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.

Impact of rituximab treatment regime on time to relapse in aquaporin-4 antibody positive neuromyelitis optica spectrum disorder.

BACKGROUND: Aquaporin-4 (AQP4) antibody associated neuromyelitis optica (NMOSD) requires long-term immunosuppression. Rituximab is increasingly used worldwide, however the optimal regime is not established. METHODS: We retrospectively examined different rituximab regimens in AQP4-NMOSD. Standard monotherapy (SM; 6 monthly infusions), SM plus oral steroids (SM+S), extended interval dosing (EID; guided by CD19 repopulation) and EID with oral steroids (EID+S) were compared. The primary outcome was time to first clinical relapse. Potential confounders including age, gender, number of previous relapses, and onset phenotype were included. RESULTS: 77 patients were included: 67 females, median onset age 35.6, median DSS at rituximab initiation 5.0. 39 were on SM+S, 20 SM, 6 EID, and 12 EID+S. 25/77 patients relapsed during a median follow-up of 44.0 months. No significant difference in time to first relapse was observed between any rituximab regimen. Pooled analyses to compare regimens that use standard monotherapy (SM and SM+S) against those that use extended interval dosing (EID and EID+S) showed no significant difference. Pooled analysis of regimens using steroids with those not using steroids also showed no significant difference. Adjusted Cox proportional hazard model revealed no significant difference between rituximab regimens or influence of demographic factors. 9 significant adverse events were recorded, 5 in the SM group and 4 in SM+S. CONCLUSIONS: This study provides some basis for further exploring EID as a viable option for long term treatment of AQP4-NMOSD. This may improve patient experience and consolidate use of hospital resources.

Characterizing mortality in patients with AQP4-Ab+ neuromyelitis optica spectrum disorder.

Neuromyelitis optica spectrum disorder is an autoimmune disease, causing severe disability due to relapses, but recent mortality data are limited. Among 396 patients seropositive for anti-aquaporin-4 antibody from 2014 to 2020 in the United Kingdom, 39 deaths occurred: 19 (48.7%) were unrelated to disease; 14 (35.9%) were severe disability- or relapse-related; and 4 (10.3%) were attributed to malignancy/infection. Mean annual mortality was 1.92% versus 0.63% in the matched population. The standardized mortality ratio was 3.04 (95% confidence interval 1.67-5.30) with 1.29% excess mortality per year in patients. Median Expanded Disability Status Scale before death was 7.0. Results highlight the importance of preventing relapses that drive disability.

Timing of MOG-IgG Testing Is Key to 2023 MOGAD Diagnostic Criteria.

BACKGROUND AND OBJECTIVES: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a recently identified autoimmune demyelinating disorder of the CNS affecting both adults and children. Diagnostic criteria for MOGAD have recently been published. We aimed to validate the 2023 MOGAD diagnostic criteria in a real-world cohort of patients with atypical CNS inflammation. METHODS: All patients referred to the National neuromyelitis optica spectrum disorder (NMOSD) specialized service at The Walton Center NHS Foundation Trust between 2012 and 2023 with an atypical demyelinating syndrome were evaluated. We systematically applied the 2023 MOGAD diagnostic criteria and previous 2018 International Diagnostic Recommendations for MOG encephalomyelitis to our retrospective cohort. RESULTS: 474 patients were screened and 66 were excluded for lack of clinical information. Preexisting diagnoses within our cohort included the following: MOGAD, n = 127; AQP4-IgG NMOSD, n = 125; seronegative NMOSD, n = 33; multiple sclerosis (MS), n = 10; and other diagnoses, n = 113. Of patients with preexisting MOGAD, 97% (123/127) fulfilled the 2023 MOGAD diagnostic criteria. Three patients with a low-positive MOG-IgG did not meet supportive features though 2/3 had insufficient investigations. Alternative diagnoses could not be excluded in 1 patient with MS-MOGAD overlap. No patients with a non-MOGAD diagnosis were found to fulfill the 2023 diagnostic criteria. The sensitivity and specificity of the 2023 MOGAD diagnostic criteria were 97% and 100% with no false positives, improving on 2018 International Diagnostic Recommendations for MOG encephalomyelitis. Low-positive MOG-IgG results were more often associated with a longer time from disease onset to sampling (p < 0.001). In addition, in patients with a MOG-IgG1 test within 6 months of clinical onset, approximately 25% can become low positive by 6 months. Of patients with preexisting MOGAD, 9% (12/127) had insufficient investigations and examinations to fully evaluate additional supportive features. However, in those who were completely evaluated, supportive features were fulfilled in 97% (111/115). DISCUSSION: The 2023 MOGAD diagnostic criteria were highly sensitive and specific and closely align with historically established cases of MOGAD. However, because additional supportive features are stipulated for patients with a low-positive MOG-IgG result, missed diagnoses may occur due to delayed testing or insufficient investigations.

