Abstract Background Neuromyelitis optica spectrum disorders (NMOSD) are associated with a high burden of depression, pain, and physical disability, all of which significantly impair quality of life. At the same time, discussions on the cost-effectiveness of treatment strategies are gaining importance. However, it is not yet known whether specific symptom burdens are particularly cost-driving. This study aims to provide a comprehensive cost analysis considering depression and pain to optimise future healthcare strategies. Methods This prospective cross-sectional multicentre study was conducted at twelve centres of the Neuromyelitis Optica Study Group (NEMOS). Over a three-year period, 115 NMOSD patients were recruited. Disease-related costs, pain, and depression were assessed using standardised questionnaires. A generalised linear model analysis and graphical sub-cost analysis were performed to identify key cost drivers. The robustness of our findings was confirmed using two independent depression rating scales. Results In our sample of 115 patients, 77% suffered from chronic pain with a median pain intensity of 4.0 on the numeric rating scale (NRS). Moreover, 56% of patients reported depressive symptoms. In multivariate regression analysis, depression emerged as a significant predictor of total costs (p < 0.001) alongside the EDSS score (p < 0.001) and age (p = 0.004). In contrast, pain was not significantly influencing total costs (p = 0.057), despite being reported by the majority of patients. Graphical analyses highlighted informal costs as the main cost driver in patients with increasing depressive symptoms. Conclusions Depressive symptoms are not only common in NMOSD patients but also represent a major cost driver alongside neurological disability. Addressing these symptoms is essential for optimal patient care and may help reduce the socioeconomic burden.

BACKGROUND:Neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD) are autoimmune inflammatory disorders of the central nervous system. Central serous chorioretinopathy (CSCR) is characterized by a serous retinal detachment with leakage of fluid through the retinal pigment epithelium accumulating under the retina. This study investigated a potential association between CSCR and these neuroinflammatory disorders. METHODS:We included people with aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive NMOSD (N = 39), multiple sclerosis (MS, N = 39), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD, N = 13), seronegative NMOSD (SN-NMOSD, N = 9), and healthy controls (HC, N = 30). Using optical coherence tomography (OCT), we assessed CSCR frequency and the thickness of the peripapillary retinal nerve fiber layer (pRNFL). RESULTS:There was a higher CSCR frequency (21.3%) throughout all investigated subgroups (AQP4-IgG seropositive NMOSD, MOGAD, and SN-NMOSD) than in the HC group (p = 0.048), with a significant association between CSCR and arterial hypertension frequency but not with these diagnoses, retinal neuroaxonal loss, or history of optic neuritis. CONCLUSION:The high frequency of CSCR suggests a potential benefit of routine monitoring of CSCR in patients with NMOSD and MOGAD using the OCT technology, a reliable method to detect and monitor CSCR in patients with neuroinflammatory disorders. Further research is necessary to establish the underlying pathophysiology and potential effects on vision.

Background:Visual symptoms are common in people with multiple sclerosis. The revised 2024 McDonald criteria include the optic nerve as a fifth anatomical region, underscoring the need for specific diagnostics. Although optical coherence tomography (OCT) and visual evoked potentials (VEP) are available, the extent of their routine pre-referral use is insufficiently documented. We evaluated pre-referral utilization and hypothesized that specific diagnostics are used less often than non-specific diagnostics and that differences are not explained by demographics alone. Methods:Retrospective cross-sectional study of 305 patients referred for visual symptoms to a tertiary neuroimmunology clinic in Germany. Analyses focused on people with multiple sclerosis (n = 112) and disease controls with neuromyelitis optica spectrum disorders or myelin oligodendrocyte glycoprotein-associated disease (pwNM; n = 36). Results:In people with multiple sclerosis, only 6.2% received OCT and 33% VEP for their visual complaints, compared to unspecific diagnostics such as cranial magnetic resonance imaging (58%) and lumbar puncture (42%) - independent of demographic factors. Conclusion:The pre-referral use of specific neurovisual tests in people with multiple sclerosis with visual symptoms was low relative to non-specific procedures. This suggests heterogeneous integration of neurovisual testing across care levels. In light of the revised McDonald Criteria 2024, prospective multicenter studies should examine implementation and clinical impact.

