Optic chiasm involvement in multiple sclerosis, aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein-associated disease.

BACKGROUND: Optic neuritis (ON) is a common feature of inflammatory demyelinating diseases (IDDs) such as multiple sclerosis (MS), aquaporin 4-antibody neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, the involvement of the optic chiasm (OC) in IDD has not been fully investigated. AIMS: To examine OC differences in non-acute IDD patients with (ON+) and without ON (ON-) using magnetisation transfer ratio (MTR), to compare differences between MS, AQP4 + NMOSD and MOGAD and understand their associations with other neuro-ophthalmological markers. METHODS: Twenty-eight relapsing-remitting multiple sclerosis (RRMS), 24 AQP4 + NMOSD, 28 MOGAD patients and 32 healthy controls (HCs) underwent clinical evaluation, MRI and optical coherence tomography (OCT) scan. Multivariable linear regression models were applied. RESULTS: ON + IDD patients showed lower OC MTR than HCs (28.87 ± 4.58 vs 31.65 ± 4.93; p = 0.004). When compared with HCs, lower OC MTR was found in ON + AQP4 + NMOSD (28.55 ± 4.18 vs 31.65 ± 4.93; p = 0.020) and MOGAD (28.73 ± 4.99 vs 31.65 ± 4.93; p = 0.007) and in ON- AQP4 + NMOSD (28.37 ± 7.27 vs 31.65 ± 4.93; p = 0.035). ON+ RRMS had lower MTR than ON- RRMS (28.87 ± 4.58 vs 30.99 ± 4.76; p = 0.038). Lower OC MTR was associated with higher number of ON (regression coefficient (RC) = -1.15, 95% confidence interval (CI) = -1.819 to -0.490, p = 0.001), worse visual acuity (RC = -0.026, 95% CI = -0.041 to -0.011, p = 0.001) and lower peripapillary retinal nerve fibre layer (pRNFL) thickness (RC = 1.129, 95% CI = 0.199 to 2.059, p = 0.018) when considering the whole IDD group. CONCLUSION: OC microstructural damage indicates prior ON in IDD and is linked to reduced vision and thinner pRNFL.

The absence of antibodies in longitudinally extensive transverse myelitis may predict a more favourable prognosis.

BACKGROUND: Isolated first episodes of longitudinally extensive transverse myelitis (LETM) have typically been associated with neuromyelitis optica spectrum disorder (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, in some cases, serological testing and screening for other aetiologies are negative, a condition referred to as double seronegative longitudinally extensive transverse myelitis (dsLETM). OBJECTIVE: The objective of this study was to evaluate comparative outcomes of dsLETM, MOGAD-LETM and NMOSD-LETM. METHODS: Cohort study of LETM cases seen in the UK NMOSD Highly Specialised Service between January 2008 and March 2022. RESULTS: LETM = 87 cases were identified (median onset age = 46 years (15-85); median follow-up = 46 months (1-144); 47% NMOSD-LETM = 41 (aquaporin-4 antibodies (AQP4-IgG) positive = 36), 20% MOGAD-LETM = 17 and 33% dsLETM = 29). Despite similar Expanded Disability Status Scale (EDSS) at nadir, last EDSS was higher in AQP4-IgG and seronegative NMOSD-LETM (sNMOSD) (p = 0.006). Relapses were less common in dsLETM compared to AQP4-IgG NMOSD-LETM and sNMOSD-LETM (19% vs 60% vs 100%; p = 0.001). Poor prognosis could be predicted by AQP4-IgG (odds ratio (OR) = 38.86 (95% confidence interval (CI) = 1.36-1112.86); p = 0.03) and EDSS 3 months after onset (OR = 65.85 (95% CI = 3.65-1188.60); p = 0.005). CONCLUSION: dsLETM remains clinically challenging and difficult to classify with existing nosological terminology. Despite a similar EDSS at nadir, patients with dsLETM relapsed less and had a better long-term prognosis than NMOSD-LETM.

Acetaminophen: A Liver Killer or Thriller.

Acetaminophen, or paracetamol, ranks among the most extensively utilized analgesic and antipyretic medications globally. The administration of acetaminophen to individuals with underlying liver disease has long sparked concerns regarding the potential risk of hepatotoxicity. However, the available literature and recommendations consider it a safe option in all forms of liver diseases and is deemed safe when used at recommended doses. This article aims to offer a concise review of the pharmacokinetics, toxicity profile, and the intricate considerations surrounding the safety of acetaminophen in patients with liver disease. By delving into the liver-acetaminophen interactions, we seek to provide a nuanced perspective on the use of acetaminophen in this critical patient population.

