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BACKGROUND AND OBJECTIVES: Recovery of vision after acute optic neuritis (AON) is critical to improving the quality of life of people with demyelinating diseases. The objective of the study was to prospectively assess the changes in visual acuity, retinal layer thickness, and cortical visual network in patients with AON to identify the predictors of permanent visual disability. METHODS: We studied a prospective cohort of 88 consecutive patients with AON with 6-month follow-up using high and low-contrast (2.5%) visual acuity, color vision, retinal thickness from optical coherence tomography, latencies and amplitudes of multifocal visual evoked potentials, mean deviation of visual fields, and diffusion-based structural (n = 53) and functional (n = 19) brain MRI to analyze the cortical visual network. The primary outcome was 2.5% low-contrast vision, and data were analyzed with mixed-effects and multivariate regression models. RESULTS: We found that after 6 months, low-contrast vision and quality of vision remained moderately impaired. The thickness of the ganglion cell layer at baseline was a predictor of low-contrast vision 6 months later (ß = 0.49 [CI 0.11-0.88], p = 0.012). The structural cortical visual network at baseline predicted low-contrast vision, the best predictors being the betweenness of the right parahippocampal cortex (ß = -036 [CI -0.66 to 0.06], p = 0.021), the node strength of the right V3 (ß = 1.72 [CI 0.29-3.15], p = 0.02), and the clustering coefficient of the left intraparietal sulcus (ß = 57.8 [CI 12.3-103.4], p = 0.015). The functional cortical visual network at baseline also predicted low-contrast vision, the best predictors being the betweenness of the left ventral occipital cortex (ß = 8.6 [CI: 4.03-13.3], p = 0.009), the node strength of the right intraparietal sulcus (ß = -2.79 [CI: -5.1-0.4], p = 0.03), and the clustering coefficient of the left superior parietal lobule (ß = 501.5 [CI 50.8-952.2], p = 0.03). DISCUSSION: The assessment of the visual pathway at baseline predicts permanent vision disability after AON, indicating that damage is produced early after disease onset and that it can be used for defining vision impairment and guiding therapy.
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Neuritis Óptica , Recuperación de la Función , Tomografía de Coherencia Óptica , Humanos , Neuritis Óptica/fisiopatología , Neuritis Óptica/diagnóstico por imagen , Masculino , Femenino , Adulto , Persona de Mediana Edad , Recuperación de la Función/fisiología , Estudios Prospectivos , Potenciales Evocados Visuales/fisiología , Vías Visuales/fisiopatología , Vías Visuales/diagnóstico por imagen , Agudeza Visual/fisiología , Estudios de Seguimiento , Imagen por Resonancia Magnética , Retina/fisiopatología , Retina/diagnóstico por imagen , Trastornos de la Visión/fisiopatología , Trastornos de la Visión/etiología , Corteza Visual/diagnóstico por imagen , Corteza Visual/fisiopatologíaRESUMEN
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.
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Biomarcadores , Electrorretinografía , Encefalomielitis Autoinmune Experimental , Ratones Endogámicos C57BL , Neuritis Óptica , Células Ganglionares de la Retina , Tomografía de Coherencia Óptica , Animales , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Neuritis Óptica/patología , Neuritis Óptica/fisiopatología , Neuritis Óptica/inmunología , Ratones , Femenino , Electrorretinografía/métodos , Células Ganglionares de la Retina/patología , Nervio Óptico/patología , Glicoproteína Mielina-Oligodendrócito/inmunología , Modelos Animales de EnfermedadRESUMEN
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.
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Axones , Progresión de la Enfermedad , Esclerosis Múltiple Recurrente-Remitente , Neuritis Óptica , Tomografía de Coherencia Óptica , Humanos , Femenino , Adulto , Masculino , Axones/patología , Neuritis Óptica/patología , Neuritis Óptica/fisiopatología , Neuritis Óptica/diagnóstico por imagen , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Inflamación/patología , Potenciales Evocados Visuales/fisiología , Imagen de Difusión Tensora , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/diagnóstico por imagen , Imagen por Resonancia Magnética , Enfermedad CrónicaRESUMEN
BACKGROUND: Optic neuritis (ON), one of the clinical manifestations of the human neurological disease multiple sclerosis (MS), was also reported in patients with COVID-19 infection, highlighting one potential neurological manifestation of SARS-CoV-2. However, the mechanism of ON in these patients is poorly understood. EVIDENCE ACQUISITION: Insight may be gained by studying the neurotropic mouse hepatitis virus (MHV-A59), a ß-coronavirus that belongs to the same family as SARS-CoV-2. RESULTS: Mouse hepatitis virus-A59, or its isogenic spike protein recombinant strains, inoculation in mice provides an important experimental model to understand underpinning mechanisms of neuroinflammatory demyelination in association with acute stage optic nerve inflammation and chronic stage optic nerve demyelination concurrent with axonal loss. Spike is a surface protein that mediates viral binding and entry into host cells, as well as cell-cell fusion and viral spread. Studies have implicated spike-mediated mechanisms of virus-induced neuroinflammatory demyelination by comparing naturally occurring demyelinating (DM) and nondemyelinating (NDM) MHV strains. CONCLUSIONS: Here, we summarize findings in MHV-induced experimental ON and myelitis, using natural DM and NDM strains as well as engineered recombinant strains of MHV to understand the role of spike protein in inducing ON and demyelinating disease pathology. Potential parallels in human coronavirus-mediated ON and demyelination, and insight into potential therapeutic strategies, are discussed.
