A dynamic view of the blood–brain barrier in active multiple sclerosis lesions

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, pathologically defined by the presence of focal demyelinated lesions in the white matter of the brain and spinal cord. Brain inflammation is associated with disturbance of the blood–brain barrier, which can be visualized in magnetic resonance imaging (MRI) through leakage of the paramagnetic marker gadolinium (Gd) diethylenetriamine pentaacetic acid (contrast enhancement). In active MS lesions, contrast enhancement is a very early event and may appear as a nodular or ringlike enhancement. It is currently not clear whether these different enhancement patterns reflect stages in lesion development or different mechanisms of inflammation or tissue injury. This question is addressed in a study appearing in this issue of Annals of Neurology that analyzes the dynamic changes of enhancement in newly appearing active lesions. The authors analyzed short-term changes of Gd distribution in the lesions, which occur within minutes after injection of the tracer. In addition, they describe enhancement patterns within the same lesion within days after their first appearance in MRI scans. The authors used high-resolution scans obtained at 3T. The authors describe that in lesions showing nodular enhancement in the first scan, the tracer spreads within minutes in a centrifugal pattern, increasing the size of the original enhancement area. In contrast, in lesions that show ring enhancement in the first scan, the tracer spreads in a centripetal manner, increasing the thickness of the ring or even resulting in nodular enhancement. When 2 scans were performed in a timeframe of days, those that initially appeared with a nodular enhancement pattern changed in the second scan into ring enhancing lesions. These results highlight 2 different aspects of Gd distribution within active lesions: the sites of initial blood–brain barrier injury and the diffusion of tracer within the lesions. Regarding the location of leaky vessels, the data suggest that in initial lesions leakage mainly occurs in the inflamed central vein, and the tracer spreads into the surrounding injured tissue. In contrast, in established lesions with radial expansion, leakage mainly occurs at the active margin, whereas blood–brain barrier integrity is already re-established in the central vein. Due to loss of tissue and increased extracellular space, preferential spreading of the tracer occurs toward the lesion core, and there is little diffusion into the more normal periplaque white matter. These results imply that nodular versus ring enhancement patterns in active lesions reflect the dynamics of lesion evolution rather than substantially different mechanisms of tissue injury. Furthermore, the data provide evidence that open rings reflect lesions that expand into the gray matter or that touch the ventricular surface. The results presented in this study are not unexpected, considering the knowledge on the structure of active lesions obtained in earlier pathological studies. However, the authors directly document the dynamic changes of tracer leakage and diffusion, which cannot be seen in the snapshot images in pathology. MS lesions are centered by inflamed veins, and the fingerlike extensions of periventricular lesions (Dawson fingers), as well as the dynamics of lesion formation seen in serial biopsies, strongly support the view that these inflamed vessels are the initial site of their formation. The distribution of serum proteins within the lesions and more specifically molecular markers for leaky endothelial cells confirmed that inflamed vessels in MS lesions are sites of increased blood–brain barrier permeability. Furthermore, similar studies have also shown that in expanding active lesions, small vessels with blood–brain barrier damage are present at the peripheral margin, at sites of lesion expansion, which in part also occurs in the absence of perivascular inflammatory infiltrates. The centripetal diffusion patterns of the tracer in ring enhancing lesions reflect the expanded extracellular space in the lesion core in comparison to that in the periplaque white matter. Finally, the absence of enhancement in lesions at sites where they expand into the cortex (open ring enhancement) reflects the low degree of blood–brain disturbance, described previously in active gray matter lesions. Despite the clear and impressive results on the dynamic patterns of contrast enhancement provided in the study by Gaitan et al, one has to keep in mind that the view of an open versus closed blood–brain barrier, based on enhancement in MRI, cannot be accepted without some reservation. Regarding the distribution of