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1.
Lancet Reg Health Eur ; 44: 100977, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39444703

RESUMO

Multiple sclerosis is a chronic, inflammatory, and neurodegenerative disease of the central nervous system and a major cause of neurological disability in young adults. Its prevalence and incidence are increasing, and it has been estimated at over 2.8 million cases worldwide, in addition to recent trends towards a shift in MS prevalence to older ages, with peak prevalence estimates in the sixth decade of life. Although historically the relapsing and progressive phases of the disease have been considered separate clinical entities, recent evidence of progression independent of relapse activity (PIRA) has led to a reconsideration of multiple sclerosis as a continuum, in which relapsing and progressive features variably coexist from the earliest stages of the disease, challenging the traditional view of the disease course. In this Series article, we provide an overview of how the traditional description of the clinical course of MS and epidemiological trends in Europe have evolved. For this purpose, we focus on the concept of PIRA, discussing its potential as the main mechanism by which patients acquire disability, how its definition varies between studies, and ongoing research in this field. We emphasise the importance of incorporating the assessment of hidden clinical manifestations into patient management to help uncover and quantify the PIRA phenomenon and the possible implications for future changes in the clinical classification of the disease. At the same time, we provide insights into overcoming the challenges of identifying and defining PIRA and adopting a new understanding of the clinical course of MS.

3.
Artigo em Inglês | MEDLINE | ID: mdl-39038948

RESUMO

BACKGROUND: In multiple sclerosis (MS), both lesion accrual and brain atrophy predict clinical outcomes. However, it is unclear whether these prognostic features are equally relevant throughout the course of MS. Among 103 participants recruited following a clinically isolated syndrome (CIS) and followed up over 30 years, we explored (1) whether white matter lesions were prognostically more relevant earlier and brain atrophy later in the disease course towards development of secondary progressive (SP) disease; (2) if so, when the balance in prognostic contribution shifts and (3) whether optimised prognostic models predicting SP disease should include different features dependent on disease duration. METHODS: Binary logistic regression models were built using age, gender, brain lesion counts and locations, and linear atrophy measures (third ventricular width and medullary width) at each time point up to 20 years, using either single time point data alone or adjusted for baseline measures. RESULTS: By 30 years, 27 participants remained CIS while 60 had MS (26 SPMS and 16 MS-related death). Lesions counts were prognostically significant from baseline and at all later time points while linear atrophy measure models reached significance from 5 years. When adjusted for baseline, in combined MRI models including lesion count and linear atrophy measures, only lesion counts were significant predictors. In combined models including relapse measures, Expanded Disability Status Scale scores and MRI measures, only infratentorial lesions were significant predictors throughout. CONCLUSIONS: While SPMS progression is associated with brain atrophy, in predictive models only infratentorial lesions were consistently prognostically significant.

5.
Neurology ; 103(1): e209444, 2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-38889384

RESUMO

Progression independent of relapse activity (PIRA), a recent concept to formalize disability accrual in multiple sclerosis (MS) independent of relapses, has gained popularity as a potential clinical trial outcome. We discuss its shortcomings and appraise the challenges of implementing it in clinical settings, experimental trials, and research. The current definition of PIRA assumes that acute inflammation, which can manifest as a relapse, and neurodegeneration, manifesting as progressive disability accrual, can be disentangled by introducing specific time windows between the onset of relapses and the observed increase in disability. The term PIRMA (progression independent of relapse and MRI activity) was recently introduced to indicate disability accrual in the absence of both clinical relapses and new brain and spinal cord MRI lesions. Assessing PIRMA in clinical practice is highly challenging because it necessitates frequent clinical assessments and brain and spinal cord MRI scans. PIRA is commonly assessed using Expanded Disability Status Scale, a scale heavily weighted toward motor disability, whereas a more granular assessment of disability deterioration, including cognitive decline, using composite measures or other tools, such as digital tools, would possess greater utility. Similarly, using PIRA as an outcome measure in randomized clinical trials is also challenging and requires methodological considerations. The underpinning pathobiology of disability accumulation, that is not associated with relapses, may encompass chronic active lesions (slowly expanding lesions and paramagnetic rim lesions), cortical lesions, brain and spinal cord atrophy, particularly in the gray matter, diffuse and focal microglial activation, persistent leptomeningeal enhancement, and white matter tract damage. We propose to use PIRA to understand the main determinant of disability accrual in observational, cohort studies, where regular MRI scans are not included, and introduce the term of "advanced-PIRMA" to investigate the contributions to disability accrual of the abovementioned processes, using conventional and advanced imaging. This is supported by the knowledge that MRI reflects the MS pathogenic mechanisms better than purely clinical descriptors. Any residual disability accrual, which remains unexplained after considering all these mechanisms with imaging, will highlight future research priorities to help complete our understanding of MS pathogenesis.


