The accumulation of irreversible impairment and disability in MS is believed to occur via two mechanisms. Attack-related disability may occur in patients with relapsing MS (i.e., RRMS or SPMS with ongoing exacerbations). Although most MS patients recover after an exacerbation, some may experience a step-wise decline in neurologic function. In one study, approximately 40% of patients had residual deficit of at least 0.5, and 28% had residual deficit of >1 expanded disability status scale (EDSS) units on an average of 64 days after an exacerbation, suggesting that MS exacerbations produce a measurable and sustained effect on disability (76). On the other hand, progression-related disability may occur in patients with progressive forms of the disease (i.e., PPMS or SPMS with or without superimposed exacerbations) and is characterized by gradual decline in neurologic function that occurs independent of clinical exacerbations or MRI evidence of lesion activity.
Both relapse-related and progression-related disabilities may eventually lead to permanent neurological impairment; however, the pathologic mechanisms leading to this irreversible disability may be different. Furthermore, a complex relationship exists between inflammatory demyelination and neurodegeneration in MS. To what extent these pathologic processes may occur independent of one another must be clarified in order to develop effective therapeutic strategies that limit the accumulation of disability in MS. Pathological, clinical, experimental, and neuroimaging studies provide important clues, which may help dissect this complex relationship.
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