Measurement and clinical effect of grey matter pathology in multiple sclerosis

Summary

During the past 10 years, the intense involvement of the grey matter of the CNS in the pathology of multiple sclerosis has become evident. On gross inspection, demyelination in the grey matter is rather inconspicuous, and lesions in the grey matter are mostly undetectable with traditional MRI sequences. However, the results of immunohistochemical studies have shown extensive involvement of grey matter, and researchers have developed and applied new MRI acquisition methods as a result. Imaging techniques specifically developed to visualise grey matter lesions indicate early involvement, and image analysis techniques designed to measure the volume of grey matter show progressive loss. Together, these techniques have shown that grey matter pathology is associated with neurological and neuropsychological disability, and the strength of this association exceeds that related to white matter lesions or whole brain atrophy. By focusing on the latest insights into the in-vivo measurement of grey matter lesions and atrophy, we can assess their clinical effects.

Introduction

Multiple sclerosis has long been regarded as a typical white matter disease, with a primary autoimmune response directed against myelin components, resulting in focal inflammatory demyelination throughout the white matter. However, the involvement of the grey matter has become increasingly clear. As is the case in white matter, axons in the grey matter are myelinated, and demyelination of axons in grey matter regions has been seen on post-mortem examination of patients with multiple sclerosis since the beginning of the twentieth century.1, 2 However, following those early studies, this finding was mainly disregarded for many years. In a seminal report published in 1962, Brownell and Hughes described 1594 lesions from 22 selected patients with multiple sclerosis, and reported that 26% of the demyelinated brain lesions were located within, or partly within, the cortex.³ Of the 26% grey matter-associated lesions, 17% were located at the junction of the cortex and the subcortical white matter. These numbers were probably an underestimation of the actual number of lesions present in the grey matter of patients with progressive multiple sclerosis (as defined in pathological studies4, 5 based on retrospective chart analysis). Conventional histochemical stains, such as Luxol Fast Blue (also known as Klüver–Barrera), that detect myelin lipids miss most of the superficially located cortical lesions, which are the most frequent cortical lesion type in multiple sclerosis.⁵ These subpial cortical, or type III, lesions were shown on later investigation with more modern myelin immunohistochemical stains to be extensive, and many involved several neighbouring gyri.⁵ Other, less frequent, types of cortical lesion are type II (small, perivascular) and type IV (large, cortex-spanning).⁶ Type II and IV lesions are also best detected by myelin immunohistochemistry. Mixed white matter and grey matter, or type I, lesions are far less common in multiple sclerosis, although they can be detected with standard Luxol Fast Blue stains, which probably explains the high number of mixed lesions reported in the 1962 study. The different cortical lesion types as described in this Review have been defined by Bö and colleagues (figure 1).⁶