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.

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.

A multicenter comparison of MOG-IgG cell-based assays.

OBJECTIVES: To compares 3 different myelin oligodendrocyte glycoprotein-immunoglobulin G (IgG) cell-based assays (CBAs) from 3 international centers. METHODS: Serum samples from 394 patients were as follows: acute disseminated encephalomyelitis (28), seronegative neuromyelitis optica (27), optic neuritis (21 single, 2 relapsing), and longitudinally extensive (10 single, 3 recurrent). The control samples were from patients with multiple sclerosis (244), hypergammaglobulinemia (42), and other (17). Seropositivity was determined by visual observation on a fluorescence microscope (Euroimmun fixed CBA, Oxford live cell CBA) or flow cytometry (Mayo live cell fluorescence-activated cell sorting assay). RESULTS: Of 25 samples positive by any methodology, 21 were concordant on all 3 assays, 2 were positive at Oxford and Euroimmun, and 2 were positive only at Oxford. Euroimmun, Mayo, and Oxford results were as follows: clinical specificity 98.1%, 99.6%, and 100%; positive predictive values (PPVs) 82.1%, 95.5%, and 100%; and negative predictive values 79.0%, 78.8%, and 79.8%. Of 5 false-positives, 1 was positive at both Euroimmun and Mayo and 4 were positive at Euroimmun alone. CONCLUSIONS: Overall, a high degree of agreement was observed across 3 different MOG-IgG CBAs. Both live cell-based methodologies had superior PPVs to the fixed cell assays, indicating that positive results in these assays are more reliable indicators of MOG autoimmune spectrum disorders.

Glutamate receptor δ2 serum antibodies in pediatric opsoclonus myoclonus ataxia syndrome.

OBJECTIVE: To identify neuronal surface antibodies in opsoclonus myoclonus ataxia syndrome (OMAS) using contemporary antigen discovery methodology. METHODS: OMAS patient serum immunoglobulin G immunohistochemistry using age-equivalent rat cerebellar tissue was followed by immunoprecipitation, gel electrophoresis, and mass spectrometry. Data are available via ProteomeXchange (identifier PXD009578). This generated a list of potential neuronal surface cerebellar autoantigens. Live cell-based assays were used to confirm membrane-surface antigens and adsorb antigen-specific immunoglobulin Gs. The serologic results were compared to the clinical data. RESULTS: Four of the 6 OMAS sera tested bound rat cerebellar sections. Two of these sera with similar immunoreactivities were used in immunoprecipitation experiments using cerebellum from postnatal rat pups (P18). Mass spectrometry identified 12 cell-surface proteins, of which glutamate receptor δ2 (GluD2), a predominately cerebellar-expressed protein, was found at a 3-fold-higher concentration than the other 11 proteins. Antibodies to GluD2 were identified in 14/16 (87%) OMAS samples, compared with 5/139 (5%) pediatric and 1/38 (2.6%) adult serum controls (p < 0.0001), and in 2/4 sera from patients with neuroblastoma without neurologic features. Adsorption of positive OMAS sera against GluD2-transfected cells substantially reduced but did not eliminate reactivity toward cerebellar sections. CONCLUSION: Autoantibodies to GluD2 are common in patients with OMAS, bind to surface determinants, and are potentially pathogenic.

Update on biomarkers in neuromyelitis optica.

Neuromyelitis optica (NMO) (and NMO spectrum disorder) is an autoimmune inflammatory disease of the CNS primarily affecting spinal cord and optic nerves. Reliable and sensitive biomarkers for onset, relapse, and progression in NMO are urgently needed because of the heterogeneous clinical presentation, severity of neurologic disability following relapses, and variability of therapeutic response. Detecting aquaporin-4 (AQP4) antibodies (AQP4-IgG or NMO-IgG) in serum supports the diagnosis of seropositive NMO. However, whether AQP4-IgG levels correlate with disease activity, severity, response to therapy, or long-term outcomes is unclear. Moreover, biomarkers for patients with seronegative NMO have yet to be defined and validated. Collaborative international studies hold great promise for establishing and validating biomarkers that are useful in therapeutic trials and clinical management. In this review, we discuss known and potential biomarkers for NMO.

Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders.

