RESUMO
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.
Assuntos
Biomarcadores , Eletrorretinografia , Encefalomielite Autoimune Experimental , Camundongos Endogâmicos C57BL , Neurite Óptica , Células Ganglionares da Retina , Tomografia de Coerência Óptica , Animais , Encefalomielite Autoimune Experimental/patologia , Encefalomielite Autoimune Experimental/fisiopatologia , Neurite Óptica/patologia , Neurite Óptica/fisiopatologia , Neurite Óptica/imunologia , Camundongos , Feminino , Eletrorretinografia/métodos , Células Ganglionares da Retina/patologia , Nervo Óptico/patologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Modelos Animais de DoençasRESUMO
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 Animais de Doenças , Vírus da Hepatite Murina , Neurite Óptica , SARS-CoV-2 , Glicoproteína da Espícula de Coronavírus , Animais , Neurite Óptica/virologia , Neurite Óptica/etiologia , Neurite Óptica/metabolismo , Neurite Óptica/fisiopatologia , Glicoproteína da Espícula de Coronavírus/metabolismo , Glicoproteína da Espícula de Coronavírus/genética , Camundongos , COVID-19/complicações , Vírus da Hepatite Murina/fisiologia , Humanos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/fisiopatologia , Betacoronavirus 1/metabolismoRESUMO
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.
Assuntos
Potenciais Evocados Visuais , Esclerose Múltipla , Neurite Óptica , Humanos , Potenciais Evocados Visuais/fisiologia , Neurite Óptica/diagnóstico , Neurite Óptica/fisiopatologia , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/fisiopatologia , Feminino , Masculino , Adulto , Campos Visuais/fisiologia , Córtex Visual/fisiopatologia , Eletroencefalografia/instrumentação , Pessoa de Meia-Idade , Projetos Piloto , Estimulação LuminosaRESUMO
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.
Assuntos
Drusas do Disco Óptico , Disco Óptico , Doenças do Nervo Óptico , Papiledema , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Estudos Retrospectivos , Tomografia de Coerência Óptica/métodos , Criança , Feminino , Masculino , Acuidade Visual/fisiologia , Adolescente , Prevalência , Papiledema/diagnóstico , Papiledema/fisiopatologia , Disco Óptico/patologia , Disco Óptico/diagnóstico por imagem , Pré-Escolar , Doenças do Nervo Óptico/diagnóstico , Doenças do Nervo Óptico/fisiopatologia , Drusas do Disco Óptico/fisiopatologia , Drusas do Disco Óptico/diagnóstico , Campos Visuais/fisiologia , Fibras Nervosas/patologia , Células Ganglionares da Retina/patologia , Neurite Óptica/fisiopatologia , Neurite Óptica/diagnóstico , LactenteRESUMO
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.
Assuntos
Progressão da Doença , Esclerose Múltipla , Vasos Retinianos , Tomografia de Coerência Óptica , Humanos , Tomografia de Coerência Óptica/métodos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/fisiopatologia , Vasos Retinianos/diagnóstico por imagem , Angiofluoresceinografia/métodos , Microcirculação/fisiologia , Neurite Óptica/diagnóstico , Neurite Óptica/etiologia , Neurite Óptica/diagnóstico por imagem , Neurite Óptica/fisiopatologia , Reprodutibilidade dos TestesRESUMO
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.
Assuntos
Autoanticorpos , Glicoproteína Mielina-Oligodendrócito , Neurite Óptica , Humanos , Neurite Óptica/diagnóstico , Neurite Óptica/fisiopatologia , Neurite Óptica/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Autoanticorpos/sangue , Tomografia de Coerência Óptica , Potenciais Evocados Visuais , Imageamento por Ressonância Magnética , Glucocorticoides/uso terapêuticoRESUMO
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.
Assuntos
Potenciais Evocados Visuais , Corpos Geniculados , Esclerose Múltipla , Vias Visuais , Humanos , Masculino , Feminino , Corpos Geniculados/fisiopatologia , Corpos Geniculados/diagnóstico por imagem , Adulto , Potenciais Evocados Visuais/fisiologia , Vias Visuais/fisiopatologia , Vias Visuais/diagnóstico por imagem , Pessoa de Meia-Idade , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/diagnóstico por imagem , Tomografia de Coerência Óptica/métodos , Imageamento por Ressonância Magnética , Neurite Óptica/fisiopatologia , Neurite Óptica/diagnóstico por imagemRESUMO
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.
