Greater loss of axons in primary progressive multiple sclerosis plaques compared to secondary progressive disease
1 Department of Clinical Neurology, School of Clinical Sciences, University of Nottingham, UK 2 Department of Neurology, National Competence Centre for Multiple Sclerosis, Haukeland University Hospital, Bergen, Norway 3 Department of Clinical Medicine, University of Bergen, Bergen, Norway 4 Department of Pathology, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands 5 School of Economics, University of Nottingham, UK 6 Multiple Sclerosis Centre, Vrije Universiteit Medical Centre, Amsterdam, The Netherlands 7 School of Molecular Medical Sciences, University of Nottingham, UK 8 Department of Neurology, Nottingham University Hospital NHS Trust, Nottingham, UK
Correspondence to: Nikos Evangelou, Department of Neurology, Nottingham University Hospital NHS Trust, Nottingham NG7 2UH, UK E-mail: nikos.evangelou{at}nuh.nhs.uk
The pathological substrate of progressive disability in multiple sclerosis is hypothesized to be axonal loss. Differences in the demographic, pathological and radiological features of patients with primary progressive compared with secondary progressive multiple sclerosis raise the question as to whether they actually represent separate clinical entities. So far, large pathological studies comparing axonal damage between primary progressive and secondary progressive multiple sclerosis have not been reported. In this clinico-pathological study we examined the cervical spinal cord in patients with primary and secondary progressive multiple sclerosis. Human cervical spinal cord was derived at autopsy from 54 patients (17 primary progressive, 30 secondary progressive and 7 controls). Tissue was stained immunohistochemically and examined to determine: (i) the number of surviving corticospinal tract axons; (ii) the extent of grey and white matter demyelination; (iii) the degree of inflammation inside and outside of lesions; and (iv) the relationship between demyelination and axonal loss. Associated clinical data was used to calculate expanded disability status scale for each patient preceding death. Motor disability in the primary progressive and secondary progressive groups was similar preceding death. Secondary progressive multiple sclerosis patients showed considerably more extensive demyelination of both the white and grey matter of the cervical spinal cord. The total number of corticospinal axons was equally low in primary progressive and secondary progressive multiple sclerosis groups versus controls. The reduction of axonal density in demyelinated regions compared to normal appearing white matter was significantly more extensive in primary progressive versus secondary progressive patients (33% reduction versus 16% reduction, P < 0.001). These findings suggest axonal loss is the pathological substrate of progressive disability in both primary progressive and secondary progressive multiple sclerosis with a common plaque-centred mechanism. More extensive axonal loss within areas of demyelination in primary progressive multiple sclerosis could explain high levels of axonal loss observed in these patients despite low levels of demyelination.
Key Words: multiple sclerosis; axonal loss; primary progressive; secondary progressive
Received January 27, 2009. Revised April 3, 2009. Accepted April 3, 2009.