Elsevier

The Lancet Neurology

Volume 5, Issue 2, February 2006, Pages 158-170
The Lancet Neurology

Review
The measurement and clinical relevance of brain atrophy in multiple sclerosis

https://doi.org/10.1016/S1474-4422(06)70349-0Get rights and content

Summary

Brain atrophy has emerged as a clinically relevant component of disease progression in multiple sclerosis. Progressive loss of brain tissue bulk can be detected in vivo in a sensitive and reproducible manner by MRI. Clinical studies have shown that brain atrophy begins early in the disease course. The increasing amount of data linking brain atrophy to clinical impairments suggest that irreversible tissue destruction is an important determinant of disease progression to a greater extent than can be explained by conventional lesion assessments. In this review, we will summarise the proposed mechanisms contributing to brain atrophy in patients with multiple sclerosis. We will critically discuss the wide range of MRI-based methods used to quantify regional and whole-brain-volume loss. Based on a review of current information, we will summarise the rate of atrophy among phenotypes for multiple sclerosis, the clinical relevance of brain atrophy, and the effect of disease-modifying treatments on its progression.

Section snippets

Historical background

Brain-volume loss was reported as a component of multiple sclerosis in early descriptions of the pathology. In 1938, Robert Carswell discussed multiple sclerosis in an article on atrophy in his Atlas of Pathology.1 In 1963, German pathologist Eduard Rindfleisch reported focal atrophy of brain tissue in his description of the perivascular nature of multiple sclerosis lesions.2 With advances in technology,3 structural neuroimaging provides increasingly sensitive methods of monitoring brain

Pathogenesis

Although brain atrophy is probably an endpoint of irreversible tissue loss in multiple sclerosis, it is not pathologically specific. The underlying mechanisms for brain atrophy are diverse and complex. Some proposed mechanisms are directly related to the multifocal inflammatory disease process, whereas others are indirectly related to or are independent from traditional measures of overt lesions.9

Qualitative measures

Clinically, brain atrophy can be identified from qualitative images by the recognition of an increase in cerebrospinal fluid spaces or a reduction in size of parenchymal structures compared with the normal appearance for age (figure 4). Upon review of serial studies, progressive atrophy can be detected by comparison of images (figure 5). Such relatively simple determinations are easy to implement in routine patient care or for semiquantitative analysis,44 and can help to assess disease severity

Clinically isolated syndrome

There is increasing evidence that brain atrophy is not restricted to the later progressive stages, but begins in the earliest stages of multiple sclerosis.6 In patients with clinically isolated demyelinating syndrome, whole-brain atrophy is detectable in those who go on to develop multiple sclerosis.86, 87 Patients who meet the international panel criteria for multiple sclerosis88 (but who have had only a single demyelinating event) had detectable ventricular enlargement over the subsequent

Physical disability

Lesion-load measures on MRI are associated only weakly with physical disability in cross-sectional studies, which has led to the traditional “clinical-imaging paradox” of multiple sclerosis.105 Lesions can appear on MRI without any progression in physical disability, and conversely, patients can progress in disability without the appearance of new lesions. Whole-brain atrophy has a stronger, yet moderate, imaging association with physical disability, and is a stronger predictor of future

Effect of technical or other factors on volume measurement

A prerequisite for the use of brain volume as a surrogate marker for irreversible tissue damage and neurodegeneration in patients with multiple sclerosis is the need to understand the potential effect of other factors such as MRI-related technical error and biological factors that can affect brain volume independent of tissue destruction.

Effect of disease-modifying treatments

Brain atrophy, because of its clinical relevance and ability to serve as a sensitive, reproducible quantitative measure of irreversible tissue destruction, is now commonly used as a secondary therapeutic outcome measure in clinical trials for multiple sclerosis.5, 136

Conclusions

Brain atrophy has emerged as a clinically relevant component of the multiple sclerosis disease process. Progressive loss of brain tissue bulk can be identified in-vivo in a sensitive and reproducible manner by MRI. Brain atrophy begins early in the disease course. The increasing amount of data linking brain atrophy to clinical impairments suggest that irreversible tissue destruction is a major determinant of disease progression to a greater extent than can be explained by conventional lesion

Search strategy and selection criteria

References for this review were identifed by searches of PubMed from 1985 to October 2005 with the terms “brain atrophy” or “spinal cord atrophy” and “multiple sclerosis”. Articles resulting from that search as well as references cited in those articles were considered for this review of brain atrophy. Articles were also identifed through searches of the authors' own files. Only papers published in English were reviewed.

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