Consequences of Axonal Injury Within Demyelinated Plaques

Disruption of the axonal continuity within a demyeli-nated plaque has necessarily to result in degenerations of the distal portion of the nerve fiber. In addition, axon disruption may also lead to retrograde degeneration, affecting the proximal axon and the neuron of origin. It has thus to be expected that degenerative alterations occur in MS brain outside the classical plaques.

Many studies have shown the presence of secondary (Wallerian) tract degeneration in MS brains (see Kornek and Lassmann, 1999). As an example, the extent of fiber degeneration and atrophy in the corpus callosum correlated well with the size and destructiveness of demyelinated plaques in the adjacent cerebral hemispheres (Evangelou et al., 2000a). The situation is even more impressive in the spinal cord. In this area of the CNS, loss of axons in defined tract systems is similar within demyelinated plaques compared to that in spinal cord areas not affected by focal demyelinated lesions (Lovas et al., 2000; Ganter et al., 1999). This is at first glance a paradox, which resolves when it is considered that axonal degeneration in a single plaque in a defined tract sys

Figure 2 Acute axonal injury in active multiple sclerosis plaques. (A) Multiple large axonal swellings (spheroids) reactive for nonphosphorylated neurofilament (x 600). (B) Longitudinal section of an axon within an active demyelinating plaque; multiple small beadlike swellings within the course of the axon, suggesting disturbance of axonal transport; immunocytochemistry for nonphosphorylated neurofilament (x 600). (C) Small axonal spheroids, reactive for Alzheimer amyloid precursor protein, as a sign of disturbed axonal transport (x 600).

Figure 2 Acute axonal injury in active multiple sclerosis plaques. (A) Multiple large axonal swellings (spheroids) reactive for nonphosphorylated neurofilament (x 600). (B) Longitudinal section of an axon within an active demyelinating plaque; multiple small beadlike swellings within the course of the axon, suggesting disturbance of axonal transport; immunocytochemistry for nonphosphorylated neurofilament (x 600). (C) Small axonal spheroids, reactive for Alzheimer amyloid precursor protein, as a sign of disturbed axonal transport (x 600).

tem has inevitably to result in secondary Wallerian degeneration of the whole distal portion.

Much less evidence is available for retrograde degeneration of axons and neurons in MS. Only a few studies described swollen "chromatolytic" neurons suggestive of a retrograde reaction due to axonal injury (Lumsden, 1970). In our experience this may occur sometimes in the cortex of patients with very destructive lesions, located in the subcortical white matter (Fig. 3). Whether the recently described signs of neuronal apoptosis in the cerebral cortex (Peterson et al., 2001) are related to retrograde degeneration or to active demyelinating lesions in the cerebral cortex is unresolved. In addition, in a single case neuronophagia by microglia cells was described and regarded as evidence for profound neuronal damage (Fraenkel and Jakob, 1913). In this particular case, however, it remained open whether the pronounced neuronal degeneration in the cortex was due to a superimposed meningoencephalitis. Whether the cortical atrophy, seen in quantitative MRI studies at later stages of the disease (Bozzali et al., 2002), is mainly due to cortical demyelina-tion or to secondary retrograde degeneration, is currently unresolved.

These alterations, secondary to axonal degeneration in the plaques, which affect the brain as a whole, have been summarized under the term multiple sclerosis encephalopathy (Jellinger, 1969). This condition is characterized by tissue atrophy, which is more pronounced in the white than in the gray matter, and reflected by the progressive dilation of the lateral cerebral ventricles with increasing disease duration. On a fine structural basis, this diffuse brain damage is associated with chronic activation of microglia and a diffuse astrocytic scarring in the "normal" white matter.

For a long time, it has been believed that all diffuse abnormalities in the "normal" white matter of patients with

Figure 3 Retrograde neuronal reaction in the cerebral cortex in multiple sclerosis. (A) Large demyelinated subcortical plaque in a patient with acute multiple sclerosis. The staining by Bielschowsky's silver impregnation shows massive reduction of axonal density in the subcortical plaque. The alterations in the superimposed cortex (arrow) are shown in B and C (x 2). (B, C) Neuronal reaction in the cortex, superimposed over a plaque with massive axonal injury; the neurons show an enlarged pericaryon, eccentric positioning of the nucleus and massive expression of phosphory-lated neurofilament epitopes, features which are typical for a retrograde reaction following axotomy (x 500).

Figure 3 Retrograde neuronal reaction in the cerebral cortex in multiple sclerosis. (A) Large demyelinated subcortical plaque in a patient with acute multiple sclerosis. The staining by Bielschowsky's silver impregnation shows massive reduction of axonal density in the subcortical plaque. The alterations in the superimposed cortex (arrow) are shown in B and C (x 2). (B, C) Neuronal reaction in the cortex, superimposed over a plaque with massive axonal injury; the neurons show an enlarged pericaryon, eccentric positioning of the nucleus and massive expression of phosphory-lated neurofilament epitopes, features which are typical for a retrograde reaction following axotomy (x 500).

MS are secondary to axonal degeneration within the plaques; however, this seems not to be the case. In particular, in patients with primary progressive MS, a massive diffuse damage of the whole "normal" white matter is seen, which frequently occurs in spite of only very few local plaques. Such diffuse changes cannot be explained by secondary alterations occurring as a consequence of axonal degeneration in the plaques (Pelletier et al., 2003).

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