Neuro-ophthalmic Mechanisms Of Disease

National Eye Institute

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Abstract

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. 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. In the past year we showed that short latency ocular following responses to visual motion stimuli are strongly affected by temporal modulation of the visual content during the fixation period. One dimensional pink noise stimuli of different types were noted to decrease ocular following responses. Suppression selective for orientation and spatial frequency accounted for a large fraction of the total suppression. Changes in stimulus temporal structure led to changes in the spatial frequency tuning of the suppression. By presenting transparent motion during the fixation period, with opposite motion signals having different spatial frequency content, we noted a direction-selective component of suppression. This suppression depended on both the frequency and the direction of the moving stimulus. This study contributes to our understanding of motion vision. 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 with medication. In recent years we have observed some of our MAS patients exhibit optic disc edema, so we undertook to 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. Optic disc edema is an uncommon but potentially serious complication of craniofacial FD, which may occur more frequently in pediatric patients and those with structural craniofacial abnormalities. 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. 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 among other ocular effects. We reported on a new fibroblast growth factor receptor tyrosine kinase inhibitor, Infigratinib, which in 5 study patients being treated for tumor induced osteomalacia caused bilateral adverse corneal changes, e.g. epitheliopathy and descemets and basement membrane haze which resolved with stopping therapy. 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 and neurodegenerative disease cohorts seen at NIH.