Sex ratio and age of onset in AQP4 antibody-associated NMOSD: a review and meta-analysis.

BACKGROUND: Aquaporin-4 (AQP4) antibody-associated neuromyelitis optica spectrum disorder (NMOSD) is an antibody-mediated inflammatory disease of the central nervous system. We have undertaken a systematic review and meta-analysis to ascertain the sex ratio and mean age of onset for AQP4 antibody associated NMOSD. We have also explored factors that impact on these demographic data. METHODS: A systematic search of databases was conducted according to the PRISMA guidelines. Articles reporting sex distribution and age of onset for AQP4 antibody-associated NMSOD were reviewed. An initially inclusive approach involving exploration with regression meta-analysis was followed by an analysis of just AQP4 antibody positive cases. RESULTS: A total of 528 articles were screened to yield 89 articles covering 19,415 individuals from 88 population samples. The female:male sex ratio was significantly influenced by the proportion of AQP4 antibody positive cases in the samples studied (p < 0.001). For AQP4 antibody-positive cases the overall estimate of the sex ratio was 8.89 (95% CI 7.78-10.15). For paediatric populations the estimate was 5.68 (95% CI 4.01-8.03) and for late-onset cases, it was 5.48 (95% CI 4.10-7.33). The mean age of onset was significantly associated with the mean life expectancy of the population sampled (p < 0.001). The mean age of onset for AQP4 antibody-positive cases in long-lived populations was 41.7 years versus 33.3 years in the remainder. CONCLUSIONS: The female:male sex ratio and the mean age of onset of AQP4 antibody-associated NMOSD are significantly higher than MS. The sex ratio increases with the proportion of cases that are positive for AQP4 antibodies and the mean age of onset increases with population life expectancy.

MR Imaging Features of Critical Spinal Demyelinating Lesions Associated with Progressive Motor Impairment.

BACKGROUND AND PURPOSE: Progressive MS is typically heralded by a myelopathic pattern of asymmetric progressive motor weakness. Focal individual "critical" demyelinating spinal cord lesions anatomically associated with progressive motor impairment may be a compelling explanation for this clinical presentation as described in progressive solitary sclerosis (single CNS demyelinating lesion), progressive demyelination with highly restricted MR imaging lesion burden (2-5 total CNS demyelinating lesions; progressive paucisclerotic MS), and progressive, exclusively unilateral hemi- or monoparetic MS (>5 CNS demyelinating progressive unilateral hemi- or monoparetic MS [PUHMS] lesions). Critical demyelinating lesions appear strikingly similar across these cohorts, and we describe their specific spinal cord MR imaging characteristics. MATERIALS AND METHODS: We performed a retrospective, observational MR imaging study comparing spinal cord critical demyelinating lesions anatomically associated with progressive motor impairment with any additional "noncritical" (not anatomically associated with progressive motor impairment) spinal cord demyelinating lesions. All spinal cord MR images (302 cervical and 91 thoracic) were reviewed by an experienced neuroradiologist with final radiologic assessment on the most recent MR imaging. Anatomic association with clinical progressive motor impairment was confirmed independently by MS subspecialists. RESULTS: Ninety-one individuals (PUHMS, 37 [41%], progressive paucisclerosis 35 [38%], progressive solitary sclerosis 19 [21%]) with 91 critical and 98 noncritical spinal cord MR imaging demyelinating lesions were evaluated. MR imaging characteristics that favored critical spinal cord demyelinating lesions over noncritical lesions included moderate-to-severe, focal, lesion-associated spinal cord atrophy: 41/91 (45%) versus 0/98 (0%) (OR, 161.91; 9.43 to >999.9); lateral column axial location (OR, 10.43; 3.88-28.07); central region (OR, 3.23; 1.78-5.88); ventral column (OR, 2.98; 1.55-5.72); and larger lesion size of the axial width (OR, 2.01;1.49-2.72), transverse axial size (OR, 1.66; 1.36-2.01), or lesion area (OR, 1.14; 1.08-1.2). Multiple regression analysis revealed focal atrophy and lateral axial location as having the strongest association with critical demyelinating lesions. CONCLUSIONS: Focal, lesion-associated atrophy, lateral column axial location, and larger lesion size are spinal cord MR imaging characteristics of critical demyelinating lesions. The presence of critical demyelinating lesions should be sought as these features may be associated with the development of progressive motor impairment in MS.

