Diagnosis and classification of optic neuritis

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an immune-mediated inflammatory central nervous system (CNS) disease that has been gradually recognized in recent years and is currently considered as a distinct disease entity distinguished from multiple sclerosis and neuromyelitis optica spectrum disorder. Lately, the new diagnostic criteria for MOGAD proposed by the International MOGAD Panel were published.1 The new criteria cover six core clinical phenotypes (optic neuritis, myelitis, acute disseminated encephalomyelitis, cerebral monofocal or polyfocal deficits, brainstem or cerebellar deficits, and cerebral cortical encephalitis often with seizures), emphasize the positive serum MOG-immunoglobulin G (IgG) test (determined using cell-based assay) and exclusion of alternative causes, and include supporting clinical/neuroimaging features to offset possible deficiencies in antibody detection, aiming to provide precise diagnosis of MOGAD and avoid overdiagnosis. MOGAD, with diverse clinico-radiological manifestations, is deemed to be the “great mimic”. While the new diagnostic criteria may be relatively strict in clinical practice, we are concerned that some patients suffering from MOGAD may be omitted according to the current standards. For instance, some patients, who clearly tested positive for serum MOG-IgG, presented with fever, headache, and leptomeningeal enhancement on brain magnetic resonance imaging (MRI). In this clinical setting, MOG antibody-associated aseptic meningitis is the most reasonable diagnosis.2, 3 However, these patients are unlikely to be diagnosed with MOGAD according to the new criteria, given that meningitis does not fit into any of the six defined phenotype classifications. In another scenario, a few patients with seizures (a relatively common presentation in MOGAD4) may have normal brain MRI (especially at the disease onset),5 and may not sufficiently fulfil the new criteria, which can affect the early diagnosis of MOGAD, thus delaying immunotherapy. In addition, short segment myelitis (SSM, < 3 contiguous vertebral segments in length) is not uncommon in MOGAD. Ciron et al. evaluated 73 patients with MOGAD and found 28 (38.4%) had short lesions and 45 (61.6%) had long lesions at the first episode of myelitis.6 Moreover, the occurrence of conus medullaris involvement varied in different populations, which seems to be more uncommon in patients presenting in China (2/59 [3.4%]7), than those in Europe (22/73 [30.1%]6) and North America (21/51 [41.2%]8). Similarly, in our center with recent 5-year data, conus medullaris injury was observed in 2/17 [11.8%] cases with myelitis as the onset manifestation. SSM, with eccentric lesions and without conus medullaris involvement, can occur with low positive serum MOG-IgG. These patients would also fail to meet with the current criteria, but their clinical findings may still be relevant to MOG-IgG. Furthermore, MOG-IgG associated myelitis with negative initial spinal cord MRI occurred in 7/73 patients with MOGAD.9 For the patients with MRI-negative myelitis, if detected with low positive serum MOG-IgG, also challenge the diagnosis of MOGAD according to the new criteria, which may lead to the therapeutic dilemma. Moving forward, detailed studies of MOGAD are likely to identify additional clinico-radiological phenotypes, and the frequency of existing phenotypes will also change, and the diagnostic criteria need to be revised and updated with the times. Although there is still room for improvement, the publication of the 2023 criteria is a key step towards unifying and standardizing the diagnosis of MOGAD, pushing its research into a new era. We expect that the next version of MOGAD criteria will include the uncommon clinical phenotypes, which would allow clinicians to be more vigilant in identifying patients with MOGAD that are presenting with atypical manifestations. Furthermore, we suggest it would be beneficial to define levels of diagnostic certainty (such as possible/probable/definite MOGAD), similar to the diagnostic criteria for autoimmune encephalitis and paraneoplastic neurological syndromes. We believe that these approaches may be more advantageous in clinical diagnosis and management strategies, compensating for lower sensitivity from the current strict diagnostic criteria in the pursuit of higher specificity, so as to decrease underdiagnosis. Given that MOGAD is a treatable disease, but therapeutic regimens are still different from those for other inflammatory CNS diseases, early identification can facilitate timely and optimal treatment, thus improving the prognosis. Not applicable. The authors declare no conflict of interest. Not applicable. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Although cupping of the optic nerve is classically a sign of glaucomatous optic neuropathy, it has been shown that cupping can sometimes occur after an episode of optic neuritis (ON). The purpose of this study was to compare cupping in patients after ON from multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to investigate the relationship between cupping and retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thinning. This was a retrospective cohort involving patients (≥18 years) with ON from 3 institutions. Patients were eligible if they had optical coherence tomography (Cirrus, OCT) performed ≥6 months after a single unilateral ON. The amount of thinning and cupping was estimated from the difference in the OCT parameters between affected and unaffected eyes. Univariable and multivariable regressions were used to investigate the relationship between cupping and ON etiology. Pearson correlation was used to investigate the relationship between cupping and RNFL and GCC. Eighty-six subjects (MS: 35, NMOSD: 26, and MOGAD: 25) were included. There was no significant difference in gender and race between the groups, and most patients (86.1%) were female. Patients with NMOSD were significantly older than patients with MS or MOGAD ( P = 0.002). In the univariate model, cupping was significantly higher in the NMOSD group ( P = 0.017); however, after adjusting for age, GCC, and RNFL of the affected eye, the difference was no longer statistically significant ( P = 0.949). The correlation between cupping asymmetry and RNFL and GCC of the affected eye was inversely strong in patients with MS (R = -0.60 and R = -0.64, respectively), inversely moderate in patients with MOGAD (R = -0.34 and R = -0.40, respectively), and weak in patients with NMOSD (R = -0.03 and R = -0.17, respectively). Our results demonstrated that cupping after ON is correlated with RNFL and GCC thinning; although cupping was overall greater in the NMOSD group, once adjusted for age, RNFL, and GCC, it did not differ among patients with MS, NMOSD, and MOGAD.

