Neuro-ophthalmic Mechanisms Of Disease

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In this report I will concentrate on studies of various neuro-degenerative diseases which have characteristic oculomotor abnormalities, and also in diseases that affect the optic nerve or have neuro-ophthalmic consequences such as fibrous dysplasia and neurofibromatosis. 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 recorded eye movements in patients with neurodegenerative and genetic diseases to characterize their ocular motility disorder, to help make a specific diagnosis, to correlate phenotype to genotype, to stage disease progression, and to give insight into the processes underlying eye movement generation. We recently published the results of following a cohort of 15 patients with Gaucher type 3 disease. Significant findings include vertical saccade slowing with downward saccades more severely affected and evidence of slow progression of the disease with time as noted by saccadic recordings. Another publication examined twins with Gaucher disease exhibiting highly discordant Gaucher phenotypes demonstrating the poor predictability of phenotype given a specific genotypic diagnosis. 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. 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 80 patients with fibrous dysplasia continue to be followed longitudinally with neuro-ophthalmologic exams to track the natural history of this disease. In the past year a meta-analysis was published comparing watchful waiting versus optic nerve decompression surgery in craniofacial fibrous dysplasia. The study confirmed that watchful waiting is the recommended course. Another publication presented the outcome of a meeting held at NIH on fibrous dysplasia along with recommended clinical guidelines. Lastly, a preliminary report comparing two groups with controlled and uncontrolled high growth hormone levels suggested that controlling excess growth hormone from a young age reduces the risk of optic neuropathy. Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder. Plexiform neurofibromas develop in about 25% of patients and these are among the most debilitating complication of NF1. There is also a higher incidence of central nervous system gliomas and other neuro-ophthalmic manifestations. In collaboration with Brigitte Wideman of NCI, NF1 patients are being enrolled in a natural disease study and continue to be examined in the eye clinic. Longitudinally,several parameters are followed including Lisch nodules, vision, and ocular motility. Complete neuro-ophthalmic exams and imaging are performed. Currently we are examining the irides of these patients for comparison of their Lisch nodules with other disease measures. Another ongoing natural history protocol follows patients with neurofibromatosis type 2 (NF2). These patients have acoustic neuromas and compression from these (or from surgical correction of vestibular schwannomas) can lead to facial palsy with poor lid closure, corneal anesthesia, and dry eyes. These complications put their eyes at risk for vision loss. NF2 patients may also present with cataracts and retinal hamartomas. In collaboration with Boris Sheliga and Christian Quaia of the NEI, we continue to probe the visual motion system using ocular following response techniques pioneered by Fred Miles of the NEI. In the past year two publications examined the interactions of size and sppatial frequency of moving vertical sine wave gratings and on their spatial arrangement. These approaches use the machine like eye movements made in response to differing stimuli to help understand the mechanisms underlying motion vision.