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COVID-19 , Modelos Animales de Enfermedad , Virus de la Hepatitis Murina , Neuritis Óptica , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Animales , Neuritis Óptica/virología , Neuritis Óptica/etiología , Neuritis Óptica/metabolismo , Neuritis Óptica/fisiopatología , Glicoproteína de la Espiga del Coronavirus/metabolismo , Glicoproteína de la Espiga del Coronavirus/genética , Ratones , COVID-19/complicaciones , Virus de la Hepatitis Murina/fisiología , Humanos , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/fisiopatología , Betacoronavirus 1/metabolismoRESUMEN
BACKGROUND: Peripapillary hyperreflective ovoid mass-like structures (PHOMS) are a recently defined optical coherence tomography (OCT) finding. The purpose of this study was to characterize the presence of PHOMS and their visual significance in pediatric patients with and without optic nerve pathologies. METHODS: This retrospective study evaluated 400 patients (<18 years of age) including normal control subjects and patients with optic neuritis, papillitis, optic nerve head drusen (ONHD), and papilledema. Information on demographics, visual function, and structural parameters were obtained. RESULTS: PHOMS were found in 7 of 258 normal control eyes (2.7%), 9 of 59 eyes with optic neuritis (15.3%), 58 of 76 eyes with ONHD (76.3%), 3 of 11 eyes with papillitis (27.3%), and 180 of 308 eyes with papilledema (58.4%). PHOMS were more prevalent in the papilledema (P < 0.001), ONHD (P < 0.001), and optic neuritis (P = 0.028) eyes than in control eyes. We identified 5 cases where PHOMS developed de novo. This occurred over an average of 2.3 years (range, 0.2-7.4 years). Sixteen cases of PHOMS resolved over an average of 1.1 years (range, 0.3-4.0 years). Cross-sectionally, PHOMS were not associated with visual acuity (P = 0.551), retinal nerve fiber layer thickness (P = 0.068), ganglion cell volume (P = 0.375), or visual field mean deviation (P = 0.795). CONCLUSIONS: PHOMS are present in a majority of children with papilledema or ONHD. PHOMS are dynamic and may form de novo over time with optic nerve pathology and may resolve either through treatment or atrophy. There was no relationship between the presence of PHOMS and poor visual function in our study cohort.
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Drusas del Disco Óptico , Disco Óptico , Enfermedades del Nervio Óptico , Papiledema , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Estudios Retrospectivos , Tomografía de Coherencia Óptica/métodos , Niño , Femenino , Masculino , Agudeza Visual/fisiología , Adolescente , Prevalencia , Papiledema/diagnóstico , Papiledema/fisiopatología , Disco Óptico/patología , Disco Óptico/diagnóstico por imagen , Preescolar , Enfermedades del Nervio Óptico/diagnóstico , Enfermedades del Nervio Óptico/fisiopatología , Drusas del Disco Óptico/fisiopatología , Drusas del Disco Óptico/diagnóstico , Campos Visuales/fisiología , Fibras Nerviosas/patología , Células Ganglionares de la Retina/patología , Neuritis Óptica/fisiopatología , Neuritis Óptica/diagnóstico , LactanteRESUMEN
PURPOSE: Multiple sclerosis (MS) is a neuro-inflammatory disease affecting the central nervous system (CNS), where the immune system targets and damages the protective myelin sheath surrounding nerve fibers, inhibiting axonal signal transmission. Demyelinating optic neuritis (ON), a common MS symptom, involves optic nerve damage. We've developed NeuroVEP, a portable, wireless diagnostic system that delivers visual stimuli through a smartphone in a headset and measures evoked potentials at the visual cortex from the scalp using custom electroencephalography electrodes. METHODS: Subject vision is evaluated using a short 2.5-min full-field visual evoked potentials (ffVEP) test, followed by a 12.5-min multifocal VEP (mfVEP) test. The ffVEP evaluates the integrity of the visual pathway by analyzing the P100 component from each eye, while the mfVEP evaluates 36 individual regions of the visual field for abnormalities. Extensive signal processing, feature extraction methods, and machine learning algorithms were explored for analyzing the mfVEPs. Key metrics from patients' ffVEP results were statistically evaluated against data collected from a group of subjects with normal vision. Custom visual stimuli with simulated defects were used to validate the mfVEP results which yielded 91% accuracy of classification. RESULTS: 20 subjects, 10 controls and 10 with MS and/or ON were tested with the NeuroVEP device and a standard-of-care (SOC) VEP testing device which delivers only ffVEP stimuli. In 91% of the cases, the ffVEP results agreed between NeuroVEP and SOC device. Where available, the NeuroVEP mfVEP results were in good agreement with Humphrey Automated Perimetry visual field analysis. The lesion locations deduced from the mfVEP data were consistent with Magnetic Resonance Imaging and Optical Coherence Tomography findings. CONCLUSION: This pilot study indicates that NeuroVEP has the potential to be a reliable, portable, and objective diagnostic device for electrophysiology and visual field analysis for neuro-visual disorders.
