Investigative Ophthalmology & Visual Science, Vol. 32, No. 3, March 1991 Copyright © Association for Research in Vision and Ophthalmology
Retinal Ganglion Cell Loss Is Size Dependent in Experimental Glaucoma
Yoseph Glovinsky,* Harry A. Quigley,f and Gregory R. Dunkelbergerf
Thirty-two areas located in the temporal midperipheral retina were evaluated in whole-mount prepara- tions from four monkeys with monocular experimental glaucoma. Diameter frequency distributions of remaining ganglion cells in the glaucomatous eye were compared with corresponding areas in the normal fellow eye. Large cells were significantly more vulnerable at each stage of cell damage as determined by linear-regression analysis. The magnitude of size-dependent loss was moderate at an early stage (20% loss), peaked at 50% total cell loss, and decreased in advanced damage (70% loss). In glaucomatous eyes, the lower retina had significantly more large cell loss than the corresponding areas of the upper retina. In optic nerve zones that matched the retinal areas studied, large axons selectively were damaged first. Psychophysical testing aimed at functions subserved by larger ganglion cells is recommended for detection and follow-up of early glaucoma; however, assessment of functions unique to small cells is more appropriate for detecting change in advanced glaucoma. Invest Ophthalmol Vis Sci 32:484-491, 1991
Current psychophysical tests do not detect glau- tage of ideal cellular preservation. Eyes with mild, comatous damage until a substantial minority of reti- moderate, and late damage were evaluated. In addi- nal ganglion cells have died.1'2 To develop more sen- tion, we correlated the damage patterns in the retinas sitive tests, a comprehensive understanding of the and optic nerves of the glaucomatous eyes. patterns of glaucomatous ganglion cell damage is es- sential. Retinal ganglion cells of different sizes have Materials and Methods distinct physiologic functions. Small cells that project to the parvocellular layers of the lateral geniculate This investigation adhered to the principles of the body belong to the "P pathway" or the "color sys- ARVO Resolution on Use of Animals in Research tem," while large cells that project to the magnocel- and was approved and monitored by the Institutional lular layers, belong to the "M pathway" or the "lumi- Animal Care and Use Committee of the Johns Hop- 3 kins University School of Medicine. nance system." Large optic nerve fibers selectively 7 are lost in chronic experimental and human glau- Monocular glaucoma was induced in four cyno- coma.4'5 Furthermore, in human glaucomatous eyes, molgus monkeys (Macaca fascicularis) by argon laser large ganglion cells die faster in studies of the mid- trabecular treatment. In another monkey, one optic peripheral retina.2 We studied the number and size of nerve was surgically transected 6 mm posterior to the remaining retinal ganglion cells in monkey eyes with globe. Both glaucomatous and transected animals experimental glaucoma, comparing them with nor- were monitored serially by applanation tonometry, slit mal fellow eyes. Chronic experimental glaucoma in lamp and fundus examination, and color stereopho- monkeys is similar to chronic human glaucoma both tography of the disc. After at least several months of clinically and histopathologically6 and has the advan- pressure elevation (intraocular pressure [IOP] range, 24-55 mm Hg; disease duration range, 6-24 months), various levels of optic nerve damage occurred, and From the tGlaucoma Service, Wilmer Ophthalmological Insti- disc pallor developed in the transected eye. tute, Johns Hopkins University School of Medicine, Baltimore, The monkeys were killed by exsanguination under Maryland, and the *Goldshleger Eye Institute, Sackler School of Medicine, Tel-Aviv University, Israel. sodium pentobarbital intravenous anesthesia. The Supported in part by PHS Research Grants EY 02120 (H.A.Q.), monkey with the transected eye was killed 6 months EY 01765 (Core Facility Grant, Wilmer Institute), a Senior Inves- after the operation. The eyes were then rapidly enu- tigator Award from Research to Prevent Blindness, Inc., New cleated and immersed in cold 2% paraformaldehyde York, New York, and by a Kreiger Foundation Grant. in 0.1 M phosphate buffer. The retinas were sepa- Submitted for publication: September 10, 1990; accepted Oc- tober 17, 1990. rated from the remainder of the globes and further Reprint requests: Harry A. Quigley, Maumenee Bl 10, Wilmer, fixed for at least 2 hr. The vitreous humor was re- Johns Hopkins Hospital, 600 N. Wolfe, Baltimore, MD 21205. moved mechanically as completely as possible. Five
