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Supplemental material, sj-docx-1-msj-10.1177_13524585231172145 for Attack adjudication in neuromyelitis optica spectrum disorder: Substantiation of criteria by magnetic resonance imaging and biomarkers in N-MOmentum by Brian G Weinshenker, Dean M Wingerchuk, Ari J Green, Jeffrey L Bennett, Ho Jin Kim, Sean J Pittock, Kazuo Fujihara, Friedemann Paul, Gary Cutter, Romain Marignier, Orhan Aktas, Hans-Peter Hartung, Dewei She, Michael Smith, William Rees, Kristina Patterson, Daniel Cimbora, Eliezer Katz and Bruce AC Cree in Multiple Sclerosis Journal

BackgroundInebilizumab is an anti-CD19 antibody approved for the treatment of neuromyelitis optica spectrum disorder (NMOSD) in adults with aquaporin-4 autoantibodies. The relationship between B-cell, plasma-cell (PC), and immunoglobulin depletion with longitudinal reductions in NMOSD activity after inebilizumab treatment was characterised post hoc in an exploratory analysis from the N-MOmentum study (NCT02200770).MethodsPeripheral blood CD20+ B cells, PC gene signature, and immunoglobulin levels were assessed throughout N-MOmentum (follow-up ≥2.5 years); correlations with clinical metrics and magnetic resonance imaging (MRI) lesion activity were assessed.FindingsInebilizumab induced durable B-cell and PC depletion within 1 week versus placebo. Although no association was observed between B-cell counts at time of attack and NMOSD activity, depth of B-cell depletion after the first dosing period correlated with clinical outcomes. All participants receiving inebilizumab demonstrated a robust long-term therapeutic response, and participants with ≤4cells/μL after the first 6-month dosing interval had persistently deeper B-cell depletion, lower annualised attack rates (estimated rate [95% CI]: 0.034 [0.024-0.04] vs 0.086 [0.056-0.12]; p=0.045), fewer new/enlarging T2 MRI lesions (0.49 [0.43-0.56] vs 1.36 [1.12-1.61]; p&nbsp

In recent years, the use of magnetic resonance imaging (MRI) for the diagnostic work-up of multiple sclerosis (MS) has evolved considerably. The 2017 McDonald criteria show high sensitivity and accuracy in predicting a second clinical attack in patients with a typical clinically isolated syndrome and allow an earlier diagnosis of MS. They have been validated, are evidence-based, simplify the clinical use of MRI criteria and improve MS patients’ management. However, to limit the risk of misdiagnosis, they should be applied by expert clinicians only after the careful exclusion of alternative diagnoses. Recently, new MRI markers have been proposed to improve diagnostic specificity for MS and reduce the risk of misdiagnosis. The central vein sign and chronic active lesions (i.e., paramagnetic rim lesions) may increase the specificity of MS diagnostic criteria, but further effort is necessary to validate and standardize their assessment before implementing them in the clinical setting. The feasibility of subpial demyelination assessment and the clinical relevance of leptomeningeal enhancement evaluation in the diagnostic work-up of MS appear more limited. Artificial intelligence tools may capture MRI attributes that are beyond the human perception, and, in the future, artificial intelligence may complement human assessment to further ameliorate the diagnostic work-up and patients’ classification. However, guidelines that ensure reliability, interpretability, and validity of findings obtained from artificial intelligence approaches are still needed to implement them in the clinical scenario. This review provides a summary of the most recent updates regarding the application of MRI for the diagnosis of MS.

