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BACKGROUND AND OBJECTIVES: Cognitive impairment (CI) in multiple sclerosis (MS) is frequent and determined by a complex interplay between inflammatory and neurodegenerative processes. We aimed to investigate whether CSF parvalbumin (PVALB), measured at the time of diagnosis, may have a prognostic role in patients with MS. METHODS: In this cohort study, CSF analysis of PVALB and Nf-L levels was performed on all patients at diagnosis (T0) and combined with physical, cognitive, and MRI assessment after an average of 4 years of follow-up (T4) from diagnosis. Cognitive performance was evaluated with a comprehensive neuropsychologic battery: both global (cognitively normal, CN, mildly CI, mCI, and severely CI, sCI) and domain cognitive status (normal/impaired in memory, attention/information processing speed, and executive functions) were considered. Cortical thickness and gray matter volume data were acquired using 3T MRI scanner. RESULTS: A total of 72 patients with MS were included. At diagnosis, PVALB levels were higher in those patients who showed a worsening physical disability after 4 years of follow-up (p = 0.011). CSF PVALB levels were higher in sCI patients than in CN (p = 0.033). Moreover, higher PVALB levels significantly correlated with worse global cognitive (p = 0.024) and memory functioning (p = 0.044). A preliminary clinical threshold for PVALB levels at diagnosis was proposed (2.57 ng/mL), which maximizes the risk of showing CI (in particular, sCI) at follow-up, with a sensitivity of 91% (specificity 30%). No significant results were found for these associations with Nf-L. In addition, patients with higher levels of PVALB at diagnosis showed higher cognitive (p = 0.024) and global fatigue (p = 0.043) at follow-up. Finally, higher PVALB levels also correlated significantly with more pronounced CTh/volume at T4 in the inferior frontal gyrus (p = 0.044), postcentral gyrus (p = 0.025), frontal pole (p = 0.042), transverse temporal gyrus (p = 0.008), and cerebellar cortex (p = 0.041) and higher atrophy (change T0-T4) in the right thalamus (p = 0.038), pericalcarine cortex (p = 0.009), lingual gyrus (p = 0.045), and medial frontal gyrus (p = 0.028). DISCUSSION: The significant association found between parvalbumin levels in the CSF at diagnosis and cognitive, clinical, and neuroradiologic worsening after 4 years of follow-up support the idea that parvalbumin, in addition to Nf-L, might represent a new potential prognostic biomarker, reflecting MS neurodegenerative processes occurring since early disease stages.

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Disfunción Cognitiva , Fatiga , Sustancia Gris , Esclerosis Múltiple , Parvalbúminas , Humanos , Masculino , Femenino , Disfunción Cognitiva/líquido cefalorraquídeo , Disfunción Cognitiva/etiología , Disfunción Cognitiva/diagnóstico , Persona de Mediana Edad , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Adulto , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/diagnóstico por imagen , Parvalbúminas/líquido cefalorraquídeo , Fatiga/líquido cefalorraquídeo , Fatiga/etiología , Imagen por Resonancia Magnética , Pronóstico , Estudios de Seguimiento , Estudios de Cohortes , Progresión de la Enfermedad , Biomarcadores/líquido cefalorraquídeo , Proteínas de Neurofilamentos

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OBJECTIVE: The aim of this study was to provide a classification of the upper limb patterns in patients with upper limb spasticity due to multiple sclerosis. DESIGN: Pilot observational study. PATIENTS: Twenty-five adult patients with multiple sclerosis suffering from upper limb spasticity who underwent one segmental (i.e., proximal and distal upper limb) botulinum toxin treatment cycle were recruited. METHODS: Patients remained in a sitting position during the evaluation. Upper limb spasticity postures (i.e., postural attitude of a single joint/anatomical region) were evaluated and recorded for the shoulder (adducted/internally rotated), elbow (flexed/extended), forearm (pronated/supinated/neutral), wrist (flexed/extended/neutral) and hand (fingers flexed/thumb in palm). RESULTS: On the basis of the clinical observations, 6 patterns (i.e., sets of limb postures) of upper limb spasticity have been described according to the postures of the shoulder, elbow, forearm, and wrist. CONCLUSION: The patterns of upper limb spasticity in patients with multiple sclerosis described by this pilot study do not completely overlap with those observed in patients with post-stroke spasticity. This further supports the need to consider the features of spasticity related to its aetiology in order to manage patients appropriately.

