Selective cell death in glaucoma: does it really occur?

Glaucoma is associated with retinal ganglion cell death and consequent deterioration in visual field. However, the association between these events is not straightforward since a substantial proportion of the ganglion cell population may be lost before visual field defects can be detected using conventional perimetric methods. '2 Clinically, ganglion cell loss manifests as optic disc cupping and defects in the nerve fibre layer3 before the onset ofvisual field changes. In recent years a number of studies have suggested that some ganglion cells may have a greater susceptibility to the damaging effects of glaucoma and this idea has become central to a number of strategies designed to detect the earliest changes in this disease. Such ideas rest on the fact that the retinal ganglion population is not homogeneous. It comprises cell groups with different physiological and anatomical properties that enable the complex parallel visual analysis thought to occur in the primate.47 Cells can be divided broadly into those of the parasol type that comprise the M visual pathway and those of the midget type that comprise the P pathway. For simplicity, in this review, I will refer to the respective retinal ganglion cells as M or P cells.8 M cells form approximately 10% of the retinal ganglion cell population, have high luminance and contrast sensitivity, large receptive fields, and lack spectral selectivity. P cells have lower luminance sensitivity, smaller receptive fields, and do show spectral sensitivity. "' Anatomically, at any retinal eccentricity M cells have larger cell soma, axons, and dendritic fields than the P cells and project almost exclusively to the magnocellular laminae ofthe lateral geniculate nucleus. P cells project to the more dorsal parvocellular laminae. ' It has been reported that cells with a larger soma and axon diameter may be selectively damaged early in glaucoma12-15 raising the exciting prospect that psychophysical tests that are sensitive to and specific for the properties of M cells may be able to detect the 'silent' cell death occurring in the early phase of the disease. 6 17 The hypothesis that ganglion cell death is selective in early glaucoma is attractive and has become widely accepted in the ophthalmic community. Large cells are more susceptible to glaucomatous damage than small cells and, since cell size correlates with type, it follows that this indicates a selective vulnerability of cells of a particular physiological class (theM cells). There are two important aspects to this hypothesis. Firstly, that glaucomatous cell damage is selective for cell size and, secondly, that it is selective for cell type. The evidence in favour of cell size related change is persuasive though there are some caveats that should be considered when reviewing the data. The effects that would be expected on particular cell types are more complicated and require close analysis in the light of recent anatomical and psychophysical data. I will consider both of these aspects in turn. The earliest anatomical indications of selective loss came from the analysis of optic nerve axon counts in both the human and monkey that showed, in glaucomatous subjects, loss of axons with diameters greater than the mean when compared with normal optic nerves. '2 13 Corresponding loss was also seen in the ganglion cell layer in flat mounted retinal preparations2 148 where, away from the fovea, cell size histograms indicated a reduction in the number of cells at the upper end of the cell diameter range. A similar effect was subsequently observed in tissue taken from the macular zone and examined in the transverse plane. "9 It seemed reasonable to assume that these changes in the axon and cell diameter distributions would be reflected as a change in the proportion of the types of remaining ganglion cells. The first aspect ofthese cell size distributions to consider is whether they result from a mechanism of cell death that is influenced by cell size. Taken on its own, this point is important since it has implications for the mechanism of cell death in glaucoma.20 There are a number of possible explanations for the published distributions that have been considered. Cell shrinkage, for example, has been considered as a mechanism to account for the cell size distributions'4 and it is instructive to consider the arguments concerning this mechanism. Cell shrinkage, in its simplest form could occur nonselectively throughout the entire ganglion cell distribution. If all cells underwent the same percentage shrinkage the absolute effect of this change would be greater for the larger cells. It is conceivable, therefore, that this may generate cell size distributions in which larger cells appear to have been selectively affected. In Figure 1 the size frequencies for a hypothetical cell population have been plotted whose mean size and standard deviation approximate that in the monkey model. The cell distribution is Gaussian and as such is an oversimplification ofactual distributions. In Figure IA all the cells from which this distribution has been derived underwent 5% cell shrinkage. The frequency distribution for this population was then replotted and, to model the effect of cell death, the number of cells in each bin reduced by 20% (a percentage cell death value for which cell distributions have been published'4). The decrease in the height on the glaucomatous distribution is obvious but there does not, at first glance, appear to have been selective death of the larger cells. However, if the number of remaining cells in the shrunken distribution is plotted on the same graph, it can be seen that this effect is quite marked for the larger cells. An important argument against cell shrinkage is that this might in the early stages be reflected in a left shift in the cell population. Such a shift has not been seen to occur in the macaque monkey model though there is a suggestion that it occurs in some of the cell size distributions in the human (see Quigley et al2 figures 7, 8, and 11). Figure lB shows the sort of left shift that might be expected with a higher degree of cell death where cells have undergone 10% shrinkage and 20% cell death. The percentage cell death at each cell size is also superimposed on this plot and quite clearly there is a strong trend for cell loss as a function ofcell size. The third graph (Figure IC) shows how this left shift may be hidden where the proportion of cell death in relation to cell shrinkage is increased. In this plot the tendency for cell loss to increase with cell size is marked and there appears to be little tendency for the distribution to shift beyond the lower limits of the normal distribution. The important point to stress about these models is that they do 875