Neuro-ophthalmic Mechanisms Of Disease

疾病的神经眼科机制

• 批准号: 10266878
• 负责人: Edmond J FitzGibbon
• 金额: $ 54.11万
• 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/10266878
• 关键词: Affect; Angiography; Anterior; Basal Ganglia; Blindness; Blood Vessels; Brain; CADASIL; Cafe-au-Lait Spot; Cell Nucleus; Characteristics; Cherry - dietary; Child; Childhood; Collaborations; Complication; Coupling; Cranial Nerves; Dental; Diagnosis; Disease; Disease Progression; Dyskinetic syndrome; Dysplasia; Endocrine; Etiology; Extramural Activities; Eye Movements; Fluorescein; Frequencies; Future; Gaucher Disease; Genotype; Goals; Image; Inflammation; Institutes; Institution; Intervention Studies; Laboratories; Leadership; Lipomucopolysaccharidoses; Magnetic Resonance Imaging; Maps; McCune-Albright Syndrome; Measurement; Medial; Modeling; Motion; Mutation; National Heart, Lung, and Blood Institute; National Human Genome Research Institute; National Institute of Neurological Disorders and Stroke; Natural History; Nerve compression syndrome; Neuraminidase; Neurodegenerative Disorders; Neurologic; Operative Surgical Procedures; Ophthalmic examination and evaluation; Ophthalmology; Optic Nerve; Optical Coherence Tomography; Other Genetics; Output; Paper; Parkinson Disease; Patients; Pattern; Perception; Pharmaceutical Preparations; Phenotype; Polyostotic fibrous dysplasia; Pontine structure; Population; Publishing; Rare Diseases; Reflex eye movement; Reporting; Reticular Formation; Retina; Risk; Saccades; Short Interspersed Nucleotide Elements; Somatotrophin increased; Somatotropin; Sphenoid bone structure; Spottings; Staging; Stroke; Structure; Sum; Surgical Decompression; Syndrome; System; Techniques; Testing; Therapeutic Clinical Trial; Thick; Thinness; Tissues; United States National Institutes of Health; Vision; Visual; Visual Fields; Visual Motion; Visual system structure; Visualization; Wing; X-Ray Computed Tomography; attentional modulation; base; bone; cerebral atrophy; clinical center; cohort; disease natural history; enzyme replacement therapy; exome; experience; experimental study; gaze palsy; genome sequencing; glycosylation; horizontal gaze; human subject; insight; leukodystrophy; macula; middle age; motor deficit; notch protein; optic nerve disorder; orbit muscle; patient oriented; response; retinal nerve fiber layer; skull base; superior colliculus Corpora quadrigemina; tractography; vascular abnormality; visual motor; visual stimulus

Several neuro-degenerative diseases have characteristic eye movement abnormalities that can be used to diagnose and stage disease progression and also used as a bio-surrogate in therapeutic clinical trials. Often eye movements can be used to gain insights into brain mechanisms. Parkinson patients were recently studied using eye movement recordings. In a collaboration with Dr. Lance Optican (NEI) and Dr. Hallett (NINDS) we recorded saccadic eye movements to visual targets in Parkinson patients. Based on the timing of responses, we found evidence that increased basal ganglia inhibitory output to the intermediate layer of the superior colliculus disturbed the normal coupling of action and perception. These findings support the hypothesis that a prominence map in the intermediate layer of the superior colliculus ties action and perception through modulation of attention. This could underlie visual deficits, including common misperceptions and visual-motor deficits often observed in Parkinsons disease. Eye movement recordings can be used to study short latency, small amplitude, reflexive eye movements to patterned targets which can give insight into the motion visual system. In collaboration with Boris Sheliga, Christian Quaia, and Bruce Cumming of the NEI, we continue to probe the visual motion system using ocular-following response techniques. These approaches use the machine-like eye movements subjects make in response to differing visual stimuli to help elucidate the mechanisms underlying motion and stereo vision. We recorded horizontal ocular-following responses to pairs of superimposed vertical sine wave gratings moving in opposite directions in human subjects. Experiments with gratings that differ in spatial and temporal frequency were done and show that all cases can be described as a weighted sum of the responses to each grating presented alone. That this relatively simple model successfully captures the ocular-following responses over a wide range of spatial/temporal frequency and contrast parameters suggests that these interactions reflect a simple underlying mechanism. Cohorts of patients with rare or unusual diseases are followed at NIH in natural history studies and many undergo neuro-ophthalmic exams. These studies help genotype