Evolution of the blood-brain barrier in newly forming multiple sclerosis lesions

Abstract

Objective: Multiple sclerosis (MS) lesions develop around small, inflamed veins. New lesions enhance with gadolinium on magnetic resonance imaging (MRI), reflecting disruption of the blood-brain barrier (BBB). Single time point results from pathology and standard MRI cannot capture the spatiotemporal expansion of lesions. We investigated the development and expansion of new MS lesions, focusing on the dynamics of BBB permeability.

Methods: We performed dynamic contrast-enhanced (DCE) MRI in relapsing-remitting MS. We obtained data over 65 minutes, during and after gadolinium injection. We labeled spatiotemporal enhancement dynamics as centrifugal when initially central enhancement expanded outward and centripetal when initially peripheral enhancement gradually filled the center.

Results: We detected 34 enhancing lesions in 200 DCE-MRI scans. In 65%, enhancement first appeared as a closed ring; in 18%, as a nodule; and in 18%, as an open ring. Lesions with initially nodular enhancement were smaller than those initially enhancing as rings (p < 0.0001). All initially nodular lesions enhanced centrifugally, whereas initially ringlike lesions enhanced centripetally, becoming nodular if small (82%) or nearly nodular if larger (18%). Open-ring lesions were periventricular or juxtacortical and enhanced centripetally. Centrifugally enhancing lesions evolved into centripetally enhancing lesions over several days.

Interpretation: The rapid change of enhancement dynamics from centrifugal to centripetal reflects the outward growth of MS lesions around their central vein and suggests that factors mediating lesion growth and tissue repair derive from different locations at different times. We propose a model of new lesion growth that unites our imaging observations with existing pathology data.

Figure 1

Enhancement and expansion dynamics in a new lesion observed in a 40-year-old man with relapsing-remitting multiple sclerosis. On “Day 1” (A), the scan on which the lesion was first observed, the enhancement pattern was centrifugal. By “Day 5” (B), the enhancement pattern had become centripetal, and this pattern persisted on Day 25 (C). Corresponding high-resolution T1-weighted scans are shown in (D) Day 1, 9.5 mm in diameter, 40 min after gadolinium injection; (E) Day 5, 11 mm in diameter, 6 min after gadolinium injection; and (F) Day 25, 12 mm in diameter, 6 min after gadolinium injection. The change in signal intensity over time, normalized to the pre-gadolinium scan, is shown for regions of interest in the center (G) and periphery (H) of the lesions. In the center, the slope and absolute values of enhancement intensity became progressively shallower as the lesion aged, whereas in the periphery the slope and the absolute values became progressively steeper.

Figure 2

Open ring-enhancing multiple sclerosis lesions (arrows) facing the lateral ventricles and cerebral cortex. (A) 40-year old man; (B) 30-year old woman; (C) 49-year-old man.

Figure 3

Dynamics of blood-brain-barrier permeability in newly forming multiple-sclerosis lesions. (A) Perivascular cuff, the likely site of MS lesion initiation. (B) Opening of the central vein’s blood-brain barrier, with outward spread of gadolinium (black bolts) resulting in the centrifugal enhancement. At this stage, peripheral vessels that are within and just beyond the border of the still expanding lesion are not yet open. (C) Secondary opening of the blood-brain barrier in peripheral vessels at the leading edge of the expanding lesion (blue bolts). Enhancement dynamics begin to change from centrifugal to centripetal. Gray shading represents the peripheral ring where centripetal enhancement begins. (D) Closing of the central vein, a relatively fast process (within 5 days in the lesion shown in Figure 1), which results in fully centripetal enhancement dynamics. As the lesion stops expanding and tissue repair begins, the blood-brain barrier closes even in peripheral vessels, and enhancement gradually ceases.