Should Spinal MRI Be Routinely Performed in Patients With Clinically Isolated Optic Neuritis?

Central nervous system (CNS) inflammatory demyelinating diseases (IDDs) associated with COVID-19: A case series and review

ObjectivesTo examine volumetric magnetic resonance imaging (vMRI) in myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD), compared to multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and healthy controls (HC).MethodsStandardized vMRI in MOGAD were compared to age, sex, and disease duration matched MS (5:1), and non‐matched NMOSD and HC, in mixed linear models with time and group interactions. Disability assessments included; patient determined disease steps (PDDS), manual dexterity (MDT), walking speed (WST), processing speed (PST), and contrast sensitivity tests (CST). Correlations between vMRI and disability in MOGAD were examined.ResultsA total of 293 patients were included; 32 MOGAD, 160 MS, 49 NMOSD, and 52 HC. MOGAD had a faster rate of volume loss in all brain regions compared to HC (p < 0.05). At baseline, MOGAD had preserved thalamic (0.000507, p = 0.005), caudate (0.000287, p = 0.004), and putamen (0.000341, p = 0.007) fractions than MS. Longitudinally, MOGAD had increased lateral ventricle fraction (LVF) (−0.000645, p = 0.032), but less hippocampal (0.000031, p = 0.044) and upper cervical cord area (UCCA) loss (1.482887, p = 0.005), compared to NMOSD. MOGAD had increased LVF (0.00529, p < 0.001), but less UCCA loss (0.538656, p = 0.042) longitudinally compared to MS. Among MOGAD, UCCA was associated with PDDS (−0.72, p = 0.004) and CST (0.60, p = 0.014). Whole brain fraction (WBF) was associated with PDDS (−0.66, p = 0.01) and PST (0.52, p = 0.019). LVF was associated with PDDS (0.78, p < 0.001).InterpretationMOGAD showed longitudinal brain volume loss compared to HC. Deep gray matter was relatively preserved compared to MS, while MS and NMOSD had greater UCCA loss, indicating regional differences in atrophy. Despite less overall atrophy, volume loss in MOGAD was associated with disability. ANN NEUROL 2025;98:1044–1056

Optic neuritis (ON) can present as the first demyelinating attack in both multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), which may require different treatment depending on the final diagnosis. We present 2 young Hispanic women who presented with ON during pregnancy, one of whom was diagnosed with MS and the other with MOGAD. We describe key clinical features to help differentiate between MS and MOGAD including ON features, brain and spinal MRI, CSF profiles, and serum MOG and aquaporin-4 (AQP-4) antibodies, which all can help guide clinicians to an ultimate diagnosis. Pregnancy is usually considered an immunotolerant state because complex immunologic shifts arising to support tolerance of the developing fetus seem to decrease the risk of relapses. However, relapses may still occur during pregnancy, and relapse rates increase immediately postpartum. Our cases raise the possibility that young Hispanic patients may face increased risk of demyelinating disease activity even during the relatively immunotolerant state of pregnancy. A high index of suspicion for demyelinating disease should be maintained to accelerate diagnosis and prevent disability.

Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria

ABSTRACTBackgroundComorbidities occur in aquaporin‐4 antibody‐positive neuromyelitis optica spectrum disorder (AQP4‐NMOSD), myelin oligodendrocyte glycoprotein antibody‐associated disease (MOGAD), and double seronegative NMOSD (DN‐NMOSD), potentially contributing to a less favorable disease course.ObjectivesTo characterize comorbidities in AQP4‐NMOSD, MOGAD, and DN‐NMOSD and assess their association with optic neuritis (ON) outcomes by optical coherence tomography (OCT) in AQP4‐NMOSD.MethodsFour hundred and forty‐two participants from the CROCTINO cohort were evaluated for comorbidities.ResultsIn AQP4‐NMOSD patients (n = 360), 43.5% (n = 161) had comorbidities, equally divided between single and multiple. In MOGAD (n = 49), 40.8% had comorbidities, with 75% (n = 15) single and 25% (n = 5) multiple. In DN‐NMOSD (n = 33), 36.4% (n = 12) had comorbidities equally split. AQP4‐NMOSD patients had more multiple comorbidities (50%, n = 81/161) than MOGAD (25%, n = 5/20, p = 0.03) and more autoimmune disorders (AID) (40.4%, n = 65) than MOGAD (20%, n = 4, p = 0.09) and DN‐NMOSD (none, p = 0.004). Cardiovascular comorbidities and related risk factors (CVC/RF) occurred in 34.8% (n = 56) of AQP4‐NMOSD, 50% (n = 10) of MOGAD, and 33.3% (n = 4) of DN‐NMOSD. Expanded Disability Status Scale was higher in MOGAD (3.0 vs. 2.0, p = 0.006) and DN‐NMOSD (5.0 vs. 2.0, p = 0.008) with comorbidities. AQP4‐NMOSD patients with CVC/RF had higher ON relapse rates than those with AID (1.06 ± 3.33 vs. 0.49 ± 0.98, p < 0.001). OCT revealed reduced inner nuclear layer thickness in AQP4‐NMOSD with comorbidities compared to non‐comorbidity (B = −1.52, p = 0.047), more pronounced with CVC/RF (B = −2.96, p = 0.009).ConclusionComorbidities are frequent in AQP4‐NMOSD and MOGAD and are associated with ON frequency and disability. These findings highlight the need for proactive comorbidity management to improve patient care.

Optic neuritis (ON) is an inflammatory condition of the optic nerve associated with demyelinating diseases like multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease. The complement system is crucial in ON pathogenesis, driving blood-optic nerve barrier disruption, inflammation, and tissue damage. This review explores the complement activation pathways-classical, alternative, and lectin-and their roles in ON progression. Key proteins such as C3, C5, and terminal pathway components are highlighted as central to disease mechanisms. Recent advances in complement-targeted therapies, including C1q blockers, C3 and C5 inhibitors, show promising results in clinical and preclinical studies. Novel therapies, like anaphylatoxin receptor blockers and recombinant factor H, expand the treatment landscape, while plasma exchange remains vital for severe, corticosteroid-resistant cases. Challenges remain, such as ON heterogeneity, the long-term safety of complement inhibition, and the need for personalized approaches. Future studies should focus on unraveling complement-mediated mechanisms, identifying biomarkers, and refining therapeutic strategies. This review highlights the critical role of complement in ON and the latest therapeutic advances to improve patient outcomes.