phenotype correlations and provide a basis for future interventional studies. Fibrous dysplasia (FD) is a disease where normal bone is replaced with fibro-osseous tissue. Patients with McCune Albright syndrome have polyostotic fibrous dysplasia, endocrine abnormalities, and cafe au lait spots. In McCune Albright syndrome, 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. The management of fibrous dysplasia encased optic nerves is controversial, 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 100 patients with fibrous dysplasia continue to be followed longitudinally with neuro-ophthalmologic exams for over 20 years to track the natural history of this disease. Our experience in this cohort is that optic neuropathy is rare, and we recommend that surgical decompression not be done. However, patients with high growth hormone are at risk for optic neuropathy but only if the growth hormone excess is not controlled with medication. A recent study suggested that optical coherence tomography (OCT) of the retinal nerve fiber layer could be used to diagnose optic neuropathy from compression and if present, then do decompression surgery. Our group examined our cohort comparing OCT measurements vs. computed tomography (CT) of the optic nerve canal. OCT retinal nerve fiber layer (RNFL) thickness of 71 m accurately identified optic neuropathy (ON) in this population, and was superior to CT. By establishing the difference in rate of RNFL thinning in patients with and without ON, clinicians may distinguish between patients at risk for ON and intervene before irreversible damage. We also observed that RNFL measurements increase in childhood. If RNFL is noted to decrease in children then this would warrant further work up. OCT measurements thus would be especially helpful in the pediatric population where visual field exam can be difficult. An extramural/intramural collaborative study at the NIH Clinical Center of patients with Moebius syndrome and related disorders is continuing under the leadership of Dr. Francis Collins and Dr. Irini Manoli, along with many other intramural and extramural collaborators. Several patients have been evaluated to date at NIH and other academic institutions. The goals include phenotype-genotype correlation of these patients who have unusual congenital extraocular muscle and cranial nerve problems. These patients all undergo complete neuro-ophthalmic assessment and often exome and other specialized genome sequencing, along with other testing to help characterize their disorder. Several papers have been published by this consortium. Recently a paper studying MRI tractography in this cohort demonstrated volume reduction in the region of the paramedian pontine reticular formation and surprisingly, the medial longitudinal fasciculus, important structures for the initiation and coordination of conjugate horizontal gaze. These MRI findings differentiated affected patients and controls. This technique may be useful to help diagnose patients with hypoplasia or atrophy of brain nuclei and structures and dysinnervation syndromes. In a collaboration with Dr. Camilo Toro of NHGRI and the NEI, a cohort of patients with sialidosis type 1 were examined. These patients have a deficiency of the lysosomal sialidase, neuraminidase 1 (NEU1) and have a characteristic cherry-red spot in the retina. We published the ophthalmic findings in our cohort and demonstrated increased macular reflectivity by OCT in these patients. This latter finding may be helpful to make the diagnosis in patients where visualization of the cherry-red spot is not clear. Patients with Gaucher disease have a genetic defect in glycosylation and require replacement enzyme therapy. In type 3 disease there is neurologic involvement, typically with characteristic horizontal supranuclear gaze palsy. We have recorded saccadic eye movements in Gaucher patients as a means of staging the disease. In collaboration with Dr Ellen Sidransky of NHGRI, we published a paper describing the ophthalmic findings in Gaucher disease and another paper documenting 5 patients with white vitreous opacities uncommonly noted in Gaucher type 3. Of note, enzyme replacement therapy did not prevent or inhibit the progression of these opacities. Another extramural/intramural collaboration with Dr. Manfred Boehm of NHLBI involves examining patients with CADASIL. Patients with this leukodystrophy have a genetic defect of Notch 3 and develop blood vessel wall inflammation leading to strokes in middle age. Eye exams with fluorescein angiograms are performed looking for vessel abnormalities and have found abnormalities in the retinal vasculature. This group is now expanding to patients with other genetic vascular abnormalities.

