Case Report: Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disorder Masquerading as Multiple Sclerosis: An Under-Recognized Entity?

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) covers a wide spectrum of manifestations and is defined by the presence of MOG seropositivity. However, in a proportion of patients, there may be an overlap in some of the clinical and radiological manifestations between MOGAD and multiple sclerosis (MS). Being wary of this entity is critical to ensure appropriate therapy. Herein, we present a case with recurrent episodes of short-segment myelitis typical for multiple sclerosis, but later diagnosed as MOGAD by MOG antibody seropositivity. This case, along with previous reports, highlights an increasingly recognized subgroup in MOGAD with initial clinical phenotypes suggestive of MS, but later showing a disease course and therapeutic response compatible with MOGAD. Given the potential overlap of some clinical phenotypes in patients with MS and those with MOGAD, we recommend MOG antibody testing in all patients with recurrent short-segment myelitis, conus medullaris involvement, and those who demonstrated steroid dependence.

Tumefactive Demyelination Appearing as Multiple Cystic Brain Lesions.

Tumefactive demyelinating lesions (TDLs) are a rare sequelae of idiopathic inflammatory demyelinating diseases of the central nervous system. Their propensity to mimic tumor and abscess poses a diagnostic challenge for the clinician. Our case depicts TDLs causing right-hand focal sensory seizures in an otherwise healthy 35-year-old female. The differential diagnosis of metastatic disease and infection were excluded on histology. Ensuing magnetic resonance imaging of the cord, in addition to cerebral spinal fluid analysis, supported the diagnosis of idiopathic inflammatory demyelinating diseases. This case highlights the need to consider the rare diagnosis of TDL when imaging shows cystic brain lesions in an otherwise healthy young adult.

High-salt diet suppresses autoimmune demyelination by regulating the blood-brain barrier permeability.

Sodium chloride, "salt," is an essential component of daily food and vitally contributes to the body's homeostasis. However, excessive salt intake has often been held responsible for numerous health risks associated with the cardiovascular system and kidney. Recent reports linked a high-salt diet (HSD) to the exacerbation of artificially induced central nervous system (CNS) autoimmune pathology through changes in microbiota and enhanced TH17 cell differentiation [M. Kleinewietfeld et al., Nature 496, 518-522 (2013); C. Wu et al., Nature 496, 513-517 (2013); N. Wilck et al., Nature 551, 585-589 (2017)]. However, there is no evidence that dietary salt promotes or worsens a spontaneous autoimmune disease. Here we show that HSD suppresses autoimmune disease development in a mouse model of spontaneous CNS autoimmunity. We found that HSD consumption increased the circulating serum levels of the glucocorticoid hormone corticosterone. Corticosterone enhanced the expression of tight junction molecules on the brain endothelial cells and promoted the tightening of the blood-brain barrier (BBB) thereby controlling the entry of inflammatory T cells into the CNS. Our results demonstrate the multifaceted and potentially beneficial effects of moderately increased salt consumption in CNS autoimmunity.

Anti-MOG antibodies associated demyelination following encephalomeningitis: Case report.

Myelin oligodendrocyte glycoprotein (MOG) antibodies have been found in a broad range of demyelination diseases. In the present study, we reported three cases of patients with anti-MOG antibodies associated disorders (MOG-ADs) who initially presented as intracranial infection like encephalomeningitis with no evidence of demyelination injury, but were subsequently found the expression of MOG antibodies and other demyelination presentations. Our findings suggested that MOG-ADs can start as an intracranial infection like prodromal symptoms prior to the lesions of optic nerve, spinal cord, and white matter. Therefore, clinicians should be cautious of MOG-ADs in cases of encephalomeningitis even without demyelination injury.

Heparanome-Mediated Rescue of Oligodendrocyte Progenitor Quiescence following Inflammatory Demyelination.

