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 plus 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. It is likely that this is due to the blood brain barrier preventing the enzyme from access to the brain. A new medication, OGT-918 was tested in a phase 1 drug trial and eye movements were 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. This new drug works by reducing the substrate for the defective enzyme. Eye movement recordings looking particularly at saccadic velocity were performed as we clinically examine these patients, and they were 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 but did have some benefit in pulmonary function and in lowering levels of chitotriosidase, a marker of disease severity. A paper reporting these findings is in press. 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 were followed at Columbia University and came 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 completed this study. OGT918 (Zavesca) was found to be somewhat helpful in NPC and there was evidence that saccadic velocities were improved by the drug. A new cohort of patients are currently being enrolled and followed longitudinally in a collaborative study with Dr. Forbes Porter of NICHD in a natural history protocol. Again eye movements recordings will help to characterize the disease stage and progression. 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. 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 60 patients with fibrous dysplasia have been examined and many of these patients continue 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 (the triad of fibrous dysplasia, endocrinopathies and cafe au lait spots) who have high growth hormone levels and skull involvement should be clinically followed closely, since their optic nerves are more likely to be affected by orbital changes. 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 a higher incidence of central nervous system gliomas and other neuro-ophthalmic manifestations. In collaboration with Brigitte Wideman of NCI, two groups of patients with NF1 are being followed in the eye clinic. NF1 patients will be enrolled in a natural history study and followed longitudinally noting several parameters including Lisch nodules, vision, and ocular motility. NF1 patients with CNS glioma will be enrolled in a phase 1 clinical trial of peginterferon alfa-2b (Pegintron). Both study groups will be followed with complete neuro-ophthalmic exams and imaging.