Safety and efficacy of inebilizumab for the treatment of neuromyelitis optica spectrum disorder: end-of-study results from the open-label period of the N-MOmentum trial.

BACKGROUND: Inebilizumab, an anti-CD19 B-cell-depleting antibody, demonstrated safety and efficacy in neuromyelitis optica spectrum disorder in the randomised controlled period of the N-MOmentum trial. Here, end-of-study data, including the randomised controlled period and open-label extension period, are reported. METHODS: In the double-blind, randomised, placebo-controlled, phase 2/3 N-MOmentum trial, adults aged 18 years and older with an neuromyelitis optica spectrum disorder diagnosis, Expanded Disability Status Scale score of 8·0 or less, and history of either at least one acute inflammatory attack requiring rescue therapy in the past year or two attacks requiring rescue therapy in the past 2 years, were recruited from 81 outpatient specialty clinics or hospitals in 24 countries. Eligible participants were randomly assigned (3:1), using a central interactive voice system or interactive web response system, and a permuted block randomisation scheme (block size of 4), to receive intravenous inebilizumab (300 mg) or identical placebo on days 1 and 15 of the randomised period, which lasted up to 197 days. Participants and all study staff were masked to treatment assignment. The primary endpoint of the randomised period of the trial was time to onset of adjudicated neuromyelitis optica spectrum disorder attack on or before day 197. Participants in the randomised controlled period who had an adjudicated attack, completed 197 days in the study, or were in the randomised controlled period when enrolment stopped, could voluntarily enter the open-label period. In the open-label period, participants either initiated inebilizumab if assigned placebo (receiving 300 mg on days 1 and 15 of the open-label period) or continued treatment if assigned inebilizumab (receiving 300 mg on day 1 and placebo on day 15, to maintain B-cell depletion and masking of the randomised controlled period). All participants subsequently received inebilizumab 300 mg every 6 months for a minimum of 2 years. The end-of-study analysis endpoints were time to adjudicated attack and annualised attack rate (assessed in all participants who received inebilizumab at any point during the randomised controlled period or open-label period [any inebilizumab population] and the aquaporin-4 [AQP4]-IgG seropositive subgroup [any inebilizumab-AQP4-IgG seropositive population]) and safety outcomes (in all participants who were exposed to inebilizumab, analysed as-treated). This study is registered with ClinicalTrials.gov, NCT02200770, and is now complete. FINDINGS: Between Jan 6, 2015, and Sept 24, 2018, 467 individuals were screened, 231 were randomly assigned, and 230 received at least one dose of inebilizumab (n=174) or placebo (n=56). Between May 19, 2015, and Nov 8, 2018, 165 (95%) of 174 participants in the inebilizumab group and 51 (91%) of 56 in the placebo group entered the open-label period (mean age 42·9 years [SD 12·4], 197 [91%] of 216 were female, 19 [9%] were male, 115 [53%] were White, 45 [21%] were Asian, 19 [9%] were American Indian or Alaskan Native, and 19 [9%] were Black or African American). As of data cutoff for this end of study analysis (Dec 18, 2020; median exposure 1178 days [IQR 856-1538], total exposure of 730 person-years) 225 participants formed the any inebilizumab population, and 208 (92%) participants were AQP4-IgG seropositive. Overall, 63 adjudicated neuromyelitis optica spectrum disorder attacks occurred in 47 (21%) of 225 treated participants (60 attacks occurred in 44 [21%] of 208 in the AQP4-IgG seropositive subgroup); 40 (63%) of 63 attacks occurred in 34 (15%) of 225 treated participants during the first year of treatment. Of individuals who had an adjudicated attack while receiving inebilizumab, 36 (77%) of 47 were subsequently attack-free at the end of 4 years. Annualised attack rates decreased year-on-year, with end-of-study adjusted annualised attack rates being similar in the any inebilizumab-AQP4-IgG seropositive subgroup (0·097 [95% CI 0·070-0·14]) and any inebilizumab populations (0·092 [0·067-0·13]). Overall, 208 (92%) of 225 participants who received any inebilizumab had at least one treatment-emergent adverse event, the most frequent of which were urinary tract infection (59 [26%]), nasopharyngitis (47 [21%]), and arthralgia (39 [17%]). Infection rates did not increase over 4 years. Three (1%) of 225 participants in the any inebilizumab population died during the open-label period (one each due to a CNS event of unknown cause and pneumonia, respiratory insufficiency resulting from an neuromyelitis optica spectrum disorder attack and viral pneumonia related to COVID-19), all of which were deemed to be unrelated to treatment. INTERPRETATION: Data from the end-of-study analysis of the N-MOmentum trial showed continued and sustained clinical benefits of long-term inebilizumab treatment in individuals with neuromyelitis optica spectrum disorder, which supports the role of inebilizumab as a CD19+ B-cell-depleting therapy in neuromyelitis optica spectrum disorder. FUNDING: MedImmune and Viela Bio/Horizon Therapeutics, now part of Amgen.

