Size-selective neuronal changes in the anterior optic pathways suggest a differential susceptibility to injury in multiple sclerosis

Axonal damage is found in both acute and chronic lesions of multiple sclero sis. Direct axon counting in post-mortem tissue has suggested that smaller axons might have a greater susceptibility to damage, but methodological lim itations have precluded unequivocal interpretation. However, as neuronal an d axonal sizes are linked and neuronal changes would be expected with retro grade or transsynaptic degeneration following axon injury, we hypothesized that an alternative strategy for studying this phenomenon would be to defin e multiple sclerosis-associated changes in neurones. To test this hypothesi s, we measured both axonal loss and neuronal size changes in the anterior o ptic pathway [including the optic nerve (ON), optic tract (OT) and lateral geniculate nucleus] of the brains of eight patients who died with multiple sclerosis and in eight control brains. The ONs and OTs in brains from the m ultiple sclerosis patients showed a trend to smaller mean cross-sectional a reas (ON, multiple sclerosis = 6.84 mm(2), controls = 9.25 mm(2); and OT, m ultiple sclerosis = 6.45 mm(2), controls = 7.94 mm(2), P = 0.08) and had re duced axonal densities (ON, multiple sclerosis = 1.1 x 10(5)/mm(2), control s = 1.7 x 10(5)/mm(2); and OT, multiple sclerosis = 1.4 x 10(5)/mm(2), cont rols = 1.8 x 10(5)/mm(2), P = 0.006). Estimated total axonal counts were re duced by 32 (OT)-45% (ON) in the patients relative to controls (ON, multipl e sclerosis = 8.1 x 10(5) axons, controls = 14.8 x10(5), P = 0.05; and OT, multiple sclerosis = 9.1 x 10(5), controls = 13.3 x 10(5), P = 0.02). The s ize distributions of the magnocellular cells in the lateral geniculate nucl eus were similar for the two groups, but in multiple sclerosis brains the p arvocellular cells were significantly smaller (mean sizes: multiple scleros is = 226 mum(2), controls = 230 mum(2), P < 0.001) and had a larger variati on in size, suggesting a greater proportion of atrophic neurones. Axon loss in the optic nerves of multiple sclerosis patients correlated strongly wit h measures of increased dispersion of cell sizes in the parvocellular layer (r = 0.8, P < 0.04). These data demonstrate that both atrophy and decrease d density contribute to the substantial axonal loss in the anterior visual pathway of these patients. This appears related to a relatively selective a trophy of the smaller neurones of the parvocellular layer in the lateral ge niculate nucleus, supporting the hypothesis that smaller axons may be prefe rentially susceptible to injury in multiple sclerosis.