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Background: Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may be associated with relapsing disease, but clinical progression independent of relapse activity is rare. Objectives: To report progressive disease in a patient with MOGAD. Methods: A single retrospective case report. Results: At 4 years of age, the patient had a single episode of acute disseminated encephalomyelitis. She remained well until age 17 years but over the next 9 years developed progressive spastic quadriparesis, cognitive and bulbar dysfunction. Brain imaging showed a leukodystrophy-like pattern of white matter abnormality with contrast enhancement at different time points. Myelin oligodendrocyte glycoprotein (MOG)-IgG was repeatedly positive by live cell-based assay. Conclusion: Secondary progression may be a rare presentation of MOG-IgG-associated disease.

Autoimmune neurological disorders are commonly treated with immunosuppressive therapy. In patients with refractory conditions, standard immunosuppression is often insufficient for complete recovery or to prevent relapses. These patients rely on other treatments to manage their disease. While treatment of refractory cases differs between diseases, intravenous immunoglobulin, plasma exchange (PLEX), and immune-modulating treatments are commonly used. In this review, we focus on five autoimmune neurological disorders that were the themes of the 2018 Midlands Neurological Society meeting on PLEX in refractory neurology: Autoimmune Encephalitis (AE), Multiple Sclerosis (MS), Neuromyelitis Optica Spectrum disorders (NMOSD), Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) and Myasthenia Gravis (MG). The diagnosis of inflammatory neuropathies is often challenging, and while PLEX can be very effective in refractory autoimmune diseases, its ineffectiveness can be confounded by misdiagnosis. One example is POEMS syndrome (characterized by Polyneuropathy Organomegaly, Endocrinopathy, Myeloma protein, Skin changes), which is often wrongly diagnosed as CIDP; and while CIDP responds well to PLEX, POEMS does not. Accurate diagnosis is therefore essential. Success rates can also differ within ‘one’ disease: e.g. response rates to PLEX are considerably higher in refractory relapsing remitting MS compared to primary or secondary progressive MS. When sufficient efforts are made to correctly pinpoint the diagnosis along with the type and subtype of refractory autoimmune disease, PLEX and other immunotherapies can play a valuable role in the patient management. Graphical abstract

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.

Neuromyelitis optica spectrum disorders (NMOSDs) are caused by immunoglobulin G (IgG) autoantibodies directed against the water channel aquaporin-4 (AQP4). In NMOSDs, discrete clinical relapses lead to disability and are robustly prevented by the anti-CD20 therapeutic rituximab; however, its mechanism of action in autoantibody-mediated disorders remains poorly understood. We hypothesized that AQP4-IgG production in germinal centers (GCs) was a core feature of NMOSDs and could be terminated by rituximab. To investigate this directly, deep cervical lymph node (dCLN) aspirates (n = 36) and blood (n = 406) were studied in a total of 63 NMOSD patients. Clinical relapses were associated with AQP4-IgM generation or shifts in AQP4-IgG subclasses (odds ratio = 6.0; range of 3.3 to 10.8; P < 0.0001), features consistent with GC activity. From seven dCLN aspirates of patients not administered rituximab, AQP4-IgGs were detected alongside specific intranodal synthesis of AQP4-IgG. AQP4-reactive B cells were isolated from unmutated naive and mutated memory populations in both blood and dCLNs. After rituximab administration, fewer clinical relapses (annual relapse rate of 0.79 to 0; P < 0.001) were accompanied by marked reductions in both AQP4-IgG (fourfold; P = 0.004) and intranodal B cells (430-fold; P < 0.0001) from 11 dCLNs. Our findings implicate ongoing GC activity as a rituximab-sensitive driver of AQP4 antibody production. They may explain rituximab’s clinical efficacy in several autoantibody-mediated diseases and highlight the potential value of direct GC measurements across autoimmune conditions.

Improvements in assays for detecting serum antibodies against myelin oligodendrocyte glycoprotein (MOG) have led to the appreciation of MOG‐antibody‐associated disease (MOGAD) as a novel disorder. However, much remains unknown about its etiology. We performed human leukocyte antigen (HLA) analysis in 82 MOGAD patients of European ancestry in the UK population. No HLA class II associations were observed, thus questioning the mechanism of anti‐MOG antibody generation. A weak protective association of HLA‐C*03:04 was observed (OR = 0.26, 95% CI = 0.10‐0.71, pc = 0.013), suggesting a need for continued efforts to better understand MOGAD genetics and pathophysiology.

Background and ObjectivesTo 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).MethodsAnnualized 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.ResultsPatients 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.DiscussionThis study provides Class III evidence that long-term TCZ therapy is safe and reduces relapse probability in MOGAD and AQP4-IgG+ NMOSD.

Background Neuromyelitis optica spectrum disorder (NMOSD) is a rare, neurological disease that places a significant burden on patients, their carers, and healthcare systems. Objectives To estimate patient and carer health utilities and costs of NMOSD within the UK setting. Methods Patients with NMOSD and their carers, recruited via a regional specialist treatment centre, completed a postal questionnaire that included a resource use measure, the EuroQoL (EQ)-5D-5L, EQ-5D-VAS, Vision and Quality of Life Index (VisQoL), Carer Experience Survey (CES) and the Expanded Disability Status Scale (EDSS). The questionnaire asked about respondents’ use of health and community care services, non-medical costs, informal care and work capacity. Data were analysed descriptively. Uncertainties in costs and utilities were assessed using bootstrap analysis. Results 117 patients and 74 informal carers responded to the survey. Patients’ mean EQ-5D-5L and VisQoL health utilities (95% central range) were 0.54 (− 0.29, 1.00) and 0.79 (0.11, 0.99), respectively. EQ-5D-5L utility decreased with increasing EDSS score bandings, from 0.80 (0.75, 0.85) for EDSS ≤ 4.0, to 0.20 (− 0.29, 0.56) for EDSS 8.0 to 9.5. Mean, 3-month total costs were £5623 (£2096, £12,156), but ranged from £562 (£381, £812) to £32,717 (£2888, £98,568) for these EDSS bandings. Carer-reported EQ-5D-5L utility and CES index scores were 0.85 (0.82, 0.89) and 57.67 (52.69, 62.66). Mean, 3-month costs of informal care were £13,150 to £24,560. Conclusions NMOSD has significant impacts on health utilities and NHS and carer costs. These data can be used as inputs to cost-effectiveness analyses of new medicines for NMOSD.