Microfibrillar-associated protein 4 as a potential marker of acute relapse in inflammatory demyelinating diseases of the central nervous system: Pathological and clinical aspects.

BACKGROUND: Microfibrillar-associated protein 4 (MFAP4) is an extracellular matrix protein not previously described in the human central nervous system (CNS). OBJECTIVES: We determined MFAP4 CNS expression and measured cerebrospinal fluid (CSF) and serum levels. METHODS: Tissue was sampled at autopsy from patients with acute multiple sclerosis (MS) (n = 3), progressive MS (n = 3), neuromyelitis optica spectrum disorder (NMOSD) (n = 2), and controls (n = 9), including 6 healthy controls (HC). MFAP4 levels were measured in 152 patients: 49 MS, 62 NMOSD, 22 myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and 19 isolated optic neuritis (ION). RESULTS: MFAP4 localized to meninges and vascular/perivascular spaces, intense in the optic nerve. At sites of active inflammation, MFAP4 reactivity was reduced in NMOSD and acute MS and less in progressive MS. CSF MFAP4 levels were reduced during relapse and at the onset of diseases (mean U/mL: MS 14.3, MOGAD 9.7, and ION 14.6 relative to HC 17.9. (p = 0.013, p = 0.000, and p = 0.019, respectively). Patients with acute ON (n = 68) had reduced CSF MFAP4 (mean U/mL: 14.5, p = 0.006). CSF MFAP4 levels correlated negatively with relapse severity (rho = -0.41, p = 0.017). CONCLUSION: MFAP4 immunoreactivity was reduced at sites of active inflammation. CSF levels of MFAP4 were reduced following relapse and may reflect disease activity.

Inebilizumab reduces neuromyelitis optica spectrum disorder risk independent of FCGR3A polymorphism.

Inebilizumab, a humanized, glycoengineered, IgG1 monoclonal antibody that depletes CD19+ B-cells, is approved to treat aquaporin 4 (AQP4) IgG-seropositive neuromyelitis optica spectrum disorder (NMOSD). Inebilizumab is afucosylated and engineered for enhanced affinity to Fc receptor III-A (FCGR3A) receptors on natural killer cells to maximize antibody-dependent cellular cytotoxicity. Previously, the F allele polymorphism at amino acid 158 of the FCGR3A gene (F158) was shown to decrease IgG-binding affinity and reduce rituximab (anti-CD20) efficacy for NMOSD attack prevention. In contrast, our current findings from inebilizumab-treated NMOSD patients indicate similar clinical outcomes between those with F158 and V158 allele genotypes.

Laboratory evaluation for the differential diagnosis of possible multiple sclerosis in the United States: A physician survey.

