Age-related macular degeneration (AMD) does not follow the same disease course from one patient to another, conclude researchers who suggest that phenotyping may be important before initiating a therapeutic trial.
“Clearly, it would be attractive to have a single treatment for early AMD, whereby transition to late disease [was] modulated, but the current evidence implies this is unlikely to occur”, say Alan Bird (pictured) from Moorfields Eye Hospital in London, UK, and colleagues.
They documented photoreceptor and retinal pigment epithelium (RPE) cell loss as well as other changes at the RPE-choroid interface in 37 donated human eyes with visual loss due to geographic atrophy (GA). Previous studies suggest that photoreceptor cells are lost early in the disease trajectory, possibly as a result of RPE dysfunction, and that thickening of the Bruch membrane (BM) also plays a role in the genesis of the disease.
The team used light, autofluorescence, and electron microscopy to examine the structural changes of the outer retina, BM and choroid of the eyes. They took measurements at two locations: 1 to 2 mm and 12 to 13 mm from the foveal center in the infero-temporal quadrant.
Reporting recently, Bird et al say that RPE cells were absent over wide areas from the internal edge of the GA, although there was a scattering of cells in some specimens. A small number of cone nuclei were present in all eyes, and were more abundant where RPE cells still existed.
In five eyes, at the edge of the GA, a few cone nuclei sharply transitioned to four to five rows of photoreceptor cells, both rods and cones, with inner and outer segments. But for the majority of eyes, the transition zone was large and contained only cone photoreceptors, which were no more than two rows of nuclei thick.
“If the spatial pattern of change can be equated with the temporal course of the disease, it is evident that the demise of photoreceptor cells occurs earlier than the loss of RPE cells in most cases,” remark Bird and colleagues.
In most eyes, BM was thickened as a result of basal laminar deposits (BLD); however, this varied greatly from one tissue specimen to another and showed no correlation with photoreceptor survival, reports the team. Furthermore, an inverse relationship emerged between area of BLD per unit length of BM (representing BM thickness) and the area occupied by autofluorescent residual bodies suggesting “a functional relationship” between the two entities.
“Thus, there was variability of physical changes in choroid, BM, RPE, and photoreceptor cells relative one to another and from one eye to another,” say the researchers.
They add: “If a specific treatment were directed to unselected cases of GA with the objective of slowing or preventing photoreceptor loss, the therapeutic approach would not address the major problem in a large proportion of cases recruited to a study, which would reduce the chance of identifying treatment benefit.”
Robust phenotyping would enable patient selection for appropriate therapeutic trials according to their specific disease characteristics, the team notes.
Illustration: Moorfields Eye Hospital.
Abstract (JAMA Ophthalmology; Vol. 132, No. 3, 338-345 (03/2014))