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Esclerosis Múltiple , Espasticidad Muscular , Extremidad Superior , Humanos , Espasticidad Muscular/etiología , Espasticidad Muscular/fisiopatología , Proyectos Piloto , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/fisiopatología , Femenino , Masculino , Persona de Mediana Edad , Extremidad Superior/fisiopatología , Adulto , Postura/fisiología , Anciano

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Progression independent of relapse activity (PIRA) has been recently proposed in multiple sclerosis (MS) as a model identifying a continuous silent progression of disability without the manifestation of new clinical and magnetic resonance imaging (MRI) events that contribute to MS worsening. Despite evidence suggesting that clinical MS manifestations often affect cognitive functioning and the importance of neuropsychological monitoring over time, attention to silent cognitive progression is lacking, and the PIRA concept does not include a measure of cognitive function. In this personal viewpoint, we highlight the need to include cognition in the PIRA model to have a more comprehensive understanding of clinical progression in patients with MS.

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Tumor necrosis factor (TNF) is a pleiotropic cytokine regulating many physiological and pathological immune-mediated processes. Specifically, it has been recognized as an essential pro-inflammatory cytokine implicated in multiple sclerosis (MS) pathogenesis and progression. MS is a chronic immune-mediated disease of the central nervous system, characterized by multifocal acute and chronic inflammatory demyelination in white and grey matter, along with neuroaxonal loss. A recent concept in the field of MS research is disability resulting from Progression Independent of Relapse Activity (PIRA). PIRA recognizes that disability accumulation since the early phase of the disease can occur independently of relapse activity overcoming the traditional dualistic view of MS as either a relapsing-inflammatory or a progressive-neurodegenerative disease. Several studies have demonstrated an upregulation in TNF expression in both acute and chronic active MS brain lesions. Additionally, elevated TNF levels have been observed in the serum and cerebrospinal fluid of MS patients. TNF appears to play a significant role in maintaining chronic intrathecal inflammation, promoting axonal damage neurodegeneration, and consequently contributing to disease progression and disability accumulation. In summary, this review highlights the current understanding of TNF and its receptors in MS progression, specifically focusing on the relatively unexplored PIRA condition. Further research in this area holds promise for potential therapeutic interventions targeting TNF to mitigate disability in MS patients.

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Progresión de la Enfermedad , Esclerosis Múltiple , Factor de Necrosis Tumoral alfa , Humanos , Esclerosis Múltiple/patología , Esclerosis Múltiple/metabolismo , Animales , Factor de Necrosis Tumoral alfa/metabolismo , Recurrencia

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Despite therapeutic suppression of relapses, multiple sclerosis (MS) patients often experience subtle deterioration, which extends beyond the definition of "progression independent of relapsing activity." We propose the concept of smouldering-associated-worsening (SAW), encompassing physical and cognitive symptoms, resulting from smouldering pathological processes, which remain unmet therapeutic targets. We provide a consensus-based framework of possible pathological substrates and manifestations of smouldering MS, and we discuss clinical, radiological, and serum/cerebrospinal fluid biomarkers for potentially monitoring SAW. Finally, we share considerations for optimizing disease surveillance and implications for clinical trials to promote the integration of smouldering MS into routine practice and future research efforts. ANN NEUROL 2024.

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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.

