Danish Multiple Sclerosis Center
Neurology

Author Of 1 Presentation

Observational Studies Oral Presentation

PS02.04 - Relation between perivascular mononuclear infiltrates and plaque formation in the cortex and basal ganglia in progressive multiple sclerosis (MS).

Speakers
Presentation Number
PS02.04
Presentation Topic
Observational Studies
Lecture Time
10:57 - 11:09

Abstract

Background

Cortical plaque loads in primary progressive (PP) and secondary progressive MS (SP) appear equal whereas meningeal perivascular mononuclear/lymphocytic infiltration (PMI) may be more pronounced in SP. Basal ganglia may also be a predilection site in progressive MS.

Objectives

To compare cortical and basal ganglia plaque formation and PMI in large tissue areas from clinically well-defined PP and SP patients.

Methods

Large brain sections from clinically well-described patients with PP (N=12), SP (N=14) and 11 age-matched controls were stained with HE, Luxol-fast blue and in patients additionally for proteolipid protein and CD68. T- and B-cells were confirmed in PMI’s by CD3 and CD 20 in 3 PP and 3 SP patients. We measured total plaque, microglia-rimmed slowly expanding plaque and macrophage-filled filled active plaque area loads (% of cortex or basal ganglia area), PMI densities (#/Cm2 or #/Cm meningeal length) and mean PMI size. PMI’s with min. size score one had 3-4 perivascular cell rows and 20-50 cells whereas max. score six had >19 rows and >500 cells. In one PP patient, cortical slowly expanding rims were confirmed by immunofluorescence showing IgG. Expanded Disability Status Scale (EDSS) score was estimated by chart review in a blinded fashion among 20 patients (10 PP and 12SP) from whom charts were available from two time points including one within three yrs. before death. Among these, we calculated ΔEDSS/yr. before death.

Results

Tissue areas and meningeal lengths were similar in PP and SP. Both groups displayed similarly elevated cortical plaque loads and PMI densities in the cortex and meninges. However, meningeal PMI size as well as basal ganglia (6 SP vs 8 PP) plaque load and PMI density tended to be higher in SP vs PP. Meningeal PMI density correlated with total cortical plaque load while meningeal PMI size correlated with cortical slowly expanding plaque. Cortical PMI density and size correlated with active and slowly expanding (but not total) cortical plaque. PMI’s and plaque also correlated in the basal ganglia, albeit only in SP. Overall, age at death correlated negatively with PMI’s in the meninges, cortex and in the basal ganglia. Δ EDSS/yr. before death correlated with plaque load and tended to correlate with PMI’s, albeit only in the basal ganglia.

Conclusions

Perivascular immune activation in the meninges, cortex and basal ganglia may be pathogenic, driving grey matter demyelination in progressive MS.

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Author Of 2 Presentations

Observational Studies Poster Presentation

P0868 - Early experience with ocrelizumab in Denmark. A population-based registry study (ID 804)

Abstract

Background

Ocrelizumab (OCR) is a humanized monoclonal antibody targeting CD20-positive B cells. In Denmark, OCR treatment is recommended for patients with highly active relapsing-remitting multiple sclerosis (RRMS) or with early active primary progressive MS (PPMS) and moderate disability.

Objectives

To describe the real-world experience of patients initiating OCR by characterizing baseline demographic and disease attributes, as well as treatment outcomes, of an unselected adult MS population.

Methods

Observational cohort study with prospectively enrolled cases from January 2018 to April 2020 using data from the near complete nationwide population-based Danish Multiple Sclerosis Registry.

