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Serum antibodies directed against myelin oligodendrocyte glycoprotein (MOG) are found in patients with acquired CNS demyelinating syndromes that are distinct from multiple sclerosis and aquaporin-4-seropositive neuromyelitis optica spectrum disorder. Based on an extensive literature review and a structured consensus process, we propose diagnostic criteria for MOG antibody-associated disease (MOGAD) in which the presence of MOG-IgG is a core criterion. According to our proposed criteria, MOGAD is typically associated with acute disseminated encephalomyelitis, optic neuritis, or transverse myelitis, and is less commonly associated with cerebral cortical encephalitis, brainstem presentations, or cerebellar presentations. MOGAD can present as either a monophasic or relapsing disease course, and MOG-IgG cell-based assays are important for diagnostic accuracy. Diagnoses such as multiple sclerosis need to be excluded, but not all patients with multiple sclerosis should undergo screening for MOG-IgG. These proposed diagnostic criteria require validation but have the potential to improve identification of individuals with MOGAD, which is essential to define long-term clinical outcomes, refine inclusion criteria for clinical trials, and identify predictors of a relapsing versus a monophasic disease course.

There is accumulating evidence of endothelial dysfunction, muscle and cerebral hypoperfusion in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). In this paper we deduce the pathomechanisms resulting in central nervous pathology and the myriad of neurocognitive symptoms. We outline tentative mechanisms of impaired cerebral blood flow, increase in intracranial pressure and central adrenergic hyperactivity and how they can well explain the key symptoms of cognitive impairment, brain fog, headache, hypersensitivity, sleep disturbances and dysautonomia.

Background Fatigue, exertion intolerance and post-exertional malaise are among the most frequent symptoms of Post-COVID Syndrome (PCS), with a subset of patients fulfilling criteria for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). As SARS-CoV-2 infects endothelial cells, causing endotheliitis and damaging the endothelium, we investigated endothelial dysfunction (ED) and endothelial biomarkers in patients with PCS. Methods We studied the endothelial function in 30 PCS patients with persistent fatigue and exertion intolerance as well as in 15 age- and sex matched seronegative healthy controls (HCs). 14 patients fulfilled the diagnostic criteria for ME/CFS. The other patients were considered to have PCS. Peripheral endothelial function was assessed by the reactive hyperaemia index (RHI) using peripheral arterial tonometry (PAT) in patients and HCs. In a larger cohort of patients and HCs, including post-COVID reconvalescents (PCHCs), Endothelin-1 (ET-1), Angiopoietin-2 (Ang-2), Endocan (ESM-1), IL-8, Angiotensin-Converting Enzyme (ACE) and ACE2 were analysed as endothelial biomarkers. Results Five of the 14 post-COVID ME/CFS patients and five of the 16 PCS patients showed ED defined by a diminished RHI (< 1.67), but none of HCs exhibited this finding. A paradoxical positive correlation of RHI with age, blood pressure and BMI was found in PCS but not ME/CFS patients. The ET-1 concentration was significantly elevated in both ME/CFS and PCS patients compared to HCs and PCHCs. The serum Ang-2 concentration was lower in both PCS patients and PCHCs compared to HCs. Conclusion A subset of PCS patients display evidence for ED shown by a diminished RHI and altered endothelial biomarkers. Different associations of the RHI with clinical parameters as well as varying biomarker profiles may suggest distinct pathomechanisms among patient subgroups.

The introduction of low cost optical 3D motion tracking sensors provides new options for effective quantification of motor dysfunction. The present study aimed to evaluate the Kinect V2 sensor against a gold standard motion capture system with respect to accuracy of tracked landmark movements and accuracy and repeatability of derived clinical parameters. Nineteen healthy subjects were concurrently recorded with a Kinect V2 sensor and an optical motion tracking system (Vicon). Six different movement tasks were recorded with 3D full-body kinematics from both systems. Tasks included walking in different conditions, balance and adaptive postural control. After temporal and spatial alignment, agreement of movements signals was described by Pearson's correlation coefficient and signal to noise ratios per dimension. From these movement signals, 45 clinical parameters were calculated, including ranges of motions, torso sway, movement velocities and cadence. Accuracy of parameters was described as absolute agreement, consistency agreement and limits of agreement. Intra-session reliability of 3 to 5 measurement repetitions was described as repeatability coefficient and standard error of measurement for each system. Accuracy of Kinect V2 landmark movements was moderate to excellent and depended on movement dimension, landmark location and performed task. Signal to noise ratio provided information about Kinect V2 landmark stability and indicated larger noise behaviour in feet and ankles. Most of the derived clinical parameters showed good to excellent absolute agreement (30 parameters showed ICC(3,1) > 0.7) and consistency (38 parameters showed r > 0.7) between both systems. Given that this system is low-cost, portable and does not require any sensors to be attached to the body, it could provide numerous advantages when compared to established marker- or wearable sensor based system. The Kinect V2 has the potential to be used as a reliable and valid clinical measurement tool.

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.

Stronger adaptive immune responses in females can be observed in different mammals, resulting in better control of infections compared to males. However, this presumably evolutionary difference likely also drives higher incidence of autoimmune diseases observed in humans. Here, we summarize sex differences in the most common autoimmune diseases of the central nervous system (CNS) and discuss recent advances in the understanding of possible underlying immunological and CNS intrinsic mechanisms. In multiple sclerosis (MS), the most common inflammatory disease of the CNS, but also in rarer conditions, such as neuromyelitis optica spectrum disorders (NMOSD) or neuronal autoantibody–mediated autoimmune encephalitis (AE), sex is one of the top risk factors, with women being more often affected than men. Immunological mechanisms driving the sex bias in autoimmune CNS diseases are complex and include hormonal as well as genetic and epigenetic effects, which could also be exerted indirectly via modulation of the microbiome. Furthermore, CNS intrinsic differences could underlie the sex bias in autoimmunity by differential responses to injury. The strong effects of sex on incidence and possibly also activity and progression of autoimmune CNS disorders suggest that treatments need to be tailored to each sex to optimize efficacy. To date, however, due to a lack of systematic studies on treatment responses in males versus females, evidence in this area is still sparse. We argue that studies taking sex differences into account could pave the way for sex-specific and therefore personalized treatment.