ObjectiveTo assess treatment effects on Expanded Disability Status Scale (EDSS) score worsening and modified Rankin Scale (mRS) scores in the N-MOmentum trial of inebilizumab, a humanized anti-CD19 monoclonal antibody, in participants with neuromyelitis optica spectrum disorder (NMOSD).MethodsAdults (N = 230) with aquaporin-4 immunoglobulin G-seropositive NMOSD or -seronegative neuromyelitis optica and an EDSS score ≤8 were randomized (3:1) to receive inebilizumab 300 mg or placebo on days 1 and 15. The randomized controlled period (RCP) was 28 weeks or until adjudicated attack, with an option to enter the inebilizumab open-label period. Three-month EDSS-confirmed disability progression (CDP) was assessed using a Cox proportional hazard model. The effect of baseline subgroups on disability was assessed by interaction tests. mRS scores from the RCP were analyzed by the Wilcoxon-Mann-Whitney odds approach.ResultsCompared with placebo, inebilizumab reduced the risk of 3-month CDP (hazard ratio [HR]: 0.375; 95% CI: 0.148-0.952; p = 0.0390). Baseline disability, prestudy attack frequency, and disease duration did not affect the treatment effect observed with inebilizumab (HRs: 0.213-0.503; interaction tests: all p > 0.05, indicating no effect of baseline covariates on outcome). Mean EDSS scores improved with longer-term treatment. Inebilizumab-treated participants were more likely to have a favorable mRS outcome at the end of the RCP (OR: 1.663; 95% CI: 1.195-2.385; p = 0.0023).ConclusionsDisability outcomes were more favorable with inebilizumab vs placebo in participants with NMOSD.Classification of evidenceThis study provides Class II evidence that for patients with NMOSD, inebilizumab reduces the risk of worsening disability. N-MOmentum is registered at ClinicalTrials.gov: NCT02200770.

Supplemental material, sj-pdf-1-msj-10.1177_1352458521988926 for Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD by Bruce AC Cree, Jeffrey L Bennett, Ho Jin Kim, Brian G Weinshenker, Sean J Pittock, Dean Wingerchuk, Kazuo Fujihara, Friedemann Paul, Gary R Cutter, Romain Marignier, Ari J Green, Orhan Aktas, Hans-Peter Hartung, Ian M Williams, Jorn Drappa, Dewei She, Daniel Cimbora, William Rees, John N Ratchford and Eliezer Katz in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-mso-10.1177_20552173211052656 for Diagnostic value of aquaporin-4-IgG live cell based assay in neuromyelitis optica spectrum disorders by Vyanka Redenbaugh, Mayra Montalvo, Elia Sechi, Marina Buciuc, James P. Fryer, Andrew McKeon, Vanda A. Lennon, John R. Mills, Brian G. Weinshenker, Dean M. Wingerchuk, John J. Chen, M. Tariq Bhatti, A. Sebastian Lopez Chiriboga, Sean J. Pittock and Eoin P. Flanagan in Multiple Sclerosis Journal ��� Experimental, Translational and Clinical

Supplemental material, sj-pdf-1-msj-10.1177_1352458521988926 for Sensitivity analysis of the primary endpoint from the N-MOmentum study of inebilizumab in NMOSD by Bruce AC Cree, Jeffrey L Bennett, Ho Jin Kim, Brian G Weinshenker, Sean J Pittock, Dean Wingerchuk, Kazuo Fujihara, Friedemann Paul, Gary R Cutter, Romain Marignier, Ari J Green, Orhan Aktas, Hans-Peter Hartung, Ian M Williams, Jorn Drappa, Dewei She, Daniel Cimbora, William Rees, John N Ratchford and Eliezer Katz in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-mso-10.1177_20552173211052656 for Diagnostic value of aquaporin-4-IgG live cell based assay in neuromyelitis optica spectrum disorders by Vyanka Redenbaugh, Mayra Montalvo, Elia Sechi, Marina Buciuc, James P. Fryer, Andrew McKeon, Vanda A. Lennon, John R. Mills, Brian G. Weinshenker, Dean M. Wingerchuk, John J. Chen, M. Tariq Bhatti, A. Sebastian Lopez Chiriboga, Sean J. Pittock and Eoin P. Flanagan in Multiple Sclerosis Journal ��� Experimental, Translational and Clinical

Supplemental material, sj-pdf-1-msj-10.1177_13524585211048401 for Multiple sclerosis diagnosis: Knowledge gaps and opportunities for educational intervention in neurologists in the United States by Andrew J Solomon, Marwa Kaisey, Stephen C Krieger, Salim Chahin, Robert T Naismith, Sarah M Weinstein, Russell T Shinohara and Brian G Weinshenker in Multiple Sclerosis Journal

