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，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的工作，这是一种可以影响视神经的疾病，以及具有特征性动眼运动异常的各种神经退行性疾病的研究。 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。围绕包裹视神经的纤维结构不良的处理存在争议，因为视神经病变导致视力丧失是最常见的神经系统并发症，并且有强烈的支持者预防性神经外科减压术。在与牙科研究所的Michael Collins博士和Janice Lee博士的合作下，我前瞻性地检查了69名纤维异常增殖症患者，其中38人纳入了这项研究。这些患者都通过CT和全面的神经眼科检查对他们的视神经管进行了详细的测量。我们在《新英格兰杂志》上发表的研究表明，与流行观点相反，纤维发育不良患者不会因为视神经受压而失明，因此预防性手术干预是没有根据的。这些患者将继续接受纵向跟踪。 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。我们对神经退行性和遗传性疾病患者进行了眼球运动记录，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、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，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。它的工作原理是减少葡萄糖分解酶的底物。眼球运动记录，特别是眼球跳动速度，现在正在进行临床检查，他们将被纵向跟踪疾病进展。在服用药物的患者治疗前和一年后进行眼动记录，并与对照组进行比较。这些眼动记录是该方案中的一项主要结果研究。 正在考虑的治疗高谢病的相同药物也正在研究中，作为治疗尼曼·皮克C型疾病的药物，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。这些患者将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。在这项研究中，眼球跳动参数将再次成为主要的测量结果。 神经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，他们的扫视出现了分馏和减慢，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，数年后导致死亡，其特征是眼球运动的特殊缺陷，即垂直核上性瘫痪。在过去的12年里，我的实验室与NINDS合作，为超过35名患有这种疾病的患者进行了眼科咨询和眼动记录。我们使用了眼跳速度标准和其他眼动参数来描述疾病的分期。在过去的4年里，也有几名患有另一种具有相似临床表现的退行性疾病--皮质基底变性(CBD)的患者也被研究过，并与PSP组进行了比较。这可能很难区分这些诊断，并在早期阶段将这些疾病与更常见的帕金森病区分开来。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疗法的反应。NINDS正在研究治疗PSP的新方法，包括脑内注射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, 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.