Progressive multiple sclerosis: pathology and pathogenesis

Nat Rev Neurol. 2012 Nov 5;8(11):647-56. doi: 10.1038/nrneurol.2012.168. Epub 2012 Sep 25.


Major progress has been made during the past three decades in understanding the inflammatory process and pathogenetic mechanisms in multiple sclerosis (MS). Consequently, effective anti-inflammatory and immunomodulatory treatments are now available for patients in the relapsing-remitting stage of the disease. This Review summarizes studies on the pathology of progressive MS and discusses new data on the mechanisms underlying its pathogenesis. In progressive MS, as in relapsing-remitting MS, active tissue injury is associated with inflammation, but the inflammatory response in the progressive phase occurs at least partly behind the blood-brain barrier, which makes it more difficult to treat. The other mechanisms that drive disease in patients with primary or secondary progressive MS are currently unresolved, although oxidative stress resulting in mitochondrial injury might participate in the induction of demyelination and neurodegeneration in both the relapsing-remitting and progressive stages of MS. Oxidative stress seems to be mainly driven by inflammation and oxidative burst in microglia; however, its effects might be amplified in patients with progressive MS by age-dependent iron accumulation in the brain and by mitochondrial gene deletions, triggered by the chronic inflammatory process.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Animals
  • Disease Progression*
  • Humans
  • Immunologic Factors / pharmacology
  • Immunologic Factors / therapeutic use
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Mitochondria / pathology
  • Multiple Sclerosis, Chronic Progressive / etiology*
  • Multiple Sclerosis, Chronic Progressive / pathology*
  • Multiple Sclerosis, Chronic Progressive / physiopathology
  • Oxidative Stress / drug effects
  • Oxidative Stress / physiology


  • Immunologic Factors