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。我们记录了患有神经退行性疾病和遗传性疾病的患者的眼球运动，以表征他们的眼球运动障碍，以帮助做出特定的诊断，将表型与基因型相关联，分期疾病进展，并深入了解眼球运动产生的过程。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。在过去的10多年里，这种方法在减少肝脾和骨髓受累方面具有一定的疗效。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。OGT-918是一种新药，在1期药物试验中进行了测试，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戈谢3型患者和戈谢1型患者的唯一标准。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。在我们临床检查这些患者时，进行了眼动记录，特别是扫视速度，并对疾病进展进行了纵向随访。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，但在肺功能和降低壳三糖苷酶水平方面确实有一些益处，壳三糖苷酶是疾病严重程度的标志。 一份报告这些发现的论文即将出版。 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测量，所有患者都完成了这项研究。OGT 918（Zorecca）被发现在NPC中有一定的帮助，并且有证据表明该药物改善了扫视速度。一个新的患者队列目前正在招募，并在与NICHD的福布斯波特博士的自然史协议的合作研究中进行纵向随访。同样，眼球运动记录将有助于表征疾病阶段和进展。 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。视神经纤维异常增殖症的治疗是有争议的，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，其中许多患者继续接受神经眼科检查纵向随访，以跟踪这种疾病的自然史。 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McCune Albright综合征（纤维性发育不良、内分泌病和咖啡Au lait斑的三联征）的患者，如果生长激素水平高且颅骨受累，应密切进行临床随访，因为他们的视神经更容易受到眼眶变化的影响。 1型神经纤维瘤病（NF 1）是一种常见的常染色体显性遗传病。 丛状神经纤维瘤发生在约25%的患者中，这些是NF 1最令人衰弱的并发症。中枢神经系统胶质瘤和其他神经眼科表现的发病率较高。 与NCI的Brigitte Wideman合作，两组NF 1患者正在眼科诊所接受随访。 NF 1患者将入组自然史研究，并纵向随访，记录几个参数，包括Lisch结节、视力和眼球运动。 患有CNS神经胶质瘤的NF 1患者将被纳入聚乙二醇干扰素α-2b（Pegintron）的1期临床试验。两个研究组均将接受完整的神经眼科检查和成像。

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 plus 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. It is likely that this is due to the blood brain barrier preventing the enzyme from access to the brain. A new medication, OGT-918 was tested in a phase 1 drug trial and eye movements were 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. This new drug works by reducing the substrate for the defective enzyme. Eye movement recordings looking particularly at saccadic velocity were performed as we clinically examine these patients, and they were 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 but did have some benefit in pulmonary function and in lowering levels of chitotriosidase, a marker of disease severity. A paper reporting these findings is in press. 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 were followed at Columbia University and came 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 completed this study. OGT918 (Zavesca) was found to be somewhat helpful in NPC and there was evidence that saccadic velocities were improved by the drug. A new cohort of patients are currently being enrolled and followed longitudinally in a collaborative study with Dr. Forbes Porter of NICHD in a natural history protocol. Again eye movements recordings will help to characterize the disease stage and progression. 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. The management of fibrous dysplasia encased optic nerves is controversial, 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 many of these patients continue 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 (the triad of fibrous dysplasia, endocrinopathies and cafe au lait spots) who have high growth hormone levels and skull involvement should be clinically followed closely, since their optic nerves are more likely to be affected by orbital changes. Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder. Plexiform neurofibromas develop in about 25% of patients and these are among the most debilitating complication of NF1. There is a higher incidence of central nervous system gliomas and other neuro-ophthalmic manifestations. In collaboration with Brigitte Wideman of NCI, two groups of patients with NF1 are being followed in the eye clinic. NF1 patients will be enrolled in a natural history study and followed longitudinally noting several parameters including Lisch nodules, vision, and ocular motility. NF1 patients with CNS glioma will be enrolled in a phase 1 clinical trial of peginterferon alfa-2b (Pegintron). Both study groups will be followed with complete neuro-ophthalmic exams and imaging.