Supplemental material, sj-docx-1-mso-10.1177_20552173211048761 for Clinical Significance of Myelin Oligodendrocyte Glycoprotein Autoantibodies in Patients with Typical MS Lesions on MRI by Pietro Zara, Valentina Floris, Eoin P. Flanagan, A. Sebastian Lopez-Chiriboga, Brian G. Weinshenker, Paolo Solla and Elia Sechi in Multiple Sclerosis Journal ��� Experimental, Translational and Clinical

Supplemental material, sj-pdf-2-msj-10.1177_13524585211048401 for Multiple sclerosis diagnosis: Knowledge gaps and opportunities for educational intervention in neurologists in the United States by Andrew J Solomon, Marwa Kaisey, Stephen C Krieger, Salim Chahin, Robert T Naismith, Sarah M Weinstein, Russell T Shinohara and Brian G Weinshenker in Multiple Sclerosis Journal

Supplemental material, sj-pdf-2-msj-10.1177_13524585211048401 for Multiple sclerosis diagnosis: Knowledge gaps and opportunities for educational intervention in neurologists in the United States by Andrew J Solomon, Marwa Kaisey, Stephen C Krieger, Salim Chahin, Robert T Naismith, Sarah M Weinstein, Russell T Shinohara and Brian G Weinshenker in Multiple Sclerosis Journal

Supplemental material, sj-pdf-1-msj-10.1177_13524585211048401 for Multiple sclerosis diagnosis: Knowledge gaps and opportunities for educational intervention in neurologists in the United States by Andrew J Solomon, Marwa Kaisey, Stephen C Krieger, Salim Chahin, Robert T Naismith, Sarah M Weinstein, Russell T Shinohara and Brian G Weinshenker in Multiple Sclerosis Journal

Supplemental material, MSJ951046_supplement for MOG-IgG1 and co-existence of neuronal autoantibodies by Amy Kunchok, Eoin P Flanagan, Karl N Krecke, John J Chen, J Alfredo Caceres, Justin Dominick, Ian Ferguson, Revere Kinkel, John C Probasco, Miguel Ruvalcaba, Jonathan D Santoro, Kurt Sieloff, Jeremy Timothy, Brian G Weinshenker, Andrew McKeon and Sean J Pittock in Multiple Sclerosis Journal

Supplemental material, MSJ933884_supplemental_material for Coexisting systemic and organ-specific autoimmunity in MOG-IgG1-associated disorders versus AQP4-IgG+ NMOSD by Amy Kunchok, Eoin P Flanagan, Melissa Snyder, Ruba Saadeh, John J Chen, Brian G Weinshenker, Andrew McKeon and Sean J Pittock in Multiple Sclerosis Journal

Objective To assess whether cervical spinal cord atrophy heralds the onset of progressive MS. Methods We studied 34 individuals with radiologically isolated syndrome (RIS) and 31 patients with relapsing-remitting MS (RRMS) age matched to 25 patients within a year of onset of secondary progressive MS (SPMS). Two raters independently measured (twice per rater) the cervical spinal cord average segmental area (CASA) (mm2) of axial T2-weighted images between C2 and C7 landmarks. The midsagittal T2-weighted image from the end of C2 to the end of C7 vertebra was used to measure the cervical spine (c-spine) length (mm). Sex, age at cervical MRI, number and location of cervical spinal cord lesions, c-spine length, and diagnoses were analyzed against the outcome measures of CASA and C2 and C7 slice segmental areas. Results Intrarater and interrater agreement was excellent (intraclass correlation coefficient >0.97). The CASA area (p = 0.03) and C7 area (p = 0.002) were smaller in SPMS compared with RRMS. The C2 area (p = 0.027), CASA (p = 0.004), and C7 area (p = 0.003) were smaller in SPMS compared with RIS. The C2 area did not differ between SPMS and RRMS (p = 0.09). The C2 area (p = 0.349), CASA (p = 0.136), and C7 area (p = 0.228) did not differ between RIS and MS (SPMS and RRMS combined). In the multivariable model, ≥2 cervical spinal cord lesions were associated with the C2 area (p = 0.008), CASA (p = 0.009), and C7 area independent of disease course (p = 0.017). Progressive disease course was associated with the C7 area independent of the cervical spinal cord lesion number (p = 0.004). Conclusion Cervical spinal cord atrophy is evident at the onset of progressive MS and seems partially independent of the number of cervical spinal cord lesions. Classification of evidence This study provides Class III evidence that MRI cervical spinal cord atrophy distinguishes patients at the onset of progressive MS from those with RIS and RRMS.

