Getting to grips with myelin injury in progressive multiple sclerosis.

Inflammatory-mediated demyelination of the central nervous system with well-recognized axonal injury has been described for over a hundred years. Yet, many pathologic aspects of multiple sclerosis remain poorly understood (Noseworthy et al., 2000). Clinically, a high proportion of patients with relapsing–remitting disease advance to the secondary progressive stage of the disease (Lublin and Reingold, 1996). In contrast, 15% of patients never experience clinical relapses and demonstrate a steadily progressive phenotype from onset. The ability of available therapies, approved for the relapsing–remitting form of the illness, to modify the disease course in secondary or primary progressive multiple sclerosis is dismal (Compston and Coles, 2008). Paradoxically, success of the immunopathologic ‘line of thinking’ has revealed numerous deficiencies in our understanding of the neurobiology of the disease, including interdependence of the axon and oligodendrocyte (Piaton et al., 2010). At the heart of this broadening discussion of multiple sclerosis pathology is the question of what triggers disease progression and the mechanisms that lead to increased disability. One area of research germane to this question is the expansion of focal inflammatory demyelinating lesions and the remyelinating capacity of the central nervous system in progressive phenotypes, i.e. secondary and primary progressive multiple sclerosis. Extensive cortical demyelination is a cardinal feature of progressive disease and presumably the cause of many symptoms of late-stage multiple sclerosis. Axonal injury and loss occur in association with activity of the adaptive immune response, thus leading to the question as to why this inflammation is resistant to the anti-inflammatory effects of existing therapies (Kutzelnigg et al., 2005; Frischer et al., 2009). The answer may partly lie in the slowly expanding demyelinating ‘front’ and the remyelinating capacity of focal lesions in the central nervous system, although much has yet to be learned about axonal–glial interactions and the state of virtual tissue hypoxia in the central nervous system that may ultimately determine the irreversible decline seen in progressive forms of multiple sclerosis (Trapp and Stys, 2009). In this issue of Brain, Bramow and colleagues report findings from an autopsy study of 51 patients with progressive multiple sclerosis (34 secondary progressive and 17 primary progressive) and 12 matched controls (page 2983). Using planimetric analysis of paraffin-embedded archived brain and spinal cords from patients with multiple sclerosis, they performed an exhaustive histopathological study that focused on demyelination and remyelination. They examined demyelinating ‘frontlines’ as the border zone between areas of inflammatory demyelination and the surrounding white matter. However, they also describe a novel method for quantifying demyelinating plaques as ‘1st hit’ demyelination and ‘2nd hit’ demyelination. The former showed demyelinating frontlines affecting the white matter without evidence of prior deor remyelination in the surrounding white matter, whereas the latter displayed demyelinating frontlines in previously demyelinated areas that had evidence for varying degrees of remyelination. This approach allowed estimation of vulnerability to inflammatory demyelination in remyelinated areas relative to the white matter area. They further validated this complex histopathological approach by quantifying ‘1st hit’ demyelination per cm in the white matter and the number of ‘2nd hit’ demyelinating areas per cm of remyelinating area. Based on this methodology, Bramow and colleagues make five key observations: