Aquaporin-4 Antibody Positive Neuromyelitis Optica Research Articles

Rheumatoid arthritis with aquaporin-4 antibody-positive neuromyelitis optica receiving rituximab therapy

Rheumatoid arthritis with aquaporin-4 antibody-positive neuromyelitis optica receiving rituximab therapy

Serum GFAP and NfL as disease severity and prognostic biomarkers in patients with aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is a frequently disabling neuroinflammatory syndrome with a relapsing course. Blood-based disease severity and prognostic biomarkers for NMOSD are a yet unmet clinical need. Here, we evaluated serum glial fibrillary acidic protein (sGFAP) and neurofilament light (sNfL) as disease severity and prognostic biomarkers in patients with aquaporin-4 immunoglobulin (Ig)G positive (AQP4-IgG+) NMOSD.MethodssGFAP and sNfL were determined by single-molecule array technology in a prospective cohort of 33 AQP4-IgG+ patients with NMOSD, 32 of which were in clinical remission at study baseline. Sixteen myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) patients and 38 healthy persons were included as controls. Attacks were recorded in all AQP4-IgG+ patients over a median observation period of 4.25 years.ResultsIn patients with AQP4-IgG+ NMOSD, median sGFAP (109.2 pg/ml) was non-significantly higher than in MOG-IgG+ patients (81.1 pg/ml; p = 0.83) and healthy controls (67.7 pg/ml; p = 0.07); sNfL did not substantially differ between groups. Yet, in AQP4-IgG+, but not MOG-IgG+ patients, higher sGFAP was associated with worse clinical disability scores, including the Expanded Disability Status Scale (EDSS, standardized effect size = 1.30, p = 0.007) and Multiple Sclerosis Functional Composite (MSFC, standardized effect size = − 1.28, p = 0.01). While in AQP4-IgG+, but not MOG-IgG+ patients, baseline sGFAP and sNfL were positively associated (standardized effect size = 2.24, p = 0.001), higher sNfL was only non-significantly associated with worse EDSS (standardized effect size = 1.09, p = 0.15) and MSFC (standardized effect size = − 1.75, p = 0.06) in patients with AQP4-IgG+ NMOSD. Patients with AQP4-IgG+ NMOSD with sGFAP > 90 pg/ml at baseline had a shorter time to a future attack than those with sGFAP ≤ 90 pg/ml (adjusted hazard ratio [95% confidence interval] = 11.6 [1.3–105.6], p = 0.03). In contrast, baseline sNfL levels above the 75th age adjusted percentile were not associated with a shorter time to a future attack in patients with AQP4-IgG+ NMOSD.ConclusionThese findings suggest a potential role for sGFAP as biomarker for disease severity and future disease activity in patients with AQP4-IgG+ NMOSD in phases of clinical remission.

Central vein sign and other radiographic features distinguishing myelin oligodendrocyte glycoprotein antibody disease from multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica

Background: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) can radiographically mimic multiple sclerosis (MS) and aquaporin-4 (AQP4) antibody-positive neuromyelitis optica spectrum disorder (NMOSD). Central vein sign (CVS) prevalence has not yet been well-established in MOGAD. Objective: Characterize the magnetic resonance imaging (MRI) appearance and CVS prevalence of MOGAD patients in comparison to matched cohorts of MS and AQP4+ NMOSD. Methods: Clinical MRIs from 26 MOGAD patients were compared to matched cohorts of MS and AQP4+ NMOSD. Brain MRIs were assessed for involvement within predefined regions of interest. CVS was assessed by overlaying fluid-attenuated inversion recovery (FLAIR) and susceptibility-weighted sequences. Topographic analyses were performed on spinal cord and orbital MRIs when available. Results: MOGAD patients had fewer brain lesions and average CVS+ rate of 12.1%, compared to 44.4% in MS patients (p = 0.0008). MOGAD spinal cord and optic nerve involvement was lengthier than MS (5.8 vs 1.0 vertebral segments, p = 0.020; 3.0 vs 0.5 cm, p < 0.0001). MOGAD patients tended to have bilateral/anterior optic nerve pathology with perineural contrast enhancement, contrasting with posterior optic nerve involvement in NMOSD. Conclusion: CVS+ rate and longer segments of involvement in the spinal cord and optic nerve can differentiate MOGAD from MS, but do not discriminate as well between MOGAD and AQP4+ NMOSD.