Do we still need OCBs in MS diagnosis and how many?

BACKGROUND: CSF-specific oligoclonal bands (CSF-OCBs) can be used for dissemination in time (DIT) in the 2017 multiple sclerosis (MS) diagnostic criteria. A cut-off of ≥2 CSF-OCBs was recommended but studies have suggested ≥3 CSF-OCBs may be superior. OBJECTIVES: To assess utility of ≥2 and ≥3 CSF-OCBs as a cut-off for MS diagnosis. METHODS: Paired serum and CSF-OCBs sent to the Walton Centre, UK between July 2018 and June 2020 were included. CSF-OCBs were assessed using isoelectric focussing and reviewed by two blinded raters. Case records were reviewed. RESULTS: Of 1334 paired serum and CSF-OCB requests, 945 cases had sufficient clinical information. More than 1 CSF-OCB was detected in 268/945(28%) cases. Of these, 252 had ≥2 and 230 had ≥3 CSF-OCBs. The sensitivity and specificity for MS with ≥2 and ≥3 CSF-OCBs were 91.7%, 91.2%, 90.2% and 93.8% respectively. Only 3/22 patients with 2 CSF-OCBs had MS. In 25% of patients, CSF-OCBs reduced time to MS diagnosis (median 437.5 days (28-1332)). CONCLUSION: Although cut-offs of ≥2 or ≥3 CSF-OCBs performed similarly well, 2 CSF-OCBs were frequently seen with non-inflammatory pathology. Use of ≥3 CSF-OCBs for MS diagnosis should be considered. CSF analysis reduced time to MS diagnosis by approximately 14 months.

Multicentre Observational Study of Treatment Satisfaction with Cladribine Tablets in the Management of Relapsing Multiple Sclerosis in the Arabian Gulf: The CLUE Study.

INTRODUCTION: Inconvenient administration and side effects of some disease-modifying therapies (DMTs) for relapsing multiple sclerosis (RMS) can deter adherence. We evaluated treatment satisfaction with cladribine tablets (CladT) for RMS in the Arabian Gulf. METHODS: This was a non-interventional, multicentre, prospective observational study in non-pregnant/lactating adults (aged ≥ 18 years) with RMS eligible for 1st treatment with CladT (EU labelling). The primary outcome was overall treatment satisfaction at 6 months (Treatment Satisfaction Questionnaire for Medication [TSQM]-14, v. 1.4), Global Satisfaction subscale. Secondary endpoints were TSQM-14 scores for convenience, satisfaction with side effects and satisfaction with effectiveness. Patients provided written informed consent. RESULTS: Of 63 patients screened, 58 received CladT and 55 completed the study. Mean age was 33 ± 9 years; mean weight 73 ± 17 kg; 31% male/69% female; mostly from the United Arab Emirates (52%) or Kuwait (30%). All had RMS (mean 0.9 ± 1.1 relapses in the past year), mean Expanded Disability Status Scale (EDSS) 1.4 ± 1.2; 36% were DMT-naïve. Mean [95% CI] score was high for overall treatment satisfaction (77.8 [73.0-82.6]), ease of use (87.4 [83.7-91.0]), tolerability (94.2 [91.0-97.3]) and effectiveness (76.2 [71.6-80.7]). Scores were similar irrespective of DMT history, age, gender, relapse history or EDSS. No relapses or serious treatment-emergent adverse events (TEAE) occurred. Two severe TEAE occurred (fatigue, headache) and 16% reported lymphopenia (two cases of grade 3 lymphopenia). Absolute lymphocyte counts at baseline and 6 months were 2.2 ± 0.8 × 109/L and 1.3 ± 0.3 × 109/L, respectively. CONCLUSIONS: Treatment satisfaction, ease of use, tolerability and patient-perceived effectiveness for CladT were high, irrespective of baseline demographics, disease characteristics and prior treatment.

Comparison of IVIg and TPE efficacy in the treatment of neurological disorders: a systematic literature review.

