Axonal hyperexcitability: Mechanisms and role in symptom production in demyelinating diseases

Some of the symptoms associated with demyelinating disorders are believed to originate from spurious impulses arising ectopically in axons at the site of demyelination. This review describes such "positive" symptoms and the patterns of impulses that may be associated with them, including continuous trains of impulses, as well as spontaneous and triggered impulse bursts. The mechanisms underlying the generation of such trains by individual axons are described, including the roles of sodium and potassium currents, the composition of the extracellular fluid, impulse "reflection" at demyelinated sites, and stretch-sensitive ion channels. The contribution of ephaptic transmission to symptom production and its potential role in the generation of ectopic impulses are discussed. The factors involved in the generation of massed discharges are also examined as a basis for certain paroxysmal clinical phenomena.