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon antibody-mediated disease of the central nervous system. Long segments of spinal cord inflammation (myelitis), severe optic neuritis, and/or bouts of intractable vomiting and hiccoughs (area postrema syndrome) are classic presentations of the disease and may alert the clinician to the diagnosis. Untreated, approximately 50% of NMOSD patients will be wheelchair users and blind, and a third will have died within 5 years of their first attack. Unlike multiple sclerosis, a progressive clinical course is very unusual and the accrual of disability is related to relapses. Approximately 75% of patients have antibodies against aquaporin-4, a water channel expressed on astrocytes. Relapses are treated aggressively to prevent residual disability with high-dose steroids and often plasma exchange. Relapse prevention is crucial and achieved with long-term immunosuppression. In this article we review the pathogenesis, clinical features, diagnosis and management of NMOSD.

Background and ObjectivesTo determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts.MethodsThe cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG–seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA).ResultsEyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, p < 0.001). GCIP layer loss (−22.7 μm) after the first ON was higher than after the next (−3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC.DiscussionOur results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation.

Background: patients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort. Method: 197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site. Results: no significant thinning of OPL (25.02 +/- 2.03 mu m) or ONL (61.63 +/- 7.04 mu m) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10 +/- 2.00 mu m; ONL: 64.71 +/- 7.87 mu m) or healthy controls (OPL: 24.58 +/- 1.64 mu m; ONL: 63.59 +/- 5.78 mu m). Eyes of patients who were AQP4-IgG+ (19.84 +/- 5.09 mu m, p=0.027) and MOG-IgG+ (19.82 +/- 4.78 mu m, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99 +/- 5.14 mu m); this was not observed elsewhere. Conclusion: the results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates., Guthy Jackson Charitable Foundation (GJCF); German Research Foundation (DFG)

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.

Objective:Since the last epidemiological review of NMO/NMOSD, 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence and basic demographic characteristics of NMOSD, and provide a critical overview of studies.Methods:PubMed, Ovid Medline and EMBASE using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); age-, sex-, and ethnic group-specific incidence or prevalence.Results:We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region [0.73/100 000 person-years (95% CI: 0.45-1.01) and 10/100 000 persons (95% CI: 6.8-13.2)]. The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand [0.037/100 000 person-years (95% CI: 0.036-0.038) and 0.7/100 000 persons (95% CI: 0.66-0.74)]. There was prominent female predominance in adults and the AQP4-Ab seropositive subpopulation. Incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas white Caucasian ethnicity had the lowest. No remarkable trend of incidence was described over time.Conclusion:NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiological studies to identify genetic effects and etiological factors.

Background Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT. Methods In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity. Results The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder. Conclusion Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate. Trial registration NCT01892345 (ClinicalTrials.gov).

Objective: To assess the effect of anti-CD20 B-cell depletion with rituximab (RTX) on relapse rates in myelin oligodendrocyte glycoprotein antibody-associated disorder (MOGAD). Methods: Retrospective review of RTX-treated MOGAD patients from 29 centres in 13 countries. The primary outcome measure was change in relapse rate after starting rituximab (Poisson regression model). Results: Data on 121 patients were analysed, including 30 (24.8%) children. Twenty/121 (16.5%) were treated after one attack, of whom 14/20 (70.0%) remained relapse-free after median (IQR) 11.2 (6.3–14.1) months. The remainder (101/121, 83.5%) were treated after two or more attacks, of whom 53/101 (52.5%) remained relapse-free after median 12.1 (6.3–24.9) months. In this ‘relapsing group’, relapse rate declined by 37% (95%CI=19–52%, p Conclusion: RTX reduced relapse rates in MOGAD. However, many patients continued to relapse despite apparent B-cell depletion. Prospective controlled studies are needed to validate these results.

Neuromyelitis Optica Spectrum Disorder (NMOSD) is an inflammatory demyelinating disease of the central nervous system (CNS) primarily affecting the optic nerves and spinal cord, but also involving other regions of the CNS including the area postrema, periaqueductal gray matter, and hypothalamus. Knowledge related to pediatric manifestations of NMOSD has grown in recent years, particularly in light of newer information regarding the importance of not only antibodies to aquaporin 4 (AQP4-IgG) but also myelin oligodendrocyte glycoprotein (MOG-IgG) in children manifesting clinically with this syndrome. In this review, we describe the current state of the knowledge related to clinical manifestations, diagnosis, and chronic therapies for children with NMOSD, with emphasis on literature that has been published in the last 5 years. Following the review, we propose recommendations for the assessment/follow up clinical care, and treatment of this population.

Neuromyelitis optica spectrum disorder (NMOSD) is an uncommon inflammatory disease of the central nervous system, manifesting clinically as optic neuritis, myelitis, and certain brain and brainstem syndromes. Cases clinically diagnosed as NMOSD may include aquaporin 4 (AQP4)-antibody-seropositive autoimmune astrocytopathic disease, myelin oligodendrocyte glycoprotein (MOG)-antibody-seropositive inflammatory demyelinating disease, and double-seronegative disease. AQP4-antibody disease has a high female-to-male ratio (up to 9:1), and its mean age at onset of ~40 years is later than that seen in multiple sclerosis. For MOG-antibody disease, its gender ratio is closer to 1:1, and it is more common in children than in adults. Its clinical phenotypes differ but overlap with those of AQP4-antibody disease and include acute disseminated encephalomyelitis, brainstem and cerebral cortical encephalitis, as well as optic neuritis and myelitis. Double-seronegative disease requires further research and clarification. Population-based studies over the past two decades report the prevalence and incidence of NMOSD in different populations worldwide. One relevant finding is the varying prevalence observed in different racial groups. Consistently, the prevalence of NMOSD among Whites is ~1/100,000 population, with an annual incidence of

Objective Since the last epidemiologic review of neuromyelitis optica/neuromyelitis optica spectrum disorder (NMO/NMOSD), 22 additional studies have been conducted. We systematically review the worldwide prevalence, incidence, and basic demographic characteristics of NMOSD and provide a critical overview of studies. Methods PubMed, Ovid MEDLINE, and Embase using Medical Subject Headings and keyword search terms and reference lists of retrieved articles were searched from 1999 until August 2019. We collected data on the country; region; methods of case assessment and aquaporin-4 antibody (AQP4-Ab) test; study period; limitations; incidence (per 100,000 person-years); prevalence (per 100,000 persons); and age-, sex-, and ethnic group–specific incidence or prevalence. Results We identified 33 relevant articles. The results indicated the highest estimates of incidence and prevalence of NMOSD in Afro-Caribbean region (0.73/100 000 person-years [95% CI: 0.45–1.01] and 10/100 000 persons [95% CI: 6.8–13.2]). The lowest incidence and prevalence of NMOSD were found in Australia and New Zealand (0.037/100 000 person-years [95% CI: 0.036–0.038] and 0.7/100,000 persons [95% CI: 0.66–0.74]). There was prominent female predominance in adults and the AQP4-Ab–seropositive subpopulation. The incidence and prevalence peaked in middle-aged adults. African ethnicity had the highest incidence and prevalence of NMOSD, whereas White ethnicity had the lowest. No remarkable trend of incidence was described over time. Conclusion NMOSD is a rare disease worldwide. Variations in prevalence and incidence have been described among different geographic areas and ethnicities. These are only partially explained by different study methods and NMO/NMOSD definitions, highlighting the need for specifically designed epidemiologic studies to identify genetic effects and etiologic factors.

