Neuro-ophthalmic Mechanisms Of Disease

疾病的神经眼科机制

基本信息

批准号：
7594074
负责人：
Edmond J FitzGibbon
金额：
$ 43.27万
依托单位：
NATIONAL EYE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
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/7594074
关键词：
Affect Anterior Blindness Blood - brain barrier anatomy Bone Marrow Brain Brain Diseases Brain Part Characteristics Collaborations Complication Decompressive incision Defect Degenerative Disorder Dental Deposition Diagnosis Disease Disease Progression Dysplasia Enzymes Etiology Exhibits Eye Movements Galactosidase Gaucher Disease Generations Genotype Goals Hereditary Disease Image Inherited Institutes Laboratories Lipids Liver Marrow McCune-Albright Syndrome Metabolic National Institute of Child Health and Human Development Nerve Degeneration Neuraxis Neurologic Neurologic Symptoms Neurological observations Niemann-Pick Diseases Ocular Motility Disorders Operative Surgical Procedures Optic Nerve Optics Outcome Measure Paralysed Patients Pharmaceutical Preparations Phase Phenotype Process Protocols documentation Reporting Saccades Somatotropin Sphenoid bone structure Spleen Staging Subgroup Supraoptic Vertical Ophthalmoplegia Testing Tissues United States National Institutes of Health Universities Viscera Visual Wing Work Zavesca beta Glucosidases beta-Glucosidase bone cohort cranium disease natural history external Decompression insight oculomotor optic nerve disorder prevent prophylactic skull base

项目摘要

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.

在本报告中，我将集中研究具有特征性眼动异常的各种神经变性疾病以及影响视神经（例如纤维发育异常）的疾病。动眼控制分布在整个大脑中，对大脑的一部分有差异化的疾病会以不同的，通常特定的方式影响眼睛运动。我们记录了神经退行性和遗传疾病的患者的眼球运动，以表征其眼运动障碍，以帮助做出特定的诊断，将表型与基因型相关，阶段疾病进展，并深入了解眼动运动产生的过程。下面显示了几个示例。在Gaucher疾病中，酶β-葡萄糖苷酶的A缺陷导致代谢副产品沉积在肝脏和脾脏，骨髓和大脑中。一个亚组（Gaucher 3型）呈现出神经系统发现，包括眼睛异常运动。通常，这些患者有水平的上麻痹，偶尔会出现眼动失障。通过取代其缺乏的半乳糖苷酶活性来治疗该疾病的酶是Cerezmye。在过去的10年中，这已经使用了，在减少肝脏和骨髓参与方面有一些功效。但是，该酶对眼睛运动异常和神经系统症状的影响不大。也许这是由于血脑屏障阻止酶进入大脑。一种新的药物，即OGT-918，目前正在一项1期药物试验中，而眼睛运动对于研究其功效至关重要，因为异常的眼动运动有时是将Gaucher 3类型与Gaucher类型1区分开的唯一标准。而且，挑剔的运动也很容易量化和参数。新药通过减少缺陷酶的底物来起作用。当我们临床检查这些患者时，正在进行尤其是saccadic速度的眼动记录，并将继续纵向跟随疾病进展。服用药物的患者的记录已经完成，很明显，OGT918并未显着影响眼球运动。同样的药物OGT-918也被研究为niemann Pick型C（NPC）疾病患者的治疗，这是一种影响内脏和中枢神经系统的遗传脂质储存障碍。这些患者患有鞘磷脂酶缺乏症，并且会出现垂直的上核瘫痪。这些患者在哥伦比亚大学被跟随，并来到NIH进行眼动录音。一项与为高雪氏病开发的协议已经完成。同样，Saccadic眼动参数是一项主要的结果指标，所有患者现已完成。尽管OGT918（Zavesca）对NPC有所帮助，但眼睛运动并未受到药物的显着影响。目前，在与NICHD的Denny Porter博士的一项合作研究中，目前正在一系列新的患者进行纵向跟踪。纤维发育不良（FD）是一种疾病，正常骨被纤维骨组织代替。在多质体形式中，颅底碱经常涉及包括蝶骨骨头。视神经穿过蝶翅，通常被发现被CT成像上的FD包裹。争议围绕着纤维发育不良包含的视神经的治疗，因为导致视力丧失的视神经病变是最常报道的神经系统并发症。与牙科研究所的迈克尔·柯林斯（Michael Collins）合作，已经检查了60多名纤维发育不良患者的队列，并且该队列的患者继续进行纵向遵循神经性跨科学检查，以追踪这种疾病的自然史。我们报告说，即使视管用发育不良的骨头包裹，视觉变化也很少发生。这种观察的重要性是劝阻预防性的运河减压手术，因为它们的可能性更大。另一个警告是，由于其视神经更有可能受到轨道变化的影响，因此应紧紧遵循具有高生长激素水平和颅骨受累的麦考纳·奥尔布赖特综合症患者。