Imag(in)ing multiple sclerosis: Time to take better pictures

Abstract

Magnetic resonance imaging (MRI) has led to the identification of widespread brain abnormalities in multiple sclerosis (MS) that extend far beyond the classic white matter lesion. These findings have generated the idea that MS should be understood as a disease of the whole brain, not just the white matter. While it is no doubt the case that many different pathways are ultimately involved in the destruction of brain tissue that occurs in MS, the implications of the accumulated evidence for understanding disease pathophysiology - and hence the overall significance of these imaging findings - are doubtful. Here, I argue that the principled use of imaging can, in fact, address questions about the genesis of these whole-brain abnormalities, rather than simply describe them.

Keywords: Magnetic resonance imaging; Multiple sclerosis.

Figure 1

A: Left, axial T2-weighted fluid-attenuation inversion recovery (FLAIR) image from a 33-year-old woman with MS, showing a focal lesion in the posterior limb of the left internal capsule. Right, axial diffusion-weighted image showing an acute lacunar infarct in a similar location. B: Axial FLAIR image from a 36-year-old man with relapsing-remitting MS, showing extensive involvement of the white matter.

Figure 2

A: Axial MRI scans through the centrum semiovale in a 40-year-old woman with relapsing-remitting MS, obtained in 1994. Top-left: proton density-weighted; bottom-left: T2-weighted; top-right: T1-weighted; bottom-right: T1-weighted after intravenous administration of gadolinium-based contrast material. The arrows point to a lesion that enhances following contrast administration, meaning that it is bright on the post-contrast T1-weighted image. It is invisible on the pre-contrast T1-weighted image. B: Axial 3D T1-weighted scan from the same individual 8 years later. Note the degree to which lesions (arrows) are visible as hypointense foci on this type of T1-weighted image relative to the 2D spin-echo image in panel A (top-right). Note also the inhomogeneity of the signal within each of the lesions, suggesting differential sensitivity to intralesional pathological processes.

Figure 3

Sagittal T2-weighted MRI scans of the cervical spinal cord in individuals with primary-progressive (A, 51-year-old man) and relapsing-remitting MS (B, 41-year-old man). C: Axial T2-weighted FLAIR MRI from the relapsing-remitting MS case whose cervical cord is shown in B. A preponderance of spinal cord lesions and paucity of cerebral lesions are thought to be typical of primary-progressive MS, but this is not the case here.

Figure 4

One slice from five different registration methods for three subjects (one subject on each row). The Montreal Neurological Institute template, which is the registration target, is at the top left. From Eloyan A, Shou H, Shinohara RT, Sweeney EM, Nebel MB, et al. (2014) Health Effects of Lesion Localization in Multiple Sclerosis: Spatial Registration and Confounding Adjustment. PLoS ONE 9(9): e107263. doi:10.1371/journal.pone.0107263

Figure 5

Sagittal T2*-weighted gradient-echo MRI scan of the corpus callosum in a healthy volunteer.

Figure 6

A: The first published MRI scan of a person with MS (Young, I. R., Hall, A. S., Pallis, C. A., Legg, N. J., Bydder, G. M., & Steiner, R. E. (1981). Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet, 2(8255), 1063–1066. http://doi.org/10.1016/S0140-6736(81)91273-3). The scan has T1-weighting, and arrows point to focal lesions that are hypointense relative to background white matter. B: A 7-tesla T2*-weighted MRI scan of an MS case showing focal hyperintense lesions with central hypointense veins and, in some cases, peripheral hypointense rims.

Figure 7

7-tesla MRI of the brain of a 48-year-old woman with secondary-progressive MS. In A, the lesion demonstrates contrast-enhancement on the gadolinium-enhanced T1-weighted (T1w) image. On T2*-weighted pre-gadolinium imaging, the lesion shows a clear hypointense rim on both magnitude and phase reconstructions. The lesion’s central vein is also clearly seen as a hypointense line running through the middle of the lesion. One month later (B), the lesion no longer enhances with contrast, and the rim (but not the central vein) is no longer apparent. Adapted from Gaitán, M. I., Sati, P., Inati, S. J., & Reich, D. S. (2013). Initial investigation of the blood-brain barrier in MS lesions at 7 tesla. Multiple Sclerosis (Houndmills, Basingstoke, England), 19(8), 1068–1073. http://doi.org/10.1177/1352458512471093

Figure 8

Top row: Left, T2*-weighted 7-tesla MRI of the formalin-fixed bran of a marmoset with experimental autoimmune encephalomyelitis (EAE). The circle highlights a focal white matter lesion. Center, corresponding in-vivo MRI, which depicts the lesion’s central vein as a focal hypointensity. Right, whole-mount hematoxylin-and-eosin (H&E)-stained section at the same level. Middle row, close-up images of the lesion circled in the top row as seen on H&E staining and immunohistochemistry for CNPase (a myelin marker), Iba-1 (a microglial marker), and CD3 (a T cell marker); details in Maggi, P., Macri, S. M. C., Gaitán, M. I., Leibovitch, E., Wholer, J. E., Knight, H. L., et al. (2014). The formation of inflammatory demyelinated lesions in cerebral white matter. Annals of Neurology, 76(4), 594–608. http://doi.org/10.1002/ana.24242. Bottom row, evolution of EAE in the same marmoset from day 0 (pre-immunization) to day 134 (the terminal MRI scan prior to sacrifice).

Figure 9

A: Axial T2-weighted FLAIR scan in a 29-year-old healthy man who was taking part in a clinical research protocol at the NIH. B: Axial T2-FLAIR (left) and post-contrast T1-weighted (right) scans 14 years later after presentation with clinically isolated syndrome, showing interval development of several non-enhancing lesions (open arrows) and a contrast-enhancing lesion in the left corona radiata.