International audience; Recombinant interferon alpha is used to treat several immunological, oncological, and infectious diseases,1 and various serious side-effects have been associated with its therapeutic use. We want to bring attention to the development of neuromyelitis optica spectrum disorder (NMOSD) [...]

B-cell depleting anti-CD20 monoclonal antibody therapies are being increasingly used as long-term maintenance therapy for neuroinflammatory disease compared to many non-neurological diseases where they are used as remission-inducing agents. While hypogammaglobulinaemia is known to occur in over half of patients treated with medium to long-term B-cell-depleting therapy (in our cohort IgG 38, IgM 56 and IgA 18%), the risk of infections it poses seems to be under-recognised. Here, we report five cases of serious infections associated with hypogammaglobulinaemia occurring in patients receiving rituximab for neuromyelitis optica spectrum disorders. Sixty-four per cent of the whole cohort of patients studied had hypogammaglobulinemia. We discuss the implications of these cases to the wider use of anti-CD20 therapy in neuroinflammatory disease.

Antibodies to myelin oligodendrocyte glycoprotein (MOG-IgG) have been described in patients with neuromyelitis optica spectrum disorders (NMOSD) without aquaporin-4 antibodies (AQP4-IgG). We aimed to identify the proportion of AQP4-IgG-negative NMOSD patients who are seropositive for MOG-IgG. In a cross sectional study, we reviewed all patients seen in the National NMO clinic over the last 4 years (after the availability of MOG-IgG testing), including clinical information, MRI, and antibody tests. 261 unique patients were identified. 132 cases satisfied the 2015 NMOSD diagnostic criteria. Of these, 96 (73%) were AQP4-IgG positive and 36 (27%) were AQP4-IgG negative. These 36 patients were tested for MOG-IgG and 15/36 (42%) tested positive. 20% (25/125) of the patients who did not satisfy NMOSD criteria had MOG-IgG. Approximately half of seronegative NMOSD is MOG-Ig seropositive and one in five of non-NMOSD/non-MS demyelination is MOG-IgG positive. Since MOG-associated demyelinating disease is likely different from AQP4-IgG disease in terms of underlying disease mechanisms, relapse risk and possibly treatment, testing for MOG-IgG in patients with AQP4-IgG-negative NMOSD and other non-MS demyelination may have significant implications to management and clinical trials.

ObjectiveTo define the frequency, duration, and severity of intractable nausea, vomiting, or hiccups in aquaporin-4–immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and propose diagnostic criteria and a severity scale for area postrema syndrome (APS).MethodsAn International NMOSD database was interrogated for frequency of APS. Patients with AQP4-IgG–positive NMOSD completed an APS symptom questionnaire. Nausea and vomiting severity was derived from the Pregnancy-Unique Quantification of Emesis and Nausea (PUQE) score. The diagnostic criteria, severity scale, and immunotherapy response was applied to a prospective validation cohort of patients from multiple centers.ResultsAnalysis of an international database for AQP4-IgG–seropositive NMOSD (n = 430) revealed a high prevalence of isolated APS attacks (onset 7.1%–10.3%; subsequent 9.4%–14.5%) across continents. For 100 patients with 157 episodes of APS, nausea (n = 127, 81%) lasted for a median of 14 days (range 2–365), vomiting (113, 72%) with a median of 5 episodes/d (2–40) lasted 1–20 minutes, and hiccups (102, 65%) lasted a median of 14 days (2–365). Symptoms consistently and completely resolved following immunotherapy. Data were used to propose APS diagnostic criteria and repurpose PUQE score (hiccups severity grade based on symptom duration). The clinical utility was demonstrated in a prospective validation cohort.ConclusionIsolated APS attacks are frequently encountered both at onset and during the NMOSD course. The diagnostic criteria proposed here will assist clinicians in recognizing APS. Diagnosis of an APS attack earlier than 48 hours is possible if a dorsal medulla lesion is detected. Accurate diagnosis and evaluation of APS attack severity will assist in outcome measurement in NMOSD clinical trials.

Background Currently, there is no evidence-based definition of attacks in neuromyelitis optica spectrum disorders (NMOSD). However, to allow their stringent use as valid endpoints, recent phase III trials in NMOSD defined criteria and adjudication of these events in context of these trials. The objective of this study was to investigate diagnostic procedures currently used in routine adjudication of suspected attacks in NMOSD, and to assess whether the standardized attack-criteria from two pivotal trials may be feasible in routine clinical care. Methods Four global clinical networks were surveyed using an online questionnaire: NEMOS (Neuromyelitis Optica Study Group), IMSVISUAL (International Multiple Sclerosis Visual System Consortium), GJCF-ICC (Guthy Jackson Charitable Foundation-International Clinical Consortium) and NOMADMUS (Devic's neuromyelitis optica and related neurological disorders study group). Results Seventy-eight responses were received from September 2018 to February 2019. Median annual number of patients seen with suspected attacks was 10 (range 2–130). Immediate access to MRI was reported by 59.0% of all participants and the majority performs an MRI for new patients with a myelitis, optic neuritis or other symptoms. In patients with established NMOSD diagnosis presenting during routine clinical visits only 10.5% or 9.2% always perform a brain or spinal cord MRI, respectively. Digital records of patients' visits are kept by 98.7% of all participants and 88.5% have direct access to case history. An expert neurological examination is performed for 94.9% of participants reported to perform an expert neurological examination in patients with acute attacs, while only 30.8% seem to perform the assessments according to the Neurostatus-Expanded Disability Status Scale (EDSS) definitions.. The Sakura Star study criteria which are based solely on clinical assessment could be feasible in routine care, provided that more centers use the Neurostatus-EDSS, while only 9% of participants fulfill all requirements for adjudication of the N-Momentum study criteria. Conclusions The high percentage of centers using digital records is encouraging. However, routine adjudication of clinical events in NMOSD seems highly heterogeneous. MRI is the mainstay in the majority of queried centers, but its immediate availability is limited. Only a minority of centers are equipped for trial-grade classification of attacks, if this is not solely clinically based. Thus, standard and feasible guidelines for attack adjudication are urgently needed to standardize routine care, optimize future clinical trials and allow studying long-term safety and efficacy of newly approved drugs in phase IV trials.

