Neuro-ophthalmic Mechanisms Of 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报告的神经系统并发症，并且有强烈的预防性神经外科减压的支持者。与牙科研究所的Michael柯林斯博士合作，对超过69例前瞻性检查的纤维结构不良患者进行了检查，其中38例纳入本研究。这些患者均通过CT和全面的神经眼科检查进行了详细的视神经管测量。我们发表在《新英格兰杂志》上的研究表明，与流行观点相反，纤维性结构不良患者往往不会因视神经压迫而丧失视力，因此预防性手术干预是不必要的。这些患者继续接受纵向随访。对这一规则的一个警告是，高生长激素的患者可能更有视力丧失的风险，肢端肥大症和纤维结构不良的患者应密切观察视神经病变。 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。我们记录了神经退行性疾病和遗传性疾病患者的眼球运动，以描述他们的眼球运动障碍，帮助做出具体诊断，将表型与基因型关联起来，分期疾病进展，并深入了解眼球运动产生的潜在过程。以下是几个例子。 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）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目前正在进行第一阶段药物试验，眼动被认为是研究其疗效的关键。这种药物通过减少葡萄糖脑苷脂酶的底物起作用。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，并将纵向跟踪疾病进展。将在治疗前、治疗一年和两年后对服用药物的患者进行眼动记录，并与未服用药物的对照组进行比较。这项研究目前已完成一半。 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，他们发展为垂直核上性麻痹。这些患者将在哥伦比亚大学接受随访，并前往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，扫视眼球运动参数将是一个主要的结果测量，这项研究也是完成一半。 神经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。这些记录显示了他们的眼跳的分级和减慢，这在以前没有报道过。 进行性核上性麻痹（PSP）是一种退行性脑部疾病，导致数年后死亡，其特征是眼球运动的特定缺陷，这是一种垂直核上性麻痹。在过去的12年里，超过35例患有这种疾病的患者在我的实验室与NINDS合作进行眼科咨询和眼动记录。我们使用扫视速度标准和其他眼球运动参数来表征疾病的阶段。在过去的4年中，还研究了几例患有另一种退行性疾病（具有相似的临床表现，皮质基底节变性（CBD））的患者，并与PSP组进行了比较。很难区分这些诊断，并且在早期阶段将这些疾病与更常见的帕金森病分开。眼动记录已被证明有助于做出正确的诊断，并有望有助于研究对实验治疗的反应。NINDS正在研究PSP的新治疗方法，包括脑内注入胶质源性神经生长因子。

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, and there are strong proponents of prophylactic neurosurgical decompression. In collaboration with Dr. Michael Collins of the Dental Institute, a cohort of more than 69 prospectively examined patients with fibrous dysplasia were examined, 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 continue to be followed longitudinally. One caveat to the rule is that patients with high growth hormone may be more at risk for vision loss, and patients with both acromegaly and fibrous dysplasia should be watched closely for optic neuropathy. 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 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, OGT-918, is currently in a phase 1 drug trial and eye movements are felt to be crucial to studying its efficacy. The drug works by reducing the substrate for the enzyme glucocerbrocidase. Eye movement recordings looking particularly at saccadic velocity are being performed as we clinically examine these patients, and they will be followed longitudinally for disease progression. Eye movement recordings in patients taking the medication will be performed before treatment, and after one and two years and compared to a control group not on medication. This study is currently halfway through completion. 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 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 and this study is also halfway through completion. 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.