The proinflammatory cytokine IFN-γ, which is chronically elevated in multiple sclerosis, induces pathologic quiescence in human oligodendrocyte progenitor cells (OPCs) via upregulation of the transcription factor PRRX1. In this study using animals of both sexes, we investigated the role of heparan sulfate proteoglycans in the modulation of IFN-γ signaling following demyelination. We found that IFN-γ profoundly impaired OPC proliferation and recruitment following adult spinal cord demyelination. IFN-γ-induced quiescence was mediated by direct signaling in OPCs as conditional genetic ablation of IFNγR1 (Ifngr1) in adult NG2+ OPCs completely abrogated these inhibitory effects. Intriguingly, OPC-specific IFN-γ signaling contributed to failed oligodendrocyte differentiation, which was associated with hyperactive Wnt/Bmp target gene expression in OPCs. We found that PI-88, a heparan sulfate mimetic, directly antagonized IFN-γ to rescue human OPC proliferation and differentiation in vitro and blocked the IFN-γ-mediated inhibitory effects on OPC recruitment in vivo Importantly, heparanase modulation by PI-88 or OGT2155 in demyelinated lesions rescued IFN-γ-mediated axonal damage and demyelination. In addition to OPC-specific effects, IFN-γ-augmented lesions were characterized by increased size, reactive astrogliosis, and proinflammatory microglial/macrophage activation along with exacerbated axonal injury and cell death. Heparanase inhibitor treatment rescued many of the negative IFN-γ-induced sequelae suggesting a profound modulation of the lesion environment. Together, these results suggest that the modulation of the heparanome represents a rational approach to mitigate the negative effects of proinflammatory signaling and rescuing pathologic quiescence in the inflamed and demyelinated human brain.SIGNIFICANCE STATEMENT The failure of remyelination in multiple sclerosis contributes to neurologic dysfunction and neurodegeneration. The activation and proliferation of oligodendrocyte progenitor cells (OPCs) is a necessary step in the recruitment phase of remyelination. Here, we show that the proinflammatory cytokine interferon-γ directly acts on OPCs to induce pathologic quiescence and thereby limit recruitment following demyelination. Heparan sulfate is a highly structured sulfated carbohydrate polymer that is present on the cell surface and regulates several aspects of the signaling microenvironment. We find that pathologic interferon-γ can be blocked by modulation of the heparanome following demyelination using either a heparan mimetic or by treatment with heparanase inhibitor. These studies establish the potential for modulation of heparanome as a regenerative approach in demyelinating disease.

Bilateral symmetrical deep gray matter involvement and leptomeningeal enhancement in a child with MOG-IgG-associated encephalomyelitis.

BACKGROUND: Currently, myelin oligodendrocyte glycoprotein (MOG)-IgG-associated encephalomyelitis (MOG-EM) is regarded as an independent inflammatory demyelinating disease. Magnetic resonance imaging (MRI) abnormalities occur in 44.4% of patients with MOG-EM. However, symmetrical deep gray matter involvement with leptomeningeal enhancement is rarely described in the literature. CASE PRESENTATION: A 3-year-old boy was admitted to our hospital because of acute onset fever, headache, vomiting and disturbance of consciousness. Neurological examination showed somnolence, neck stiffness and positive Kernig's sign. Brain MRI demonstrated bilateral symmetrical lesions in the basal ganglia and thalamus as well as diffuse leptomeningeal enhancement along the sulci of bilateral hemisphere. Cerebrospinal fluid analysis demonstrated increased cell count (7 cells/mm3, mononuclear cells dominant) and protein (1.17 g/L) without glucose and chloride abnormality. Work-up for infectious and autoimmune causes, serum MOG IgG was positive by cell based assay. Therefore, a diagnosis of MOG-EM was established according to the international recommendatory criteria in 2018. He was administrated with intravenous methylprednisolone followed by oral corticosteroids and had recovered completely within 1 week. CONCLUSIONS: In the setting of meningoencephalitis-like clinical presentation with bilateral symmetrical deep gray matter involvement, MOG-EM should be distinguished from other infectious and autoimmune disorders, such as Epstein-Barr virus (EBV) encephalitis, Japanese encephalitis and Anti-NMDA receptor (NMDAR) encephalitis. Besides, aseptic meningitis associated with leptomeningeal enhancement may be an atypical phenotype of MOG-EM.

