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Page 52 Griffiths et al. Neuroimmunol Neuroinflammation 2020;7:51-67 I http://dx.doi.org/10.20517/2347-8659.2019.21

structures. White matter lesion area was unchanged when compared with the progressive MS cases with little
subpial cortical demyelination.

Conclusion: Analysis of whole coronal macrosections reveals cortical demyelination is more extensive than reported
by conventional histological methods. Cases of progressive MS with substantial subpial cortical demyelination that
is independent of underlying white matter lesion area support the implications that these lesions may in-part arise
through different pathogenetic mechanisms. Biomarkers and/or imaging correlates of this subpial pathology are
required if we are to fully comprehend the clinical disease process.

Keywords: Leptomeninges, B cell follicle, microglia activation, normal appearing grey matter.

INTRODUCTION
Neocortical grey matter demyelination, microglial activation and neurodegeneration, which may in-part be
driven by inflammation of the overlying leptomeninges, are important pathological processes influencing
[1]
the clinical severity and outcome of multiple sclerosis (MS) . No biomarker or widely available imaging
technology can fully report the extent of neocortical pathology, which is essential for optimal disease
management.

[2-5]
Neocortical and cerebellar cortical pathology is evident from the earliest stages of MS . It is a pathological
[1,2]
[6]
hallmark of progressive MS and closely associates with clinical severity at all stages . For example,
the extent of cortical pathology is better at predicting disease outcome than white matter pathology .
[7]
Radiological imaging of grey matter and cortical atrophy are predictive of the conversion to clinically
definite MS [8-10] or the risk of transitioning to the progressive phase and disability [7,11] . Nevertheless, even
high fidelity, non-routine, imaging technologies fail to identify lesions of the most superficial cortical
layers, whilst neuropathological assessment of standard size tissue blocks often underestimates the extent of
cortical lesions, which can occupy the cortical ribbon over multiple contiguous gyri and sulci [2,12] .

Lesions of the superficial layers of the neocortex (subpial cortical grey matter lesions) are more numerous
and sometimes associate topographically with leptomeningeal foci of immune cell aggregates that resemble
lymphoid-like structures (alternatively termed ectopic B cell follicle structures) seen in other autoimmune,
chronic inflammatory and infectious diseases [13,14] . Progressive MS cases with leptomeningeal lymphoid-
like structures exhibit a gradient of cortical tissue damage extending away from the pial surface, suggestive
of factor(s) in the CSF that promote underlying cortical inflammation and injury [15-17] , possibly through the
activation of microglia. The degree of leptomeningeal inflammation correlates with the extent of cortical
demyelination, neurodegeneration and microglial activation in acute and progressive stages [4,13,18,19] , whilst
white matter lesion area is not changed. These findings suggest that subpial cortical lesions may arise
through partly independent mechanisms compared with lesions located further from the CSF-filled spaces
[17]
of the pia or ventricular lumen .
The study of whole bi-hemispheric coronal macrosections, although technically challenging, can reveal
hitherto undisclosed aspects of MS pathology and better report the extent of global pathology. We analysed
the distribution and histological characteristics of cortical grey matter, white matter and deep grey matter
lesions, together with inflammation of the brain and overlying leptomeninges, using whole brain coronal
sections from 22 cases of progressive MS. We demonstrate the sometimes surprising extent of subpial
cortical grey matter demyelinating pathology that can be seen and highlight the association between
subpial and periventricular grey matter lesions, the dissociation between subpial lesion load and white
matter lesion area, and confirm the close relationship between leptomeningeal inflammation and subpial