BACKGROUND AND OBJECTIVES:AQP4 antibody-positive NMOSD (AQP4-NMOSD), MOG antibody-associated disease (MOGAD), and seronegative NMOSD (SN-NMOSD) are neuroautoimmune conditions that have overlapping clinical manifestations. Yet, important differences exist in these diseases, particularly in B-cell depletion (BCD) efficacy. Yet, the biology driving these differences remains unclear. Our study aims to clarify biological pathways distinguishing these diseases beyond autoantibodies and investigate variable BCD effects through proteomic comparisons.METHODS:In a retrospective study, 1,463 serum proteins were measured in 53 AQP4-NMOSD, 25 MOGAD, 18 SN-NMOSD, and 49 healthy individuals. To identify disease subtype-associated signatures, we examined serum proteins in patients without anti-CD20 B-cell depletion (NoBCD). We then assessed the effect of BCD treatment within each subtype by comparing proteins between BCD-treated and NoBCD-treated patients.RESULTS:In NoBCD-treated patients, serum profiles distinguished the 3 diseases. AQP4-NMOSD showed elevated type I interferon-induced chemokines (CXCL9 and CXCL10) and TFH chemokine (CXCL13). MOGAD exhibited increased cytotoxic T-cell proteases (granzyme B and granzyme H), while SN-NMOSD displayed elevated Wnt inhibitory factor 1, a marker for nerve injury. Across all subtypes, BCD-treated patients showed reduction of B-cell-associated proteins. In AQP4-NMOSD, BCD led to a decrease in several inflammatory pathways, including IL-17 signaling, cytokine storm, and macrophage activation. By contrast, BCD elevated these pathways in patients with MOGAD. BCD had no effect on these pathways in SN-NMOSD.DISCUSSION:Proteomic profiles show unique biological pathways that distinguish AQP4-NMOSD, MOGAD, or SN-NMOSD. Furthermore, BCD uniquely affects inflammatory pathways in each disease type, providing an explanation for the disparate therapeutic response in AQP4-NMOSD and MOGAD.

Background Post-COVID-19 syndrome (PCS) is characterised by a wide range of symptoms, primarily fatigue and exertion intolerance. While disease courses in the early months post-infection have been well-described, the longterm health consequences for patients with PCS with disabling fatigue remain unclear. Methods In this prospective observational cohort study, we evaluated symptom severity and various biomarkers, including hand grip strength (HGS), cardiovascular function, and laboratory parameters, in 106 patients with PCS with moderate to severe fatigue and exertion intolerance at three time points after infection (3-8, 9-16, and 17-20 months). The study was conducted at the Charite's Fatigue Centre and the Charite's outpatient clinic for neuroimmunology at Berlin, Germany from July 16, 2020, to February 18, 2022. A subset of patients (PCS-ME/CFS) met the diagnostic criteria for myalgic encephalomyelitis/chronic fatigue syndrome according to the Canadian Consensus Criteria (CCC). The aim was to determine differences in the disease course between the two patient groups (i.e., PCS vs PCS-ME/CFS) and identify correlating biomarkers. Findings Patients with PCS-ME/CFS reported persistently high severity of most symptoms up to 20 months after infection, while patients with PCS showed overall health improvement. Although fatigue and post-exertional malaise (PEM), hallmarks of post-infectious fatigue syndromes, were still evident in both groups, they remained more pronounced in PCS-ME/CFS. Inflammatory biomarkers decreased in both groups, but not antinuclear antibodies. Lower HGS at onset correlated with symptom persistence, particularly in patients with PCS-ME/CFS. Interpretation Our findings suggest that PCS can persist beyond 20 months post-infection and encompass the full scope of post-infectious ME/CFS as defined by the CCC. Sub-classifying patients with PCS based on the CCC can assist in the management and monitoring of patients with PCS-ME/CFS due to their persistently higher symptom severity. 2023;63: Published https://doi.org/10. 1016/j.eclinm.2023. 102146