Neuromyelitis optica (NMO) is an inflammatory CNS syndrome distinct from multiple sclerosis (MS) that is associated with serum aquaporin-4 immunoglobulin G antibodies (AQP4-IgG). Prior NMO diagnostic criteria required optic nerve and spinal cord involvement but more restricted or more extensive CNS involvement may occur. The International Panel for NMO Diagnosis (IPND) was convened to develop revised diagnostic criteria using systematic literature reviews and electronic surveys to facilitate consensus. The new nomenclature defines the unifying term NMO spectrum disorders (NMOSD), which is stratified further by serologic testing (NMOSD with or without AQP4-IgG). The core clinical characteristics required for patients with NMOSD with AQP4-IgG include clinical syndromes or MRI findings related to optic nerve, spinal cord, area postrema, other brainstem, diencephalic, or cerebral presentations. More stringent clinical criteria, with additional neuroimaging findings, are required for diagnosis of NMOSD without AQP4-IgG or when serologic testing is unavailable. The IPND also proposed validation strategies and achieved consensus on pediatric NMOSD diagnosis and the concepts of monophasic NMOSD and opticospinal MS. consensus development conference journal article practice guideline research support, non-u.s. gov't 2015 Jul 14 2015 06 19 imported

Current management of neuromyelitis optica (NMO) is noncurative and only partially effective. Immunosuppressive or immunomodulatory agents are the mainstays of maintenance treatment. Safer, better-tolerated, and proven effective treatments are needed. The perceived rarity of NMO has impeded clinical trials for this disease. However, a diagnostic biomarker and recognition of a wider spectrum of NMO presentations has expanded the patient population from which study candidates might be recruited. Emerging insights into the pathogenesis of NMO have provided rationale for exploring new therapeutic targets. Academic, pharmaceutical, and regulatory communities are increasingly interested in meeting the unmet needs of patients with NMO. Clinical trials powered to yield unambiguous outcomes and designed to facilitate rapid evaluation of an expanding pipeline of experimental agents are needed. NMO-related disability occurs incrementally as a result of attacks; thus, limiting attack frequency and severity are critical treatment goals. Yet, the severity of NMO and perception that currently available agents are effective pose challenges to study design. We propose strategies for NMO clinical trials to evaluate agents targeting recovery from acute attacks and prevention of relapses, the 2 primary goals of NMO treatment. Aligning the interests of all stakeholders is an essential step to this end.

Short transverse myelitis (STM;3 vertebral segments) is considered noncharacteristic of neuromyelitis optica (NMO) spectrum disorders (NMOSDs). Nonappreciation of the potential for STM to occur in NMOSD may lead to increased disability from delay in diagnosis and appropriate treatment.To determine the frequency of short lesions at the initial myelitis manifestation of NMOSD and to compare the demographic, clinical, and radiological characteristics of aquaporin-4-IgG (AQP4-IgG) seropositive and seronegative STM.We reviewed the records and images of patients at the Mayo Clinic who were identified as AQP4-IgG positive from 1996 to 2014. Inclusion criteria were first STM episode, magnetic resonance imaging performed 90 days or less from symptom onset, spinal cord T2-hyperintense lesion less than 3 vertebral segments, AQP4-IgG seropositivity, and a final diagnosis of NMO or NMOSD. Patients with an initial longitudinally extensive transverse myelitis were excluded (n = 151). Patients with STM who were seronegative for AQP4-IgG among an Olmsted County population-based cohort of inflammatory demyelinating disorders of the central nervous system were used as a control group.Delay to diagnosis in months, clinical and radiological characteristics, and disability measured by ambulatory status.Twenty-five patients who were AQP4-IgG seropositive with an initial STM represented 14% of initial myelitis episodes among patients with NMOSD. The STM episode was defined as the first manifestation of NMOSD in 10 patients (40%) preceded by optic neuritis in 13 patients (52%) and preceded by a nausea and vomiting episode in 2 patients (8%). In comparison with the excluded patients with NMOSD who had an initial longitudinally extensive transverse myelitis, delay to diagnosis/treatment was greater when initial lesions were short (P = .02). In AQP4-IgG-positive STM cases, subsequent myelitis episodes were longitudinally extensive in 92%. Attributes more common in patients with AQP4-IgG-positive STM than in 27 population-based patients with AQP4-IgG-negative STM included the following: nonwhite race/ethnicity; tonic spasms; coexisting autoimmunity; magnetic resonance imaging (central cord lesions, T1 hypointensity, and a brain inconsistent with multiple sclerosis); and cerebrospinal fluid (oligoclonal bands lacking).Short transverse myelitis is not uncommon in NMOSD and, when it is present, delays diagnosis and treatment. Clinical and radiological characteristics identified in this study may help select patients with STM who are at the highest risk for an NMOSD. Short transverse myelitis does not exclude consideration of AQP4-IgG testing or NMOSD diagnosis.

