Diffuse inflammation is associated with less permanent remyelination and reduced survival in progressive multiple sclerosis
ECTRIMS Learn. Bramow S. 10/03/13; 38825
Disclosure(s): Stephan Bramow performed one lecture for Genzyme/Sanofi (2013)
Per Soelberg Sorensen has served on scientific advisory boards Biogen Idec, Merck Serono, Novartis, Genmab, TEVA, Elan, GSK; has been on steering committees or independent data monitoring boards in clinical trials sponsored by Merck Serono, Genmab, TEVA, GSK, Bayer Schering, and he has received funding of travel for these activities; has received speaker honoraria from Biogen Idec, Merck Serono, TEVA, Bayer Schering, Sanofi-aventis, Genzyme, and Novartis. His research unit has received research support from Biogen Idec, Bayer Schering, Merck Serono, Sanofi-Aventis and Novartis.
Stephan Bramow
Contributions
Contributions
Abstract
Background: Vulnerability of remyelinated areas to renewed demyelination may limit permanent remyelination and could result in recurrence of relapses with similar symptoms in multiple sclerosis. The underlying reasons are unknown.
Methods: We prepared 6 µm hemispheric sections from 15 patients with progressive multiple sclerosis and brain blocks from 12 age-matched controls. 5 patients had primary, 8 secondary (SPMS) and 2 progressive disease with unknown onset. Sections were stained with haematoxylin-eosin, luxol fast blue and immunohistochemically for proteolipid protein and CD68.
We counted monocytic infiltrates (>20 cells) and CD68-positive microglia nodules (>5 cells) across whole hemispheres. Actively demyelinating areas (in % of total white matter area) contained macrophages with myelin debris. Remyelinated areas (in % of total plaque area) contained uniformly thin myelin sheaths and no macrophages. From 13 patients, we had clinical charts allowing >1 EDSS estimate; the most recent < 1 year before death.
Results: We confirmed diffuse inflammation in normal appearing white matter in patients (NAWM) compared to controls. Even more inflammation was found inside remyelinated areas (P<0,01 vs. NAWM) and this finding was validated by digital densitometry. Microglia nodules in the white matter correlated positively with active demyelination (r=0,61; P=0,016) and negatively with survival. Similar trends applied for infiltrates and correlations were strongest in SPMS. Active demyelination correlated negatively with survival (r=0.71, P=0,003) and positively with delta-EDSS/year before death. Microglia nodules inside remyelinated areas correlated with less permanent remyelination (r= -0,55; P=0,034).
Conclusion: In the brain, there may be an interrelation between diffuse inflammation and active plaque formation, at least in SPMS. Residual inflammation inside remyelinated areas could, thus, lead to renewed demyelination and lack of permanent remyelination in progressive multiple sclerosis.
Methods: We prepared 6 µm hemispheric sections from 15 patients with progressive multiple sclerosis and brain blocks from 12 age-matched controls. 5 patients had primary, 8 secondary (SPMS) and 2 progressive disease with unknown onset. Sections were stained with haematoxylin-eosin, luxol fast blue and immunohistochemically for proteolipid protein and CD68.
We counted monocytic infiltrates (>20 cells) and CD68-positive microglia nodules (>5 cells) across whole hemispheres. Actively demyelinating areas (in % of total white matter area) contained macrophages with myelin debris. Remyelinated areas (in % of total plaque area) contained uniformly thin myelin sheaths and no macrophages. From 13 patients, we had clinical charts allowing >1 EDSS estimate; the most recent < 1 year before death.
Results: We confirmed diffuse inflammation in normal appearing white matter in patients (NAWM) compared to controls. Even more inflammation was found inside remyelinated areas (P<0,01 vs. NAWM) and this finding was validated by digital densitometry. Microglia nodules in the white matter correlated positively with active demyelination (r=0,61; P=0,016) and negatively with survival. Similar trends applied for infiltrates and correlations were strongest in SPMS. Active demyelination correlated negatively with survival (r=0.71, P=0,003) and positively with delta-EDSS/year before death. Microglia nodules inside remyelinated areas correlated with less permanent remyelination (r= -0,55; P=0,034).
