Background
Quantitative in vivo imaging of myelin loss and repair in patients with multiple sclerosis (MS) is essential to understand the pathogenesis of the disease and to evaluate promyelinating ...therapies. Selectively binding myelin in the central nervous system white matter, Pittsburgh compound B (11CPiB) can be used as a positron emission tomography (PET) tracer to explore myelin dynamics in MS.
Methods
Patients with active relapsing‐remitting MS (n = 20) and healthy controls (n = 8) were included in a longitudinal trial combining PET with 11CPiB and magnetic resonance imaging. Voxel‐wise maps of 11CPiB distribution volume ratio, reflecting myelin content, were derived. Three dynamic indices were calculated for each patient: the global index of myelin content change; the index of demyelination; and the index of remyelination.
Results
At baseline, there was a progressive reduction in 11CPiB binding from the normal‐appearing white matter to MS lesions, reflecting a decline in myelin content. White matter lesions were characterized by a centripetal decrease in the tracer binding at the voxel level. During follow‐up, high between‐patient variability was found for all indices of myelin content change. Dynamic remyelination was inversely correlated with clinical disability (p = 0.006 and beta‐coefficient = –0.67 with the Expanded Disability Status Scale; p = 0.003 and beta‐coefficient = –0.68 with the MS Severity Scale), whereas no significant clinical correlation was found for the demyelination index.
Interpretation
11CPiB PET allows quantification of myelin dynamics in MS and enables stratification of patients depending on their individual remyelination potential, which significantly correlates with clinical disability. This technique should be considered to assess novel promyelinating drugs. Ann Neurol 2016;79:726–738
We used a surface-based analysis of T2* relaxation rates at 7 T magnetic resonance imaging, which allows sampling quantitative T2* throughout the cortical width, to map in vivo the spatial ...distribution of intracortical pathology in multiple sclerosis. Ultra-high resolution quantitative T2* maps were obtained in 10 subjects with clinically isolated syndrome/early multiple sclerosis (≤ 3 years disease duration), 18 subjects with relapsing-remitting multiple sclerosis (≥ 4 years disease duration), 13 subjects with secondary progressive multiple sclerosis, and in 17 age-matched healthy controls. Quantitative T2* maps were registered to anatomical cortical surfaces for sampling T2* at 25%, 50% and 75% depth from the pial surface. Differences in laminar quantitative T2* between each patient group and controls were assessed using general linear model (P < 0.05 corrected for multiple comparisons). In all 41 multiple sclerosis cases, we tested for associations between laminar quantitative T2*, neurological disability, Multiple Sclerosis Severity Score, cortical thickness, and white matter lesions. In patients, we measured, T2* in intracortical lesions and in the intracortical portion of leukocortical lesions visually detected on 7 T scans. Cortical lesional T2* was compared with patients' normal-appearing cortical grey matter T2* (paired t-test) and with mean cortical T2* in controls (linear regression using age as nuisance factor). Subjects with multiple sclerosis exhibited relative to controls, independent from cortical thickness, significantly increased T2*, consistent with cortical myelin and iron loss. In early disease, T2* changes were focal and mainly confined at 25% depth, and in cortical sulci. In later disease stages T2* changes involved deeper cortical laminae, multiple cortical areas and gyri. In patients, T2* in intracortical and leukocortical lesions was increased compared with normal-appearing cortical grey matter (P < 10(-10) and P < 10(-7)), and mean cortical T2* in controls (P < 10(-5) and P < 10(-6)). In secondary progressive multiple sclerosis, T2* in normal-appearing cortical grey matter was significantly increased relative to controls (P < 0.001). Laminar T2* changes may, thus, result from cortical pathology within and outside focal cortical lesions. Neurological disability and Multiple Sclerosis Severity Score correlated each with the degree of laminar quantitative T2* changes, independently from white matter lesions, the greatest association being at 25% depth, while they did not correlate with cortical thickness and volume. These findings demonstrate a gradient in the expression of cortical pathology throughout stages of multiple sclerosis, which was associated with worse disability and provides in vivo evidence for the existence of a cortical pathological process driven from the pial surface.
Our objective was to develop a novel approach to generate individual maps of white matter (WM) innate immune cell activation using
F-DPA-714 translocator protein PET and to explore the relationship ...between these maps and individual trajectories of worsening disability in patients with multiple sclerosis (MS).