Qki is an essential regulator of microglial phagocytosis in demyelination.

The mechanism underpinning the regulation of microglial phagocytosis in demyelinating diseases is unclear. Here, we showed that the Quaking protein (Qki) in microglia was greatly induced by demyelination in the brains of both mice and humans. Deletion of the Quaking gene (Qk) in microglia severely impaired the clearance of myelin debris. Transcriptomic profiling indicated that depletion of Qki impaired total RNA levels and splicing of the genes involved in phagosome formation and maturation. RNA immunoprecipitation (RIP) confirmed the physical interactions between the Qki protein and the mRNAs of Qki targets that are involved in phagocytosis, indicating that Qki regulates their RNA stability. Both Qki depletion and inhibition of Qki target Cd36 greatly reduced the phagocytic activity of microglia and macrophages. The defective uptake and degradation of myelin debris caused by Qki depletion in microglia resulted in unresolved myelin debris that impaired axon integrity, oligodendrocyte maturation, and subsequent remyelination. Thus, our results demonstrate that Qki is an essential regulator of microglia's phagocytic activity under demyelinating conditions.

E.U. paediatric MOG consortium consensus: Part 2 - Neuroimaging features of paediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

Imaging plays a crucial role in differentiating the spectrum of paediatric acquired demyelinating syndromes (ADS), which apart from myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) includes paediatric multiple sclerosis (MS), aquaporin-4 antibody neuromyelitis optica spectrum disorders (NMOSD) and unclassified patients with both monophasic and relapsing ADS. In contrast to the imaging characteristics of children with MS, children with MOGAD present with diverse imaging patterns which correlate with the main demyelinating phenotypes as well as age at presentation. In this review we describe the common neuroradiological features of children with MOGAD such as acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, AQP4 negative NMOSD. In addition, we report newly recognized presentations also associated with MOG-ab such as the 'leukodystophy-like' phenotype and autoimmune encephalitis with predominant involvement of cortical and deep grey matter structures. We further delineate the features, which may help to distinguish MOGAD from other ADS and discuss the future role of MR-imaging in regards to treatment decisions and prognosis in children with MOGAD. Finally, we propose an MRI protocol for routine examination and discuss new imaging techniques, which may help to better understand the neurobiology of MOGAD.

Inflammatory Demyelinating Pseudotumor With Liver Dysfunction: IgG4 Related Disease With Primary Biliary Cholangitis.

Immunoglobulin G4 related disease (IgG4-RD) is a recently recognized immune-mediated disease which is far from understanding. A case of inflammatory demyelinating pseudotumor had been confirmed as IgG4-RD according to pathology features and clinical context. Combined with liver dysfunction, IgG4 related sclerotic cholangitis was suspected. However, primary biliary cholangitis was finally diagnosed by immune marks and histopathological findings. This is the first report in which mass lesions in the brain parenchyma were caused by IgG4-RD while liver dysfunction was due to primary biliary cholangitis. The clinical features of IgG4-RD are miscellaneous, and the accumulation of case reports might enrich clinicians experience and broaden their horizons about this condition.

Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study.

Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.

Different distribution of demyelination in chronic inflammatory demyelinating polyneuropathy subtypes.

