From enhancing lesions to brain atrophy in relapsing MS

https://doi.org/10.1016/S0165-5728(99)00075-2Get rights and content

Abstract

Based on observations from MR imaging studies, the natural history of the MS lesion appears to be progression from an acute enhancing lesion, corresponding to the early inflammatory stage, with evolution to a chronic T2 hyperintense lesion, which is the non-specific `footprint' of the prior event. In addition to accumulation of these relatively non-specific lesions, we find in longitudinal evaluations that patients with only mild to modest disability are already developing significant cerebral atrophy. Atrophy, particularly that resulting from volume loss around the third ventricle, appears to be predicted by the presence of prior temporally and anatomically distant enhancing lesions. One can speculate that the initial enhancing-inflammatory lesion events in the brain, place into motion, at an early stage, the processes that ultimately lead to cerebral atrophy, and these processes may include early axonal injury.

Introduction

Magnetic resonance (MR) imaging and spectroscopy studies have made important contributions to our understanding of the events in the brain that occur as a result of multiple sclerosis (MS). Longitudinal study designs in particular have been especially important in clarifying the course and tempo of events, based on the perspective of the individual enhancing MS lesion, and dynamic changes affecting the brain in general, such as the accumulation of the T2 hyperintense (T2) lesion load over time.

The purpose of this discussion is to review the natural history of events in the brain observed in an untreated population of patients with relapsing MS—with emphasis on the relationships between several MR-based measures of disease, and the development of cerebral atrophy. With an understanding of the natural history of MS-related events in the brain, it has become feasible to evaluate several factors that may become important in predicting the course and prognosis of the disease.

Section snippets

The natural history of MS by MR imaging

Longitudinal MR studies reveal that subsequent to the first appearance of the acute, enhancing MS lesion in the brain, the lesion undergoes a series of relatively characteristic changes over periods of days to months. The acute lesion in relapsing and/or progressive MS has a leaky blood–brain barrier, and as a result shows contrast enhancement on T1-weighted MR imaging after intravenous administration of gadolinium-chelate (Simon, 1997). Correlative studies show that these contrast enhancing

Methodology

Details of the MSCRG trial design and primary outcomes have been reported (Jacobs et al., 1995, Jacobs et al., 1996). All patients had relapsing MS, and prior to entrance had had at least two exacerbations over the previous 3 years. By protocol, the last exacerbations were required to have occurred at least 2 months prior to study entry. High field MR studies of the brain were acquired at baseline and at 1 and 2 years after treatment initiation. These included 5-mm thick sagittal T1-weighted

Results

Because of the known intra-individual variation in enhancing lesions seen on monthly MR imaging studies (McFarland et al., 1992), strong relationships at a single observation in time between enhancing lesions and T2 lesion loads were not originally anticipated. However, we did observe a modest correlation between enhancing lesions and T2 lesion load (r=0.43; p<0.001) on the baseline studies. Fig. 1 shows that there is, in fact, a reasonably strong relationship between the T2 lesion volume that

Discussion

The natural history of the MS lesion in the brain based primarily on MR imaging and neuropathology studies is now understood to include evolution from an acute inflammatory lesion, with blood–brain barrier disruption as indicated by gadolinium-enhancing lesions, to relatively stable, smaller lesions with variable amounts of tissue damage. Over time, multiple independent attacks result in progressive increases in the overall lesion load in the brain and spinal cord. T2 lesion load increases are

Acknowledgements

This work was supported by National Institutes of Health, NINDS grant RO1-26321 and by Biogen, Cambridge, MA. The author wishes to acknowledge the invaluable contributions of the MSCRG collaborators, including Lawrence Jacobs, Richard Rudick, Robert Herndon, Andres Salazar, John Richert, Diane Cookfair, Jill Fischer and including the special efforts in statistical analysis and guidance provided by Marilyn Campion, Karl Wende and Anna Martens-Davidson.

References (37)

  • C Pozzilli et al.

    Anterior corpus callosum atrophy and verbal fluency in multiple sclerosis

    Cortex

    (1991)
  • C Pozzilli et al.

    Relationship between corpus callosum atrophy and cerebral metabolic asymmetries in multiple sclerosis

    J. Neurol. Sci.

    (1992)
  • F Barkhof et al.

    Relapsing–remitting multiple sclerosis: sequential enhanced MR imaging vs. clinical findings in determining disease activity

    AJR

    (1992)
  • R.O Barnard et al.

    Corpus callosum in multiple sclerosis

    J. Neurol. Neurosurg. Psychiatry

    (1974)
  • D Barnes et al.

    The long-standing MS lesion: a quantitative MRI and electron microscopic study

    Brain

    (1991)
  • W Bruck et al.

    Inflammatory central nervous system: correlation of magnetic resonance imaging findings with lesion pathology

    Ann. Neurol.

    (1997)
  • C.A Davie et al.

    Persistent function deficit in multiple sclerosis and autosomal dominant cerebellar ataxia is associated with axon loss

    Brain

    (1995)
  • N DeStefano et al.

    Chemical pathology of acute demyelinating lesions and its correlation with disability

    Ann. Neurol.

    (1995)
  • J.L Dietemann et al.

    Multiple sclerosis and corpus callosum atrophy: relationship of MRI findings to clinical data

    Neuroradiology

    (1988)
  • M.L Estes et al.

    Stereotactic biopsy of an active multiple sclerosis lesion. immunocytochemical analysis and neuropathologic correlation with magnetic resonance imaging

    Arch. Neurol.

    (1990)
  • M Filippi et al.

    A spinal cord MRI study of benign and secondary progressive multiple sclerosis

    J. Neurol.

    (1996)
  • A Gass et al.

    Correlation of magnetization transfer ratio with clinical disability in multiple sclerosis

    Ann. Neurol.

    (1994)
  • S.J Huber et al.

    Magnetic resonance imaging correlates of dementia in multiple sclerosis

    Arch. Neurol.

    (1987)
  • Interferon beta-1b is effective in relapsing–remitting multiple sclerosis: I. Clinical results of a multicenter, randomized,double blind, placebo-controlled trial

    Neurology

    (1993)
  • Interferon beta-1b in the treatment of multiple sclerosis: final outcome of the randomized controlled trial

    Neurology

    (1995)
  • L.D Jacobs et al.

    A phase III trial of intramuscular recombinant interferon beta as treatment for exacerbating–remitting multiple sclerosis: design and conduct of study and baseline characteristics of patients

    Mult. Scler.

    (1995)
  • L.D Jacobs et al.

    Intramuscular interferon beta-1a for disease progression in relapsing multiple sclerosis

    Ann. Neurol.

    (1996)
  • K.P Johnson et al.

    Copolymer I reduces relapse rate and improves disability in relapsing–remitting multiple sclerosis: results of a phase III multicenter, double blind, placebo-controlled trial

    Neurology

    (1995)
  • Cited by (63)

    • MRI outcomes in the diagnosis and disease course of multiple sclerosis

      2014, Handbook of Clinical Neurology
      Citation Excerpt :

      Contrast-enhancing lesion number also predicts T1 black hole volume in subsequent years (Simon et al., 2000a, b; Morgen et al., 2005). Although the relationship between enhancing lesions and brain atrophy is weak over short intervals (Rudick et al., 1999; Simon, 1999; Simon et al., 1999), correlations become stronger over longer intervals. It is now recognized that impact of treatment on relapses correlates well with impact on enhancement (Sormani et al., 2009; Sormani and Bruzzi, 2013).

    View all citing articles on Scopus
    View full text