BACKGROUND: There is limited evidence and lack of guidelines for diagnostic laboratory evaluation of patients with possible multiple sclerosis (MS). OBJECTIVE: To survey neurologists on their practice of laboratory testing in patients with possible MS. METHODS: An online survey was developed to query the frequency of serum and cerebrospinal fluid (CSF) studies ordered in the routine evaluation of patients with possible MS, and in three hypothetical clinical cases. Non-MS specialist neurologists who evaluate patients for MS in their practice were invited to participate by MedSurvey (a medical market research company). RESULTS: The survey was completed by 190 neurologists. A mean of 17.2 (SD: 17.0) tests in serum and CSF were reported "always" ordered in the evaluation of patients with possible MS. CSF oligoclonal bands was the most frequently selected ("always" among 73.7% of participants). Antinuclear antibody (43.2%), erythrocyte sedimentation rate (34.2%), and thyroid stimulating hormone (31.6%) were also among the most frequently ordered. DISCUSSION: Extensive laboratory evaluations are often completed in the evaluation of possible MS. However, many of these tests have poor specificity and false positive results could yield unnecessary increased costs, diagnostic delay, and potentially misdiagnosis. Further research is needed to identify optimal laboratory approaches for possible MS.

Attack adjudication in neuromyelitis optica spectrum disorder: Substantiation of criteria by magnetic resonance imaging and biomarkers in N-MOmentum.

BACKGROUND: The N-MOmentum trial investigated safety and efficacy of inebilizumab in participants with neuromyelitis optica spectrum disorder (NMOSD). OBJECTIVE: Evaluate the attack identification process and adjudication committee (AC) performance in N-MOmentum. METHODS: Adults (n = 230) with NMOSD and Expanded Disability Status Scale score ⩽8 were randomized (3:1) to inebilizumab 300 mg or placebo. The randomized controlled period was 28 weeks or until adjudicated attack. Attacks were adjudicated according to 18 predefined criteria. Magnetic resonance imaging (MRI) and biomarker (serum glial fibrillary acidic protein [sGFAP]) analyses were performed. RESULTS: A total of 64 participant-reported neurological events occurred; 51 (80%) were investigator-determined to be attacks. The AC confirmed 43 of the investigator-determined attacks (84%). There was high inter- and intra-AC-member agreement. In 25/64 events (39%) and 14/43 AC-adjudicated attacks (33%), MRI was reviewed during adjudication. Retrospective analysis revealed new domain-specific T1 and T2 MRI lesions in 90% of adjudicated attacks. Increased mean sGFAP concentrations (>2-fold change) from baseline were observed in 56% of adjudicated attacks versus 14% of investigator-determined attacks rejected by the AC and 31% of participant-reported events determined not to be attacks. CONCLUSION: AC adjudication of NMOSD attacks according to predefined criteria appears robust. MRI lesion correlates and sGFAP elevations were found in most adjudicated attacks.

Serum neurofilament light chain levels at attack predict post-attack disability worsening and are mitigated by inebilizumab: analysis of four potential biomarkers in neuromyelitis optica spectrum disorder.

OBJECTIVE: To investigate relationships between serum neurofilament light chain (sNfL), ubiquitin C-terminal hydrolase L1 (sUCHL1), tau (sTau) and glial fibrillary acidic protein (sGFAP) levels and disease activity/disability in neuromyelitis optica spectrum disorder (NMOSD), and the effects of inebilizumab on these biomarkers in N-MOmentum. METHODS: N-MOmentum randomised participants to receive inebilizumab or placebo with a randomised controlled period (RCP) of 28 weeks and an open-label follow-up period of ≥2 years. The sNfL, sUCHL1, sTau and sGFAP were measured using single-molecule arrays in 1260 scheduled and attack-related samples from N-MOmentum participants (immunoglobulin G (IgG) autoantibodies to aquaporin-4-positive, myelin oligodendrocyte glycoprotein-IgG-positive or double autoantibody-negative) and two control groups (healthy donors and patients with relapsing-remitting multiple sclerosis). RESULTS: The concentration of all four biomarkers increased during NMOSD attacks. At attack, sNfL had the strongest correlation with disability worsening during attacks (Spearman R2=0.40; p=0.01) and prediction of disability worsening after attacks (sNfL cut-off 32 pg/mL; area under the curve 0.71 (95% CI 0.51 to 0.89); p=0.02), but only sGFAP predicted upcoming attacks. At RCP end, fewer inebilizumab-treated than placebo-treated participants had sNfL>16 pg/mL (22% vs 45%; OR 0.36 (95% CI 0.17 to 0.76); p=0.004). CONCLUSIONS: Compared with sGFAP, sTau and sUCHL1, sNfL at attack was the strongest predictor of disability worsening at attack and follow-up, suggesting a role for identifying participants with NMOSD at risk of limited post-relapse recovery. Treatment with inebilizumab was associated with lower levels of sGFAP and sNfL than placebo. TRIAL REGISTRATION NUMBER: NCT02200770.