Type I interferon (IFN-I) and T helper 17 (TH17) drive pathology in neuromyelitis optica spectrum disorder (NMOSD) and in TH17-induced experimental autoimmune encephalomyelitis (TH17-EAE). This is paradoxical because the prevalent theory is that IFN-I inhibits TH17 function. Here we report that a cascade involving IFN-I, IL-6 and B cells promotes TH17-mediated neuro-autoimmunity. In NMOSD, elevated IFN-I signatures, IL-6 and IL-17 are associated with severe disability. Furthermore, IL-6 and IL-17 levels are lower in patients on anti-CD20 therapy. In mice, IFN-I elevates IL-6 and exacerbates TH17-EAE. Strikingly, IL-6 blockade attenuates disease only in mice treated with IFN-I. By contrast, B-cell-deficiency attenuates TH17-EAE in the presence or absence of IFN-I treatment. Finally, IFN-I stimulates B cells to produce IL-6 to drive pathogenic TH17 differentiation in vitro. Our data thus provide an explanation for the paradox surrounding IFN-I and TH17 in neuro-autoimmunity, and may have utility in predicting therapeutic response in NMOSD. Type I IFN has apposing effects in neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). Here the authors perform molecular profiling of NMOSD patients and mouse mechanistic experiments of neuro-inflammation to show that IFN-I stimulates pathogenic Th17 via IL-6 production by B cells.

Susac syndrome is an important differential diagnosis in many neurological disorders, but our understanding of this rare disease has largely been limited to reports of single cases and small case series. In this article, Dörr and colleagues review all reported cases of Susac syndrome to provide a comprehensive overview of demographic, clinical and diagnostic data on this disorder. On the basis of their findings, Dörr et al . make recommendations for diagnosis and management of individuals with suspected Susac syndrome. In Susac syndrome, occlusions of microvessels—presumed to be mediated by an autoimmune response to an as yet unknown antigen—lead to a characteristic clinical triad of CNS dysfunction, branch retinal artery occlusions, and sensorineural hearing impairment. Susac syndrome is considered a rare but important differential diagnosis in numerous neurological, psychiatric, ophthalmological, and ear, nose and throat disorders. Improved understanding of this disorder is crucial, therefore, to ensure that patients receive appropriate treatment and care. Current knowledge on Susac syndrome is largely based on reports of single patients, small case series, and nonsystematic reviews. The aim of this Review is to extend these previous, primarily anecdotal findings by compiling data from all 304 cases of Susac syndrome that have been published worldwide, which were identified following a literature search with predefined search, inclusion and exclusion criteria. From this data, we present an overview of demographic, clinical and diagnostic data on Susac syndrome, providing a reliable basis for our current understanding of this rare disease. Where possible, we make recommendations for clinical diagnosis, differential diagnosis, and management of patients with suspected Susac syndrome. Key Points Susac syndrome is a rare but important differential diagnosis in numerous neurological, psychiatric, ophthalmological, and ear, nose and throat disorders On the basis of data obtained from 304 published cases, the mean age of onset of Susac syndrome is estimated at 31.6 years, with a male-to-female ratio of 1:3.5 Presentation with the full clinical triad of symptoms (CNS, eye and ear symptoms) at disease onset is rare and, therefore, diagnosis should not rely solely on presence of the triad Presence of oligoclonal bands and/or intrathecal IgG does not exclude a diagnosis of Susac syndrome, but lack of both signs remains an important criterion for differentiation from multiple sclerosis Invasive diagnostic procedures such as brain biopsy or cerebral angiography do not aid establishment of a diagnosis of Susac syndrome, so should be reserved for exceptional cases The role of antibodies targeting endothelial cells in the pathophysiology and diagnosis of Susac syndrome remains to be determined

Viscoelastic properties indicate structural alterations in biological tissues at multiple scales with high sensitivity. Magnetic Resonance Elastography (MRE) is a novel technique that directly visualizes and quantitatively measures biomechanical tissue properties in vivo. MRE recently revealed that early relapsing-remitting multiple sclerosis (MS) is associated with a global decrease of the cerebral mechanical integrity. This study addresses MRE and MR volumetry in chronic-progressive disease courses of MS. We determined viscoelastic parameters of the brain parenchyma in 23 MS patients with primary or secondary chronic progressive disease course in comparison to 38 age- and gender-matched healthy individuals by multifrequency MRE, and correlated the results with clinical data, T2 lesion load and brain volume. Two viscoelastic parameters, the shear elasticity μ and the powerlaw exponent α, were deduced according to the springpot model and compared to literature values of relapsing-remitting MS. In chronic-progressive MS patients, μ and α were reduced by 20.5% and 6.1%, respectively, compared to healthy controls. MR volumetry yielded a weaker correlation: Total brain volume loss in MS patients was in the range of 7.5% and 1.7% considering the brain parenchymal fraction. All findings were significant (P<0.001). Chronic-progressive MS disease courses show a pronounced reduction of the cerebral shear elasticity compared to early relapsing-remitting disease. The powerlaw exponent α decreased only in the chronic-progressive stage of MS, suggesting an alteration in the geometry of the cerebral mechanical network due to chronic neuroinflammation.