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to, seven relaxing incisions were made radially to 29 31 29 allow a flat mount of the retina, ganglion cell side up. <$) 2 Each retina was stained in 0.05% cresyl-violet. A 26 32 *; 29 31 cross-section of the retrolaminar optic nerve was i> 29 fixed in the same paraformaldehyde, postfixed in 1% 31 31 A 30 29 A * 8 osmium tetroxide, and embedded in epoxy resin. 32 32 32 32 33 30 29 One-micron sections of the nerve of the four glau- A I" 33 comatous and one transected eye were stained with 31 33 36 33 • 31 1 toluidine blue. The Zeiss IBAS image (Carl Zeiss, 34 32 6A 35 - • • 30 ' Inc., Thornwood, NY) analysis system was used to A i) measure the number and diameter distribution of 32 32 30 <§) 32 33 !• 32 30 fibers in 16 zones of the optic nerve.5 As expected, 30 31 33 34 31 there were no remaining fibers in the transected <$) nerve. The quantitative data from the glaucomatous 30 34 32 31 30 29 eyes were compared with a data base of ten normal cynomolgus nerves identically prepared and counted. 29 29 31 32 This seemed appropriate as our previous research has shown that substantial variation in fiber number Fig. 1. Humphrey field projection of the eight retinal areas (•) among monkeys can be partially compensated by studied in every monkey, plotted as a left eye. 1 mm on the retina using a larger sample of controls. equals 4° of visual angle. Distances from the fovea were 13°, 15°, 17°, and 21°. Ganglion cell diameter was determined by man- ually encircling at least 100 cells in each retinal area, using a camera lucida attached to a microscope at pared with their normal fellow eyes. Cell loss was 1000 X magnification and a planimeter connected to then correlated to the cell diameter by linear-regres- a personal computer. The diameter was calculated sion analysis.9 A significant correlation with positive from the circumference, assuming a circular shape. slope would indicate that large cells were more vul- Ganglion cell size distribution was determined in nerable. The slope of the regression line indicated the eight retinal areas of glaucomatous eyes and com- magnitude of the size-selective damage. A standard- pared statistically to the same areas in their normal ized regression coefficient10 was calculated by multi- fellow eyes. These eight areas corresponded to eight plying the regression coefficient by the ratio of the locations that are tested in the 30-2 program of the standard deviation of the independent variable to the Allergan-Humphrey Field Analyzer (San Leandro, standard deviation of the dependent variable. This CA) (Fig. 1). The cells were considered to be ganglion resulted in a dimensionless coefficient (beta) that rep- cells if they were round or oval and had large nuclei resents the slope of the regression line when both with some metachromatically stained cytoplasm. variables are expressed as standardized scores. Retinal capillary endothelial cells, pericytes, and as- trocytes that are found in the ganglion cell layer were Results easily excluded from counting. However, to estimate Normal Eyes the possibility that we included amacrine cells in our ganglion cell data, six areas of the retina from the The average ganglion cell densities in the different transected eye were similarly assessed. Since all gan- retinal locations were inversely correlated to their glion cells had atrophied, only amacrine cells would distance from the fovea (Fig. 2), ranging from 3705 be expected to remain and possibly to fulfill our ±556 cells/mm2 at 13° to 1476 ± 472 cells/mm2 at criteria. 21°. The variance among monkeys was substantial. In the normal eyes of monkeys 2 and 4, only the The 95% confidence interval width for pooled density upper retina was technically suitable for cell size mea- data of four upper retinal areas in the four monkeys surements. Since upper and lower size distributions was 26% of the mean value. In two normal eyes, we were found to be indistinguishable, we used the upper were able to compare the upper and the lower retina. retina as the control for both the upper and lower As previously reported," we found 14% greater den- areas in these monkeys. In all monkeys data could sity of cells in the four lower retinal areas compared not be obtained from the retina in the central 10° with their matching upper ones. The cell diameter (within 3 mm of the foveal center) due to the dense distribution peaked at about 14 ^m and had a posi- overlapping of cells. tive skewness toward the larger diameters. The size The percent cell loss was calculated for each diame- distribution of the upper and the lower areas had ter grouping (bin) in the glaucomatous eyes com- similar patterns (Fig. 3).
