Cortical demyelination and diffuse white matter injury in multiple sclerosis
Kutzelnigg A, Lucchinetti CF, Stadelmann C, Bruck W, et al. ;
Commented by , 22 Nov 2005
Background
Multiple sclerosis (MS) pathology has classically been ascribed to focal changes affecting myelinated white-matter CNS axons. MRI and necropsy studies have shown that diffuse degenerative processes are present in normal appearing white matter (NAWM), and gray matter also seem to be extensively involved.
It has been discussed whether the extent of diffuse CNS pathology actually determines disease course and outcome in MS.
Aim
To describe the neuropathological changes in MS patients with acute (AMS) relapsing remitting (RRMS), secondary progressive (SPMS) and primary progressive (PPMS) disease course.
Methods
The authors used archival formalin fixed and paraffin embedded autopsies from 52 MS cases (11 AMS, 6 RRMS, 15 PPMS and 20 SPMS), 15 cases of advanced Alzheimer’s disease and 15 normal controls. The samples were analyzed using a quantitative morphological technique without knowledge of the clinical data.
The area and characteristics of white matter lesions (WML) was determined, as well as inflammatory changes in NAWM, perivascular inflammatory infiltrates, axonal injury (spheroids), evaluation of macrophage and microglia activation.
Results
- Active white matter lesions were mainly present in patients with AMS and RRMS, whereas cortical demyelination was a characteristic feature of SPMS and PPMS.
- Cortical demyelination primarily affected the subpial layers in association with inflammation of the meninges.
- Diffuse mild inflammation was found in NAWM of patients with SPMS and PPMS, associated with microglia activation, which was much less pronounced in AMS and RRMS cases (p=0.003).
- Diffuse axonal damage was most prominent in NAWM of progressive MS (p<0.001).
- There was a significant correlation between cortical demyelination and global inflammation, as well as microglia activation in NAWM (p=0.001), a weak correlation between demyelination of white matter and diffuse NAWM inflammation (p=0.01), and no correlation between white matter lesion load and microglia activation or axonal injury.
Dr Blinkenberg's comments
The authors present data that histologically may distinguish acute and relapsing MS from progressive disease. These data suggest that MS start as a focal inflammatory disease, which slowly become compartmentalized in the CNS, giving rise to widespread diffuse neurodegeneration, characterized by axonal injury in the NAWM and cortical demyelination.
Although distinct pathological patterns of focal plaques, and diffuse white or gray matter changes may develop independently, the authors argue for a common stage dependent pathogenetic pathway.
The study is unique, since it describes a dynamic pathological process in MS as such, and furthermore generate a hypothesis incorporating knowledge of MS pathology, which has been published during the last decades.
It supports the notion that the diffuse, and especially cortical pathological changes, determine disease progression.
The results have important clinical relevance, since they substantiate the rationale for intervention and modulation of disease activity in the early, and pathologically focal, inflammatory stage of the disease
This should theoretically delay the compartmentalization of the disease and the following chronic progression.
In the progressive and pathologically diffuse stage of MS, neurodegeneration occurs without prominent inflammation, which may explain why immunomodulatory treatment (beta-interferon or glatiramer acetate) has no detectable effect. These processes are unfortunately still poorly characterized.