Results

Of the 851 patients initiating OCR treatment, 735 (86%) had RRMS, 61 (7%) had secondary progressive MS (SPMS) and 55 (7%) had PPMS. Of all patients, 131 were treatment naïve and, of these, 41 were PPMS. Median disease duration in years was 10.1 for RRMS (IQR 4.4-16.7), 17.8 for SPMS (13.3-24) and 3.9 for PPMS (2.5-7.8). Median baseline Expanded Disability Status Scale (EDSS) score was 3 for RRMS (IQR 2-4), 6 for SPMS (4.5-6.5) and 3.5 for PPMS (2.5-4.5). In the year prior to OCR initiation, 50% of the RRMS population had at least one relapse on another disease-modifying therapy (DMT); of these, 58% were on high efficacy DMT. Compared to RRMS, SPMS patients were older, had higher EDSS, and 34% had at least one relapse in the two years prior to OCR start. Fifty-five (90%) were previously treated with DMT, and 69% were on DMT in the year before OCR start.

The median OCR therapy duration was 0.9 years. During follow-up, 93% of all patients were relapse-free, and five patients reported more than one relapse. Out of 18 treatment discontinuations that occurred, two were due to disease breakthrough and nine were due to adverse events. Of the 383 patients with an EDSS score between 6 and 12 months, 80 (21%) showed EDSS improvement, 266 (69%) remained stable, and 37 (10%) experienced worsening. Of the 63 reported adverse events, the most common were upper respiratory tract infections (15), allergic reactions (7), and herpes simplex infections (6).

Conclusions

In this nationwide study, we present all Danish patients receiving OCR therapy in a real-world setting. Patient characteristics differed for RRMS, PPMS and particularly the SPMS group. With reservations for the short follow-up time, 93% of all patients were relapse-free and only 10% experienced disability worsening.

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Pathogenesis – the Blood-Brain Barrier Poster Presentation

P0955 - Diffuse inflammation relates to demyelination and clinical parameters in primary (PP) and secondary progressive multiple sclerosis (SP). (ID 1181)

Speakers
Presentation Number
P0955
Presentation Topic
Pathogenesis – the Blood-Brain Barrier

Abstract

Background

In primary progressive MS (PP), brain plaques are smaller and remyelinate better than in secondary progressive MS (SP) yet prognosis and response to systemic immunotherapy in PP is poor.

Objectives

To investigate relations between inflammation and myelin injury in PP vs SP and find correlates of clinical progression.

Methods

Large brain sections from clinically well-described post-mortem cohorts (12 PP, 14 SP and 11 controls) were stained with HE and Luxol-fast blue (myelin). Patients were additionally stained for proteolipid protein and CD68. We measured area loads of total plaque, microglia-rimmed slowly expanding plaque and macrophage-filled filled active plaque (% of WM area). Myelin density in the white matter overall, the normally appearing (NAWM), and the diffusely injured white matter (DIWM) was assessed by densitometry in ImageJ. In white matter compartments, we measured the density and mean size of perivascular mononuclear infiltrates (PMI; #/Cm2). The minimal PMI (grade one) had 3-4 perivascular cell rows and 20-50 cells whereas max. grade six had >19 rows and >500 cells. T- and B-cells in PMI’s were confirmed by CD3 and CD20. EDSS was estimated by chart review in a blinded fashion among 20 patients (10 PP and 12SP) from whom charts were available from two time points including one within three yrs. before death. Among these, we calculated Δ EDSS/yr before death.

In parallel, in-vivo cohorts (26 PP, 26 SP and 24 controls) were analyzed for MRI lesions with/without Gadolinium-enhancement and cerebrospinal fluid (CSF)-biomarkers of demyelination (MBP), axonal damage (NFL) and inflammation.

Results

Densities and sizes of PMI’s in NAWM as well as CSF-markers of inflammation (e.g. IgG-indices, CXCL13, MMP9) were equally increased in PP and SP and equally large PMI’s located to periventricular zones (median gr 1,8 IQR 1,5-2,1). Active and total lesion formation were higher in SP than in PP in both post-mortem and in-vivo cohorts and (post-mortem) juxtacortical and meningeal PMI’s were larger in SP than PP. By contrast, more DIWM-pathology was found in PPMS than in SPMS. The overall myelin density (post-mortem) and NAWM magnetic-transfer-ratio (in-vivo) were equally reduced while MBP and NFL levels in the CSF (in-vivo) were equally increased in both groups.