Modified models to distinguish central nervous system demyelinating diseases with brain lesions

BackgroundBrain lesions in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are indistinguishable from those with relapsing-remitting multiple sclerosis (RRMS) and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-Ab NMOSD). MethodsPatients with MOGAD, RRMS, and AQP4-Ab NMOSD with abnormal brain lesions were retrospectively reviewed and divided into training and validation sets. Discriminatory models using brain images and demographics were generated to identify optimal predictors using orthogonal partial least square discriminant analysis after principal component analysis (PCA) of clinico-radiological data without a diagnosis. Constructed models were tested in an independent cohort. ResultsPCA of 51 brain scans and demographics from patients (13 MOGAD, 24 RRMS, and 14 AQP4-Ab NMOSD) demonstrated that RRMS was distinct from antibody-mediated conditions. The best predictors between MOGAD and AQP4-Ab NMOSD were poorly demarcated lesions, large abnormalities (both predictive for MOGAD), female sex, disease duration, linear lesions adjacent to the lateral ventricle, and cerebellum involvement (all predictive for MOGAD). Periventricular, ovoid/round, juxtacortical, and callosal lesions; Dawson's fingers; T1 hypointensity (all predictive for RRMS); and fluffy as well as large lesions (for MOGAD) were the best predictors of MOGAD and RRMS. RRMS versus MOGAD and RRMS versus AQP4-Ab NMOSD models exhibited a high predictive value and perfect accuracy (100%), which was validated in an independent cohort. The model of patients with AQP4-Ab NMOSD and MOGAD exhibited lower predictive power but still achieved an accuracy of 90%. ConclusionsBrain MRI characteristics combined with demographics enables the distinction of MOGAD from RRMS and AQP4-Ab NMOSD. Fluffy and large lesions are relatively specific MRI characteristics in patients with MOGAD with brain abnormalities in Asian countries.

Cerebrospinal fluid lactate level in aquaporin-4 antibody positive neuromyelitis optica spectrum disorders: a hint on differential diagnosis and possible immunopathogenesis

BackgroundNeuromyelitis optica spectrum disorders (NMOSD) and multiple sclerosis (MS) may be similar to each other in clinical features. The differential diagnosis between them remains challenging in clinical practice. This retrospective study is aimed to describe the difference of cerebrospinal fluid (CSF) lactate level between aquaporin-4 antibody (AQP4-Ab) positive NMOSD and MS, to discuss the possible explanation upon immunopathogenesis and the significance in differential diagnosis. MethodWe retrospectively analysed cerebral biochemical results from 60 AQP4-Ab positive NMOSD and 55 MS Asian patients. To assess the diagnostic ability of cerebrospinal fluid lactate for distinguishing AQP4-Ab positive NMOSD from MS using receiver operating characteristic (ROC) curve analysis. ResultsThe cerebrospinal fluid lactate level is significantly higher in AQP4-Ab positive NMOSD than in MS based on multiple linear regression (P<0.0001). The differential diagnostic efficacy of cerebrospinal fluid lactate distinguishing AQP4-Ab positive NMOSD from MS reached an area under ROC curve (AUC) of 0.8842 (95% CI 0.82-0.95, P<0.0001), using 1.50 as the diagnostic critical point of the cerebrospinal fluid lactate level, the sensitivity was 88.3%, the specificity was 78.2%. ConclusionThe cerebrospinal fluid lactate level differs between AQP4-Ab positive NMOSD and MS, which also contributes in differential diagnosis. The distinct patterns of cerebral biochemical results may cast a light on the immunopathogenesis of AQP4-Ab positive NMOSD.

MRI characteristics of MOG-Ab associated disease in adults: An update.

Our knowledge of the radiological spectrum of myelin oligodendrocyte glycoprotein antibody associated disease (MOGAD) is growing rapidly. An update on the radiological features of the disease, and its evolution is thus necessary. Magnetic resonance imaging (MRI) has an increasingly important role in the differential diagnosis of MOGAD particularly from aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD), and multiple sclerosis (MS). Differentiating these conditions is of prime importance because the management is different between the three inflammatory diseases, and thus could prevent further attack-related disability. Therefore, identifying the MRI features suggestive of MOGAD has diagnostic and prognostic implications. We herein review optic nerve, spinal cord and the brain MRI findings from MOGAD adult patients, and compare them to AQP4-NMOSD and MS.

