Transition zones between healthy and diseased retina in choroideremia (CHM) and Stargardt disease (STGD) as compared to retinitis pigmentosa (RP)

In retinal degenerative diseases, there is a transition zone (TZ)1–3 between relatively normal retina containing healthy photoreceptors and severely affected retina with extreme photoreceptor atrophy. Through the use of frequency-domain optical coherence tomography (fdOCT), the TZ can now be visualized and quantitatively assessed.1,2 A better understanding of the TZ is of importance for two reasons. First, knowledge of which retinal layers are affected across the TZ will aid in determining the potential efficacy and optimal injection locations for gene therapy.1,4 Second, the TZ offers a potential model of disease progression. That is, it is plausible to assume that the sequence and nature of structural changes observed spatially across the TZ at one specific time (that of fdOCT acquisition) also occur at each location in the retina as the disease progresses over time. Thus far, fdOCT studies of the TZ have been limited mainly to retinitis pigmentosa (RP) and Usher syndrome.1,2 A consistent pattern of changes in the outer retina has emerged from these studies. Specifically, Hood et al.2 found that structural damage (thinning) in RP occurs first in the outer segment (OS) layer and then in the outer nuclear layer (ONL), but that retinal pigment epithelium (RPE) thickness remains relatively normal across the TZ. This pattern is consistent with the disease process associated with many genetic forms of RP, where the defect often originates with an abnormal OS protein. Our main purpose in the present study was to determine whether the pattern of changes in the photoreceptor/RPE layers within the TZ differs in the various diseases that affect the receptors. That is, to what extent is the pattern of loss specific to the disease entity? To answer this question, we chose two disease entities, one, like RP, which typically starts outside the fovea, and one that starts within the fovea. Choroideremia (CHM), an X-linked retinal disorder, causes degeneration of the choroid and outer retina. Because of the nature of the progression of this disease, beginning in the midperiphery and moving centrally, patients with CHM typically have a central retina that is both structurally and functionally near normal, but the peripheral retina is severely affected. This pattern is similar to the pattern often seen in patients with RP. Stargardt disease (STGD), an autosomal recessive disorder, is a form of juvenile macular degeneration characterized by atrophy of the retinal pigment epithelium (RPE) and photoreceptor layer. In contrast to CHM and RP, STGD usually first affects the central retina and then progresses toward the periphery. Thus, patients with STGD typically have a diseased central retina with loss of central vision, but a near-normal peripheral retina. TZs are therefore present between the healthier and affected regions in both CHM and STGD. Given that CHM is considered to be allied to RP and that the two diseases are sometimes confused because of their common symptoms of night blindness and progressively decreasing peripheral vision,5,6 there are reasons to believe that their TZs are similar. However, some studies have shown that photoreceptor degeneration in CHM occurs secondary to, or at least concurrently with, atrophy of the RPE and choriocapillaris.7–10 RPE atrophy, induced by lipofuscin accumulation, is a main feature of STGD, although there is disagreement as to whether photoreceptor loss occurs before or after the RPE is affected.3,11–14 Therefore, there are also reasons to expect some differences in the sequence and occurrence of structural changes of the RPE and photoreceptor layer across the three diseases. In the present study, the thicknesses of fdOCT layers associated with the OS, ONL, and RPE were quantified in 7 patients with CHM and 20 with STGD, and the results were compared to each other and to our previously reported results for patients with RP.2