Background: Intravenous immunoglobulin (IVIg) and therapeutic plasma exchange (TPE) are among the main immunotherapies for neurological disorders. Their benefit is greatest in immune-mediated conditions, but their distinct efficacy cannot be simply explained. Objectives: This review aimed to systematically identify studies comparing the efficacy of TPE and IVIg treatments for selected autoimmune neurological disorders and identify optimal therapies for each condition. Data Sources and Methods: PubMed, MEDLINE and Embase databases were searched for original publications from 1990 to 2021. Additional publications were identified via expert recommendations. Conference abstracts older than 2017, review articles and articles without information on TPE and IVIg comparison in title and abstract were excluded. Risks of bias were descriptively addressed, without a meta-analysis. Results: Forty-four studies were included on Guillain-Barré syndrome (20 studies - 12 adult, 5 paediatric, 3 all ages), myasthenia gravis (11 studies -8 adult, 3 paediatric), chronic immune-mediated polyradiculoneuropathy (3 studies -1 adult, 2 paediatric), encephalitis (1 study in adults), neuromyelitis optica spectrum disorders (5 studies -2 adult, 3 all ages) and other conditions (4 studies - all ages). TPE and IVIg were mostly similarly efficacious, measured by clinical outcomes and disease severity scores. Some studies recommended IVIg as easy to administer. TPE procedures, however, have been simplified and the safety has been improved. TPE is currently recommended for management of neuromyelitis optica spectrum disorder relapses and some myasthenia gravis subtypes, in which rapid removal of autoantibodies is crucial. Conclusion: Despite some limitations (e.g. the low evidence levels), this review provides an extensive 30-year-long overview of treatments for various conditions. Both IVIg and TPE are usually comparably efficacious options for autoimmune neurological disorders, with few exceptions. Treatment choices should be patient-tailored and based on available clinical resources. Better designed studies are needed to provide higher-level quality of evidence regarding clinical efficacy of TPE and IVIg treatments.

Diagnostic value of intereye difference metrics for optic neuritis in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders.

BACKGROUND: The novel optic neuritis (ON) diagnostic criteria include intereye differences (IED) of optical coherence tomography (OCT) parameters. IED has proven valuable for ON diagnosis in multiple sclerosis but has not been evaluated in aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4+NMOSD). We evaluated the diagnostic accuracy of intereye absolute (IEAD) and percentage difference (IEPD) in AQP4+NMOSD after unilateral ON >6 months before OCT as compared with healthy controls (HC). METHODS: Twenty-eight AQP4+NMOSD after unilateral ON (NMOSD-ON), 62 HC and 45 AQP4+NMOSD without ON history (NMOSD-NON) were recruited by 13 centres as part of the international Collaborative Retrospective Study on retinal OCT in Neuromyelitis Optica study. Mean thickness of peripapillary retinal nerve fibre layer (pRNFL) and macular ganglion cell and inner plexiform layer (GCIPL) were quantified by Spectralis spectral domain OCT. Threshold values of the ON diagnostic criteria (pRNFL: IEAD 5 µm, IEPD 5%; GCIPL: IEAD: 4 µm, IEPD: 4%) were evaluated using receiver operating characteristics and area under the curve (AUC) metrics. RESULTS: The discriminative power was high for NMOSD-ON versus HC for IEAD (pRNFL: AUC 0.95, specificity 82%, sensitivity 86%; GCIPL: AUC 0.93, specificity 98%, sensitivity 75%) and IEPD (pRNFL: AUC 0.96, specificity 87%, sensitivity 89%; GCIPL: AUC 0.94, specificity 96%, sensitivity 82%). The discriminative power was high/moderate for NMOSD-ON versus NMOSD-NON for IEAD (pRNFL: AUC 0.92, specificity 77%, sensitivity 86%; GCIP: AUC 0.87, specificity 85%, sensitivity 75%) and for IEPD (pRNFL: AUC 0.94, specificity 82%, sensitivity 89%; GCIP: AUC 0.88, specificity 82%, sensitivity 82%). CONCLUSIONS: Results support the validation of the IED metrics as OCT parameters of the novel diagnostic ON criteria in AQP4+NMOSD.

Differentiating Multiple Sclerosis From AQP4-Neuromyelitis Optica Spectrum Disorder and MOG-Antibody Disease With Imaging.