Frequency of NMOSD misdiagnosis in a cohort from Latin America: Impact and evaluation of different contributors.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) misdiagnosis (i.e. the incorrect diagnosis of patients who truly have NMOSD) remains an issue in clinical practice. We determined the frequency and factors associated with NMOSD misdiagnosis in patients evaluated in a cohort from Latin America. METHODS: We retrospectively reviewed the medical records of patients with NMOSD, according to the 2015 diagnostic criteria, from referral clinics in six Latin American countries (Argentina, Chile, Paraguay, Colombia, Ecuador, and Venezuela). Diagnoses prior to NMOSD and ultimate diagnoses, demographic, clinical and paraclinical data, and treatment schemes were evaluated. RESULTS: A total of 469 patients presented with an established diagnosis of NMOSD (73.2% seropositive) and after evaluation, we determined that 56 (12%) patients had been initially misdiagnosed with a disease other than NMOSD. The most frequent alternative diagnoses were multiple sclerosis (MS; 66.1%), clinically isolated syndrome (17.9%), and cerebrovascular disease (3.6%). NMOSD misdiagnosis was determined by MS/NMOSD specialists in 33.9% of cases. An atypical MS syndrome was found in 86% of misdiagnosed patients, 50% had NMOSD red flags in brain and/or spinal magnetic resonance imaging (MRI), and 71.5% were prescribed disease-modifying drugs. CONCLUSIONS: NMOSD misdiagnosis is relatively frequent in Latin America (12%). Misapplication and misinterpretation of clinical and neuroradiological findings are relevant factors associated with misdiagnosis.

Present and future of the diagnostic work-up of multiple sclerosis: the imaging perspective.

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.

Progressive motor impairment from "critical" demyelinating lesions of the cervicomedullary junction.

BACKGROUND: Progressive motor impairment anatomically associated with a "critical" lesion has been described in primary demyelinating disease. Most "critical" lesions occur within the spinal cord. OBJECTIVE: To describe the clinical and radiological features of "critical" lesions of the cervicomedullary junction (CMJ). METHODS: Observational study on people presenting with a CMJ lesion associated with primary demyelinating disease-related progressive motor impairment. Clinical data were extracted by chart review. Brain and spinal cord magnetic resonance images were reviewed to characterize the CMJ lesion and determine additional demyelination burden. RESULTS: Forty-one people were included: 29 (71%) had progression from onset and 12 (29%) had a relapse onset (secondary progressive) course. Most had progressive hemiparesis (21 (51%)) or progressive quadriparesis (15 (37%)) with a median Expanded Disability Status Scale (EDSS) of 5.5 (2.0-8.5) at last follow-up. No "critical" CMJ lesion enhanced; most were bilateral (25 (61%)). Brain magnetic resonance images were otherwise normal in 16 (39%) or with a restricted demyelination burden in 15 (37%). Cervical and thoracic cord MRIs were without additional lesions in 25 (61%) and 22/37 (59%), respectively. CONCLUSION: CMJ "critical" lesions can correlate with progressive motor impairment even with few or no additional magnetic resonance imaging (MRI) lesions. Lesion location is an important determinant of progressive motor impairment in demyelinating disease.

Association between B-cell depletion and attack risk in neuromyelitis optica spectrum disorder: An exploratory analysis from N-MOmentum, a double-blind, randomised, placebo-controlled, multicentre phase 2/3 trial.