Patients with MS (
= 37), whose trajectories of worsening disability over the 2 y preceding study entry were calculated, and healthy controls (
= 19) underwent MRI and
F-DPA-714 PET. A threshold for significant activation of
F-DPA-714 binding was calculated with a voxelwise randomized permutation-based comparison between patients and controls and used to classify each WM voxel in all subjects as characterized by a significant activation of innate immune cells (DPA+) or not. Individual maps of innate immune cell activation in the WM were used to calculate the extent of activation in WM regions of interests and to classify each WM lesion as DPA-active, DPA-inactive, or unclassified.
Compared with the WM of healthy controls, patients with MS had a significantly higher percentage of DPA+ voxels in the normal-appearing WM (NAWM) (NAWM in patients, 24.6% ± 1.4%; WM in controls, 14.6% ± 2.0%;
< 0.001). In patients with MS, the percentage of DPA+ voxels increased significantly from the NAWM to the perilesional areas, T2 hyperintense lesions, and T1 hypointense lesions (38.1% ± 2.6%, 45.0% ± 2.6%, 51.8% ± 2.6%, respectively;
< 0.001). Among the 1,379 T2 lesions identified, 512 were defined as DPA-active and 258 as DPA-inactive. A higher number of lesions classified as DPA-active (odds ratio, 1.13;
= 0.009), a higher percentage of DPA+ voxels in the NAWM (odds ratio, 1.16;
= 0.009), and a higher percentage of DPA+ voxels in T1 spin-echo lesions (odds ratio, 1.06;
= 0.036) were significantly associated with a retrospectively more severe clinical trajectory in patients with MS.
A more severe trajectory of disability worsening in MS is associated with innate immune cell activation inside and around WM lesions.
F-DPA-714 PET may provide a promising biomarker to identify patients at risk of a severe clinical trajectory.
Background:
Late-onset neutropenia (LON), defined as an absolute neutrophil count (ANC) < 1500/mm3 that develops between 4 weeks and 6 months after the last drug administration, is a rare side effect ...of anti-CD20 drugs including ocrelizumab. Although continuation of ocrelizumab after LON is not contraindicated, the risk of LON recurrence is not well known.
Cases:
We report three cases of recurrent symptomatic agranulocytosis (ANC < 500/mm3) occurring under ocrelizumab.
Conclusion:
Given the risk of recurrence of symptomatic agranulocytosis and the availability of other treatments, a therapeutic switch may be discussed after the first episode of LON.
Although vaccination against SARS-CoV-2 is recommended prior to introducing anti-CD20 therapies, limited data are available regarding the evolution of post-vaccinal immunity.
This retrospective study ...compared anti-Spike antibody titres at 6 and 12 months from SARS-CoV-2 vaccination between patients vaccinated before switching to anti-CD20 ('Switch') and two control groups: (1) patients vaccinated under disease-modifying therapies (DMTs) other than fingolimod and anti-CD20 ('Other DMTs'); (2) patients vaccinated on anti-CD20 ('Anti-CD20'). Anti-Spike-specific T-cell responses were compared between 'Switch' and 'Anti-CD20' groups.
Fifty-three patients were included in the 'Switch' group, 54 in the 'Other DMTs' group and 141 in the 'Anti-CD20' group. At 6 months, in the subset of patients who received a booster dose, the 'Switch' group had lower anti-Spike titres compared with the 'Other DMTs' group (median 241.0 IQR (88.0; 504.0) BAU/mL vs 2034 (1155; 4634) BAU/mL, p<0.001), and less patients in the 'Switch' group reached the protective threshold of 264 BAU/mL. The 'Switch' group had higher anti-Spike titres than the 'Anti-CD20' group (7.5 (0.0; 62.1) BAU/mL, p=0.001). Anti-Spike titres were not different between the 'Switch' and 'Other DMTs' groups before booster administration. These results were similar at 12 months. Spike-specific T-cell positivity was similar between the 'Switch' and 'Anti-CD20' groups at 6 and 12 months (60.4% vs 61.0%, p=0.53, and 79.4% vs 87.5%, p=0.31, respectively).
Despite a primary vaccination performed before the first anti-CD20 cycle, our results suggest weaker immune responses at 6 and 12 months and decreased booster efficacy after introducing anti-CD20. Patients vaccinated prior to anti-CD20 introduction might falsely be considered as fully protected by vaccination.