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Potenciales Evocados Visuales , Esclerosis Múltiple , Neuritis Óptica , Humanos , Potenciales Evocados Visuales/fisiología , Neuritis Óptica/diagnóstico , Neuritis Óptica/fisiopatología , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/fisiopatología , Femenino , Masculino , Adulto , Campos Visuales/fisiología , Corteza Visual/fisiopatología , Electroencefalografía/instrumentación , Persona de Mediana Edad , Proyectos Piloto , Estimulación LuminosaRESUMEN
Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is a demyelinating disorder, distinct from multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD). MOGAD most frequently presents with optic neuritis (MOG-ON), often with characteristic clinical and radiological features. Bilateral involvement, disc swelling clinically and radiologically, and longitudinally extensive optic nerve hyperintensity with associated optic perineuritis on MRI are key characteristics that can help distinguish MOG-ON from optic neuritis due to other aetiologies. The detection of serum MOG immunoglobulin G utilising a live cell-based assay in a patient with a compatible clinical phenotype is highly specific for the diagnosis of MOGAD. This review will highlight the key clinical and radiological features which expedite diagnosis, as well as ancillary investigations such as visual fields, visual evoked potentials and cerebrospinal fluid analysis, which may be less discriminatory. Optical coherence tomography can identify optic nerve swelling acutely, and atrophy chronically, and may transpire to have utility as a diagnostic and prognostic biomarker. MOG-ON appears to be largely responsive to corticosteroids, which are often the mainstay of acute management. However, relapses are common in patients in whom follow-up is prolonged, often in the context of early or rapid corticosteroid tapering. Establishing optimal acute therapy, the role of maintenance steroid-sparing immunotherapy for long-term relapse prevention, and identifying predictors of relapsing disease remain key research priorities in MOG-ON.
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Autoanticuerpos , Glicoproteína Mielina-Oligodendrócito , Neuritis Óptica , Humanos , Neuritis Óptica/diagnóstico , Neuritis Óptica/fisiopatología , Neuritis Óptica/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Autoanticuerpos/sangre , Tomografía de Coherencia Óptica , Potenciales Evocados Visuales , Imagen por Resonancia Magnética , Glucocorticoides/uso terapéuticoRESUMEN
PURPOSE: This study analyzes the main changes in retinal microcirculation in patients with multiple sclerosis (MS) and their relationship with the type of disease course. MATERIAL AND METHODS: 159 patients (318 eyes) were examined. The groups were formed according to the type of course and duration of MS: group 1 - 37 patients (74 eyes; 23.27%) with relapsing-remitting MS (RRMS) less than 1 year; group 2 - 47 patients (94 eyes; 29.56%) with RRMS from 1 year to 10 years; group 3 - 44 patients (86 eyes; 27.05%) with RRMS >10 years; group 4 - 32 patients (64 eyes; 20.12%) with secondary progressive MS (SPMS). Subgroups A and B were allocated within each group depending on the absence or presence of optic neuritis (ON). Patients underwent standard ophthalmological examination, including optical coherence tomography angiography (OCTA). RESULTS: A decrease in the vessel density (wiVD) and perfusion density (wiPD) in the macular and peripapillary regions was revealed, progressing with the duration of the disease and with its transition to the progressive type. The minimum values were observed in patients with SPMS (group 4), with the most pronounced in the subgroup with ON (wiVD = 16.06±3.65 mm/mm2, wiPD = 39.38±9.46%, ppwiPD = 44.06±3.09%, ppwiF = 0.41±0.05). CONCLUSION: OCTA provides the ability to detect subclinical vascular changes and can be considered a comprehensive, reliable method for early diagnosis and monitoring of MS progression.