BACKGROUND AND OBJECTIVES: Relapsing-remitting multiple sclerosis (RRMS), aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) may have overlapping clinical features. There is an unmet need for imaging markers that differentiate between them when serologic testing is unavailable or ambiguous. We assessed whether imaging characteristics typical of MS discriminate RRMS from AQP4-NMOSD and MOGAD, alone and in combination. METHODS: Adult, nonacute patients with RRMS, APQ4-NMOSD, and MOGAD and healthy controls were prospectively recruited at the National Hospital for Neurology and Neurosurgery (London, United Kingdom) and the Walton Centre (Liverpool, United Kingdom) between 2014 and 2019. They underwent conventional and advanced brain, cord, and optic nerve MRI and optical coherence tomography (OCT). RESULTS: A total of 91 consecutive patients (31 RRMS, 30 APQ4-NMOSD, and 30 MOGAD) and 34 healthy controls were recruited. The most accurate measures differentiating RRMS from AQP4-NMOSD were the proportion of lesions with the central vein sign (CVS) (84% vs 33%, accuracy/specificity/sensitivity: 91/88/93%, p < 0.001), followed by cortical lesions (median: 2 [range: 1-14] vs 1 [0-1], accuracy/specificity/sensitivity: 84/90/77%, p = 0.002) and white matter lesions (mean: 39.07 [±25.8] vs 9.5 [±14], accuracy/specificity/sensitivity: 78/84/73%, p = 0.001). The combination of higher proportion of CVS, cortical lesions, and optic nerve magnetization transfer ratio reached the highest accuracy in distinguishing RRMS from AQP4-NMOSD (accuracy/specificity/sensitivity: 95/92/97%, p < 0.001). The most accurate measures favoring RRMS over MOGAD were white matter lesions (39.07 [±25.8] vs 1 [±2.3], accuracy/specificity/sensitivity: 94/94/93%, p = 0.006), followed by cortical lesions (2 [1-14] vs 1 [0-1], accuracy/specificity/sensitivity: 84/97/71%, p = 0.004), and retinal nerve fiber layer thickness (RNFL) (mean: 87.54 [±13.83] vs 75.54 [±20.33], accuracy/specificity/sensitivity: 80/79/81%, p = 0.009). Higher cortical lesion number combined with higher RNFL thickness best differentiated RRMS from MOGAD (accuracy/specificity/sensitivity: 84/92/77%, p < 0.001). DISCUSSION: Cortical lesions, CVS, and optic nerve markers achieve a high accuracy in distinguishing RRMS from APQ4-NMOSD and MOGAD. This information may be useful in clinical practice, especially outside the acute phase and when serologic testing is ambiguous or not promptly available. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that selected conventional and advanced brain, cord, and optic nerve MRI and OCT markers distinguish adult patients with RRMS from AQP4-NMOSD and MOGAD.

Clinical and MRI measures to identify non-acute MOG-antibody disease in adults.

MRI and clinical features of myelin oligodendrocyte glycoprotein (MOG)-antibody disease may overlap with those of other inflammatory demyelinating conditions posing diagnostic challenges, especially in non-acute phases and when serologic testing for MOG antibodies is unavailable or shows uncertain results. We aimed to identify MRI and clinical markers that differentiate non-acute MOG-antibody disease from aquaporin 4 (AQP4)-antibody neuromyelitis optica spectrum disorder and relapsing remitting multiple sclerosis, guiding in the identification of patients with MOG-antibody disease in clinical practice. In this cross-sectional retrospective study, data from 16 MAGNIMS centres were included. Data collection and analyses were conducted from 2019 to 2021. Inclusion criteria were: diagnosis of MOG-antibody disease; AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis; brain and cord MRI at least 6 months from relapse; and Expanded Disability Status Scale (EDSS) score on the day of MRI. Brain white matter T2 lesions, T1-hypointense lesions, cortical and cord lesions were identified. Random forest models were constructed to classify patients as MOG-antibody disease/AQP4-neuromyelitis optica spectrum disorder/multiple sclerosis; a leave one out cross-validation procedure assessed the performance of the models. Based on the best discriminators between diseases, we proposed a guide to target investigations for MOG-antibody disease. One hundred and sixty-two patients with MOG-antibody disease [99 females, mean age: 41 (±14) years, median EDSS: 2 (0-7.5)], 162 with AQP4-neuromyelitis optica spectrum disorder [132 females, mean age: 51 (±14) years, median EDSS: 3.5 (0-8)], 189 with multiple sclerosis (132 females, mean age: 40 (±10) years, median EDSS: 2 (0-8)] and 152 healthy controls (91 females) were studied. In young patients (<34 years), with low disability (EDSS < 3), the absence of Dawson's fingers, temporal lobe lesions and longitudinally extensive lesions in the cervical cord pointed towards a diagnosis of MOG-antibody disease instead of the other two diseases (accuracy: 76%, sensitivity: 81%, specificity: 84%, P < 0.001). In these non-acute patients, the number of brain lesions < 6 predicted MOG-antibody disease versus multiple sclerosis (accuracy: 83%, sensitivity: 82%, specificity: 83%, P < 0.001). An EDSS < 3 and the absence of longitudinally extensive lesions in the cervical cord predicted MOG-antibody disease versus AQP4-neuromyelitis optica spectrum disorder (accuracy: 76%, sensitivity: 89%, specificity: 62%, P < 0.001). A workflow with sequential tests and supporting features is proposed to guide better identification of patients with MOG-antibody disease. Adult patients with non-acute MOG-antibody disease showed distinctive clinical and MRI features when compared to AQP4-neuromyelitis optica spectrum disorder and multiple sclerosis. A careful inspection of the morphology of brain and cord lesions together with clinical information can guide further analyses towards the diagnosis of MOG-antibody disease in clinical practice.

