Background: A subset of patients with neuromyelitis optica spectrum disorders (NMOSD) has been shown to be seropositive for myelin oligodendrocyte glycoprotein antibodies (MOG-IgG).Objective: To describe the epidemiological, clinical, radiological, cerebrospinal fluid (CSF), and electrophysiological features of a large cohort of MOG-IgG-positive patients with optic neuritis (ON) and/or myelitis (n = 50) as well as attack and long-term treatment outcomes.Methods: Retrospective multicenter study. Results: The sex ratio was 1:2.8 (m:f). Median age at onset was 31 years (range 6-70). The disease followed a multiphasic course in 80% (median time-to-first-relapse 5 months; annualized relapse rate 0.92) and resulted in significant disability in 40% (mean follow-up 75 ± 46.5 months), with severe visual impairment or functional blindness (36%) and markedly impaired ambulation due to paresis or ataxia (25%) as the most common long-term sequelae. Functional blindness in one or both eyes was noted during at least one ON attack in around 70%. Perioptic enhancement was present in several patients. Besides acute tetra-/paraparesis, dysesthesia and pain were common in acute myelitis (70%). Longitudinally extensive spinal cord lesions were frequent, but short lesions occurred at least once in 44%. Fourty-one percent had a history of simultaneous ON and myelitis. Clinical or radiological involvement of the brain, brainstem, or cerebellum was present in 50%; extra-opticospinal symptoms included intractable nausea and vomiting and respiratory insufficiency (fatal in one). CSF pleocytosis (partly neutrophilic) was present in 70%, oligoclonal bands in only 13%, and blood-CSF-barrier dysfunction in 32%. Intravenous methylprednisolone (IVMP) and long-term immunosuppression were often effective; however, treatment failure leading to rapid accumulation of disability was noted in many patients as well as flare-ups after steroid withdrawal. Full recovery was achieved by plasma exchange in some cases, including after IVMP failure. Breakthrough attacks under azathioprine were linked to the drug-specific latency period and a lack of cotreatment with oral steroids. Methotrexate was effective in 5/6 patients. Interferon-beta was associated with ongoing or increasing disease activity. Rituximab and ofatumumab were effective in some patients. However, treatment with rituximab was followed by early relapses in several cases; end-of-dose relapses occurred 9-12 months after the first infusion. Coexisting autoimmunity was rare (9%). Wingerchuk's 2006 and 2015 criteria for NMO(SD) and Barkhof and McDonald criteria for multiple sclerosis (MS) were met by 28%, 32%, 15%, 33%, respectively; MS had been suspected in 36%. Disease onset or relapses were preceded by infection, vaccination, or pregnancy/delivery in several cases. Conclusion: Our findings from a predominantly Caucasian cohort strongly argue against the concept of MOG-IgG denoting a mild and usually monophasic variant of NMOSD. The predominantly relapsing and often severe disease course ...

BackgroundAntibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been suggested to play a role in a subset of patients with neuromyelitis optica and related disorders.ObjectiveTo assess (i) the frequency of MOG-IgG in a large and predominantly Caucasian cohort of patients with optic neuritis (ON) and/or myelitis; (ii) the frequency of MOG-IgG among AQP4-IgG-positive patients and vice versa; (iii) the origin and frequency of MOG-IgG in the cerebrospinal fluid (CSF); (iv) the presence of MOG-IgG at disease onset; and (v) the influence of disease activity and treatment status on MOG-IgG titers.Methods614 serum samples from patients with ON and/or myelitis and from controls, including 92 follow-up samples from 55 subjects, and 18 CSF samples were tested for MOG-IgG using a live cell-based assay (CBA) employing full-length human MOG-transfected HEK293A cells.ResultsMOG-IgG was detected in 95 sera from 50 patients with ON and/or myelitis, including 22/54 (40.7 %) patients with a history of both ON and myelitis, 22/103 (21.4 %) with a history of ON but no myelitis and 6/45 (13.3 %) with a history of longitudinally extensive transverse myelitis but no ON, and in 1 control patient with encephalitis and a connective tissue disorder, all of whom were negative for AQP4-IgG. MOG-IgG was absent in 221 further controls, including 83 patients with AQP4-IgG-seropositive neuromyelitis optica spectrum disorders and 85 with multiple sclerosis (MS). MOG-IgG was found in 12/18 (67 %) CSF samples from MOG-IgG-seropositive patients; the MOG-IgG-specific antibody index was negative in all cases, indicating a predominantly peripheral origin of CSF MOG-IgG. Serum and CSF MOG-IgG belonged to the complement-activating IgG1 subclass. MOG-IgG was present already at disease onset. The antibodies remained detectable in 40/45 (89 %) follow-up samples obtained over a median period of 16.5 months (range 0–123). Serum titers were higher during attacks than during remission (p < 0.0001), highest during attacks of simultaneous myelitis and ON, lowest during acute isolated ON, and declined following treatment.ConclusionsTo date, this is the largest cohort studied for IgG to human full-length MOG by means of an up-to-date CBA. MOG-IgG is present in a substantial subset of patients with ON and/or myelitis, but not in classical MS. Co-existence of MOG-IgG and AQP4-IgG is highly uncommon. CSF MOG-IgG is of extrathecal origin. Serum MOG-IgG is present already at disease onset and remains detectable in the long-term course. Serum titers depend on disease activity and treatment status.