OBJECTIVE: To evaluate clinical features among patients with neuromyelitis optica spectrum disorders (NMOSD) who have myelin oligodendrocyte glycoprotein (MOG) antibodies, aquaporin-4 (AQP4) antibodies, or seronegativity for both antibodies. METHODS: Sera from patients diagnosed with NMOSD in 1 of 3 centers (2 sites in Brazil and 1 site in Japan) were tested for MOG and AQP4 antibodies using cell-based assays with live transfected cells. RESULTS: Among the 215 patients with NMOSD, 7.4% (16/215) were positive for MOG antibodies and 64.7% (139/215) were positive for AQP4 antibodies. No patients were positive for both antibodies. Patients with MOG antibodies represented 21.1% (16/76) of the patients negative for AQP4 antibodies. Compared with patients with AQP4 antibodies or patients who were seronegative, patients with MOG antibodies were more frequently male, had a more restricted phenotype (optic nerve more than spinal cord), more frequently had bilateral simultaneous optic neuritis, more often had a single attack, had spinal cord lesions distributed in the lower portion of the spinal cord, and usually demonstrated better functional recovery after an attack. CONCLUSIONS: Patients with NMOSD with MOG antibodies have distinct clinical features, fewer attacks, and better recovery than patients with AQP4 antibodies or patients seronegative for both antibodies.

Evaluation of aquaporin-4 antibody assays.

Aquaporin-4 (AQP4) is a water channel protein that is most highly, but not exclusively, expressed in the central nervous system. In 2005 AQP4 was shown to be the antigenic target of neuromyelitis optica-immunoglobulin G (NMO-IgG, or AQP4-IgG), an antibody found specifically in patients with NMO and in formes frustes of NMO, such as longitudinally extensive transverse myelitis (LETM) or optic neuritis (ON). This discovery facilitated the clinical, pathological, and radiological distinction of NMO and the spectrum of NMO-related disorders from classical multiple sclerosis. In addition to its use as a diagnostic tool, AQP4-IgG predicts a high risk of relapse in patients with a clinically isolated syndrome of either LETM or ON. As disability in NMO is attack-related, early diagnosis and treatment are predicted to have a major effect on long-term disability. Thus, the importance of sensitive and specific assays to detect AQP4-IgG cannot be overstated. Both academic institutions and commercial companies have developed assays to identify AQP4-IgG in patients' sera or cerebrospinal fluid. Both AQP4 isoforms from different species have been used as the antigenic target in the form of frozen tissue sections in indirect immunofluorescence assays, partially purified protein for fluorescence immunoprecipitation assay, radioimmunoprecipita-tion assay or enzyme-linked immunosorbent assay, or transfected into cells for cell based assays or flow cytometry. We carried out a systematic review of the literature reporting different methodologies used to identify AQP4-IgG, examine whether longitudinal AQP4-IgG titers predict relapses in seropositive patients, and attempt to establish a reasonable timeframe for retesting negative serum samples.

Adhesive retention of silicone and chlorinated polyethylene for maxillofacial prostheses.

STATEMENT OF PROBLEM: A key factor of a successful facial prosthesis is the retention of the prosthesis to the patient's skin, especially when there is no mechanical means and the retention depends primarily on medical skin adhesives. Studies determining which medical adhesives provide the best bond strength for maxillofacial prostheses are needed. PURPOSE: The purpose of this study was to quantify the force required to detach strips of Silastic Adhesive A/MDX4-4,210 silicone elastomer with a urethane liner (A/M-U) and experimental chlorinated polyethylene elastomer (CPE) from the skin of human subjects coated with a protective dressing using 1 of 2 medical adhesives. MATERIAL AND METHODS: With IRB approval, 8 A/M-U and CPE rubber strips (total of 208) were applied in a predetermined random order to the left and right ventral forearms of 26 human subjects. Skin-Prep Protective Dressing (SP) was applied to half of the sites just before Epithane-3 (E3) and Secure(2) Medical Adhesive (SMA) were used to adhere the strips. Strips were peeled 6 hours later in a universal testing machine at 10 cm/min. Data are reported in newton/meter (N/m). The data was compared using a 3-way, within-groups, multivariate analysis of variance (MANOVA) and the Fisher exact test (alpha=.05). Values for N/m under various conditions relating to the subjects were compared by the Tukey HSD Test for unequal N (alpha=.05). Data are reported as mean (SD). RESULTS: Statistical analysis revealed no differences (mean (SD)) and no significant interactions between the independent variables (A/M-U = 94.6 (62.1) and CPE = 98.4 (69.6) N/m, SP = 93.0 (58.8) and no SP = 99.8 (72.1) N/m, E3 = 97.6 (69.8) and SMA = 95.3 (61.8) N/m; P=.984). Debonding occurred at the skin interface for both adhesives, as evidenced by residue on prosthetic materials (Fisher exact test; P<.005). CONCLUSIONS: The adhesive bond strengths of both SMA and E3, with and without the presence of SP, were not significantly different between A/M-U and CPE maxillofacial prosthetic materials. Adhesive failure occurred at the skin interface.