Neuro-ophthalmic Mechanisms Of Disease

疾病的神经眼科机制

• 批准号: 10706104
• 负责人: Edmond J FitzGibbon
• 金额: $ 38.51万
• 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/10706104
• 关键词: 18 year old; Acute; Adrenal Cortex Hormones; Adverse effects; Affect; Aneurysmal Bone Cysts; Anterior; Antifungal Therapy; Arachnoid mater; Area; Blindness; Brain; Brain scan; CADASIL; Cafe-au-Lait Spot; Caliber; Characteristics; Clinic; Clinical; Clinical/Radiologic; Collaborations; Complication; Consult; Contracture; Cranial Nerves; Cryptococcus; Cyst; Data Set; Dental; Deposition; Diagnosis; Disease; Disease Progression; Dose; Dyskinetic syndrome; Dysplasia; Endocrine; Etiology; Exhibits; Extramural Activities; Eye; Eye Movements; Facial paralysis; Fibrosis; Fluconazole; Future; Gaucher Disease; Genotype; Goals; Gonadotropin-Releasing Hormone Analog; Immunocompromised Host; Individual; Inflammatory Response; Institutes; Institution; Intervention Studies; Intravenous; Joints; Karnofsky Performance Status; Laboratories; Leadership; Leuprolide; Lighting; Liquid substance; MEKs; McCune-Albright Syndrome; Measurement; Measures; Meningoencephalitis; Metabolic; Methylprednisolone; Missense Mutation; Motion; Muscle; National Institute of Allergy and Infectious Disease; Natural History; Nerve Degeneration; Neurodegenerative Disorders; Neurofibromatosis 1; Neurologic; Neurons; Ophthalmology; Optic Nerve; Optics; Oral; Paper; Papilledema; Patients; Pattern; Performance; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Phenotype; Physiologic pulse; Polyostotic fibrous dysplasia; Population; Prednisone; Prevalence; Publishing; Rare Diseases; Recording of previous events; Reflex eye movement; Reporting; Retinal Pigments; Risk; Somatotrophin increased; Somatotropin; Sphenoid bone structure; Staging; Stimulus; Structural defect; Surgical Decompression; Syndrome; System; Techniques; Testing; Therapeutic Clinical Trial; Time; Tissues; Toxic effect; United States National Institutes of Health; Vascular Diseases; Vision; Visual Fields; Visual Motion; Visual system structure; Wing; X-Ray Computed Tomography; base; beta Tubulin; bone; brain magnetic resonance imaging; cancer therapy; clinical center; cognitive testing; cohort; common symptom; craniofacial; disease natural history; early onset; exome; experience; genome sequencing; inhibitor; insight; malformation; mental state; mortality; neoplastic; optic nerve disorder; orbit muscle; patient oriented; radiological imaging; response; retinal nerve fiber layer; sample fixation; skull base; visual stimulus

Several neuro-degenerative diseases have characteristic eye movement abnormalities that can be used to diagnose and stage disease progression, and also be used as a bio-surrogate in therapeutic clinical trials. Often, eye movements studies help to gain insights into brain mechanisms. Eye movement recordings can be used to study short latency, small amplitude, reflexive eye movements to patterned targets which can help in understanding 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. In the past year we studied short latency ocular following responses to visual motion stimuli that depend on the history of preceding stimuli and found that temporal modulation stimuli before the fixation period reduced the response of the subsequent ocular following. Also, preceding