Guidelines for the use of magnetic resonance techniques in monitoring the treatment of multiple sclerosis

Abstract

Because of the major difficulties in measuring clinical end points in multiple sclerosis (MS) treatment trials, there has been much enthusiasm for using magnetic resonance imaging (MRI) findings as an alternative outcome. To provide international consensus guidelines for the use of MRI in MS clinical trials, a task force of the US National MS Society was convened. The recommendations of the task force are presented in this review. Given the high sensitivity for detecting pathological activity in relapsing-remitting and secondary progressive MS, monthly T2-weighted and gadolinium-enhanced brain MRI is an excellent tool for short-term exploratory trials of new agents where it serves as the primary end point; in particular, failure to demonstrate a reduction in lesion activity avoids the time, cost, and risks of a larger clinical end point study. However, conventional MRI findings have a limited correlation with disability in established MS. The primary end point of a definitive trial should therefore be clinical, although serial MRI at 6- to 12-month intervals is a useful secondary end point in providing an index of pathological progression. In trials of patients presenting with clinically isolated syndromes suggestive of MS, MRI findings can be used in the entry criteria, and as a secondary outcome measure, but conversion to clinically definite MS should be the primary outcome. The pathological substrates of irreversible disability are demyelination and axonal loss. Putative magnetic resonance markers for these processes include decreased N-acetylaspartate on proton magnetic resonance spectroscopy, decreased magnetization transfer ratios, hypointensity on T1-weighted images, and loss of short T2 water fractions, some of which relate more closely to disability than conventional MRI findings. Further technical developments should lead to more accurate quantitation, greater pathological specificity, and stronger clinical correlations.

Age-Dependent Brain Tissue Hydration, Ca Exchange and their Dose- Dependent Ouabain Sensitivity

“…It is widely recognized that although neural cell swelling can be observed under physiological conditions, for example as a result of neurotransmission or intense neuronal discharge (4,(43)(44)(45), larger changes are encountered during pathological conditions, including aging. It is known also that neuronal dehydration in older adults is a reliable predictor of increasing frailty, progressive deterioration in cognitive function and an overall reduction in quality of life [46][47][48][49]. There are a number of hypotheses on regard of detailed role of agedependent cell dehydration in deterioration in cognitive function of brain.…”

Time-Series Modeling of Multiple Sclerosis Disease Activity: A Promising Window on Disease Progression and Repair Potential?

“…24,25 Within this spectrum of measures, there are basically two avenues to obtain a measure of disease activity: 1) a marker directly linked (specific) to a particular physiological or pathological process, 2) a differential of disease severity measures, obtained at two or more different timepoints. An example of the first is the occurrence of gadolinium-diethylenetriamine penta-acetic acid (Gd-DTPA) contrast enhancement, capturing active focal blood-brain barrier patency, and an example of the second is rates of change of brain parenchymal fraction.…”

MRI for monitoring response to preventive treatment in multiple sclerosis

“…It has already been well established that conventional MRI represents a useful and accurate tool to detect signs of subclinical disease activity. The occurrence of new active lesions (i.e., gadoliniumenhancing lesions on T1-weighted postcontrast sequences) was five-to tenfold more frequent than a clinical relapse, although with a great variability among individuals [19]. In addition, it has been shown that histopathology findings better correlate with MRI than clinical signs [20].…”