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4500 After studying their morphology, we tried to avoid counting them in the eight eyes that were evaluated in 4000- this study. The cell diameter distribution in the tran- 3500- sected eye overlapped that of the four normal eyes only at the 12-/nm range (Fig. 4).
Pooled Retinal Areas Cell density (cells/mm2) was determined for each A >* of the 32 areas (8 areas per eye) in the glaucomatous eyes and compared with the density in the matching 24 areas in the normal fellow eyes (8 areas served as controls for both upper and lower retinal areas). The percentage of total cell loss was determined for each retinal area. The areas were then pooled into three groups: 9 areas with mild damage (10-40% cell loss, 14 16 18 20 22 average 21% loss), 15 with moderate damage distance from fovea (degrees) (40-60% cell loss, average 49% cell loss), and 7 se- verely damaged areas (60-90%, average 72%). In one Fig. 2. Ganglion cell density (•) in the temporal midperipheral monkey retina decreases linearly with increasing distance from the area, cell density was similar to the normal eye. fovea (r = 0.98, P < 0.05). Note the significant variance (bar ± 1 We found statistically significant, size-dependent SD). ganglion cell loss in all three stages of glaucomatous damage. However, the degree of size selectivity, as Transected Eye reflected by the slope of the linear-regression line, was not the same in all stages. The effect began as a mod- The cell size in the transected eye averaged 8.4 12 erate slope (standardized regression coefficient (beta) ± 1.4 /im. These presumed amacrine cells had large, = 0.62) at an early stage (Fig. 5) and became steeper round deeply stained nuclei and scanty cytoplasm. when 50% of the cells were gone (beta = 0.94, Fig. 6). In advanced damage (Fig. 7), the selectivity declined again (beta = 0.76), and ganglion cells between 14-21
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11 13 15 17 19 21 12 14 16 18 20 cell diameter (microns) 5 7 9 11 13 15 17 19 Fig. 3. Size distribution curves of upper (•) and lower (+) normal 6 10 12 14 16 18 20 temporal retina. Note the smilar distributions in these correspond- cell diameter (microns) ing areas. Number of cells on the Y axis is a relative number where the number of cells in the highest peak equals 100 and the number Fig. 4. Average distribution of the diameter of amacrine cells (•) of cells in all other bins are shown as percent fraction of this num- as measured in the eye with the optic nerve transection, compared ber. Patterns of the curves are identical to those with absolute with average distribution of the diameter of ganglion cells of the numbers. This system allows the use of the same scale for simulta- temporal retina (•) in the normal eyes. There is minimal size over- neous presentation of percent cell loss. lap between the two cell populations.
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11 13 15 17 19 21 11 13 15 17 19 12 14 16 18 20 12 14 16 18 20 cell diameter (microns) cell diameter (microns) Fig. 5. Ganglion cells with mild damage. Pooled data from all Fig. 7. With severe damage, the surviving cells in the glaucoma areas with 10-40% ganglion cell loss (average: 21%). Diameter dis- eyes are predominantly small (+), as compared with the matching tribution curve of the remaining cells in the eyes with glaucoma normal distribution (•). This represents pooled data from all areas (+), shows greater loss of larger cells compared with matching areas with 60-90% ganglion cell loss (average: 72%). There is significant in the normal fellow eyes (•). Percent loss in each bin size (•) positive corn Ir.tion between percent cell loss (D) and cell diameter increases with cell size as shown by the positive slope of the linear (r = 0.68, P = 0.01). The slope of the linear regression line is less regression line. The slope is moderately steep (/3 = 0.62). The cor- steep than in Figure 6 (/3 = 0.76), mainly because large cells are relation between cell diameter and percent loss is statistically signif- scarce. The same regression analysis done on the larger cell compo- icant (r = 0.62, P = 0.04). The y axis scale in this figure and in nent alone (14-20 um) results in