The aquaporin-4-specific serum autoantibody neuromyelitis optica (NMO) IgG is a validated biomarker distinguishing NMO spectrum disorders from multiple sclerosis (MS). Because fulminant attacks are more common in NMO spectrum disorders than in MS, some investigators suggest that NMO IgG may be a marker of destructive demyelination rather than a disease-specific biomarker. To our knowledge, this study is the first to compare NMO IgG serostatus among patients with fulminant central nervous system inflammatory demyelinating disease (CNS IDD).To determine whether NMO IgG distinguishes patients with NMO spectrum disorders from those with other fulminant corticosteroid-refractory CNS IDD.Descriptive historical cohort.Neuroimmunology laboratory and neurology practice, Mayo Clinic College of Medicine, Rochester, Minnesota. Patients Serum samples from 74 patients who underwent plasmapheresis between February 24, 1993, and November 22, 2007, for a corticosteroid-refractory CNS IDD were tested for NMO IgG by indirect immunofluorescence assay.Two blinded observers scored serum samples tested at 1:120 dilution. Clinical data were obtained by medical record review.Preplasmapheresis serum samples were available from 74 patients (ratio of women to men, 2:5); the mean interval between blood draw and plasmapheresis was 13 days. At the time of plasmapheresis, the mean age of patients was 46 years (age range, 7-80 years); the mean Expanded Disability Status Scale score was 7.0 (score range, 3.5-9.5 [10.0 is death]). Diagnoses included MS (18 patients with definite and 11 patients with probable), longitudinally extensive transverse myelitis involving at least 3 vertebral segments (20 patients), NMO (14 patients), transverse myelitis involving fewer than 3 vertebral segments (8 patients), optic neuritis (2 patients), and acute disseminated encephalomyelitis (1 patient). Neuromyelitis optica IgG was detected in 20 patients (27%) (10 with longitudinally extensive transverse myelitis, 9 with NMO, and 1 with recurrent optic neuritis) and was not detected in any patient with MS, short transverse myelitis, monophasic optic neuritis, or acute disseminated encephalomyelitis.Neuromyelitis optica IgG is a specific biomarker for NMO spectrum disorders and is not simply a marker of destructive CNS IDD.