The complement system is a powerful member of the innate immune system. It is highly adept at protecting against pathogens, but exists in a delicate balance between its protective functions and overactivity, which can result in autoimmune disease. A cascade of complement proteins that requires sequential activation, and numerous complement regulators, exists to regulate a proportionate response to pathogens. In spite of these mechanisms there is significant evidence for involvement of the complement system in driving the pathogenesis of variety of diseases including neuromyelitis optica spectrum disorders (NMOSD) and myasthenia gravis (MG). As an amplification cascade, there are an abundance of molecular targets that could be utilized for therapeutic intervention. Clinical trials assessing complement pathway inhibition in both these conditions have recently been completed and include the first randomized placebo-controlled trial in NMOSD showing positive results. This review aims to review and update the reader on the complement system and the evolution of complement-based therapeutics in these two disorders.

Myelin oligodendrocyte glycoprotein (MOG) antibody disease (MOG-AD) is now recognised as a nosological entity with specific clinical and paraclinical features to aid early diagnosis. Although no age group is exempt, median age of onset is within the fourth decade of life, with optic neuritis being the most frequent presenting phenotype. Disease course can be either monophasic or relapsing, with subsequent relapses most commonly involving the optic nerve. Residual disability develops in 50-80% of patients, with transverse myelitis at onset being the most significant predictor of long-term outcome. Recent advances in MOG antibody testing offer improved sensitivity and specificity. To avoid misdiagnosis, MOG antibody testing should be undertaken in selected cases presenting clinical and paraclinical features that are felt to be in keeping with MOG-AD, using a validated cell-based assay. MRI characteristics can help in differentiating MOG-AD from other neuroinflammatory disorders, including multiple sclerosis and neuromyelitis optica. Cerebrospinal fluid oligoclonal bands are uncommon. Randomised control trials are limited, but observational open-label experience suggests a role for high-dose steroids and plasma exchange in the treatment of acute attacks, and for immunosuppressive therapies, such as steroids, oral immunosuppressants and rituximab as maintenance treatment.

Using an international data set of 441 patients with AQP4-IgG positive NMOSD, and a collective history of almost 2000 attacks, Palace et al. apply mathematical modelling to predict likelihood of relapse and disability at different time points. Such estimates will help clinicians when counselling patients and aid drug trial design., Pathogenic antibodies targeting the aquaporin-4 water channel on astrocytes are associated with relapsing inflammatory neuromyelitis optica spectrum disorders. The clinical phenotype is characterized by recurrent episodes of optic neuritis, longitudinally extensive transverse myelitis, area postrema attacks and less common brainstem and cerebral events. Patients often develop major residual disability from these attacks, so early diagnosis and initiation of attackpreventing medications is important. Accurate prediction of relapse would assist physicians in counselling patients, planning treatment and designing clinical trials. We used a large multicentre dataset of 441 patients from the UK, USA, Japan and Martinique who collectively experienced 1976 attacks, and applied sophisticated mathematical modelling to predict likelihood of relapse and disability at different time points. We found that Japanese patients had a lower risk of subsequent attacks except for brainstem and cerebral events, with an overall relative relapse risk of 0.681 (P = 0.001) compared to Caucasians and African patients, who had a higher likelihood of cerebral attacks, with a relative relapse risk of 3.309 (P = 0.009) compared to Caucasians. Female patients had a higher chance of relapse than male patients (P = 0.009), and patients with younger age of onset were more likely to have optic neuritis relapses (P < 0.001). Immunosuppressant drugs reduced and multiple sclerosis disease-modifying agents increased the likelihood of relapse (P < 0.001). Patients with optic neuritis at onset were more likely to develop blindness (P < 0.001), and those with older age of onset were more likely to develop ambulatory disability. Only 25% of long-term disability was related to initial onset attack, indicating the importance of early attack prevention. With respect to selection of patients for clinical trial design, there would be no gain in power by selecting recent onset patients and only a small gain by selecting patients with recent high disease activity. We provide risk estimates of relapse and disability for patients diagnosed and treated with immunosuppressive treatments over the subsequent 2, 3, 5 and 10 years according to type of attack at onset or the first 2-year course, ethnicity, sex and onset age. This study supports significant effects of onset age, onset phenotype and ethnicity on neuromyelitis optica spectrum disorders outcomes. Our results suggest that powering clinical treatment trials based upon relapse activity in the preceding 2 years may offer little benefit in the way of attack risk yet severely hamper clinical trial success.

The field of central nervous system (CNS) inflammatory diseases has recently broadened to include a new condition associated with pathogenic serum antibodies against myelin oligodendrocyte glycoprotein (MOG). This is distinct from multiple sclerosis (MS) and aquaporin-4 (AQP4) antibody neuromyelitis optica spectrum disorders (NMOSD). MOG antibody-associated disease phenotypes are varied and range from classical neuromyelitis optica to acute demyelinating encephalomyelitis and cortical encephalitis. The diagnosis depends on using a reliable, specific and sensitive assay of the antibody. Clinical and imaging features of MOG-associated syndromes overlap with AQP4 antibody NMOSD but can be usually distinguished from MS: in particular, the silent lesions typical of MS that progressively increase lesion volume are rare in MOG antibody disease. The disease can relapse but medium-term immunosuppression appears to be protective. Permanent disability, particularly severe ambulatory and visual disability, is less frequent than in AQP4 antibody NMOSD and usually results from the onset attack. However, sphincter and sexual dysfunction after a transverse myelitis is common. Here we review the practical aspects of diagnosing and managing a patient with MOG antibody-associated disease.

Background: The international panel for neuromyelitis optica (NMO) diagnosis has proposed diagnostic criteria for neuromyelitis optica spectrum disorders (NMOSD). Objectives: We assessed the impact of these criteria on diagnostic rates in a large cohort of patients. Methods: We identified and applied the 2006 and 2015 criteria to all patients ( n = 176) seen in the NMO and non-multiple sclerosis central nervous system demyelination clinic (part of the UK NMO service) from January 2013 to May 2015. Results: The 2006 criteria classified 63 of 176 (36%) patients as NMO. A total of 42 patients (67%) were aquaporin 4 (AQP4) immunoglobulin G (IgG) +ve and 21 (33%) AQP4 IgG −ve. The 2015 criteria classified 111 of 176 (63%) patients as NMOSD, of which 81 (73%) were AQP4 IgG +ve and 30 (27%) were AQP4 IgG −ve. There was an increase of 48 patients (76%) diagnosed as NMOSD using the new criteria. Conclusion: Application of the 2015 criteria led to a rise in diagnosis of NMOSD by 76%. The rise in the AQP4 IgG +ve group contributed 62% and the seronegative group contributed 14%.