Plaque-distant (NAWM/DIWM) PMI-density (post-mortem cohort) and CSF-inflammation (in-vivo cohort) correlated with active lesion formation in SP, but not in PP. PMI-density and size in NAWM and in the white matter overall correlated with shorter survival. PMI-density in the white matter overall also correlated with slowly exp. plaque load, which in turn, correlated with Δ EDSS/yr before death in PP and in SP.

Conclusions

Perivascular inflammation is pathogenic and may contribute to white matter demyelination in PP and SP. Inflammatory demyelination in the white matter may not differ greatly but may be more diffuse and less focal in PP compared to SP.

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Presenter Of 1 Presentation

Pathogenesis – the Blood-Brain Barrier Poster Presentation

P0955 - Diffuse inflammation relates to demyelination and clinical parameters in primary (PP) and secondary progressive multiple sclerosis (SP). (ID 1181)

Speakers
Presentation Number
P0955
Presentation Topic
Pathogenesis – the Blood-Brain Barrier

Abstract

Background

In primary progressive MS (PP), brain plaques are smaller and remyelinate better than in secondary progressive MS (SP) yet prognosis and response to systemic immunotherapy in PP is poor.

Objectives

To investigate relations between inflammation and myelin injury in PP vs SP and find correlates of clinical progression.

Methods

Large brain sections from clinically well-described post-mortem cohorts (12 PP, 14 SP and 11 controls) were stained with HE and Luxol-fast blue (myelin). Patients were additionally stained for proteolipid protein and CD68. We measured area loads of total plaque, microglia-rimmed slowly expanding plaque and macrophage-filled filled active plaque (% of WM area). Myelin density in the white matter overall, the normally appearing (NAWM), and the diffusely injured white matter (DIWM) was assessed by densitometry in ImageJ. In white matter compartments, we measured the density and mean size of perivascular mononuclear infiltrates (PMI; #/Cm2). The minimal PMI (grade one) had 3-4 perivascular cell rows and 20-50 cells whereas max. grade six had >19 rows and >500 cells. T- and B-cells in PMI’s were confirmed by CD3 and CD20. EDSS was estimated by chart review in a blinded fashion among 20 patients (10 PP and 12SP) from whom charts were available from two time points including one within three yrs. before death. Among these, we calculated Δ EDSS/yr before death.

In parallel, in-vivo cohorts (26 PP, 26 SP and 24 controls) were analyzed for MRI lesions with/without Gadolinium-enhancement and cerebrospinal fluid (CSF)-biomarkers of demyelination (MBP), axonal damage (NFL) and inflammation.

Results

Densities and sizes of PMI’s in NAWM as well as CSF-markers of inflammation (e.g. IgG-indices, CXCL13, MMP9) were equally increased in PP and SP and equally large PMI’s located to periventricular zones (median gr 1,8 IQR 1,5-2,1). Active and total lesion formation were higher in SP than in PP in both post-mortem and in-vivo cohorts and (post-mortem) juxtacortical and meningeal PMI’s were larger in SP than PP. By contrast, more DIWM-pathology was found in PPMS than in SPMS. The overall myelin density (post-mortem) and NAWM magnetic-transfer-ratio (in-vivo) were equally reduced while MBP and NFL levels in the CSF (in-vivo) were equally increased in both groups.

Plaque-distant (NAWM/DIWM) PMI-density (post-mortem cohort) and CSF-inflammation (in-vivo cohort) correlated with active lesion formation in SP, but not in PP. PMI-density and size in NAWM and in the white matter overall correlated with shorter survival. PMI-density in the white matter overall also correlated with slowly exp. plaque load, which in turn, correlated with Δ EDSS/yr before death in PP and in SP.

Conclusions

Perivascular inflammation is pathogenic and may contribute to white matter demyelination in PP and SP. Inflammatory demyelination in the white matter may not differ greatly but may be more diffuse and less focal in PP compared to SP.

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