Assuntos
Idade de Início , Autoanticorpos , Imageamento por Ressonância Magnética , Glicoproteína Mielina-Oligodendrócito , Neurite Óptica , Humanos , Masculino , Feminino , Neurite Óptica/diagnóstico por imagem , Neurite Óptica/imunologia , Neurite Óptica/fisiopatologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Adulto , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem , Autoanticorpos/sangue , Acuidade Visual/fisiologia , Seguimentos , Estudos RetrospectivosRESUMO
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.
Assuntos
Glicoproteína Mielina-Oligodendrócito , Neurite Óptica , Células Ganglionares da Retina , Tomografia de Coerência Óptica , Acuidade Visual , Humanos , Glicoproteína Mielina-Oligodendrócito/imunologia , Tomografia de Coerência Óptica/métodos , Feminino , Masculino , Estudos Retrospectivos , Neurite Óptica/diagnóstico , Neurite Óptica/fisiopatologia , Neurite Óptica/imunologia , Criança , Acuidade Visual/fisiologia , Adolescente , Células Ganglionares da Retina/patologia , Fibras Nervosas/patologia , Autoanticorpos/sangue , Disco Óptico/patologia , Disco Óptico/diagnóstico por imagem , Sensibilidades de Contraste/fisiologiaAssuntos
Fatores Imunológicos/administração & dosagem , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/fisiopatologia , Transtornos da Visão/fisiopatologia , Adolescente , Humanos , Masculino , Neurite Óptica/complicações , Neurite Óptica/tratamento farmacológico , Neurite Óptica/imunologia , Transtornos da Visão/tratamento farmacológico , Transtornos da Visão/etiologiaRESUMO
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.
Assuntos
Encefalomielite Autoimune Experimental , Proteínas Ligadas por GPI , Regeneração Nervosa , Proteínas do Tecido Nervoso , Neuroproteção , Traumatismos do Nervo Óptico , Nervo Óptico , Neurite Óptica , Recuperação de Função Fisiológica , Retina , Animais , Camundongos , Cuprizona/toxicidade , Encefalomielite Autoimune Experimental/induzido quimicamente , Encefalomielite Autoimune Experimental/fisiopatologia , Proteínas Ligadas por GPI/antagonistas & inibidores , Inibidores da Monoaminoxidase/toxicidade , Regeneração Nervosa/efeitos dos fármacos , Regeneração Nervosa/fisiologia , Proteínas do Tecido Nervoso/antagonistas & inibidores , Neuroproteção/efeitos dos fármacos , Nervo Óptico/efeitos dos fármacos , Nervo Óptico/fisiologia , Traumatismos do Nervo Óptico/fisiopatologia , Neurite Óptica/fisiopatologia , Recuperação de Função Fisiológica/efeitos dos fármacos , Recuperação de Função Fisiológica/fisiologia , Retina/efeitos dos fármacos , Ressonância de Plasmônio de SuperfícieRESUMO
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.
Assuntos
Astrócitos/metabolismo , Encefalomielite Autoimune Experimental/fisiopatologia , Proteínas de Sinalização YAP/metabolismo , Animais , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/metabolismo , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/metabolismo , Doenças Neuroinflamatórias , Nervo Óptico/fisiologia , Neurite Óptica/metabolismo , Neurite Óptica/fisiopatologia , Retina/metabolismo , Retina/fisiologia , Células Ganglionares da Retina/metabolismo , Transdução de Sinais , Fator de Crescimento Transformador beta/metabolismo , Fator de Crescimento Transformador beta/fisiologia , Proteínas de Sinalização YAP/fisiologiaRESUMO
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.
Assuntos
Predisposição Genética para Doença/genética , Esclerose Múltipla/genética , Neurite Óptica/genética , Polimorfismo de Nucleotídeo Único/genética , Receptor para Produtos Finais de Glicação Avançada/genética , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/fisiopatologia , Razão de Chances , Neurite Óptica/diagnóstico , Neurite Óptica/fisiopatologia , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Acuidade Visual/fisiologia , Adulto JovemRESUMO
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.
Assuntos
Neurite Óptica/diagnóstico , Sarcoidose/diagnóstico , Humanos , Masculino , Pessoa de Meia-Idade , Neuromielite Óptica/diagnóstico , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/fisiopatologia , Neurite Óptica/tratamento farmacológico , Neurite Óptica/fisiopatologia , Sarcoidose/tratamento farmacológico , Sarcoidose/fisiopatologiaAssuntos
Encéfalo/diagnóstico por imagem , Transtornos de Enxaqueca/diagnóstico , Neurite Óptica/diagnóstico , Escotoma/fisiopatologia , Adulto , Diagnóstico Diferencial , Glucocorticoides/uso terapêutico , Humanos , Imageamento por Ressonância Magnética , Masculino , Proteína Básica da Mielina/líquido cefalorraquidiano , Neurite Óptica/líquido cefalorraquidiano , Neurite Óptica/tratamento farmacológico , Neurite Óptica/fisiopatologia , Prednisolona/uso terapêuticoRESUMO
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.