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Progresión de la Enfermedad , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/patología , Imagen por Resonancia Magnética/métodos , Recurrencia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Encéfalo/fisiopatología , Evaluación de la Discapacidad

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OBJECTIVE: Cognitive and affective symptoms in multiple sclerosis (MS) can be independently impaired and have different pathways of progression. Cognitive alterations have been described since the earliest MS stages; by contrast, the social cognition (SC) domain has never been investigated in the first year from MS diagnosis. We aimed to evaluate SC and unravel its neural bases in newly diagnosed MS patients. METHODS: Seventy MS patients underwent at diagnosis a 3 T-MRI and a neuropsychological/SC assessment (median time between diagnosis and MRI/cognitive evaluation = 0 months). We tested two matched reference samples: 31 relapsing-remitting MS patients with longer course (mean ± SD disease duration = 7.0 ± 4.5 years) and 38 healthy controls (HCs). Cortical thicknesses (CTh) and volumes of brain regions were calculated. RESULTS: Newly diagnosed MS patients performed significantly lower than HCs in facial emotion recognition (global: p < 0.001; happiness: p = 0.041, anger: p = 0.007; fear: p < 0.001; disgust: p = 0.004) and theory of mind (p = 0.005), while no difference was found between newly diagnosed and longer MS patients. Compared to lower performers, higher performers in facial emotion recognition showed greater volume of amygdala (p = 0.032) and caudate (p = 0.036); higher performers in theory of mind showed greater CTh in lingual gyrus (p = 0.006), cuneus (p = 0.024), isthmus cingulate (p = 0.038), greater volumes of putamen (p = 0.016), pallidum (p = 0.029), and amygdala (p = 0.032); patients with higher empathy showed lower cuneus CTh (p = 0.042) and putamen volume (p = 0.007). INTERPRETATIONS: SC deficits are present in MS patients since the time of diagnosis and remain persistent along the disease course. Specific basal, limbic, and occipital areas play a significant role in the pathogenesis of these alterations.

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Reconocimiento Facial , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente , Cognición Social , Humanos , Masculino , Femenino , Adulto , Reconocimiento Facial/fisiología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/patología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/diagnóstico por imagen , Persona de Mediana Edad , Teoría de la Mente/fisiología , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/patología , Esclerosis Múltiple/complicaciones , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiopatología , Corteza Cerebral/patología

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BACKGROUND AND OBJECTIVES: To evaluate CSF inflammatory markers with accumulation of cortical damage as well as disease activity in patients with early relapsing-remitting MS (RRMS). METHODS: CSF levels of osteopontin (OPN) and 66 inflammatory markers were assessed using an immune-assay multiplex technique in 107 patients with RRMS (82 F/25 M, mean age 35.7 ± 11.8 years). All patients underwent regular clinical assessment and yearly 3T MRI scans for 2 years while 39 patients had a 4-year follow-up. White matter lesion number and volume, cortical lesions (CLs) and volume, and global cortical thickness (CTh) were evaluated together with the 'no evidence of disease activity' (NEDA-3) status, defined by no relapses, no disability worsening, and no MRI activity, including CLs. RESULTS: The random forest algorithm selected OPN, CXCL13, TWEAK, TNF, IL19, sCD30, sTNFR1, IL35, IL16, and sCD163 as significantly associated with changes in global CTh. OPN and CXCL13 were most related to accumulation of atrophy after 2 and 4 years. In a multivariate linear regression model on CSF markers, OPN (p < 0.001), CXCL13 (p = 0.001), and sTNFR1 (p = 0.024) were increased in those patients with accumulating atrophy (adjusted R-squared 0.615). The 10 markers were added in a model that included all clinical, demographic, and MRI variables: OPN (p = 0.002) and IL19 (p = 0.022) levels were confirmed to be significantly increased in patients developing more CTh change over the follow-up (adjusted R-squared 0.619). CXCL13 and OPN also revealed the best association with NEDA-3 after 2 years, with OPN significantly linked to disability accumulation (OR 2.468 [1.46-5.034], p = 0.004) at the multivariate logistic regression model. DISCUSSION: These data confirm and expand our knowledge on the prognostic role of the CSF inflammatory profile in predicting changes in cortical pathology and disease activity in early MS. The data emphasize a crucial role of OPN.

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Atrofia , Corteza Cerebral , Esclerosis Múltiple Recurrente-Remitente , Osteopontina , Humanos , Osteopontina/líquido cefalorraquídeo , Femenino , Masculino , Adulto , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Atrofia/patología , Persona de Mediana Edad , Corteza Cerebral/patología , Corteza Cerebral/diagnóstico por imagen , Imagen por Resonancia Magnética , Biomarcadores/líquido cefalorraquídeo , Estudios de Seguimiento , Adulto Joven , Progresión de la Enfermedad

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Clinical, pathological, and imaging evidence in multiple sclerosis (MS) suggests that a smoldering inflammatory activity is present from the earliest stages of the disease and underlies the progression of disability, which proceeds relentlessly and independently of clinical and radiological relapses (PIRA). The complex system of pathological events driving "chronic" worsening is likely linked with the early accumulation of compartmentalized inflammation within the central nervous system as well as insufficient repair phenomena and mitochondrial failure. These mechanisms are partially lesion-independent and differ from those causing clinical relapses and the formation of new focal demyelinating lesions; they lead to neuroaxonal dysfunction and death, myelin loss, glia alterations, and finally, a neuronal network dysfunction outweighing central nervous system (CNS) compensatory mechanisms. This review aims to provide an overview of the state of the art of neuropathological, immunological, and imaging knowledge about the mechanisms underlying the smoldering disease activity, focusing on possible early biomarkers and their translation into clinical practice. ANN NEUROL 2024;96:1-20.

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Biomarcadores , Progresión de la Enfermedad , Esclerosis Múltiple , Humanos , Biomarcadores/metabolismo , Esclerosis Múltiple/patología , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/metabolismo , Recurrencia

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BACKGROUND: In the general population, maternal COVID-19 is associated with worse maternal and fetal outcomes. Two previous studies have assessed COVID-19 clinical outcomes in pregnant women with multiple sclerosis (MS), but there are no data about maternal and fetal outcomes. OBJECTIVES: In this multicenter study, we aimed to assess maternal and fetal outcomes in pregnant women with MS and COVID-19 infection. METHODS: We recruited pregnant patients with MS who contracted COVID-19 and were followed up in Italian and Turkish Centers, during 2020-2022. A control group was extracted from a previous Italian cohort. Associations between group (COVID-19 or healthy patients) and clinical outcomes (maternal complications, fetal malformations, and spontaneous abortion) were investigated with a weighted logistic regression where propensity score-based inverse probability of treatment weighting (IPTW) approach was applied for adjusting for difference in baseline confounders. RESULTS: In the multivariable analysis, COVID-19 during pregnancy was associated with a higher risk of maternal complications (odd ratio (OR) = 2.12; 95% confidence interval (CI) = 1.32-3.48; p = 0.002), while it was not associated with higher risk of spontaneous abortion and fetal malformations. CONCLUSION: Our data indicate that COVID-19 during pregnancy increases the risk of maternal complications, while it seems to have no significant impact on fetal outcomes.

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Aborto Espontáneo , COVID-19 , Esclerosis Múltiple , Resultado del Embarazo , Humanos , Femenino , Embarazo , COVID-19/complicaciones , COVID-19/epidemiología , Adulto , Esclerosis Múltiple/epidemiología , Resultado del Embarazo/epidemiología , Aborto Espontáneo/epidemiología , Italia/epidemiología , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones del Embarazo/epidemiología , Turquía/epidemiología

