Enhancing Our Understanding of Multiple Sclerosis: Tracking Contrast-enhancing Plaques with MR Imaging

Contrast enhancement in the brain of patients with multiple sclerosis (MS) is known to be very sensitive in detecting acute, inflammatory MS plaques. It has been reported that contrast-enhanced MR imaging shows active new lesions four to 10 times more frequently compared with clinically defined relapses. Despite this, there is a paucity of literature on the natural history of enhancing new brain lesions. Thus, the expected time course of development and subsequent regression of enhancing plaques is poorly understood. In the report by He and colleagues in this issue of the AJNR (page 662), the researchers attempt to broaden our understanding of the longitudinal evolution and morphology of enhancing MS plaques. But, why is it important to understand the natural history of contrast-enhancing lesions?

The presence of enhancing lesions in the brain of patients with MS has great significance for several reasons. First, in the imaging evaluation of patients presenting with symptoms for the first time, the presence of an enhancing new lesion may help to establish dissemination of lesions in time; a major criteria for diagnosis of MS. Tracking of enhancing lesions over time may also help to document disease activity and thus, aid in treatment planning or in determining response to therapy. Contrast-enhanced lesions can also help in diagnosing the most likely etiology when the imaging appearance is ambiguous, such as when there is a question between possible tumor versus a tumefactive MS lesion. In the latter example in particular, knowledge of the expected time of resolution of enhancement is of primary importance. Finally, contrast-enhanced MR imaging provides a major focus of analysis for testing of new drugs or other proposed new therapies for MS. In fact, the United States Multiple Sclerosis Society Task Force has recommended that T2-weighted and contrast-enhanced T1-weighted sequences be used as primary measures of efficacy in clinical treatment trials of new MS therapies because of the documented sensitivity of these techniques for showing progression of structural brain disease in MS (1).

He and colleagues report their analysis of a retrospective series of 25 patients in whom they identified 301 new enhancing lesions. Of these lesions, 93% disappeared within 6 months. Only seven lesions (2.3%) showed persistent enhancement in excess of 6 months. Time course analysis in the remaining 4.7% of enhancing lesions was deemed indeterminate, because the follow-up interval between successive scans was greater than 6 months. Thus, the authors conclude that enhancement in MS plaques resolves within 6 months in the overwhelming majority of lesions. This is potentially important documentation and supports observations from several prior reports. However, these results should be scrutinized carefully. From a casual reading of this report, one might infer that the overwhelming majority of enhancing MS plaques persist for a prolonged period, up to 6 months, before normalizing. But is this really the case?

The present study does not evaluate a sufficient number of time points between onset of enhancement and 6 months to determine how many plaques resolve in less than 6 months. To try to address this important question one must refer to other reports from the literature. Studies by McFarland et al (2) and Simon et al (3) (both of which He and colleagues also reference in their report) have suggested that most enhancing MS lesions in the brain characteristically undergo more rapid changes over periods of days to weeks. This time course and pattern fits with our clinical experience and implies that one can generally use a relatively short follow-up interval of 4 to 6 weeks to look for resolution or significant decrease of enhancement in questionable cases of MS. In a study by Smith et al (4), approximately 75% of enhancing lesions disappeared in less than 1 month, whereas 20% continued to enhance for greater than 1 month. Only a small minority (5%) showed persistent enhancement at 3 to 4 months. It must be pointed out that He does address this more rapid evolutionary time course of enhancing plaques and cites the study by Harris et al (5) in their discussion that showed 95% of new enhancing lesions normalized within 8 weeks of onset. My concern is that this fact might be overlooked by a casual reading of He et al's report, which emphasizes the smaller proportion of enhancing plaques that persist. Additionally, in this same series reported by Harris et al, no lesions continued to enhance after 16 weeks. Therefore, I do agree with the present report that it is important to document the fact that there is a measurable (although a minority) number of patients who demonstrate persistent contrast enhancement up to and, on rare occasions, in excess of 6 months.

Because of the broad range of time intervals and variable numbers of sequential MR images used in many MS studies, the statistics can often be confusing. This is not necessarily the fault of the authors, however. Nearly all of the studies on which these natural history statistics are based are retrospective in nature. Detection of enhancing lesions in MS is both technique- and dose-related. In many studies, including this one, there has not been a prospective attempt to incorporate natural history analysis and time course of enhancement in the study design. Thus, they lack uniformity in the intervals between successive MR imaging studies. There may also be great variability in the MR imaging techniques, in the patient population selection (relapsing remitting disease versus secondary progressive disease versus primary progressive MS), and in the contrast dose and the time interval between injection and imaging. The most valuable data regarding natural history of enhancing lesions as well as of T2 lesions comes from the early studies evaluating new drug therapies, including interferon beta-1b and interferon beta-1a. These were performed with rapid serial imaging in placebo-controlled (ie, untreated) patient populations. It is unlikely that new natural history studies of enhancing plaques in untreated MS patients will be done since there are now multiple FDA-approved drug regimens available for treatment of MS. Many appear efficacious, and it would therefore be unjustified and unethical to withhold treatment to perform such a study.

Thus, in view of the constraints that limit our ability to analyze the natural time course of contrast enhancement, this study does provide important documentation and useful information about resolution of contrast enhancement in MS plaques. This is a time-consuming study involving retrospective review of 140 MR examinations with many unavoidable variables and tracking of over 300 new enhancing lesions across serial studies. He and colleagues are to be commended for performing their retrospective analysis.

It is also important to emphasize another major point that He et al make in their report. Namely, that one must be aware that lesion activity and progression of MS disease are not limited to definition of contrast enhancement. Despite the fact that enhancing MS plaques are sensitive in detecting new, active lesions and form a major imaging marker for determining response to therapy or efficacy of new drugs; much activity is taking place that is not necessarily defined by enhancement alone. Although not perfect, contrast-enhanced MR imaging is still very valuable as a diagnostic tool and is far more sensitive than is the clinical examination alone in defining disease activity and predicting progression. Nevertheless, the clinical radiologist should understand the limitations and controversies surrounding enhancing lesions. Studies have shown good correlation between presence and number of enhancing lesions and the occurrence of clinical relapse. However, other studies have shown weak correlation between enhancing lesions and disability or impairment at 1 and 2 years as measured by Expanded Disability Status scores (6). Thus, studies of T2 lesion burden, magnetization transfer changes, and MR spectra remain important research tools that are essential for continuing our understanding and evaluation of multiple sclerosis.