Case report: Clinical features and management outcomes of isolated corneal intraepithelial neoplasia.

Purpose: To report clinical features and treatment outcome of three cases with isolated corneal intraepithelial neoplasia (CIN). Methods: This case series presents 3 patients with isolated CIN. Data collected included, presenting signs and symptoms including vision, anterior segment examination, medical and surgical outcomes and signs and symptoms at lost post-treatment visit. Results: Case 1 was a 45-year-old male who presented with an isolated grayish amoeboid corneal lesion which was excised with alcohol assisted epitheliectomy, he also received 6 cycles of topical mitomycin C (MMC) 0.02% and one injection of interferon alfa-2b with no recurrence during the 10-year follow-up period. Case 2 was 78-year-old male referred for a suspicious white corneal lesion which was completely excised, the patient also received 6 subconjunctival injections of interferon alpha-2b. However, the lesion recurred at 2.5-years post-treatment. Case 3 was a 63-year-old male patient who presented with an isolated corneal lesion that was excised using alcohol-assisted epitheliectomy, patient received four cycles of topical 5-fluorouracil with no recurrence at last follow-up visit at 6 months. Conclusion: Isolated corneal intraepithelial neoplasia (CIN) is a rare entity with few reported cases in the literature. In this case series, we report long and short-term management outcomes of combined surgical and medical therapy for isolated CIN.

Assessment of international MOGAD diagnostic criteria in patients with overlapping MOG-associated disease and multiple sclerosis phenotypes.

BACKGROUND: The clinical spectrum and diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) has evolved in the setting of an optimized anti-MOG-IgG cell-based assay and expert consensus. The McDonald criteria for MS have been revised multiple times to improve the accuracy and specificity of diagnosis on a framework based on clinical presentation, MRI findings, and CSF results. While the uses of MS and MOGAD diagnostic criteria are helpful for typical cases, such utility for patients with overlapping clinical, laboratorial, and imaging features is unknown, posing diagnostic and management uncertainties. OBJECTIVES: To report a multicenter cohort of patients with overlapping phenotypic features of MOGAD and MS and evaluate the application of new MOGAD diagnostic criteria. METHODS: A collaborative retrospective cohort study was performed to identify patients with both positive serum anti-MOG-IgG and fulfillment of the MS revised 2017 McDonald criteria. Clinical and radiographic features of patients fulfilling inclusion criteria were reviewed longitudinally, including relapses, repeated MRI, and MOG-IgG testing in detail to allow the panel of expert opinion to assign to each case. The International MOGAD Panel proposed criteria were applied at onset and last follow-up to each case and compared to the expert author diagnosis assignment based on presentation, clinical and imaging features, and response to treatment. RESULTS: Ten of 225 (4%) MOG-IgG seropositive cases met study inclusion criteria [seven of 10 were female; age at initial event: eight adults (mean age 26.8 years), two adolescents (mean age 14.5 years)]. AQP4-IgG was negative for all. Apart from serum titers of MOG-IgG, distinguishing clinical and radiographic features [i.e., clinical severity of the initial demyelinating event, radiographic features (optic nerve/spine/brain), and presence/absence of lesion normalization on serial scans] led to consensus of three separate classifications differing by degrees of shared features of MOGAD and MS. Patients were classified by expert panel into (1) Classic MOGAD even with MS-like, well-defined brain lesions, when severe events and most T2 lesions normalized (n = 5; MOG-IgG titers 1:100, 1:20, 1:160, 1:40, 1:200); (2) Classic RRMS included cases thought to have likely false positive or clinically irrelevant MOG-IgG, due to mild clinical events and no radiographic normalization of well-defined MS-like lesions (n = 3; MOG titers 1:20, 1:100, 1:40); (3) MOGAD and MS overlapping phenotype was defined by those with a combination of mild and severe clinical events, partial T2 lesion normalization, both well- and ill-defined lesions (n = 2; MOG titers 1:20, 1:100). The application of the International MOGAD Panel criteria categorized five patients (50%) in agreement with expert assignment. One additional patient was classified in agreement to assignment when MOGAD criteria were applied after serial MOG-IgG titers testing. DISCUSSION: While the International MOGAD Panel diagnostic criteria have helped with accuracy for the diagnosis of this condition, in a group of patients seropositive for MOG-IgG with overlapping clinical and imaging features of RRMS criteria review may lead to increased accuracy. Serial serologies, repeated imaging, close attention to clinical course, and response to therapy are possible variables to consider for further refinement of MOGAD diagnostic criteria.

Study of seasonality of attacks in MOG antibody-associated disease.