Background and Objectives To evaluate costs and health-related quality of life (HRQoL) of neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD). Methods In this multicenter cross-sectional study, data on consumption of medical and nonmedical resources and work ability were assessed via patient questionnaires. Costs were analyzed in Euros for 2018 from the societal perspective. HRQoL was captured by the EuroQoL Group 5 Dimension 5 Level Scale (EQ-5D-5L) questionnaire. Clinical data were retrieved from the Neuromyelitis Optica Study Group (NEMOS) database. Results Two hundred twelve patients (80% women, median age 50 [19–83] years, median disease duration 7 [0–43] years, median Expanded Disability Status Scale [EDSS] score 3.5 [0–8.5], 66% aquaporin-4 immunoglobulin G [IgG] positive, 22% MOG IgG positive, 12% double seronegative) were analyzed. The mean total annual per capita cost of illness accounted for €59,574 (95% CI 51,225–68,293 or US dollars [USD] 70,297, 95% CI 60,445–80,586), and the mean index value of the EQ-5D-5L was 0.693 (95% CI 0.65–0.73). The most important cost drivers were informal care costs (28% of total costs), indirect costs (23%), and drugs (16%), especially immunotherapeutics. Costs showed a positive correlation with disease severity (ρ = 0.56, 95% CI 0.45–0.65); in the EDSS score 6.5 to 8.5 subgroup, the mean annual costs were €129,687 (95% CI 101,946–160,336 or USD 153,031, 95% CI 120,296–189,196). The HRQoL revealed a negative correlation to disease severity (ρ = −0.69, 95% CI −0.76 to −0.61); in the EDSS score 6.5 to 8.5 subgroup, the EQ-5D-5L mean index value was 0.195 (95% CI 0.13–0.28). Neither antibody status nor disease duration influenced the total annual costs or HRQoL. Discussion These German data from the era without approved preventive immunotherapies show enormous effects of the diseases on costs and quality of life. An early and cost-effective therapy should be provided to prevent long-term disability and to preserve quality of life.

Background and Objectives To evaluate the long-term safety and efficacy of tocilizumab (TCZ), a humanized anti–interleukin-6 receptor antibody in myelin oligodendrocyte glycoprotein–IgG–associated disease (MOGAD) and neuromyelitis optica spectrum disorders (NMOSD). Methods Annualized relapse rate (ARR), Expanded Disability Status Scale score, MRI, autoantibody titers, pain, and adverse events were retrospectively evaluated in 57 patients with MOGAD (n = 14), aquaporin-4 (AQP4)-IgG seropositive (n = 36), and seronegative NMOSD (n = 7; 12%), switched to TCZ from previous immunotherapies, particularly rituximab. Results Patients received TCZ for 23.8 months (median; interquartile range 13.0–51.1 months), with an IV dose of 8.0 mg/kg (median; range 6–12 mg/kg) every 31.6 days (mean; range 26–44 days). For MOGAD, the median ARR decreased from 1.75 (range 0.5–5) to 0 (range 0–0.9; p = 0.0011) under TCZ. A similar effect was seen for AQP4-IgG+ (ARR reduction from 1.5 [range 0–5] to 0 [range 0–4.2]; p < 0.001) and for seronegative NMOSD (from 3.0 [range 1.0–3.0] to 0.2 [range 0–2.0]; p = 0.031). During TCZ, 60% of all patients were relapse free (79% for MOGAD, 56% for AQP4-IgG+, and 43% for seronegative NMOSD). Disability follow-up indicated stabilization. MRI inflammatory activity decreased in MOGAD (p = 0.04; for the brain) and in AQP4-IgG+ NMOSD (p < 0.001; for the spinal cord). Chronic pain was unchanged. Regarding only patients treated with TCZ for at least 12 months (n = 44), ARR reductions were confirmed, including the subgroups of MOGAD (n = 11) and AQP4-IgG+ patients (n = 28). Similarly, in the group of patients treated with TCZ for at least 12 months, 59% of them were relapse free, with 73% for MOGAD, 57% for AQP4-IgG+, and 40% for patients with seronegative NMOSD. No severe or unexpected safety signals were observed. Add-on therapy showed no advantage compared with TCZ monotherapy. Discussion This study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

