The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosis - A serial diffusion MRI study

The idea that the initiating event in the formation of all new multiple scl erosis lesions is a focal blood-brain barrier (BBB) leakage associated with perivascular inflammation has been challenged recently by the observation of subtle abnormalities in some quantitative magnetic resonance (MR) parame ters (including the magnetization transfer ratio) prior to lesion enhanceme nt. MR diffusion imaging can non-invasively quantify the average apparent d iffusion coefficient (ADC(av)), a measure of water molecule random motion t hat is sensitive to pathological change in multiple sclerosis lesions and t o abnormalities in the normal-appearing white matter (NAWM), We therefore u sed MR diffusion imaging to investigate the dynamic evolution of water diff usion measurements in new enhancing multiple sclerosis lesions, in the NAWM from which they arise, and in anatomically matched contralateral NAWM regi ons from which no visible lesions develop. Gadolinium diethylenetriamine-en taacetic acid (Gd)-enhanced MRI and MR diffusion studies were performed mon thly for 1 year in five multiple sclerosis patients with clinically and rad iologically active disease. The ADC(av) was calculated at each time point o f the study (before, during and after lesion appearance on Gd-enhanced scan s) for each new enhancing lesion, and for regions matched for size and posi tion in the contralateral NAWM. A steady and moderate increase in ADC(av) i n prelesion NAWM was observed, which was followed by a rapid and marked inc rease at the time of Gd enhancement and a slower decay after the cessation of enhancement. In matched contralateral NAWM regions there was a significa nt but milder increase in ADC(av) at the time of the first noted lesion enh ancement. These findings indicate that new focal lesions associated with fr ank BBB leakage are preceded by subtle, progressive alterations in tissue i ntegrity beyond the resolution of conventional MRI. The increases in ADC(av ) in anatomically matched contralateral regions after lesions have appeared supports the concept that structural damage in lesions causes damage or dy sfunction in connected areas of NAWM.