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Progresión de la Enfermedad , Esclerosis Múltiple , Vasos Retinianos , Tomografía de Coherencia Óptica , Humanos , Tomografía de Coherencia Óptica/métodos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Vasos Retinianos/diagnóstico por imagen , Angiografía con Fluoresceína/métodos , Microcirculación/fisiología , Neuritis Óptica/diagnóstico , Neuritis Óptica/etiología , Neuritis Óptica/diagnóstico por imagen , Neuritis Óptica/fisiopatología , Reproducibilidad de los ResultadosRESUMEN
OBJECTIVE: To explore associations of the main component (P100) of visual evoked potentials (VEP) to pre- and postchiasmatic damage in multiple sclerosis (MS). METHODS: 31 patients (median EDSS: 2.5), 13 with previous optic neuritis (ON), and 31 healthy controls had VEP, optical coherence tomography and magnetic resonance imaging. We tested associations of P100-latency to the peripapillary retinal nerve fiber layer (pRNFL), ganglion cell/inner plexiform layers (GCIPL), lateral geniculate nucleus volume (LGN), white matter lesions of the optic radiations (OR-WML), fractional anisotropy of non-lesional optic radiations (NAOR-FA), and to the mean thickness of primary visual cortex (V1). Effect sizes are given as marginal R2 (mR2). RESULTS: P100-latency, pRNFL, GCIPL and LGN in patients differed from controls. Within patients, P100-latency was significantly associated with GCIPL (mR2 = 0.26), and less strongly with OR-WML (mR2 = 0.17), NAOR-FA (mR2 = 0.13) and pRNFL (mR2 = 0.08). In multivariate analysis, GCIPL and NAOR-FA remained significantly associated with P100-latency (mR2 = 0.41). In ON-patients, P100-latency was significantly associated with LGN volume (mR2 = -0.56). CONCLUSIONS: P100-latency is affected by anterior and posterior visual pathway damage. In ON-patients, damage at the synapse-level (LGN) may additionally contribute to latency delay. SIGNIFICANCE: Our findings corroborate post-chiasmatic contributions to the VEP-signal, which may relate to distinct pathophysiological mechanisms in MS.
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Potenciales Evocados Visuales , Cuerpos Geniculados , Esclerosis Múltiple , Vías Visuales , Humanos , Masculino , Femenino , Cuerpos Geniculados/fisiopatología , Cuerpos Geniculados/diagnóstico por imagen , Adulto , Potenciales Evocados Visuales/fisiología , Vías Visuales/fisiopatología , Vías Visuales/diagnóstico por imagen , Persona de Mediana Edad , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/diagnóstico por imagen , Tomografía de Coherencia Óptica/métodos , Imagen por Resonancia Magnética , Neuritis Óptica/fisiopatología , Neuritis Óptica/diagnóstico por imagenRESUMEN
BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) exhibits phenotypic diversity and it varies by age. However, less is known about whether the manifestations of isolated MOG antibody-associated optic neuritis (iMOG-ON) vary across different age groups. We aimed to investigate the clinical and prognostic features of iMOG-ON in young and middle-aged adult patients. METHODS: Patients with iMOG-ON were enrolled in the Department of Neurology, Beijing Tongren Hospital, Capital Medical University between January 2018 and October 2021. Medical records were reviewed to obtain clinical data and orbital MRI images of adult patients with iMOG-ON. Multivariate linear regression analysis was performed to investigate the associations between final best-corrected visual acuity (BCVA) in logMAR and clinical characteristics. RESULTS: Based on the age of onset, 70 patients were divided into 2 groups: 38 young (< 46 years; female/male = 0.76:1) and 32 middle-aged (≥ 46 years; female/male = 5.56:1) adults. There were statistical differences in both the female-to-male ratio and frequencies of contrast enhancement of the optic nerve sheaths and surrounding orbital tissues between both groups (p = 0.001, p = 0.004, respectively). The average follow-up periods were 28.04 ± 11.22 months. The median final BCVA was 0 (0 - 0.50) logMAR and 0.5 (0.3 - 1.0) logMAR in the young and middle-aged patients, respectively (p = 0.000). The multivariate linear regression analysis indicated significant positive relationships between final BCVA and age of onset (p = 0.038, 95 % CI: 0.020 - 0.728), sex (p = 0.030, 95 % CI: -0.793 - -0.042), BCVA at nadir (p = 0.000, 95 % CI: 0.164 - 0.386), and numbers of segments of optic nerve lesions (p = 0.009, 95 % CI: 0.068 - 0.450) with a coefficient of determination (R2) of 0.359 after adjusting for prior attacks of ON, time intervals between sudden-onset vision loss and administration of intravenous methylprednisolone, and corticosteroid dosages. The worst final BCVA was observed in afflicted eyes with lesions extending across three segments of the optic nerve. CONCLUSION: Compared to young adults with iMOG-ON, the middle-aged patients tended to have a female predominance, higher frequencies of perineural enhancement, and worse visual outcomes. In addition to age of onset, visual recovery may also be influenced by patient's sex, BCVA at nadir, and lengths of longitudinally expansive lesions of the optic nerve to a certain extent.