In multiple sclerosis (MS), relapse rate is decreased by 70-80% in the third trimester of pregnancy. However, the underlying mechanisms driving this effect are poorly understood. Evidence suggests that CD56 bright NK cell frequencies increase during pregnancy. Here, we analyze pregnancy-related NK cell shifts in a large longitudinal cohort of pregnant women with and without MS, and provide in-depth phenotyping of NK cells. In healthy pregnancy and pregnancy in MS, peripheral blood NK cells showed significant frequency shifts, notably an increase of CD56 bright NK cells and a decrease of CD56 dim NK cells toward the third trimester, indicating a general rather than an MS-specific phenomenon of pregnancy. Additional follow-ups in women with MS showed a reversal of NK cell changes postpartum. Moreover, high-dimensional profiling revealed a specific CD56 bright subset with receptor expression related to cytotoxicity and cell activity (e.g., CD16 + NKp46 high NKG2D high NKG2A high phenotype) that may drive the expansion of CD56 bright NK cells during pregnancy in MS. Our data confirm that pregnancy promotes pronounced shifts of NK cells toward the regulatory CD56 bright population. Although exploratory results on in-depth CD56 bright phenotype need to be confirmed in larger studies, our findings suggest an increased regulatory NK activity, thereby potentially contributing to disease amelioration of MS during pregnancy.

BACKGROUND:Clinical outcomes in neuromyelitis optica spectrum disorders (NMOSD) vary across different regions.OBJECTIVE:To describe clinical profiles in Japanese and German NMOSD patients.METHODS:Medical records of aquaporin-4-immunoglobulin G (AQP4-IgG) positive NMOSD patients from Japan (n = 54) and Germany (n = 38) were retrospectively analyzed.RESULTS:The disability status was similar between both cohorts, although Japanese patients had a longer disease duration (13.3 ± 11.1 vs. 8.1 ± 6.9 years, p = 0.018) but similar relapse rates. Optic neuritis and myelitis were the most frequent attacks in both cohorts. Brain attacks occurred more frequently in Japanese patients (40.7% vs. 15.8%, p = 0.020). The time from disease onset (median [interquartile range] 2.3 [0.3-10.1] vs. 0.6 [0.2-1.9] years, p = 0.009) and the number of attacks (2.5 [1-7] vs. 2 [1-3], p = 0.047) until start of the first immunotherapy were higher in the Japanese cohort. Rituximab was the most common drug in the German cohort (52.6%) and not given in the Japanese cohort (p < 0.001), where oral prednisolone was the most common drug (92.6% vs. 15.8%, p < 0.001). The frequency of autoimmune comorbidities was higher in the German cohort (39.5% vs. 18.5%, p = 0.047).CONCLUSION:Compared with Japanese NMOSD patients, German patients presented with similar disability despite shorter disease duration and earlier and more frequent immunosuppressive therapy.

