Neuro-ophthalmic Mechanisms Of Disease

在本报告中，我将集中研究具有特征性动眼肌异常的各种神经退行性疾病和影响视神经的疾病，如纤维发育不良。

In this report I will concentrate on studies of various neuro-degenerative diseases which have characteristic oculomotor abnormalities and in diseases that affect the optic nerve such as fibrous dysplasia. Oculomotor control is distributed throughout the brain, and diseases differentially 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, correlate phenotype to genotype, stage disease progression, and to give insight into the processes underlying eye movement generation. Several examples appear below. In Gaucher disease a defect in the enzyme beta-glucosidase results in a metabolic byproduct being deposited in the liver and spleen, the bone marrow, and the brain. A subgroup (Gaucher type 3) presents with neurologic findings, including abnormal eye movements. Typically these patients have a horizontal supranuclear palsy and occasionally exhibit an oculomotor apraxia. An enzyme to treat this disease by replacing their deficient galactosidase activity is cerezmye. This has been used for the past 10 years with some efficacy in reducing liver-spleen and marrow involvement. However, the enzyme has had little effect on abnormal eye movements and neurologic symptoms. Perhaps this is due to the blood brain barrier preventing the enzyme from access to the brain. A new medication, OGT-918, is currently in a phase 1 drug trial and eye movements are felt to be crucial to studying its efficacy since abnormal eye movements are sometimes the only criteria differentiating patients with Gaucher type 3 from Gaucher type 1. Also eye movements are easily quantifiable and parametric. The new drug works by reducing the substrate for the defective enzyme. Eye movement recordings looking particularly at saccadic velocity are being performed as we clinically examine these patients, and they will continue to be followed longitudinally for disease progression. The recordings in patients taking the medication are complete and it is clear that OGT918 did not significantly affect saccadic eye movements. The same medication, OGT-918, was also being studied as a treatment for patients with Niemann Pick type C (NPC) disease, an inherited lipid storage disorder that affects the viscera and central nervous system. These patients have sphingomyelinase deficiency and they develop vertical supranuclear palsy. These patients are followed at Columbia University and come to NIH for their eye movement recordings. A protocol very similar to the one developed for Gaucher disease has been completed. Again, saccadic eye movement parameters were a major outcome measure and all patients have now been completed. Although OGT918 (Zavesca) was felt to be somewhat helpful in NPC, eye movements were not significantly affected by the medication. A new cohort of patients are currently being followed longitudinally in a collaborative study with Dr. Denny Porter of NICHD. Fibrous dysplasia (FD) is a disease where normal bone is replaced with fibro-osseous tissue. In the polyostotic form, 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. Controversy surrounds the management of fibrous dysplasia encased optic nerves, 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 60 patients with fibrous dysplasia have been examined and this cohort of patients continues to be followed longitudinally with neuro-ophthalmologic exams to track the natural history of this disease. We have reported that even when the optic canal is encased with dysplastic bone, visual changes rarely occur. The importance of this observation is to discourage prophylactic canal decompression surgery since their is a greater likelihood of harm. Another caveat is that patients with McCune Albright syndrome with high growth hormone levels and skull involvement should be followed closely since their optic nerves are more likely to be affected by orbital changes.