A4 Multiple sclerosis (demyelination)

Topic

Central nervous system axons conduct electrical signals thanks to the myelin sheath that coats them. In multiple sclerosis, the immune system mistakenly attacks this myelin sheath; this autoimmune attack directly alters the axon's conduction parameters—specifically, the parameters describing signal propagation along the axon (as defined by the axon's cable model) and the myelination curve (which quantifies the myelin coverage).

This immune activity against the axonal myelin sheath is not constant but fluctuating: it generates episodes of active demyelination—during which the axon rapidly loses myelin—alternating with episodes of partial remyelination, where the axon regains some, but not all, of the lost myelin. This alternation between active demyelination and partial remyelination produces the characteristic clinical pattern of multiple sclerosis, featuring flare-ups of worsening symptoms followed by partial remissions.

Whenever an axon loses myelin during an episode of active demyelination, two simultaneous changes occur: the axon's saltatory conduction velocity decreases—because the signal can no longer "jump" as efficiently between the remaining myelinated segments—and the effective capacitance of the axonal membrane increases, as the loss of myelin exposes the membrane to the electrical charge it must now handle. The more myelin the axon loses, the lower its saltatory conduction velocity and the higher its membrane's effective capacitance; together, these changes reduce the axon's propagation safety factor—the same safety factor defined in the axon's cable model. When the axon's propagation safety factor falls below unity, the axon can no longer propagate the electrical signal from one end to the other, resulting in conduction block in that segment of the axon. As long as the axon's safety factor remains above that threshold, the axon continues to conduct the signal—albeit more slowly than before; it is only when that threshold is crossed downwards that axonal conduction is completely interrupted.

Furthermore, each episode of active demyelination and each instance of conduction block leaves behind cumulative axonal damage that is not always reversed by subsequent partial remyelination. The more axonal damage accumulates over time, the greater the clinical disability exhibited by the patient—a progressive disability that is assessed here using a clinical disability scale; the final state of the axon, measured as cumulative damage, ultimately determines the extent to which the person affected by multiple sclerosis can move, feel, or function.

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