BACKGROUND: Inebilizumab 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). METHODS: Peripheral 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. FINDINGS: Inebilizumab 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 ≤4 cells/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 < 0.0001), and a trend towards decreased Expanded Disability Status Scale worsening (0.076 [0.06-0.10] vs 0.14 [0.10-0.18]; p = 0.093). Antibodies to inebilizumab, although present in a proportion of treated participants, did not alter outcomes. INTERPRETATION: This analysis suggests that compared with placebo, inebilizumab can provide specific, rapid, and durable depletion of B cells in participants with NMOSD. Although deep and persistent CD20+ B-cell depletion correlates with long-term clinical stability, early, deep B-cell depletion correlates with improved disease activity metrics in the first 2 years. FUNDING: Horizon Therapeutics (formerly from Viela Bio/MedImmune).

Aligning payer and provider strategies with the latest evidence to optimize clinical outcomes for patients with neuromyelitis optica spectrum disorder.

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disorder affecting the central nervous system that is associated with significant morbidity and mortality. Early diagnosis and treatment are essential to minimize long-term disability. Recent advances in the understanding of the pathophysiology of NMOSD have led to multiple new therapies, but significant care and knowledge gaps persist. OBJECTIVES: To summarize current knowledge about the burden of disease and diagnosis and treatment of NMOSD in order to support managed care professionals and health care providers in making collaborative, evidence-based decisions to optimize outcomes among patients with NMOSD. In addition, this review also presents findings of a patient survey that provides insight into real-world experiences of those living with NMOSD. SUMMARY: Diagnosis of NMOSD is based on detection of immunoglobulin G antibodies to the water channel protein aquaporin-4 (AQP4-IgG) in the context of compatible clinical and magnetic resonance imaging features. Patients who are AQP4-IgG seronegative and/or who are positive for myelin oligodendrocyte glycoprotein antibodies may also satisfy criteria for NMOSD. The rarity of the condition combined with the significant overlap in clinical features with other autoimmune diseases affecting the central nervous system, most notably multiple sclerosis, can delay accurate diagnosis, which in turn can delay appropriate treatment, leading to the accumulation of long-term disability. Accumulating disability associated with NMOSD has a substantial negative impact on quality of life. The disease typically evolves as relapsing (ie, repeated) acute attacks. Treatment consists of management of acute attacks, prevention of subsequent attacks, and management of acute and chronic symptoms. The armamentarium of therapies to prevent attacks consists of several monoclonal antibodies (mAbs) approved to treat AQP4-IgG-seropositive disease and several off-label therapies used for patients with either seropositive or seronegative disease. There is limited evidence to guide treatment decision-making, including which therapies to use first line, when to switch, and when to use monotherapy vs combination therapy. In addition, therapies with the greatest demonstrated safety and efficacy in NMOSD are costly and may not be accessible to all patients. Moreover, the results of the patient survey revealed significant clinical and financial burdens to patients with NMOSD including frequent attacks, delays in therapy initiation, need for urgent care and repeat hospitalizations, new and worsening symptoms, accumulating disability, and difficulties affording care. As such, key stakeholders must weigh them against the substantial economic costs of untreated or suboptimal treatment of disease. DISCLOSURES: Dr Wingerchuk has served on the advisory board or panel for Alexion, Biogen, Genentech, Horizon, Mitsubishi Tanabe, Novartis, Roche, UCB, and Viela Bio and has received grants of research support from Alexion. Dr Weinshenker has served as a consultant or on the advisory board or panel for Alexion, Genentech, Horizon, Mitsubishi Tanabe, Roche, UCB, and Viela Bio, served on the speakers bureau or other promotional education for Genentech and Roche, and has received royalties from RSR Ltd.

Frequency of Asymptomatic Optic Nerve Enhancement in a Large Retrospective Cohort of Patients With Aquaporin-4+ NMOSD.

