Neuro-ophthalmic Mechanisms Of Disease

National Eye Institute

Investigators

Linked publications & trials

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 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 and fibrous dysplasia. 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. 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 finishing up following a cohort of Erdheim Chester patients with Dr. Juvianee Estrada-Veras for neuro-ophthalmic findings. Orbital involvement was found to be uncommon with less than 20% of our cohort demonstrating orbital masses. A combination of treating with both a BRAF inhibitor (darafenib) and a MEK inhibitor (trametinib) was shown to be helpful in this disease. 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 motion vision is affected by interocular velocity differences and white noise stimuli, the latter has important consequences for experiments using digital displays. 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 to help characterize their disorder. Several papers have been published by this consortium including a study of Carey Fineman Ziter syndrome. A recent 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. Along with Dr. Camilo Toro of NHGRI patients with Sialidosis type 1 are being seen at the Clinical Center and followed in the eye clinic. Patients with this all exhibit cherry red spots and develop myoclonus, gait problems and vision loss.