In demyelinating polyneuropathies, distribution patterns of demyelination reflect underlying pathogenesis. Median and ulnar nerve conduction studies were reviewed in 85 typical chronic inflammatory demyelinating polyneuropathy (CIDP) patients and 29 multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). Distal latencies were prolonged in typical CIDP and near normal in MADSAM. Abnormal amplitude reductions in the nerve trunks were more frequent in MADSAM than typical CIDP. Presumably because the blood-nerve barrier is anatomically deficient at the distal nerve terminals, antibody-mediated demyelination is a major pathophysiology in typical CIDP. In contrast, blood-nerve barrier breakdown is likely to be predominant in MADSAM.

MOG-IgG-associated demyelination: focus on atypical features, brain histopathology and concomitant autoimmunity.

INTRODUCTION: Antibodies to myelin oligodendrocyte glycoprotein (MOG) have been demonstrated in patients with optic neuritis (ON), encephalitis and myelitis. OBJECTIVE: To describe the clinical and paraclinical features in patients with MOG-associated demyelination, focusing on unusual cases, brain biopsy and concomitant autoimmunity. METHODS: A single centre retrospective observational case series, analysing demographic, clinical, laboratory, histopathology and radiological data from MOG- positive patients. RESULTS: We identified 20 adults. The male/female ratio was 1.5. Mean age at onset was 31.6 years and mean disease duration was 7.5 years. The most frequent presentation was myelitis (45%), followed by ON (30%). One case had simultaneous myelitis and ON. Two patients had a cortical syndrome, 1 patient had an encephalopathic presentation and 1 cryptogenic focal epilepsy. Anti-neutrophil cytoplasmic antibodies (ANCA) were found in 3 cases, while 1 patient had an antibody to glutamic acid decarboxylase (GAD). Brain biopsy was performed in 2 patients. Relapsing course was identified in 60% of patients. We also discuss 3 cases with atypical features, brain histopathology and concomitant autoimmunity. CONCLUSION: MOG- associated demyelination represents a new disease entity. Unusual cases are reported, expanding the disease spectrum. Elucidating this further should be the focus of prospective studies.

MOG antibody-associated demyelinating disease mimicking typical multiple sclerosis: A case for expanding anti-MOG testing?

MOG-antibody associated demyelinating disease is a new emerging diagnostic entity. Recently, international recommendations for testing of anti-MOG antibodies were published. Herein, we describe a case of anti-MOG antibody-associated demyelinating disease initially diagnosed as typical MS, and, at presentation, not fulfilling the proposed recommendations. This case highlights the expanding spectrum of anti-MOG antibody-associated demyelinating disease, illustrating the distinct and overlapping features of MS and MOG-antibody associated demyelinating disease, providing evidence that on rare occasions these recommendations may prove too restrictive.

The clinical spectrum of anti-MOG associated acquired demyelinating disorders: Three case-reports.

BACKGROUND: The spectrum of differential diagnosis of acquired demyelinating disorders of the central nervous system has been recently broadened. There is now growing evidence that supports anti-myelin oligodendrocyte antibodies associated demyelination as a distinct disease entity, with some clinical characteristics that somehow overlap those of Multiple Sclerosis (MS) and anti-AQP4+ Neuromyelitis Optica Spectrum Disorders (AQP4+NMOSD) but different pathogenesis and treatment strategies. SUMMARY: We hereby present 3 cases of anti-MOG+ patients with different disease courses - ranging from mild to severe - all presenting with Optic neuritis (ON) at the onset. Optic neuritis (ON) is a common manifestation of different central nervous system (CNS) inflammatory disorders and can represent the first clinical event of MS and NMOSD. ON is also the most common presentation of antiMOG demyelinating disorders, followed by - and sometimes associated with - myelitis, most commonly extended over more than 2 spinal cord segments and defined as longitudinally extended transverse myelitis (LETM). All the three patients tested negative for oligoclonal bands in CSF and anti-AQP4 Ab in serum, had a relapsing disease course characterized by prominent involvement of the optic nerve and spinal cord, with good recovery after treatment with high-dose corticosteroids. However, they had a different disease course at follow-up and underwent different treatment approaches. CONCLUSIONS: Since anti-MOG+ patients can have a multiphasic disease course and accumulate disability over time, a high degree of suspicion and early diagnosis are of critical importance for treatment decision-making in clinical practice. AIM: The aim of this case report is to enhance focus on an emerging disease spectrum among acquired CNS demyelinating disorders.

