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Impaired visual function is a prevalent feature of optic neuritis (ON) in multiple sclerosis (MS). Abnormal visual evoked potential (VEP) findings of increased latencies, reduced amplitudes and abnormal waveforms as well as decreased retinal nerve fiber layer (RNFL) assessed by optical coherence tomography (OCT) are hallmarks of ON-induced visual dysfunction. Here we utilized the experimental autoimmune encephalomyelitis (EAE) mouse model of MS to investigate the functional and pathological progression during early (before any clinical symptoms), peak (initial maximal clinical symptoms), and late (chronic disease for > 3 weeks) disease stages. Demyelination and initial stages of axon damage were observed in early EAE. Significant demyelination, inflammation, increased axon damage and impaired P1/N2 amplitudes and latencies by VEP were seen in middle and late EAE groups. A decrease in RNFL thickness by OCT was observed only during late EAE. NanoString analysis of optic nerves from late EAE indicated elevated inflammation-related genes, reduced myelin-related genes, and changes in axon degeneration-related genes. Early inflammatory demyelination and functional deficits of the visual pathway, if untreated, may lead to severe irrecoverable axon damage in EAE. These studies potentially help explain the progression of visual dysfunction during MS., (© 2024. The Author(s).)

Background and Objectives: Slow-burning inflammation at the edge, and chronic demyelination at the core, of established multiple sclerosis (MS) lesions are potential mediators of disease progression. However, their relative contribution to progressive axonal damage has not been explored. Therefore, in this study, we investigated the comparative contribution of slow-burning inflammation and chronic demyelination to axonal attrition within MS lesions by measuring progressive tissue rarefaction. In addition, we use the visual system as a model to investigate the effect of chronic demyelination on the acceleration of axonal death in a sub-group of patients with unilateral optic neuritis., Methods: Pre- and post-gadolinium 3D-T1, 3D FLAIR, diffusion tensor images, Optical Coherence tomography and multifocal visual evoked potentials were acquired from 52 relapsing-remitting MS patients who completed at least 5 years follow-up. Lesion expansion was measured using custom software, and the rate of tissue rarefication inside lesion core was assessed by measuring increase of normalized mean diffusivity (nMD). Axonal loss was also examined in eyes with severe optic nerve demyelination., Results: Among the 361 lesions analyzed, 104 were expanding (a minimum of 4 % expansion per year) and 257 were stable. Expanding lesions showed a significantly higher rate of progressive tissue rarefication inside lesion (1.12 % per year) core compared to stable lesions (0.21 % per year, p = 0.01). The magnitude of nMD change was significantly correlated with the rate of lesion expansion (r = 0.4, p < 0.001). Analysis of retinal ganglion cells in eyes with severe optic nerve demyelination (Inter-eye latency delay of >10 ms) revealed a similar rate of axonal loss (0.19 %) to the degree of tissue rarefaction observed in stable lesions (0.21 %)., Discussion: The results of the study suggest that the slow-burning inflammation at the lesion's edge (as measured by lesion expansion), is likely to have a greater impact on tissue damage (as measured by nMD change), when compared to stable chronically demyelinated lesions. The similar modest degree of tissue damage was also observed in chronically demyelinated fibers of the optic nerve., Competing Interests: Declaration of competing interest Authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2024. Published by Elsevier B.V.)

Background: Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system with neuroaxonal damage. It is the principal driver of non-traumatic disability in young adults. Visual symptoms are common and optic neuritis (ON) may be the revealing feature in up to 30% of cases. Structural optical coherence tomography (OCT) represents a biomarker of central nervous system neurodegeneration in MS. OCT-angiography (OCT-A) is a noninvasive tool allowing the study of retinal vasculature and the detection of microvascular damage in neuro-retinal diseases. In this study, we aimed to assess structural and microvascular retinal changes in patients with MS with and without ON and to correlate the findings with visual function and MS disability., Methods: We conducted a cross-sectional study including patients diagnosed with MS according to the 2017 McDonald criteria. All patients underwent complete neurological examination with evaluation of the Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Severity Score (MSSS) and an ophthalmological examination including OCT and OCT-A. Patients were compared with age- and sex-matched healthy subjects. The primary endpoints were assessment of retinal nerve fiber layer (RNFL) thickness, ganglion cell layer (GCL+), and ganglion cell complex (GCL++) thicknesses on OCT. Vascular densities in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris (CC) were assessed on OCT-A, as well as central avascular zone (CAZ) parameters, lacunarity and fractal dimension., Results: A total of 160 MS eyes with and without a previous history of ON and 64 age- and gender-matched healthy eyes were analyzed. Among 160 eyes with MS, 69 had a history of ON. We observed a decrease in RNFL and GCL++ thickness in all 12 quadrants in MS patients when compared to healthy controls. Multivariate analysis by linear regression noted a significant correlation for temporal GCL++ and inferonasal RNFL thickness that were decreased in the MS group. A greater decrease in retinal layers thickness was identified in MS patients with a history of ON. On OCT-A, vascular density in (SCP) was significantly reduced in the MS group (P<0.002). A significant correlation between RNFL thickness and retinal vascular density was found but only in less than half of the hourly quadrants. A significant correlation was noted between visual acuity and CC density (P<0.0001). We also noted an inverse correlation between EDSS scores and CC density (P=0.02 and r=-0.275) and between MSSS and RNFL/GCL++ thicknesses., Conclusions: RNFL and GCL++ layers were thinner in MS patients with a history of ON and were reversely correlated with disease severity. Moreover, retinal vascular changes were observed in MS even in eyes without ON, and CC was reversely correlated with visual function and current disability. Thus, structural OCT coupled with OCT-A could represent a noninvasive and dynamic biomarker of MS severity and progression., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Purpose: Experimental autoimmune encephalomyelitis (EAE) scoring, the most commonly used primary outcome metric for an in vivo model of multiple sclerosis (MS), is highly variable and subjective. Here we explored the use of visual biomarkers in EAE as more objective and clinically relevant primary outcomes., Methods: Motor impairment in myelin oligodendrocyte glycoprotein-immunized C57BL/6J mice was quantified using a five-point EAE grading scale. Pattern electroretinography (pERG) and retinal ganglion cell/inner plexiform layer (RGC/IPL) complex thickness were measured 60 days after induction. Optic nerve histopathology was analyzed at endpoint., Results: EAE mice displayed motor impairments ranging from mild to severe. Significant correlations were seen between pERG amplitude and last EAE score, mean EAE score, and cumulative EAE score. Optical coherence tomography (OCT) analysis demonstrated a significant correlation between thinning of the RGC/IPL complex and both EAE score and pERG amplitude. Optic nerve histopathology showed significant correlations between demyelination and cumulative EAE score, pERG amplitude, and RGC/IPL complex thickness, as well as between immune cell infiltration and cumulative EAE score, pERG amplitude, and RGC/IPL complex thickness in EAE mice., Conclusions: Unlike EAE scoring, pERG and OCT show direct measurement of retinal structure and function. Therefore we conclude that visual outcomes are well suited as a direct assessment of optic nerve involvement in this EAE model of MS while also being indicative of motor impairment., Translational Relevance: Standardizing directly translatable measurements as primary outcome parameters in the murine EAE model could lead to more rapid and relevant testing of new therapeutic approaches for mitigating MS.

Background: Alterations of the superficial retinal vasculature are commonly observed in multiple sclerosis (MS) and can be visualized through optical coherence tomography angiography (OCTA)., Objectives: This study aimed to examine changes in the retinal vasculature during MS and to integrate findings into current concepts of the underlying pathology., Methods: In this cross-sectional study, including 259 relapsing-remitting MS patients and 78 healthy controls, we analyzed OCTAs using deep-learning-based segmentation algorithm tools., Results: We identified a loss of small-sized vessels (diameter < 10 µm) in the superficial vascular complex in all MS eyes, irrespective of their optic neuritis (ON) history. This alteration was associated with MS disease burden and appears independent of retinal ganglion cell loss. In contrast, an observed reduction of medium-sized vessels (diameter 10-20 µm) was specific to eyes with a history of ON and was closely linked to ganglion cell atrophy., Conclusion: These findings suggest distinct atrophy patterns in retinal vessels in patients with MS. Further studies are necessary to investigate retinal vessel alterations and their underlying pathology in MS., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: R.W. received a poster grant by Novartis. L.A. received a research grant by Novartis and travel grants by Novartis, Sanofi and Horizon therapeutics. B.H. has served on scientific advisory boards for Novartis; he has served as DMSC member for AllergyCare, Sandoz, Polpharma, Biocon and TG therapeutics; he or his institution have received speaker honoraria from Desitin; his institution received research grants from Regeneron and Roche for MS research. He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with MS and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. B.K. received travel support and speaking honoraria from Novartis Deutschland GmbH, Teva Deutschland, Merck, and Heidelberg Engineering and served at the advisory board of Merck. He received a research grant from Novartis. L.K., A.W., D.R., T.K. and M.J.M. have nothing to disclose.

