Outcome Measures Used to Measure MS Disease Severity

Magnetic resonance imaging (MRI) is a sensitive tool for measuring MS pathology in vivo. Lesions on T2-weighted and contrast-enhanced Tj-weighted MRIs are used routinely as indicators of disease activity for diagnosis and to measure the effects of therapeutic intervention. However, gadolinium-enhanced lesions and T2 lesions reflect pathological processes that are potentially reversible and reflect variable amounts of tissue injury. Furthermore, lesion measurements fluctuate over time and do not account for diffuse pathology in the normal-appearing white matter. These factors limit the usefulness of conventional lesion measurements. MRI measures are needed that more reliably reflect progression of MS. One straightforward approach is the estimation of atrophy of CNS structures. In contrast to lesions, atrophy reflects the end result of destructive, irreversible pathological processes operant in MS patients. Axonal loss, demyeli-nation, and gliosis may result in reduced volume of CNS parenchymal tissue and a corresponding increase in the volume of cerebrospinal fluid (CSF) spaces. Although loss of CNS tissue is not specific to the underlying pathology in MS patients, it is likely to reflect axonal pathology, simply because axons contribute a large proportion of normal parenchymal volume (Fig. 1).

Brain atrophy was generally mentioned but not emphasized in early descriptions of MS pathology. Historically, it was associated with late stages of MS, but this may be an artifact of the nature of cases coming to autopsy. In a chapter on the pathological features of MS, John Prineas (1990) commented, "Inspection of coronal slices of the fixed brain in patients with severe long-standing disease will usually show some ventricular enlargement, which may be marked." There is no discussion of the pathological evolution of this change.

Computed tomography (CT) scanning was the first informative in vivo imaging modality used for MS. In the first reported series of MS cases using CT scanning, brain atrophy was noted in 4 of 19 patients with MS (Cala and Mastaglia, 1976). The application of MRI to patients with MS was first reported 5 years later (Young et al., 1981). MRI detected many more brain lesions than did CT scanning, and it was immediately apparent that MRI would supersede CT scanning for this disease because of its sensitivity in detecting brain lesions.

Nearly all of the early MRI literature on MS focused on the highly conspicuous T2 bright parenchymal lesions. In 1987, however, Simon and colleagues published an impor-

Figure I Proportion of normal adult CNS contributed by CNS components. Axons constitute about 46% of brain volume; myelin 24%. (Modified from Esiri (in Miller et al. 2002.))

tant early MRI study of CNS atrophy in patients with MS (Simon et al., 1987). Atrophy affecting the corpus callosum was quantified by measuring the callosal area in the midsagittal plane in 41 patients with definite MS and 48 controls with normal MR scans. Mean midsagittal callosal area was significantly higher in the brains of the control patients compared with the patients with MS.The degree of corpus callosum atrophy paralleled estimated volumes of periventricular and corpus callosum T2-hyperintense lesions, suggesting a possible cause-effect relationship. This study suggested that atrophy was much more prevalent than previously thought, and led to a prospectively defined study, which was incorporated into a clinical trial of interferon P-1a (IFNP-1a, Avonex) initiated in 1989 (Jacobs et al., 1996). Patients in that study were relatively early in the course of MS, with average age of 36 years, average disease duration of 6 years, and mild to moderate disability. Significant increases were detected in third ventricle width at year 2 and lateral ventricle width at years 1 and 2; significant decreases were observed in corpus callosum area and brain width at 1 and 2 years (Simon et al., 1999). Regression analyses showed that the number of gadolinium-enhancing lesions at baseline correlated significantly with change in third ventricle width. Greater disability increments over 1 and 2 years were associated with more severe third ventricle enlargement. This study generated considerable interest when it was presented at the American Academy of Neurology in 1996, because it clearly documented that progressive brain atrophy occurred much earlier in the course of MS than generally appreciated. The study focused attention on brain atrophy as an important measure of the disease process.

By the end of the 1990s, groups from around the world were working on methods to quantify CNS atrophy in MS, and reports were appearing at an increasing rate in the literature. As a result, an international workshop was convened in London, England, in November 2001. At that workshop, it was noted that atrophy was an attractive disease measure because it reflected a global marker of the adverse outcome of MS pathology. The workshop attendees reached the consensus that atrophy in MS probably reflects both inflammation-induced axonal loss followed by wallerian degeneration and postinflammatory neurodegeneration that may be partly due to failure of remyelination. It was concluded that "atrophy provides a sensitive measure of the neurodegenerative component of multiple sclerosis and should be measured in trials evaluating potential anti-inflammatory, remyelinating or neuroprotective therapies" (Miller et al., 2002).

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