Objective Our primary objective was to examine the neuropsychological and psychopathological profile of patients with neuromyelitis optica (NMO) and compare these to multiple sclerosis (MS) and healthy control (HC) groups. We also examined for relationships between cognitive and psychiatric variables and clinical factors including accumulated neurological disability and disease duration. Methods A neuropsychological test battery was administered along with a structured psychiatric interview and quantitative measures of mood symptoms. Results 42 NMO, 42 MS and 42 HC participants were assessed. Cognitive impairments were observed in 67% of NMO patients. The prevalence and profile of cognitive impairments and lifetime prevalence of depression was similar between NMO and MS groups. However, significantly higher rates of recurrent depression and suicidality were observed in NMO patients. Correlational analyses revealed higher levels of anxiety symptoms were associated with shorter disease duration in NMO, while higher depression symptom levels were associated with higher neurological disability and poorer cognition. Conclusions Our results demonstrate substantial cognitive and psychiatric comorbidities in NMO patients. Similar rates of lifetime and current depression between NMO and MS appear to mask greater underlying psychiatric burden in NMO and further understandings of the course of neurobehavioural comorbidities is required to better comprehend the additional morbidity in NMO. Our data support a role for cognitive and psychiatric assessments in the comprehensive care of NMO patients.

Background Transverse myelitis (TM) associated with Neuromyelitis Optica (NMO) can be severe and is well known to reduce mobility early in the disease. However the burden of bladder and bowel dysfunction is unknown and overlooked. We studied the frequency of bladder and bowel dysfunction and their impact on quality of life. Methods A cross-sectional study of 60 patients who had AQP4-IgG positive NMO associated TM was performed using the Bladder Control Scale, Lower Urinary Tract Quality of Life, Bowel Control Scale and Neurogenic Bowel Score, Short-Form-36 Health Survey and EDSS. The relationships between the variables were analysed with multiple linear regression. Results Fifty women and 10 men participated. 78% (47/60) patients reported bladder symptoms and a similar number reported bowel problems. 87% (52/60) patients reported either bladder or bowel dysfunction. 65% (39/60) developed residual symptoms after the first episode of myelitis and the remaining by the second episode. Both bladder and bowel dysfunction reduced quality of life and required modification of lifestyle in 83% (39/47) and 70% (33/47) respectively. Conclusion Bladder and bowel dysfunction is very common in NMO associated myelitis developing early in the disease and significantly affects quality of life.

Background Neuromyelitis optica (NMO) is an auto-immune disease that can cause severe visual and mobility impairments. Research on health-related quality of life (HRQoL) in NMO is scarce, limiting knowledge on factors influencing HRQoL and support needs. Aim This study provides the first qualitative exploration of HRQoL in NMO, conducted to provide a conceptual framework for the development of an NMO patient-reported outcome measure. Method Fifteen people with NMO (aged 18–74; 11 women, 4 men) participated in semi-structured interviews; data were analysed using constant comparative analysis. Results HRQoL in NMO is a multifaceted concept incorporating highly subjective perceptions of normality and meaning. Four major themes were identified: impact of physical symptoms on daily living, utilizing support to achieve independence, expectations for life and meaningful roles in life and purpose. Discussion Themes highlighted the importance of perceived normality, and its relationship to attaining life goals comparable to peers, as underpinning evaluations of HRQoL. Many people with severe disability reported a high HRQoL, suggesting the inappropriateness of assuming a negative HRQoL on the basis of an individual's neurological impairment. Conclusions These findings further the conceptual understanding of HRQoL in NMO, informing patient-care approaches and the development of an NMO-specific patient-reported outcome measure.

ObjectiveTo assess the value of the central vein sign (CVS) on a clinical 3T scanner to distinguish between multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD).MethodsEighteen aquaporin-4-antibody-positive patients with NMOSD, 18 patients with relapsing-remitting MS, and 25 healthy controls underwent 3T MRI. The presence of a central vein in white matter lesions on susceptibility-weighted imaging, defined as a thin hypointense line or a small dot, was recorded.ResultsThe proportion of lesions with the CVS was higher in MS than NMOSD (80% vs 32%, p < 0.001). A greater proportion of lesions with the CVS predicted the diagnosis of MS, rather than NMOSD (odds ratio 1.10, 95% confidence interval [CI] 1.04 to 1.16, p = 0.001), suggesting that each percent unit increase in the proportion of lesions with the CVS in an individual patient was associated with a 10% increase in the risk of the same patient having MS. If more than 54% of the lesions on any given scan show the CVS, then the patient can be given a diagnosis of MS with an accuracy of 94% (95% CIs 81.34, 99.32, p < 0.001, sensitivity/specificity 90%/100%).ConclusionThe clinical value of the CVS in the context of the differential diagnosis between MS and NMOSD, previously suggested using 7T scanners, is now extended to clinical 3T scanners, thereby making a step towards the use of CVS in clinical practice.Classification of evidenceThis study provides Class III evidence that the CVS on 3T MRI accurately distinguishes patients with MS from those with seropositive NMOSD.

Importance: Antibodies to myelin oligodendrocyte glycoprotein IgG (MOG-IgG) are increasingly detected in patients with non–multiple sclerosis–related demyelination, some of whom manifest a neuromyelitis optica (NMO) phenotype. Cortical involvement, encephalopathy, and seizures are rare in aquaporin 4 antibody (AQP4-IgG)–related NMO in the white European population. However, the authors encountered several patients with seizures associated with MOG-IgG disease. Objective: To compare incidence of seizures and encephalitis-like presentation, or both between AQP4-IgG–positive and MOG-IgG–positive patients. Design, Setting, and Participants: Retrospective case series of all patients who were seropositive for MOG-IgG (n = 34) and the last 100 patients with AQP4-IgG disease (NMO spectrum disorder) seen in the NMO service between January 2013 and December 2016, and analysis was completed January 4, 2017. All patients were seen in a tertiary neurological center, The Walton Centre NHS Foundation Trust in Liverpool, England. Main Outcomes and Measures: The difference in seizure frequency between the AQP4-IgG–positive and MOG-IgG–positive patient groups was determined. Results: Thirty-four patients with MOG-IgG disease (20 female) with a median age at analysis of 30.5 years (interquartile range [IQR], 15-69 years), and 100 AQP4-IgG–positive patients (86 female) with a median age at analysis of 54 years (IQR, 12-91 years) were studied. Most patients were of white race. Five of the 34 patients with MOG-IgG (14.7%) had seizures compared with 1 patient with AQP4-IgG (2-sided P

Progressive myelopathy can be a manifestation of a variety of disorders including progressive multiple sclerosis. However it is extremely uncommon for a single lesion to cause a progressive myelopathy in MS. Such a myelopathy, i.e. a progressive neurological deficit from a solitary demyelinating lesion, not fulfilling the International diagnostic criteria for MS or Neuromyelitis Optica was first reported in 2012 and termed 'solitary sclerosis'.We report 3 further cases of progressive myelopathy fulfilling the diagnostic criteria for solitary sclerosis.Two patients had a single demyelinating lesion in the cervical cord and the third patient had it in the brain stem. All patients had serial MRI scans showing no dissemination or progression of lesions. Extensive diagnostic tests including aquaporin 4 antibodies were negative in all. At last follow-up at a median of 3.8 years, all patients continued to clinically progress despite immunosuppressive treatment.Solitary demyelinating lesions can cause a progressive myelopathy without clinical or radiological evidence of dissemination. Importantly, clinicians, both surgical and medical should be aware of such a diagnosis, to avoid invasive and often harmful tests particularly biopsies.

