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, 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 control. 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 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. We continue to longitudinally follow these patients and Dr. Collins' group continues to recruit patients with McCune Albright syndrome and fibrous dysplasia. 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. In a letter to the editor, our group responded by emphasizing optic neuropathy is diagnosed with a full examination including visual field, acuity, color, and contrast vision, in addition to nerve appearance and OCT. It is inappropriate to perform nerve decompression only on the basis of OCT and observation is advocated in most circumstances. 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 study. There have been some promising results, especially with evidence that MEK inhibitors help to slow tumor growth. 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 subjects make in response to stimuli to help elucidate the mechanisms underlying motion vision. In the past year, a mathematical model with only a few free parameters has been successfully used to predict the oculomotor responses to differing stimuli. 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. An 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 some abnormalities. This group is now examining normal volunteers and expanding the cohort of patients with other diseases that manifest vascular abnormalities.