Neuro-ophthalmic Mechanisms Of Disease

疾病的神经眼科机制

• 批准号: 7322372
• 负责人: Edmond J FitzGibbon
• 金额: --
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7322372
• 关键词: Neuro; ophthalmic; Mechanisms; Disease

The goal of this laboratory is to examine and study diseases which have neuro-ophthalmic manifestations with the hope of understanding etiology, aiding diagnosis and staging of disease, and formulating and testing possible therapies. In this report I will concentrate on work in fibrous dysplasia and studies of various neuro-degenerative diseases which have characteristic oculomotor abnormalities. 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 may be stretched by orbital changes. 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 were performed before treatment, and all patients recruited have now made it past one year with recordings again performed while on the study medication. These eye movement results are being tabulated and preliminary results should be available within the next several months. The same medication, OGT-918, is also being studied as a treatment for patients with Niemann Pick type C 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 is ongoing. Again, saccadic eye movement parameters are a major outcome measure and all patients have now completed at least one year on the study drug. Results from this study are being studied and preliminary conclusions will be available within the next few months. Chorea-acanthocytosis is another rare neuro-degenerative disease. Recently, three patients with this disease have had eye movement recordings in my lab. The recordings demonstrated frequent square wave jerks, along with fractionation and slowing of their saccades which has not been previously reported. Hermansky Pudlak syndrome (HPS) is a rare autosomal recessive disorder with findings of oculocutaneous albinism, bleeding, and lysosomal ceroid storage. In a collaboration with Dr. William Gahl of NHGRI , we examined 27 patients with HPS and determined that most have congenital nystagmus and many have periodic alternating nystagmus, helping to further characterize the phenotype of this disease.

该实验室的目标是检查和研究具有神经眼科表现的疾病，以期了解病因，辅助诊断和疾病分期，并制定和测试可能的治疗方法。在这份报告中，我将集中在纤维发育不良和各种神经退行性疾病的研究，这些疾病具有特征性的眼球运动异常。 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，因为他们的视神经可能会因眼眶变化而拉伸。 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。服用药物的患者在治疗前进行录音，所有招募的患者现在都已经度过了一年，在研究药物期间再次进行录音。这些眼球运动结果正在列表中，初步结果应该在接下来的几个月内公布。 同样的药物OGT-918也正在研究中，用于治疗尼曼·皮克C型疾病，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。与为高谢病开发的方案非常相似的方案正在进行中。同样，眼跳运动参数是一项主要的结果衡量标准，所有患者现在都已经完成了至少一年的研究药物治疗。这项研究的结果正在研究中，初步结论将在未来几个月内得出。 舞蹈症棘细胞增多症是另一种罕见的神经退行性疾病。最近，三名患有这种疾病的患者在我的实验室里进行了眼动记录。录音显示了频繁的方波跳动，以及之前没有报道的眼跳的分流和减慢。 Hermansky Pudlak综合征(HPS)是一种罕见的常染色体隐性遗传病，表现为眼皮肤白化、出血和溶酶体类油沉积。在与NHGRI的William Gahl博士的合作下，我们检查了27名HPS患者，确定大多数患者患有先天性眼球震颤，许多患者有周期性交替性眼球震颤，这有助于进一步描述这种疾病的表型。