Conclusion: In the brain, there may be an interrelation between diffuse inflammation and active plaque formation, at least in SPMS. Residual inflammation inside remyelinated areas could, thus, lead to renewed demyelination and lack of permanent remyelination in progressive multiple sclerosis.
Background: Vulnerability of remyelinated areas to renewed demyelination may limit permanent remyelination and could result in recurrence of relapses with similar symptoms in multiple sclerosis. The underlying reasons are unknown.
Methods: We prepared 6 µm hemispheric sections from 15 patients with progressive multiple sclerosis and brain blocks from 12 age-matched controls. 5 patients had primary, 8 secondary (SPMS) and 2 progressive disease with unknown onset. Sections were stained with haematoxylin-eosin, luxol fast blue and immunohistochemically for proteolipid protein and CD68.
We counted monocytic infiltrates (>20 cells) and CD68-positive microglia nodules (>5 cells) across whole hemispheres. Actively demyelinating areas (in % of total white matter area) contained macrophages with myelin debris. Remyelinated areas (in % of total plaque area) contained uniformly thin myelin sheaths and no macrophages. From 13 patients, we had clinical charts allowing >1 EDSS estimate; the most recent < 1 year before death.
Results: We confirmed diffuse inflammation in normal appearing white matter in patients (NAWM) compared to controls. Even more inflammation was found inside remyelinated areas (P<0,01 vs. NAWM) and this finding was validated by digital densitometry. Microglia nodules in the white matter correlated positively with active demyelination (r=0,61; P=0,016) and negatively with survival. Similar trends applied for infiltrates and correlations were strongest in SPMS. Active demyelination correlated negatively with survival (r=0.71, P=0,003) and positively with delta-EDSS/year before death. Microglia nodules inside remyelinated areas correlated with less permanent remyelination (r= -0,55; P=0,034).
Conclusion: In the brain, there may be an interrelation between diffuse inflammation and active plaque formation, at least in SPMS. Residual inflammation inside remyelinated areas could, thus, lead to renewed demyelination and lack of permanent remyelination in progressive multiple sclerosis.
Methods: We prepared 6 µm hemispheric sections from 15 patients with progressive multiple sclerosis and brain blocks from 12 age-matched controls. 5 patients had primary, 8 secondary (SPMS) and 2 progressive disease with unknown onset. Sections were stained with haematoxylin-eosin, luxol fast blue and immunohistochemically for proteolipid protein and CD68.
We counted monocytic infiltrates (>20 cells) and CD68-positive microglia nodules (>5 cells) across whole hemispheres. Actively demyelinating areas (in % of total white matter area) contained macrophages with myelin debris. Remyelinated areas (in % of total plaque area) contained uniformly thin myelin sheaths and no macrophages. From 13 patients, we had clinical charts allowing >1 EDSS estimate; the most recent < 1 year before death.
Results: We confirmed diffuse inflammation in normal appearing white matter in patients (NAWM) compared to controls. Even more inflammation was found inside remyelinated areas (P<0,01 vs. NAWM) and this finding was validated by digital densitometry. Microglia nodules in the white matter correlated positively with active demyelination (r=0,61; P=0,016) and negatively with survival. Similar trends applied for infiltrates and correlations were strongest in SPMS. Active demyelination correlated negatively with survival (r=0.71, P=0,003) and positively with delta-EDSS/year before death. Microglia nodules inside remyelinated areas correlated with less permanent remyelination (r= -0,55; P=0,034).
Conclusion: In the brain, there may be an interrelation between diffuse inflammation and active plaque formation, at least in SPMS. Residual inflammation inside remyelinated areas could, thus, lead to renewed demyelination and lack of permanent remyelination in progressive multiple sclerosis.
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