Background: Optic neuritis (ON) is a common feature of inflammatory demyelinating diseases (IDDs) such as multiple sclerosis (MS), aquaporin 4-antibody neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, the involvement of the optic chiasm (OC) in IDD has not been fully investigated., Aims: To examine OC differences in non-acute IDD patients with (ON+) and without ON (ON-) using magnetisation transfer ratio (MTR), to compare differences between MS, AQP4 + NMOSD and MOGAD and understand their associations with other neuro-ophthalmological markers., Methods: Twenty-eight relapsing-remitting multiple sclerosis (RRMS), 24 AQP4 + NMOSD, 28 MOGAD patients and 32 healthy controls (HCs) underwent clinical evaluation, MRI and optical coherence tomography (OCT) scan. Multivariable linear regression models were applied., Results: ON + IDD patients showed lower OC MTR than HCs (28.87 ± 4.58 vs 31.65 ± 4.93; p = 0.004). When compared with HCs, lower OC MTR was found in ON + AQP4 + NMOSD (28.55 ± 4.18 vs 31.65 ± 4.93; p = 0.020) and MOGAD (28.73 ± 4.99 vs 31.65 ± 4.93; p = 0.007) and in ON- AQP4 + NMOSD (28.37 ± 7.27 vs 31.65 ± 4.93; p = 0.035). ON+ RRMS had lower MTR than ON- RRMS (28.87 ± 4.58 vs 30.99 ± 4.76; p = 0.038). Lower OC MTR was associated with higher number of ON (regression coefficient (RC) = -1.15, 95% confidence interval (CI) = -1.819 to -0.490, p = 0.001), worse visual acuity (RC = -0.026, 95% CI = -0.041 to -0.011, p = 0.001) and lower peripapillary retinal nerve fibre layer (pRNFL) thickness (RC = 1.129, 95% CI = 0.199 to 2.059, p = 0.018) when considering the whole IDD group., Conclusion: OC microstructural damage indicates prior ON in IDD and is linked to reduced vision and thinner pRNFL., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: AB has received a research grant from the Italian Society of Neurology; she has been awarded a MAGNIMS-ECTRIMS fellowship in 2023. RC received speaker honoraria/travel support from Roche, Merck Serono, UCB, Sanofi-Genzyme, Novartis, and Janssen, and received a research grant from the Italian Ministry of University and Research. FP received a Guarantors of Brain fellowship 2017-2020. CT is currently being funded by a Miguel Servet contract, awarded by the Instituto de Salud Carlos III (ISCIII), Ministerio de Ciencia e Innovación de España (CP23/00117). She has also received a 2020 Junior Leader La Caixa Fellowship (fellowship code: LCF/BQ/PI20/11760008), awarded by “la Caixa” Foundation (ID 100010434), a 2021 Merck’s Award for the Investigation in MS, awarded by Fundación Merck Salud (Spain), a 2021 Research Grant (PI21/01860) awarded by the ISCIII, Ministerio de Ciencia e Innovación de España, and a FORTALECE research grant (FORT23/00034) also by the ISCIII, Ministerio de Ciencia e Innovación de España. In 2015, she received an ECTRIMS Post-doctoral Research Fellowship and has received funding from the UK MS Society. She is a member of the Editorial Board of Neurology Journal and Multiple Sclerosis Journal. She has also received honoraria from Roche, Novartis, Merck, Immunic Therapeutics, and Bristol Myers Squibb. She is a steering committee member of the O’HAND trial and of the Consensus group on Follow-on DMTs. BK is supported by the NIHR BRC at UCL. FDA has received congress fees or speaker honoraria and/or acted as a consultant for Neurology Academy, Coloplast, Janssen, Merck, Novartis, Roche,Sanofi. WJB has received speaker honoraria and/or acted as a consultant for Biogen, Janssen, Merck, Neuraxpharm, Novartis, Roche, Sanofi, Sandoz and Viatris; he is supported by the NIHR UCLH Biomedical Research Centre. FB is Steering committee or Data Safety Monitoring Board member for Biogen, Merck, ATRI/ACTC and Prothena. He is consultant for Roche, Celltrion, Rewind Therapeutics, Merck, IXICO, Jansen, Combinostics. He has research agreements with Merck, Biogen, GE Healthcare, Roche. Co-founder and shareholder of Queen Square Analytics LTD. OC is a member of independent DSMB for Novartis, gave a teaching talk on McDonald criteria in a Merck local symposium, and contributed to an Advisory Board for Biogen; she is Deputy Editor of Neurology, for which she receives an honorarium. Merck. AD, VC, DW, JS, MCY, and RN have no disclosure. ATT has speaker honoraria from Merck, Biomedia, Sereno Symposia International Foundation, Bayer and At the Limits and meeting expenses from Merck, Biogen Idec and Novartis. Supported by recent grants from the MRC (MR/S026088/1), NIHR BRC (541/CAP/OC/818837) and RoseTrees Trust (A1332 and PGL21/10079). Associate editor for Frontiers in Neurology – Neuro-ophthalmology section and on the editorial board for Neurology and Multiple Sclerosis Journal.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) featuring numerous neuropathologies, including optic neuritis (ON) in some patients. However, the molecular mechanisms of ON remain unknown. Galectins, β-galactoside-binding lectins, are involved in various pathophysiological processes. We previously showed that galectin-3 (gal-3) is associated with the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. In the current study, we investigated the expression of gal-3 in the visual pathway in EAE mice to clarify its role in the pathogenesis of ON. Immunohistochemical analysis revealed upregulation of gal-3 in the visual pathway of the EAE mice during the peak stage of the disease, compared with naïve and EAE mice during the chronic stage. Gal-3 was detected mainly in microglia/macrophages and astrocytes in the visual pathway in EAE mice. In addition, gal-3 + /Iba-1 + cells, identified as phagocytic by immunostaining for cathepsin D, accumulated in demyelinating lesions in the visual pathway during the peak disease stage of EAE. Moreover, NLRP3 expression was detected in most gal-3 + /Iba-1 + cells. These results strongly suggest that gal-3 regulates NLRP3 signaling in microglia/macrophages and neuroinflammatory demyelination in ON. In astrocytes, gal-3 was expressed from the peak to the chronic disease stages. Taken together, our findings suggest a critical role of gal-3 in the pathogenesis of ON. Thus, gal-3 in glial cells may serve as a potential therapeutic target for ON.

Optic neuritis is often an initial symptom in multiple sclerosis (MS) or clinically isolated syndrome (CIS), yet comprehensive studies using the 2017 McDonald criteria for MS are scarce. Patient records from our academic centre (2010-2018) were reviewed. Using the 2017 McDonald criteria, three groups were formed: MS optic neuritis (optic neuritis with confirmed MS), CIS optic neuritis (optic neuritis without confirmed MS) and suspected optic neuritis (sON). We compared clinical and paraclinical findings among the groups to identify predictors for CIS- or MS-optic neuritis. The study included 129 MS, 108 CIS, and 44 sON cases. The combination of visual impairment, dyschromatopsia, and retrobulbar pain was observed in 47% of MS patients, 42% of CIS patients, and 30% of sON patients. Dyschromatopsia was the strongest indicator of MS or CIS diagnosis in the backward regression model. 56% of MS patients had relative afferent pupillary defect, 61% optic nerve anomalies within magnetic resonance imaging, and 81% abnormal visual evoked potentials. Our results emphasize the challenges in diagnosing optic neuritis, as not all patients with objectively diagnosed MS exhibit the triad of typical symptoms. To address potentially missing clinical features, incorporating additional paraclinical findings is proposed., (© 2024. The Author(s).)

The differential diagnosis for optic atrophy can be challenging and requires expensive, time-consuming ancillary testing to determine the cause. While Leber's hereditary optic neuropathy (LHON) and optic neuritis (ON) are both clinically significant causes for optic atrophy, both relatively rare in the general population, contributing to limitations in obtaining large imaging datasets. This study therefore aims to develop a deep learning (DL) model based on small datasets that could distinguish the cause of optic disc atrophy using only fundus photography. We retrospectively reviewed fundus photographs of 120 normal eyes, 30 eyes (15 patients) with genetically-confirmed LHON, and 30 eyes (26 patients) with ON. Images were split into a training dataset and a test dataset and used for model training with ResNet-18. To visualize the critical regions in retinal photographs that are highly associated with disease prediction, Gradient-Weighted Class Activation Map (Grad-CAM) was used to generate image-level attention heat maps and to enhance the interpretability of the DL system. In the 3-class classification of normal, LHON, and ON, the area under the receiver operating characteristic curve (AUROC) was 1.0 for normal, 0.988 for LHON, and 0.990 for ON, clearly differentiating each class from the others with an overall total accuracy of 0.93. Specifically, when distinguishing between normal and disease cases, the precision, recall, and F1 scores were perfect at 1.0. Furthermore, in the differentiation of LHON from other conditions, ON from others, and between LHON and ON, we consistently observed precision, recall, and F1 scores of 0.8. The model performance was maintained until only 10% of the pixel values of the image, identified as important by Grad-CAM, were preserved and the rest were masked, followed by retraining and evaluation., (© 2024. The Author(s).)

Current diagnostic criteria for multiple sclerosis (MS) do not consider the optic nerve as a typical topography for establishing the diagnosis. Recent studies have proved the utility of optic nerve magnetic resonance imaging, optical coherence tomography and visual evoked potentials in detecting optic nerve lesions during the early stages of MS. In addition, emerging evidence supports the inclusion of optic nerve topography as a fifth region to fulfil the dissemination in space criteria. Anticipating a modification in the McDonald criteria, it is crucial for neurologists to familiarize with the diagnostic properties of each test in detecting optic nerve lesions and understand how to incorporate them into the MS diagnostic process. Therefore, the objective of this article is to review the existing evidence supporting the use of these tests in the diagnostic process of MS and provide a practical algorithm that can serve as a valuable guide for clinical practice., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: A.V.-J. has received support for contracts Juan Rodes (JR16/00024) and from Fondo de Investigación en Salud (PI17/02162 and PI22/01589) from Instituto de Salud Carlos III, Spain, and has engaged in consulting and/or participated as speaker in events organized by Roche, Novartis, Merck and Sanofi. J.S.-G. serves as co-editor for Europe for the Multiple Sclerosis Journal and as Editor-in-Chief of Revista de Neurología, receives research support from Fondo de Investigaciones Sanitarias (19/950 and 22/750) and in the past 12 months has served as a consultant/speaker for BMS, Roche, Sanofi, Janssen and Merck. M.T. has received compensation for consulting services, speaking honoraria and research support from Almirall, Bayer Schering Pharma, Biogen-Idec, Genzyme, Janssen, Merck-Serono, Novartis, Roche, Sanofi-Aventis, Viela Bio and Teva Pharmaceuticals. Data Safety Monitoring Board for Parexel and UCB Biopharma. A.R. served on scientific advisory boards for Novartis, Sanofi-Genzyme, Synthetic MR, TensorMedical, Roche and Biogen, and has received speaker honoraria from Bayer, Sanofi-Genzyme, Merck-Serono, Teva Pharmaceutical Industries Ltd, Novartis, Roche, Bristol-Myers and Biogen, is CMO and co-founder of TensorMedical, and receives research support from Fondo de Investigación en Salud (PI19/00950 and PI22/01589) from Instituto de Salud Carlos III, Spain. X.M. has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Abbvie, Actelion, Alexion, Biogen, Bristol-Myers Squibb/Celgene, EMD Serono, Genzyme, Hoffmann-La Roche, Immunic, Janssen Pharmaceuticals, Medday, Merck, Mylan, Nervgen, Novartis, Sandoz, Sanofi-Genzyme, Teva Pharmaceutical, TG Therapeutics, Excemed, MSIF and NMSS.

