Neuro-ophthalmic Mechanisms Of Disease

在这份报告中，我将集中在各种神经退行性疾病的研究，这些疾病具有特征性的眼部异常和影响视神经的疾病，如纤维性发育不良。 眼动控制分布在整个大脑中，不同影响大脑部分的疾病可以以不同且通常特定的方式影响眼球运动。我们记录了神经退行性疾病和遗传性疾病患者的眼球运动，以描述他们的眼球运动障碍，帮助做出具体诊断，将表型与基因型关联起来，分期疾病进展，并深入了解眼球运动产生的潜在过程。以下是几个例子。 在戈谢病中，β-葡糖苷酶的缺陷导致代谢副产物沉积在肝脏和脾脏、骨髓和大脑中。一个亚组（Gaucher 3型）表现为神经系统异常，包括眼球运动异常。这些患者通常有水平核上性麻痹，偶尔表现出眼用不能。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Cerezmye。过去10年来一直使用这种方法，在减少肝脾和骨髓受累方面有一定疗效。然而，这种酶对异常的眼球运动和神经症状几乎没有影响。这可能是由于血脑屏障阻止酶进入大脑。一种新药OGT-918目前正在进行1期药物试验，眼动被认为是研究其疗效的关键，因为眼动异常有时是区分戈谢病3型和戈谢病1型的唯一标准。此外，眼球运动很容易量化和参数化。这种新药通过减少有缺陷的酶的底物来起作用。当我们临床检查这些患者时，正在进行眼动记录，特别是扫视速度，并且将继续纵向跟踪疾病进展。服用药物的患者的记录是完整的，很明显OGT 918没有显著影响扫视眼球运动。 同样的药物OGT-918也被研究用于治疗C型尼曼匹克病（NPC）患者，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。这些患者有鞘磷脂酶缺乏症，他们发展垂直核上性麻痹。这些患者在哥伦比亚大学接受随访，并来到NIH进行眼动记录。已经完成了一项非常类似于为戈谢病制定的方案。同样，扫视眼球运动参数是一个主要的结果指标，所有患者现在都已完成。虽然OGT 918（Zelecca）被认为在NPC中有一定的帮助，但眼球运动并没有受到药物的显著影响。一个新的患者队列目前正在与NICHD的Denny Porter博士合作进行纵向研究。 纤维性发育不良（FD）是一种疾病，其中正常骨被纤维骨组织取代。多骨型常累及前颅底，包括蝶骨。视神经穿过蝶骨翼，在CT成像上经常被FD包裹。纤维结构不良包裹视神经的治疗存在争议，因为导致视力丧失的视神经病变是最常见的神经系统并发症。与牙科研究所的Michael柯林斯博士合作，对60多名纤维性结构不良患者进行了检查，并继续对这批患者进行神经眼科检查，以追踪这种疾病的自然病史。 我们曾报道过，即使视神经管被发育不良的骨质包裹，视觉改变也很少发生。该观察结果的重要性在于阻止预防性椎管减压手术，因为其伤害的可能性更大。 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容易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.