A condition associated with an autoantibody against myelin oligodendrocyte glycoprotein has been recently recognized as a new inflammatory disease of the central nervous system, but the disease course and disability outcomes are largely unknown. In this study we investigated clinical characteristics of myelin oligodendrocyte glycoprotein antibody disease on a large cohort of patients from the United KingdomWe obtained demographic and clinical data on 252 United Kingdom patients positive for serum immunoglobulin G1 myelin oligodendrocyte glycoprotein antibodies as tested by the Autoimmune Neurology Group in Oxford. Disability outcomes and disease course were analysed in more detail in a cohort followed in the Neuromyelitis Optica Oxford service (n = 75), and this included an incident cohort who were diagnosed at disease onset (n = 44)Myelin oligodendrocyte glycoprotein antibody disease affects women (57%) slightly more often than men, shows no ethnic bias and typically presents with isolated optic neuritis (55%, bilateral in almost a half), transverse myelitis (18%) or acute disseminated encephalomyelitis-like presentations (18%). In the total Oxford cohort after a median disease duration of 28 months 47% patients were left with permanent disability in at least one of the following: 16% patients had visual acuity ≤ 6/36 in at least one eye, mobility was limited in 7% (i.e. expanded disability status scale ≥ 4.0), 5% had expanded disability status scale ≥ 6.0, 28% had permanent bladder issues, 20% bowel dysfunction, and 21% of males had erectile dysfunction. Transverse myelitis at onset was a significant predictor of long-term disability. In the incident cohort 36% relapsed after median disease duration of 16 months. The annualized relapse rate was 0.2. Immunosuppression longer than 3 months following the onset attack was associated with a lower risk of a second relapse. Myelin oligodendrocyte glycoprotein antibody disease has a moderate relapse risk, which might be mitigated by medium term immunosuppression at onset. Permanent disability occurs in about half of patients and more often involves sphincter and erectile functions than vision or mobility.

Though pain in neuromyelitis optica (NMO) has been described in two recent reports, the proportion with true neuropathic pain (NP), its features, impact on activities of daily living (ADL) and quality of life has not been well characterised. A cross-sectional study of 50 NMO patients with transverse myelitis was performed using Douleur Neuropathique 4, Brief Pain Inventory, Extended Disability Status Scale and Short Form 36. NP was identified in 62% of patients. Pain was constant in 68% affecting most ADL. Pain was associated with significant reduction of the SF36 Mental Composite Score. The high prevalence of NP and associated disability necessitates an in-depth enquiry in patients with NMO.

Neuromyelitis optica typically presents at a median age of 40-50 years. The myelitis is usually of acute onset, long (>3 vertebral segments) and causes severe sensorimotor and bladder and bowel disturbances. We describe a 73-year-old Caucasian woman with aquaporin-4 antibody-positive neuromyelitis optica whose index event was intermittent paroxysmal tonic spasms (and no other myelitis features) that recurred for 6 months and was associated with a short spinal cord lesion on MRI. This case reiterates recent observations that neuromyelitis optica can occur in older persons, and its myelitis can be 'short' and clinically mild.

Neuromyelitis optica (NMO) is an uncommon, demyelinating disease that causes long-term disability in adults. Though much has recently been learned about its pathogenesis, there are still only a few studies regarding the epidemiology of NMO. The aim of the study was to describe the epidemiology of NMO among adults in the Merseyside county of the United kingdom. Multiple overlapping sources of data were used including hospital records of The Walton Centre for Neurology and Neurosurgery in Liverpool, regional district general hospital data, central Aquaporin-4 antibody testing laboratory data and the British Neurological Surveillance Unit- to identify adults with a first-ever-in-a-lifetime diagnosis of NMO. As of December 31, 2010, there were eight cases (five NMO; three NMO spectrum disorder), indicating a prevalence of 7.2/million (95 % CI 3.1-14.2). Four incident cases of NMO and three incident cases of NMO spectrum disorder were identified in this period, indicating a minimum combined average annual incidence rate of 0.8/million (95 % CI 0.3-1.6). NMO still remains an uncommon condition, but the prevalence is rising with early diagnosis.

Neuromyelitis optica (NMO) has been described as a disease clinically characterised by severe optic neuritis (ON) and transverse myelitis (TM). Other features of NMO include female preponderance, longitudinally extensive spinal cord lesions (>3 vertebral segments), and absence of oligoclonal IgG bands . In spite of these differences from multiple sclerosis (MS), the relationship between NMO and MS has long been controversial. However, since the discovery of NMO-IgG or aquaporin-4 (AQP4) antibody (AQP4-antibody), an NMO-specific autoantibody to AQP4, the dominant water channel in the central nervous system densely expressed on end-feet of astrocytes, unique clinical features, MRI and other laboratory findings in NMO have been clarified further. AQP4-antibody is now the most important laboratory finding for the diagnosis of NMO. Apart from NMO, some patients with recurrent ON or recurrent longitudinally extensive myelitis alone are also often positive for AQP4-antibody. Moreover, studies of AQP4-antibody-positive patients have revealed that brain lesions are not uncommon in NMO, and some patterns appear to be unique to NMO. Thus, the spectrum of NMO is wider than mere ON and TM. Pathological analyses of autopsied cases strongly suggest that unlike MS, astrocytic damage is the primary pathology in NMO, and experimental studies confirm the pathogenicity of AQP4-antibody. Importantly, therapeutic outcomes of some immunological treatments are different between NMO and MS, making early differential diagnosis of these two disorders crucial. We provide an overview of the epidemiology, clinical and neuroimaging features, immunopathology and therapy of NMO and NMO spectrum disorders.