changes of illumination reduced the subsequent eye movement response. We characterized this suppression using different stimuli and determined the time course of the suppression. Also, by presenting transparent motion during the fixation period, we discovered a direction dependent component of the suppression. This study contributes to our understanding of motion vision. See Reference #1 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 Fibrous dysplasia (FD) is a disease where normal bone is replaced with fibro-osseous tissue. Patients with McCune Albright syndrome (MAS) 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 and Dr. Alison Boyce 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. In recent years we have observed some of our MAS patients exhibit optic disc edema, so we undertook to investigate the prevalence and potential clinical associations of optic disc edema in our MAS cohort. Optic disc edema was diagnosed in 7/187 subjects, for a prevalence of 3.7%. All subjects with optic disc edema were diagnosed before age 18 years and had mild, non-progressive disease. Radiographic structural abnormalities, including Chiari I malformation, aneurysmal bone cysts, and arachnoid cysts, were associated with higher odds of optic disc edema. Treatment with leuprolide, a gonadotropin releasing hormone analog, was also associated with optic disc edema. There was no significant association of optic disc edema with other MAS endocrinopathies, medications, optic canal diameter, or intracranial volume. In another study we reported on the quantitative measurements of intracranial volume, optic canal area, and peripapillary retinal nerve fiber layer (RNFL) of 124 patients with FD/MAS. Seven subjects had optic disc edema. A dataset of these measurements was created that can be used to assess typical ranges of these measures in the craniofacial FD/MAS population and to assess those ranges that are concerning for optic disc edema. See References #2 & #3 Cryptococcal meningoencephalitis Along with Dr. Peter Williamson and his NIAID team, we reported our experience in following patients with cryptococcal meningoencephalitis. Cryptococcal meningoencephalitis (CM) is a major cause of mortality in immunosuppressed patients and previously healthy individuals. In the latter, a post-infectious inflammatory response syndrome (PIIRS) is associated with a poor clinical response despite antifungal therapy and negative CSF cultures. 15 consecutive previously healthy patients with CM and PIIRS were treated with pulse corticosteroid taper therapy (PCT) consisting of intravenous methylprednisolone 1 gm daily for 1 week followed by oral prednisone 1 mg/kg/d, tapered based on clinical and radiological response plus oral fluconazole. Montreal Cognitive Assessments (MOCA), Karnofsky Performance scores, MRI brain scanning, ophthalmic and audiologic exams, and CSF parameters were compared at PIIRS diagnosis and after methylprednisolone completion. All patients demonstrated significant improvements in MOCA and Karnofsky scores at 1 month. All patients with papilledema and visual field deficits also exhibited improvement. The most common symptoms at PIIRS diagnosis were altered mental status and vision changes. In summary, PCT in this small cohort of PIIRS was associated with improvements in