A surface‐in gradient of thalamic damage evolves in pediatric multiple sclerosis

Abstract

Objective Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface‐in" process of injury suggesting progressive biology may begin. Methods We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface. Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls. Voxelwise volume changes were calculated using deformation‐based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods. Results Twenty‐seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow‐up = 4.6 years, standard deviation = 1.9). A total of 282 healthy children with serial scans were included as controls. Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter. However, only children with multiple sclerosis exhibited an additional surface‐in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval [CI] = 1.44–4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12–0.54, p = 0.0021). Interpretation Our results suggest that a multiple sclerosis disease‐specific surface‐in process of damage can manifest at the earliest stages of the disease. ANN NEUROL 2019;85:340–351.

Siponimod therapy implicates Th17 cells in a preclinical model of subpial cortical injury

“…Recent findings support the concept that such soluble factors can be produced by T cells (5,38,39). In the A/T SJL/J EAE model system in SJL/J mice, we previously showed that a reduction in meningeal stromal cell remodeling could be achieved by administering anti-IL-17A/IL-17F/IL-22 blocking antibodies by the intracerebral ventricular route, and this corresponded to a diminution in EAE symptoms (22).…”

7T MRI cerebral leptomeningeal enhancement is common in relapsing-remitting multiple sclerosis and is associated with cortical and thalamic lesions

“…14 Several MRI studies have suggested that there is a gradient of MRI abnormality extending from the CSF surface to affect GM and normal-appearing WM in a pattern distinct from WM lesions, 43,44 and a surface-in thalamic gradient of damage is evident even in pediatric RRMS. 45 This "toxic CSF" hypothesis may provide a key to understanding GM injury throughout the disease course, providing a bridge to progressive disease. 14 Alternatively, the cerebral cortex and thalamus may have common GM-specific antigen expression, which differs from WM, providing a unique target for the immune response.…”

Structural and Clinical Correlates of a Periventricular Gradient of Neuroinflammation in Multiple Sclerosis

“…Recent pathological investigations have revealed a possible relationship between cerebrospinal fluid (CSF) proximity and microstructural damage in the cortex 2 , potentially related to CSF derived pro-inflammatory cytokines 3 . Advanced imaging tools have confirmed that regions facing the cerebrospinal fluid were particularly susceptible to tissue damage, by showing a correlation between periventricular lesion load and cortical thinning 4 , as well as the presence of a periventricular gradient of microstructural damage [5][6][7][8][9] . Importantly, tissue damage in the periventricular white matter has been linked to that of the cortex, suggesting a shared mechanism of injury 4,5,8,10 .…”