Importance Neuromyelitis optica spectrum disorders (NMOSD) can present with very similar clinical features to multiple sclerosis (MS), but the international diagnostic imaging criteria for MS are not necessarily helpful in distinguishing these two diseases. Objective This multicentre study tested previously reported criteria of ‘(1) at least 1 lesion adjacent to the body of the lateral ventricle and in the inferior temporal lobe; or (2) the presence of a subcortical U-fibre lesion or (3) a Dawson9s finger-type lesion’ in an independent cohort of relapsing-remitting multiple sclerosis (RRMS) and AQP4-ab NMOSD patients and also assessed their value in myelin oligodendrocyte glycoprotein (MOG)-ab positive and ab-negative NMOSD. Design Brain MRI scans were anonymised and scored on the criteria by 2 of 3 independent raters. In case of disagreement, the final opinion was made by the third rater. Participants 112 patients with NMOSD (31 AQP4-ab-positive, 21 MOG-ab-positive, 16 ab-negative) or MS (44) were selected from 3 centres (Oxford, Strasbourg and Liverpool) for the presence of brain lesions. Results MRI brain lesion distribution criteria were able to distinguish RRMS with a sensitivity of 90.9% and with a specificity of 87.1% against AQP4-ab NMOSD, 95.2% against MOG-ab NMOSD and 87.5% in the heterogenous ab-negative NMOSD cohort. Over the whole NMOSD group, the specificity was 89.7%. Conclusions This study suggests that the brain MRI criteria for differentiating RRMS from NMOSD are sensitive and specific for all phenotypes.

IMPORTANCE: Chronic, intractable neuropathic pain is a common and debilitating consequence of neuromyelitis optica spectrum disorder (NMOSD) myelitis, with no satisfactory treatment; few studies have yet to explore its aetiology. OBJECTIVE: To establish if myelitis-associated chronic pain in NMOSD is related to the craniocaudal location of spinal cord lesions. METHOD: (1) Retrospective cohort of 76 aquaporin 4-antibody (AQP4-Ab)-positive patients from Oxford and Liverpool's national NMOSD clinics, assessing current pain and craniocaudal location of cord lesion contemporary to pain onset. (2) Focused prospective study of 26 AQP4-Ab-positive Oxford patients, a subset of the retrospective cohort, assessing current craniocaudal lesion location and current pain. RESULTS: Patients with isolated thoracic cord myelitis at the time of pain onset were significantly more disabled and suffered more pain. Cervical and thoracic lesions that persisted from pain onset to 'out of relapse' follow-up (current MRI) had highly significant (p CONCLUSIONS: Persistent, caudally located (ie, thoracic) cord lesions in AQP4-Ab-positive patients associate with high postmyelitis chronic pain scores, irrespective of number of myelitis relapses, lesion length and lesion burden. Although disability correlated with pain in isolation, it became an insignificant predictor of pain when analysed alongside craniocaudal location of lesions.

Neuromyelitis optica (NMO) is a relapsing demyelinating disorder with a predilection for the optic nerves and spinal cord, associated with autoantibodies to aquaporin-4 (AQP4) water channels in most cases. It affects all races and ages, but has a striking female preponderance and is distinct from multiple sclerosis (MS). This is a pragmatic guide to treating NMO and the associated NMO spectrum disorders (NMOSDs); these include limited forms of the syndrome, such as recurrent longitudinally extensive transverse myelitis (LETM), recurrent severe optic neuritis (ON) or atypical presentations associated with serum AQP4 antibodies. Because these disorders are rare, there is no available evidence from randomised controlled trials. In contrast to MS, NMO has a high early morbidity and mortality because of severely disabling relapses and lacks a progressive phase. For example, studies report death in 25–30% of patients, after a mean of 5 years from onset.1 ,2 About half of the patients develop significant walking difficulties (at a mean time from onset of 7 years) and many patients become dependent on wheelchairs (figure 1). Visual impairment is also common, with blindness affecting at least one eye in 60–70%, at a mean time from onset of 5 years.1–3 Although most available studies (observational and retrospective) include patients treated at various times from onset, immunosuppressive treatments clearly dramatically reduce relapses, that is, around a sixfold reduction compared with pretreatment.4–8 Thus, aggressive treatment of relapses and effective prevention of relapses is the prime aim of treatment and is our single most important message. For the purposes of this review, we assume that the diagnosis of NMO or NMOSD is correct, and that similar disorders such as MS (for which the treatment is different) are excluded. The rarity of NMO and the importance of optimising treatment makes specialist input important. In …

Background: Few data are available for patients with a late onset (≥ 50 years) of neuromyelitis optica (LONMO) or neuromyelitis optica spectrum disease (LONMOSD), defined by an optic neuritis/longitudinally extensive transverse myelitis with aquaporin-4 antibodies (AQP4-Ab). Objective: To characterize LONMO and LONMOSD, and to analyze their predictive factors of disability and death. Methods: We identified 430 patients from four cohorts of NMO/NMOSD in France, Germany, Turkey and UK. We extracted the late onset patients and analyzed them for predictive factors of disability and death, using the Cox proportional model. Results: We followed up on 63 patients with LONMO and 45 with LONMOSD during a mean of 4.6 years. This LONMO/LONMOSD cohort was mainly of Caucasian origin (93%), women (80%), seropositive for AQP4-Ab (85%) and from 50 to 82.5 years of age at onset. No progressive course was noted. At last follow-up, the median Expanded Disability Status Scale (EDSS) scores were 5.5 and 6 in the LONMO and LONMOSD groups, respectively. Outcome was mainly characterized by motor disability and relatively good visual function. At last follow-up, 14 patients had died, including seven (50%) due to acute myelitis and six (43%) because of opportunistic infections. The EDSS 4 score was independently predicted by an older age at onset, as a continuous variable after 50 years of age. Death was predicted by two independent factors: an older age at onset and a high annualized relapse rate. Conclusion: LONMO/LONMOSD is particularly severe, with a high rate of motor impairment and death.

Neuromyelitis optica (NMO) and its spectrum disorder (NMOSD) is a severe autoimmune inflammatory disorder of the central nervous system, with recurrent attacks mainly focused on the optic nerves and spinal cord. Untreated, it has a high morbidity and mortality. Serum aquaporin-4 (AQP4) antibodies are present in the majority of patients, are recognised as pathogenic and are a predictor of further relapses.1 Most specialists treat AQP4 antibody-positive patients early and aggressively with immunosuppression to prevent further attacks. There have been no randomised trials in NMO, but prednisolone, azathioprine, mycophenolate mofetil, methotrexate and rituximab are among the therapies currently used and appear to have comparable efficacy.2 ,3 Because of the potentially devastating nature of NMO relapses, many clinicians would consider a single relapse on treatment to represent treatment failure and an indication to alter therapy, particularly if the relapse is severe and the therapy has had adequate time to work. This alteration can take the form of an increase in dosage of current treatment or a switch to an alternative agent. There is an urgent need to identify the most effective treatment regimens, particularly because there are many novel therapeutic candidates being developed, including those which act on the antibody-producing or complement pathways, and an AQP4 monoclonal antibody blocker.4 Current NMO study designs under discussion vary, with some regulatory authorities requesting placebo comparator arms but others accepting standard treatments (azathioprine or alternative plus low dose oral steroids)3 as comparators either as add-on or …