Clinical and laboratory features distinguishing MOG antibody disease from multiple sclerosis and AQP4 antibody-positive neuromyelitis optica

BackgroundAntibodies to myelin oligodendrocyte glycoprotein (MOG) are associated with a CNS inflammatory disorder distinct from multiple sclerosis (MS) and aquaporin-4 antibody-positive neuromyelitis optica (NMO). Knowledge of the clinical spectrum of MOG antibody disease (MOGAD) remains incomplete, particularly in comparison to two related inflammatory demyelinating diseases, MS and NMO. ObjectiveCompare demographics, clinical characteristics, estimated disability, laboratory results, and treatment responses of a U.S. MOGAD cohort with age- and sex-matched MS and NMO patients. Design, setting, and participantsThis observational, case-control, single-center study identified each group via ICD-10 diagnosis code searches through the electronic medical records of adult patients seen at the John L. Trotter MS Center between January 1, 2019 and January 1, 2020. MOGAD and NMO patients were confirmed to have at least one positive antibody test; those in the MS group had a confirmed diagnosis by a physician with MS subspecialty training. Data were collected after IRB approval. ResultsTwenty-six patients were included in each group. MOGAD patients were predominantly Caucasian (88.5%) with mean onset age of 43.9 years. MOGAD patients had no comorbid other autoimmune diseases and comparatively lower rates of family members with autoimmune disease (20.0%) than either MS (40.0%) or NMO (34.6%) matched cohorts. 91% of MOGAD attacks were monofocal, and over 70% presented with optic neuritis. Severity of MOGAD attacks was similar to that of seropositive NMO, but the robust degree of recovery was more similar to MS. Four MOGAD patients converted to negative antibody status, with no attacks occurring after conversion. Serum ANA and ENA were less frequently elevated in MOGAD (21.7%, 5.0%) than in seropositive NMO patients (66.7%, 42.9%). Elevated IgG synthesis rate and positive CSF-restricted oligoclonal bands were not seen in our MOGAD cohort, and only one MOGAD patient had an elevated IgG index. Despite anti-CD20 therapy, 28.6% of MOGAD patients continued to suffer relapses. ConclusionsMOGAD was characterized by a predominantly monofocal presentation (typically optic neuritis) and severe attacks with better recovery than seen with seropositive NMO attacks. Lack of CSF-restricted oligoclonal bands distinguished MOGAD from MS.

Diagnostic value of bright spotty lesions on MRI after a first episode of acute myelopathy

Background and purposeTo determine the diagnostic value of bright spotty lesions (BSLs) for aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (NMOSDAQP4+), the predictive value of axial-BSLs for AQP4-IgG seropositivity, and the radio-clinical differences in NMOSDAQP4+ patients with and without axial-BSLs. Materials and methodsRetrospective study that included patients aged≥16 years, with a first acute spinal cord syndrome between 2005 and 2018 and abnormal spinal cord MRI with axial and sagittal T2 sequences. Patients with MRI findings consistent with compressive myelopathy were excluded. All spinal cord MRI were retrospectively evaluated for the presence of BSLs by 2 radiologists blinded to the diagnosis of acute myelopathy. ResultsA total of 82 patients were included; 15 aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder patients (NMOSDAQP4+), and 67 other patients, considered as the other causes of myelopathy (OM) group. The specificity of axial-BSLs for NMOSDAQP4+ patients was 94.0% (95% CI [85.6 to 97.7]). The sensitivity was 40.0% (95% CI [19.8 to 64.3]). In the multivariable analysis, the only MRI characteristic associated with AQP4-IgG positivity was the presence of axial-BSLs (OR: 9.2, 95% CI [1.2 to 72.9]; P=0.022). In NMOSDAQP4+ patients, the median of cord expansion ratio was higher with axial-BSL (1.2, IQR [1.1–1.3]) than without axial-BSL (1.1, IQR [1.0–1.2]; P=0.046). ConclusionAfter a first acute spinal cord syndrome, the presence of axial-BSLs on spinal cord MRI seems very specific for NMOSDAQP4+ and seems to be a predictor radiological marker of AQP4-IgG positivity.

