Publications by authors named "Céline Louapre"

52 Publications

Health-related quality of life of multiple sclerosis patients: a European multi-country study.

Arch Public Health 2021 Mar 20;79(1):39. Epub 2021 Mar 20.

Department of Health Technology Assessment, Erasmus School of Health Policy & Management, Erasmus University Rotterdam, P.O.Box 1738/ 3000 DR, Rotterdam, The Netherlands.

Background: Inconsistent use of generic and disease-specific health-related quality of life (HRQOL) instruments in multiple sclerosis (MS) studies limits cross-country comparability. The objectives: 1) investigate real-world HRQOL of MS patients using both generic and disease-specific HRQOL instruments in the Netherlands, France, the United Kingdom, Spain, Germany and Italy; 2) compare HRQOL among these countries; 3) determine factors associated with HRQOL.

Methods: A cross-sectional, observational online web-based survey amongst MS patients was conducted in June-October 2019. Patient demographics, clinical characteristics, and two HRQOL instruments: the generic EuroQOL (EQ-5D-5L) and disease-related Multiple Sclerosis Quality of Life (MSQOL)-54, an extension of the generic Short Form-36 (SF-36) was collected. Health utility scores were calculated using country-specific value sets. Mean differences in HRQOL were analysed and predictors of HRQOL were explored in regression analyses.

Results: In total 182 patients were included (the Netherlands: n = 88; France: n = 58; the United Kingdom: n = 15; Spain: n = 10; living elsewhere: n = 11). Mean MSQOL-54 physical and mental composite scores (42.5, SD:17.2; 58.3, SD:21.5) were lower, whereas the SF-36 physical and mental composite scores (46.8, SD:22.6; 53.1, SD:22.5) were higher than reported in previous clinical trials. The mean EQ-5D utility was 0.65 (SD:0.26). Cross-country differences in HRQOL were found. A common predictor of HRQOL was disability status and primary progressive MS.

Conclusions: The effects of MS on HRQOL in real-world patients may be underestimated. Combined use of generic and disease-specific HRQOL instruments enhance the understanding of the health needs of MS patients. Consequent use of the same instruments in clinical trials and observational studies improves cross-country comparability of HRQOL.
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http://dx.doi.org/10.1186/s13690-021-00561-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980344PMC
March 2021

Human papillomavirus lesions in 16 MS patients treated with fingolimod: Outcomes and vaccination.

Mult Scler 2021 Feb 25:1352458521991433. Epub 2021 Feb 25.

Centre de Ressources et de Compétences Sclérose en plaques. AP-HP, Department of Neurology, Hôpital Pitié-Salpêtrière, Paris, France.

Few cases of human papillomavirus (HPV) diseases have been reported in multiple sclerosis (MS) patients treated with fingolimod. We describe a case series of 16 MS patients (11 women, 5 men) developing HPV lesions after the onset of fingolimod, without previous HPV history. Fingolimod had to be discontinued in six patients. Six patients received vaccination for HPV, with good tolerance. Our report highlights that systematic HPV screening and discussion about HPV vaccination before fingolimod onset are crucial. In case of occurrence of HPV lesions during fingolimod treatment, a comprehensive workup of HPV disease is necessary, with discussion of HPV vaccination to prevent secondary lesions. Prevalence studies of HPV lesions are needed in MS patients with the different disease-modifying therapies.
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http://dx.doi.org/10.1177/1352458521991433DOI Listing
February 2021

Unexpected REM sleep excess associated with a pontine lesion in multiple sclerosis.

J Clin Sleep Med 2021 Feb 4. Epub 2021 Feb 4.

AP-HP, Pitié-Salpêtrière Hospital, Department of Neurology, Paris, France.

None: Sleep disorders are prevalent in patients with multiple sclerosis. In contrast, a frank increase of REM sleep time is a rare phenomenon, mostly described in the context of REM sleep rebound (after sleep deprivation, abrupt withdrawal of antidepressants or neuroleptics, and during the first night of ventilation for severe sleep apnea), but not in link with specific brain lesions. We incidentally found an isolated, marked increase in REM sleep time (200 min, 40% of total sleep time, normative values: 18.2-20.3%) and in rapid eye movements density during REM sleep in a patient with a secondary progressive multiple sclerosis, associated with an anterior pontine demyelinating lesion on MRI. This result suggests that a network blocking REM sleep in the pons has been damaged.
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http://dx.doi.org/10.5664/jcsm.9114DOI Listing
February 2021

NeuroQ: A neurophobia screening tool assesses how roleplay challenges neurophobia.

J Neurol Sci 2021 Feb 20;421:117320. Epub 2021 Jan 20.

AP-HP, Hôpital Pitié-Salpêtrière, Département de Neurologie, Paris, France; Sorbonne Université, France; INSERM U1127, CNRS 7225, Institut du Cerveau, Paris, France.

Background: Neurophobia is a chronic disease of medical students and junior doctors. Early detection is needed to facilitate prevention and management as this fear can negatively impact patient care.

Methods: We conducted a two-part mono-centric study at the faculty of Medicine, Sorbonne University, in Paris. Part one: a cross-sectional study to validate a newly constructed neurophobia scale, NeuroQ. Part two: a prospective longitudinal study to assess the impact of The Move on student neurophobia using NeuroQ. A population-based sample of second-year medical students of the 2019 and 2020 class of the Faculty of Medicine of Sorbonne University were invited to participate.

Results: NeuroQ incorporates the main themes of the neurophobia definition and demonstrates uni-dimensionality. Three hundred and ninety-five medical students participated in the study (mean age was 20.0 years, SD: 2.1 years) assessing the effect of The Move teaching on neurophobia. Two hundred and eighty-eight (72.9%) students were female. After the Move teaching the mean NeuroQ score was significantly lower compared to the baseline NeuroQ score (mean [SD] variation, -1.1 [2.6], p < 0.001). There was a 22.3% relative reduction in the number of neurophobic students after The Move teaching.

Conclusion: Our results highlight the utility of NeuroQ in assessing (i) baseline neurophobia and (ii) the impact of pre-clinical educational interventions on neurophobia. Furthermore, we have shown the importance of pre-clinical educational interventions, such as The Move, in tackling neurophobia.
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http://dx.doi.org/10.1016/j.jns.2021.117320DOI Listing
February 2021

Determinants of therapeutic lag in multiple sclerosis.

Mult Scler 2021 Jan 11:1352458520981300. Epub 2021 Jan 11.

CORe, Department of Medicine, University of Melbourne, Melbourne, VIC, Australia/Melbourne MS Centre, Department of Neurology, Royal Melbourne Hospital, Melbourne, VIC, Australia.

Background: A delayed onset of treatment effect, termed therapeutic lag, may influence the assessment of treatment response in some patient subgroups.

Objectives: The objective of this study is to explore the associations of patient and disease characteristics with therapeutic lag on relapses and disability accumulation.

Methods: Data from MSBase, a multinational multiple sclerosis (MS) registry, and OFSEP, the French MS registry, were used. Patients diagnosed with MS, minimum 1 year of exposure to MS treatment and 3 years of pre-treatment follow-up, were included in the analysis. Studied outcomes were incidence of relapses and disability accumulation. Therapeutic lag was calculated using an objective, validated method in subgroups stratified by patient and disease characteristics. Therapeutic lag under specific circumstances was then estimated in subgroups defined by combinations of clinical and demographic determinants.

Results: High baseline disability scores, annualised relapse rate (ARR) ⩾ 1 and male sex were associated with longer therapeutic lag on disability progression in sufficiently populated groups: females with expanded disability status scale (EDSS) < 6 and ARR < 1 had mean lag of 26.6 weeks (95% CI = 18.2-34.9), males with EDSS < 6 and ARR < 1 31.0 weeks (95% CI = 25.3-36.8), females with EDSS < 6 and ARR ⩾ 1 44.8 weeks (95% CI = 24.5-65.1), and females with EDSS ⩾ 6 and ARR < 1 54.3 weeks (95% CI = 47.2-61.5).

Conclusions: Pre-treatment EDSS and ARR are the most important determinants of therapeutic lag.
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http://dx.doi.org/10.1177/1352458520981300DOI Listing
January 2021

7 Tesla MRI will soon be helpful to guide clinical practice in multiple sclerosis centres - Yes.

Mult Scler 2021 03 6;27(3):360-362. Epub 2021 Jan 6.

Sorbonne Université, Institut du Cerveau (ICM), Assistance Publique Hôpitaux de Paris (APHP), INSERM, CNRS, CIC Neuroscience, Department of Neurology, Hôpital de la Pitié Salpêtrière, Paris, France.

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http://dx.doi.org/10.1177/1352458520972270DOI Listing
March 2021

Outcomes of coronavirus disease 2019 in patients with neuromyelitis optica and associated disorders.

Eur J Neurol 2020 Oct 26. Epub 2020 Oct 26.

Service de Neurologie and CIC INSERM 1434, CHU de Strasbourg, Strasbourg, France.

Background: Outcomes of coronavirus disease 2019 (COVID-19) in patients with neuromyelitis optica spectrum disorders (NMOSD) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), often treated with immunosuppressive therapies, are still unknown.

Methods: We conducted a multicenter, retrospective, observational cohort study among all French expert centers for neuromyelitis optica and related disorders. Patients with NMOSD or MOGAD included in the study received a confirmed or highly suspected diagnosis of COVID-19 between 1 March 2020 and 30 June 2020. Main outcome was COVID-19 severity score assessed on a seven-point ordinal scale ranging from 1 (not hospitalized with no limitations on activities) to 7 (death).

Results: Fifteen cases (mean [SD] age: 39.3 [14.3] years, 11 female) were included. Five patients (33.3%) were hospitalized, all receiving rituximab. A 24-year-old patient with positive aquaporine-4 antibody, with obesity as comorbidity, needed mechanical ventilation. Outpatients were receiving anti-CD20 (5), mycophenolate mofetil (3) or azathioprine (3). They were younger (mean [SD] age: 37.0 [13.4] years), with a longer disease duration (mean [SD]: 8.3 [6.3] years) and had a lower expanded disability severity score (EDSS) score (median [range] EDSS: 2.5 [0-4]) relative to patients requiring hospitalization (mean [SD] age: 44.0 [16.4] years, mean [SD] disease duration: 5.8 [5.5] years, median [range] EDSS: 4 [0-6.5]).

Conclusions: COVID-19 outcome was overall favorable in this cohort. Larger international studies are needed to identify risk factors of severe COVID-19; however, we recommend personal protective measures to reduce risk of SARS-CoV-2 infection in this immunocompromised population.
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http://dx.doi.org/10.1111/ene.14612DOI Listing
October 2020

Activation of Macrophages by Lysophosphatidic Acid through the Lysophosphatidic Acid Receptor 1 as a Novel Mechanism in Multiple Sclerosis Pathogenesis.

Mol Neurobiol 2021 Feb 24;58(2):470-482. Epub 2020 Sep 24.

Institut du Cerveau et de la Moelle Epinière-Groupe Hospitalier Pitié-Salpêtrière, INSERM, U1127, CNRS, UMR 7225, F-75013, Paris, France.

Multiple sclerosis (MS) is a neuroinflammatory disease whose pathogenesis remains unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid involved in multiple immune cell functions and dysregulated in MS. Its receptor LPA is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair. In this study, we studied the genetic deletion and pharmaceutical inhibition of LPA in the mouse MS model, experimental autoimmune encephalomyelitis (EAE). LPA expression was analyzed in EAE mice and MS patient immune cells. The effect of LPA and LPA on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA activity induces milder clinical EAE course and that Lpar1 expression in peripheral blood mononuclear cells (PBMC) correlates with onset of relapses and severity in EAE. We see the same over-expression in PBMC from MS patients during relapse compared with progressive forms of the disease and in stimulated monocyte-derived macrophages. LPA induced a proinflammatory-like response in macrophages through LPA, providing a plausible way in which LPA and LPA dysregulation can lead to the inflammation in MS. These data show a new mechanism of LPA signaling in the MS pathogenesis, prompting further research into its use as a therapeutic target biomarker.
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http://dx.doi.org/10.1007/s12035-020-02130-xDOI Listing
February 2021

COVID-19 infection in NMO/SD patients: a French survey.

J Neurol 2021 Apr 12;268(4):1188-1190. Epub 2020 Sep 12.

Department of Neurology, Pitié Salpêtrière Hospital, APHP, Sorbonne University, 75013, Paris, France.

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http://dx.doi.org/10.1007/s00415-020-10112-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486806PMC
April 2021

Beyond COVID-19: DO MS/NMO-SD patients treated with anti-CD20 therapies develop SARS-CoV2 antibodies?

Mult Scler Relat Disord 2020 Nov 3;46:102482. Epub 2020 Sep 3.

AP-HP, Pitié-Salpêtrière Hospital, Department of Neurology, Paris, France; CRC SEP Paris, France; Sorbonne University, Paris Brain Institute, APHP, Inserm, CNRS, CIC neuroscience, Pitié-Salpêtrière Hospital, Paris, France.

Since 2019, a new coronavirus infection (COVID-19) due to an agent called SARS-CoV-2 spread rapidly worldwide. Patients with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMO-SD) are often treated with immunosuppressants. Beyond their effect on the risk of COVID-19 infection, the consequences on the long-term immune response against the coronavirus remain unknown. Among 13 MS or NMOSD patients with confirmed COVID-19 included, all 5 patients treated with anti-CD20 therapies had a negative SARS-CoV-2 serology. To date, maximal precautions to prevent coronavirus infection should be maintained in MS/NMOSD patients already exposed to COVID-19 during anti-CD20 therapy.
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http://dx.doi.org/10.1016/j.msard.2020.102482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7468278PMC
November 2020

COVID-19 in people with multiple sclerosis: A global data sharing initiative.

Mult Scler 2020 09 14;26(10):1157-1162. Epub 2020 Jul 14.

MS International Federation, London, UK.

Background: We need high-quality data to assess the determinants for COVID-19 severity in people with MS (PwMS). Several studies have recently emerged but there is great benefit in aligning data collection efforts at a global scale.

Objectives: Our mission is to scale-up COVID-19 data collection efforts and provide the MS community with data-driven insights as soon as possible.

Methods: Numerous stakeholders were brought together. Small dedicated interdisciplinary task forces were created to speed-up the formulation of the study design and work plan. First step was to agree upon a COVID-19 MS core data set. Second, we worked on providing a user-friendly and rapid pipeline to share COVID-19 data at a global scale.

Results: The COVID-19 MS core data set was agreed within 48 hours. To date, 23 data collection partners are involved and the first data imports have been performed successfully. Data processing and analysis is an on-going process.

Conclusions: We reached a consensus on a core data set and established data sharing processes with multiple partners to address an urgent need for information to guide clinical practice. First results show that partners are motivated to share data to attain the ultimate joint goal: better understand the effect of COVID-19 in PwMS.
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http://dx.doi.org/10.1177/1352458520941485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361123PMC
September 2020

Ultra-high field 7 T imaging in multiple sclerosis.

Curr Opin Neurol 2020 08;33(4):422-429

A. A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital.

Purpose Of Review: Ultra-high field 7 T MRI has multiple applications for the in vivo characterization of the heterogeneous aspects underlying multiple sclerosis including the identification of cortical lesions, characterization of the different types of white matter plaques, evaluation of structures difficult to assess with conventional MRI (thalamus, cerebellum, spinal cord, meninges).

Recent Findings: The sensitivity of cortical lesion detection at 7 T is twice than at lower field MRI, especially for subpial lesions, the most common cortical lesion type in multiple sclerosis. Cortical lesion load accrual is independent of that in the white matter and predicts disability progression.Seven Tesla MRI provides details on tissue microstructure that can be used to improve white matter lesion characterization. These include the presence of a central vein, whose identification can be used to improve multiple sclerosis diagnosis, or the appearance of an iron-rich paramagnetic rim on susceptibility-weighted images, which corresponds to iron-rich microglia at the periphery of slow expanding lesions. Improvements in cerebellar and spinal cord tissue delineation and lesion characterization have also been demonstrated.

Summary: Imaging at 7 T allows assessing more comprehensively the complementary pathophysiological aspects of multiple sclerosis, opening up novel perspectives for clinical and therapeutics evaluation.
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http://dx.doi.org/10.1097/WCO.0000000000000839DOI Listing
August 2020

Clinical Characteristics and Outcomes in Patients With Coronavirus Disease 2019 and Multiple Sclerosis.

JAMA Neurol 2020 09;77(9):1079-1088

Service de Neurologie, Clinical Investigation Center Institut National de la Santé et de la Recherche Médicale 1434, Centre Hospitalier Universitaire de Strasbourg, Strasbourg, France.

Importance: Risk factors associated with the severity of coronavirus disease 2019 (COVID-19) in patients with multiple sclerosis (MS) are unknown. Disease-modifying therapies (DMTs) may modify the risk of developing a severe COVID-19 infection, beside identified risk factors such as age and comorbidities.

Objective: To describe the clinical characteristics and outcomes in patients with MS and COVID-19 and identify factors associated with COVID-19 severity.

Design, Setting, And Participants: The Covisep registry is a multicenter, retrospective, observational cohort study conducted in MS expert centers and general hospitals and with neurologists collaborating with MS expert centers and members of the Société Francophone de la Sclérose en Plaques. The study included patients with MS presenting with a confirmed or highly suspected diagnosis of COVID-19 between March 1, 2020, and May 21, 2020.

Exposures: COVID-19 diagnosed with a polymerase chain reaction test on a nasopharyngeal swab, thoracic computed tomography, or typical symptoms.

Main Outcomes And Measures: The main outcome was COVID-19 severity assessed on a 7-point ordinal scale (ranging from 1 [not hospitalized with no limitations on activities] to 7 [death]) with a cutoff at 3 (hospitalized and not requiring supplemental oxygen). We collected demographics, neurological history, Expanded Disability Severity Scale score (EDSS; ranging from 0 to 10, with cutoffs at 3 and 6), comorbidities, COVID-19 characteristics, and outcomes. Univariate and multivariate logistic regression models were used to estimate the association of collected variables with COVID-19 outcomes.

Results: A total of 347 patients (mean [SD] age, 44.6 [12.8] years, 249 women; mean [SD] disease duration, 13.5 [10.0] years) were analyzed. Seventy-three patients (21.0%) had a COVID-19 severity score of 3 or more, and 12 patients (3.5%) died of COVID-19. The median EDSS was 2.0 (range, 0-9.5), and 284 patients (81.8%) were receiving DMT. There was a higher proportion of patients with a COVID-19 severity score of 3 or more among patients with no DMT relative to patients receiving DMTs (46.0% vs 15.5%; P < .001). Multivariate logistic regression models determined that age (odds ratio per 10 years: 1.9 [95% CI, 1.4-2.5]), EDSS (OR for EDSS ≥6, 6.3 [95% CI. 2.8-14.4]), and obesity (OR, 3.0 [95% CI, 1.0-8.7]) were independent risk factors for a COVID-19 severity score of 3 or more (indicating hospitalization or higher severity). The EDSS was associated with the highest variability of COVID-19 severe outcome (R2, 0.2), followed by age (R2, 0.06) and obesity (R2, 0.01).

Conclusions And Relevance: In this registry-based cohort study of patients with MS, age, EDSS, and obesity were independent risk factors for severe COVID-19; there was no association found between DMTs exposure and COVID-19 severity. The identification of these risk factors should provide the rationale for an individual strategy regarding clinical management of patients with MS during the COVID-19 pandemic.
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http://dx.doi.org/10.1001/jamaneurol.2020.2581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320356PMC
September 2020

Outcome and risk of recurrence in a large cohort of idiopathic longitudinally extensive transverse myelitis without AQP4/MOG antibodies.

J Neuroinflammation 2020 Apr 23;17(1):128. Epub 2020 Apr 23.

Service de neurologie, sclérose en plaques, pathologies de la myéline et neuro-inflammation, and Centre de Référence des Maladies Inflammatoires Rares du Cerveau et de la Moelle, Hôpital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677, Lyon/Bron, France.

Background: Longitudinally extensive transverse myelitis (LETM) is classically related to aquaporin (AQP4)-antibodies (Ab) neuromyelitis optica spectrum disorders (NMOSD) or more recently to myelin oligodendrocyte glycoprotein (MOG)-Ab associated disease. However, some patients remain negative for any diagnosis, despite a large work-up including AQP4-Ab and MOG-Ab. Data about natural history, disability outcome, and treatment are limited in this group of patients. We aimed to (1) describe clinical, biological, and radiological features of double seronegative LETM patients; (2) assess the clinical course and identify prognostic factors; and (3) assess the risk of recurrence, according to maintenance immunosuppressive therapy.

Methods: Retrospective evaluation of patients with a first episode of LETM, tested negative for AQP-Ab and MOG-Ab, from the French nationwide observatory study NOMADMUS.

Results: Fifty-three patients (median age 38 years (range 16-80)) with double seronegative LETM were included. Median nadir EDSS at onset was 6.0 (1-8.5), associated to a median EDSS at last follow-up of 4.0 (0-8). Recurrence was observed in 24.5% of patients in the 18 following months, with a median time to first relapse of 5.7 months. The risk of recurrence was lower in the group of patients treated early with an immunosuppressive drug (2/22, 9%), in comparison with untreated patients (10/31, 32%).

Conclusions: A first episode of a double seronegative LETM is associated to a severe outcome and a high rate of relapse in the following 18 months, suggesting that an early immunosuppressive treatment may be beneficial in that condition.
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http://dx.doi.org/10.1186/s12974-020-01773-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178729PMC
April 2020

Individual Mapping of Innate Immune Cell Activation Is a Candidate Marker of Patient-Specific Trajectories of Worsening Disability in Multiple Sclerosis.

J Nucl Med 2020 07 31;61(7):1043-1049. Epub 2020 Jan 31.

Sorbonne Universités, Institut du Cerveau et de la Moelle épinière, ICM, Hôpital de la Pitié Salpêtrière, INSERM UMR S 1127, CNRS UMR 7225, Paris, France

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.
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http://dx.doi.org/10.2967/jnumed.119.231340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383077PMC
July 2020

Profiles of cortical inflammation in multiple sclerosis by C-PBR28 MR-PET and 7 Tesla imaging.

Mult Scler 2020 10 1;26(12):1497-1509. Epub 2019 Aug 1.

Department of Radiology, Massachusetts General Hospital, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA/ Harvard Medical School, Boston, MA, USA.

Background: Neuroinflammation with microglia activation is thought to be closely related to cortical multiple sclerosis (MS) lesion pathogenesis.

Objective: Using C-PBR28 and 7 Tesla (7T) imaging, we assessed in 9 relapsing-remitting multiple sclerosis (RRMS) and 10 secondary progressive multiple sclerosis (SPMS) patients the following: (1) microglia activation in lesioned and normal-appearing cortex, (2) cortical lesion inflammatory profiles, and (3) the relationship between neuroinflammation and cortical integrity.

Methods: Mean C-PBR28 uptake was measured in focal cortical lesions, cortical areas with 7T quantitative T* (q-T*) abnormalities, and normal-appearing cortex. The relative difference in cortical C-PBR28 uptake between patients and 14 controls was used to classify cortical lesions as either active or inactive. Disease burden was investigated according to cortical lesion inflammatory profiles. The relation between q-T* and C-PBR28 uptake along the cortex was assessed.

Results: C-PBR28 uptake was abnormally high in cortical lesions in RRMS and SPMS; in SPMS, tracer uptake was significantly increased also in normal-appearing cortex. C-PBR28 uptake and q-T* correlated positively in many cortical areas, negatively in some regions. Patients with high cortical lesion inflammation had worse clinical outcome and higher intracortical lesion burden than patients with low inflammation.

Conclusion: C-PBR28 and 7T imaging reveal distinct profiles of cortical inflammation in MS, which are related to disease burden.
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http://dx.doi.org/10.1177/1352458519867320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994367PMC
October 2020

Longitudinal Characterization of Cortical Lesion Development and Evolution in Multiple Sclerosis with 7.0-T MRI.

Radiology 2019 06 9;291(3):740-749. Epub 2019 Apr 9.

From the A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Bldg 149, 13th St, Charleston, MA 02129 (C.A.T., T.E.G., E.H., R.A.O., C.L., C.M.); Harvard Medical School, Boston, MA (C.A.T., T.E.G., E.H., C.L., C.M.); Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden (T.E.G.); Department of Health Sciences (DISSAL), University of Genoa, Genoa, Italy (M.P.S.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (J.A.S.); and Department of Neurosciences, University of California San Diego, San Diego, CA (R.P.K.).

Background Cortical lesions develop early in multiple sclerosis (MS) and play a major role in disease progression. MRI at 7.0 T shows high sensitivity for detection of cortical lesions as well as better spatial resolution and signal-to-noise ratio compared with lower field strengths. Purpose To longitudinally characterize the development and evolution of cortical lesions in multiple sclerosis across the cortical width, sulci, and gyri; their relation with white matter lesion accrual; and the contribution of 7.0-T cortical and white matter lesion load and cortical thickness to neurologic disability. Materials and Methods Twenty participants with relapsing-remitting MS and 13 with secondary progressive MS, along with 10 age-matched healthy controls, were prospectively recruited from 2010 to 2016 to acquire, in two imaging sessions (mean interval, 1.5 years), 7.0-T MRI T2*-weighted gradient-echo images (0.33 × 0.33 × 1.0 mm) for cortical and white matter lesion segmentation and 3.0-T T1-weighted images for cortical surface reconstruction and cortical thickness estimation. Cortical lesions were sampled through the cortex to quantify cortical lesion distribution. The Expanded Disability Status Scale (EDSS) was used to assess neurologic disability. Nonparametric statistics assessed differences between and within groups in MRI metrics of cortical and white matter lesion burden; regression analysis explored associations of disability with MRI metrics. Results Twenty-five of 31 (81%) participants developed new cortical lesions per year (intracortical, 1.3 ± 1.7 vs leukocortical, 0.7 ± 1.9; = .04), surpassing white matter lesion accrual (cortical, 2.0 ± 2.8 vs white matter, 0.7 ± 0.6; = .01). In contrast to white matter lesions, cortical lesion accrual was greater in participants with secondary progressive MS than with relapsing-remitting MS (3.6 lesions/year ± 4.2 vs 1.1 lesions/year ± 0.9, respectively; = .03) and preferentially localized in sulci. Total cortical lesion volume independently predicted baseline EDSS (β = 1.5, < .001) and EDSS changes at follow-up (β = 0.5, = .003). Conclusion Cortical lesions predominantly develop intracortically and within sulci, suggesting an inflammatory cerebrospinal fluid-mediated lesion pathogenesis. Cortical lesion accumulation was prominent at 7.0 T and independently predicted neurologic disability progression. © RSNA, 2019 See also the editorial by Filippi and Rocca in this issue.
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http://dx.doi.org/10.1148/radiol.2019181719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6543899PMC
June 2019

False hepatitis B and C viral serologies in patients with multiple sclerosis receiving high-dose biotin.

Mult Scler 2020 02 11;26(2):257-258. Epub 2018 Dec 11.

Department of Neurology, Hôpital Pitié-Salpêtrière, AP-HP, Paris, France.

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http://dx.doi.org/10.1177/1352458518818294DOI Listing
February 2020

Rituximab in chronic inflammatory demyelinating polyradiculoneuropathy with associated diseases.

J Peripher Nerv Syst 2018 12 7;23(4):235-240. Epub 2018 Oct 7.

Department of Clinical Neurophysiology, APHP, Pitié-Salpêtrière Hospital, Paris, France.

We aimed to analyse the response to rituximab in a cohort of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients with associated disorders. We conducted a clinical and electrophysiological retrospective monocentric study in 28 CIDP patients. Response to rituximab was defined as (a) a five-point increase in the Medical Research Council sum score or a one-point decrease in the Overall Neuropathy Limitations Scale score, compared to the score at the first rituximab infusion, or (b) the discontinuation of, or reduced need for, the last treatments before rituximab initiation. Twenty-one patients (75%) were responders to rituximab. The median time before response was 6 months (1-10 months). Only two patients needed to be treated again during a median follow-up of 2.0 years (0.75-9 years). Interestingly, the response rate was good in patients with associated autoimmune disease (5/8) and similar to the response rate observed in patients with a haematological disease (16/20) (P = 0.63). A shorter disease duration was associated with a better clinical response to rituximab (odds ratio 0.81, P = 0.025) and the response rate was better (P = 0.05) in common forms (83.3%) than in sensory forms (42.9%). No major adverse events were recorded. Rituximab is efficacious in CIDP patients with haematological or autoimmune disease. It improves clinical response and decreases dependence on first-line treatments.
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http://dx.doi.org/10.1111/jns.12287DOI Listing
December 2018

Miming neurological syndromes improves medical student's long-term retention and delayed recall of neurology.

J Neurol Sci 2018 08 7;391:143-148. Epub 2018 Jun 7.

Faculty of Medicine of Sorbonne University, University Pierre-et-Marie-Curie (UPMC), 91, boulevard de l'Hôpital, 75013 Paris, France; Department of Internal Medicine, Hôpital Tenon, AP-HP, 4, rue de la Chine, 75020 Paris, France.

Basic examination and diagnostic skills in neurology are important for every graduating medical student. However, a majority of medical students consider neurology as complex and difficult to master. We evaluate the impact a learner-friendly, innovative simulation-based training programme has on long-term retention and delayed recall of neurological semiology amongst third-year medical students from the University Pierre et Marie Curie in Paris, France. The 2013 class received standard teaching in neurological semiology. The 2015 class who received the same standard teaching in neurological semiology were also invited to voluntarily participate in The Move, a mime-based role-play training programme of neurological semiology. During the Move, students were trained to simulate a patient with a neurological syndrome or the physician examining the patient. Students were evaluated with an assessment thirty months after their neurological rotation, including 15 questions to evaluate long-term retention of neurological semiology, and 10 to test background knowledge in general semiology. The semiology test was performed by 366/377 students from the 2013 class (standard education group) and by 272/391 students from the 2015 class, among which 186 participated in The Move (The Move group) and 86 did not (standard education group). The mean neurological semiology score was higher in the 2015 class compared to the 2013 class (p = 0.007) and remained so after adjustment for the general semiology performance (p = 0.003). The adjusted mean neurological semiology score was 1.21/15 points higher [95% CI 0.66, 1.75] in The Move group compared to the standard education group, corresponding to a 14% better ranking. The Move programme improves medical student's long-term retention and delayed recall of neurological semiology. This learner-friendly interactive teaching may in turn enhance clinical proficiency of future physicians in neurological semiology.
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http://dx.doi.org/10.1016/j.jns.2018.06.003DOI Listing
August 2018

Can we use regional grey matter atrophy sequence to stage neurodegeneration in multiple sclerosis?

Brain 2018 06;141(6):1580-1583

Institut du Cerveau et de la Moelle épinière, ICM, Sorbonne Universités, Hôpital de la Pitié Salpêtrière, Inserm UMR S 1127, CNRS UMR 7225, Paris, France.

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http://dx.doi.org/10.1093/brain/awy114DOI Listing
June 2018

Early relapse after RTX initiation in a patient with NMO/MS overlap syndrome: How long to conclude to a failure treatment?

Mult Scler Relat Disord 2018 Feb 6;20:220-222. Epub 2018 Feb 6.

AP-HP, Neurology Department, Pitié-Salpêtrière hospital, 47-83 Boulevard de l'Hôpital, F-75013 Paris, France.

Background: We report a dramatic clinical and radiological worsening within two months after rituximab initiation in a patient with NeuroMyelitis Optica/Multiple Sclerosis (NMO/MS) overlap syndrome.

Methods: Case study.

Results: A 45-year-old Caucasian woman with NMO/MS overlap syndrome experienced a severe myelitis nine weeks after first rituximab infusion, with extensive new gadolinium-enhanced spinal cord lesions.

Conclusion: This case report illustrates the limits of MS and NMO-Spectrum Disorder classification and challenges the criteria of therapeutic failure within the 6 months after rituximab initiation.
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http://dx.doi.org/10.1016/j.msard.2018.02.004DOI Listing
February 2018

Changes in structural network are associated with cortical demyelination in early multiple sclerosis.

Hum Brain Mapp 2018 05 6;39(5):2133-2146. Epub 2018 Feb 6.

Institute of Biomedical Engineering, Polytechnique Montreal, Montreal, Quebec, Canada.

The aim of this study was to investigate the interplay between structural connectivity and cortical demyelination in early multiple sclerosis. About 27 multiple sclerosis patients and 18 age-matched controls underwent two MRI scanning sessions. The first was done at 7T and involved acquiring quantitative T and T * high-resolution maps to estimate cortical myelination. The second was done on a Connectom scanner and consisted of acquiring high angular resolution diffusion-weighted images to compute white matter structural connectivity metrics: strength, clustering and local efficiency. To further investigate the interplay between structural connectivity and cortical demyelination, patients were divided into four groups according to disease-duration: 0-1 year, 1-2 years, 2-3 years, and >3 years. ANOVA and Spearman's correlations were used to highlight relations between metrics. ANOVA detected a significant effect between disease duration and both cortical myelin (p = 2 × 10 ) and connectivity metrics (p < 10 ). We observed significant cortical myelin loss in the shorter disease-duration cohorts (0-1 year, p = .0015), and an increase in connectivity in the longer disease-duration cohort (2-3 years, strength: p = .01, local efficiency: p = .002, clustering: p = .001). Moreover, significant covariations between myelin estimation and white matter connectivity metrics were observed: Spearman's Rho correlation coefficients of 0.52 (p = .0003), 0.55 (p = .0001), and 0.53 (p = .0001) for strength, local efficiency, and clustering, respectively. An association between cortical myelin loss and changes in white matter connectivity in early multiple sclerosis was detected. These changes in network organization might be the result of compensatory mechanisms in response to the ongoing cortical diffuse damage in the early stages of multiple sclerosis.
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http://dx.doi.org/10.1002/hbm.23993DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5895520PMC
May 2018

Multiple sclerosis and aging.

Geriatr Psychol Neuropsychiatr Vieil 2017 Dec;15(4):402-408

Département de neurologie, Hôpital Pitié Salpêtrière, APHP, Paris ; UPMC Université Paris 06, UMR S 1127, CNRS UMR 7225 et ICM, Paris, France.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, whose incidental peak occurs around 30 years. This review focuses on epidemiologic, physiopathological, clinical and therapeutic characteristics of MS in elderly patients in two different situations: 1) late-onset MS (after 50 years), 2) aging in MS with young adult-onset. Epidemiologic studies established that MS occurs after 50 years in 5% of cases. As opposed to young adult-onset MS, late-onset MS is characterized by a predominant progressive course, a longer diagnosis delay, a higher prevalence of motor disability, while cognitive impairment is similar in terms of frequency and affected cognitive domains. Improvement of MS patients' global healthcare together with life expectancy increase has led to an increased number of elderly patients with MS, regardless of age at onset. Care providers must take into account the potential more frequent comorbidities in this specific population and pharmacological differences with younger subjects to adapt and optimize the risk/balance benefit of disease-modifying therapies.
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http://dx.doi.org/10.1684/pnv.2017.0685DOI Listing
December 2017

In vivo characterization of cortical and white matter neuroaxonal pathology in early multiple sclerosis.

Brain 2017 Nov;140(11):2912-2926

Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Charlestown, MA, USA.

Neuroaxonal pathology is a main determinant of disease progression in multiple sclerosis; however, its underlying pathophysiological mechanisms, including its link to inflammatory demyelination and temporal occurrence in the disease course are still unknown. We used ultra-high field (7 T), ultra-high gradient strength diffusion and T1/T2-weighted myelin-sensitive magnetic resonance imaging to characterize microstructural changes in myelin and neuroaxonal integrity in the cortex and white matter in early stage multiple sclerosis, their distribution in lesional and normal-appearing tissue, and their correlations with neurological disability. Twenty-six early stage multiple sclerosis subjects (disease duration ≤5 years) and 24 age-matched healthy controls underwent 7 T T2*-weighted imaging for cortical lesion segmentation and 3 T T1/T2-weighted myelin-sensitive imaging and neurite orientation dispersion and density imaging for assessing microstructural myelin, axonal and dendrite integrity in lesional and normal-appearing tissue of the cortex and the white matter. Conventional mean diffusivity and fractional anisotropy metrics were also assessed for comparison. Cortical lesions were identified in 92% of early multiple sclerosis subjects and they were characterized by lower intracellular volume fraction (P = 0.015 by paired t-test), lower myelin-sensitive contrast (P = 0.030 by related-samples Wilcoxon signed-rank test) and higher mean diffusivity (P = 0.022 by related-samples Wilcoxon signed-rank test) relative to the contralateral normal-appearing cortex. Similar findings were observed in white matter lesions relative to normal-appearing white matter (all P < 0.001), accompanied by an increased orientation dispersion (P < 0.001 by paired t-test) and lower fractional anisotropy (P < 0.001 by related-samples Wilcoxon signed-rank test) suggestive of less coherent underlying fibre orientation. Additionally, the normal-appearing white matter in multiple sclerosis subjects had diffusely lower intracellular volume fractions than the white matter in controls (P = 0.029 by unpaired t-test). Cortical thickness did not differ significantly between multiple sclerosis subjects and controls. Higher orientation dispersion in the left primary motor-somatosensory cortex was associated with increased Expanded Disability Status Scale scores in surface-based general linear modelling (P < 0.05). Microstructural pathology was frequent in early multiple sclerosis, and present mainly focally in cortical lesions, whereas more diffusely in white matter. These results suggest early demyelination with loss of cells and/or cell volumes in cortical and white matter lesions, with additional axonal dispersion in white matter lesions. In the cortex, focal lesion changes might precede diffuse atrophy with cortical thinning. Findings in the normal-appearing white matter reveal early axonal pathology outside inflammatory demyelinating lesions.
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http://dx.doi.org/10.1093/brain/awx247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841207PMC
November 2017

Unraveling cortical pathology in multiple sclerosis using the T1-/T2-weighted ratio?

Ann Neurol 2017 10;82(4):516-518

UPMC University Paris 06, UMR S 1127, and CNRS UMR 7225, and ICM, Paris, France.

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http://dx.doi.org/10.1002/ana.25063DOI Listing
October 2017

Heterogeneous pathological processes account for thalamic degeneration in multiple sclerosis: Insights from 7 T imaging.

Mult Scler 2018 10 14;24(11):1433-1444. Epub 2017 Aug 14.

A. A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, MA, USA/Harvard Medical School, Boston, MA, USA.

Background: Thalamic degeneration impacts multiple sclerosis (MS) prognosis.

Objective: To investigate heterogeneous thalamic pathology, its correlation with white matter (WM), cortical lesions and thickness, and as function of distance from cerebrospinal fluid (CSF).

Methods: In 41 MS subjects and 17 controls, using 3 and 7 T imaging, we tested for (1) differences in thalamic volume and quantitative T* (q-T*) (2) globally and (3) within concentric bands originating from the CSF/thalamus interface; (4) the relation between thalamic, cortical, and WM metrics; and (5) the contribution of magnetic resonance imaging (MRI) metrics to clinical scores. We also assessed MS thalamic lesion distribution as a function of distance from CSF.

Results: Thalamic lesions were mainly located next to the ventricles. Thalamic volume was decreased in MS versus controls ( p < 10); global q-T* was longer in secondary progressive multiple sclerosis (SPMS) only ( p < 10), indicating myelin and/or iron loss. Thalamic atrophy and longer q-T* correlated with WM lesion volume ( p < 0.01). In relapsing-remitting MS, q-T* thalamic abnormalities were located next to the WM ( p < 0.01 (uncorrected), p = 0.09 (corrected)), while they were homogeneously distributed in SPMS. Cortical MRI metrics were the strongest predictors of clinical outcome.

Conclusion: Heterogeneous pathological processes affect the thalamus in MS. While focal lesions are likely mainly driven by CSF-mediated factors, overall thalamic degeneration develops in association with WM lesions.
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http://dx.doi.org/10.1177/1352458517726382DOI Listing
October 2018

Natalizumab-PML survivors with subsequent MS treatment: Clinico-radiologic outcome.

Neurol Neuroimmunol Neuroinflamm 2017 May 14;4(3):e346. Epub 2017 Apr 14.

Department of Neurology (E.M., C. Louapre, C. Lubetzki, C.P.), Pitié-Salpêtrière Hospital, APHP, Paris; Department of Gerontology (J.-S.V.), Broca Hospital, APHP, Paris; Department of Neurology (D.B.), University Hospital of Toulouse; Department of Neurology (B.S.), Saint-Antoine Hospital, APHP, Paris; Department of Neurology (A.F., T.M.), University Hospital of Dijon; Department of Neurology (J.d.S.), University Hospital of Strasbourg; Department of Neurology (F.T., P.C.), University Hospital of Clermont-Ferrand; Department of Neurology (B.B.), University Hospital of Rouen, France; Department of Neurology (V.D.), University Hospital of Liège, Belgium; APHM (A.R., J.P.), Hôpital de la Timone, Pôle de Neurosciences Cliniques, Service de Neurologie, Marseille; Department of Neurology (P.L.), University Hospital of Montpellier; Department of Neurology (A.T.), University Hospital of Reims, URCA Reims, and LPN EA 2027 University Paris 8, Saint-Denis; and Department of Neurology (C. Lebrun), University Hospital of Nice, France.

Objective: To describe the clinico-radiologic outcome of MS patients with natalizumab-related progressive multifocal leukoencephalopathy (Nz-PML) surviving and receiving disease-modifying therapy (DMT).

Methods: We describe clinical and radiologic evolution of Nz-PML survivors in an observational retrospective multicenter cohort to clarify the effect of different subsequent MS DMT strategies. Twenty-three patients from 11 centers were analyzed. Outcomes were (1) clinical efficacy of post-PML MS DMT, (2) radiologic efficacy of post-PML MS DMT, (3) radiologic evolution of PML lesion, and (4) disability progression.

Results: There was no clinical worsening of PML symptoms with a stability of Expanded Disability Status Scale at the last follow-up. No relapse was reported with fingolimod and dimethyl fumarate. No radiologic worsening of Nz-PML lesion was observed at the end of the follow-up.

Conclusion: In this large cohort of patients with Nz-PML, MS therapies given after Nz discontinuation were not associated with PML worsening. A larger cohort with longer follow-up will be necessary to confirm this therapeutic strategy.
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http://dx.doi.org/10.1212/NXI.0000000000000346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5462603PMC
May 2017

Imaging markers of multiple sclerosis prognosis.

Curr Opin Neurol 2017 06;30(3):231-236

aCNRS UMR 7225, ICM Institut du Cerveau et de la Moelle épinière, INSERM UMR S 1127, Hopital Pitie-Salpetriere, Paris-Sorbonne University, UPMC bDépartement de Neurologie, APHP, Hopital Pitie-Salpetriere cAPHP, Hopital Saint-Antoine, Paris, France dDepartment of Neurology, University of Texas Health Science Center at Houston, McGovern Medical School, Houston, Texas, USA.

Purpose Of Review: Studies of large longitudinal cohorts of patients with multiple sclerosis (MS) have emphasized the prognostic value of conventional MRI markers, at least during early stages. Advanced imaging metrics derived from quantitative MRI and PET provide relevant information about microstructural damage within and outside visible lesions that may be more sensitive to predict long-term disability. Here, we summarize the most recent findings regarding the prognostic value of imaging markers throughout MS stages.

Recent Findings: In clinically isolated syndrome, the presence of at least one brain or spinal cord T2 lesion strongly increases the risk of conversion to clinically definite MS (hazard ratio ranging from 5 to 11). Similarly, the occurrence of new white matter lesions is strongly predictive of subsequent relapse rate and response to current disease modifying therapies. Beyond white matter lesions, volumetric changes in the grey matter and normal-appearing tissue damage are more sensitive prognostic markers for physical and cognitive disability, especially in progressive MS.

Summary: Although white matter lesion number and volume still remains the imaging metric used in daily clinical practice, further development of advanced imaging predictors of long-term disability should allow a better stratification of patients in future clinical trials aimed at promoting repair or neuroprotection.
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http://dx.doi.org/10.1097/WCO.0000000000000456DOI Listing
June 2017