Objectives: To evaluate the diagnostic performance of the extraocular muscle volume index at the orbital apex (AMI) and the signal intensity ratio (SIR) of the optic nerve in dysthyroid optic neuropathy (DON)., Methods: Clinical data and magnetic resonance imaging were collected retrospectively from 63 Graves' ophthalmopathy patients, including 24 patients with DON and 39 without DON. The volume of these structures was obtained by reconstructing their orbital fat and extraocular muscles. The SIR of the optic nerve and axial length of eyeball were also measured. The posterior 3/5 of the retrobulbar space volume was used as the orbital apex to compare parameters in patients with or without DON. Area under the receiver operating characteristic curve (AUC) analysis was used to select the morphological and inflammatory parameters with the highest diagnostic value. A logistic regression was performed to identify the risk factors of DON., Results: One hundred twenty-six orbits (35 with DON and 91 without DON) were analyzed. Most of the parameters in DON patients were significantly higher than in non-DON patients. However, the SIR 3 mm behind the eyeball of the optic nerve and AMI had the highest diagnostic value in these parameters and are independent risk factors of DON by stepwise multivariate logistic regression analysis. Combining AMI and SIR had a higher diagnostic value than a single index., Conclusions: Combining AMI with SIR 3 mm behind the eyeball's orbital nerve can be a potential parameter for diagnosing DON., Clinical Relevance Statement: The present study provided a quantitative index based on morphological and signal changes to assess the DON, allowing clinicians and radiologists to monitor DON patients timely., Key Points: The extraocular muscle volume index at the orbital apex (AMI) has excellent diagnostic performance for dysthyroid optic neuropathy. A signal intensity ratio (SIR) of 3 mm behind the eyeball has a higher AUC compared to other slices. Combining AMI and SIR has a higher diagnostic value than a single index., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

Background: Optical coherence tomography angiography (OCTA) allows non-invasive assessment of retinal vessel structures. Thinning and loss of retinal vessels is evident in eyes of patients with multiple sclerosis (MS) and might be associated with a proinflammatory disease phenotype and worse prognosis. We investigated whether changes of the retinal vasculature are linked to brain atrophy and disability in MS., Material and Methods: This study includes one longitudinal observational cohort (n=79) of patients with relapsing-remitting MS. Patients underwent annual assessment of the expanded disability status scale (EDSS), timed 25-foot walk, symbol digit modalities test (SDMT), retinal optical coherence tomography (OCT), OCTA, and brain MRI during a follow-up duration of at least 20 months. We investigated intra-individual associations between changes in the retinal architecture, vasculature, brain atrophy and disability. Eyes with a history of optic neuritis (ON) were excluded., Results: We included 79 patients with a median disease duration of 12 (interquartile range 2 - 49) months and a median EDSS of 1.0 (0 - 2.0). Longitudinal retinal axonal and ganglion cell loss were linked to grey matter atrophy, cortical atrophy, and volume loss of the putamen. We observed an association between vessel loss of the superficial vascular complex (SVC) and both grey and white matter atrophy. Both observations were independent of retinal ganglion cell loss. Moreover, patients with worsening of the EDSS and SDMT revealed a pronounced longitudinal rarefication of the SVC and the deep vascular complex., Discussion: ON-independent narrowing of the retinal vasculature might be linked to brain atrophy and disability in MS. Our findings suggest that retinal OCTA might be a new tool for monitoring neurodegeneration during MS., Competing Interests: LA received travel and research support by Novartis Deutschland GmbH. RW received a poster grant from Novartis Deutschland GmbH. AB has received consulting and/or speaker fees from Alexion, Bayer Healthcare, Biogen, Celgene, Novartis Deutschland GmbH, Roche and Sandoz/Hexal. CM is a medical advisor to Heidelberg Engineering, Heidelberg, Germany, receives lecture honorarium by Heidelberg Engineering and Bayer AG, Leverkusen, Germany. CZ has served on scientific advisory boards for Philips and Bayer Schering; serves as co-editor on the Advisory Board of Clinical Neuroradiology; has received speaker honoraria from Bayer-Schering and Philips and has received research support and investigator fees for clinical studies from Biogen Idec, Quintiles, MSD Sharp & Dome, Boehringer Ingelheim, Inventive Health Clinical UK Ltd., Advance Cor, Brainsgate, Pfizer, Bayer-Schering, Novartis, Roche, Servier, Penumbra, WCT GmbH, Syngis, SSS Internartional Clinical Research, PPD Germany GmbH, Worldwide Clinical Trials Ltd., Phenox, Covidien, Actelion, Medivation, Medtronic, Harrison Clinical Research, Concentric, Penumbra, Pharmtrace, Reverse Medical Corp., Premier Research Germany Ltd., Surpass Medical Ltd. and GlaxoSmithKline. TK received travel support and speaking honoraria from Novartis Deutschland GmbH and Merck. BH has served on scientific advisory boards for Novartis Deutschland GmbH; he has served as DMSC member for AllergyCare, Sandoz, Polpharma and TG therapeutics; he or his institution have received speaker honoraria from Desitin; his institution received research grants from Regeneron for multiple sclerosis research. He holds part of two patents; one for the detection of antibodies against KIR4.1 in a subpopulation of patients with multiple sclerosis and one for genetic determinants of neutralizing antibodies to interferon. All conflicts are not relevant to the topic of the study. JK received speaking honoraria from Novartis Deutschland GmbH. BK received travel support and speaking honoraria from Novartis Deutschland GmbH, Teva, Heidelberg Engineering and served at the advisory board of Merck. He received a research grant from Novartis Deutschland GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Romahn, Wiltgen, Bussas, Aly, Wicklein, Noll, Berthele, Dehmelt, Mardin, Zimmer, Korn, Hemmer, Kirschke, Mühlau and Knier.)

Optic neuritis, a characteristic feature of multiple sclerosis (MS), involves the inflammation of the optic nerve and the degeneration of retinal ganglion cells (RGCs). Although previous studies suggest that retinal blood flow alterations occur during optic neuritis, the precise location, the degree of impairment, and the underlying mechanisms remain unclear. In this study, we utilized two emerging non-invasive imaging techniques, laser speckle flowgraphy (LSFG) and optical coherence tomography angiography (OCTA), to investigate retinal vascular changes in a mouse model of MS, known as experimental autoimmune encephalomyelitis (EAE). We associated these changes with leukostasis, RGC injury, and the overall progression of EAE. LSFG imaging revealed a progressive reduction in retinal blood flow velocity and increased vascular resistance near the optic nerve head in the EAE model, indicating impaired ocular blood flow. OCTA imaging demonstrated significant decreases in vessel density, number of junctions, and total vessel length in the intermediate and deep capillary plexus of the EAE mice. Furthermore, our analysis of leukostasis revealed a significant increase in adherent leukocytes in the retinal vasculature of the EAE mice, suggesting the occurrence of vascular inflammation in the early development of EAE pathology. The abovechanges preceded or were accompanied by the characteristic hallmarks of optic neuritis, such as RGC loss and reduced visual acuity. Overall, our study sheds light on the intricate relationship between retinal vascular alterations and the progression of optic neuritis as well as MS clinical score. It also highlights the potential for the development of image-based biomarkers for the diagnosis and monitoring of optic neuritis as well as MS, particularly in response to emerging treatments.

Purpose: To apply adaptive optics-optical coherence tomography (AO-OCT) to quantify multiple sclerosis (MS)-induced changes in axonal bundles in the macular nerve fiber layer, ganglion cell somas, and macrophage-like cells at the vitreomacular interface., Methods: We used AO-OCT imaging in a pilot study of MS participants (n = 10), including those without and with a history of optic neuritis (ON, n = 4), and healthy volunteers (HV, n = 9) to reveal pathologic changes to inner retinal cells and structures affected by MS., Results: We found that nerve fiber layer axonal bundles had 38% lower volume in MS participants (1.5 × 10-3 mm3) compared to HVs (2.4 × 10-3 mm3; P < 0.001). Retinal ganglion cell (RGC) density was 51% lower in MS participants (12.3 cells/mm2 × 1000) compared to HVs (25.0 cells/mm2 × 1000; P < 0.001). Spatial differences across the macula were observed in RGC density. RGC diameter was 15% higher in MS participants (11.7 µm) compared to HVs (10.1 µm; P < 0.001). A nonsignificant trend of higher density of macrophage-like cells in MS eyes was also observed. For all AO-OCT measures, outcomes were worse for MS participants with a history of ON compared to MS participants without a history of ON. AO-OCT measures were associated with key visual and physical disabilities in the MS cohort., Conclusions: Our findings demonstrate the utility of AO-OCT for highly sensitive and specific detection of neurodegenerative changes in MS. Moreover, the results shed light on the mechanisms that underpin specific neuronal pathology that occurs when MS attacks the retina. The new findings support the further development of AO-based biomarkers for MS.

Retinal ischaemia/reperfusion (I/R) injury is a common cause of retinal ganglion cell (RGC) apoptosis and axonal degeneration, resulting in irreversible visual impairment. However, there are no available neuroprotective and neurorestorative therapies for retinal I/R injury, and more effective therapeutic approaches are needed. The role of the myelin sheath of the optic nerve after retinal I/R remains unknown. Here, we report that demyelination of the optic nerve is an early pathological feature of retinal I/R and identify sphingosine-1-phosphate receptor 2 (S1PR2) as a therapeutic target for alleviating demyelination in a model of retinal I/R caused by rapid changes in intraocular pressure. Targeting the myelin sheath via S1PR2 protected RGCs and visual function. In our experiment, we observed early damage to the myelin sheath and persistent demyelination accompanied by S1PR2 overexpression after injury. Blockade of S1PR2 by the pharmacological inhibitor JTE-013 reversed demyelination, increased the number of oligodendrocytes, and inhibited microglial activation, contributing to the survival of RGCs and alleviating axonal damage. Finally, we evaluated the postoperative recovery of visual function by recording visual evoked potentials and assessing the quantitative optomotor response. In conclusion, this study is the first to reveal that alleviating demyelination by inhibiting S1PR2 overexpression may be a therapeutic strategy for retinal I/R-related visual impairment., (© 2023 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.)

Purpose: To study the spatial association of magnetic resonance imaging (MRI) contrast enhancement (CE) areas with visual field defect (VFD) asymmetry in initial cases of optic neuritis (ON) with altitudinal hemianopsia (AH) with reference to nonarteritic anterior ischemic optic neuropathy (NAION) with AH., Study Design: Multicenter, cross-sectional study., Methods: The present study comprised 19 ON patients and 20 NAION patients with AH who underwent orbital contrast fat-suppressed MRI. The signal-to-intensity ratio (SIR) was calculated by dividing the maximum CE of the optic nerve by the mean CE of the cerebral white matter in 11 coronal sections at 3-mm intervals from immediately posterior to the eyeball to the optic chiasm. Sections in ON patients with an SIR exceeding the mean plus 2 standard deviations of the SIR at the corresponding section in the NAION group were considered abnormal. The correlation between upper-to-lower CE asymmetry in the maximum SIR section and VFD counterpart was determined., Results: The ON group had significantly higher maximum SIR than that of the NAION group (1.77 ± 0.88 vs. 1.25 ± 0.32; P < .01). Seven of the 19 patients had sections with abnormally high CE extending posteriorly beyond the orbital apex. Significant spatial correspondence was observed between CE and VFD asymmetry (r s = 0.563; P = .015) in the ON group but not in the NAION group (r s  = - 0. 048; P = .850)., Conclusions: ON patients with AH frequently show CE even in the intracerebral optic nerve, maintaining a moderate structure-function correspondence., (© 2023. Japanese Ophthalmological Society.)

