Neuro-ophthalmic Mechanisms Of Disease

疾病的神经眼科机制

• 批准号: 6826927
• 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/6826927
• 关键词: bone development disorder; clinical research; computed axial tomography; congenital eye disorder; eye movements; human subject; longitudinal human study; neuropathology; nystagmus; ophthalmoscopy; optic nerve disorder; saccades

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, a disease which can affect the optic nerve, 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, and there are strong proponents of prophylactic neurosurgical decompression. In collaboration with Dr. Michael Collins and Dr. Janice Lee of the Dental Institute, I prospectively examined 69 patients with fibrous dysplasia, of which 38 were included in this study. These patients all had detailed measurements made of their optic canals by CT and comprehensive neuro-ophthalmic exams. Our study published in the New England Journal demonstrated that, contrary to popular opinion, patients with fibrous dysplasia do not tend to lose vision from optic nerve compression and thus prophylactic surgical intervention is unwarranted. These patients will continue to be followed longitudinally. 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 made eye movement recordings on 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 metabolic byproduct is 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 is currently in a phase 1 drug trial and eye movements are felt to be crucial to studying its efficacy. It works by reducing the substrate for the enzyme glucocerbrocidase. Eye movement recordings looking particularly at saccadic velocity are now being performed as we clinically examine these patients, and they will be followed longitudinally for disease progression. Eye movement recordings will be performed before treatment and after one year in patients taking the medication and compared to a control group. These eye movement recordings are a major outcome study in this protocol. The same medication being considered for Gaucher disease 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 a vertical supranuclear palsy. These patients will be 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 will be a major outcome measure in this study. Neuroacanthocytosis is another rare neuro-degenerative disease. Recently, three patients with this disease have had eye movement recordings in my lab. The recordings demonstrated fractionation and slowing of their saccades which has not been previously reported. Progressive supranuclear palsy (PSP) is a degenerative brain disease which leads to death after several years and is characterized by a specific defect in eye movements, which is a vertical supranuclear palsy. Over the past 12 years more than 35 patients with this disorder have been seen for ophthalmic consultation and eye movement recordings in my lab in collaboration with NINDS. We have used saccadic velocity criteria and other eye movement parameters to characterize the stage of the disease. In the past 4 years several patients with another degenerative disease which has a similar clinical presentation, cortico-basal degeneration (CBD), have also been studied and compared with the PSP group. It can be difficult to distinguish between these diagnoses, and in early stages to separate these diseases from Parkinson's disease which is much more common. Eye movement recordings have proved helpful in making the correct diagnosis and are expected to be helpful in studying the response to experimental therapies. NINDS is examining new treatments for PSP, including intracerebral infusion of a glial derived nerve growth factor.

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，帮助疾病的诊断和分期，并制定和测试可能的疗法。在本报告中，我将重点关注纤维发育不良（一种影响视神经的疾病）的工作，以及对具有特征性动眼神经异常的各种神经退行性疾病的研究。 纤维性发育不良（FD）是一种正常骨被纤维骨组织取代的疾病。在多骨症中，前颅底经常受累，包括蝶骨。视神经穿过蝶骨翼，在 CT 成像上经常发现被 FD 包裹。围绕视神经纤维发育不良的治疗存在争议，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，并且强烈支持预防性神经外科减压。我与牙科研究所的 Michael Collins 博士和 Janice Lee 博士合作，前瞻性地检查了 69 名纤维性发育不良患者，其中 38 名患者纳入本研究。这些患者都通过 CT 和综合神经眼科检查对视神经管进行了详细测量。我们发表在《新英格兰杂志》上的研究表明，与流行观点相反，纤维性发育不良患者不会因视神经压迫而丧失视力，因此预防性手术干预是没有根据的。这些患者将继续进行纵向随访。 动眼神经控制分布在整个大脑中，对大脑各部分有不同影响的疾病可以以不同且通常是特定的方式影响眼球运动。我们对患有神经退行性疾病和遗传性疾病的患者进行了眼动记录，以表征他们的眼动障碍，从而帮助做出具体的诊断，将表型与基因型相关联，分期疾病进展，并深入了解眼动产生的过程。下面有几个例子。 在戈谢病中，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）出现神经系统症状，包括眼球运动异常。通常，这些患者患有水平核上性麻痹，偶尔表现出动眼神经失用症。 cerezmye 是一种通过替代其缺陷的半乳糖苷酶活性来治疗这种疾病的酶。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具有一定功效。然而，这种酶对异常眼球运动和神经系统症状影响甚微。也许这是由于血脑屏障阻止酶进入大脑。一种新药物目前正处于第一阶段药物试验中，眼球运动被认为对于研究其功效至关重要。它的作用是减少葡萄糖苷酶的底物。当我们对这些患者进行临床检查时，现在正在进行眼动记录，特别是扫视速度，并将纵向跟踪他们的疾病进展。将在治疗前和服用药物一年后对患者进行眼动记录，并与对照组进行比较。这些眼球运动记录是该协议中的主要结果研究。 正在研究用于治疗戈谢病的相同药物用于治疗尼曼皮克 C 型疾病患者，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。这些患者患有鞘磷脂酶缺乏症，并出现垂直核上性麻痹。这些患者将在哥伦比亚大学接受跟踪，并前往美国国立卫生研究院进行眼动记录。一项与针对戈谢病开发的方案非常相似的方案正在进行中。同样，眼跳眼动参数将是本研究的主要结果指标。 神经棘细胞增多症是另一种罕见的神经退行性疾病。最近，我的实验室对三名患有这种疾病的患者进行了眼动记录。录音显示了他们的眼跳的分裂和减慢，这是以前没有报道过的。 进行性核上性麻痹（PSP）是一种退行性脑部疾病，可导致数年后死亡，其特征是眼球运动的特定缺陷，即垂直核上性麻痹。在过去的 12 年里，我的实验室与 NINDS 合作，对超过 35 名患有这种疾病的患者进行了眼科咨询和眼球运动记录。我们使用扫视速度标准和其他眼动参数来表征疾病的阶段。在过去的 4 年里，我们还对几位患有另一种退行性疾病的患者进行了研究，并与 PSP 组进行了比较，该退行性疾病具有相似的临床表现，即皮质基底节变性 (CBD)。区分这些诊断可能很困难，并且在早期阶段很难将这些疾病与更为常见的帕金森病区分开来。事实证明，眼动记录有助于做出正确的诊断，并有望有助于研究对实验疗法的反应。 NINDS 正在研究 PSP 的新疗法，包括脑内注射神经胶质源性神经生长因子。