BACKGROUND:Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune astrocytopathy characterized by aquaporin-4 antibodies, whose prognosis is influenced by onset age, race, environmental exposures and immunosuppression. Distinguishing the contribution of environment from genetics is challenging. We aimed to compare neuromyelitis optica spectrum disorder (NMOSD) patient outcomes according to self-identified racial group and place of residence. METHODS:This retrospective analysis of prospectively collected data included non-white anti-aquaporin-4 antibody positive NMOSD patients under follow-up from 15 centers [United Kingdom, France, Germany, Denmark, Martinique, United States of America, Japan, South Korea, Singapore, Thailand, China (including Hong Kong) and India]. Racial groups were designated: African/Caribbean; South Asian; East Asian (including Southeast Asia). Patients from these racial groups residing outside Africa/Caribbean or Asia were compared with those living in the Caribbean or the Asian areas. Kaplan-Meier survival curves and Cox models were generated using time to sustained Expanded Disability Status Scale≥6.0 or death; time to sustained Kurtzke Visual Function Score≥3.0 or a composite endpoint of all three. RESULTS:Among 821 patients, African/Caribbean patients (n = 206) had the shortest time to immunosuppression and higher visual disability at onset. South Asian patients (n = 65) were younger, had lower visual disability at onset and higher mortality rate. East Asians (n = 550) had the lowest relapse rate and lowest accrued motor disability. Survival analysis of African/Caribbean outside Africa/Caribbean vs those in the Caribbean showed a significant difference in the composite endpoint (p = 0.024,log-rank test), not apparently related to treatment differences. No significant differences between native and those residing outside Asia were found for other racial groups. CONCLUSION:This NMOSD study reports the effects of place of residence on the outcomes in different races. Place of residence may not be a significant driver of disability among Asian patients, while it may influence African/Caribbean patient outcomes. Validating these findings could help distinguish between genetic causes and potentially modifiable environmental factors.

While complement-dependent cytotoxicity (CDC) is a known effector mechanism in aquaporin-4immunoglobulin (Ig)G-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD), the role of CDC in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is less clear. We determined complement C3 and C4 plasma concentrations in patients with clinically stable AQP4-IgG+ NMOSD (n = 16), MOGAD (n = 15), early multiple sclerosis (MS, n = 19) and in healthy controls (HC, n = 18). C4 was lower in AQP4-IgG+ NMOSD than in MOGAD, MS and HC (p < 0.05, pairwise comparisons). C3 was lower in AQP4-IgG+ NMOSD than in MS (p = 0.034). These findings suggest subtle complement consumption in clinically stable AQP4-IgG+ NMOSD, but not in MOGAD.

Background: Neuromyelitis optica spectrum disorder (NMOSD) is a clinically defined, inflammatory central nervous system (CNS) disease of unknown cause, associated with humoral autoimmune findings such as anti-aquaporin 4 (AQP4)-IgG. Recent clinical trials showed a benefit of anti-B cell and anti-complement-antibodies in NMOSD, suggesting relevance of anti-AQP4-IgG in disease pathogenesis. Objective: AQP4-IgG in NMOSD is clearly defined, yet up to 40% of the patients are negative for AQP4-IgG. This may indicate that AQP4-IgG is not disease-driving in NMOSD or defines a distinct patient endotype. Methods: We established a biobank of 63 clinically well-characterized NMOSD patients with an extensive annotation of 351 symptoms, patient characteristics, laboratory results and clinical scores. We used phylogenetic clustering, heatmaps, principal component and longitudinal causal interference analyses to test for the relevance of anti-AQP4-IgG. Results: Anti-AQP4-IgG was undetectable in 29 (46%) of the 63 NMOSD patients. Within anti-AQP4-IgG-positive patients, anti-AQP4-IgG titers did not correlate with clinical disease activity. Comparing anti-AQP4-IgG-positive vs. -negative patients did not delineate any clinically defined subgroup. However, anti-AQP4-IgG positive patients had a significantly (p = 0.022) higher rate of additional autoimmune diagnoses. Conclusion: Our results challenge the assumption that anti-AQP4-IgG alone plays a disease-driving role in NMOSD. Anti-AQP4-IgG might represent an epiphenomenon associated with NMOSD, may represent one of several immune mechanisms that collectively contribute to the pathogenesis of this disease or indeed, anti-AQP4-IgG might be the relevant factor in only a subgroup of patients.