Infection Risk in Patients with Complement-Mediated Neurological Disorders Receiving Eculizumab: Findings from Two Phase 3 Studies and Their Extensions in Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder (AQP4+ NMOSD) and Acetylcholine-Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis (AChR+ gMG) (1829)

Infection Risk in Patients with Complement-Mediated Neurological Disorders Receiving Eculizumab: Findings from Two Phase 3 Studies and Their Extensions in Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder (AQP4+ NMOSD) and Acetylcholine-Receptor Antibody-Positive Refractory Generalized Myasthenia Gravis (AChR+ gMG) (1829)

Benefit of Eculizumab for a Broad Range of Patients with Aquaporin-4 Antibody-positive Neuromyelitis Optica Spectrum Disorder: Findings from the Phase 3 PREVENT Study (1299)

Benefit of Eculizumab for a Broad Range of Patients with Aquaporin-4 Antibody-positive Neuromyelitis Optica Spectrum Disorder: Findings from the Phase 3 PREVENT Study (1299)

Serum biomarkers and patient age in multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders (2263)

Serum biomarkers and patient age in multiple sclerosis and aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders (2263)

Impact of Eculizumab on Disability Worsening and Quality of Life in Patients with Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder: Results from the Phase 3 PREVENT Study (1658)

Impact of Eculizumab on Disability Worsening and Quality of Life in Patients with Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder: Results from the Phase 3 PREVENT Study (1658)

Impact of Eculizumab on Hospitalization Rates and Relapse Treatment in Patients with Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder: the Phase 3 PREVENT Study (1780)

Impact of Eculizumab on Hospitalization Rates and Relapse Treatment in Patients with Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder: the Phase 3 PREVENT Study (1780)

Impact of Eculizumab on Health Outcomes in Patients with Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder: Findings from the PREVENT Study (1765)

Impact of Eculizumab on Health Outcomes in Patients with Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder: Findings from the PREVENT Study (1765)

Alterations in the Brain Structure and Functional Connectivity in Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder.

PurposeTo investigate the mechanisms underlying the gray matter volume (GMV) and functional connectivity (FC) changes in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (NMOSD) patients.MethodsThis cross-sectional study consisted of 21 patients with aquaporin-4 antibody-positive NMOSD and 22 age- and sex-matched healthy controls. All participants underwent cerebral magnetic resonance imaging and testing each individual’s visual acuity was done.ResultsNeuromyelitis optica spectrum disorder patients showed significantly reduced GMV in the left calcarine, left thalamus and right lingual gyrus of the NMOSD patients when compared to HC (P < 0.05). NMOSD patients showed significantly decreased FC values (P < 0.05) in both the left and right calcarine, right lingual gyrus and left thalamus, respectively, when compared to HC. We also observed a positive correlation between the FC values of the left thalamus, bilateral calcarine gyrus and the visual acuity, respectively (P < 0.05). Furthermore, a negative association was seen between the duration of the disease, frequency of optic neuritis, and the FC values in the lingual gyrus, bilateral calcarine gyrus, and right lingual gyrus, respectively (P < 0.05).ConclusionReduced visual acuity and frequency of optic neuritis are associated with alterations in the GMV and FC in NMOSD. Our current study, which provides imaging evidence on the impairment involved in NMOSD, sheds light on pathophysiological responses of optic neuritis attack on the brain especially on the visual network.

Myelin Oligodendrocyte Glycoprotein (MOG) Antibody-Associated CNS Demyelination: Clinical Spectrum and Comparison with Aquaporin-4 Antibody Positive Neuromyelitis Optica Spectrum Disorder.

