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，希望了解病因，帮助诊断和分期疾病，并制定和测试可能的治疗方法。在这份报告中，我将集中在纤维结构不良的工作和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。 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McCune Albright综合征的高生长激素水平和颅骨受累的患者应密切随访，因为他们的视神经可能会因眼眶变化而拉伸。 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。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。在治疗前对服用药物的患者进行记录，并且所有招募的患者现在都已经超过一年，在服用研究药物时再次进行记录。这些眼动结果正在制表，初步结果应在未来几个月内公布。 同样的药物，OGT-918，也正在研究作为治疗C型尼曼匹克病，一种遗传性脂质储存障碍，影响内脏和中枢神经系统的患者。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。目前正在制定一项与戈谢病非常相似的方案。同样，扫视眼球运动参数是一个主要的结果指标，所有患者现在都完成了至少一年的研究药物治疗。我们现正研究这项研究的结果，并会在未来数月内得出初步结论。 舞蹈症-棘红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进行了眼动记录。这些记录显示了频繁的方波抽搐，沿着他们的扫视的分离和减慢，这在以前没有报道过。 Hermansky Pudlak综合征（HPS）是一种罕见的常染色体隐性遗传病，表现为眼皮肤白化病、出血和溶酶体蜡样物质沉积。在与NHGRI的William Gahl博士的合作中，我们检查了27名HPS患者，并确定大多数患者患有先天性眼球震颤，许多患者患有周期性交替性眼球震颤，这有助于进一步表征这种疾病的表型。