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Edad de Inicio , Autoanticuerpos , Imagen por Resonancia Magnética , Glicoproteína Mielina-Oligodendrócito , Neuritis Óptica , Humanos , Masculino , Femenino , Neuritis Óptica/diagnóstico por imagen , Neuritis Óptica/inmunología , Neuritis Óptica/fisiopatología , Glicoproteína Mielina-Oligodendrócito/inmunología , Adulto , Persona de Mediana Edad , Pronóstico , Adulto Joven , Autoanticuerpos/sangre , Agudeza Visual/fisiología , Estudios de Seguimiento , Estudios RetrospectivosRESUMEN
BACKGROUND: Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) is a demyelinating disorder that most commonly presents with optic neuritis (ON) and affects children more often than adults. We report 8 pediatric patients with MOG-associated ON and characterize focal optical coherence tomography (OCT) abnormalities over time that help distinguish this condition from the trajectories of other demyelinating disorders. These OCT findings are examined in the context of longitudinal visual function testing. METHODS: This is a retrospective case series of 8 pediatric patients with MOG-associated ON who were referred for neuro-ophthalmic evaluation. Longitudinal data for demographics, clinical history, physical examination, and OCT obtained in the course of clinical evaluations were collected through retrospective medical record review. RESULTS: Patients demonstrated acute peripapillary retinal nerve fiber layer (RNFL) thickening in one or both eyes, consistent with optic disc swelling. This was followed by steady patterns of average RNFL thinning, with 9 of 16 eyes reaching significantly low RNFL thickness using OCT platform reference databases ( P < 0.01), accompanied by paradoxical recovery of high-contrast visual acuity (HCVA) in every patient. There was no correlation between HCVA and any OCT measures, although contrast sensitivity (CS) was associated with global thickness, PMB thickness, and nasal/temporal (N/T) ratio, and color vision was associated with PMB thickness. There was a lower global and papillomacular bundle (PMB) thickness ( P < 0.01) in clinically affected eyes compared with unaffected eyes. There was also a significantly higher N:T ratio in clinically affected eyes compared with unaffected eyes in the acute MOG-ON setting ( P = 0.03), but not in the long-term setting. CONCLUSIONS: MOG shows a pattern of prominent retinal atrophy, as demonstrated by global RNFL thinning, with remarkable preservation of HCVA but remaining deficits in CS and color vision. These tests may be better clinical markers of vision changes secondary to MOG-ON. Of the OCT parameters measured, PMB thickness demonstrated the most consistent correlation between structural and functional measures. Thus, it may be a more sensitive marker of clinically significant retinal atrophy in MOG-ON. The N:T ratio in acute clinically affected MOG-ON eyes in our study was higher than the N:T ratio of neuromyelitis optica (NMO)-ON eyes and similar to the N:T ratio in multiple sclerosis (MS)-ON eyes as presented in the prior literature. Therefore, MOG may share a more similar pathophysiology to MS compared with NMO.
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Glicoproteína Mielina-Oligodendrócito , Neuritis Óptica , Células Ganglionares de la Retina , Tomografía de Coherencia Óptica , Agudeza Visual , Humanos , Glicoproteína Mielina-Oligodendrócito/inmunología , Tomografía de Coherencia Óptica/métodos , Femenino , Masculino , Estudios Retrospectivos , Neuritis Óptica/diagnóstico , Neuritis Óptica/fisiopatología , Neuritis Óptica/inmunología , Niño , Agudeza Visual/fisiología , Adolescente , Células Ganglionares de la Retina/patología , Fibras Nerviosas/patología , Autoanticuerpos/sangre , Disco Óptico/patología , Disco Óptico/diagnóstico por imagen , Sensibilidad de Contraste/fisiologíaAsunto(s)
Factores Inmunológicos/administración & dosificación , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuritis Óptica/fisiopatología , Trastornos de la Visión/fisiopatología , Adolescente , Humanos , Masculino , Neuritis Óptica/complicaciones , Neuritis Óptica/tratamiento farmacológico , Neuritis Óptica/inmunología , Trastornos de la Visión/tratamiento farmacológico , Trastornos de la Visión/etiologíaRESUMEN
Repulsive guidance molecule A (RGMa) is a potent inhibitor of axonal growth and a regulator of neuronal cell death. It is up-regulated following neuronal injury and accumulates in chronic neurodegenerative diseases. Neutralizing RGMa has the potential to promote neuroregeneration and neuroprotection. Previously we reported that a rat anti-N terminal RGMa (N-RGMa) antibody r5F9 and its humanized version h5F9 (ABT-207) promote neuroprotection and neuroregeneration in preclinical neurodegenerative disease models. However, due to its cross-reactivity to RGMc/hemojuvelin, ABT-207 causes iron accumulation in vivo, which could present a safety liability. Here we report the generation and characterization of a novel RGMa-selective anti-N-RGMa antibody elezanumab, which is currently under Phase 2 clinical evaluation in multiple disease indications. Elezanumab, a human monoclonal antibody generated by in vitro PROfusion mRNA display technology, competes with ABT-207 in binding to N-RGMa but lacks RGMc cross-reactivity with no impact on iron metabolism. It neutralizes repulsive activity of soluble RGMa in vitro and blocks membrane RGMa mediated BMP signaling. In the optic nerve crush and optic neuritis models, elezanumab promotes axonal regeneration and prevents retinal nerve fiber layer degeneration. In the spinal targeted experimental autoimmune encephalomyelitis (EAE) model, elezanumab promotes axonal regeneration and remyelination, decreases inflammatory lesion area and improves functional recovery. Finally, in the mouse cuprizone model, elezanumab reduces demyelination, which is consistent with its inhibitory effect on BMP signaling. Taken together, these preclinical data demonstrate that elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism, thus providing a compelling rationale for its clinical development in neurodegenerative diseases.
