The goal of this laboratory is to examine and study diseases which have neuro-ophthalmic manifestations with the hope of understanding etiology, aiding diagnosis and staging of disease, and formulating and testing possible therapies. In this report I will concentrate on work in fibrous dysplasia and studies of various neuro-degenerative diseases which have characteristic oculomotor abnormalities. 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, and there are strong proponents of prophylactic neurosurgical decompression. In collaboration with Dr. Michael Collins of the Dental Institute, a cohort of more than 69 prospectively examined patients with fibrous dysplasia were examined, of which 38 were included in this study. These patients all had detailed measurements made of their optic canals by CT and comprehensive neuro-ophthalmic exams. Our study published in the New England Journal demonstrated that, contrary to popular opinion, patients with fibrous dysplasia do not tend to lose vision from optic nerve compression and thus prophylactic surgical intervention is unwarranted. These patients continue to be followed longitudinally. One caveat to the rule is that patients with high growth hormone may be more at risk for vision loss, and patients with both acromegaly and fibrous dysplasia should be watched closely for optic neuropathy. 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 metabolic byproduct is 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. The drug works by reducing the substrate for the enzyme glucocerbrocidase. Eye movement recordings looking particularly at saccadic velocity are being performed as we clinically examine these patients, and they will be followed longitudinally for disease progression. Eye movement recordings in patients taking the medication will be performed before treatment, and after one and two years and compared to a control group not on medication. This study is currently halfway through completion. The same medication, OGT-918, is also being studied as a treatment for patients with Niemann Pick type C disease, an inherited lipid storage disorder that affects the viscera and central nervous system. These patients have sphingomyelinase deficiency and they develop a vertical supranuclear palsy. These patients will be followed at Columbia University and come to NIH for their eye movement recordings. A protocol very similar to the one developed for Gaucher disease is ongoing. Again, saccadic eye movement parameters will be a major outcome measure and this study is also halfway through completion. Neuroacanthocytosis is another rare neuro-degenerative disease. Recently, three patients with this disease have had eye movement recordings in my lab. The recordings demonstrated fractionation and slowing of their saccades which has not been previously reported. Progressive supranuclear palsy (PSP) is a degenerative brain disease which leads to death after several years and is characterized by a specific defect in eye movements, which is a vertical supranuclear palsy. Over the past 12 years more than 35 patients with this disorder have been seen for ophthalmic consultation and eye movement recordings in my lab in collaboration with NINDS. We have used saccadic velocity criteria and other eye movement parameters to characterize the stage of the disease. In the past 4 years several patients with another degenerative disease which has a similar clinical presentation, cortico-basal degeneration (CBD), have also been studied and compared with the PSP group. It can be difficult to distinguish between these diagnoses, and in early stages to separate these diseases from Parkinson's disease which is much more common. Eye movement recordings have proved helpful in making the correct diagnosis and are expected to be helpful in studying the response to experimental therapies. NINDS is examining new treatments for PSP, including intracerebral infusion of a glial derived nerve growth factor.
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