Background Neuropathic pain (NP) is frequent in neuromyelitis optica spectrum disorders (NMOSD). The ventral posterior nucleus (VPN) of the thalamus receives sensory afferences from the spinothalamic tracts and is associated with central pain in other conditions. Objective To investigate associations between NP and VPN volume in aquaporin-4-IgG- positive (AQP4-IgG+) NMOSD. Methods This cross-sectional study included 32 AQP4-IgG+ NMOSD patients and 37 healthy controls. NP intensity was determined by the PainDetect Questionnaire. Spinal cord lesion number and location as well as VPN volume were assessed by MRI, the latter using a multi-atlas-based automated segmentation. Results Twenty-five patients (78%) suffered from NP and seven had no pain. Mean VPN volume did not differ between patients with and without NP (p=0.533) or between patients and controls. However, mean VPN volume correlated with average (rho=-0.486, p=0.019) and worst pain intensity (rho=-0.593, p=0.003). Of note, no other thalamic nuclei volumes correlated with measures of pain intensity. Compared to pain-free patients, patients with NP had more lesions involving the thoracic spinal cord (p=0.007). The relationships between VPN and pain intensity measures remained after adjustment for age, myelitis count, and spinal cord lesion location. Conclusion Our data support a model where thoracic spinal cord lesions are associated with the development of NP in AQP4-IgG+ NMOSD and the VPN plays a role in the modulation of NP intensity. VPN volume as assessed in our study may be a clinically meaningful imaging marker of pain severity in AQP4-IgG+ NMOSD.

Objective To differentiate between visual cortical network topology changes following optic neuritis (ON) stemming from different inflammatory disease types, we used mathematical graph theory-based tools to analyze functional imaging data. Methods Sixty-two patients were recruited into this cross-sectional study, 23 of whom had neuromyelitis optica spectrum disorder (NMOSD) with ON, 18 with clinically isolated syndrome (CIS)-ON, and 21 with other CIS episodes. Twenty-six healthy controls (HCs) were also recruited. All participants underwent resting-state functional MRI. Visual networks were defined using 50 visual regions of interest. Analysis included graph theory metrics, including degree, density, modularity, and local and global efficiency. Results Visual network density shows decreased connectivity in all patient groups compared with controls. A higher degree of connections is seen in both ON groups (CIS and NMOSD) compared with the the non-ON group. This pattern is most pronounced in dorsal-lateral regions. Information transfer efficiency and modularity were reduced in both CIS groups, but not in the NMOSD group, compared with the HC group. Conclusions Visual network density appears affected by the neurologic deficit sustained (ON), and connectivity changes are more evident in dorsal-lateral regions. Efficiency and modularity appear to be associated with the specific disease type (CIS vs NMOSD). Thus, topological cortical changes in the visual system are associated with the type of neurologic deficit within the limits set on them by the underlying pathophysiology. We suggest that cortical patterns of activity should be considered in the outcome of the patients despite the localized nature of ON.

Objectives We aimed to evaluate optic chiasm (OC) measures as potential imaging marker for anterior optic pathway damage assessment in the context of neuromyelitis optica spectrum disorders (NMOSD). Materials and method This cross-sectional study included 39 patients exclusively with aquaporin 4-IgG seropositive NMOSD of which 25 patients had a history of optic neuritis (NMOSD-ON) and 37 age- and sex-matched healthy controls (HC). OC heights, width, and area were measured using standard 3D T1-weighted MRI. Sensitivity of these measures to detect neurodegeneration in the anterior optic pathway was assessed in receiver operating characteristics analyses. Correlation coefficients were used to assess associations with structural measures of the anterior optic pathway (optic nerve dimensions, retinal ganglion cell loss) and clinical measures (visual function and disease duration). Results OC heights and area were significantly smaller in NMOSD-ON compared to HC (NMOSD-ON vs. HC p < 0.0001). An OC area smaller than 22.5 mm 2 yielded a sensitivity of 0.92 and a specificity of 0.92 in separating chiasms of NMOSD-ON from HC. OC area correlated well with structural and clinical measures in NMOSD-ON: optic nerve diameter ( r = 0.4, p = 0.047), peripapillary retinal nerve fiber layer thickness ( r = 0.59, p = 0 .003), global visual acuity ( r = − 0.57, p = 0.013), and diseases duration ( r = − 0.5, p = 0.012). Conclusion Our results suggest that OC measures are promising and easily accessible imaging markers for the assessment of anterior optic pathway damage. Key Points • Optic chiasm dimensions were smaller in neuromyelitis optica spectrum disorder patients compared to healthy controls. • Optic chiasm dimensions are associated with retinal measures and visual dysfunction. • The optic chiasm might be used as an easily accessible imaging marker of neurodegeneration in the anterior optic pathway with potential functional relevance.

