Neuro-ophthalmic Mechanisms Of Disease

在这份报告中，我将专注于各种神经退行性疾病的研究，这些疾病具有特征性的动眼神经异常，以及影响视神经的疾病，如纤维发育不良。 眼球运动控制分布在整个大脑中，而影响大脑不同部位的疾病可以以不同的、往往是特定的方式影响眼球运动。我们记录了神经退行性和遗传性疾病患者的眼球运动，以表征他们的眼球运动障碍，帮助做出特定的诊断，将表型与基因、疾病进展阶段相关联，并深入了解眼球运动产生的潜在过程。下面是几个例子。 在高谢病中，酶β-葡萄糖苷酶的缺陷会导致代谢副产物沉积在肝和脾、骨髓和大脑中。一个亚型(Gaucher 3型)表现为神经学发现，包括异常眼球运动。典型的这些患者有水平的核上性麻痹，偶尔还会表现出动眼失用。一种通过取代其缺乏的半乳糖苷酶活性来治疗这种疾病的酶是蜡霉。在过去的10年里，这种疗法在减少肝脾和骨髓受累方面取得了一定的效果。然而，这种酶对异常眼球运动和神经症状几乎没有作用。也许这是因为血脑屏障阻止了这种酶进入大脑。一种名为OGT-918的新药目前正处于一期药物试验阶段，眼球运动被认为是研究其疗效的关键，因为异常的眼球运动有时是区分高谢尔3型患者和高谢尔1型患者的唯一标准。此外，眼睛运动很容易量化和参数。这种新药通过减少缺陷酶的底物起作用。我们在临床检查这些患者时，会进行眼球运动记录，特别是眼跳速度，并将继续纵向跟踪这些患者的病情进展。服用该药物的患者的记录是完整的，很明显，OGT918对眼球跳动没有显著影响。 同样的药物OGT-918也被研究用于治疗Niemann Pick C型(NPC)病，这是一种影响内脏和中枢神经系统的遗传性脂质储存障碍。这些患者患有鞘磷脂酶缺乏症，并发展为垂直核上性瘫痪。这些患者在哥伦比亚大学接受跟踪，并来到NIH进行眼动记录。一项与针对高谢病开发的方案非常相似的方案已经完成。再一次，眼跳运动参数是一项主要的结果衡量标准，所有的患者现在都已经完成了。虽然OGT918(Zavesca)被认为对鼻咽癌有一定的帮助，但该药物对眼球运动没有显著影响。在与NICHD的Denny Porter博士合作的一项研究中，一组新的患者目前正在接受纵向跟踪。 纤维异常增殖症(FD)是一种正常骨骼被纤维骨组织取代的疾病。在多发性骨型中，前颅底经常受累，包括蝶骨。视神经穿过蝶骨翼，在CT影像上常可见其被FD包裹。由于视神经病变导致视力丧失是最常见的神经系统并发症，围绕着包裹着视神经的纤维结构不良的处理存在争议。与牙科研究所的迈克尔·柯林斯博士合作，对60多名纤维发育不良患者进行了检查，并继续对这组患者进行纵向神经眼科检查，以追踪这种疾病的自然病史。我们已经报道过，即使视神经管被发育不良的骨包裹，视觉变化也很少发生。这一观察的重要性是为了阻止预防性的椎管减压手术，因为它们更有可能造成伤害。另一个警告是，患有高生长激素水平和颅骨受累的McCune Albright综合征的患者应该密切关注，因为他们的视神经更有可能受到眼眶变化的影响。

In this report I will concentrate on studies of various neuro-degenerative diseases which have characteristic oculomotor abnormalities and in diseases that affect the optic nerve such as fibrous dysplasia. Oculomotor control is distributed throughout the brain, and diseases differentially affecting parts of the brain can affect eye movements in different, and often specific ways. We have recorded eye movements in patients with neurodegenerative and genetic diseases to characterize their ocular motility disorder, to help make a specific diagnosis, correlate phenotype to genotype, stage disease progression, and to give insight into the processes underlying eye movement generation. Several examples appear below. In Gaucher disease a defect in the enzyme beta-glucosidase results in a metabolic byproduct being deposited in the liver and spleen, the bone marrow, and the brain. A subgroup (Gaucher type 3) presents with neurologic findings, including abnormal eye movements. Typically these patients have a horizontal supranuclear palsy and occasionally exhibit an oculomotor apraxia. An enzyme to treat this disease by replacing their deficient galactosidase activity is cerezmye. This has been used for the past 10 years with some efficacy in reducing liver-spleen and marrow involvement. However, the enzyme has had little effect on abnormal eye movements and neurologic symptoms. Perhaps this is due to the blood brain barrier preventing the enzyme from access to the brain. A new medication, OGT-918, is currently in a phase 1 drug trial and eye movements are felt to be crucial to studying its efficacy since abnormal eye movements are sometimes the only criteria differentiating patients with Gaucher type 3 from Gaucher type 1. Also eye movements are easily quantifiable and parametric. The new drug works by reducing the substrate for the defective enzyme. Eye movement recordings looking particularly at saccadic velocity are being performed as we clinically examine these patients, and they will continue to be followed longitudinally for disease progression. The recordings in patients taking the medication are complete and it is clear that OGT918 did not significantly affect saccadic eye movements. The same medication, OGT-918, was also being studied as a treatment for patients with Niemann Pick type C (NPC) disease, an inherited lipid storage disorder that affects the viscera and central nervous system. These patients have sphingomyelinase deficiency and they develop vertical supranuclear palsy. These patients are followed at Columbia University and come to NIH for their eye movement recordings. A protocol very similar to the one developed for Gaucher disease has been completed. Again, saccadic eye movement parameters were a major outcome measure and all patients have now been completed. Although OGT918 (Zavesca) was felt to be somewhat helpful in NPC, eye movements were not significantly affected by the medication. A new cohort of patients are currently being followed longitudinally in a collaborative study with Dr. Denny Porter of NICHD. Fibrous dysplasia (FD) is a disease where normal bone is replaced with fibro-osseous tissue. In the polyostotic form, the anterior cranial base is frequently involved, including the sphenoid bones. The optic nerve passes through the sphenoid wing and is often found to be encased by FD on CT imaging. Controversy surrounds the management of fibrous dysplasia encased optic nerves, as optic neuropathy resulting in vision loss is the most frequently reported neurological complication. In collaboration with Dr. Michael Collins of the Dental Institute, a cohort of more than 60 patients with fibrous dysplasia have been examined and this cohort of patients continues to be followed longitudinally with neuro-ophthalmologic exams to track the natural history of this disease. We have reported that even when the optic canal is encased with dysplastic bone, visual changes rarely occur. The importance of this observation is to discourage prophylactic canal decompression surgery since their is a greater likelihood of harm. Another caveat is that patients with McCune Albright syndrome with high growth hormone levels and skull involvement should be followed closely since their optic nerves are more likely to be affected by orbital changes.