Assuntos
Doenças Autoimunes do Sistema Nervoso , Neurite Óptica/fisiopatologia , Retina , Transtornos da Visão/fisiopatologia , Acuidade Visual , Adolescente , Adulto , Fatores Etários , Atrofia/imunologia , Doenças Autoimunes do Sistema Nervoso/classificação , Doenças Autoimunes do Sistema Nervoso/complicações , Doenças Autoimunes do Sistema Nervoso/diagnóstico por imagem , Criança , Pré-Escolar , Estudos de Coortes , Potenciais Evocados Visuais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/complicações , Neurite Óptica/imunologia , Recuperação de Função Fisiológica , Retina/diagnóstico por imagem , Retina/imunologia , Retina/fisiopatologia , Degeneração Retiniana/imunologia , Degeneração Retiniana/fisiopatologia , Tomografia de Coerência Óptica , Transtornos da Visão/imunologia , Acuidade Visual/imunologiaRESUMO
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.
Assuntos
Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/fisiopatologia , Esclerose Múltipla/fisiopatologia , Transtornos da Visão/fisiopatologia , Vias Visuais/fisiopatologia , Animais , Encefalomielite Autoimune Experimental/imunologia , Humanos , Esclerose Múltipla/imunologia , Neurite Óptica/imunologia , Neurite Óptica/fisiopatologia , Uveíte/imunologia , Uveíte/fisiopatologia , Transtornos da Visão/imunologia , Vias Visuais/imunologiaRESUMO
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.
Assuntos
DNA Viral/líquido cefalorraquidiano , Infecções por Vírus Epstein-Barr/fisiopatologia , Herpesvirus Humano 4/genética , Imunocompetência , Encefalite Infecciosa/fisiopatologia , Meningite/fisiopatologia , Adulto , Idoso , Coinfecção , Infecções por Citomegalovirus/líquido cefalorraquidiano , Infecções por Citomegalovirus/complicações , Infecções por Citomegalovirus/fisiopatologia , Encefalite por Herpes Simples/líquido cefalorraquidiano , Encefalite por Herpes Simples/complicações , Encefalite por Herpes Simples/fisiopatologia , Encefalite Viral/líquido cefalorraquidiano , Encefalite Viral/complicações , Encefalite Viral/fisiopatologia , Enterococcus faecalis , Infecções por Vírus Epstein-Barr/líquido cefalorraquidiano , Infecções por Vírus Epstein-Barr/complicações , Feminino , Infecções por Bactérias Gram-Positivas/líquido cefalorraquidiano , Infecções por Bactérias Gram-Positivas/complicações , Infecções por Bactérias Gram-Positivas/fisiopatologia , Síndrome de Guillain-Barré/líquido cefalorraquidiano , Síndrome de Guillain-Barré/complicações , Síndrome de Guillain-Barré/fisiopatologia , Humanos , Encefalite Infecciosa/líquido cefalorraquidiano , Encefalite Infecciosa/complicações , Encefalite Infecciosa/microbiologia , Unidades de Terapia Intensiva , Hipotensão Intracraniana/líquido cefalorraquidiano , Hipotensão Intracraniana/complicações , Hipotensão Intracraniana/fisiopatologia , Masculino , Meningite/líquido cefalorraquidiano , Meningite/complicações , Meningite/microbiologia , Meningite Pneumocócica/líquido cefalorraquidiano , Meningite Pneumocócica/complicações , Meningite Pneumocócica/fisiopatologia , Meningite Viral/líquido cefalorraquidiano , Meningite Viral/complicações , Meningite Viral/fisiopatologia , Pessoa de Meia-Idade , Neurite Óptica/líquido cefalorraquidiano , Neurite Óptica/complicações , Neurite Óptica/fisiopatologia , Infecções Estreptocócicas/líquido cefalorraquidiano , Infecções Estreptocócicas/complicações , Infecções Estreptocócicas/fisiopatologia , Streptococcus pneumoniae , Infecção pelo Vírus da Varicela-Zoster/líquido cefalorraquidiano , Infecção pelo Vírus da Varicela-Zoster/complicaçõesRESUMO
Rhinogenous optic neuritis, which causes neuropathy associated with visual dysfunction, greatly reduces patient quality of life and requires suitable early treatment. This study aimed to analyze visual outcome predictors in patients with rhinogenous optic neuritis and to develop and investigate the usefulness of an algorithm to facilitate early treatment. Prospective and retrospective investigations were conducted at the Department of Otorhinolaryngology. The visual outcomes after sinus surgery of 24 of 53 patients suspected of having rhinogenous optic neuritis were analyzed. Furthermore, the usefulness of the treatment algorithm was evaluated