MS Relapses (Continued)

Clinical Features of an MS Relapse: Events during the clinically apparent phase of a relapse, as with its prelude, involve a series of steps.

STEP SIX

Conduction Block. The symptoms of a relapse begin as CD4⁺ T_E cells and macrophages move across the GL into the CNS parenchyma. MS relapses include inflammation, demyelination and reactive changes in astrocytes within MS plaques. The inflammatory infiltrate that was formerly purely perivascular now becomes largely intraparenchymal. Tissue-invading T cells, macrophages, and newly activated CNS-resident microglial cells release multiple proinflammatory cytokines, glutamate, reactive oxygen and nitric oxide intermediates, other free radicals, and proteolytic enzymes, including MMPs. Collectively, these elements damage axons as the initial clinically relevant event of an MS relapse. Early toxic damage is centered on nodes of Ranvier and abutting paranodes, with morphologic changes that provide markers of compromised axonal function. The initial event is a disruption of the coupling of glial end foot NF155 to axonal CASPR at the paranode with retraction of the end feet and their separation from one another. This is followed by an uncoupling of nodal Na_v1.6 sodium channels from their anchoring NF186. Saltatory conduction requires a complete separation of nodal sodium channels from juxtaparanodal potassium channels. As these channels intermingle nerve impulse conduction fails. Calcium entry at the node causes nodal swelling and axoplasmic flow ceases. This can be readily recognized by the development of amyloid precursor protein (APP)- containing spheroids that accumulate at those nodes of Ranvier where axoplasmic flow has been interrupted. Such spheroids are seen at sites of irreversible axonal severing, but only some axons that develop spheroids are doomed. As axoplasmic flow recovers, spheroids may regress and axonal conduction of nerve impulses may resume.

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