Neuro-ophthalmic Mechanisms Of Disease

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In this report I will concentrate on studies of various diseases which have characteristic oculomotor abnormalities, and also on diseases that affect vision, or have neuro-ophthalmic consequences, such as fibrous dysplasia and neurofibromatosis. Oculomotor control is distributed throughout the brain, and diseases 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. 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 90 patients with fibrous dysplasia continue to be followed longitudinally with neuro-ophthalmologic exams to track the natural history of this disease. Our experience in this cohort is that optic neuropathy is unusual and we recommend that surgical decompression not be done. Patients with high growth hormone are at risk for optic neuropathy but not if the growth hormone excess can be controlled. We continue to longitudinally follow these patients and Dr. Collins' group continues to recruit patients with McCune Albright syndrome. 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 Widemann of NCI, NF1 patients enrolled in a natural disease study continue to be examined in the eye clinic. Several parameters are followed including Lisch nodules, vision, ocular motility and lid function. Complete neuro-ophthalmic exams and imaging are performed. A new study headed by Dr. Widemann involves patients with plexiform neurofibromas of the orbit and visual pathways. These patients receive an experimental MEK inhibitor in hopes of decreasing or arresting tumor growth. They receive baseline and ongoing neuro-ophthalmic exams during the study. Erdheim Chester disease is a rare histiocytosis typically developing in patient in their 5th decade of life. Collections of histiocytes may be found in the long bones, retroperitoneal space, in the kidneys, lungs and the orbits among other spaces. Presentation in the orbit can lead to proptosis, diplopia, and optic neuropathy. We are longitudinally following a cohort of Erdheim Chester patients with Dr. Juvianee Estrada Veras for neuro-ophthalmic findingss. Orbital involvement is uncommon with less than 20% of our cohort demonstrating orbital masses. 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 pioneered by Fred Miles of the NEI. These approaches use the machine like eye movements made in response to differing stimuli to help understand the mechanisms underlying motion vision. In the past year experiments demonstrated how ocular following responses are constrained by early stages of the human visual system. With Drs. Lance Optican and Elena Pretgiani Parkinson disease patients' eye movements were recorded in response to gap/overlap saccadic tasks. Impaired temporal coupling of action and perception was found in Parkinsons disease. An extramural/intramural collaborative study at the NIH Clinical Center of patients with Moebius syndrome and related disorders started under the leadership of Dr. Francis Collins and Dr. Irini Manoli, along with many other 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 in order to characterize their disorder.