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Encefalomielitis Autoinmune Experimental , Proteínas Ligadas a GPI , Regeneración Nerviosa , Proteínas del Tejido Nervioso , Neuroprotección , Traumatismos del Nervio Óptico , Nervio Óptico , Neuritis Óptica , Recuperación de la Función , Retina , Animales , Ratones , Cuprizona/toxicidad , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/fisiopatología , Proteínas Ligadas a GPI/antagonistas & inhibidores , Inhibidores de la Monoaminooxidasa/toxicidad , Regeneración Nerviosa/efectos de los fármacos , Regeneración Nerviosa/fisiología , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Neuroprotección/efectos de los fármacos , Nervio Óptico/efectos de los fármacos , Nervio Óptico/fisiología , Traumatismos del Nervio Óptico/fisiopatología , Neuritis Óptica/fisiopatología , Recuperación de la Función/efectos de los fármacos , Recuperación de la Función/fisiología , Retina/efectos de los fármacos , Resonancia por Plasmón de SuperficieRESUMEN
Rationale: Optic neuritis is one of main symptoms in multiple sclerosis (MS) that causes visual disability. Astrocytes are pivotal regulators of neuroinflammation in MS, and astrocytic yes-associated protein (YAP) plays a critical role in neuroinflammation. Meanwhile, YAP signaling is involved in visual impairment, including glaucoma, retinal choroidal atrophy and retinal detachment. However, the roles and underlying mechanisms of astrocytic YAP in neuroinflammation and demyelination of MS-related optic neuritis (MS-ON) remains unclear. Methods: To assess the functions of YAP in MS-ON, experimental autoimmune encephalomyelitis (EAE, a common model of MS) was established, and mice that conditional knockout (CKO) of YAP in astrocytes, YAPGFAP-CKO mice, were successfully generated. Behavior tests, immunostaining, Nissl staining, Hematoxylin-Eosin (HE) staining, TUNEL staining, Luxol Fast Blue (LFB) staining, electron microscopy (EM), quantitative real-time PCR (qPCR), gene set enrichment analysis (GSEA) and gene set variation analysis (GSVA) by RNA sequencing were used to examine the function and mechanism of YAP signaling based on these YAPGFAP-CKO mice and EAE model mice. To further explore the potential treatment of YAP signaling in EAE, EAE mice were treated with various drugs, including SRI-011381 that is an agonist of transforming growth factor-ß (TGF-ß) pathway, and XMU-MP-1 which inhibits Hippo kinase MST1/2 to activate YAP. Results: We found that YAP was significantly upregulated and activated in the astrocytes of optic nerve in EAE mice. Conditional knockout of YAP in astrocytes caused more severe inflammatory infiltration and demyelination in optic nerve, and damage of retinal ganglion cells (RGCs) in EAE mice. Moreover, YAP deletion in astrocytes promoted the activation of astrocytes and microglia, but inhibited the proliferation of astrocytes of optic nerve in EAE mice. Mechanically, TGF-ß signaling pathway was significantly down-regulated after YAP deletion in astrocytes. Additionally, both qPCR and immunofluorescence assays confirmed the reduction of TGF-ß signaling pathway in YAPGFAP-CKO EAE mice. Interestingly, SRI-011381 partially rescued the deficits in optic nerve and retina of YAPGFAP-CKO EAE mice. Finally, activation of YAP signaling by XMU-MP-1 relieved the neuroinflammation and demyelination in optic nerve of EAE mice. Conclusions: These results suggest astrocytic YAP may prevent the neuroinflammatory infiltration and demyelination through upregulation of TGF-ß signaling and provide targets for the development of therapeutic strategies tailored for MS-ON.