Voluntary running wheel attenuates motor deterioration and brain damage in cuprizone-induced demyelination.

Growing data from human and animal studies indicate the beneficial effects of exercise on several clinical outcomes in patients with multiple sclerosis (MS), an autoimmune, demyelinating disease, suggesting that it may slow down the disease progression, by reducing brain damage. However, the mechanisms involved are still elusive. Aim of this study was to address the effects of voluntary running wheel in a toxic-demyelinating model of MS, in which demyelination and brain inflammation occur in response to cuprizone (CPZ) treatment. Mice were housed in standard or wheel-equipped cages starting from the day of CPZ or normal chow feeding for three or six weeks and evaluated for weight changes, locomotor skills and neuromuscular functions over the course of the experimental design. Biochemical, molecular biology and immunohistochemical analyses were performed. Exercise prevented early weight loss caused by CPZ, indicating improved wellness in these mice. Both neuromuscular function and motor coordination were significantly enhanced by exercise in CPZ-treated mice. Moreover, exercise induced an early protection against axonal damage and the loss of the myelin associated proteins, myelin basic protein (MBP) and 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase), in the striatum and the corpus callosum, in coincidence of a strongly attenuated microglia activation in both brain areas. Further, during the late phase of the treatment, exercise in CPZ mice reduced the recruitment of new OLs compared to sedentary CPZ mice, likely due to the precocious protection against myelin damage. Overall, these results suggest that life-style interventions can be effective against the demyelinating-inflammatory processes occurring in the brains of MS patients.

Pseudotumoral demyelinating lesions: diagnostic approach and long-term outcome.

PURPOSE OF REVIEW: To review the clinical findings, differential diagnosis, treatment and outcome of pseudotumoral demyelinating lesions including tumefactive demyelination and Baló's concentric sclerosis. RECENT FINDINGS: MRI findings, such as dynamic restricted diffusion changes at the edge of pseudotumoral lesions help to discriminate atypical demyelination from key differential diagnoses, and together with histopathological data, indicate that tissue hypoxia may be important aetiologically. CT-PET imaging can help to distinguish pseudotumoral lesions from high-grade tumours. Although most patients with pseudotumoral lesions have or later develop multiple sclerosis, a proportion will experience a monophasic course or be diagnosed with neuromyelitis optica spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination or acute disseminated encephalomyelitis (ADEM). Many patients with pseudotumoral demyelinating lesions have a favourable prognosis. SUMMARY: Not all patients with pseudotumoral lesions require a brain biopsy but close follow-up of biopsied and nonbiopsied lesions is indicated once a diagnosis is established. Testing for AQP4-IgG and MOG-IgG is recommended when a pseudotumoral demyelinating lesion is identified. In the absence of large, prospective studies, it seems reasonable that patients with pseudotumoral lesions who fulfil multiple sclerosis diagnostic criteria are treated with multiple sclerosis therapies.

A surface-in gradient of thalamic damage evolves in pediatric multiple sclerosis.

OBJECTIVE: Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface-in" process of injury suggesting progressive biology may begin. METHODS: We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface. Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls. Voxelwise volume changes were calculated using deformation-based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods. RESULTS: Twenty-seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow-up = 4.6 years, standard deviation = 1.9). A total of 282 healthy children with serial scans were included as controls. Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter. However, only children with multiple sclerosis exhibited an additional surface-in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval [CI] = 1.44-4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12-0.54, p = 0.0021). INTERPRETATION: Our results suggest that a multiple sclerosis disease-specific surface-in process of damage can manifest at the earliest stages of the disease. ANN NEUROL 2019;85:340-351.