Background: Optic pathway is considered an ideal model to study the interaction between inflammation and neurodegeneration in multiple sclerosis (MS)., Methods: Optical Coherence Tomography (OCT) and 3.0 T magnetic resonance imaging (MRI) were acquired in 92 relapsing remitting (RR) MS at clinical onset. Peripapillary RNFL (pRNFL) and macular layers were measured. White matter (WM) and gray matter (GM) lesion volumes (LV), lateral geniculate nucleus (LGN) volume, optic radiations (OR) WM LV, thickness of pericalcarine cortex were evaluated. OCT and MRI control groups (healthy controls [HC]-OCT and HC-MRI) were included., Results: A significant thinning of temporal pRNFL and papillo-macular bundle (PMB) was observed (p<0.001) in 16 (17%) patients presented with monocular optic neuritis (MSON+), compared to 76 MSON- and 30 HC (-15 μm). In MSON-, PMB was reduced (-3 μm) compared to HC OCT (p<0.05). INL total volume was increased both in MSON+ (p<0.001) and MSON- (p = 0.033). Inner retinal layers volumes (macular RNFL, GCL and IPL) were significantly decreased in MSON+ compared to HC (p<0.001) and MSON- (p<0.001). Reduced GCL volume in the parafoveal ring was observed in MSON- compared to HCOCT (p < 0.05). LGN volume was significantly reduced only in MSON+ patients compared to HC-MRI (p<0.001) and MSON- (p<0.007). GCL, IPL and GCIP volumes associated with ipsilateral LGN volume in MSON+ and MSON-. Finally, LGN volume associated with visual cortex thickness with no significant difference between MSON+ and MSON-., Conclusions: Anterograde trans-synaptic degeneration is early detectable in RRMS presenting with optic neuritis but does not involve LGN., Competing Interests: Declaration of Competing Interest M.S., M.A., C.L., Mo.M., S.P., Pe.M., S.E., D.M., F.S., B.A. have no conflict to disclose. Ma.M. reports grants and personal fees from Almiral. She was awarded a MAGNIMS-ECTRIMS fellowship in 2020. Pu.M. reports grants from Almirall, Teva, Sanofi Genzyme, Merck Serono, Biogen Italy, Novartis, consultancy for Novartis, Biogen Italy, and Sanofi. G.P. reports grants from Almirall, Teva, Sanofi Genzyme, Merck Serono, Biogen Italy, Novartis, Roche, Bristol Myers Squibb; consultancy for Novartis, Biogen Italy, Sanofi Genzyme, Roche, Bristol Myers Squibb; board membership Sanofi Genzyme, Novartis, Biogen Italy, Roche, Merck Serono, Bristol Myers Squibb., (Copyright © 2023. Published by Elsevier B.V.)

Background: The multi-order visual system represents an excellent testing site regarding the process of trans-synaptic degeneration. The presence and extent of global versus trans-synaptic neurodegeneration in people with multiple sclerosis (pwMS) is not clear., Objective: To explore cross-sectional and longitudinal relationships between retinal, thalamic and cortical changes in pwMS with and without MS-related optic neuritis (pwMSON and pwoMSON) using MRI and optical coherence tomography (OCT)., Methods: 162 pwMS and 47 healthy controls (HCs) underwent OCT and brain MRI at baseline and 5.5-years follow-up. Peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell inner plexiform layer (mGCIPL) thicknesses were determined. Global volume measures of brain parenchymal volume (BPV)/percent brain volume change (PBVC), thalamic volume and T2-lesion volume (LV) were derived using standard analysis protocols. Regional cortical thickness was determined using FreeSurfer. Cross-sectional and longitudinal relationship between the retinal measures, thalamic volume and cortical thickness were assessed using age, BPV/PBVC and T2-LV adjusted correlations and regressions., Results: After age, BPV and T2-LV adjustment, the thalamic volume explained additional variance in the thickness of pericalcarine (R 2 increase of 0.066, standardized β = 0.299, p = 0.039) and lateral occipital (R2 increase of 0.024, standardized β = 0.299, p = 0.039) gyrii in pwMSON. In pwoMSON, the thalamic volume was a significant predictor only of control (frontal) regions of pars opercularis. There was no relationship between thalamic atrophy and cortical thinning over the follow-up in both pwMS with and without MSON. While numerically lower in the pwMSON group, the inter-eye difference was not able to predict the presence of MSON., Conclusions: MSON can induce a measurable amount of trans-synaptic pathology on second-order cortical regions., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

Aim: To investigate the structural and functional magnetic resonance imaging (MRI) alterations and their clinical significance for predicting visual outcomes at 3 years in clinically isolated optic neuritis (CION)., Materials and Methods: Forty-three CION patients and 44 matched healthy controls (HC) underwent a three dimensional (3D) T1-weighted and resting-state functional MRI using a 3 T MRI system. Grey-matter volume (GMV) and functional MRI measures were compared among HC and CION patients with good and poor outcomes. The correlations between MRI measures and visual outcomes were investigated, and a binary logistic regression model was performed to predict the visual outcome., Results: CION patients with good and poor outcomes showed similar patterns of decreased GMV and increased functional MRI activities compared to HC. Compared to patients with good visual recovery, CION patients with poor visual recovery showed significantly reduced GMV in the insula and superior temporal gyrus (STG), decreased amplitude of low-frequency fluctuation (ALFF) in the inferior frontal gyrus (IFG), and increased functional activities in the middle frontal gyrus (MFG) and middle temporal gyrus (MTG). Binary logistic regression analysis predicted poor visual recovery, including decreased GMV in the bilateral insula (right insula: odds ratio [OR] = 17.46, p<0.001; left insula: OR=10.538, p=0.001; respectively) and STG (OR=16.551, p<0.001) and increased ALFF (OR=17.148, p<0.001) and regional homogeneity (OR=10.068, p=0.002) in the left MTG., Conclusion: CION patients showed decreased GMV and increased functional activities predominantly located in visual- and cognition-related areas. Decreased GMV and increased ALFF or regional homogeneity in the high-order visual regions (insula, STG, and MTG) are promising imaging markers predicting poor visual outcomes at the 3-year follow-up., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Predicting the long-term disability outcomes of multiple sclerosis (MS) cases is challenging., Objective: We prospectively analysed our previous MS cohort with initial cerebrospinal fluid (CSF) proteomics data to reveal disability markers after 8.2±2.2 years of follow-up., Methods: Patients with regular follow-up visits were assigned into two groups: those with an age-related MS severity (ARMSS) score ≥5 (unfavourable course group, N = 27) and ARMSS score <5 (favourable course group, N = 67). A machine learning-based algorithm was applied to reveal candidate poor prognosis-associated initial CSF proteins, which were measured in an independent MS cohort (verification group, N = 40) by ELISA. Additionally, the correlation of initial clinical and radiological parameters with long-term disability was analysed., Results: CSF alpha-2-macroglobulin (P = 0.0015), apo-A1 (P = 0.0016), and haptoglobin (P = 0.0003) protein levels, as well as cerebral lesion load (>9 lesions) on magnetic resonance imaging, gait disturbance (P = 0.04), and bladder/bowel symptoms (P = 0.01) were significantly higher in the unfavourable course group than in the favourable course group. Optic nerve involvement evident on initial magnetic resonance imaging (P = 0.002) and optic neuritis (P = 0.01) were more frequent in the favourable course group., Conclusion: The herein identified initial CSF protein levels, in addition to the clinical and radiological parameters at disease onset, have predictive value for long-term disability in MS cases., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Everest et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Transorbital sonography (TOS) could be a swift and convenient method to detect the atrophy of the optic nerve, possibly providing a marker that might reflect other quantitative structural markers of multiple sclerosis (MS). Here we evaluate the utility of TOS as a complementary tool for assessing optic nerve atrophy, and investigate how TOS-derived measures correspond to volumetric brain markers in MS. We recruited 25 healthy controls (HC) and 45 patients with relapsing-remitting MS and performed B-mode ultrasonographic examination of the optic nerve. Patients additionally underwent MRI scans to obtain T1-weighted, FLAIR and STIR images. Optic nerve diameters (OND) were compared between HC, MS patients with and without history of optic neuritis (non-ON) using a mixed-effects ANOVA model. The relationship between within-subject-average OND and global and regional brain volumetric measures was investigated using FSL SIENAX, voxel-based morphometry and FSL FIRST. OND was significantly different between HC-MS (HC = 3.2 ± 0.4 mm, MS = 3 ± 0.4 mm; p < 0.019) and we found significant correlation between average OND and normalised whole brain (β = 0.42, p < 0.005), grey matter (β = 0.33, p < 0.035), white matter (β = 0.38, p < 0.012) and ventricular cerebrospinal fluid volume (β = - 0.36, p < 0.021) in the MS group. History of ON had no impact on the association between OND and volumetric data. In conclusion, OND is a promising surrogate marker in MS, that can be simply and reliably measured using TOS, and its derived measures correspond to brain volumetric measures. It should be further explored in larger and longitudinal studies., (© 2023. The Author(s).)

Objectives: We investigated choroid plexus (CP) volume in patients presenting with optic neuritis (ON) as a clinically isolated syndrome (CIS), compared to a cohort with established relapsing-remitting multiple sclerosis (RRMS) and healthy controls (HCs)., Methods: Three-dimensional (3D) T1, T2-FLAIR and diffusion-weighted sequences were acquired from 44 ON CIS patients at baseline, 1, 3, 6 and 12 months after the onset of ON. Fifty RRMS patients and 50 HCs were also included for comparison., Results: CP volumes was larger in both ON CIS and RRMS groups compared to HCs, but not significantly different between ON CIS and RRMS patients (analysis of covariance (ANCOVA) adjusted for multiple comparisons). Twenty-three ON CIS patients who converted to clinically definite MS (MS) demonstrated CP volume similar to RRMS patients, but significantly larger compared to HCs. In this sub-group, CP volume was not associated with the severity of optic nerve inflammation or long-term axonal loss, not with brain lesion load. A transient increase of CP volume was observed following an occurrence of new MS lesions on brain magnetic resonance imaging (MRI)., Interpretation: Enlarged CP can be observed very early in a disease. It transiently reacts to acute inflammation, but not associated with the degree of tissue destruction.

