Axonal Damage in Multiple Sclerosis
Abstract
Multiple sclerosis is a debilitating disease of the central nervous system that has been characteristically classified as an immune-mediated destruction of myelin, the protective coating on nerve fibers. Although the mechanisms responsible for the immune attack to central nervous system myelin have been the subject of intense investigation, more recent studies have focused on the neurodegenerative component, which is cause of clinical disability in young adults and appears to be only partially controlled by immunomodulatory therapies. Here, we review distinct, but not mutually exclusive, mechanisms of pathogenesis of axonal damage in multiple sclerosis patients that are either consequent to long-term demyelination or independent from it. We propose that the complexity of axonal degeneration and the heterogeneity of the underlying pathogenetic mechanisms should be taken into consideration for the design of targeted therapeutic intervention.
Multiple sclerosis (MS) is a debilitating neurological disorder of young adults with a high prevalence in North America and Europe, afflicting almost 2.5 million individuals worldwide,1,2 and with an incidence rate that continues to rise.3 Approximately 85% of MS patients begin with a relapsing-remitting (RRMS) course of the disease, characterized by clinically debilitating events followed by return to baseline.4 After a variable period of time, the majority of RRMS patients develop a secondary progressive (SPMS) form of the disease, which is characterized by persistent and progressive disease advancement without remissions.5 In a small proportion of MS patients (10%–15%), the disease advances rapidly without periods of remittance and is termed primary progressive MS (PPMS).6 Historically, axonal damage has been recognized as a histopathological hallmark of MS since the very early descriptions of the disease by Charcot in the late 1800s.7 More recent clinical, histopathological, and neuroimaging evidence has shed new light on these early findings and supported the concept that the debilitating disease course and long-term disability in MS patients was consequent to axonal loss possibly consequent to demyelination.8,9 The features of axonal damage in MS, however, were similar to those detected in other neurological diseases lacking demyelination, such as amyotrophic lateral sclerosis (ALS), and suggested the possibility that axonal damage in MS might be concurrent to demyelination, but not necessarily consequent to myelin destruction.10 This review discusses the hypothesis that axonal damage underlying the debilitating disease progression observed in MS patients may be caused by mechanisms other than long-term demyelination.
Axonal damage in multiple sclerosis might be concurrent to demyelination, but not necessarily consequent to myelin destruction.