Mechanisms of conduction block in immune-mediated polyneuropathies

Abstract

Multifocal motor neuropathy (MMN) and chronic inflammatory demyelinating polyneuropathy (CIDP) are immune-mediated neuropathies. Despite treatment being available, patients suffer from disabling weakness of arm and leg muscles and fatigue. Pathogenesis of MMN and CIDP is unclear, but the development of conduction block plays an important role. Conduction block may originate from demyelination, Na-channel damage at the node of Ranvier, and permanently changed resting membrane potential. Better understanding of underlying mechanisms is needed in the search for new targets for therapy. Two observations may point to specific mechanisms of conduction block. Cold paresis is suggested by complaints of increased weakness in cold and was only reported in single cases of MMN. Activity-dependent weakness, an abnormal increase in weakness during activity, was described in selected MMN and CIDP patients. The objective of this thesis is to further explore cold paresis and activity-dependent weakness in MMN and CIDP. Cold paresis was attributed to conduction block arising in axons affected by inflammation with permanently depolarized axons that just conduct at normal temperature, but fail to conduct at lower temperatures.We showed that MMN patients experience cold paresis more often than patients with other peripheral nervous system disorders including CIDP and progressive spinal muscular atrophy (PSMA). This supports a specific underlying mechanism in MMN, as was previously proposed. When cold paresis was objectively assessed by muscle force testing, muscle force in MMN did not decrease following cooling. This may, however, be compatible with cold paresis as normal controls showed an increase in force. As similar effects of cooling were found in MMN and PSMA, cold paresis may be related to reinnervated muscle fibers. Nerve excitability studies suggested hyperpolarization in MMN and changes following cooling similar to normal subjects in MMN and CIDP. Taken together, our findings do not clearly support the hypothesis of conduction block arising in depolarizing inflammatory nerve lesions in MMN. Activity-dependent weakness was ascribed to increased activity of the electrogenic Na/K pump causing axonal hyperpolarization, leading to conduction block in already injured demyelinated axons. We showed that MMN and CIDP patients report activity-dependent weakness more frequently than normal subjects. The fact that this was also true for patients with sporadic progressive spinal muscular atrophy (PSMA) suggests that other mechanisms, not related to demyelination cause activity-dependent weakness. Muscle strength testing during isometric maximal voluntary contraction showed that activity-dependent weakness was more prominent in MMN than in PSMA and normal controls. Activity-dependent conduction block could, however, not be demonstrated in any of 353 nerve segments in MMN and was found in only 1 out of 285 nerve segments in CIDP. Muscle contraction did induce an increase in segmental duration prolongation in segments with signs of demyelination. Taken together, our findings suggest that activity-dependent weakness in MMN is common, but it does not result from overt activity-dependent conduction block. Alternatively, it may result from temporal dispersion of nerve action potentials, impulse blocking at distal axonal motor branch points, or impulse blocking in muscle fibers