Demyelinating diseases constitute the most frequent cause of non-traumatic neurological disability in the pediatric population. Conventional MRI, while sensitive to focal white matter injury, lacks specificity to discern between edema, demyelination and axonal loss. This study aimed to employ advanced MRI biomarkers-specifically macromolecular tissue volume (MTV) and neurite orientation dispersion and density imaging (NODDI)-derived metrics-to assess myelin integrity (myelin volume fraction, MVF), axonal density (neurite density index, NDI), and the g-ratio in pediatric patients with multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Thirty-nine pediatric patients (MS, n = 15; NMOSD, n = 6; MOGAD, n = 11), including 7 age-matched heathy controls, underwent 3 Tesla MRI as part of a cross-sectional study. Multi-echo gradient echo and multi-shell diffusion sequences were acquired to compute MTV and NODDI metrics. Lesional and normal-appearing white matter (NAWM) were segmented, and imaging metrics (MVF, NDI, and g-ratio) were compared across groups. Correlations between imaging biomarkers and clinical measures were also examined. MS demonstrated significantly higher lesional g-ratio than MOGAD (p = 0.02) and NMOSD (p = 0.02) and lower MVF than NMOSD (p = 0.006), indicating greater relative myelin loss. NAWM partitioning identified higher deep-NAWM ODI in MS patients than controls (p = 0.04). Within the MS cohort, 25ftW was associated with g-ratio, MVF, and NDI measures for both whole-brain and deep NAWM. Advanced MRI biomarkers provide a more nuanced characterization of microstructural alterations in pediatric demyelinating diseases. The distinct imaging profiles-highlighting greater demyelination in MS versus MOGAD and NMOSD-support the utility of these metrics for targeted clinical management and therapeutic stratification. Future longitudinal studies are warranted to further validate their role in monitoring disease progression and treatment response.

Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is the most recently defined inflammatory demyelinating disease of the central nervous system (CNS). Over the last decade, several studies have helped delineate the characteristic clinical-MRI phenotypes of the disease, allowing distinction from aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (AQP4-IgG+NMOSD) and multiple sclerosis (MS). The clinical manifestations of MOGAD are heterogeneous, ranging from isolated optic neuritis or myelitis to multifocal CNS demyelination often in the form of acute disseminated encephalomyelitis (ADEM), or cortical encephalitis. A relapsing course is observed in approximately 50% of patients. Characteristic MRI features have been described that increase the diagnostic suspicion (e.g., perineural optic nerve enhancement, spinal cord H-sign, T2-lesion resolution over time) and help discriminate from MS and AQP4+NMOSD, despite some overlap. The detection of MOG-IgG in the serum (and sometimes CSF) confirms the diagnosis in patients with compatible clinical-MRI phenotypes, but false positive results are occasionally encountered, especially with indiscriminate testing of large unselected populations. The type of cell-based assay used to evaluate for MOG-IgG (fixed vs. live) and antibody end-titer (low vs. high) can influence the likelihood of MOGAD diagnosis. International consensus diagnostic criteria for MOGAD are currently being compiled and will assist in clinical diagnosis and be useful for enrolment in clinical trials. Although randomized controlled trials are lacking, MOGAD acute attacks appear to be very responsive to high dose steroids and plasma exchange may be considered in refractory cases. Attack-prevention treatments also lack class-I data and empiric maintenance treatment is generally reserved for relapsing cases or patients with severe residual disability after the presenting attack. A variety of empiric steroid-sparing immunosuppressants can be considered and may be efficacious based on retrospective or prospective observational studies but prospective randomized placebo-controlled trials are needed to better guide treatment. In summary, this article will review our rapidly evolving understanding of MOGAD diagnosis and management.

Grey matter (GM) atrophies are observed in multiple sclerosis, neuromyelitis optica spectrum disorders [NMOSD; both anti-aquaporin-4 antibody-positive (AQP4+) and -negative (AQP4-) subtypes] and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Revealing the pathogenesis of brain atrophy in these disorders would help their differential diagnosis and guide therapeutic strategies. To determine the neurobiological underpinnings of GM atrophies in multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD and MOGAD, we conducted a virtual histology analysis that links T1-weighted image derived GM atrophy and gene expression using a multicentre cohort of 324 patients with multiple sclerosis, 197 patients with AQP4+ NMOSD, 75 patients with AQP4- NMOSD, 47 patients with MOGAD and 2169 healthy control subjects. First, interregional GM atrophy profiles across the cortical and subcortical regions were determined using Cohen's d between patients with multiple sclerosis, AQP4+ NMOSD, AQP4- NMOSD or MOGAD and healthy controls. The GM atrophy profiles were then spatially correlated with the gene expression levels extracted from the Allen Human Brain Atlas, respectively. Finally, we explored the virtual histology of clinical-feature relevant GM atrophy using a subgroup analysis that stratified by physical disability, disease duration, number of relapses, lesion burden and cognitive function. Multiple sclerosis showed a severe widespread GM atrophy pattern, mainly involving subcortical nuclei and brainstem. AQP4+ NMOSD showed an obvious widespread pattern of GM atrophy, predominately located in occipital cortex as well as cerebellum. AQP4- NMOSD showed a mild widespread GM atrophy pattern, mainly located in frontal and parietal cortices. MOGAD showed GM atrophy mainly involving the frontal and temporal cortices. High expression of genes specific to microglia, astrocytes, oligodendrocytes and endothelial cells in multiple sclerosis, S1 pyramidal cells in AQP4+ NMOSD, as well as S1 and CA1 pyramidal cells in MOGAD, had spatial correlations with GM atrophy profile, while no atrophy profile-related gene expression was found in AQP4- NMOSD. Virtual histology of clinical feature-relevant GM atrophy pointed mainly to the shared neuronal and endothelial cells, among the four neuroinflammatory diseases. The unique underlying virtual histology patterns were microglia, astrocytes and oligodendrocytes for multiple sclerosis; astrocytes for AQP4+ NMOSD; and oligodendrocytes for MOGAD. Neuronal and endothelial cells were shared potential targets across these neuroinflammatory diseases. These findings may help the differential diagnoses of these diseases and promote the use of optimal therapeutic strategies.

