Contributions
Abstract: 137
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 21 Imaging
Background: Subpial cortical pathology in multiple sclerosis (MS) is linked with progressive disease and reportedly exhibits a cerebrospinal fluid (CSF) 'surface-in' gradient of damage implicating a distinct injury mechanism. It is unknown, however, how early such a process may begin. The thalamus has both CSF and white matter (WM) interfaces and reduced thalamic volume is noted in both adult- and pediatric-onset MS. We considered whether careful analysis of the pattern of thalamic injury in pediatric-onset MS may implicate a CSF-'surface in' process early in disease course. We further sought histologic evidence of such an injury gradient in the MS thalamus, using available adult MS post-mortem tissue.
Methods: 100 children (27 MS; 73 non-MS acquired demyelinating syndromes (ADS)) were prospectively followed from incident attack with yearly brain MRI (mean follow-up 4.6 years). 282 healthy children with serial MRIs were included as controls. Voxelwise Jacobian determinants were calculated in the thalamus from non-linear registration of scans to the baseline, averaged over each isodistant surface from the CSF, then analysed using non-linear mixed effect modelling. Quantitative histologic analysis of distance-related changes in cell density was done in thalami of 5 secondary progressive MS (SPMS) patients and 3 controls.
Results: While both MS and non-MS ADS children exhibit abnormal growth in WM-adjacent thalamic regions, only MS children exhibit an additional and striking CSF 'surface-in' gradient of injury. This MS-specific abnormality was already notable in the first year of disease (p= 0.0002) and worsened over time (p= 0.0021). Pathologic study in SPMS cases compared to controls showed similar distance-related thalamic abnormalities with substantial neuronal cell loss and microglial activation in proximity to the CSF interface.
Conclusion: We report the presence and evolution of an MS specific 'surface-in' thalamic injury in pediatric-onset MS. A 'surface-in' gradient of thalamic cellular abnormalities (similar to those previously reported in the MS cortex) is present histopathologically in available MS autopsy material, consistent with an injury mechanism involving superficial diffusion of toxic CSF factors. Our findings challenge the commonly-held concept that progressive MS mechanisms are triggered late in disease. The suggestion that such a process manifests much earlier in the disease spectrum has important therapeutic implications.
Disclosure: G. Fadda has nothing to disclose.
R. A. Brown has received personal compensation for consulting services from Biogen Idec and NeuroRx Research.
R. Magliozzi has nothing to disclose.
B. Aubert-Broche has nothing to disclose.
J. O'Mahony has nothing to disclose.
B. Banwell has served as a consultant for Novartis. Dr. Banwell serves as a non-remunerated advisor on clinical trial design for Biogen-IDEC, Sanofi, and Teva Neuroscience. Has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Biogen Idec, Diogenix, Roche/Genentech, Sanofi-Genzyme, GlaxoSmithKline, Medimmune, Novartis, Ono Pharma, Teva Neuroscience, Celgene/Receptos Inc, and Merck/EMD Serono.
D.L. Collins has received personal compensation for consulting & training from NeuroRx inc.
D. Arnold has served on advisory boards, received speaker honoraria, served as a consultant, or received research support from Adelphi, Biogen, Celgene, Genentech, Genzyme, Medday, NeuroRx Research, Novartis, Pfizer, Receptos, Roche, Sanofi, the Canadian Institutes of Health Research, and the Multiple Sclerosis Society of Canada; and holds stock in NeuroRx Research.
A. Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Biogen Idec, Diogenix, Roche/Genentech, Sanofi-Genzyme, GlaxoSmithKline, Medimmune, Novartis, Ono Pharma, Teva Neuroscience, Celgene/Receptos Inc, and Merck/EMD Serono.
Abstract: 137
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 21 Imaging
Background: Subpial cortical pathology in multiple sclerosis (MS) is linked with progressive disease and reportedly exhibits a cerebrospinal fluid (CSF) 'surface-in' gradient of damage implicating a distinct injury mechanism. It is unknown, however, how early such a process may begin. The thalamus has both CSF and white matter (WM) interfaces and reduced thalamic volume is noted in both adult- and pediatric-onset MS. We considered whether careful analysis of the pattern of thalamic injury in pediatric-onset MS may implicate a CSF-'surface in' process early in disease course. We further sought histologic evidence of such an injury gradient in the MS thalamus, using available adult MS post-mortem tissue.
Methods: 100 children (27 MS; 73 non-MS acquired demyelinating syndromes (ADS)) were prospectively followed from incident attack with yearly brain MRI (mean follow-up 4.6 years). 282 healthy children with serial MRIs were included as controls. Voxelwise Jacobian determinants were calculated in the thalamus from non-linear registration of scans to the baseline, averaged over each isodistant surface from the CSF, then analysed using non-linear mixed effect modelling. Quantitative histologic analysis of distance-related changes in cell density was done in thalami of 5 secondary progressive MS (SPMS) patients and 3 controls.
Results: While both MS and non-MS ADS children exhibit abnormal growth in WM-adjacent thalamic regions, only MS children exhibit an additional and striking CSF 'surface-in' gradient of injury. This MS-specific abnormality was already notable in the first year of disease (p= 0.0002) and worsened over time (p= 0.0021). Pathologic study in SPMS cases compared to controls showed similar distance-related thalamic abnormalities with substantial neuronal cell loss and microglial activation in proximity to the CSF interface.
Conclusion: We report the presence and evolution of an MS specific 'surface-in' thalamic injury in pediatric-onset MS. A 'surface-in' gradient of thalamic cellular abnormalities (similar to those previously reported in the MS cortex) is present histopathologically in available MS autopsy material, consistent with an injury mechanism involving superficial diffusion of toxic CSF factors. Our findings challenge the commonly-held concept that progressive MS mechanisms are triggered late in disease. The suggestion that such a process manifests much earlier in the disease spectrum has important therapeutic implications.
Disclosure: G. Fadda has nothing to disclose.
R. A. Brown has received personal compensation for consulting services from Biogen Idec and NeuroRx Research.
R. Magliozzi has nothing to disclose.
B. Aubert-Broche has nothing to disclose.
J. O'Mahony has nothing to disclose.
B. Banwell has served as a consultant for Novartis. Dr. Banwell serves as a non-remunerated advisor on clinical trial design for Biogen-IDEC, Sanofi, and Teva Neuroscience. Has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Biogen Idec, Diogenix, Roche/Genentech, Sanofi-Genzyme, GlaxoSmithKline, Medimmune, Novartis, Ono Pharma, Teva Neuroscience, Celgene/Receptos Inc, and Merck/EMD Serono.
D.L. Collins has received personal compensation for consulting & training from NeuroRx inc.
D. Arnold has served on advisory boards, received speaker honoraria, served as a consultant, or received research support from Adelphi, Biogen, Celgene, Genentech, Genzyme, Medday, NeuroRx Research, Novartis, Pfizer, Receptos, Roche, Sanofi, the Canadian Institutes of Health Research, and the Multiple Sclerosis Society of Canada; and holds stock in NeuroRx Research.
A. Bar-Or has participated as a speaker in meetings sponsored by and received consulting fees and/or grant support from Biogen Idec, Diogenix, Roche/Genentech, Sanofi-Genzyme, GlaxoSmithKline, Medimmune, Novartis, Ono Pharma, Teva Neuroscience, Celgene/Receptos Inc, and Merck/EMD Serono.