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Astrocitos/metabolismo , Encefalomielitis Autoinmune Experimental/fisiopatología , Proteínas Señalizadoras YAP/metabolismo , Animales , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/metabolismo , Enfermedades Neuroinflamatorias , Nervio Óptico/fisiología , Neuritis Óptica/metabolismo , Neuritis Óptica/fisiopatología , Retina/metabolismo , Retina/fisiología , Células Ganglionares de la Retina/metabolismo , Transducción de Señal , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/fisiología , Proteínas Señalizadoras YAP/fisiologíaRESUMEN
Optic neuritis (ON) is demyelinating acute inflammatory disease which affects the optic nerve. ON is classified as a typical (demyelinating) or an atypical (idiopathic). Patients often complain having a periocular pain or a visual loss. The main factor causing the optic neuritis is still unknown. It is believed that it might be a combination of genetic and environmental factors. As the optic neuritis is an inflammation disease, the RAGE gene was selected as it is a part of the inflammation process. AIM: to determine the relation between RAGE rs1800624 and rs1800625 genotypes of patients who have a manifestation of optic neuritis and optic neuritis with multiple sclerosis together in Lithuanian population and visual acuity recovery. OBJECTIVES: patients with optic neuritis and healthy controls individuals were examined. Genotyping was carried out by using the instrument of real-time polymerase chain reaction called StepOnePlus (AppliedBiosystems). Statistical analysis was performed using IBM SPSS Statistics 20.0 software and free PLINK software (version 1.07). RESULTS: Results indicate that rs1800624 polymorphism is not statistically significant in optic neuritis manifestation (p = .392), while rs1800625 GG genotype is associated with 7.5-fold increased odds of ON development under the codominant model (OR = 7.5; 95% CI:1.796-31.313; p = .006) and with 6.9-fold increased odds under the recessive model OR = 6.862; 95% CI:1.665-28.288; p = .008); and each allele G is associated with 1.9-fold increased odds of ON development under the additive model (OR = 1.879; 95% CI:1.149-3.072; p = .012). The haplotype containing A-G alleles in rs1800624 and rs1800625 was statistically significantly associated with increased risk for ON development (χ2 = 13.23; p < .001). Both polymorphisms do not have statistically significant importance in relation to visual acuity recovery. CONCLUSIONS: RAGE rs1800625 AA genotype decreases the risk of optic neuritis. The single nucleotide polymorphisms RAGE rs1800624 and rs1800625 do not have a statistically significant importance in relation with visual acuity recovery.
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Predisposición Genética a la Enfermedad/genética , Esclerosis Múltiple/genética , Neuritis Óptica/genética , Polimorfismo de Nucleótido Simple/genética , Receptor para Productos Finales de Glicación Avanzada/genética , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Técnicas de Genotipaje , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/fisiopatología , Oportunidad Relativa , Neuritis Óptica/diagnóstico , Neuritis Óptica/fisiopatología , Reacción en Cadena en Tiempo Real de la Polimerasa , Factores de Riesgo , Agudeza Visual/fisiología , Adulto JovenAsunto(s)
Encéfalo/diagnóstico por imagen , Trastornos Migrañosos/diagnóstico , Neuritis Óptica/diagnóstico , Escotoma/fisiopatología , Adulto , Diagnóstico Diferencial , Glucocorticoides/uso terapéutico , Humanos , Imagen por Resonancia Magnética , Masculino , Proteína Básica de Mielina/líquido cefalorraquídeo , Neuritis Óptica/líquido cefalorraquídeo , Neuritis Óptica/tratamiento farmacológico , Neuritis Óptica/fisiopatología , Prednisolona/uso terapéuticoRESUMEN
We present a case of atypical recurrent optic neuritis. A man in his 50s presented with right optic neuritis and profound visual loss, associated with elevated inflammatory markers. Lymph-node biopsy was consistent with sarcoidosis. Aquaporin-4 antibodies were also present. Three months following corticosteroid treatment, his right optic neuritis relapsed, again with raised inflammatory markers. He was started on azathioprine and prednisolone with good effect. A dual diagnosis of sarcoidosis and neuromyelitis optica with aquaporin-4 antibodies is very rare. Long-term immunosuppression is required. The case highlights the importance of identifying the features and cause of atypical optic neuritis.
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Neuritis Óptica/diagnóstico , Sarcoidosis/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/tratamiento farmacológico , Neuromielitis Óptica/fisiopatología , Neuritis Óptica/tratamiento farmacológico , Neuritis Óptica/fisiopatología , Sarcoidosis/tratamiento farmacológico , Sarcoidosis/fisiopatologíaRESUMEN
BACKGROUND: To investigate age-related severity, patterns of retinal structural damage, and functional visual recovery in pediatric and adult cohorts of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) optic neuritis (ON). METHODS: All MOGAD patients from the 5 participating centers were included. Patients with initial manifestation <18 years were included in the pediatric (MOGADped) cohort and patients with ≥18 years in the adult (MOGADadult) cohort. For patients with MOGAD ON, examinations at least ≥6 months after ON onset were included in the analyses. Using spectral domain optical coherence tomography (SD-OCT), we acquired peripapillary retinal nerve fiber layer thickness (pRNFL) and volumes of combined ganglion cell and inner plexiform layer (GCIPL). High- and 2.5% low-contrast visual acuity (HCVA, LCVA) and visual-evoked potentials (VEP) were obtained. RESULTS: Twenty MOGADped (10.3±3.7 years, 30 MOGAD ON eyes) and 39 MOGADadult (34.9±11.6 years, 42 MOGAD ON eyes) patients were included. The average number of ON episodes per ON eye was similar in both groups (1.8±1.3 and 2.0±1.7). In both pediatric and adult MOGAD, ON led to pronounced neuroaxonal retinal atrophy (pRNFL: 63.1±18.7 and 64.3±22.9 µm; GCIPL: 0.42±0.09 and 0.44±0.13 mm3, respectively) and moderate delay of the VEP latencies (117.9±10.7 and 118.0±14.5 ms). In contrast, visual acuity was substantially better in children (HCVA: 51.4±9.3 vs. 35.0±20.6 raw letters, p=0.001; LCVA: 22.8±14.6 vs. 13.5±16.4, p=0.028). Complete visual recovery (HCVA-logMAR 0.0) occurred in 73.3% of MOGADped and 31% MOGADadults ON eyes, while 3.3% and 31% demonstrated moderate to severe (logMAR > 0.5) visual impairment. Independent of retinal atrophy, age at ON onset significantly correlated with visual outcome. CONCLUSION: Pediatric MOGAD ON showed better visual recovery than adult MOGAD ON despite profound and almost identical neuroaxonal retinal atrophy. Age-related cortical neuroplasticity may account for the substantial discrepancy between structural changes and functional outcomes.
