Patients with early-stage multiple sclerosis (MS) show cortical demyelinating lesions that are numerous, inflammatory, and strongly linked with meningeal inflammation, according to a study published in the December 8, 2011, New England Journal of Medicine.
Prior research into cortical lesions has centered on autopsies of patients with a long history of chronic, progressive MS and has supported the hypothesis that these lesions are not inflammatory. However, the new study, coauthored by Claudia F. Lucchinetti, MD, Professor of Neurology at the Mayo Clinic Rochester in Minnesota, examined biopsies of cortical tissues obtained from white-matter lesions in patients with early-stage MS, all diagnosed within days or weeks of presentation.
“We found that cortical demyelination is common early in MS, and our characterization of the lesion underscored its inflammatory character. Cortical demyelination that occurs close to the onset of MS differs substantially from that seen in chronic MS,” stated Dr. Lucchinetti. “These findings do not support a primary (non-inflammatory) neurodegenerative process during early-stage MS.”
Examining Patients With Early-Stage MS
The collaborative study involved researchers at the Mayo Clinic and co-lead author Richard Ransohoff, MD, Professor of Neurology at the Cleveland Clinic, and included 563 participants who underwent white-matter biopsies, most with the intention of detecting suspected tumors that were later designated as MS.
The median age of the cohort at biopsy was 40.5, and patients were diagnosed with MS according to the McDonald or Poser criteria. Patients with other diseases of the CNS were excluded from the study.
“A separate paper is addressing the details on the clinical spectrum in the cohort,” Dr. Lucchinetti told Neurology Reviews.
Of the 563 eligible patients with MS, only 138 had enough cortex in their biopsies to allow evaluation of the prevalence and character of cortical demyelination.
The investigators used immunohistochemistry to characterize patients’ cortical lesions in four areas—demyelinating activity, inflammatory infiltrates, the presence of meningeal inflammation, and topical association between cortical demyelination and meningeal inflammation.
Identifying Demyelination and Inflammation
Overall, cortical demyelination was identified in 53 (38%) patients (104 lesions and 222 tissue blocks) of the 138 with sufficient cortex to allow analysis, and cortical demyelination was not present in 85 patients (121 tissue blocks). After undergoing long-term, comprehensive follow-up, 25 patients with cortical demyelination, as well as 33 patients without cortical demyelination, showed definite MS.
Dr. Lucchinetti’s group also looked for CD3+ T cells in 71 lesions from patients with an acceptable amount of representative tissue, and they documented perivascular CD3+ T-cell inflammation in 58 of 71 cortical plaques (82%). “Leukocortical lesions were highly inflammatory,” the researchers noted. “The majority of intracortical and subpial plaques contained perivascular CD3+ and CD8+ T-cell infiltrates.” The investigators also observed macrophage-associated demyelination in 32 of 78 lesions (41%).
Furthermore, in patients with confirmed clinically isolated syndrome (CIS) or MS, there was a strong link between meningeal inflammation and cortical demyelination. “Remarkably, there was a 90% probability that moderate-to-marked meningeal inflammation was topographically associated with cortical demyelination,” the study authors wrote.
Gray Matter Implications
MS has traditionally been viewed as a disease of the white matter, though in recent years researchers have acknowledged the role of gray matter disease as part of MS progression. However, until now, investigators had not seen strong evidence supporting the idea that the immune system plays an active role in the gray matter of patients with MS. Myelin-laden macrophages, the sign of an active plaque, were not previously observed in cortical tissue, and many researchers have viewed MS as a degenerative rather than inflammatory disease.
In an accompanying editorial, Peter A. Calabresi, MD, Professor of Neurology at the Johns Hopkins School of Medicine in Baltimore, called the findings “provocative” and said that they “provide definitive evidence that inflammatory disease of the gray matter commences early in the pathogenesis of some cases of MS.”
The results enhance the understanding of MS as an inflammatory disease, which might allow researchers to explore different treatment approaches, according to Dr. Calabresi.
“Other studies have led to the concept that the underlying substrate of permanent disability in MS is not inflammation or demyelination, both of which are potentially reversible, but rather neuroaxonal disease,” stated Dr. Calabresi. “The study by Lucchinetti et al suggests that cortical neuronal loss is directly associated with inflammatory demyelination, and therefore early therapeutic efforts to suppress inflammation may be neuroprotective in both gray-matter and white-matter compartments.”
—Lauren LeBano