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The complex pathogenesis of multiple sclerosis includes inflammation and potentially disabling focal lesions that are associated with heterogeneous, often destructive pathologic changes disseminated throughout the white matter of the central nervous system.1 The usual pathologic changes include demyelination, some remyelination, axonal damage, and scar formation (gliosis). In recent years, researchers have refocused attention on axonal injury and its causes. Axons are damaged by bouts of autoimmune inflammation, the target of which seems to be myelin or the oligodendrocytes that form myelin.2 In addition, chronically demyelinated axons may become structurally and metabolically abnormal and vulnerable to other types of damage; gradually, they may become dysfunctional and die.

Remyelination does occur in the central nervous system,3 and it is most likely an important factor in the reestablishment of conduction in previously demyelinated axons, if the axon survives. Axonal death is permanent and is probably the chief factor in the chronic, progressive neurologic disability that occurs in patients with multiple sclerosis.

The report in this issue of the Journal by Chang and colleagues4 focuses on the oligodendrocytes and their precursors in lesions of multiple sclerosis. Using immunohistochemical staining and confocal microscopy, these investigators have visualized oligodendrocyte precursors5 and mature oligodendrocytes in three dimensions. These types of cells were numerous in the lesions examined. Oligodendrocyte precursors were present more often in the lesions of patients with disease of short duration than in the lesions of those with long-standing disease. In lesions that did not show remyelination, processes from premyelinating oligodendrocytes seemed to be interacting with naked axons that looked dystrophic, but these oligodendrocytes did not appear to produce myelin. Mature oligodendrocytes were seen in lesions that did not show evidence of remyelination.

Premyelinating oligodendrocytes were not seen in the chronic lesions with remyelination. Chang et al. conclude that since oligodendrocytes and premyelinating oligodendrocytes can be found in lesions of multiple sclerosis that do not show remyelination, remyelination is not limited by the depletion of oligodendrocytes within the lesions. The authors suggest that the limiting factor may be that the chronic lesions of multiple sclerosis are not receptive for remyelination, perhaps because of dystrophic changes in the axons.

These findings are important to an understanding of the remyelination of lesions of multiple sclerosis and imply that transplantation of oligodendrocyte precursor cells will probably not be an effective therapy for multiple sclerosis. Rather, if the controlling factors can be identified, the stimulation of remyelination in vivo could help to reestablish functioning in recently demyelinated axons.

This issue of the Journal also includes an important report by Brex et al.6 about research on multiple sclerosis from the National Hospital for Neurology and Neurosurgery in London. These researchers have been using magnetic resonance imaging (MRI) to study the progression of lesions. Specific lesions were identified on MRI, measured, and then followed to assess the evolution of the abnormalities.1

One research project followed a cohort of patients who were first seen between 1984 and 1987 with initial symptoms suggestive of multiple sclerosis or with isolated syndromes such as optic neuritis. MRI and clinical evaluations were performed at the time of enrollment and 5,7,8 10,9 and now 146 years later. It is clear from these careful studies that the presence of lesions of multiple sclerosis on MRI at the onset of symptoms of multiple sclerosis and the changes on MRI over time have predictive value. The correlations were strongest at 5 years but were still present at 14 years. The number and extent of the lesions, especially in the early years, were significant predictors of prognosis. According to the correlation coefficients, the extent and number of lesions on T2-weighted MRI account for 37 percent of the clinical disability at five years as measured by the Expanded Disability Status Scale (EDSS), which tends to neglect cognitive and emotional changes due to multiple sclerosis and, therefore, employability.10 Fourteen years after presentation, almost all the patients who had an abnormality on the initial MRI study had had a second attack and had clinically definite multiple sclerosis; the results on MRI at onset have implications for long-term follow-up.

With the advent of disease-modifying drugs, multiple sclerosis can now be treated with a moderate effect.11 However, the opportunity for effective treatment may be greatest if patients are treated at the very earliest stages, when inflammation predominates and before substantial, irreversible axonal loss occurs.12,13 Treatment may also be more effective at an early stage because focal inflammatory abnormalities may be more important determinants of disability in the early stages of the disease.

Efforts to stimulate reparative processes such as remyelination also seem to have the best chance of success in the initial stages of disease. New diagnostic criteria should facilitate the early, accurate diagnosis of multiple sclerosis.14 Advances in imaging (including both confocal microscopy and MRI) and immunohistochemical techniques, together with systematic follow-up of patients, have provided important insights into the evolution of the pathologic process in multiple sclerosis. Such studies will permit a better understanding of the impact of disease-modifying drugs on specific abnormalities in multiple sclerosis and, along with clinical examination, will provide more insight into the evolution and prognosis of the disease.

Both studies in this week's issue4,6 make important contributions to the understanding of this enigmatic disease, which brings together the sciences of autoimmune inflammation, virology, genetics, neurology, and sophisticated imaging techniques. Future directions will include further clarification of the specific pathologic changes that occur in patients with multiple sclerosis, in order to have a better understanding of the origins of neurologic disability (including cognitive disability). We need information to design immunomodulatory therapies that will be specific to particular pathologic changes. The presence of axonal injury and the inhibition of remyelination early in the disease suggest that strategies to enhance neuroprotection and remyelination may also have an important place in future therapies for multiple sclerosis, particularly if they are used in the early phases.

Donald W. Paty, M.D.

Vancouver Hospital

Vancouver, BC V6T 2B5, Canada

Douglas L. Arnold, M.D.

Montreal Neurological Hospital

Montreal, QC H3A 2B4, Canada

References

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12.Jacobs LD, Beck RW, Simon JH, et al. Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. N Engl J Med 2000;343:898-904.[Abstract/Full Text]

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14.McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121-127.[Medline]