Neuro-ophthalmic Mechanisms Of Disease

National Eye Institute

Investigators

Linked publications, trials & patents

Abstract

In this report, I will concentrate on research studies of various diseases which have characteristic oculomotor abnormalities such as Gaucher disease, but also on diseases that affect vision, or have neuro-ophthalmic consequences, such as fibrous dysplasia and neurofibromatosis. With Dr. Lance Optican of the LSR in collaboration with NINDS, patients with Parkinson disease were examined and then performed an eye movement perceptual task. The results supported the hypothesis that a prominence map in the intermediate layers of the superior colliculus couples action and perception through modulation of attention. A dysfunction of this network in Parkinsons disease may underlie visual and visual-motor deficits commonly seen in this disease. This work has been accepted for publication. 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. A published chapter describes characteristics of motion and disparity processing contrasting the differences based on ocular-following experiments. Recently, Dr. Quaia has developed a test using ocular-following based on binocular summation. This test could prove clinically useful to help diagnose stereo-deficiencies and lead to earlier treatment in young children. 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 100 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 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. A recent study suggested that optical coherence tomography (OCT) of the retinal nerve fiber layer could be used to diagnose optic neuropathy from compression and if present then do decompression surgery. Our group wrote a letter to the editor advocating caution in considering surgery based on OCT data alone. Patients with Gaucher disease have a genetic defect in glycosylation and require replacement enzyme therapy. In type 3 disease there is neurologic involvement, typically with characteristic horizontal supranuclear palsy. We have recorded saccadic eye movements in Gaucher patients as a means of staging the disease. In collaboration with Dr Ellen Sidransky of NHGRI, we published a short review paper on ophthalmic findings in Gaucher disease. 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. Recently a paper studying MRI tractography in this cohort showed that the medial longitudinal fasciculus in involved in addition to the expected cranial nuclei. A paper has been submitted for review. Another extramural/intramural collaboration with Dr. Manfred Boehm of NHLBI involves examining patients with CADASIL. Patients with this leukodystrophy have a genetic defect of Notch 3 and develop blood vessel wall inflammation leading to strokes in middle age. Eye exams with fluorescein angiograms are performed looking for vessel abnormalities and have found abnormalities in the retinal vasculature. This group is now examining normal volunteers and expanding to patients with other genetic vascular abnormalities. 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 are enrolled in trials to try to prevent or slow the growth of neurofibromas. Complete neuro-ophthalmic exams and imaging are performed. One study 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 interventional study. There have been some promising results.