BACKGROUND: Seasonal variation in attacks of acute disseminated encephalomyelitis (ADEM1) is reported in some studies. Myelin oligodendrocyte glycoprotein (MOG) antibodies are found in up to 50 % of ADEM cases. Despite this, there has been no adequately powered study of seasonality in MOG antibody-associated disease (MOGAD). We sought to determine whether there was an effect of season on incidence of total attacks and onset attacks of MOGAD. METHODS: We searched the large national Oxford-based NMO Service database to identify attacks of MOGAD occurring between 2010 and 2021. Month of each attack was extracted and Edwards' test of seasonal variation was applied to determine whether there was a seasonal effect on total attacks and onset attacks. RESULTS: Neither incidence of total attacks nor incidence of onset attacks varied significantly by month. CONCLUSION: There is no evidence of seasonal fluctuations in the incidence of MOGAD attacks in the UK.

Predictors of azathioprine and mycophenolate mofetil response in patients with neuromyelitis optica spectrum disorder: A cohort study.

BACKGROUND: Relapse rates of 47 % have been reported in patients with neuromyelitis optica (NMOSD) using Azathioprine (AZA) and mycophenolate mofetil (MMF). Prediction of non-responders could help determine which patients are most likely to benefit from newer monoclonal antibody treatments from the outset. OBJECTIVES: To identify predictors of AZA and MMF treatment response in NMOSD. METHODS: Multicenter cohort study of NMOSD patients from Brazil and the United Kingdom, treated with AZA and MMF. An unsatisfactory response was defined as one severe or two non-severe attacks in a year. Cox regression was used to identify predictive factors of unsatisfactory response to AZA and MMF. RESULTS: 103 NMOSD patients, mean age 38 years, 83% female, and 65% of Black ethnic group were included. An unsatisfactory IS response was observed in 42% of patients over 2.5 years (IQR 1.0-8.8) years. A severe preceding attack was more common in non-responders (31.1% x 76.7%, p = <0.001). In multivariable analysis, severe attack (RR 3.13; 95 % CI 1.37-7.18, p = 0.007) or higher annualized relapse rate (RR 4.84; 95 % CI 2.01-11.65, p = < 0.001) predicted an unsatisfactory response. Interestingly, Black NMOSD patients had a lower risk of poor response (RR 0.39, 95 % CI 0.17-0.85, p = 0.019). CONCLUSION: Severe attack and a higher annualized relapse rate before AZA or MMF initiation were associated with an unsatisfactory IS response. In patients with these characteristics, treatment with higher-efficacy drugs should be considered from the outset.

A retrospective multicenter study on clinical and serological parameters in patients with MuSK myasthenia gravis with and without general immunosuppression.

Introduction: Muscle-specific kinase (MuSK)- myasthenia gravis (MG) is caused by pathogenic autoantibodies against MuSK that correlate with disease severity and are predominantly of the IgG4 subclass. The first-line treatment for MuSK-MG is general immunosuppression with corticosteroids, but the effect of treatment on IgG4 and MuSK IgG4 levels has not been studied. Methods: We analyzed the clinical data and sera from 52 MuSK-MG patients (45 female, 7 male, median age 49 (range 17-79) years) from Italy, the Netherlands, Greece and Belgium, and 43 AChR-MG patients (22 female, 21 male, median age 63 (range 2-82) years) from Italy, receiving different types of immunosuppression, and sera from 46 age- and sex-matched non-disease controls (with no diagnosed diseases, 38 female, 8 male, median age 51.5 (range 20-68) years) from the Netherlands. We analyzed the disease severity (assessed by MGFA or QMG score), and measured concentrations of MuSK IgG4, MuSK IgG, total IgG4 and total IgG in the sera by ELISA, RIA and nephelometry. Results: We observed that MuSK-MG patients showed a robust clinical improvement and reduction of MuSK IgG after therapy, and that MuSK IgG4 concentrations, but not total IgG4 concentrations, correlated with clinical severity. MuSK IgG and MuSK IgG4 concentrations were reduced after immunosuppression in 4/5 individuals with before-after data, but data from non-linked patient samples showed no difference. Total serum IgG4 levels were within the normal range, with IgG4 levels above threshold (1.35g/L) in 1/52 MuSK-MG, 2/43 AChR-MG patients and 1/45 non-disease controls. MuSK-MG patients improved within the first four years after disease onset, but no further clinical improvement or reduction of MuSK IgG4 were observed four years later, and only 14/52 (26.92%) patients in total, of which 13 (93.3%) received general immunosuppression, reached clinical remission. Discussion: We conclude that MuSK-MG patients improve clinically with general immunosuppression but may require further treatment to reach remission. Longitudinal testing of individual patients may be clinically more useful than single measurements of MuSK IgG4. No significant differences in the serum IgG4 concentrations and IgG4/IgG ratio between AChR- and MuSK-MG patients were found during follow-up. Further studies with larger patient and control cohorts are necessary to validate the findings.