Novel Clinical and Ocular Imaging Outcomes with Long-Term Follow-Up in MS

描述（由申请人提供）：视觉功能障碍是多发性硬化症（MS）中一种常见且经常不可逆转的致残原因。包括视神经、视网膜、视交叉和束在内的前视通路是炎症和脱髓鞘的常见部位，这些结构内的轴突神经元变性是导致永久性视力丧失的最终常见途径。被MS专家认可为临床试验结果评估的一个关键维度，视力已经成为一个重要的研究领域，导致低对比度字母敏锐度被确定为一种新的测量方法。低对比度字母视力甚至可以检测到高对比度视力（VA）无法捕捉到的细微视力障碍，并在最近的两个3期试验中证明了治疗效果。非侵入性眼部成像，包括光学相干断层扫描（OCT）和可变角膜补偿扫描激光偏振仪（GDx），也越来越被认为是多发性硬化轴突和神经元损失的潜在标志。视网膜神经纤维层（RNFL）变薄和黄斑总体积减少与单个时间点的低对比视力下降相关，初步数据表明，即使在没有急性视神经炎（ON）的情况下，随着时间的推移，RNFL轴突损失与视觉功能恶化有关。这些独特的结构-功能相关性使前视通路成为MS临床试验中检验治疗效果的一个有吸引力的模型，特别是对于预计将涉及神经保护剂的下一代试验。虽然我们的横断面、初步纵向和临床试验数据代表了完善和验证MS和ON的视觉和眼部成像结果的重要一步，但重要的问题仍然存在，只能通过统一研究的大规模合作研究来解决，异质性MS队列和急性ON患者。该建议将使用前视通路作为模型来检查MS中结构和功能（视力和生活质量）的相关性：目标1：完善和验证低对比度的信锐度，OCT （OCT-3和超高分辨率）和GDx的RNFL厚度，以及OCT的黄斑总体积，作为MS临床试验的潜在措施。以急性视神经炎（ON）为具体模型，检查视网膜厚度和黄斑体积变化的时间，并定义OCT和GDx测量如何提供跨视网膜象限的模式以及轴突、神经元和功能丧失的相对时间。目的3：确定在MS和ON的纵向研究中，低对比度字母敏度、RNFL厚度和黄斑总体积如何影响视力特异性和总体健康相关生活质量（HRQOL）。

DESCRIPTION (provided by applicant): Visual dysfunction is a common and frequently irreversible cause of disability in multiple sclerosis (MS). The anterior visual pathways, including the optic nerves, retina, chiasm, and tracts, are frequent sites for inflammation and demyelization, and axonal neuronal degeneration within these structures is a final common pathway to permanent visual loss. Recognized by MS experts as a critical dimension for clinical trial outcomes assessment, vision has been an important area of study that has resulted in identification of low-contrast letter acuity as a new measure. Low-contrast letter acuity detects even subtle visual impairment not captured by high-contrast visual acuity (VA) and demonstrated treatment effects in two recent phase 3 trials. Non-invasive ocular imaging, including optical coherence tomography (OCT) and scanning laser polarimetry with variable corneal compensation (GDx), has also become increasingly recognized in MS as a potential marker for axonal and neuronal loss. Retinal nerve fiber layer (RNFL) thinning and reductions in total macular volume correlate with reductions in low-contrast acuity at a single time point, and preliminary data suggest that RNFL axonal loss over time is associated with worsening visual function, even in the absence of acute optic neuritis (ON). These unique structure-function correlations make the anterior visual pathways an attractive model for examining therapeutic efficacy in MS clinical trials, particularly for the anticipated next generation of trials that will involve neuroprotective agents. While our cross-sectional, preliminary longitudinal, and clinical trial data represent a significant step toward refining and validating visual and ocular imaging outcomes for MS and ON, important questions remain that can only be addressed by large-scale collaborative studies of uniformly studied, heterogeneous MS cohorts and of patients with acute ON. This proposal will use the anterior visual pathways as a model for examining correlations of structure and function (vision and quality of life) in MS: Aim 1: Refine and validate low-contrast letter acuity, RNFL thickness by OCT (OCT-3 and ultra-high resolution) and GDx, and total macular volume by OCT as potential measures for clinical trials in MS. Aim 2: Using acute optic neuritis (ON) as a specific model, examine the timing of changes in RNFL thickness and macular volume, and define how OCT and GDx measures may provide insight into patterns across retinal quadrants and relative timing of axonal, neuronal, and functional loss for an MS lesion. Aim 3: Determine how low-contrast letter acuity, RNFL thickness, and total macular volume impact vision specific and overall health-related quality of life (HRQOL) in longitudinal studies of MS and ON.