几种神经退行性疾病具有特征性眼动异常，可用于诊断和分期疾病进展，也可用作治疗性临床试验中的生物替代品。 通常，眼球运动可用于深入了解大脑机制。 最近使用眼球运动记录对帕金森病患者进行了研究。 我们与 Lance Optican 博士 (NEI) 和 Hallett 博士 (NINDS) 合作，记录了帕金森患者对视觉目标的眼跳运动。 根据反应的时间，我们发现证据表明基底神经节对上丘中间层的抑制输出增加扰乱了动作和感知的正常耦合。这些发现支持这样的假设：上丘中间层的突出图通过注意力的调节将行动和感知联系起来。 这可能是视觉缺陷的基础，包括帕金森病中常见的常见误解和视觉运动缺陷。 眼动记录可用于研究针对图案目标的短延迟、小幅度、反射性眼动，从而深入了解运动视觉系统。 我们与 NEI 的 Boris Sheliga、Christian Quaia 和 Bruce Cumming 合作，继续使用眼部跟随反应技术来探索视觉运动系统。这些方法利用受试者响应不同视觉刺激而做出的类似机器的眼球运动，以帮助阐明运动和立体视觉的机制。 我们记录了人类受试者对成对叠加的垂直正弦波光栅沿相反方向移动的水平眼球跟随反应。对空间和时间频率不同的光栅进行的实验表明，所有情况都可以描述为对单独呈现的每个光栅的响应的加权和。这个相对简单的模型成功地捕获了广泛的空间/时间频率和对比度参数的眼部跟随响应，这表明这些相互作用反映了一个简单的潜在机制。 美国国立卫生研究院对患有罕见或不寻常疾病的患者进行自然史研究，其中许多患者接受了神经眼科检查。这些研究有助于对基因表型相关性进行分型，并为未来的干预研究提供基础。 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。麦库恩奥尔布赖特综合征患者患有多骨性纤维发育不良、内分泌异常和牛奶咖啡斑。在 McCune Albright 综合征中，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。视神经纤维异常增生的治疗存在争议，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。与牙科研究所的 Michael Collins 博士合作，对 100 多名纤维异常增殖症患者进行了 20 多年的纵向跟踪神经眼科检查，以追踪这种疾病的自然史。 我们在该队列中的经验是，视神经病变很少见，我们建议不要进行手术减压。然而，生长激素水平高的患者有患视神经病变的风险，但前提是生长激素过量不能通过药物控制。最近的一项研究表明，视网膜神经纤维层的光学相干断层扫描（OCT）可用于诊断受压引起的视神经病变，如果存在，则进行减压手术。我们小组检查了我们的队列，比较了视神经管的 OCT 测量与计算机断层扫描 (CT)。 OCT 视网膜神经纤维层 (RNFL) 厚度为 71 m，可以准确识别该人群中的视神经病变 (ON)，并且优于 CT。通过确定患有和不患有ON的患者RNFL变薄率的差异，临床医生可以区分有ON风险的患者，并在不可逆转的损害之前进行干预。我们还观察到 RNFL 测量值在儿童时期有所增加。如果发现 RNFL 儿童人数减少，则需要进一步开展工作。因此，OCT 测量对于视野检查可能很困难的儿科人群特别有帮助。 在 Francis Collins 博士和 Irini Manoli 博士以及许多其他校内和校外合作者的领导下，NIH 临床中心正在继续开展一项针对莫比斯综合征和相关疾病患者的校外/校内合作研究。迄今为止，美国国立卫生研究院和其他学术机构已对几名患者进行了评估。目标包括这些患有异常先天性眼外肌和脑神经问题的患者的表型-基因型相关性。这些患者都接受完整的神经眼科评估，通常还进行外显子组和其他专门的基因组测序，以及其他测试来帮助表征他们的疾病。该联盟已发表多篇论文。最近，一篇研究该队列中 MRI 纤维束成像的论文表明，桥脑旁正中网状结构区域的体积减少，令人惊讶的是，内侧纵束（启动和协调共轭水平凝视的重要结构）也出现了体积减少。 这些 MRI 结果区分了受影响的患者和对照组。这项技术可能有助于诊断患有脑核和结构发育不全或萎缩以及神经失调综合征的患者。 与 NHGRI 和 NEI 的 Camilo Toro 博士合作，对一组 1 型唾液酸贮积症患者进行了检查。这些患者缺乏溶酶体唾液酸酶、神经氨酸酶 1 (NEU1)，并且视网膜上有特征性的樱桃红斑点。 我们在队列中发表了眼科研究结果，并通过 OCT 证明了这些患者黄斑反射率的增加。后一个发现可能有助于对樱桃红色斑点不清晰的患者进行诊断。 戈谢病患者存在糖基化遗传缺陷，需要替代酶治疗。 3 型疾病存在神经系统受累，通常伴有特征性水平核上性凝视麻痹。我们记录了戈谢病患者的眼球扫视运动，作为疾病分期的一种手段。我们与 NHGRI 的 Ellen Sidransky 博士合作，发表了一篇论文，描述了戈谢病的眼科发现，另一篇论文记录了 5 名患有罕见的 3 型戈谢病白色玻璃体混浊的患者。值得注意的是，酶替代疗法并不能预防或抑制这些混浊的进展。 与 NHLBI 的 Manfred Boehm 博士的另一项校外/校内合作涉及检查 CADASIL 患者。患有这种脑白质营养不良的患者存在 Notch 3 基因缺陷，并会出现血管壁炎症，导致中年中风。使用荧光素血管造影进行眼部检查以寻找血管异常，并发现视网膜血管系统异常。该组现在正在扩展到患有其他遗传性血管异常的患者。