Aims: To explore differences in advanced brain magnetic resonance imaging (MRI) characteristics between myelin oligodendrocyte (MOG) immunoglobulin (IgG) and aquaporin-4 (AQP4) IgG seropositive (+) neuromyelitis optica spectrum disorders (NMOSD). Methods: 33 AQP4-IgG and 18 MOG-IgG seropositive NMOSD patients and 61 healthy control (HC) subjects were included. All 112 participants were scanned with the same standardized MRI-protocol on a 3-Tesla MRI-scanner. Brain volume and diffusion tensor imaging (DTI) parameters were assessed. Results: MOG-IgG+ patients showed reduced parallel diffusivity within white matter tracts compared to HC whereas AQP4-IgG+ showed no significant brain parenchymal damage in DTI analysis. AQP4-IgG+ patients showed reduced whole brain volumes and reduced volumes of several deep gray matter structures compared to HC whereas MOG-IgG+ patients did not show reduced brain or deep gray matter volumes compared to HC. Conclusions: Microstructural brain parenchymal damage in MOG-IgG+ patients was more pronounced than in AQP4-IgG+ patients, compared with HC, whereas normalized brain volume reduction was more severe in AQP4-IgG+ patients. Longitudinal imaging studies are warranted to further investigate this trend in NMOSD. Our results suggest that MOG-IgG+ and AQP4-IgG+ NMOSD patients differ in cerebral MRI characteristics. Advanced MRI analysis did not help to differentiate between MOG-IgG+ and AQP4-IgG+ patients in our study.

Thursday, April 30April 14, 2020Free AccessCharacterization of T cells in NMOSD patients - an emerging role for T cells in disease pathogenesis (4017)Maren Lindner, Urvashi Bhatia, Andreas Schulte-Mecklenbeck, Timo Wirth, Catharina Gross, Tyge Schmidt, Melanie Korsen, … Show All … , Tilman Schneider-Hohendorf, Nicholas Schwab, Sumanta Barman, Orhan Aktas, Norbert Goebels, Anne Winkler, Christine Stadelmann-Nessler, Wolfgang Brueck, Tania Kuempfel, Nadja Siebert, Friedemann Paul, Ingo Kleiter, Heinz Wiendl, Tanja Kuhlmann, Marius Ringelstein, and Luisa Klotz Show FewerAuthors Info & AffiliationsApril 14, 2020 issue94 (15_supplement)https://doi.org/10.1212/WNL.94.15_supplement.4017 Letters to the Editor

Background Neurological disorders with IgG antibodies against myelin-oligodendrocyte glycoprotein (MOG-IgG) have been increasingly recognised as a new type of neuroinflammatory disorder. Objective The study aimed to identify regional and ethnic differences in clinical profiles of MOG-IgG–associated disorders between East Asian (Japanese) and Caucasian (German) patients. Methods Demographic, clinical and therapeutic data from 68 MOG-IgG–positive adults were collected (Japanese, n=44; German, n=24). Results Age and sex were similar between cohorts, with optic neuritis occurring most frequently at onset (Japanese: 61%; German: 58%). However, Japanese patients had a lower annualised relapse rate (0.4 vs 0.8, p=0.019; no relapse, 64% vs 25%, p=0.002) and lower Expanded Disability Status Scale score at the last visit (1.0 vs 2.0; p=0.008), despite similar follow-up periods (mean, 73.9 months vs 73.4 months), than those of German patients, respectively. Cerebral syndromes were more common (27% vs 4%; p=0.021) and myelitis less common (21% vs 50%; p=0.012) in Japanese than in German patients, respectively. Japanese patients were more commonly treated with long-term corticosteroids (73%), whereas German patients were more commonly treated with rituximab or other immunosuppressants (63%). Conclusions Among patients with MOG-IgG, Japanese tended to have a monophasic milder disease, whereas the majority of German patients had a relapsing course and more frequent myelitis, findings compatible with neuromyelitis optica spectrum disorder. Although the attack-prevention treatment regimens were considerably different, genetic and environmental factors may be important to determine clinical phenotypes and disease activity.