Objective
To determine the prognostic value of persisting neuroinflammation in multiple sclerosis (MS) lesions, we developed a 18 kDa‐translocator‐protein‐positron emission tomography (PET) ‐based ...classification of each lesion according to innate immune cell content and localization. We assessed the respective predictive value of lesion phenotype and diffuse inflammation on atrophy and disability progression over 2 years.
Methods
Thirty‐six people with MS (disease duration 9 ± 6 years; 12 with relapsing–remitting, 13 with secondary‐progressive, and 11 with primary‐progressive) and 19 healthy controls (HCs) underwent a dynamic 18F‐DPA‐714‐PET. At baseline and after 2 years, the patients also underwent a magnetic resonance imaging (MRI) and neurological examination. Based on a threshold of significant inflammation defined by a comparison of 18F‐DPA‐714 binding between patients with MS and HCs, white matter lesions were classified as homogeneously active (active center), rim‐active (inactive center and active periphery), or nonactive. Longitudinal cortical atrophy was measured using Jacobian integration.
Results
Patients with MS had higher innate inflammation in normal‐appearing white matter (NAWM) and cortex than HCs (respective standardized effect size = 1.15, 0.89, p = 0.003 and < 0.001). Out of 1,335 non‐gadolinium‐enhancing lesions, 53% were classified as homogeneously‐active (median = 17 per patient with MS), 6% rim‐active (median = 1 per patient with MS), and 41% non‐active (median = 14 per patient with MS). The number of homogenously‐active lesions was the strongest predictor of longitudinal changes, associating with cortical atrophy (β = 0.49, p = 0.023) and Expanded Disability Status Scale (EDSS) changes (β = 0.35, p = 0.023) over 2 years. NAWM and cortical binding were not associated to volumetric and clinical changes.
Interpretation
The 18F‐DPA‐714‐PET revealed that an unexpectedly high proportion of MS lesions have a smoldering component, which predicts atrophy and clinical progression. This suggests that following the acute phase, most lesions develop a chronic inflammatory component, promoting neurodegeneration and clinical progression. ANN NEUROL 2023;94:366–383
The teaching of medical humanities is increasingly being integrated into medical school curricula. We developed a podcast called Le Serment d'Augusta (Augusta's Oath), consisting of six episodes ...tackling hot topics in the modern world of healthcare related to the patient-doctor relationship, professionalism, and ethics. This podcast aimed to provide scientific content in an entertaining way, while promoting debate among medical students. The Le Serment d'Augusta podcast was proposed as one of the various optional modules included in the second- to fifth-year curriculum at the School of Medicine of Sorbonne University (Paris). We asked students to report their lived experience of listening to the podcast. We then used a text-mining approach focusing on two main aspects: i) students' perspective of the use of this educational podcast to learn about medical humanities; ii) self-reported change in their perception of and knowledge about core elements of healthcare after listening to the podcast. 478 students were included. Students were grateful for the opportunity to participate in this teaching module. They greatly enjoyed this kind of learning tool and reported that it gave them autonomy in learning. They appreciated the content as well as the format, highlighting that the topics were related to the very essence of medical practice and that the numerous testimonies were of great added value. Listening to the podcast resulted in knowledge acquisition and significant change of perspective. These findings further support the use of podcasts in medical education, especially to teach medical humanities, and their implementation in the curriculum.The teaching of medical humanities is increasingly being integrated into medical school curricula. We developed a podcast called Le Serment d'Augusta (Augusta's Oath), consisting of six episodes tackling hot topics in the modern world of healthcare related to the patient-doctor relationship, professionalism, and ethics. This podcast aimed to provide scientific content in an entertaining way, while promoting debate among medical students. The Le Serment d'Augusta podcast was proposed as one of the various optional modules included in the second- to fifth-year curriculum at the School of Medicine of Sorbonne University (Paris). We asked students to report their lived experience of listening to the podcast. We then used a text-mining approach focusing on two main aspects: i) students' perspective of the use of this educational podcast to learn about medical humanities; ii) self-reported change in their perception of and knowledge about core elements of healthcare after listening to the podcast. 478 students were included. Students were grateful for the opportunity to participate in this teaching module. They greatly enjoyed this kind of learning tool and reported that it gave them autonomy in learning. They appreciated the content as well as the format, highlighting that the topics were related to the very essence of medical practice and that the numerous testimonies were of great added value. Listening to the podcast resulted in knowledge acquisition and significant change of perspective. These findings further support the use of podcasts in medical education, especially to teach medical humanities, and their implementation in the curriculum.
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