To investigate differences in clinical features based on magnetic resonance imaging (MRI) in idiopathic isolated optic neuritis patients. We retrospectively analyzed 68 eyes of 59 patients diagnosed with optic neuritis and showed inflammatory findings indicative of optic neuritis on MRI. We investigated clinical features, such as the presence of accompanying pain, visual acuity, and optic disc swelling. Optic disc swelling was classified as normal, mild, or severe. The MRI results were divided into intraorbital, intracanalicular, and whole optic nerve according to the lesion, and these were compared and analyzed with clinical features. The study included 29 men and 30 women, with a mean age of 42.6 ± 16.6 years. Among 59 patients, 48 (81.4%) complained of pain. Optic disc swelling was not observed in 48.5% of patients (33 eyes). Inflammatory changes were the most common in the intraorbital region (33 eyes), intracanalicular region (20 eyes), and the entire optic nerve (15 eyes). There was no statistical difference in the pain pattern according to the location of the lesion (p = .677), but when inflammation was present in the entire optic nerve, optic disc swelling was severe (p = .023). The initial and final visual acuity did not significantly correlate with the MRI pattern, presence of pain, or optic disc swelling (p = .156, p = .714, and p = .436). The MRI contrast enhancement pattern was associated with optic disc swelling but was not associated with pain or initial visual acuity. It should be noted that it is insufficient to judge the clinical features of optic neuritis based on MRI findings., (© 2023. The Author(s).)

Background/aims: The aim of this study was to identify specific MRI characteristics of anterior ischaemic optic neuropathy (AION) and optic neuritis (ON) that would aid in the differentiation between these two diagnoses., Methods: We retrospectively analysed a consecutive case series including all patients with an MRI study of brain and orbit and the clinical diagnosis of either ON or AION. We examined the scans for restricted diffusion of the optic nerve, optic sheath diameter, enhancement and location of enhancement of the optic nerve and distribution of the white matter lesions., Results: Fifty patients met the inclusion criteria. We found an accuracy of 0.98 for the discrimination between AION and ON based solely on parameters extracted from MRI data. Dominance analysis to determine the most influential parameters showed that the enhancement pattern of the optic nerve and distribution of the white matter lesions had the biggest impact on the classification and led to a discrimination accuracy of 0.9 when used alone., Conclusion: In patients with an inconclusive clinical diagnosis, optic nerve enhancement pattern and distribution of white matter lesions can aid in the diagnosis and differentiation between AION and ON. Diffusion-weighted imaging did not add significant information to the diagnosis or help to differentiate between the two conditions., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Asymptomatic optic nerve lesions are frequent in multiple sclerosis (MS) and their impact on cognition and/or brain volume has never been taken into account., Patients and Methods: We used the data from the cross-sectional Visual Ways in MS (VWIMS) study including relapsing remitting MS. All patients underwent brain and optic nerve Magnetic Resonance Imaging (MRI) including Double Inversion Recuperation (DIR) sequence, retinal OCT, and cognitive evaluation with the Brief International Cognitive Assessment in MS (BICAMS). We measured the association between OCT findings (thickness/volume of retinal layers) and extra-visual parameters (cerebral volumes and BICAMS scores) in optic nerves with and/or without the presence of DIR asymptomatic optic nerve hypersignal., Results: Between March and December 2017, we included 98 patients. Two patients were excluded. Over the 192 eyes, 73 had at least one clinical history of optic neuritis (ON-eyes) whereas 119 were asymptomatic (NON-eyes). Among the 119 NON-eyes, 58 had 3D-DIR optic nerve hypersignal (48.7%). We confirmed significant associations between some retinal OCT measures and some extra-visual parameters (cerebral volumes, cognitive scores) in NON-eyes. Unexpectedly, these associations were found when an asymptomatic optic nerve DIR-hypersignal was present on MRI, but not when it was absent., Conclusion: Our study showed a relation between OCT measures and extra-visual parameters in NON-eyes MS patients. As a confusion factor, asymptomatic optic nerve lesions may be the explanation of the relation between OCT measures and extra-visual parameters. Retinal OCT seems to be far more a "window over the optic nerve" than a "window over the brain"., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The anterior optic pathway is one of the preferential sites of involvement in CNS inflammatory demyelinating diseases, such as multiple sclerosis and neuromyelitis optica, with optic neuritis being a common presenting symptom. What is more, optic nerve involvement in these diseases is often subclinical, with optical coherence tomography demonstrating progressive neuroretinal thinning in the absence of optic neuritis. The pathological substrate for these findings is poorly understood and requires investigation. We had access to post-mortem tissue samples of optic nerves, chiasms and tracts from 29 multiple sclerosis (mean age 59.5, range 25-84 years; 73 samples), six neuromyelitis optica spectrum disorders (mean age 56, range 18-84 years; 22 samples), six acute disseminated encephalomyelitis (mean age 25, range 10-39 years; 12 samples) cases and five non-neurological controls (mean age 55.2, range 44-64 years; 16 samples). Formalin-fixed paraffin-embedded samples were immunolabelled for myelin, inflammation (microglial/macrophage, T- and B-cells, complement), acute axonal injury and astrocytes. We assessed the extent and distribution of these markers along the anterior optic pathway for each case in all compartments (i.e. parenchymal, perivascular and meningeal), where relevant. Demyelinated plaques were classified as active based on established criteria. In multiple sclerosis, demyelination was present in 82.8% of cases, of which 75% showed activity. Microglia/macrophage and lymphocyte inflammation were frequently found both in the parenchymal and meningeal compartments in non-demyelinated regions. Acute axonal injury affected 41.4% of cases and correlated with extent of inflammatory activity in each compartment, even in cases that died at advanced age with over 20 years of disease duration. An antero-posterior gradient of anterior optic pathway involvement was observed with optic nerves being most severely affected by inflammation and acute axonal injury compared with the optic tract, where a higher proportion of remyelinated plaques were seen. In neuromyelitis optica spectrum disorder, cases with a history of optic neuritis had extensive demyelination and lost aquaporin-4 reactivity. In contrast, those without prior optic neuritis did not have demyelination but rather diffuse microglial/macrophage, T- and B-lymphocyte inflammation in both parenchymal and meningeal compartments, and acute axonal injury was present in 75% of cases. Acute demyelinating encephalomyelitis featured intense inflammation, and perivenular demyelination in 33% of cases. Our findings suggest that chronic inflammation is frequent and leads to neurodegeneration in multiple sclerosis and neuromyelitis optica, regardless of disease stage. The chronic inflammation and subsequent neurodegeneration occurring along the optic pathway broadens the plaque-centred view of these diseases and partly explains the progressive neuroretinal changes observed in optic coherence tomography studies., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Purpose: To identify the underlying etiologies and to evaluate the differential diagnostic value of posterior segment spectral domain OCT measurements and their correlation with best-corrected visual acuity (BCVA) in a group of patients with OCT documented bilateral optic neuropathy limited to the temporal quadrants., Methods: Retrospective study., Results: We included 61 patients: 35 presented with presumed "classic" acquired mitochondrial optic neuropathy (MON) (18 nutritional, 11 toxic, 6 mixed toxic-nutritional) and 2 with suspected hereditary MON. Nine patients were identified as 'MON mimickers' (especially multiple sclerosis), and 4 were found to have a mixed mechanism, while 11 remained undiagnosed. Across all etiologies, the strongest positive relationship between BCVA and tested OCT parameters was with macular GCL (ganglion cell layer) and GCIPL (combined ganglion cell and inner plexiform layer) volumes rather than peripapillary retinal nerve fiber layer (RNFL) thicknesses (all statistically significant). There was an inverse relationship between BCVA and inner nuclear layer (INL) volumes, with significant differences for BCVA and all tested OCT parameters between eyes with and without INL microcystoid lesions. OCT (absolute values and intereye differences) was not helpful in distinguishing between presumed acquired mitochondrial disease and patients with multiple sclerosis without optic neuritis. However, significantly greater intereye differences in global RNFL and inner plexiform layer and GCIPL volumes were found in patients with a previous history of unilateral optic neuritis., Conclusions: The strongest positive relationship with BCVA was found for macular GCL and GCIPL volumes. OCT could not differentiate between acquired mitochondrial disease and multiple sclerosis without optic neuritis., (© 2022. The Author(s), under exclusive licence to Springer Nature B.V.)

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease driven by inflammation and demyelination in the brain, spinal cord, and optic nerve. Optic neuritis, characterized by inflammation and demyelination of the optic nerve, is a symptom in many patients with MS. The optic nerve is the highway for visual information transmitted from the retina to the brain. It contains axons from the retinal ganglion cells (RGCs) that reside in the retina, myelin forming oligodendrocytes and resident microglia and astrocytes. Inflammation, demyelination, and axonal degeneration are also present in the optic nerve of mice subjected to experimental autoimmune encephalomyelitis (EAE), a preclinical mouse model of MS. Monitoring the optic nerve in EAE is a useful strategy to study the presentation and progression of pathology in the visual system; however, current approaches have relied on sectioning, staining and manual quantification. Further, information regarding the spatial load of lesions and inflammation is dependent on the area of sectioning. To better characterize cellular pathology in the EAE model, we employed a tissue clearing and 3D immunolabelling and imaging protocol to observe patterns of immune cell infiltration and activation throughout the optic nerve. Increased density of TOPRO staining for nuclei captured immune cell infiltration and Iba1 immunostaining was employed to monitor microglia and macrophages. Axonal degeneration was monitored by neurofilament immunolabelling to reveal axonal swellings throughout the optic nerve. In parallel, we developed a convolutional neural network with a UNet architecture (CNN-UNet) called BlebNet for automated identification and quantification of axonal swellings in whole mount optic nerves. Together this constitutes a toolkit for 3-dimensional immunostaining to monitor general optic nerve pathology and fast automated quantification of axonal defects that could also be adapted to monitor axonal degeneration and inflammation in other neurodegenerative disease models.

Acute optic neuritis (ON) is a common cause of vision loss and is often associated with multiple sclerosis (MS). Cholesterol recycling has been identified as a key limiting factor in recovery after demyelination events. Thus, the purpose of our study was to determine if the augmentation of cholesterol transport by gentisic acid (GA) benefits retinal ganglion cell (RGC) development and myelination in organoid systems and enables the recovery of the ocular phenotype upon systemic GA treatment in a MOG-induced experimental autoimmune encephalomyelitis (EAE) ON model. The retinal organoids treated with GA demonstrate an accelerated maturation when compared to the conventionally derived organoids, which was evidenced by the improved organization of Brn3a-GFP + RGC and increased synaptogenesis. A GA supplementation in brain organoids leads to a 10-fold increase in NG2 and Olig2 expression. Weekly GA injections of EAE mice significantly lessened motor-sensory impairment, protected amplitudes in pattern electroretinogram recordings, and preserved visual acuity over the study period of 56 days. Furthermore, GA-treated EAE mice revealed diminished GCL/IPL complex thinning when compared to the untreated EAE mice. An optic nerve histopathology revealed less severe grades of demyelination in the GA-treated EAE cohort and fewer infiltrating cells were observed. Interventions to improve cholesterol homeostasis may be a viable approach to promoting the rehabilitation of MS patients.

