PURPOSE To compare functional and structural changes in the retina in patients with aquaporin-4 immunoglobulin G (AQP4-IgG)-positive neuromyelitis optica spectrum disorder (NMOSD) and multiple sclerosis (MS). DESIGN Cross-sectional study; biochemical study of human retinas. PARTICIPANTS A total of 181 participants, including 22 consecutive patients (44 eyes) with NMOSD, 131 patients (262 eyes) with multiple sclerosis (MS), and 28 normal subjects (56 eyes). In addition, 8 eyeballs from healthy donors were used for biochemical analysis. METHODS Full-field electroretinography (ERG) and spectral-domain OCT were performed in all the subjects. Topography of AQP4 expression and Müller glial distribution were analyzed using Western blotting and immunohistochemistry. MAIN OUTCOME MEASURES Full-field ERG parameters, including amplitudes and peak times. Tissue volume of each of the retinal layers at the fovea by OCT segmentation. Levels of AQP4 expression at different retinal regions. RESULTS The b-wave amplitude was significantly reduced in patients with AQP4-IgG+ NMOSD in scotopic ERGs (compared with AQP4-IgG- subjects, patients with MS, and normal controls) but not in photopic ERGs. Further analysis showed that this b-wave change was mainly caused by reduction of the slow PII component, suggesting specific Müller cell dysfunction. We also found thinning of specific retinal layers at the fovea in patients with AQP4-IgG+ NMOSD, in the Henle fiber outer nuclear layer (HFONL) and the inner segment (IS) layer, but not in the inner nuclear layer (INL), outer plexiform layer (OPL), or outer segment (OS) layer. Furthermore, there was a significant association between foveal HFONL-IS complex thinning and scotopic b-wave amplitude reduction (P = 0.005∼0.01, fixed-effects model). Western blotting demonstrated that Müller cell-specific AQP4 was expressed at a higher level at the fovea than the peripheral retina. Immunohistochemical studies revealed that the specific foveal thinning reflected the topography of AQP4 expression and Müller glial distribution in the human macula. CONCLUSIONS This study provides in vivo structural and functional evidence of Müller glial dysfunction in eyes of patients with AQP4-IgG+ NMOSD. Topography of retinal structural change is supported by distribution of Müller cells and patterns of AQP4 expression. The study suggests that visual electrophysiology and retinal imaging could be useful biomarkers to assess the potential retinal astrocytopathy in NMOSD.

中文翻译：

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Aquaporin-4免疫球蛋白G阳性视神经脊髓炎Optica光谱障碍患者中Müller胶质细胞功能障碍的证据。

目的比较Aquaporin-4免疫球蛋白G（AQP4-IgG）阳性的神经脊髓炎视神经频谱疾病（NMOSD）和多发性硬化症（MS）患者视网膜的功能和结构变化。设计横断面研究；人体视网膜的生化研究。参与者共有181名参与者，包括22例NMOSD连续患者（44眼），131例多发性硬化症（MS）患者（262眼）和28名正常受试者（56眼）。此外，将来自健康捐献者的8个眼球用于生化分析。方法对所有受试者进行全场视网膜电图（ERG）和光谱域OCT检查。使用蛋白质印迹和免疫组织化学分析了AQP4表达的拓扑结构和Müller胶质分布。主要观察指标全视野ERG参数，包括幅度和峰值时间。通过OCT分割，在中央凹处的每个视网膜层的组织体积。不同视网膜区域的AQP4表达水平。结果在暗视ERG中（与AQP4-IgG-受试者，MS患者和正常对照者相比），AQP4-IgG + NMOSD患者的b波幅度显着降低，而在明视ERG中则没有。进一步的分析表明，这种b波变化主要是由缓慢的PII成分减少引起的，提示特定的Müller细胞功能异常。我们还发现，AQP4-IgG + NMOSD患者的中央凹处特定的视网膜层变薄，在Henle纤维外核层（HFONL）和内部节段（IS）层变薄，但在内部核层（INL）的外部则没有变薄丛状层（OPL）或外层（OS）层。此外，中心凹HFONL-IS复合体变薄与暗视b波振幅降低之间存在显着相关性（P = 0.005〜0.01，固定效应模型）。Western印迹表明，Müller细胞特异性AQP4在中央凹处的表达水平高于周围视网膜。免疫组织化学研究表明，特定的中央凹变薄反映了人类黄斑中AQP4表达的地形和Müller神经胶质分布。结论本研究为AQP4-IgG + NMOSD患者眼睛中的Müller神经胶质功能障碍提供了体内结构和功能证据。穆勒细胞的分布和AQP4表达模式可支持视网膜结构变化的地形图。