The clinical phenotypes of myelin oligodendrocyte glycoprotein (MOG) antibody disease, its disease course, and treatment are poorly understood and much work needs to be done towards this. To characterize the clinico-radiologic spectrum and treatment outcomes of MOG antibody disease and differentiate it from aquaporin-4 (AQP-4) antibody positive neuromyelitis optica spectrum disorders (NMO-SD). A single-center, observational study from Western India during 2017-2019, of 48 patients with either MOG antibody positive (21 patients) or AQP-4 antibody positive (27 patients) central nervous system demyelination. MOG antibody group had median age 32.2 years, no gender bias, median disease duration 40 months, relapses in 9 patients (43%), and median 2.5 (1-16) episodes per patient. Onset phenotypes included isolated bilateral optic neuritis (ON) (43%), isolated unilateral ON (19%), acute brainstem syndrome (19%), simultaneous ON with myelitis (9%), isolated myelitis (5%), and acute disseminated encephalomyelitis optic neuritis (ADEM-ON) (5%). Characteristic neuroimaging abnormalities were anterior segment longitudinally extensive ON, upper brainstem, and thoracic cord involvement (both short and long segment lesions). Most patients (86%) responded well to steroids, only 3/21 required rescue immunotherapy. In total, 6 out of 46 eyes affected developed permanent visual disability, while one patient had motor disability. The features differentiating MOG from AQP-4 antibody group were: no female predilection, preferential optic nerve involvement, characteristic neuroimaging abnormalities, and favorable therapeutic response and outcome. MOG disease commonly presents as severe ON, myelitis, acute brainstem syndrome, ADEM or their combinations. Early identification, treatment, and maintenance immunosuppression are necessary. It can easily be differentiated from NMO-SD using clinico-radiological features and therapeutic response.

Update on pediatric optic neuritis.

To summarize recent developments in the classification, investigation and management of pediatric optic neuritis (PON). A recent surge in interest surrounding antibodies to myelin oligodendrocyte glycoprotein antibody (MOG-Ab) has instigated a paradigm shift in our assessment of children with PON. This serological marker is associated with a broad spectrum of demyelinating syndromes that are clinically and radiologically distinct from multiple sclerosis (MS) and aquaporin-4 antibody positive neuromyelitis optica spectrum disorder (AQP4+NMOSD). Optic neuritis is the most common presenting phenotype of MOG-Ab positive-associated disease (MOG+AD). MOG-Ab seropositivity is much more common in the pediatric population and it predicts a better prognosis than MS or AQP4+NMOSD, except in the subset that exhibit a recurrent phenotype. A better grasp of MOG+AD features and its natural history has facilitated more accurate risk stratification of children after a presenting episode of PON. Consequently, the initial investigation of PON has broadened to include serology, along with neuroimaging and cerebrospinal fluid analysis. Acute treatment of PON and chronic immunotherapy is also becoming better tailored to the suspected or confirmed diagnoses of MS, AQP4+NMOSD and MOG+AD.

Neuromyelitis optica after splenectomy: A secondary autoimmune phenomenon

We describe the case of a 53-year-old woman who undergoes total splenectomy and later presents with aquaporin-4 antibody positive neuromyelitis optica (NMO). The occurrence of NMO after acquired immunosuppression raises the possibility of NMO as a form of secondary autoimmunity.

Peripapillary and parafoveal vascular network assessment by optical coherence tomography angiography in aquaporin-4 antibody-positive neuromyelitis optica spectrum disorders

Background/aimsCurrent understanding of the alterations in the retinal vascular network in neuromyelitis optica spectrum disorders (NMOSDs) is limited. We aim to assess the peripapillary and parafoveal vessel density in aquaporin-4...

Aquaporin-4 antibody positive neuromyelitis optica spectrum disorder associated with esophageal cancer

Autoimmune diseases are sometimes associated with neoplasms. A 70-year-old Japanese woman with myelitis, seropositive for aquaporin-4 (AQP4) antibody, was diagnosed with neuromyelitis optica spectrum disorder (NMOSD); thereafter an esophageal squamous cell carcinoma was identified. Immunohistochemically, her cancer was anti-AQP4 antibody negative. Her symptoms, imaging findings and AQP4 titer markedly improved with corticosteroid and anti-cancer therapies. Although AQP4 may be a paraneoplastic antigen, paraneoplastic syndrome could not be definitively diagnosed in this case. Nevertheless, this is the first report of an association between AQP4 antibody-seropositive NMOSD and esophageal cancer. The possibility of underlying malignancy should be considered in patients diagnosed with NMOSD.