Abstract
PURPOSE: The purpose of this study was to evaluate fixation location and oculomotor characteristics of 15 patients with Leber congenital amaurosis (LCA) caused by RPE65 mutations (RPE65-LCA) who underwent retinal gene therapy. METHODS: Eye movements were quantified under infrared imaging of the retina while the subject fixated on a stationary target. In a subset of patients, letter recognition under retinal imaging was performed. Cortical responses to visual stimulation were measured using functional magnetic resonance imaging (fMRI) in two patients before and after therapy. RESULTS: All patients were able to fixate on a 1° diameter visible target in the dark. The preferred retinal locus of fixation was either at the anatomical fovea or at an extrafoveal locus. There were a wide range of oculomotor abnormalities. Natural history showed little change in oculomotor abnormalities if target illuminance was increased to maintain target visibility as the disease progressed. Eleven of 15 study eyes treated with gene therapy showed no differences from baseline fixation locations or instability over an average of follow-up of 3.5 years. Four of 15 eyes developed new pseudo-foveas in the treated retinal regions 9 to 12 months after therapy that persisted for up to 6 years; patients used their pseudo-foveas for letter identification. fMRI studies demonstrated that preservation of light sensitivity was restricted to the cortical projection zone of the pseudo-foveas. CONCLUSIONS: The slow emergence of pseudo-foveas many months after the initial increases in light sensitivity points to a substantial plasticity of the adult visual system and a complex interaction between it and the progression of underlying retinal disease. The visual significance of pseudo-foveas suggests careful consideration of treatment zones for future gene therapy trials. (ClinicalTrials.gov number, NCT00481546.).