a minimal slope (0 = 0.18). Figures 6, 7, 10, and 11 represents both relative axon number and percent cell loss on scales from 0-100. ixm in diameter showed almost the same severe loss (beta = 0.18). Based on our empiric findings, we constructed a model in which each 1-^m increase in cell diameter accounts for 2.5% more cell loss per unit time. We applied this model to the normal cell population in Figure 6 and calculated the frequency distributions that would result from this rate of selectivity at var- ious stages of damage (Fig. 8). We then plotted the size-loss curves for three stages: 20, 50, and 72% total cell loss. These curves closely fit our empiric data for the corresponding stages (Fig. 9). The changes in the regression slopes appear to result from an accumula- tive effect of a constant size-selective process. This peaks toward the stage of 50% total cell loss and then decreases when only a few large cells remain. 11 13 15 17 19 21 12 14 16 18 20 Upper Versus Lower Retina cell diameter (microns) Fig. 6. With moderate damage, illustrated by pooled data from The lower four retinal areas were more damaged all areas with 40-60% ganglion cell loss (average: 49%), the re- than the upper ones in all four monkeys (paired t-test, maining cells in the glaucoma eyes (+) are smaller than the normal difference = -17% ± 16%; P = 0.0004). The 32 reti- matching areas (•). Increase in percent cell loss (D) is steady and consistent with increasing diameter (r = 0.93, P = 0.0002). The nal areas in the glaucomatous eyes made 16 corre- slope of the linear regression line is maximally steep (/3 = 0.94) in sponding upper-lower pairs. Eight pairs showed simi- these moderately damaged areas. lar upper-lower cell loss; in the other eight pairs the
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13 15 17 19 21 13 15 17 19 21 12 14 16 18 20 12 14 16 18 20 cell diameter (microns) cell diameter (microns) Fig. 8. These curves were generated after a size-dependent loss Fig. 9. Theoretic size-loss curves for the 20%, 50%, and 72% loss model was applied to the normal diameter distribution curve (A) shown in Figure 8. The actual data points from our study for the taken from the data in Figure 6. The resulting curves after 20% (•), same total percent loss (20%, •), (50%, •) and (72%, S) are super- 50% (•), and 72% (IS)) total cell loss are shown. imposed on the theoretic lines. The empiric data fit closely to the model.
lower area had at least 15% more cell loss than the corresponding upper area. In these 16 areas, the Discussion paired upper-lower data showed a significantly We found a selectively greater loss of large ganglion greater loss of large cells (Fig. 10). cells in experimental glaucoma. In comparisons of
Correlation of Optic Nerve and Retina
Axons from the temporal retina, 13° to 21° away from the fovea, converge into the superior and infe- rior peripheral zones of the optic nerve.13 We there- fore examined the axon number and diameter distri- bution in the portion of the optic nerve cross-section that most likely contained fibers from the retinal areas we had studied. There was a significant linear 'g correlation between the degree of axonal and gan- •a glion cell damage in the optic nerve zones and their matching retinal areas (r = 0.71, P = 0.046). How- ever, there was a slightly greater depletion of axons than ganglion cells in the matching optic nerve-reti- nal pairs (paired t-test, difference = -13% ± 19%; P = 0.05). Of the total of eight zones, there was one with mild damage (4%), three with moderate damage (51.5%; range, 50-53%), and four with severe damage 11 13 15 17 19 12 14 16 18 20 (76%; range, 63-100%). We found significant size- cell diameter (microns) dependent axonal loss in all three stages of the dam- age (Fig. 11). The selective large cell loss was slightly Fig. 10. The more damaged areas of the inferior retina (+) are compared with the less-affected superior ones (•) from the eyes less prominent at late stage (beta = 0.79, 0.78, and with glaucoma. More large cells were lost in the lower retina. Per- 0.76 for mild, moderate, and severe damage, respec- cent difference between lower and upper retina is shown (•) as well tively). as regression line (r = 0.68, P = 0.03).
