Although conduction is initially blocked by segmental demyelination, the block is not necessarily permanent. The loss of the myelin triggers a series of adaptive responses in the axon, including changes in the ion channel population along the demyelinated membrane (see Chapters 7 and 8). If several conditions are favorable, these changes can result in the restoration of conduction. In peripheral axons, conduction can be restored within only a week of the initiation of demyelina-tion (Smith et al., 1982; Smith and Hall, 1980), although restoration often takes longer in central axons (e.g., 2 to 3 weeks after lesion induction) (Smith et al., 1981). The presence of conduction in demyelinated axons was first proven in elegant experiments that examined conduction along rat spinal roots experimentally demyelinated with diphtheria toxin (Bostock and Sears, 1978). A sophisticated recording technique revealed that the action potential crossed the demyeli-nated region by reverting from the normal saltatory mode of conduction, exhibited along the myelinated portion of the axon, to a slow, continuous (see later) mode of conduction along the demyelinated axolemma; saltatory conduction was resumed along the normal tissue on the other side of the lesion. Subsequent experiments revealed that conduction along axons demyelinated by the action of lysolecithin proceeded not in a continuous manner, but rather by adopting a microsaltatory mode of conduction (Smith et al., 1982), perhaps reflecting the organization of sodium channels into new nodelike foci, termed phi-nodes. These foci occurred along the demyelinated axolemma every 100 to 400 |im (mean, 255 |im) and were probably formed in preparation for remyelination.
That conduction could occur in central demyelinated axons was proven in a study where the conduction properties of single axons passing through demyelinated lesions were determined electrophysiologically, and then the axons were labeled so that they could be identified and recon structed in three dimensions at the electron microscope level (Fig. 1) (Felts et al., 1997). This study established that conduction could occur along central demyelinated axons in which several internodes of myelin had been lost, and in the proven absence of any repair by remyelination (Felts et al., 1997). Furthermore, the demyelinated central axons were able to conduct even when at least 88% of their surface area was deprived of glial contacts for several internodes; glial ensheathment, even without myelin formation, is likely to aid conduction by affecting the passive cable properties of the axons (Shrager and Rubinstein, 1990). Thus conduction may be possible even in "open" MS lesions (Barnes et al., 1991), where there is a paucity of glial processes and a greatly expanded extracellular space.
Figure I Correlating the electrophysiological and ultrastructural properties of A l The ultrastructural description of a central demyelinated axon with known conduction properties. Recordings from the axon (diagram) revealed that it conducted through the lesion with a slow velocity and prolonged refractory period for transmission. The axon was labeled by the iontophoresis of horseradish peroxidase (HRP) so that it could later be identified microscopically. Longitudinal sections through the lesion (A) allowed the identification of the labeled axon (B), the only axon in the tissue for which the conduction properties were known. Transverse sections through the axon (C-F) were studied at different locations taken over several millimeters, using light (C) and electron (D-F) microscopy. The axon passed through regions where it was demyelinated but ensheathed by a Schwann cell (D, two adjacent axons are remyelinated), or demyelinated and largely (E) or entirely (F) free of glial processes. The axon is embedded in vesicular myelin debris in F. (Reproduced modified from Felts et al., 1997.)
It seems reasonable to believe that the restoration of conduction to demyelinated axons will tend to reverse symptoms imposed by demyelination-induced conduction block, and so to believe that the restoration may make an important contribution to remissions. The presence of conduction in demyelinated axons can also explain the observation that large, but clinically "silent" (i.e., asymptomatic) demyeli-nating lesions can occur in patients in pathways where symptoms may have been expected (Wisniewski et al., 1976; Ghatak et al., 1974; Phadke and Best, 1983).
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