Neuro-ophthalmic Mechanisms Of Disease

点击翻译按钮获取中文摘要

Several neuro-degenerative diseases have characteristic eye movement abnormalities that can be used to diagnose and stage disease progression and also used as a bio-surrogate in therapeutic clinical trials. Often eye movements can be used to gain insights into brain mechanisms. Parkinson patients were recently studied using eye movement recordings. In a collaboration with Dr. Lance Optican (NEI) and Dr. Hallett (NINDS) we recorded saccadic eye movements to visual targets in Parkinson patients. Based on the timing of responses, we found evidence that increased basal ganglia inhibitory output to the intermediate layer of the superior colliculus disturbed the normal coupling of action and perception. These findings support the hypothesis that a prominence map in the intermediate layer of the superior colliculus ties action and perception through modulation of attention. This could underlie visual deficits, including common misperceptions and visual-motor deficits often observed in Parkinsons disease. Eye movement recordings can be used to study short latency, small amplitude, reflexive eye movements to patterned targets which can give insight into the motion visual system. 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. We recorded horizontal ocular-following responses to pairs of superimposed vertical sine wave gratings moving in opposite directions in human subjects. Experiments with gratings that differ in spatial and temporal frequency were done and show that all cases can be described as a weighted sum of the responses to each grating presented alone. That this relatively simple model successfully captures the ocular-following responses over a wide range of spatial/temporal frequency and contrast parameters suggests that these interactions reflect a simple underlying mechanism. Cohorts of patients with rare or unusual diseases are followed at NIH in natural history studies and many undergo neuro-ophthalmic exams. These studies help genotype phenotype correlations and provide a basis for future interventional studies. 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 for over 20 years 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 examined our cohort comparing OCT measurements vs. computed tomography (CT) of the optic nerve canal. OCT retinal nerve fiber layer (RNFL) thickness of 71 m accurately identified optic neuropathy (ON) in this population, and was superior to CT. By establishing the difference in rate of RNFL thinning in patients with and without ON, clinicians may distinguish between patients at risk for ON and intervene before irreversible damage. We also observed that RNFL measurements increase in childhood. If RNFL is noted to decrease in children then this would warrant further work up. OCT measurements thus would be especially helpful in the pediatric population where visual field exam can be difficult. 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 demonstrated volume reduction in the region of the paramedian pontine reticular formation and surprisingly, the medial longitudinal fasciculus, important structures for the initiation and coordination of conjugate horizontal gaze. These MRI findings differentiated affected patients and controls. This technique may be useful to help diagnose patients with hypoplasia or atrophy of brain nuclei and structures and dysinnervation syndromes. In a collaboration with Dr. Camilo Toro of NHGRI and the NEI, a cohort of patients with sialidosis type 1 were examined. These patients have a deficiency of the lysosomal sialidase, neuraminidase 1 (NEU1) and have a characteristic cherry-red spot in the retina. We published the ophthalmic findings in our cohort and demonstrated increased macular reflectivity by OCT in these patients. This latter finding may be helpful to make the diagnosis in patients where visualization of the cherry-red spot is not clear. 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 gaze 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 paper describing the ophthalmic findings in Gaucher disease and another paper documenting 5 patients with white vitreous opacities uncommonly noted in Gaucher type 3. Of note, enzyme replacement therapy did not prevent or inhibit the progression of these opacities. 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 expanding to patients with other genetic vascular abnormalities.