Rituximab abrogates aquaporin-4-specific germinal center activity in patients with neuromyelitis optica spectrum disorders.

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.

Progressive myelin oligodendrocyte glycoprotein-associated demyelination mimicking leukodystrophy.

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.

Insertion of S2 into Donor-Acceptor Cyclopropanes: Access to Dithiolanes and Their Conversion to Thietane Dioxides.

A facile and efficient route to dithiolanes starting from donor-acceptor cyclopropanes is reported. Potassium p-toluenethiosulfonate has been established as the reagent of choice for this formal insertion of the disulfide moiety. Using this methodology, dithiolanes have been synthesized in moderate to good yields with high functional group tolerance. Upon treatment with an excess of mCPBA, the corresponding dithiolanes delivered four-membered thietane dioxides, the formal (3+1)-cycloaddition product of D-A cyclopropanes, and sulfur dioxide.

Health utilities and costs for neuromyelitis optica spectrum disorder.

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.

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

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

Interleukin-6 Receptor Blockade in Treatment-Refractory MOG-IgG-Associated Disease and Neuromyelitis Optica Spectrum Disorders.

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.

Astrocytic outer retinal layer thinning is not a feature in AQP4-IgG seropositive neuromyelitis optica spectrum disorders.

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 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); 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.

Predictors of relapse in MOG antibody associated disease: a cohort study.

OBJECTIVE: To identify factors predictive of relapse risk and disability in myelin oligodendrocyte glycoprotein associated disease (MOGAD). SETTING: Patients were seen by the neuromyelitis optica spectrum disorders (NMOSD) service in Liverpool, UK, a national referral centre for adult patients with MOGAD, NMOSD and related conditions. PARTICIPANTS: Patients with MOGAD=76 from England, Northern Ireland and Scotland were included in this cohort study. RESULTS: Relapsing disease was observed in 55% (42/76) of cases. Steroid treatment >1 month (OR 0.2, 95% CI 0.05 to 0.80; p=0.022), transverse myelitis (TM) at first attack (OR 0.03, 95% CI 0.004 to 0.23; p=0.001) and male sex (OR 0.16, 95% CI 0.04 to 0.68; p=0.014) were associated with monophasic disease (area under the curve=0.85). Male sex (HR 0.46, 95% CI 0.24 to 0.89; p=0.011) and TM at disease onset (HR 0.42, 95% CI 0.22 to 0.82; p=0.011) were also associated with an increased latency to first relapse. 45% (32/71) of patients became MOG-antibody negative and in relapsing patients negative seroconversion was associated with a lower relapse risk (relative risk 0.11 95% CI 0.05 to 0.26; p<0.001). No specific factors were predictive of visual or overall disability. CONCLUSIONS: Male patients with spinal cord involvement at disease onset have a lower risk of relapsing disease and longer latency to first relapse. Steroid treatment for at least 1 month at first attack was also associated with a monophasic disease course. MOG-antibody negative seroconversion was associated with a lower risk of relapse and may help inform treatment decisions and duration.