Background: Azathioprine (AZA) is a common immunosuppressive drug used for relapse prevention in neuromyelitis optica (NMO). Objectives: The objective of this paper is to assess efficacy, tolerability and retention of AZA in a large NMO cohort. Methods: We conducted a retrospective review of medical records of 103 aquaporin-4 antibody-positive NMO and NMO spectrum disorder (NMOSD) patients treated with AZA. Results: This is the largest reported cohort of AQP4-Ab positive patients treated with AZA. Eighty-nine per cent ( n = 92) had reduction in median annualised relapse rates from 1.5 (IQR 0.6–4.0) to 0 (IQR 0–0.27, p < 0.00005) with treatment. Sixty-one per cent ( n = 63) remained relapse free at a median follow-up of 18 months. Neurological function improved or stabilised in 78%. At last follow-up, treatment was discontinued in 46% ( n = 47). Of these, 62% ( n = 29) were because of side effects, 19% ( n = 9) because of death, 15% ( n = 7) because of ongoing disease activity, and 2% ( n = 1) because of pregnancy. Using Kaplan-Meyer curves, we estimate that 73%, 58%, 47% and 33% of patients will remain on AZA for longer than one, three, five and 10 years, respectively, after initiation of treatment. Conclusions: AZA is a modestly effective treatment for NMO. However, many patients discontinue AZA over time and this seems to reflect poor tolerability more than lack of efficacy.

Aim: Neuromyelitis optica (NMO) is a rare neuro-inflammatory condition characterized by acute relapses causing severe visual or physical disability. The impact on family members and their experiences have not been studied. The study aims were to explore the lived experience of partners of people with NMO and to investigate potential carer burden in this population.Method: A mixed-method design was used; 11 partners of people with NMO completed semi-structured interviews; 54 partners completed Zarit Burden Interview and Hospital Anxiety and Depression Scale.Results: Three qualitative themes influenced partners’ quality of life (QoL): role/relationship; it’s all about them; and the impact of NMO. Life changed dramatically for participants after the first NMO attack, necessitating responsibility for physical, financial, social, and emotional support. As NMO symptoms improved and stabilized, freedom and QoL for spouses also improved, albeit with on-going worries regarding the impact of potential devastating future relapses. Quantitative findings showed mild/moderate carer burden (46%), mild/moderate anxiety (59%), and mild/moderate depression (24%). No partner indicated severe carer burden, anxiety, or depression.Conclusion: Participants regarded themselves as partners rather than carers whom require assessment and support for their emotional and health well-being. Health-care professionals need to acknowledge the important role partners play in the dynamics of the family unit, through greater discussion and inclusion.Implications for RehabilitationNMO has a strong impact on couples, resulting in both physical caregiving needs and anxiety regarding the unpredictability of potential devastating relapses.Partners do not necessarily experience clinically significant “burden”, anxiety or depression, and tools which screen for this may not capture the nature of their experiences.Health-care professionals need to acknowledge, consult, and respect the experience of partners during assessment and implementation of action plans.Partners should be individually assessed based upon the physical and emotional dependency created by NMO to improve their health and well-being.

Background: Neuropathic pruritus (itch) is an uncommon, but well described, symptom in neurology. There are itch-specific neurons in the dorsal horn of the spinal cord. We noted excessive pruritus in patients with neuromyelitis optica (NMO). Objective: We aimed to explore the characteristics of pruritus in NMO patients. Methods: We reviewed case records of a well-defined cohort of 45 serial aquaporin-4 antibody-positive patients visiting the national NMO service. All patients were interviewed. Results: Of the 45 antibody-positive NMO patients, 44 had myelitis and 12 of those 44 (27.3%) patients reported pruritus within a week of other symptoms of transverse myelitis with central cord involvement. In three patients, pruritus was the first symptom of a relapse, while in one case, pruritus was the very first symptom of the index episode of NMO. Conclusion: Neuropathic pruritus seems to be a common, but under-recognised symptom of myelitis associated with NMO.

Neuromyelitis optica and neuromyelitis optica spectrum disorders have been recently associated with the disease-specific autoantibody aquaporin-4, thought to be pathogenic. Identifying this antibody has allowed the clinical phenotype to be broadened. It is clear that some patients with similar clinical features do not have this antibody and may have a different condition with different outcomes and prognosis. Previous clinical neuromyelitis optica and neuromyelitis optica spectrum disorder studies have included such patients. We investigated clinical outcomes and prognostic characteristics of 106 aquaporin-4 antibody-seropositive patients from the UK and Japan. We looked at predictors of disability outcomes, namely visual disability (permanent bilateral visual loss with visual acuity of

Distinguishing aquaporin-4 IgG(AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD) from opticospinal predominant multiple sclerosis (MS) is a clinical challenge with important treatment implications. The objective of the study was to examine whether expert clinicians diagnose and treat NMO/MS overlapping patients in a similar way. 12 AQP4-IgG-negative patients were selected to cover the range of clinical scenarios encountered in an NMO clinic. 27 NMO and MS experts reviewed their clinical vignettes, including relevant imaging and laboratory tests. Diagnoses were categorized into four groups (NMO, MS, indeterminate, other) and management into three groups (MS drugs, immunosuppression, no treatment). The mean proportion of agreement for the diagnosis was low (p o = 0.51) and ranged from 0.25 to 0.73 for individual patients. The majority opinion was divided between NMOSD versus: MS (nine cases), monophasic longitudinally extensive transverse myelitis (LETM) (1), acute disseminated encephalomyelitis (ADEM) (1) and recurrent isolated optic neuritis (RION) (1). Typical NMO features (e.g., LETM) influenced the diagnosis more than features more consistent with MS (e.g., short TM). Agreement on the treatment of patients was higher (p o = 0.64) than that on the diagnosis with immunosuppression being the most common choice not only in patients with the diagnosis of NMO (98 %) but also in those indeterminate between NMO and MS (74 %). The diagnosis in AQP4-IgG-negative NMO/MS overlap syndromes is challenging and diverse. The classification of such patients currently requires new diagnostic categories, which incorporate lesser degrees of diagnostic confidence. Long-term follow-up may identify early features or biomarkers, which can more accurately distinguish the underlying disorder.

Neuromyelitis optica (NMO) is an idiopathic demyelinating disease which predominantly affects the optic nerve and spinal cord. Multiplex NMO pedigrees have been reported but the genetic risk factors conferring this increased familial susceptibility have not yet been determined. OPA1 mutations have recently been identified in families with progressive visual failure and spastic paraparesis, raising the possibility that OPA1 genetic variants could contribute to the aetiology of NMO. We therefore screened for OPA1 in 32 patients with NMO. No pathogenic mutations were found, and none of the 13 single-nucleotide polymorphisms identified were associated with an increased risk of developing NMO.