Background: Myelin oligodendrocyte glycoprotein antibody (MOG-Ab) disease is an inflammatory autoimmune condition of the central nervous system, defined by antibodies (Abs) against MOG. Of the various clinical phenotypes optic neuritis (ON) is the commonest. We have observed that some patients with MOG-Ab ON present with a severe associated headache. Objective: To highlight the importance of headache in MOG-Ab related optic neuritis. Methods: Clinical and MRI data from MOG-Ab patients with ON (n = 129) were obtained from observational cohort studies and clinical notes at the NeuroCure Clinical Research Center, Charite Berlin and at the Diagnostic and Advisory Service for Neuromyelitis Optica, John Radcliffe Hospital, Oxford. Results: Sixty-four of 129 MOG-Ab patients (49.6%) reported >= 1 headache-related ON. Headache usually started a few days prior to visual loss and extended from the ocular region to the periorbital and fronto-temporal area, sometimes mimicking migraine. Of those, thirty-two patients (50%) reported severe headache. Two patients did not have headache. No headache history was recorded for 63 patients. MRIs performed acutely during headache-related MOG-Ab ON (n = 15) showed anterior ON with extensive swelling and edema of the optic nerve/s in all patients, either unilaterally (n = 5) or bilaterally (n = 10). Peri-optic cerebro-spinal fluid (CSF) was undetectable due to the inflammatory extension in 12 out of 15 patients. Conclusion: Our findings indicate that acute MOG-Ab ON shows florid intra-orbital and peri-optic inflammation, likely to involve meninges and nociceptive fibers around the optic nerve. This may explain the frequent and often severe headache that precedes the visual deficit, sometimes misdiagnosed as migraine.

Neuromyelitis optica spectrum disorders lack imaging biomarkers associated with disease course and supporting prognosis. This complex and heterogeneous set of disorders affects many regions of the central nervous system, including the spinal cord and visual pathway. Here, we use graph theory-based multimodal network analysis to investigate hypothesis-free mixed networks and associations between clinical disease with neuroimaging markers in 40 aquaporin-4-immunoglobulin G antibody seropositive patients (age = 48.16 ± 14.3 years, female:male = 36:4) and 31 healthy controls (age = 45.92 ± 13.3 years, female:male = 24:7). Magnetic resonance imaging measures included total brain and deep grey matter volumes, cortical thickness and spinal cord atrophy. Optical coherence tomography measures of the retina and clinical measures comprised of clinical attack types and expanded disability status scale were also utilized. For multimodal network analysis, all measures were introduced as nodes and tested for directed connectivity from clinical attack types and disease duration to systematic imaging and clinical disability measures. Analysis of variance, with group interactions, gave weights and significance for each nodal association (hyperedges). Connectivity matrices from 80% and 95% F-distribution networks were analyzed and revealed the number of combined attack types and disease duration as the most connected nodes, directly affecting changes in several regions of the central nervous system. Subsequent multivariable regression models, including interaction effects with clinical parameters, identified associations between decreased nucleus accumbens (β = -0.85, P = 0.021) and caudate nucleus (β = -0.61, P = 0.011) volumes with higher combined attack type count and longer disease duration, respectively. We also confirmed previously reported associations between spinal cord atrophy with increased number of clinical myelitis attacks. Age was the most important factor associated with normalized brain volume, pallidum volume, cortical thickness and the expanded disability status scale score. The identified imaging biomarker candidates warrant further investigation in larger-scale studies. Graph theory-based multimodal networks allow for connectivity and interaction analysis, where this method may be applied in other complex heterogeneous disease investigations with different outcome measures.