Figure 5. Overview of the pathological mechanisms in MS that might contribute to sodium MRI signal elevation in acute lesions.

The pathogenesis of MS involves a cascade of pathological events, including focal lymphocytic infiltration, microglia and macrophage activation, demyelination, and axonal degeneration². Na_v1.6 is the predominant sodium channel expressed in microglia and macrophages, and is up regulated upon activation of these cells in EAE and acute MS lesions³⁵,³⁶. Activated microglia and macrophages produce reactive-oxygen species⁴ and nitric oxide³ and thus induce mitochondrial dysfunction in neurons³⁷,³⁸ with subsequently reduced energy supply. Concurrently, re-distribution of Na_v1.6 along demyelinated axons in EAE³¹ and acute MS lesions¹¹ increases energy demand. The mismatch between reduced energy supply and elevated demand creates a virtual hypoxia³⁹, which also impairs the sodium-potassium pump⁹, and leads to an intracellular accumulation of sodium ions¹². This ionic imbalance promotes the sodium-calcium exchanger to operate in reverse¹³. Consecutive calcium import leads to injurious intracellular calcium levels with deleterious sequelae to the neuron⁹. Mechanisms of MS associated with intracellular sodium accumulation that possibly contribute to elevated average and fluid-attenuated sodium MRI signals are marked in blue. Also, hyper-cellularity itself might cause an increased fluid-attenuated signal. In fact, it may well be that both, intracellular sodium accumulation and hyper-cellularity contribute to the increased sodium signals observed in acute MS lesions as both are part of the same pathophysiologic mechanism.