Optic neuritis, a primary clinical manifestation commonly observed in multiple sclerosis (MS), is a major factor leading to permanent loss of vision. Despite decreased vision (optic neuritis), diplopia, and nystagmus, the immunopathology of the optic nerve in MS is unclear. Here, we have characterized the optic nerve pathology in a large cohort of MS cases (n = 154), focusing on the immune responses in a sub-cohort of MS (n = 30) and control (n = 6) cases. Immunohistochemistry was used to characterize the myeloid (HLA-DR, CD68, Iba1, TMEM119, and P2RY12) and adaptive immune cells (CD4, CD8, and CD138) in the parenchyma, perivascular spaces, and meninges in optic nerve tissues from MS and control cases. Of the 154 MS cases, 122 (79%) reported visual problems; of which, 99 (81%) optic nerves showed evidence of damage. Of the 31 cases with no visual disturbances, 19 (61%) showed evidence of pathology. A pattern of myeloid cell activity and demyelination in the optic nerve was similar to white matter lesions in the brain and spinal cord. In the optic nerves, adaptive immune cells were more abundant in the meninges close to active and chronic active lesions, and significantly higher compared with the parenchyma. Similar to brain tissues in this Dutch cohort, B-cell follicles in the meninges were absent. Our study reveals that optic nerve pathology is a frequent event in MS and may occur in the absence of clinical symptoms., (© Crown copyright 2022.)

Introduction: Cognitive impairment and retinal atrophy have been proposed as two potential markers of neurodegeneration in multiple sclerosis (MS). We aimed at assessing the relation between peripapillary retinal nerve fiber layer (pRNFL) and macular ganglion cell layer (mGCL) atrophy and cognitive performance in early MS., Methods: This is a multicenter cross-sectional study on patients with early MS (clinically isolated syndrome and relapsing-remitting MS), with an EDSS score ≤ 3.0. Patients with previous optic neuritis, other ocular diseases, psychiatric illness, or recent relapse were excluded. All patients underwent standardized optical coherence tomography (OCT) and neuropsychological evaluation with validated tests for MS patients. Cognitive impairment was defined as having two cognitive tasks below age- and education-adjusted norms., Results: We recruited 52 patients with early MS, with an average age of 37 years (SD = 10.5), an average disease duration of 3.69 years (SD = 2.3), and a median EDSS of 1.0 (IQR = 0.5). In this sample, 15/52 patients presented cognitive impairment. Regarding OCT measurements, 7/52 patients had an average pRNFL below the 5th percentile and 2/52 had an average mGCL below the 5th percentile. The average pRNFL thickness was comparable in cognitively impaired and cognitively preserved patients (100.3 μm vs 103.1 μm, p = 0.52); the average mGCL thickness had also similar values between groups (50.5 μm vs 53 μm, p = 0.38)., Conclusions: Cognitive impairment was frequent in our sample of early MS. However, no association with reduced pRNFL or mGCL thickness was found. When compared to OCT, cognitive assessment could provide an earlier marker of neurodegeneration in MS., (© 2022. Fondazione Società Italiana di Neurologia.)

Background and Objectives: Microglia, the resident immune cell of the brain and retina, is widespread activated in the white and gray matter (GM) in multiple sclerosis (MS). The objective of this study is to evaluate the presence and number of hyperreflecting foci (HRF), considered clusters of activated and proliferating retinal microglia, and their association with clinical and radiologic disease parameters in relapsing-remitting MS (RRMS)., Methods: At baseline, 80 patients with RRMS underwent optical coherence tomography (OCT) and 3T-MRI (including 3-dimensional T1, fluid-attenuated inversion recovery, and double inversion recovery sequences), closed to their disease onset (6.3 ± 5.1 months). These patients were then clinically and radiologically followed up for a mean of 43 months, evaluating the no evidence of disease activity (NEDA) condition, further divided into clinical (cNEDA) and radiologic (rNEDA). Patients with a clinical history or MRI/OCT findings suggestive of optic neuritis (ON) were excluded from the study., Results: Compared with healthy controls, the HRF number was significantly higher in the inner nuclear layer (INL) of patients with RRMS (19.55 ± 5.65 vs 13.84 ± 2.57, p < 0.001) and associated with INL volume (β: 1.21, p < 0.001). GM lesion volume significantly correlated with the INL HRF count ( p = 0.008). Survival analysis revealed a significant association between INL HRF and both cNEDA ( p = 0.017) and rNEDA ( p = 0.002)., Discussion: We found a strong association between retinal microglial proliferation and cortical pathology in RRMS, a finding suggesting a possible underlying common immunopathologic mechanism. Furthermore, microglial activation at baseline was observed to predict subsequent inflammatory events, indicating that HRF might be a candidate prognostic biomarker worthy of further investigation., Classification of Evidence: This study provides Class II evidence that in patients with early RRMS but without ON, the number of HRF on OCT of the retinal inner nuclear layer is associated with cNEDA and rNEDA., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Objectives: To assess the impact of timing from visual symptoms' onset to diffusion-weighted (DW) 3 T MRI completion to detect ischemic changes of the optic disc and optic nerve in AION patients., Methods: This IRB-approved retrospective single-center study included 3 T MRI data from 126 patients with AION and 111 controls with optic neuritis treated between January 2015 and May 2020. Two radiologists blinded to all data individually analyzed imaging. A senior neuroradiologist resolved any discrepancies by consensus. The primary judgment criterion was the restricted diffusion of the optic disc and/or the optic nerve assessed subjectively on the ADC maps. ADC values were also measured. Spearman rank correlations were used to examine the relationships between timing from visual symptoms' onset to MRI completion and both the restricted diffusion and the ADC values., Results: One hundred twenty-six patients (47/126 [37.3%] women and 79/126 [62.7%] men, mean age 69.1 ± 13.7 years) with AION were included. Restricted diffusion of the optic disc in AION eyes was more frequent in the early MRI group than in the late MRI group: 35/49 (71.4%) eyes versus 3/83 (3.6%) eyes, p < 0.001. ADC values of the pathological optic discs and optic nerves were lower in the early MRI group than in the late MRI group: 0.61 [0.52-0.94] × 10 -3 mm 2 /s versus 1.28 [1.01-1.44] × 10 -3 mm 2 /s, p < 0.001, and 0.74 [0.61-0.88] × 10 -3 mm 2 /s versus 0.89 [0.72-1.10] × 10 -3 mm 2 /s, p < 0.001, respectively., Conclusions: DWI MRI showed good diagnostic performance to detect AION when performed early after the onset of visual symptoms., Key Points: • Restricted diffusion of the optic disc in eyes affected by AION was significantly more likely to be observed in patients who had undergone MRI within 5 days after onset of visual symptoms. • ADC values of the pathological optic discs and optic nerves were significantly lower in patients who had undergone MRI within 5 days after onset of visual symptoms of AION: 0.61 × 10 -3 mm 2 /s versus 1.28 × 10 -3 mm 2 /s, p < 0.001, and 0.74 × 10 -3 mm 2 /s versus 0.89 × 10 -3 mm 2 /s, p < 0.001, respectively. • The optimal threshold for timing from visual symptoms' onset to MRI completion to detect restricted diffusion of the optic disc and/or optic nerve was 5 days, with an AUC of 0.88 (CI 95% : 0.82-0.94)., (© 2021. The Author(s), under exclusive licence to European Society of Radiology.)

Optic neuritis (ON) is a general term for inflammation of any part of the optic nerve resulting from demyelination or infection. The number of patients with MOG-lgG antibody-related optic neuritis is increasing recently. Our study uses the fractional amplitude of low-frequency fluctuation (fALFF) method to compare the activity of specific brain regions in MOG-lgG ON patients and healthy controls (HCs). We selected a total of 21 MOG-lgG ON patients and 21 HCs were included in the study. All subjects underwent resting-state functional magnetic resonance imaging (rs-fMRI). The independent-samples t -test was used to compare demographic data and average fALFF values between groups. The specificity and sensitivity of fALFF values for distinguishing between MOG-lgG ON patients and HCs were evaluated by receiver operating characteristic (ROC) curve analysis. Pearson's correlation analysis was used to analyze the relationship between fALFF values and clinical characteristics in MOG-lgG ON patients. Our results showed that fALFF values of the right cerebellum and left middle cingulum were lower whereas those of bilateral inferior temporal lobes, right gyrus rectus, and the left superior and right middle frontal lobes of MOG-lgG ON patients were higher than those of HCs ( P < 0.05). The average fALFF value of the left superior frontal lobe in MOG-lgG ON patients was positively correlated with Hospital Anxiety and Depression Scale score (HADS) (r = 0.6004; P < 0.05) and duration of MOG-lgG ON (r = 6487; P < 0.05). Thus, patients with MOG-lgG ON have abnormal activity in the brain regions related to vision. Changes in fALFF value can reflect functional sequelae of MOG-lgG ON, including abnormal anxiety or depressive emotional changes., Competing Interests: The authors declare no conflict of interest., (© 2022 The Author(s). Published by IMR Press.)