in 27 of these 53 patients. Data from 24 patients who underwent surgery were included in a multiple regression analysis to investigate the associations between visual outcomes and concomitant symptoms and the time from symptom onset to surgery. The mean time from the initial examination to a request for otorhinolaryngological examination to assess the usefulness of the treatment algorithm was compared in 27 patients who did not undergo an initial otorhinolaryngological examination. Visual acuity improved in 23 participants who underwent surgery. Multivariate analysis identified the time from onset to surgery and headache as significant predictors of postoperative visual acuity. The mean time from the initial examination to a request for otorhinolaryngological examination was significantly shorter after the algorithm was introduced (1.13 days, 8 patients; P = .008). Early surgical treatment is essential to avoid further postoperative visual acuity decreases in patients with rhinogenous optic neuritis. Patients who experience headache may have poorer postoperative outcomes.
Assuntos
Algoritmos , Neurite Óptica/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Prevenção Secundária , Transtornos da Visão/prevenção & controle , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Cefaleia/etiologia , Cefaleia/fisiopatologia , Humanos , Masculino , Pessoa de Meia-Idade , Procedimentos Cirúrgicos Nasais/métodos , Neurite Óptica/complicações , Neurite Óptica/fisiopatologia , Seios Paranasais/cirurgia , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/fisiopatologia , Período Pós-Operatório , Estudos Prospectivos , Qualidade de Vida , Análise de Regressão , Estudos Retrospectivos , Resultado do Tratamento , Transtornos da Visão/etiologia , Transtornos da Visão/fisiopatologia , Acuidade Visual , Adulto JovemRESUMO
BACKGROUND: The steady-state pattern electroretinogram (PERG) is a sensitive measure of retinal ganglion cell (RGC) function that includes within-test progressive changes-adaptation-reflecting RGC autoregulatory dynamics. Comprehensive PERG assessment in patients with multiple sclerosis (MS) (with or without optic neuritis [ON]) may provide unique information about RGC dysfunction and its progression, as well as a comparison between functional loss and structural loss as measured by optical coherence tomography (OCT). The goal of this project was to measure steady-state PERG components and their associations with intraretinal layer thicknesses in MS. METHODS: One hundred forty eyes of 70 patients with relapsing-remitting MS and 126 eyes of 63 age- and sex-matched healthy control subjects (HC) were investigated using a new-generation PERG method and ultrahigh-resolution OCT. Of MS eyes, there were 30 eyes with ON (MSON), 22 non-ON fellow eyes (MSFE), and 88 non-ON MS eyes (MSNON). PERG amplitude, phase (latency), and adaptation of amplitude and phase were measured and correlated with OCT-determined thicknesses of intraretinal layers. RESULTS: The average PERG amplitude in MSON eyes was significantly lower than MSFE (P = 0.007), MSNON (P = 0.002), and HC (P < 0.001). The PERG amplitude in MSFE eyes was also significantly lower than HC (P = 0.039). The PERG latency in MSON eyes was significantly shorter than in MSFE (P = 0.001), MSNON (P = 0.002), and HC (P < 0.001). The PERG latency in MSFE (P = 0.007) and MSNON (P = 0.002) was significantly shorter than in HC. However, no significant differences were found between MSFE and MSNON (P > 0.05). PERG adaptation of amplitude in MSON was significantly lower than that in MSNON (P = 0.039) and HC (P = 0.037). Both the amplitude and latency in the MS eyes were significantly correlated with the thicknesses of the macular retinal nerve fiber layer (mRNFL) and ganglion cell-inner plexiform layer (GCIPL). CONCLUSIONS: Shortened PERG latency and impaired autoregulatory dynamics occurred in MS, suggesting preferential dysfunction of small, slower RGC axons and decreased ability of RGC to autoregulate their gain in response to PERG stimulus. The established relations of PERG measurements with intraretinal thickness measurements suggested that PERG losses were primarily associated with GCIPL and mRNFL thinning.