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nal ganglion cells to the dorsal lateral geniculate nu- cleus [in preparation].) Selective large ganglion cell loss has been reported in human glaucomatous eyes;217 however, we had been unsure whether this was true in the early stages of the disease. Our data show that size-selective damage does start at an early stage. It becomes more prominent with progression of the disease and subsides at a late stage. Similar dynamics were observed in patterns of axonal loss in the optic nerve.4'5 As explained by the model, the inherent vulnerability of the larger cells and the ef- fects of injury may not change during the glaucoma- tous process, yet small to large cell proportions will vary with progression of the disease. What are the implications of our findings for better design of psychophysical testings for glaucoma? Early detection is crucial for timely initiation of treat- ment.18 Current visual field tests do not detect initial 2 axon diameter (microns) ganglion cell damage, probably because of overlap- ping ganglion cell receptive fieldstha t provide the eye Fig. 11. The distribution of normal axon diameter (•) is com- with a substantial functional reserve.19 Hence, plan- pared with that from zones with moderate optic nerve damage (+). As with ganglion cell body size, there is a significant size-dependent ning for the most sensitive and specific psychophysi- loss of axons (r = 0.6, P < 0.01). This was also true in zones of mild cal test for early glaucoma must consider two factors: and severe optic nerve damage (r = 0.53 and 0.58, P = 0.03 and the vulnerability of the cell type to chronic intraocu- 0.01, respectively; graphic data not shown). lar pressure elevation and the functional reserve of this group of cells. Ganglion cells that project to the lateral geniculate body are functionally divided into P glaucomatous to normal fellow eyes, 40-85% of the cells (80% of the total in the retina, projecting to the observed variability in cell loss could be explained by parvocellular layers of the lateral geniculate nuclei) cell size alone. The greater susceptibility of large gan- and M cells (10% of the total, projecting to the mag- glion cells was also evident in comparisons in the nocellular layers).11 The M cells have larger cell same retina of the glaucoma eyes. This second bodies20 and are more vulnerable to glaucomatous method uses each eye as its own control and mini- damage. However, despite comprising only 10% of mizes artifacts caused by asymmetric tissue shrinkage the retinal ganglion cells in the retina, because of their during fixation and staining. Although the amacrine extremely large receptive fields, each point in the ret- cell diameter distribution is largely below the range of ina is estimated to be covered by receptive fields of the ganglion cells sizes in the retinal areas that we 3.4 M cells and only 1.9 P cells.21 Moreover, the size- studied, the possibility that some amacrines were dependent damage cannot be explained by early counted as ganglion cells cannot be excluded. There death of M cells alone, since they comprise only a was also size-selective axonal damage in the optic small minority of the ganglion cells in the retina. nerve sections that contain axons from the retinal Therefore the early death of larger P cells also proba- areas that we studied. This further supports the gan- bly accounts for some of the effect. We propose, then, glion cell findings and provides additional evidence that the large P cell may be an appropriate cell type that amacrine cells did not affect our results. for psychophysical assessment in early glaucoma Large ganglion cells have large axons11U that pref- along with the M cell. erentially project to the magnocellular layers of the The results of recent psychophysical studies pro- lateral geniculate body.15 The results of this study vide some supportive evidence for greater vulnerabil- therefore agree with previous reports on selective ity to glaucomatous damage among the larger P cells. large axonal loss in experimental and human glau- "Blue-on center" ganglion cell bodies are about 50% coma,4'5 and with selectively more glaucomatous larger than "green" or "red center" ones.22 Visual damage to the magnocellular pathway in the lateral field with blue-yellow color contrast generates larger geniculate body of monkeys.16 (Also Dandona L, scotomas than conventional white light perimetry in Hendrickson A, and Quigley HA: Selective effects of patients with glaucoma.23 Similarly central field test- experimental glaucoma on axonal transport by reti- ing with blue stimuli is abnormal in 19% of ocular
