Axonal loss in the pathology of MS: consequences for understanding the progressive phase of the disease

Axonal injury caused by inflammatory demyelination in an active MS lesion. Substances produced by activated immune and glial cells may mediate tissue damage, including axonal transection. Axons degenerate rapidly distal to the site of transection. In contrast, CNS myelin can persist for a long time and form empty tubes, or later degenerating ovoids. The white matter distal to the lesion may appear normal on conventional MRI images or routine histological examination. Denervation of target neurons causes functional loss and possibly downstream effects.

Loss of axons in a spinal cord lesion from a paralyzed patient with secondary progressive MS and long disease duration. Neurofilament staining demonstrates axonal density in control (A) and in a demyelinated area in the gracile fasciculus of MS cervical spinal cord (B). This chronic MS lesion exhibits significant axonal loss. Scale bar=25 μm (from Bjartmar et al. [25]).

Loss of spinal cord axons correlate with irreversible neurological disability in mice with chronic EAE. (A–D) Neurofilament stained axons in the dorsolateral spinal cord from control (A) and EAE mice with clinical scores of 0 (B), 2 (C) and 4 (D). (E) Density of axons in cervical (white bars) and lumbar (black bars) spinal cord, expressed as percent axonal loss relative to controls. Axonal loss increased significantly for each higher clinical score (Spearman's rank correlation test; cervical cord: ρ=0.75; p=0.0001, and lumbar cord: ρ=0.63; p=0.004). Scale bars (A–D)=10 μm (from Wujek et al. [16]).