The questions surrounding idiopathic macular telangiectasia type 2, a disease that occurs more often than thought, is more severe than thought, and has confirmed systemic associations, slowly are being answered as a result of a new project.
Chicago-The questions surrounding idiopathic macular telangiectasia type 2, a disease that occurs more often than thought, is more severe than thought, and has confirmed systemic associations, slowly are being answered as a result of the 5-year-old ongoing MacTel Project. However, information about disease pathogenesis remains elusive.
The MacTel Project, which is under way in 26 centers around the world, set out to observe the natural disease course, follow the progression, and conduct a genetic study of patients and families in order to identify genes and genetic variants. An eye donor program also has been initiated to collect and study the disease pathology. About 500 patients have been enrolled, according to Dr. Gillies, scientific manager of the MacTel Project and professor of ophthalmology at the Save Sight Institute, University of Sydney, Australia.
Based on the population of the Beaver Dam Eye Study, the incidence of macular telangiectasia, characterized by loss of central luteal pigment and Müller cell markers in the central retina, was 0.1% of patients over 45 years, but this may have been an underestimation considering that only color photographs were examined.
"This condition may be as common as or more common than retinitis pigmentosa," Dr. Gillies said.
The severity of macular telangiectasia also is worse than previously suspected, with loss of cones and dense central scotomas resulting in paracentral scotomas that cause significantly greater dysfunction than is found in patients with age-related macular degeneration (AMD) with similar visual acuity. In particular, the general vision, distance vision, and near vision were reported as worse by patients with macular telangiectasia compared with those with AMD, and these patients have a higher prevalence of diabetes, hypertension, obesity, and coronary artery disease.
Familial transmission of the disease is recognized, but the gene has not yet been identified. Of the 500 enrolled participants in the study, 24 families have been identified with another family member affected, mostly sibling pairs. A 3.5-megabase region on chromosome 1 has been identified with a LOD score of 3.45, indicating the likelihood of a genetic defect.
Clinical scientists working on the project have found that autofluorescence is the most sensitive and specific marker for macular telangiectasia type 2.
No treatment has been established. Laser treatment is not helpful. Anti-vascular endothelial growth factor (VEGF) drugs for subretinal neovascularization can be used for subretinal neovascularization and these patients can do well, according to Dr. Gillies.
Some research has been done in Germany to test the efficacy of anti-VEGF drugs administered before the development of subretinal neovascularization. The effect on angiographic hyperfluorescence in patients without subretinal neovascularization was observed after monthly injections of ranibizumab (Lucentis, Genentech).
"The treatment worked, and after 12 injections there was little fluorescence visible, but it recurred," he said. "These patients would likely need to be treated indefinitely to maintain the effect. The concern was the development in one treated eye of a very dense scotoma in the area where macular telangiectasia type 2 almost always starts, which is about 600 μm temporal to the center of the fovea and just beneath the horizontal midline. This scotoma might have been due to a neural toxic effect of VEGF inhibition. The recommendation was to stop treatment."
Causes of the disease are speculative. Dr. Gillies suggested that it may result from Müller cell injury.
"The retinal damage may then proceed down a vascular pathway, with angiographic leakage and eventual subretinal neovascularization," he said. "The retinal damage could also proceed down a neuronal pathway independently or concurrently, with increased reflectivity of the outer nuclear layer leading to inner and outer retinal cavitation."
Dr. Gillies and colleagues created a murine Müller cell knockout model. The mice developed macular telangiectasia 12 weeks after selective knockout of Müller cells.
The apoptosis in the outer nuclear layer was inhibited by injection of recombinant ciliary neurotrophic factor (CNTF). Exploratory trials of candidate therapies are considered for 2011.
Study of subclinical disease, especially with adaptive optics, likely will help determine the underlying disease mechanism. The project will conduct additional research to identify related gene defects, develop other animal models, use adaptive optics to study photoreceptor changes in the earliest clinical phenotype of the disease, as well as identify potential treatments.
Mark C. Gillies, MB BS, PhD, FRANZCO
Dr. Gillies has no financial interest in this research. The research was supported by the Lowry Medical Research Institute.