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hypertensive patients.24 Other tests that assess visual these cells and shrinkage of another group of cells that functions subserved by M cells are reportedly abnor- then die, and so on. We could not find an initial shift mal in patients with elevated IOP and normal man- in cell size distribution even when areas with very ual or automated visual field tests. These include early damage (0-20%) were pooled and compared motion detection,25 scotopic visual fields,26 flicker with normal matching areas. This seems to deny the sensitivity,27 stereopsis,28 and sensitivity to diffuse first possibility. With regard to the second possibility, dim light.29 the increasing slope of size-dependent damage with In advanced glaucoma, most of the large cells are progression from 20%-50% total cell loss suggests gone. An assessment of visual field stability is impor- that dying cells are larger than the remaining cells. As tant for proper patient management at this stage. It larger cells die faster, the gap between small and large seems more likely that assessment of visual functions cells increases, and the slope becomes steeper. If cells related to small P cells, such as red-green discrimina- were to shrink before death, we would not have ob- tion or other foveal functions,3 may be more sensitive served the steepening of the slope of the percent loss to progression at this stage. curve. Therefore, we did not find support for the hy- Glaucomatous neuronal damage is associated with pothesis that our large cell susceptibility results from obstruction of axonal transport at the level of the cell shrinkage before death. We were unable to deter- lamina cribrosa.30 We found somewhat more loss of mine whether cells in the central 10° of the retina 216 axons than ganglion cells in matching optic nerve- show size-dependent damage. It is impossible retina segments. Perhaps this happens because axons quantitatively to evaluate cell diameter in this area in degenerate distal to the lamina before the cell bodies our whole-mount preparations due to multiple gan- 12 die. Ganglion cell bodies do survive 3-4 weeks longer glion cell layers and mechanical packing. Retinal than their distal axons after complete optic nerve tissue studied under different conditions may eluci- transection.31 Since events in experimental monkey date this issue. glaucoma occur over several months, this may ex- plain why we were able to detect a difference between Key words: experimental glaucoma, monkeys, ganglion axonal and cell death. If we included amacrine cells cells, cell diameter, optic nerve pathology, retina as ganglion cells, the cell body counts would be higher than axon counts. This is unlikely because most re- References maining cells were larger than 12 nm in size. A final 1. Quigley HA, Addicks EM, and Green WR: Optic nerve dam- possibility is that axons from the retinal areas that we age in human glaucoma: III. Quantitative correlation of nerve sampled converge into other optic nerve segments, fiber loss and visual field defect in glaucoma, ischemic neurop- and zones with greater atrophy contributed their athy, disc edema, and toxic neuropathy. Arch Ophthalmol axons to the nerve zone that we sampled. It is possi- 100:135, 1982. 2. Quigley HA, Dunkelberger GR, and Green WR: Studies of ble, however, that this finding is not an artifact. This retinal ganglion cell atrophy correlated with automated perim- would be a consideration in comparisons of ganglion etry in human eyes with glaucoma. Am J Ophthalmol 107:453, cell number to known psychophysical test results. An 1989. overestimation of the psychophysical test sensitivity 3. Shapley R: Visual sensitivity and parallel retinocortical chan- may result from such comparisons, since remaining nels. Annu Rev Psychol 41:635, 1990. 4. Quigley HA, Sanchez RM, Dunkelberger GR, L'Hernault NL, ganglion cells without a viable axon would not con- and Baginski TA: Chronic glaucoma selectively damages large tribute to the visual process. This finding may also optic nerve fibers.Inves t Ophthalmol Vis Sci 28:913, 1987. explain the 0 dB sensitivity found in retinal areas of 5. Quigley HA, Dunkelberger GR, and Green WR: Chronic human glaucomatous eyes where 10% of the ganglion human glaucoma causes selectively greater loss of large optic cells still survived.2 nerve fibers. Ophthalmology 95:357, 1988. 6. Radius RL and Pederson JE: Laser induced primate glaucoma: The reason for increased susceptibility of large cells II. Histopathology. Arch Ophthalmol 102:1693, 1984. to elevated IOP damage is obscure. The mechanism 7. Quigley HA and Hohman RM: Laser energy levels for trabecu- of glaucoma damage may involve mechanical, isch- lar meshwork damage in the primate eye. Invest Ophthalmol emic, or other processes. It is possible that larger Vis Sci 104:1648, 1986. 8. Sanchez RM, Dunkelberger GR, and Quigley HA: The num- axons have poor resistance to external compressive ber and diameter distribution of axons in the monkey optic pressure, or they may tolerate ischemia poorly be- nerve. Invest Ophthalmol Vis Sci 27:1342, 1986. 32 cause of a smaller surface-to-volume ratio. 9. Armitage P: Statistical Methods in Medical Research. New We may argue that the apparent size-selective dam- York, John Wiley and Sons, 1974, p. 150. age is a result of cell shrinkage before death. This may 10. Norusis MJ: SPSS-X Advanced Statistics Guide. New York, McGraw-Hill, 1985, p. 14. occur in one of two ways. First, all cells might shrink 11. Perry VH, Oehler R, and Cowey A: Retinal ganglion cells that followed by a nonselective cell death. 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