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

几种神经化学疾病具有特征性的眼球运动异常，可用于诊断和分期疾病进展，并且在治疗临床试验中也被用作生物酸盐。通常，眼动研究有助于了解大脑机制。 眼动记录可用于研究短潜伏期，小幅度，反射性眼动向图案靶标，这可以帮助理解运动视觉系统。 通过与NEI的Boris Sheliga，Christian Quaia和Bruce Cumming合作，我们继续使用眼部跟随响应技术探究视觉运动系统。这些方法使用类似机器的眼动主体来响应不同的视觉刺激，以帮助阐明运动的基础机制和立体视觉。在过去的一年中，我们研究了依赖于先前刺激史的视觉运动刺激的反应后，我们研究了短等待眼，发现固定期之前的时间调节刺激减少了后续的眼部跟随的响应。 同样，在照明的变化会减少随后的眼动反应。 我们使用不同的刺激表征了这种抑制，并确定了抑制的时间过程。 同样，通过在固定期间呈现透明运动，我们发现了抑制的方向依赖性组成部分。这项研究有助于我们对运动视觉的理解。 请参阅参考＃1 在自然史研究中，NIH伴随着罕见或异常疾病的患者队列，许多患者接受了神经性检查。这些研究有助于基因型 - 表型相关性，并为将来的介入研究提供了基础。 纤维发育不良 纤维发育不良（FD）是一种疾病，正常骨被纤维骨组织代替。 McCune Albright综合征（MAS）患者患有多稳性纤维发育不良，内分泌异常和Cafe au au lait Spots。在麦考纳·奥尔布赖特综合症中，经常涉及前颅骨，包括蝶骨骨骼。视神经穿过蝶翅，通常被发现被CT成像上的FD包裹。纤维发育不良包裹的视神经的管理是有争议的，因为导致视力丧失的视神经病变是最常见的神经系统并发症。与牙科研究所的迈克尔·柯林斯（Michael Collins）和艾莉森·博伊斯（Alison Boyce）博士合作，一名纤维发育不良的100多名患者在20多年的纵向上进行了纵向遵循神经嗜血杆菌检查，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，我们建议不要进行手术减压。但是，高生长激素的患者面临着神经病变的风险，但前提是未控制生长激素过量。 近年来，我们观察到一些MAS患者表现出视盘水肿，因此我们进行了研究，以研究MAS同类中视盘水肿的患病率和潜在临床关联。在7/187名受试者中诊断出光盘水肿，患病率为3.7％。所有患有光盘水肿的受试者均在18岁之前诊断出，患有轻度，非疾病。放射学结构异常，包括Chiari I畸形，动脉瘤骨囊肿和蛛网膜囊肿，与较高的视盘水肿几率有关。用促促性腺激素释放激素类似物的luuprolide治疗也与视盘水肿有关。光盘水肿与其他MAS内分泌病，药物，视管直径或颅内体积没有显着关联。 在另一项研究中，我们报道了124例FD/MAS患者的颅内体积，视管区域和乳头状视网膜神经纤维层（RNFL）的定量测​​量。 七个受试者具有视盘水肿。 创建了这些测量值的数据集，可用于评估颅面FD/MAS种群中这些度量的典型范围，并评估有关视盘水肿的范围。 请参阅参考＃2＆＃3 隐球菌脑膜脑炎 我们与彼得·威廉姆森（Peter Williamson）博士和他的NIAID团队一起报告了我们在关注隐球菌脑膜脑炎患者的经验。隐球菌脑膜脑炎（CM）是免疫抑制患者和以前健康的个体死亡率的主要原因。在后者中，尽管抗真菌治疗和CSF培养阴性，但感染后炎症反应综合征（PIIRS）与临床反应差有关。 15例先前健康的CM和PIIRS患者接受脉搏皮质固醇锥度治疗（PCT）治疗，由静脉内甲基丙醇酮1克组成1 gm，持续1周，然后由基于临床和放射学反应以及口服反应加口腔氟甲唑的口服泼尼松1 mg/kg/d。蒙特利尔认知评估（MOCA），Karnofsky性能得分，MRI脑扫描，眼科和听力学考试以及CSF参数在PIIRS诊断和甲基甲索尔完成后进行了比较。所有患者在1个月时表现出MOCA和KARNOFSKY评分的显着改善。所有患有乳头状果皮和视野缺陷的患者也表现出改善。 PIIRS诊断时最常见的症状是精神状态和视力改变改变。总而言之，这一小群PIIRS中的PCT与CM相关并发症的改善有关，在急性环境中毒性最小。 请参阅参考＃4 癌症治疗的眼部不良反应 许多癌症治疗可能对眼睛产生不利影响。一个例子是MEK抑制剂，它可能导致视网膜色素升高或视网膜下液体积累以及其他眼部作用。一个例子是Solumetinib，事实证明对我们在Eye Clinic咨询的1型神经纤维瘤病患者非常有帮助。 我们注意到，几名接受辛um替尼的患者中的小凹下液下液沉积物，但这些变化很少影响视力，并且也依赖于剂量。 在弗朗西斯·柯林斯（Francis Collins）博士和艾里尼·马诺利（Irini Manoli）博士的领导下，在NIH临床中心的NIH临床中心和相关疾病的患者以及许多其他壁内和壁外合作者的领导下，一项壁外/壁内合作研究正在继续。迄今为止，已在NIH和其他学术机构对几名患者进行了评估。目标包括这些患有异常先天性外肌和颅神经问题的患者的表型基因型相关性。这些患者都接受了完整的神经性评估，并且经常进行外显子组和其他专门的基因组测序，以及其他测试以帮助表征其疾病。该联盟已经发表了几篇论文。 最近的一篇论文描述了一种可识别的综合征，包括眼内肌肉的先天性纤维化（CFEOM3），面部麻痹，关节染色体和早期发作周围神经病，这归因于TUBB3中的错义突变，该突变编码了神经元特异性β纤维蛋白质的同型。 请参阅参考＃6 我们继续研究并遵循NIH研究患有Gaucher疾病，Cadasil和相关血管疾病的患者的神经性跨性方面，以及NIH看到的其他代谢性，神经退行性疾病和神经退行性疾病和神经退行性疾病同类。请参阅参考＃8