Direct MRI detection of impending plaque development in multiple sclerosis

DISCUSSION

Some novel observations about MS lesion development in vivo derive from the present analysis. In approximately 15% of new active lesions, parenchymal enhancement has directly visible antecedent MRI changes that, in cases where the T2*-weighted sequence was available for investigation, are centered on the central vein. In contrast to previous assessments,^{4,–,6,8,–,10} the abnormalities seen here are not inferred statistically on the basis of group-level analysis but directly visualized at the patient/lesion level, providing the opportunity to better study associated morphologic features. In particular, we took advantage of optimized T2*-weighted sequences at 3T and 7T to confirm the primary role of the central vein in early stages of lesion development, specifically before BBB disruption.

In line with the venulocentric model of lesion development, we discerned the presence of linear enhancement along the central vein preceding the parenchymal enhancement on postcontrast T1-weighted scans by days to weeks (figure 1). Slow flow associated with leukocyte rolling and/or entrapment of contrast agent within the perivascular space without passage through the glia limitans may explain this finding. In some cases, small parenchymal signal changes on T2-FLAIR or T2*-weighted scans around the vein were detected days to weeks before parenchymal enhancement (figure 1), which might reflect hypercellularity (possibly reactive astrocytes, activated microglia, and some lymphocytes),¹¹ minimal parenchymal edema, axonal dysfunction,¹² and/or initial demyelination in the presence of a still partially intact BBB.

In other cases, newly forming lesions arise from longer-lasting (months to years) areas of already-abnormal MRI signal (figure 2). This may indeed suggest the presence of preexisting or aborted demyelination centered on the same vein that does not meet the traditional MRI-based definition of an MS lesion (generally ≥3 mm diameter). These data raise the intriguing possibility that perivenular areas already subjected to previous inflammation may have increased susceptibility to subsequent demyelination.

Taken together, our data suggest that early perivenular processes, probably related largely to cellular infiltration but relatively limited in scope, occur frequently in MS but are not necessarily visible with gadolinium. It is possible that the relatively low frequency of pre-enhancement findings reported here may relate to selective permeability of the BBB in some lesions, which might be overcome by the use of higher doses of gadolinium or perhaps an entirely different contrast agent. Further increases in spatial resolution and frequent scanning of patients developing active lesions might allow detection of additional short-term perivenular changes. Our retrospective study design, which marshaled data from an existing natural history protocol, kept us from evaluating these possibilities. The same design limitations prevented us from directly comparing our results to prior group-level analyses using quantitative MRI methods.^{4,–,6,8,–,10} Despite these limitations, our data suggest that parenchymal gadolinium leakage in lesions heralds the onset of processes directly related to demyelination. Such processes may include massive recruitment of blood-derived macrophages, which have been shown to be essential for clearance of myelin debris and initiation of tissue repair.^13,–,15