Deep grey matter injury in multiple sclerosis: a NAIMS consensus statement

Abstract

Although multiple sclerosis has traditionally been considered a white matter disease, extensive research documents the presence and importance of grey matter injury including cortical and deep regions. The deep grey matter exhibits a broad range of pathology and is uniquely suited to study the mechanisms and clinical relevance of tissue injury in multiple sclerosis using magnetic resonance techniques. Deep grey matter injury has been associated with clinical and cognitive disability. Recently, MRI characterization of deep grey matter properties, such as thalamic volume, have been tested as potential clinical trial end points associated with neurodegenerative aspects of multiple sclerosis. Given this emerging area of interest and its potential clinical trial relevance, the North American Imaging in Multiple Sclerosis (NAIMS) Cooperative held a workshop and reached consensus on imaging topics related to deep grey matter. Herein, we review current knowledge regarding deep grey matter injury in multiple sclerosis from an imaging perspective, including insights from histopathology, image acquisition and post-processing for deep grey matter. We discuss the clinical relevance of deep grey matter injury and specific regions of interest within the deep grey matter. We highlight unanswered questions and propose future directions, with the aim of focusing research priorities towards better methods, analysis, and interpretation of results.

Keywords: MRI; atrophy; deep grey matter; multiple sclerosis; thalamus.

Figure 1

Demonstration of thalamic demyelinating lesion types. (A) Thalamic lesions are represented in coronal (left) and axial (right) planes. Lesions can either border the lateral and third ventricles (termed subependymal lesions, in orange) or have an ovoid appearance around blood vessels (termed perivascular, in purple). (B) Thalamic lesions (perivascular labelled with an asterisk and subependymal with a red open arrowhead) on T₂-weighted coronal 3 T MRI from a post-mortem multiple sclerosis case, and matching histological images from the same case (C–F), highlighting that subependymal lesions are more difficult to visualize. Myelin proteolipid protein immunohistochemistry demonstrates demyelination in perivascular and subependymal lesions (low magnification in C; higher magnification of subependymal lesion in D). Activated microglia/macrophages (MHC class II) immunohistochemistry demonstrating a chronic-active perivascular lesion and a rim at the border of the subependymal lesion (low magnification in E, higher magnification in F). Panel A is reprinted with permission, Cleveland Clinic Center for Medical Art & Photography ©2020. All Rights Reserved.

Figure 2

Mechanisms of thalamic neuronal degeneration pathology in multiple sclerosis. The figure shows representations of afferent/efferent neuronal cell bodies and axons in the thalamus and outflow/inflow tracts. Under ‘Anterograde Degeneration’, a focal white matter lesion in a thalamic afferent with secondary anterograde degeneration in the axon is depicted. Under ‘Retrograde Degeneration’, a focal white matter lesion in a thalamic efferent is depicted. Under ‘Trans-synaptic Degeneration’, secondary injury in the neuron as a result of degeneration of the axon with which it forms a synapse is demonstrated. Under ‘Primary Neurodegeneration’, neuronal injury independent of a direct connection to an axon is illustrated. Under ‘Deafferentation Induced Apoptosis’ we illustrate loss of neurons resulting as a consequence of axonal transection. Reprinted with permission, Cleveland Clinic Center for Medical Art & Photography ©2020. All Rights Reserved.