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Enfermedades Autoinmunes del Sistema Nervioso , Neuritis Óptica/fisiopatología , Retina , Trastornos de la Visión/fisiopatología , Agudeza Visual , Adolescente , Adulto , Factores de Edad , Atrofia/inmunología , Enfermedades Autoinmunes del Sistema Nervioso/clasificación , Enfermedades Autoinmunes del Sistema Nervioso/complicaciones , Enfermedades Autoinmunes del Sistema Nervioso/diagnóstico por imagen , Niño , Preescolar , Estudios de Cohortes , Potenciales Evocados Visuales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuritis Óptica/complicaciones , Neuritis Óptica/inmunología , Recuperación de la Función , Retina/diagnóstico por imagen , Retina/inmunología , Retina/fisiopatología , Degeneración Retiniana/inmunología , Degeneración Retiniana/fisiopatología , Tomografía de Coherencia Óptica , Trastornos de la Visión/inmunología , Agudeza Visual/inmunologíaRESUMEN
Visual disabilities in central nervous system autoimmune diseases such as multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), are important symptoms. Past studies have focused on neuro-inflammatory changes and demyelination in the white matter of the brain and spinal cord. In MS, neuro-inflammatory lesions have been diagnosed in the visual pathway; the lesions may perturb visual function. Similarly, neuropathological changes in the retina and optic nerves have been found in animals with chronic EAE. Although the retina and optic nerves are immunologically privileged sites via the blood-retina barrier and blood-brain barrier, respectively, inflammation can occur via other routes, such as the uvea (e.g., iris and choroid) and cerebrospinal fluid in the meninges. This review primarily addresses the direct involvement of the blood-retina barrier and the blood-brain barrier in the development of retinitis and optic neuritis in EAE models. Additional routes, including pro-inflammatory mediator-filled choroidal and subarachnoid spaces, are also discussed with respect to their roles in EAE-induced visual disability and as analogues of MS in humans.
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Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/fisiopatología , Esclerosis Múltiple/fisiopatología , Trastornos de la Visión/fisiopatología , Vías Visuales/fisiopatología , Animales , Encefalomielitis Autoinmune Experimental/inmunología , Humanos , Esclerosis Múltiple/inmunología , Neuritis Óptica/inmunología , Neuritis Óptica/fisiopatología , Uveítis/inmunología , Uveítis/fisiopatología , Trastornos de la Visión/inmunología , Vías Visuales/inmunologíaRESUMEN
INTRODUCTION: Polymerase chain reaction (PCR)-based testing of cerebrospinal fluid (CSF) samples has greatly facilitated the diagnosis of central nervous system (CNS) infections. However, the clinical significance of Epstein-Barr virus (EBV) DNA in CSF of individuals with suspected CNS infection remains unclear. We wanted to gain a better understanding of EBV as an infectious agent in immunocompetent patients with CNS disorders. METHODS: We identified cases of EBV-associated CNS infections and reviewed their clinical and laboratory characteristics. The study population was drawn from patients with EBV PCR positivity in CSF who visited Pusan National University Hospital between 2010 and 2019. RESULTS: Of the 780 CSF samples examined during the 10-year study period, 42 (5.4 %) were positive for EBV DNA; 9 of the patients (21.4 %) were diagnosed with non-CNS infectious diseases, such as optic neuritis, Guillain-Barré syndrome, and idiopathic intracranial hypotension, and the other 33 cases were classified as CNS infections (22 as encephalitis and 11 as meningitis). Intensive care unit admission (13/33 patients, 39.3 %) and presence of severe neurological sequelae at discharge (8/33 patients, 24.2 %) were relatively frequent. In 10 patients (30.3 %), the following pathogens were detected in CSF in addition to EBV: varicella-zoster virus (n = 3), cytomegalovirus (n = 2), herpes simplex virus 1 (n = 1), herpes simplex virus 2 (n = 1), Streptococcus pneumomiae (n = 2), and Enterococcus faecalis (n = 1). The EBV-only group (n = 23) and the co-infection group (n = 10) did not differ in age, gender, laboratory data, results of brain imaging studies, clinical manifestations, or prognosis; however, the co-infected patients had higher CSF protein levels. CONCLUSION: EBV DNA in CSF is occasionally found in the immunocompetent population; the virus was commonly associated with encephalitis and poor prognosis, and frequently found together with other microbes in CSF.