CM-related complications with minimal toxicity in the acute setting. See Reference #4 Ocular adverse effects of cancer treatment Many cancer treatments can have adverse effects on the eye. One example is MEK inhibitors which can cause retinal pigment elevations or subretinal fluid accumulations among other ocular effects. One example is Solumetinib that has proven to be very helpful in patients with neurofibromatosis type 1 that we follow in consult in the eye clinic. We have noted small foveal subretinal fluid deposits in several patients receiving Solumetinib, but these changes rarely affected vision and are also dose dependent. 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. A recent paper describes a recognizable syndrome including congenital fibrosis of the intraocular muscles (CFEOM3), facial palsy, joint contractures and early onset peripheral neuropathy that is attributable to missense mutations in TUBB3 which encodes a neuron specific beta tubulin isotype. See Reference #6 We continue to study and follow the neuro-ophthalmic aspects of NIH study patients with Gaucher disease, CADASIL and associated vascular diseases, and other metabolic, neurodegenerative and neoplastic disease cohorts seen at NIH. See Reference #8

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，眼球运动研究有助于深入了解大脑机制。 眼动记录可用于研究对图案目标的短延迟、小幅度、反射性眼动，这有助于理解运动视觉系统。 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。在过去的一年中，我们研究了对视觉运动刺激的短潜伏期眼部跟随反应，这些反应取决于先前刺激的历史，并发现注视期之前的时间调制刺激会降低随后的眼部跟随反应。 此外，先前的照明变化会降低随后的眼球运动反应。 我们使用不同的刺激来表征这种抑制，并确定抑制的时间过程。 此外，通过在注视期间呈现透明运动，我们发现了抑制的方向依赖成分。这项研究有助于我们对运动视觉的理解。 请参阅参考文献 #1 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。这些研究有助于基因型与表型的相关性，并为未来的干预研究提供基础。 纤维异常增殖症 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。麦库尼奥尔布赖特综合征 (MAS) 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。与牙科研究所的迈克尔·柯林斯 (Michael Collins) 博士和艾莉森·博伊斯 (Alison Boyce) 博士合作，对 100 多名纤维性发育不良患者进行了长达 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未得到控制。 近年来，我们观察到一些 MAS 患者出现视盘水肿，因此我们着手调查 MAS 队列中视盘水肿的患病率和潜在的临床关联。 7/187 名受试者被诊断为视盘水肿，患病率为 3.7%。所有患有视盘水肿的受试者均在 18 岁之前被诊断出来，并且患有轻度、非进展性疾病。影像学结构异常，包括 Chiari I 畸形、动脉瘤性骨囊肿和蛛网膜囊肿，与视盘水肿的发生率较高有关。亮丙瑞林（一种促性腺激素释放激素类似物）治疗也与视盘水肿有关。视盘水肿与其他 MAS 内分泌疾病、药物、视神经管直径或颅内容积没有显着相关性。 在另一项研究中，我们报告了 124 名 FD/MAS 患者的颅内容量、视神经管面积和视乳头周围视网膜神经纤维层 (RNFL) 的定量测量结果。 七名受试者患有视盘水肿。 创建了这些测量值的数据集，可用于评估颅面 FD/MAS 人群中这些测量值的典型范围，并评估与视盘水肿有关的那些范围。 请参阅参考文献 #2 和 #3 隐球菌性脑膜脑炎 我们与 Peter Williamson 博士和他的 NIAID 团队一起报告了我们跟踪隐球菌性脑膜脑炎患者的经验。隐球菌性脑膜脑炎 (CM) 是免疫抑制患者和既往健康个体死亡的主要原因。在后者中，尽管进行了抗真菌治疗且脑脊液培养呈阴性，但感染后炎症反应综合征 (PIIRS) 仍与临床反应不佳相关。连续 15 名既往健康的 CM 和 PIIRS 患者接受脉冲皮质类固醇逐渐减量疗法 (PCT)，包括静脉注射甲泼尼龙，每天 1 gm，持续 1 周，然后口服泼尼松 1 mg/kg/d，根据临床和放射学反应逐渐减量，加上口服氟康唑。在 PIIRS 诊断时和甲基强的松龙完成后，对蒙特利尔认知评估 (MOCA)、卡诺夫斯基表现评分、MRI 脑部扫描、眼科和听力检查以及脑脊液参数进行比较。所有患者在 1 个月时 MOCA 和卡诺夫斯基评分均表现出显着改善。所有患有视乳头水肿和视野缺损的患者也表现出改善。 PIIRS 诊断时最常见的症状是精神状态改变和视力变化。总之，在这一小规模 PIRS 队列中，PCT 与 CM 相关并发症的改善相关，并且急性环境中的毒性最小。 请参阅参考文献 #4 癌症治疗的眼部不良反应 许多癌症治疗会对眼睛产生不良影响。 MEK 抑制剂就是一个例子，它会导致视网膜色素升高或视网膜下液体积聚以及其他眼部影响。一个例子是 Solumetinib，它已被证明对我们在眼科诊所咨询的 1 型神经纤维瘤病患者非常有帮助。 我们注意到几位接受索美替尼治疗的患者出现小黄斑视网膜下液体沉积，但这些变化很少影响视力，而且还具有剂量依赖性。 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。 最近的一篇论文描述了一种可识别的综合征，包括先天性眼内肌纤维化 (CFEOM3)、面瘫、关节挛缩和早发性周围神经病变，这些综合征可归因于编码神经元特异性 β 微管蛋白同种型的 TUBB3 的错义突变。 请参阅参考文献 #6 我们继续研究和跟踪 NIH 研究中患有戈谢病、CADASIL 和相关血管疾病的患者以及 NIH 发现的其他代谢、神经退行性和肿瘤疾病队列患者的神经眼科方面的情况。请参阅参考文献#8