Objective:To trace microstructural changes in patients with aquaporin-4 antibody (AQP4-ab)-seropositive neuromyelitis optica spectrum disorders (NMOSDs) by investigating the afferent visual system in patients without clinically overt visual symptoms or visual pathway lesions.Methods:Of 51 screened patients with NMOSD from a longitudinal observational cohort study, we compared 6 AQP4-ab–seropositive NMOSD patients with longitudinally extensive transverse myelitis (LETM) but no history of optic neuritis (ON) or other bout (NMOSD-LETM) to 19 AQP4-ab–seropositive NMOSD patients with previous ON (NMOSD-ON) and 26 healthy controls (HCs). Foveal thickness (FT), peripapillary retinal nerve fiber layer (pRNFL) thickness, and ganglion cell and inner plexiform layer (GCIPL) thickness were measured with optical coherence tomography (OCT). Microstructural changes in the optic radiation (OR) were investigated using diffusion tensor imaging (DTI). Visual function was determined by high-contrast visual acuity (VA). OCT results were confirmed in a second independent cohort.Results:FT was reduced in both patients with NMOSD-LETM (p = 3.52e−14) and NMOSD-ON (p = 1.24e−16) in comparison with HC. Probabilistic tractography showed fractional anisotropy reduction in the OR in patients with NMOSD-LETM (p = 0.046) and NMOSD-ON (p = 1.50e−5) compared with HC. Only patients with NMOSD-ON but not NMOSD-LETM showed neuroaxonal damage in the form of pRNFL and GCIPL thinning. VA was normal in patients with NMOSD-LETM and was not associated with OCT or DTI parameters.Conclusions:Patients with AQP4-ab–seropositive NMOSD without a history of ON have microstructural changes in the afferent visual system. The localization of retinal changes around the Müller-cell rich fovea supports a retinal astrocytopathy.

Machine learning-based imaging diagnostics has recently reached or even superseded the level of clinical experts in several clinical domains. However, classification decisions of a trained machine learning system are typically non-transparent, a major hindrance for clinical integration, error tracking or knowledge discovery. In this study, we present a transparent deep learning framework relying on convolutional neural networks (CNNs) and layer-wise relevance propagation (LRP) for diagnosing multiple sclerosis (MS), the most widespread autoimmune neuroinflammatory disease. MS is commonly diagnosed utilizing a combination of clinical presentation and conventional magnetic resonance imaging (MRI), specifically the occurrence and presentation of white matter lesions in T2-weighted images. We hypothesized that using LRP in a naive predictive model would enable us to uncover relevant image features that a trained CNN uses for decision-making. Since imaging markers in MS are well-established this would enable us to validate the respective CNN model. First, we pre-trained a CNN on MRI data from the Alzheimer's Disease Neuroimaging Initiative (n = 921), afterwards specializing the CNN to discriminate between MS patients and healthy controls (n = 147). Using LRP, we then produced a heatmap for each subject in the holdout set depicting the voxel-wise relevance for a particular classification decision. The resulting CNN model resulted in a balanced accuracy of 87.04% and an area under the curve of 96.08% in a receiver operating characteristic curve. The subsequent LRP visualization revealed that the CNN model focuses indeed on individual lesions, but also incorporates additional information such as lesion location, non-lesional white matter or gray matter areas such as the thalamus, which are established conventional and advanced MRI markers in MS. We conclude that LRP and the proposed framework have the capability to make diagnostic decisions of CNN models transparent, which could serve to justify classification decisions for clinical review, verify diagnosis-relevant features and potentially gather new disease knowledge. ability in patients [2]. The current quasi-standard for diagnosing MS, the McDonald criteria, relies on clinical presentation and the presence of lesions visible in conventional T2-weighted brain magnetic resonance imaging (MRI) data [3]. Most common are fluid-suppressed T2-weighted image sequences, which are sensitive towards MS-relevant white matter lesions, but also relatively unspecific with respect to underlying disease processes [4]. Several other imaging markers have been described including neurodegeneration, thalamic atrophy, cortical lesions, altered functional connectivity or central vein signs