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We compared choroid plexus (ChP) manual segmentation on non-contrast-enhanced (non-CE) sequences and reference standard CE T1- weighted (T1w) sequences in 61 multiple sclerosis patients prospectively included. ChP was separately segmented on T1w, T2-weighted (T2w) fluid-attenuated inversion-recovery (FLAIR), and CE-T1w sequences. Inter-rater variability assessed on 10 subjects showed high reproducibility between sequences measured by intraclass correlation coefficient (T1w 0.93, FLAIR 0.93, CE-T1w 0.99). CE-T1w showed higher signal-to-noise ratio and contrast-to-noise ratio (CE-T1w 23.77 and 18.49, T1w 13.73 and 7.44, FLAIR 13.09 and 10.77, respectively). Manual segmentation of ChP resulted 3.073 ± 0.563 mL (mean ± standard deviation) on T1w, 3.787 ± 0.679 mL on FLAIR, and 2.984 ± 0.506 mL on CE-T1w images, with an error of 28.02 ± 19.02% for FLAIR and 3.52 ± 12.61% for T1w. FLAIR overestimated ChP volume compared to CE-T1w (p < 0.001). The Dice similarity coefficient of CE-T1w versus T1w and FLAIR was 0.67 ± 0.05 and 0.68 ± 0.05, respectively. Spatial error distribution per slice was calculated after nonlinear coregistration to the standard MNI152 space and showed a heterogeneous profile along the ChP especially near the fornix and the hippocampus. Quantitative analyses suggest T1w as a surrogate of CE-T1w to estimate ChP volume.Relevance statement To estimate the ChP volume, CE-T1w can be replaced by non-CE T1w sequences because the error is acceptable, while FLAIR overestimates the ChP volume. This encourages the development of automatic tools for ChP segmentation, also improving the understanding of the role of the ChP volume in multiple sclerosis, promoting longitudinal studies.Key points • CE-T1w sequences are considered the reference standard for ChP manual segmentation.• FLAIR sequences showed a higher CNR than T1w sequences but overestimated the ChP volume.• Non-CE T1w sequences can be a surrogate of CE-T1w sequences for manual segmentation of ChP.

Asunto(s)

Esclerosis Múltiple , Humanos , Esclerosis Múltiple/diagnóstico por imagen , Reproducibilidad de los Resultados , Plexo Coroideo/diagnóstico por imagen , Imagen por Resonancia Magnética , Relación Señal-Ruido

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Background: Cladribine has been introduced as a high-efficacy drug for treating relapsing-remitting multiple sclerosis (RRMS). Initial cohort studies showed early disease activity in the first year after drug initiation. Biomarkers that can predict early disease activity are needed. Aim: To estimate cerebrospinal fluid (CSF) markers of clinical and radiological responses after initiation of cladribine. Methods: Forty-two RRMS patients (30F/12M) treated with cladribine were included in a longitudinal prospective study. All patients underwent a CSF examination at treatment initiation, clinical follow-up including Expanded Disability Status Scale (EDSS) assessment, and a 3T MRI scan after 6,12 and 24 months, including the evaluation of white matter (WM) and cortical lesions (CLs). CSF levels of 67 inflammatory markers were assessed with immune-assay multiplex techniques. The 'no evidence of disease activity' (NEDA-3) status was assessed after two years and defined by no relapses, no disability worsening measured by EDSS and no MRI activity, including CLs. Results: Three patients were lost at follow-up. At the end of follow-up, 19 (48%) patients remained free from disease activity. IFNgamma, Chitinase3like1, IL32, Osteopontin, IL12(p40), IL34, IL28A, sTNFR2, IL20 and CCL2 showed the best association with disease activity. When added in a multivariate regression model including age, sex, and baseline EDSS, Chitinase 3 like1 (p = 0.049) significantly increased in those patients with disease activity. Finally, ROC analysis with Chitinase3like1 added to a model with EDSS, sex, age previous relapses, WM lesion number, CLs, number of Gad enhancing lesions and spinal cord lesions provided an AUC of 0.76 (95%CI 0.60-0.91). Conclusions: CSF Chitinase 3 like1 might provide prognostic information for predicting disease activity in the first years after initiation of cladribine. The drug's effect on chronic macrophage and microglia activation deserves further evaluation.

Asunto(s)

Proteína 1 Similar a Quitinasa-3 , Cladribina , Esclerosis Múltiple Recurrente-Remitente , Humanos , Cladribina/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Estudios Prospectivos , