MS pathology has traditionally focused on demyelinating lesions centred around venules. However, recent work highlights vascular changes beyond lesions as key factors in disease activity and neurodegeneration. The spinal cord is particularly relevant to disability in MS but little is known about vascular pathology in this region.

To characterise vascular pathology in the Multiple sclerosis (MS) spinal cord

Spinal cord samples (cervical, thoracic, lumbar) from 46 MS and 20 controls were stained for haematoxylin/eosin, elastin Van-Giessen, and Luxol Fast-Blue. Systematic assessment of measures of small vessel disease included vascular thickness, perivascular space dilation, fibrosis, hyalinotic changes, and myelin pallor. Fibrinogen, a marker for blood-brain barrier integrity, was examined in a subset of 42 MS and 6 controls using quantitative and semiquantitative methods.

Controls showed age-related vascular thickening with hyalinotic and fibrotic changes, and perivascular space dilation. In non-lesional tissue, MS cases had 89% more vascular fibrosis (p=0.002) than controls. In non-lesional white matter, myelin pallor increased by 66% (p<0.001) in MS compared to controls with both groups showing a symmetrical topographical pattern of myelin pallor. Perivascular space dilation increased by 93% in white (p<0.001) and 82% in grey matter (p<0.001) compared to controls. Striking fibrinogen deposition was observed in non-lesional MS areas, both extracellularly and within hypertrophic astrocytes. Extracellular fibrinogen was over 200 times more common in MS (p<0.0001) and correlated with increased inflammation and faster rate to wheelchair dependency. Fibrinogen-positive astrocyte coverage increased by 247% and hypertrophy by 83% (both p<0.001), both correlating with age at wheelchair dependence. MS lesions showed a further increase in vascular fibrosis, extracellular and astrocytic fibrinogen compared to the surrounding non-lesional tissue (all p<0.001).

These findings highlight that vascular abnormalities and blood-brain barrier leakage outside the paradigmatic demyelinated lesion are key features of MS spinal cord pathology and relate to inflammation and disease severity.