BACKGROUND AND OBJECTIVES: Asymptomatic or persistent optic nerve enhancement in aquaporin-4 (AQP4)-immunoglobulin G (IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) is thought to be rare. Improved understanding may have important implications for assessment of treatment efficacy in clinical trials and in clinical practice. Our objective was to characterize NMOSD interattack optic nerve enhancement. METHODS: This was a retrospective cohort study performed between 2000 and 2019 (median follow-up 5.5 [range 1-35] years) of patients with AQP4-IgG-positive optic neuritis (ON) evaluated at Mayo Clinic. MRI orbits were reviewed by a neuroradiologist, neuro-ophthalmologist, and neuroimmunologist blinded to the clinical history. Interattack optic nerve enhancement (>30 days after attack) was measured. The correlation between interattack enhancement and Snellen visual acuity (VA), converted to logarithm of the minimum angle of resolution (logMAR), at attack and at follow-up were assessed. RESULTS: A total of 198 MRI scans in 100 patients with AQP4-IgG+ NMOSD were identified, with 107 interattack MRIs from 78 unique patients reviewed. Seven scans were performed before any ON (median 61 days before attack [range 21-271 days]) and 100 after ON (median 400 days after attack [33-4,623 days]). Optic nerve enhancement was present on 18/107 (16.8%) interattack scans (median 192.5 days from attack [33-2,943]) of patients with preceding ON. On 15 scans, enhancement occurred at the site of prior attacks; the lesion location was unchanged, but the lesion length was shorter. Two scans (1.8%) demonstrated new asymptomatic lesions (prior scan demonstrated no enhancement). In a third patient with subjective blurry vision, MRI showed enhancement preceding detectable eye abnormalities on examination noted 15 days later. There was no difference in VA at preceding attack nadir (logMAR VA 1.7 vs 2.1; p = 0.79) or long-term VA (logMAR VA 0.4 vs 0.2, p = 0.56) between those with and without interattack optic nerve enhancement. DISCUSSION: Asymptomatic optic nerve enhancement occurred in 17% of patients with NMOSD predominantly at the site of prior ON attacks and may represent intermittent blood-brain barrier breakdown or subclinical ON. New asymptomatic enhancement was seen only in 2% of patients. Therapeutic clinical trials for NMOSD require blinded relapse adjudication when assessing treatment efficacy, and it is important to recognize that asymptomatic optic nerve enhancement can occur in patients with ON.

Confirming a Historical Diagnosis of Multiple Sclerosis: Challenges and Recommendations.

Patients with a historical diagnosis of multiple sclerosis (MS)-a patient presenting with a diagnosis of MS made previously and by a different clinician-present specific diagnostic and therapeutic challenges in clinical practice. Application of the McDonald criteria is most straightforward when applied contemporaneously with a syndrome typical of an MS attack or relapse; however, retrospective application of the criteria in some patients with a historical diagnosis of MS can be problematic. Limited patient recollection of symptoms and evolution of neurologic examination and MRI findings complicate confirmation of an earlier MS diagnosis and assessment of subsequent disease activity or clinical progression. Adequate records for review of prior clinical examinations, laboratory results, and/or MRI scans obtained at the time of diagnosis or during ensuing care may be inadequate or unavailable. This article provides recommendations for a clinical approach to the evaluation of patients with a historical diagnosis of MS to aid diagnostic confirmation, avoid misdiagnosis, and inform therapeutic decision making.

Neuromotor control associates with muscle weakness observed with McArdle sign of multiple sclerosis.

OBJECTIVE: Multiple Sclerosis (MS) is often accompanied by myelopathy, which may be associated with progressive worsening. A specific finding of MS-associated myelopathy is McArdle sign, wherein neck flexion is associated with prominent increased limb weakness relative to that detected with neck extension. In this study, we characterized neuromotor control properties of finger extensors in association with the McArdle sign. METHODS: A custom-built device was utilized to monitor torque production of the wrist extensors with simultaneous recording of surface electromyography of the extensor digitorum. The electromyography was decomposed and analyzed via both linear and nominal regressions. RESULTS: Linear regressions demonstrated a strong difference between groups for MS from healthy controls and other myelopathies for motor unit action potential amplitude and average firing rate (p < 0.001). Further, linear regression demonstrated good correlations of neuromotor variables to mechanical torque output (0.24 ≤ R2 ≤ 0.76). Nominal regression distinguished MS from healthy controls with an AUC of 0.87, specificity of 0.97, and sensitivity of 0.64. Nominal regression of MS from other myelopathies demonstrated an AUC of 0.88, specificity of 0.85, and sensitivity of 0.79. INTERPRETATION: These data demonstrate the neuromotor control factors that largely determine muscle force production change with the observation of McArdle sign; these neuromotor control factors can differentiate MS from both healthy controls and other myelopathy conditions.