Diagnosing neuromyelitis optica spectrum disorder (NMOSD) may be challenging owing to overlapping clinical features with multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), particularly in AQP4-IgG seronegative NMOSD patients. We evaluated cerebrospinal fluid (CSF) biomarkers, specifically glial fibrillary acidic protein (GFAP) and albumin quotient (QAlb), to improve diagnostic accuracy in NMOSD. In this retrospective study, we analyzed CSF samples for biomarkers GFAP, QAlb, neurofilament light, and total-Tau, from patients with AQP4-NMOSD, DNNMOSD, MOGAD, and MS in the Region Västra Götaland, Sweden. Receiver operating characteristic (ROC) analysis with calculation of the area under the curve (AUC) was used to identify optimal cut-off levels for discriminating AQP4-NMOSD from the other groups. Logistic regression models assessed the diagnostic power of GFAP and QAlb combined. Patients with AQP4-NMOSD (N = 19) had significantly higher CSF GFAP levels than the others: median 2470 ng/L vs 330 ng/L (p < 0.001). The GFAP cutoff >715 ng/L gave a sensitivity of 81 % and specificity of 92 %. Combining GFAP and QAlb further increased the diagnostic accuracy (AUC = 0.96). MOGAD patients (N = 29) had the highest CSF lymphocyte counts, with elevated lymphocyte counts correlating with polyphasic MOGAD (R = 0.63; p = 0.016). CSF GFAP is a valuable biomarker for distinguishing AQP4-NMOSD from other demyelinating diseases: Combining GFAP with QAlb enhances diagnostic precision.

ABSTRACTIntroduction:The involvement of ocular system especially optic neuritis (ON) is an important clinical aspect of inflammatory demyelinating disease (IDD) of the central nervous system. The primary IDD spectrum includes neuromyelitis optica spectrum disorders (NMOSD), myelin oligodendrocyte glycoprotein-associated diseases (MOGAD), multiple sclerosis (MS), and clinically isolated syndrome (CIS). The clinical presentation of ON varies according to disease pathophysiology.Aim:We aimed to determine the clinical characteristics of treatment-naïve ON at baseline and on the 6-month follow-up and assessed the predictors of visual outcome.Methods:A prospective study of patients with treatment-naïve ON was performed with structural and functional ophthalmological evaluation. Univariate and multivariate logistic regression analyses were used to determine the predictive factors of visual outcome.Results:Out of 46 patients of IDD, ON occurred in 30 patients. The etiological subtyping included NMOSD (10), CIS (8), MOGAD (7), and MS (5) patients in our study. The ON group showed female preponderance, greater delay in diagnosis, and significant relapsing course. Bilaterality occurred predominantly in NMOSD followed by MOGAD. Optical coherence tomography analysis showed predominant thinning of superior and inferior quadrants in retinal nerve fiber layer (RNFL) and global thinning of Ganglion cell inner plexiform layer (GC-IPL) in NMOSD, but the values were not statistically significant. Univariate analysis for predictors of visual outcome showed age at onset, delay in diagnosis, NMOSD, longitudinally extensive ON (LEON) and chiasmal lesions were associated with poor outcome, while multivariate analysis showed statistical association of NMOSD and LEON with poor outcome.Conclusion:NMOSD and longitudinally extensive optic neuritis showed poor ophthalmological outcome and optical coherence tomography was unyielding.

Prognosis biomarkers in MOGAD: What can we learn from observational studies?