Background and Objectives: Acute optic neuritis (ON) is a classical presenting symptom of multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), and anti-MOG-associated disorders. The resulting visual impairment is variable and can be severe. Clinicians are in need of predictive biomarkers to optimize the management of acute ON. In this longitudinal study (IRMANO, NCT03651662), we evaluated the ability of optic nerve lesion length measured on MRI at the acute phase of ON to predict retinal neuro-axonal loss and visual impairment at a chronic stage., Methods: We conducted a longitudinal study (IRMANO, NCT03651662) of patients who presented a clinical episode of ON (≤8 weeks). All patients underwent a retinal optical coherence tomography (OCT) and a brain/optic nerve MRI, including 3D double-inversion recovery (DIR) sequence at the acute phase of ON and 12 months later. Primary outcomes were optic nerve DIR hypersignal lesion length, macular ganglion cell-inner plexiform layer (GCIPL) volume measured on OCT, and low-contrast monocular visual acuity (LCMVA)., Results: The study group included 51 patients (33 women, mean age of 32.4 years ± 7.9). We recruited patients with a clinically isolated syndrome (n = 20), a relapsing-remitting MS (n = 23), an isolated ON (n = 6), and a first clinical episode of NMOSD (n = 2). Optic nerve DIR hypersignal was observed in all but 1 symptomatic optic nerves. At inclusion, the mean optic nerve lesion length (in mm) was 12.35 ± 5.98. The mean GCIPL volume (in mm 3 ) significantly decreased between inclusion (1.90 ± 0.18) and M 12 (1.67 ± 0.21; p < 0.0001). Optic nerve lesion length at inclusion was significantly associated with GCIPL thinning (estimate ± SD; -0.012 ± 0.004; p = 0.0016) and LCMVA at M 12 (0.016 ± 0.003; p < 0.001). Optic nerve lesion length significantly increased at M 12 (15.76 ± 8.70; p = 0.0007). The increase in optic nerve lesion length was significantly associated with the GCIPL thinning between inclusion and M 12 (-0.012 ± 0.003; p = 0.0011)., Discussion: At the acute phase of ON, optic nerve lesion length is an imaging biomarker predictive of retinal neuro-axonal loss and chronic visual impairment, which can help to stratify future therapeutic strategies in acute ON., Classification of Evidence: This study provides Class I evidence that optic nerve lesion length measured on MRI during the acute phase of a first episode of ON is associated with long-term retinal neuro-axonal loss and visual impairment., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-antibody-associated disease (MOGAD) are antibody mediated CNS disorders mostly affecting the optic nerve and spinal cord with potential severe impact on the visual pathway. Here, we investigated inflammation and degeneration of the visual system in a spontaneous encephalomyelitis animal model. We used double-transgenic (2D2/Th) mice which develop a spontaneous opticospinal encephalomyelitis (OSE). Retinal morphology and its function were evaluated via spectral domain optical coherence tomography (SD-OCT) and electroretinography (ERG) in 6- and 8-week-old mice. Immunohistochemistry of retina and optic nerve and examination of the retina via RT-qPCR were performed using markers for inflammation, immune cells and the complement pathway. OSE mice showed clinical signs of encephalomyelitis with an incidence of 75% at day 38. A progressive retinal thinning was detected in OSE mice via SD-OCT. An impairment in photoreceptor signal transmission occurred. This was accompanied by cellular infiltration and demyelination of optic nerves. The number of microglia/macrophages was increased in OSE optic nerves and retinas. Analysis of the retina revealed a reduced retinal ganglion cell number and downregulated Pou4f1 mRNA expression in OSE retinas. RT-qPCR revealed an elevation of microglia markers and the cytokines Tnfa and Tgfb . We also documented an upregulation of the complement system via the classical pathway. In summary, we describe characteristics of inflammation and degeneration of the visual system in a spontaneous encephalomyelitis model, characterized by coinciding inflammatory and degenerative mechanisms in both retina and optic nerve with involvement of the complement system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Petrikowski, Reinehr, Haupeltshofer, Deppe, Graz, Kleiter, Dick, Gold, Faissner and Joachim.)

Chronic inflammation drives synaptic loss in multiple sclerosis (MS) and is also commonly observed in other neurodegenerative diseases. Clinically approved treatments for MS provide symptomatic relief but fail to halt neurodegeneration and neurological decline. Studies in animal disease models have demonstrated that the neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) exhibits anti-inflammatory, neuroprotective and regenerative properties. Anti-inflammatory actions appear to be mediated primarily by two receptors, VPAC1 and VPAC2, which also bind vasoactive intestinal peptide (VIP). Pharmacological experiments indicate that another receptor, PAC1 (ADCYAP1R1), which is highly selective for PACAP, provides protection to neurons, although genetic evidence and other mechanistic information is lacking. To determine if PAC1 receptors protect neurons in a cell-autonomous manner, we used adeno-associated virus (AAV2) to deliver Cre recombinase to the retina of mice harboring floxed PAC1 alleles. Mice were then subjected to chronic experimental autoimmune encephalomyelitis (EAE), a disease model that recapitulates major clinical and pathological features of MS and associated optic neuritis. Unexpectedly, deletion of PAC1 in naïve mice resulted in a deficit of retinal ganglionic neurons (RGNs) and their dendrites, suggesting a homeostatic role of PAC1. Moreover, deletion of PAC1 resulted in increased EAE-induced loss of a subpopulation of RGNs purported to be vulnerable in animal models of glaucoma. Increased axonal pathology and increased secondary presence of microglia/macrophages was also prominently seen in the optic nerve. These findings demonstrate that neuronal PAC1 receptors play a homeostatic role in protecting RGNs and directly protects neurons and their axons against neuroinflammatory challenge. SIGNIFICANCE STATEMENT: Chronic inflammation is a major component of neurodegenerative diseases and plays a central role in multiple sclerosis (MS). Current treatments for MS do not prevent neurodegeneration and/or neurological decline. The neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to have anti-inflammatory, neuroprotective and regenerative properties but the cell type- and receptor-specific mechanisms are not clear. To test whether the protective effects of PACAP are direct on the PAC1 receptor subtype on neurons, we delete PAC1 receptors from neurons and investigate neuropathologigical changes in an animal model of MS. The findings demonstrate that PAC1 receptors on neurons play a homeostatic role in maintaining neuron health and can directly protect neurons and their axons during neuroinflammatory disease., (Copyright © 2021. Published by Elsevier Inc.)

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) characterized by varying degrees of secondary neurodegeneration. Retinal ganglion cells (RGC) are lost in MS in association with optic neuritis but the mechanisms of neuronal injury remain unclear. Complement component C3 has been implicated in retinal and cerebral synaptic pathology that may precede neurodegeneration. Herein, we examined post-mortem MS retinas, and then used a mouse model, experimental autoimmune encephalomyelitis (EAE), to examine the role of C3 in the pathogenesis of RGC loss associated with optic neuritis. First, we show extensive C3 expression in astrocytes (C3 + /GFAP + cells) and significant RGC loss (RBPMS + cells) in post-mortem retinas from people with MS compared to retinas from non-MS individuals. A patient with progressive MS with a remote history of optic neuritis showed marked reactive astrogliosis with C3 expression in the inner retina extending into deeper layers in the affected eye more than the unaffected eye. To study whether C3 mediates retinal degeneration, we utilized global C3 -/- EAE mice and found that they had less RGC loss and partially preserved neurites in the retina compared with C3 +/+ EAE mice. C3 -/- EAE mice had fewer axonal swellings in the optic nerve, reflecting reduced axonal injury, but had no changes in demyelination or T cell infiltration into the CNS. Using a C3-tdTomato reporter mouse line, we show definitive evidence of C3 expression in astrocytes in the retina and optic nerves of EAE mice. Conditional deletion of C3 in astrocytes showed RGC protection replicating the effects seen in the global knockouts. These data implicate astrocyte C3 expression as a critical mediator of retinal neuronal pathology in EAE and MS, and are consistent with recent studies showing C3 gene variants are associated with faster rates of retinal neurodegeneration in human disease., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Visual dysfunction resulting from optic neuritis (ON) is one of the most common clinical manifestations of multiple sclerosis (MS), characterized by loss of retinal ganglion cells, thinning of the nerve fiber layer, and inflammation to the optic nerve. Current treatments available for ON or MS are only partially effective, specifically target the inflammatory phase, and have limited effects on long-term disability. Fingolimod (FTY) is an FDA-approved immunomodulatory agent for MS therapy. The objective of the current study was to evaluate the neuroprotective properties of FTY in the cellular model of ON-associated neuronal damage. R28 retinal neuronal cell damage was induced through treatment with tumor necrosis factor-α (TNFα). In our cell viability analysis, FTY treatment showed significantly reduced TNFα-induced neuronal death. Treatment with FTY attenuated the TNFα-induced changes in cell survival and cell stress signaling molecules. Furthermore, immunofluorescence studies performed using various markers indicated that FTY treatment protects the R28 cells against the TNFα-induced neurodegenerative changes by suppressing reactive oxygen species generation and promoting the expression of neuronal markers. In conclusion, our study suggests neuroprotective effects of FTY in an in vitro model of optic neuritis.

Background and Objectives: To determine optic nerve and retinal damage in aquaporin-4 antibody (AQP4-IgG)-seropositive neuromyelitis optica spectrum disorders (NMOSD) in a large international cohort after previous studies have been limited by small and heterogeneous cohorts., Methods: The cross-sectional Collaborative Retrospective Study on retinal optical coherence tomography (OCT) in neuromyelitis optica collected retrospective data from 22 centers. Of 653 screened participants, we included 283 AQP4-IgG-seropositive patients with NMOSD and 72 healthy controls (HCs). Participants underwent OCT with central reading including quality control and intraretinal segmentation. The primary outcome was thickness of combined ganglion cell and inner plexiform (GCIP) layer; secondary outcomes were thickness of peripapillary retinal nerve fiber layer (pRNFL) and visual acuity (VA)., Results: Eyes with ON (NMOSD-ON, N = 260) or without ON (NMOSD-NON, N = 241) were assessed compared with HCs (N = 136). In NMOSD-ON, GCIP layer (57.4 ± 12.2 μm) was reduced compared with HC (GCIP layer: 81.4 ± 5.7 μm, p < 0.001). GCIP layer loss (-22.7 μm) after the first ON was higher than after the next (-3.5 μm) and subsequent episodes. pRNFL observations were similar. NMOSD-NON exhibited reduced GCIP layer but not pRNFL compared with HC. VA was greatly reduced in NMOSD-ON compared with HC eyes, but did not differ between NMOSD-NON and HC., Discussion: Our results emphasize that attack prevention is key to avoid severe neuroaxonal damage and vision loss caused by ON in NMOSD. Therapies ameliorating attack-related damage, especially during a first attack, are an unmet clinical need. Mild signs of neuroaxonal changes without apparent vision loss in ON-unaffected eyes might be solely due to contralateral ON attacks and do not suggest clinically relevant progression but need further investigation., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

To evaluate the clinical characteristics of optic neuritis (ON) with different phenotypes. This prospective study recruited patients with new-onset ON between January 2015 and March 2017 who were followed-up for 3 years. They were divided into the myelin oligodendrocyte glycoprotein-seropositive (MOG-ON), aquaporin-4-seropositive (AQP4-ON), and double-seronegative (seronegative-ON) groups, and their clinical characteristics and imaging findings were evaluated and compared. Two-hundred-eighty patients (405 eyes) were included (MOG-ON: n = 57, 20.4%; AQP4-ON: n = 98, 35.0%; seronegative-ON: n = 125, 44.6%). The proportion of eyes with best-corrected visual acuity > 20/25 at the 3-year follow-up was similar between the MOG-ON and seronegative-ON groups; the proportion in both groups was higher than that in the AQP4-ON group (p < 0.001). Relapse rates were higher in the MOG-ON and AQP4-ON groups than in the seronegative-ON group (p < 0.001). Average retinal nerve fiber layer (RNFL) thickness at 3 years was similar between the MOG-ON and AQP4-ON groups (63.41 ± 13.39 and 59.40 ± 11.46 μm, p = 0.476) but both were thinner than the seronegative-ON group (74.06 ± 11.14 μm, p < 0.001). Macular ganglion cell-inner plexiform layer (GCIPL) revealed the same pattern. Despite RNFL and GCIPL thinning, the MOG-ON group's outcome was as favorable as that of the seronegative-ON group, whereas the AQP4-ON group showed unsatisfactory results., (© 2021. The Author(s).)