Background Many studies in multiple sclerosis (MS) have investigated the retina. Little however is known about the effect of MS on the cornea, which is innervated by the trigeminal nerve. It is the site of neural-immune interaction with local dendritic cells reacting in response- to environmental stimuli. Objective This study aims to investigate the effect of MS on- corneal nerve fibres and dendritic cells in the subbasal nerve plexus using in vivo confocal microscopy (IVCM). Methods We measured the corneal nerve fibre and dendritic cell density in 26 MS patients and matched healthy controls using a Heidelberg Retina Tomograph with Cornea Module. Disease severity was assessed with the Multiple Sclerosis Functional Composite, Expanded Disability Status Scale, visual acuity and retinal optical coherence tomography. Results We observed significant reduction in total corneal nerve fibre density in MS patients compared to controls. Dendritic cell density was similar in both groups. Reduced total nerve fibre density was associated with worse clinical severity, but not with previous clinical trigeminal symptoms, retinal neuroaxonal damage, visual acuity, or disease duration. Conclusion Corneal nerve fibre density is a promising new imaging marker for the assessment of disease severity in MS and should be investigated further.

Background: Women are more susceptible to multiple sclerosis (MS) than men by a ratio of approximately 3:1. However, being male is a risk factor for worse disability progression. Inflammatory genes have been linked to susceptibility, while neurodegeneration underlies disability progression. Thus, there appears to be a differential effect of sex on inflammation versus neurodegeneration. Further, gray matter (GM) atrophy is not uniform across the brain in MS, but instead shows regional variation. Here, we study sex differences in neurodegeneration by comparing regional GM atrophy in a cohort of men and women with MS versus their respective age-and sexmatched healthy controls. Methods: Voxel-based morphometry (VBM), deep GM substructure volumetry, and cortical thinning were used to examine regional GM atrophy. Results: VBM analysis showed deep GM atrophy in the thalamic area in both men and women with MS, whereas men had additional atrophy in the putamen as well as in localized cortical regions. Volumetry confirmed deep GM loss, while localized cortical thinning confirmed GM loss in the cerebral cortex. Further, MS males exhibited worse performance on the 9-hole peg test (9HPT) than MS females. We observed a strong correlation between thalamic volume and 9HPT performance in MS males, but not in MS females. Conclusion: More regional GM atrophy was observed in men with MS than women with MS, consistent with previous observations that male sex is a risk factor for worse disease progression.

• The hypothesis of a widespread brain damage in NMOSD is challenged. • The optic radiation (OR) is the most severely affected region. • OR-affection is likely due to secondary degeneration following optic neuritis. • DTI is currently the most sensitive technique for NMOSD-related brain-damage detection. • DTI is currently the most reliable technique for NMOSD-related brain-damage detection.

Objective:To assess volumes and microstructural integrity of deep gray matter structures in a homogeneous cohort of patients with neuromyelitis optica spectrum disorder (NMOSD).Methods:This was a cross-sectional study including 36 aquaporin-4 antibody-positive (AQP4 Ab-positive) Caucasian patients with NMOSD and healthy controls matched for age, sex, and education. Volumetry of deep gray matter structures (DGM; thalamus, caudate, putamen, globus pallidus, hippocampus, amygdala, nucleus accumbens) was performed using 2 independent automated methods. Microstructural integrity was assessed based on diffusion tensor imaging.Results:Both volumetric analysis methods consistently revealed similar volumes of DGM structures in patients and controls without significant group differences. Moreover, no differences in DGM microstructural integrity were observed between groups.Conclusions:Deep gray matter structures are not affected in AQP4 Ab-positive Caucasian patients with NMOSD. NMOSD imaging studies should be interpreted with respect to Ab status, educational background, and ethnicity of included patients.