Background: Optic neuritis (ON) is often an early inflammatory, demyelinating event of multiple sclerosis (MS). We proffer that cytokine and chemokine profiles may (a) differ between patients with MS-related ON and those with non-MS-related ON and (b) predict conversion to MS in patients presenting with a first attack of ON. Methods: We recruited patients with acute, isolated ON as a prospective cohort between 2014 and 2016. Patients underwent clinical examination and sampling of blood and cerebrospinal fluid (CSF). Fifty-two patients with ON were included in the study. Of those, 39 patients had serum and CSF samples taken within the acute phase of onset and prior to glucocorticoid treatment (median interval from onset of symptoms 14 days, range 2-59). Twenty-six were females, 13 were males. The median age was 36 years (range 16-66). Overall, 17/39 patients were diagnosed with MS during one year follow-up. Blood and CSF IL-1β, IL-6, IL-10, IL-17, and TNF-α were measured on the highly sensitive Simoa™ platform from Quanterix, MA, US. CXCL13 was measured with an ELISA from Euroimmun, Lübeck, Germany with a stated detection limit of 10 pg/ml. For statistical analyses, multiple t-tests with Holm-Šidák correction or Fisher's exact test were used as appropriate. Results: CSF levels of TNF-α and IL-10 were significantly higher in patients who converted to MS compared to those who remained with isolated ON (TNF-α: median 0.370 pg/ml vs. 0.164 pg/ml, p=0.010; IL-10: median 0.398 pg/ml vs. 0.082 pg/ml, p=0.009). Similarly, CXCL13 in the CSF was detected more frequently in the MS-ON group than in those who did not convert (8/17 versus 2/22, p=0.0107). CSF pleocytosis, oligoclonal bands as well as increased IgG-index and albumin ratio were more frequent in patients who converted to MS than those with acute isolated ON (p< 0.0001, p=0.0013, p=0.009 and p=0.041, respectively). The cytokines IL-1β, IL-6 and IL-17 were measurable in CSF and serum, levels did not differ between groups. Conclusions: Levels of CSF TNF-α and IL-10 and CXCL13 differed between acute isolated ON patients who had converted to MS at follow-up compared to those who had not. These findings are of potential relevance to our understanding of the pathogenesis of MS and may predict conversion of ON to MS.

The 2010 McDonald criteria for the diagnosis of multiple sclerosis are widely used in research and clinical practice. Scientific advances in the past 7 years suggest that they might no longer provide the most up-to-date guidance for clinicians and researchers. The International Panel on Diagnosis of Multiple Sclerosis reviewed the 2010 McDonald criteria and recommended revisions. The 2017 McDonald criteria continue to apply primarily to patients experiencing a typical clinically isolated syndrome, define what is needed to fulfil dissemination in time and space of lesions in the CNS, and stress the need for no better explanation for the presentation. The following changes were made: in patients with a typical clinically isolated syndrome and clinical or MRI demonstration of dissemination in space, the presence of CSF-specific oligoclonal bands allows a diagnosis of multiple sclerosis; symptomatic lesions can be used to demonstrate dissemination in space or time in patients with supratentorial, infratentorial, or spinal cord syndrome; and cortical lesions can be used to demonstrate dissemination in space. Research to further refine the criteria should focus on optic nerve involvement, validation in diverse populations, and incorporation of advanced imaging, neurophysiological, and body fluid markers.

MRI has improved the diagnostic work-up of multiple sclerosis, but inappropriate image interpretation has contributed to misdiagnosis. Filippi et al. provide a practical guide to the proper recognition of multiple sclerosis lesions, including a thorough description and illustration of typical MRI features, as well as a discussion of red flags suggestive of alternative diagnoses., MRI has improved the diagnostic work-up of multiple sclerosis, but inappropriate image interpretation and application of MRI diagnostic criteria contribute to misdiagnosis. Some diseases, now recognized as conditions distinct from multiple sclerosis, may satisfy the MRI criteria for multiple sclerosis (e.g. neuromyelitis optica spectrum disorders, Susac syndrome), thus making the diagnosis of multiple sclerosis more challenging, especially if biomarker testing (such as serum anti-AQP4 antibodies) is not informative. Improvements in MRI technology contribute and promise to better define the typical features of multiple sclerosis lesions (e.g. juxtacortical and periventricular location, cortical involvement). Greater understanding of some key aspects of multiple sclerosis pathobiology has allowed the identification of characteristics more specific to multiple sclerosis (e.g. central vein sign, subpial demyelination and lesional rims), which are not included in the current multiple sclerosis diagnostic criteria. In this review, we provide the clinicians and researchers with a practical guide to enhance the proper recognition of multiple sclerosis lesions, including a thorough definition and illustration of typical MRI features, as well as a discussion of red flags suggestive of alternative diagnoses. We also discuss the possible place of emerging qualitative features of lesions which may become important in the near future.