Purpose: This study investigated the role of limitrin in the pathogenesis of demyelinating optic neuritis using an experimental autoimmune optic neuritis (EAON) model., Methods: EAON was induced in mice via subcutaneous injection with myelin oligodendrocyte glycoprotein peptide. Limitrin protein and mRNA expression were examined in the optic nerve before and after EAON induction. Proinflammatory cytokine expression profiles and degree of glial activation were compared between wild-type (WT) and limitrin knockout mice by real-time PCR and histologic analysis, respectively, after EAON induction. Plasma limitrin levels in patients with optic neuritis and healthy controls were measured by ELISA., Results: Limitrin expression, observed in astrocytes in the optic nerve of WT mice, was lower in EAON-induced than in naïve WT mice. A comparative analysis of WT and limitrin knockout mice revealed that limitrin deficiency induced more severe neuroinflammation and glial hyperactivation in the optic nerve after EAON induction. Limitrin-deficient astrocytes were more chemotactically responsive to neuroinflammatory stimulation than WT astrocytes. Patients with optic neuritis demonstrated higher plasma limitrin levels than healthy controls (P = 0.0001), which was negatively correlated with visual acuity at the nadir of the optic neuritis attack (r = 0.46, P = 0.036)., Conclusions: Limitrin deficiency induced severe neuroinflammation and reactive gliosis in the optic nerve after EAON induction. Our results imply that astrocyte-derived limitrin may protect against neuroinflammation by decreasing immune cell infiltration into the optic nerve. The plasma limitrin level may reflect the extent of blood-brain barrier disruption and provide a valuable biomarker reflecting the severity of optic neuritis.

Objective: Retinal nerve fiber layer thickness (RNFL) is a biomarker of neuroaxonal loss and index of visual function in multiple sclerosis (MS). We aimed to assess the correlation between radiomic features and RNFL, visual acuity (VA) at patients' presentation, visual outcome (VO), and clinical diagnosis., Methods: We reviewed imaging and clinical data of 25 patients with a first episode of optic neuritis (ON) (14 females, 11 males; 5 bilateral ON; 7 left ON; 13 right ON). All patients underwent a complete ophthalmological assessment, including visual acuity and RNFL, neurological evaluation, orbits MRI. Segmentation of the optic nerves was performed through 3D slicer open software to get radiomics analysis. All patients underwent a complete neuro-ophthalmological follow-up at 6 months to assess the VO, classified as: complete recovery, partial recovery, deficit persistence/relapse, or visual worsening and were diagnosed as MS or clinically isolated syndrome., Results: We observed significant correlations between radiomic features and RNFL and between radiomic features and VA. Regression model analysis identified 1 radiomic feature with significant association with VO (Gray Level non-uniformity Normalized, p = 0.004) and 6 radiomic features with significant correlation with diagnosis (High Gray Level Zone Emphasis, p < 0.001; Entropy, p < 0.001, for T1 segmentation; Mean Absolute Deviation, p < 0.001; Coarseness < 0.001; Small Area Low Gray Level Emphasis, p < 0.001; Contrast, p = 0.008, for STIR segmentation)., Conclusion: Orbits MRI analysis at the first episode of ON has the potential to assess the visual function and VO in ON patients, and predict MS development.

Vision impairment due to optic neuritis (ON) is one of the major clinical presentations in Multiple Sclerosis (MS) and is characterized by inflammation and degeneration of the optic nerve and retina. Currently available treatments are only partially effective and have a limited impact on the neuroinflammatory pathology of the disease. A recent study from our laboratory highlighted the beneficial effect of arginase 2 (A2) deletion in suppressing retinal neurodegeneration and inflammation in an experimental model of MS. Utilizing the same model, the present study investigated the impact of A2 deficiency on MS-induced optic neuritis. Experimental autoimmune encephalomyelitis (EAE) was induced in wild-type (WT) and A2 knockout (A2-/-) mice. EAE-induced cellular infiltration, as well as activation of microglia and macrophages, were reduced in A2-/- optic nerves. Axonal degeneration and demyelination seen in EAE optic nerves were observed to be reduced with A2 deletion. Further, the lack of A2 significantly ameliorated astrogliosis induced by EAE. In conclusion, our findings demonstrate a critical involvement of arginase 2 in mediating neuroinflammation in optic neuritis and suggest the potential of A2 blockade as a targeted therapy for MS-induced optic neuritis., Competing Interests: The authors have declared that no competing interests exist.

Background: The etiology of the inflammatory ON is multifactorial. Much attention is paid to the inflammatory and immune processes that are likely to contribute to the demyelination and MS development. IL-6, VEGFA , and TIMP-3 genes are thought to be involved in the inflammatory processes and manifestation of CNS demyelination, so we aimed to determine the relationship between VEGFA rs1413711, TIMP-3 rs9621532, IL-6 rs1800796 gene polymorphisms and ON, and ON with MS., Materials and Methods: Patients with ON, ON with MS, and a random sample of healthy population were enrolled. The genotyping of VEGFA rs1413711, TIMP-3 rs9621532, and IL-6 rs1800796 polymorphisms was carried out using the real-time polymerase chain reaction method., Results: T/C and C/C genotypes of VEGFA rs1413711 were associated with about threefold increased odds of developing ON in the dominant and codominant models. Each allele C at VEGFA rs1413711 was associated with 1.7-fold increased odds of ON development. IL-6 rs1800796 allele C was more frequent in the ON with MS group compared to the control: 17.6% vs. 7.5%, respectively ( p = .040). No statistically significant associations were found between TIMP-3 rs9621532 and the ON development., Conclusion: Vegfa: rs1413711 is associated with the ON development.

ST266 is the biological secretome of cultured Amnion-derived Multipotent Progenitor cells containing multiple growth factors and cytokines. While intranasally-administered ST266 improves the phenotype in experimental optic neuritis, specific ST266 components mediating these effects are not known. We compared the effects of ST266 with and without removal of large molecular weight proteins both in vitro and in the multiple sclerosis model experimental autoimmune encephalomyelitis (EAE) in C57BL/6J mice. Mice were treated daily with intranasal vehicle, ST266 or lower molecular weight fraction of ST266. Retinal ganglion cells were counted in isolated retinas, and optic nerves were assessed for inflammation and demyelination. ST266 treatment significantly improved retinal ganglion cell survival and reduced optic nerve demyelination in EAE mice. The lower molecular weight ST266 fraction significantly improved optic nerve demyelination, but only showed a trend towards improved retinal ganglion cell survival. ST266 fractions below 50kDa increased Schwann cell proliferation in vitro, but were less effective than non-fractionated ST266. Demyelination attenuation was partially associated with the lower molecular weight ST266 fraction, but removal of higher molecular weight biomolecules from ST266 diminishes its neuroprotective effects, suggesting at least some high molecular weight proteins play a role in ST266-mediated neuroprotection., Competing Interests: The ST266 therapy studied here is proprietary property of Noveome Biotherapeutics, Inc. I, Kenneth Shindler, corresponding author for this manuscript, have previously received honoraria from and served on Scientific Advisory Boards from Noveome, and have received sponsored research funding from Noveome for other projects in the past, with no current funding. For the in vivo studies described in the current manuscript, Noveome provided ST266 to my lab at no cost, but funding for all other study materials and personnel was provided by grants from NIH and non-profit foundations. The manuscript does also include in vitro cell assay data from experiments performed by our collaborators at Noveome. Co-authors (HW, ZK, JS, AE, LB) from Noveome were involved in design and completion of the in vitro studies, but all in vivo studies on optic neuritis, which represent the majority of experiments in this manuscript, were designed and conducted without influence from any of the Noveome employees to reduce any potential conflicts of interest. Neither I, nor any of my lab members (coauthors KW, RK, KD), have any financial stake in Noveome or ST266. These competing interests do not alter our adherence to PLOS ONE policies on sharing data and materials.

Purpose: Confocal laser scanning microscopy (CLSM) is a non-invasive technique for cellular in vivo imaging of the human cornea. CLSM screening was evaluated for early detection of corneal nerve morphology changes and neuropathogenic events in different stage multiple myeloma (MM) patients. As MM patients show disease as well as therapy-related neuropathological symptoms, CLSM potentially provides a tool for non-invasive early detection of neuropathogenic events. CLSM findings were compared with the severity of peripheral neuropathic (PNP) symptoms., Methods: The study enrolled 25 MM patients in which bilateral ophthalmologic examination was performed including unilateral CLSM. Further peripheral nerve function was clinically evaluated using the conventional neuropathy symptom and neuropathy deficit scores (NDSs)., Results: In 18/25 MM patients, CLSM detected atypical morphological appearance of bulb-like enlarged nerve endings in the corneal sub-basal nerve plexus. These neuromas were only found in patients showing moderate to severe PNP, in patients with mild or lacking PNP neuromas were absent., Conclusions: CLSM provides a novel non-invasive diagnostic tool for identification of neuromas in cancer patients affected by therapy or disease-related neuropathologies, perspectival allowing early neuronal degenerative process detection and monitoring., (© 2020 The Author(s).)

Purpose: To investigate the effect of multiple sclerosis (MS) on corneal and retinal nerve fiber by quantifying corneal subbasal nerve fibers and retinal ganglion cells., Methods: A total of 46 eyes of 23 patients with MS and 42 eyes of 21 healthy subjects were included in the study. All patients and healthy subjects underwent a comprehensive ocular examination. In vivo confocal microscopy with Heidelberg Retina Tomograph in association with Rostock Cornea Module (Heidelberg Engineering, Heidelberg, Germany) and a swept-source optical coherence tomography (Topcon Corporation) were performed in all patients and healthy subjects. The number of subbasal nerve fibers and the nerve fiber density were calculated. Student t test was used to compare eyes with MS with control eyes. The normal distribution was first confirmed with the Shapiro-Wilk test., Results: A statistically significant (P < 0.05) decrease was found for nerve fiber number, ganglion cell-inner plexiform layer, and retinal nerve fiber layer in patients with MS compared with those of healthy subjects. Moreover, an inverse correlation was found between retinal nerve fiber layer (r = -0.32), nerve fiber number (r = -0.47), and ganglion cell-inner plexiform layer (r = -0.51) and Expanded Disability Status Scale. A direct correlation between Expanded Disability Status Scale and optic neuritis frequency was found (r = 0.322)., Conclusions: In vivo confocal microscopy showed a difference in corneal morphological parameters and retinal damage; moreover, these changes seemed to be related to the degree of neurological disability. Both retinal ganglion and trigeminal cell atrophy measurements could become affordable and accessible biomarkers for clinical trials in progressive disease.