Assuntos
Progressão da Doença , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico por imagem , Esclerose Múltipla/fisiopatologia , Esclerose Múltipla/patologia , Imageamento por Ressonância Magnética/métodos , Recidiva , Encéfalo/diagnóstico por imagem , Encéfalo/patologia , Encéfalo/fisiopatologia , Avaliação da Deficiência
6.
Mult Scler ; 30(7): 767-784, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38738527

RESUMO

Artificial intelligence (AI) is the branch of science aiming at creating algorithms able to carry out tasks that typically require human intelligence. In medicine, there has been a tremendous increase in AI applications thanks to increasingly powerful computers and the emergence of big data repositories. Multiple sclerosis (MS) is a chronic autoimmune condition affecting the central nervous system with a complex pathogenesis, a challenging diagnostic process strongly relying on magnetic resonance imaging (MRI) and a high and largely unexplained variability across patients. Therefore, AI applications in MS have the great potential of helping us better support the diagnosis, find markers for prognosis to eventually design more powerful randomised clinical trials and improve patient management in clinical practice and eventually understand the mechanisms of the disease. This topical review aims to summarise the recent advances in AI applied to MRI data in MS to illustrate its achievements, limitations and future directions.


Assuntos
Inteligência Artificial , Imageamento por Ressonância Magnética , Esclerose Múltipla , Humanos , Esclerose Múltipla/diagnóstico por imagem , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos
7.
Mult Scler ; 30(6): 674-686, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38646958

RESUMO

BACKGROUND: Optic neuritis (ON) is a common feature of inflammatory demyelinating diseases (IDDs) such as multiple sclerosis (MS), aquaporin 4-antibody neuromyelitis optica spectrum disorder (AQP4 + NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). However, the involvement of the optic chiasm (OC) in IDD has not been fully investigated. AIMS: To examine OC differences in non-acute IDD patients with (ON+) and without ON (ON-) using magnetisation transfer ratio (MTR), to compare differences between MS, AQP4 + NMOSD and MOGAD and understand their associations with other neuro-ophthalmological markers. METHODS: Twenty-eight relapsing-remitting multiple sclerosis (RRMS), 24 AQP4 + NMOSD, 28 MOGAD patients and 32 healthy controls (HCs) underwent clinical evaluation, MRI and optical coherence tomography (OCT) scan. Multivariable linear regression models were applied. RESULTS: ON + IDD patients showed lower OC MTR than HCs (28.87 ± 4.58 vs 31.65 ± 4.93; p = 0.004). When compared with HCs, lower OC MTR was found in ON + AQP4 + NMOSD (28.55 ± 4.18 vs 31.65 ± 4.93; p = 0.020) and MOGAD (28.73 ± 4.99 vs 31.65 ± 4.93; p = 0.007) and in ON- AQP4 + NMOSD (28.37 ± 7.27 vs 31.65 ± 4.93; p = 0.035). ON+ RRMS had lower MTR than ON- RRMS (28.87 ± 4.58 vs 30.99 ± 4.76; p = 0.038). Lower OC MTR was associated with higher number of ON (regression coefficient (RC) = -1.15, 95% confidence interval (CI) = -1.819 to -0.490, p = 0.001), worse visual acuity (RC = -0.026, 95% CI = -0.041 to -0.011, p = 0.001) and lower peripapillary retinal nerve fibre layer (pRNFL) thickness (RC = 1.129, 95% CI = 0.199 to 2.059, p = 0.018) when considering the whole IDD group. CONCLUSION: OC microstructural damage indicates prior ON in IDD and is linked to reduced vision and thinner pRNFL.


Assuntos
Aquaporina 4 , Autoanticorpos , Esclerose Múltipla Recidivante-Remitente , Glicoproteína Mielina-Oligodendrócito , Neuromielite Óptica , Quiasma Óptico , Tomografia de Coerência Óptica , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Aquaporina 4/imunologia , Autoanticorpos/sangue , Imageamento por Ressonância Magnética , Esclerose Múltipla Recidivante-Remitente/diagnóstico por imagem , Esclerose Múltipla Recidivante-Remitente/imunologia , Esclerose Múltipla Recidivante-Remitente/patologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/patologia , Quiasma Óptico/patologia , Quiasma Óptico/diagnóstico por imagem , Neurite Óptica/imunologia , Neurite Óptica/diagnóstico por imagem , Neurite Óptica/patologia , Adulto Jovem
8.
JAMA Netw Open ; 7(4): e246345, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38607624

RESUMO

Importance: Vaccination in patients with highly active multiple sclerosis (MS) requiring prompt treatment initiation may result in impaired vaccine responses and/or treatment delay. Objective: To assess the immunogenicity and safety of inactivated vaccines administered during natalizumab treatment. Design, Setting, and Participants: This self-controlled, prospective cohort study followed adult patients with MS from 1 study center in Spain from September 2016 to February 2022. Eligible participants included adults with MS who completed immunization for hepatitis B virus (HBV), hepatitis A virus (HAV), and COVID-19 during natalizumab therapy. Data analysis was conducted from November 2022 to February 2023. Exposures: Patients were categorized according to their time receiving natalizumab treatment at the time of vaccine administration as short-term (≤1 year) or long-term (>1 year). Main Outcomes and Measures: Demographic, clinical, and radiological characteristics were collected during the year before vaccination (prevaccination period) and the year after vaccination (postvaccination period). Seroprotection rates and postvaccination immunoglobulin G titers were determined for each vaccine within both periods. Additionally, differences in annualized relapse rate (ARR), new T2 lesions (NT2L), Expanded Disability Status Scale (EDSS) scores, and John Cunningham virus (JCV) serostatus between the 2 periods were assessed. Results: Sixty patients with MS (mean [SD] age, 43.2 [9.4] years; 44 female [73.3%]; 16 male [26.7%]; mean [SD] disease duration, 17.0 [8.7] years) completed HBV, HAV, and mRNA COVID-19 immunization during natalizumab treatment, with 12 patients in the short-term group and 48 patients in the long-term group. The global seroprotection rate was 93% (95% CI, 86%-98%), with individual vaccine rates of 92% for HAV (95% CI, 73%-99%), 93% for HBV (95% CI, 76%-99%), and 100% for the COVID-19 messenger RNA vaccine (95% CI, 84%-100%). Between the prevaccination and postvaccination periods there was a significant reduction in the mean (SD) ARR (0.28 [0.66] vs 0.01 [0.12]; P = .004) and median (IQR) NT2L (5.00 [2.00-10.00] vs 0.81 [0.00-0.50]; P = .01). No changes in disability accumulation were detected (median [IQR] EDSS score 3.5 [2.0-6.0] vs 3.5 [2.0-6.0]; P = .62). No differences in safety and immunogenicity were observed for all vaccines concerning the duration of natalizumab treatment. Conclusions and Relevance: The findings of this cohort study suggest that immunization with inactivated vaccines during natalizumab therapy was both safe and immunogenic, regardless of the treatment duration. Natalizumab may be a valuable option for proper immunization, averting treatment delays in patients with highly active MS; however, this strategy needs to be formally evaluated.


Assuntos
Imunogenicidade da Vacina , Esclerose Múltipla , Natalizumab , Vacinas de Produtos Inativados , Adulto , Feminino , Humanos , Masculino , Estudos de Coortes , Esclerose Múltipla/tratamento farmacológico , Natalizumab/administração & dosagem , Estudos Prospectivos , Vacinas de Produtos Inativados/imunologia , Pessoa de Meia-Idade
9.
Neurology ; 102(7): e209156, 2024 Apr 09.
Artigo em Inglês | MEDLINE | ID: mdl-38447105

RESUMO

BACKGROUND AND OBJECTIVES: We aimed to assess the presence of retinal neurodegeneration independent of optic neuritis (ON) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and to investigate the development of trans-synaptic anterograde degeneration in these patients after ON. METHODS: Cross-sectional, retrospective study of 34 adult patients with MOGAD and 23 healthy controls (HC). Clinical, optical coherence tomography (OCT), and MRI data were collected. Peripapillary retinal nerve fiber layer (pRNFL) and ganglion cell inner plexiform layer (GCIPL) were obtained using Heidelberg Spectralis. FreeSurfer7 was used to obtain the lateral geniculate nucleus (LGN), occipital volume fractions (to total estimated intracranial volume), and occipital cortical thickness. For the anterior visual pathway, the analysis was conducted using eyes, classified based on the history of ON (Eye-ON and Eye-NON) and compared with Eye-HC. The analysis of OCT and brain volumetric measures was conducted comparing MOGAD-ON, MOGAD-NON, and HC groups. The analysis of covariance with a Bonferroni-adjusted post hoc test was used to test differences between groups and linear regression analysis to evaluate OCT/MRI associations; age and sex were considered as covariates. RESULTS: 24 (70.5%) patients had a prior ON. Median pRNFL and GCIPL thickness (um) was significantly reduced in Eye-ON vs EyeNON and HC (pRNFL: 69.4 (17.3), 89.6 (13.7), 98.2 (11.7), p < 0.001; GCIPL: 55.8 (8.7), 67.39 (8.7), 72.6 (4.5), p < 0.001). pRNFL and GCIPL thickness had a negative correlation with the number of ON episodes (p = 0.025 and p = 0.031, respectively). LGN volume fraction was significantly lower in patients with MOGAD-ON than in HC (0.33 (0.05) vs 0.39 (0.04), p = 0.002). The occipital cortical thickness was lower in MOGAD-ON compared with MOGAD-NON and HC (p = 0.010). In patients with MOGAD-ON, pRNFL correlated with LGN volume (p = 0.006), occipital thickness (p = 0.002), and the medial occipital cortex (p = 0.002), but not the lateral occipital lobe. DISCUSSION: Compared with HC, MOGAD-ON exhibits reduced retinal thickness, primarily influenced by the presence and the number of prior ON episodes. Moreover, MOGAD-ON demonstrates significant atrophy in the retinal, subcortical, and cortical regions of the visual pathway, distinguishing them from MOGAD-NON and HC. These findings suggest that in patients with MOGAD neurodegeneration is tightly correlated with damage to the involved pathway.


Assuntos
Neurite Óptica , Vias Visuais , Adulto , Humanos , Glicoproteína Mielina-Oligodendrócito , Vias Visuais/diagnóstico por imagem , Estudos Transversais , Degeneração Retrógrada , Estudos Retrospectivos , Neurite Óptica/diagnóstico por imagem , Retina
10.
Mult Scler ; 30(7): 820-832, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38551315

RESUMO

BACKGROUND: Limited data exist regarding treatment response prediction to oral disease-modifying therapies (DMTs) in multiple sclerosis (MS). OBJECTIVES: We assessed the capacity of available scoring systems to anticipate disease activity parameters in naïve relapsing-remitting MS (RRMS) patients initiating daily oral DMTs, hypothesizing that they exhibit different predictive potentials. METHODS: We conducted a retrospective study and applied the Rio Score (RS), modified Rio Score (mRS), and MAGNIMS Score 12 months after DMT initiation. At 36 months, we examined their ability to predict evidence of disease activity (EDA) components and treatment failure by logistic regression analysis. RESULTS: Notably, 218 patients (62.4% females) initiating dimethyl fumarate, teriflunomide, and fingolimod were included. At 36 months, the RS high-risk group predicted evidence of clinical activity (odds ratio (OR) 10 [2.7-36.9]) and treatment failure (OR 10.6 [3.4-32.5]) but did not predict radiological activity (OR 1.9 [0.7-5]). The mRS non-responders group did not predict EDA and treatment failure. RS, mRS, and MAGNIMS 0 categories showed significantly lower EDA and treatment failure than the remainder. CONCLUSION: Scoring systems present different predictive abilities for disease activity parameters at 36 months in MS patients initiating daily oral therapies, warranting further adjustments (i.e. introduction of fluid biomarkers) to depict disease activity status fully.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Falha de Tratamento , Humanos , Esclerose Múltipla Recidivante-Remitente/tratamento farmacológico , Feminino , Adulto , Masculino , Estudos Retrospectivos , Administração Oral , Pessoa de Meia-Idade , Cloridrato de Fingolimode/administração & dosagem , Fumarato de Dimetilo/administração & dosagem , Crotonatos/administração & dosagem , Hidroxibutiratos , Toluidinas/administração & dosagem , Imunossupressores/administração & dosagem , Nitrilas/administração & dosagem , Prognóstico , Fatores Imunológicos/administração & dosagem
11.
Mult Scler ; 30(4-5): 516-534, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38372019

RESUMO

BACKGROUND: We assessed the ability of a brain-and-cord-matched quantitative magnetic resonance imaging (qMRI) protocol to differentiate patients with progressive multiple sclerosis (PMS) from controls, in terms of normal-appearing (NA) tissue abnormalities, and explain disability. METHODS: A total of 27 patients and 16 controls were assessed on the Expanded Disability Status Scale (EDSS), 25-foot timed walk (TWT), 9-hole peg (9HPT) and symbol digit modalities (SDMT) tests. All underwent 3T brain and (C2-C3) cord structural imaging and qMRI (relaxometry, quantitative magnetisation transfer, multi-shell diffusion-weighted imaging), using a fast brain-and-cord-matched protocol with brain-and-cord-unified imaging readouts. Lesion and NA-tissue volumes and qMRI metrics reflecting demyelination and axonal loss were obtained. Random forest analyses identified the most relevant volumetric/qMRI measures to clinical outcomes. Confounder-adjusted linear regression estimated the actual MRI-clinical associations. RESULTS: Several qMRI/volumetric differences between patients and controls were observed (p < 0.01). Higher NA-deep grey matter quantitative-T1 (EDSS: beta = 7.96, p = 0.006; 9HPT: beta = -0.09, p = 0.004), higher NA-white matter orientation dispersion index (TWT: beta = -3.21, p = 0.005; SDMT: beta = -847.10, p < 0.001), lower whole-cord bound pool fraction (9HPT: beta = 0.79, p = 0.001) and higher NA-cortical grey matter quantitative-T1 (SDMT = -94.31, p < 0.001) emerged as particularly relevant predictors of greater disability. CONCLUSION: Fast brain-and-cord-matched qMRI protocols are feasible and identify demyelination - combined with other mechanisms - as key for disability accumulation in PMS.


Assuntos
Medula Cervical , Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Medula Cervical/patologia , Esclerose Múltipla/patologia , Encéfalo/patologia , Imageamento por Ressonância Magnética/métodos , Esclerose Múltipla Crônica Progressiva/patologia , Substância Cinzenta/patologia
12.
Lancet Infect Dis ; 24(4): 386-394, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38218195

RESUMO

BACKGROUND: Treatment with benznidazole for chronic Chagas disease is associated with low cure rates and substantial toxicity. We aimed to compare the parasitological efficacy and safety of 3 different benznidazole regimens in adult patients with chronic Chagas disease. METHODS: The MULTIBENZ trial was an international, randomised, double-blind, phase 2b trial performed in Argentina, Brazil, Colombia, and Spain. We included participants aged 18 years and older diagnosed with Chagas disease with two different serological tests and detectable T cruzi DNA by qPCR in blood. Previously treated people, pregnant women, and people with severe cardiac forms were excluded. Participants were randomly assigned 1:1:1, using a balanced block randomisation scheme stratified by country, to receive benznidazole at three different doses: 300 mg/day for 60 days (control group), 150 mg/day for 60 days (low dose group), or 400 mg/day for 15 days (short treatment group). The primary outcome was the proportion of patients with a sustained parasitological negativity by qPCR during a follow-up period of 12 months. The primary safety outcome was the proportion of people who permanently discontinued the treatment. Both primary efficacy analysis and primary safety analysis were done in the intention-to-treat population. The trial is registered with EudraCT, 2016-003789-21, and ClinicalTrials.gov, NCT03191162, and is completed. FINDINGS: From April 20, 2017, to Sept 20, 2020, 245 people were enrolled, and 234 were randomly assigned: 78 to the control group, 77 to the low dose group, and 79 to the short treatment group. Sustained parasitological negativity was observed in 42 (54%) of 78 participants in the control group, 47 (61%) of 77 in the low dose group, and 46 (58%) of 79 in the short treatment group. Odds ratios were 1·41 (95% CI 0·69-2·88; p=0·34) when comparing the low dose and control groups and 1·23 (0·61-2·50; p=0·55) when comparing short treatment and control groups. 177 participants (76%) had an adverse event: 62 (79%) in the control group, 56 (73%) in the low dose group, and 59 (77%) in the short treatment group. However, discontinuations were less frequent in the short treatment group compared with the control group (2 [2%] vs 11 [14%]; OR 0·20, 95% CI 0·04-0·95; p=0·044). INTERPRETATION: Participants had a similar parasitological responses. However, reducing the usual treatment from 8 weeks to 2 weeks might maintain the same response while facilitating adherence and increasing treatment coverage. These findings should be confirmed in a phase 3 clinical trial. FUNDING: European Community's 7th Framework Programme.


Assuntos
Doença de Chagas , Nitroimidazóis , Adulto , Humanos , Doença de Chagas/tratamento farmacológico , Método Duplo-Cego , Nitroimidazóis/administração & dosagem , Resultado do Tratamento
13.
Neurology ; 102(1): e207936, 2024 01 09.
Artigo em Inglês | MEDLINE | ID: mdl-38165383

RESUMO

Progression independent of relapse activity (PIRA) is one of the main mechanisms of disability accrual in multiple sclerosis (MS) even in people with relapsing-remitting MS (RRMS).1 PIRA can occur at any stage of the disease and is associated with unfavorable long-term outcomes, especially if PIRA occurs early in the disease course.2 The pathologic substrates of PIRA are not yet well understood, although there is growing evidence suggesting that PIRA may occur mainly in a predominant neurodegenerative context,3-6 sometimes in combination with an acute inflammatory activity.2,5 A deeper understanding of the pathologic processes underlying PIRA represents a vital initial stride toward averting the accumulation of irreversible disability in MS.


Assuntos
Esclerose Múltipla Recidivante-Remitente , Esclerose Múltipla , Humanos , Doença Crônica
14.
J Neurol Neurosurg Psychiatry ; 95(5): 426-433, 2024 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-37979966

RESUMO

BACKGROUND: Lesion resolution is often observed in children with myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and asymptomatic lesions are less commonly reported in MOGAD than in multiple sclerosis (MS). OBJECTIVE: We aimed to evaluate brain MRI changes over time in paediatric MOGAD. METHODS: Retrospective study in eight UK paediatric neuroscience centres. Acute brain MRI and available follow-up MRIs were reviewed. Predictors for lesion dynamic were evaluated using multivariable regression and Kaplan-Meier survival analyses were used to predict risk of relapse, disability and MOG-Ab status. RESULTS: 200 children were included (MOGAD 97; MS 103). At first MRI post attack, new symptomatic and asymptomatic lesions were seen more often in MS versus MOGAD (52/103 vs 28/97; p=0.002 and 37/103 vs 11/97; p<0.001); 83% of patients with MOGAD showed at least one lesion's resolution at first follow-up scan, and 23% had normal MRI. Only 1 patient with MS had single lesion resolution; none had normal MRI. Disappearing lesions in MOGAD were seen in 40% after the second attack, 21% after third attack and none after the fourth attack.New lesions at first follow-up scan were associated with increased likelihood of relapse (p=0.02) and persistent MOG-Ab serostatus (p=0.0016) compared with those with no new lesions. Plasma exchange was associated with increased likelihood of lesion resolution (p=0.01). Longer time from symptom onset to steroids was associated with increased likelihood of new lesions; 50% increase at 20 days (p=0.01). CONCLUSIONS: These striking differences in lesion dynamics between MOGAD and MS suggest greater potential to repair. Early treatment with steroids and plasma exchange is associated with reduced likelihood of new lesions.


Assuntos
Imageamento por Ressonância Magnética , Esclerose Múltipla , Criança , Humanos , Autoanticorpos , Encéfalo/diagnóstico por imagem , Progressão da Doença , Esclerose Múltipla/diagnóstico por imagem , Glicoproteína Mielina-Oligodendrócito , Recidiva , Estudos Retrospectivos , Esteroides
15.
Eur J Neurol ; 31(1): e16092, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-37823722

RESUMO

BACKGROUND AND PURPOSE: Newly appearing lesions in multiple sclerosis (MS) may evolve into chronically active, slowly expanding lesions (SELs), leading to sustained disability progression. The aim of this study was to evaluate the incidence of newly appearing lesions developing into SELs, and their correlation to clinical evolution and treatment. METHODS: A retrospective analysis of a fingolimod trial in primary progressive MS (PPMS; INFORMS, NCT00731692) was undertaken. Data were available from 324 patients with magnetic resonance imaging scans up to 3 years after screening. New lesions at year 1 were identified with convolutional neural networks, and SELs obtained through a deformation-based method. Clinical disability was assessed annually by Expanded Disability Status Scale (EDSS), Nine-Hole Peg Test, Timed 25-Foot Walk, and Paced Auditory Serial Addition Test. Linear, logistic, and mixed-effect models were used to assess the relationship between the Jacobian expansion in new lesions and SELs, disability scores, and treatment status. RESULTS: One hundred seventy patients had ≥1 new lesions at year 1 and had a higher lesion count at screening compared to patients with no new lesions (median = 27 vs. 22, p = 0.007). Among the new lesions (median = 2 per patient), 37% evolved into definite or possible SELs. Higher SEL volume and count were associated with EDSS worsening and confirmed disability progression. Treated patients had lower volume and count of definite SELs (ß = -0.04, 95% confidence interval [CI] = -0.07 to -0.01, p = 0.015; ß = -0.36, 95% CI = -0.67 to -0.06, p = 0.019, respectively). CONCLUSIONS: Incident chronic active lesions are common in PPMS, and fingolimod treatment can reduce their number.


Assuntos
Esclerose Múltipla Crônica Progressiva , Esclerose Múltipla , Humanos , Esclerose Múltipla/tratamento farmacológico , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/patologia , Cloridrato de Fingolimode/uso terapêutico , Estudos Retrospectivos , Incidência , Imageamento por Ressonância Magnética , Esclerose Múltipla Crônica Progressiva/tratamento farmacológico , Esclerose Múltipla Crônica Progressiva/epidemiologia
16.
Lancet Neurol ; 23(1): 22-24, 2024 01.
Artigo em Inglês | MEDLINE | ID: mdl-38101890
17.
Brain Commun ; 5(5): fcad255, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37841069

RESUMO

Multiple sclerosis risk has a well-established polygenic component, yet the genetic contribution to disease course and severity remains unclear and difficult to examine. Accurately measuring disease progression requires long-term study of clinical and radiological outcomes with sufficient follow-up duration to confidently confirm disability accrual and multiple sclerosis phenotypes. In this retrospective study, we explore genetic influences on long-term disease course and severity; in a unique cohort of clinically isolated syndrome patients with homogenous 30-year disease duration, deep clinical phenotyping and advanced MRI metrics. Sixty-one clinically isolated syndrome patients [41 female (67%): 20 male (33%)] underwent clinical and MRI assessment at baseline, 1-, 5-, 10-, 14-, 20- and 30-year follow-up (mean age ± standard deviation: 60.9 ± 6.5 years). After 30 years, 29 patients developed relapsing-remitting multiple sclerosis, 15 developed secondary progressive multiple sclerosis and 17 still had a clinically isolated syndrome. Twenty-seven genes were investigated for associations with clinical outcomes [including disease course and Expanded Disability Status Scale (EDSS)] and brain MRI (including white matter lesions, cortical lesions, and brain tissue volumes) at the 30-year follow-up. Genetic associations with changes in EDSS, relapses, white matter lesions and brain atrophy (third ventricular and medullary measurements) over 30 years were assessed using mixed-effects models. HLA-DRB1*1501-positive (n = 26) patients showed faster white matter lesion accrual [+1.96 lesions/year (0.64-3.29), P = 3.8 × 10-3], greater 30-year white matter lesion volumes [+11.60 ml, (5.49-18.29), P = 1.27 × 10-3] and higher annualized relapse rates [+0.06 relapses/year (0.005-0.11), P = 0.031] compared with HLA-DRB1*1501-negative patients (n = 35). PVRL2-positive patients (n = 41) had more cortical lesions (+0.83 [0.08-1.66], P = 0.042), faster EDSS worsening [+0.06 points/year (0.02-0.11), P = 0.010], greater 30-year EDSS [+1.72 (0.49-2.93), P = 0.013; multiple sclerosis cases: +2.60 (1.30-3.87), P = 2.02 × 10-3], and greater risk of secondary progressive multiple sclerosis [odds ratio (OR) = 12.25 (1.15-23.10), P = 0.031] than PVRL2-negative patients (n = 18). In contrast, IRX1-positive (n = 30) patients had preserved 30-year grey matter fraction [+0.76% (0.28-1.29), P = 8.4 × 10-3], lower risk of cortical lesions [OR = 0.22 (0.05-0.99), P = 0.049] and lower 30-year EDSS [-1.35 (-0.87,-3.44), P = 0.026; multiple sclerosis cases: -2.12 (-0.87, -3.44), P = 5.02 × 10-3] than IRX1-negative patients (n = 30). In multiple sclerosis cases, IRX1-positive patients also had slower EDSS worsening [-0.07 points/year (-0.01,-0.13), P = 0.015] and lower risk of secondary progressive multiple sclerosis [OR = 0.19 (0.04-0.92), P = 0.042]. These exploratory findings support diverse genetic influences on pathological mechanisms associated with multiple sclerosis disease course. HLA-DRB1*1501 influenced white matter inflammation and relapses, while IRX1 (protective) and PVRL2 (adverse) were associated with grey matter pathology (cortical lesions and atrophy), long-term disability worsening and the risk of developing secondary progressive multiple sclerosis.

18.
J Magn Reson Imaging ; 2023 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-37803817

RESUMO

BACKGROUND: The combination of anatomical MRI and deep learning-based methods such as convolutional neural networks (CNNs) is a promising strategy to build predictive models of multiple sclerosis (MS) prognosis. However, studies assessing the effect of different input strategies on model's performance are lacking. PURPOSE: To compare whole-brain input sampling strategies and regional/specific-tissue strategies, which focus on a priori known relevant areas for disability accrual, to stratify MS patients based on their disability level. STUDY TYPE: Retrospective. SUBJECTS: Three hundred nineteen MS patients (382 brain MRI scans) with clinical assessment of disability level performed within the following 6 months (~70% training/~15% validation/~15% inference in-house dataset) and 440 MS patients from multiple centers (independent external validation cohort). FIELD STRENGTH/SEQUENCE: Single vendor 1.5 T or 3.0 T. Magnetization-Prepared Rapid Gradient-Echo and Fluid-Attenuated Inversion Recovery sequences. ASSESSMENT: A 7-fold patient cross validation strategy was used to train a 3D-CNN to classify patients into two groups, Expanded Disability Status Scale score (EDSS) ≥ 3.0 or EDSS < 3.0. Two strategies were investigated: 1) a global approach, taking the whole brain volume as input and 2) regional approaches using five different regions-of-interest: white matter, gray matter, subcortical gray matter, ventricles, and brainstem structures. The performance of the models was assessed in the in-house and the independent external cohorts. STATISTICAL TESTS: Balanced accuracy, sensitivity, specificity, area under receiver operating characteristic (ROC) curve (AUC). RESULTS: With the in-house dataset, the gray matter regional model showed the highest stratification accuracy (81%), followed by the global approach (79%). In the external dataset, without any further retraining, an accuracy of 72% was achieved for the white matter model and 71% for the global approach. DATA CONCLUSION: The global approach offered the best trade-off between internal performance and external validation to stratify MS patients based on accumulated disability. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.

19.
Mult Scler ; 29(14): 1841-1848, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37728389

RESUMO

BACKGROUND: Mumps-Measles-Rubella (MMR) and Varicella zoster vaccines (VAR) are live attenuated vaccines, usually administered in a two-dose scheme at least 4 weeks apart. However, single-dose immunization schemes may also be effective and can reduce delays in immunosuppressive treatment initiation in patients with multiple sclerosis (pwMS) who need to be immunized. OBJECTIVES: To evaluate the immunogenicity of a single-dose attempt (SDA) versus the standard immunization scheme (SIS) with VAR and/or MMR in pwMS. METHODS: Retrospective observational study in pwMS vaccinated against VAR and/or MMR. We compared seroprotection rates and antibody geometric mean titers (GMTs) between the two strategies. RESULTS: Ninety-six patients were included. Thirty-one patients received VAR and 67 MMR. In the SDA group, the seroprotection rate was 66.7% (95% confidence interval (CI): 53.3-78.3) versus 97.2% (95% CI: 85.5-99.9) in the SIS (p < 0.001). For the seroprotected patients, GMTs were similar for both schemes. CONCLUSION: An SDA of VAR and/or MMR vaccines could be sufficient to protect almost two-thirds of patients. Testing immunogenicity after a single dose of VZ and/or MMR could be included in routine clinical practice to achieve rapid immunization.


Assuntos
Sarampo , Esclerose Múltipla , Caxumba , Rubéola (Sarampo Alemão) , Humanos , Lactente , Vacina contra Varicela , Vacinas Atenuadas , Rubéola (Sarampo Alemão)/prevenção & controle , Esclerose Múltipla/tratamento farmacológico , Caxumba/prevenção & controle , Sarampo/prevenção & controle , Vacinação , Anticorpos Antivirais
20.
Ann Neurol ; 2023 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-37705507

RESUMO

OBJECTIVE: Myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) distinguish multiple sclerosis (MS) from MOG-associated disease in most cases. However, studies analyzing MOG-Ab at the time of a first demyelinating event suggestive of MS in adults are lacking. We aimed to (1) evaluate the prevalence of MOG-Ab in a first demyelinating event suggestive of MS and (2) compare clinical and paraclinical features between seropositive (MOG-Ab+) and seronegative (MOG-Ab-) patients. METHODS: Six hundred thirty adult patients with available serum samples obtained within 6 months from the first event were included. MOG-Ab were analyzed using a live cell-based assay. Statistical analyses included parametric and nonparametric tests, logistic regression, and survival models. RESULTS: MOG-Ab were positive in 17 of 630 (2.7%). Fourteen out of 17 (82.4%) MOG-Ab+ patients presented with optic neuritis (ON) compared to 227of 613 (37.0%) MOG-Ab- patients (p = 0.009). Cerebrospinal fluid-restricted oligoclonal bands (CSF-OBs) were found in 2 of 16 (12.5%) MOG-Ab+ versus 371 of 601 (61.7%) MOG-Ab- subjects (p < 0.001). Baseline brain magnetic resonance imaging (MRI) was normal in 9 of 17 (52.9%) MOG-Ab+ versus 153 of 585 (26.2%) MOG-Ab- patients (p = 0.029). Absence of CSF-OBs and ON at onset were independently associated with MOG-Ab positivity (odds ratio [OR] = 9.03, 95% confidence interval [CI] = 2.04-53.6, p = 0.009; and OR = 4.17, 95% CI = 1.15-19.8, p = 0.042, respectively). Of MOG-Ab+ patients, 22.9% (95% CI = 0.0-42.7) compared to 67.6% (95% CI = 63.3-71.3) of MOG-Ab- patients fulfilled McDonald 2017 criteria at 5 years (log-rank p = 0.003). INTERPRETATION: MOG-Ab are infrequent in adults with a first demyelinating event suggestive of MS. However, based on our results, we suggest to determine these antibodies in those patients with ON and absence of CSF-OBs, as long as the brain MRI is not suggestive of MS. ANN NEUROL 2023.

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