Persistence of Conduction Block

Although conduction can be restored to demyelinated axons, conduction block remains a common feature of such axons. Whether conduction is restored in practice depends

Figure 2 Clustering of Nav1.6 sodium channels at a node of Ranvier. The Nav1.6 channels (black) are flanked by Caspr (a constituent of the paranodal axoglial junction; white) without significant overlap. This flourescent image of a node after immunostaining for Nav1.6 and Caspr was merged with a differential interference image to show the myelin on either side of the node. (Modified from Black et al., 2002.)

Figure 2 Clustering of Nav1.6 sodium channels at a node of Ranvier. The Nav1.6 channels (black) are flanked by Caspr (a constituent of the paranodal axoglial junction; white) without significant overlap. This flourescent image of a node after immunostaining for Nav1.6 and Caspr was merged with a differential interference image to show the myelin on either side of the node. (Modified from Black et al., 2002.)

on a number of factors. Factors favoring the persistence of conduction block include a large axon diameter (Bostock and Sears, 1978; Waxman, 1989); a long internode preceding the demyelinated region (especially if the internode is partially demyelinated) (Waxman and Brill, 1978; Shrager and Rubinstein, 1990; Bostock, 1994); a long overall length of demyelination (e.g., many internodes lost); the dysregula-tion of the composition of the extracellular fluid due, for example, to failure of the blood-brain barrier; the presence of factors deleterious for conduction such as nitric oxide and other factors associated with inflammation (Redford et al., 1997); the absence of any glial ensheathment (Shrager and Rubinstein, 1990); a short period of time elapsed since the occurrence of demyelination; a recent (seconds/minutes) history of sustained impulse conduction (see later); an inopportune composition of ion channels and pumps along the demyelinated axolemma, perhaps theoretically influenced by genetic background; and a warm body temperature (see later). Some of these points deserve further comment, and with regard to axon diameter, it is known that conduction can occur in demyelinated axons as large as 5.5 mm in diameter (Felts et al., 1997). As most demyelinated axons are smaller than this, especially in the central nervous system (CNS), it seems likely that most peripheral and central demyelinated axons should be capable of conduction if conditions are optimal. Also with regard to the preceding list, a long internode before the demyelinated region impedes the depolarization of the demyelinated axolemma by reducing the local current available at this site due to capacitative and resistive loss over the internode (Fig. 3). Even limited remyelination at the margin of an otherwise demyelinated lesion can therefore be expected to promote the restoration of conduction along the axon, as remyelinated internodes are short. Glial ensheathment is probably beneficial to conduction even in the absence of myelin formation as, even apart from any passive electrical benefit conferred by the apposition of glial membranes, glial contacts can be associated with morphological evidence of nodelike axolemmal specializations suggestive of increased excitability (Blakemore and Smith, 1983; Rosenbluth et al., 1985). It is likely that the efficacy of the repair process could vary over time (Black and Waxman, 1996).

Given this list of reasons why conduction may fail in demyelinated axons, it is less surprising that conduction block can persist for years in axons affected by multifocal motor neuropathy, despite the maintenance of axonal continuity (Lewis et al., 1982). Although the pathology of such axons is not yet certain, threshold tracking techniques have suggested that the axons might be hyperpolarized distal to the site of the block, perhaps linked to a depolarization within the lesion itself (Kiernan et al., 2002); such depolarization could favor conduction block. Whether similar mechanisms might contribute to persistent conduction block in MS currently remains unclear.

Figure 3 Computer simulations showing conduction through a focally demyelinated axon. Action potentials at nodes 1, 2, 3, the demyelinated region (DrD4), and nodes 4, 5, and 6 are shown. A high density of sodium channels (similar to the density in the nodal membrane) was built into the demyelinated part of the axon (D1-D4). (A) Even in the presence of a high density of sodium channels in the demyelinated zone, conduction can fail as a result of impedance mismatch. (B) Interposition of two short myelinated internodes, just proximal to the demyelinated zone, provides impedance matching that facilitates conduction into, and then through, the demyelinated zone. (Reproduced from Waxman and Brill, 1978.)

Figure 3 Computer simulations showing conduction through a focally demyelinated axon. Action potentials at nodes 1, 2, 3, the demyelinated region (DrD4), and nodes 4, 5, and 6 are shown. A high density of sodium channels (similar to the density in the nodal membrane) was built into the demyelinated part of the axon (D1-D4). (A) Even in the presence of a high density of sodium channels in the demyelinated zone, conduction can fail as a result of impedance mismatch. (B) Interposition of two short myelinated internodes, just proximal to the demyelinated zone, provides impedance matching that facilitates conduction into, and then through, the demyelinated zone. (Reproduced from Waxman and Brill, 1978.)

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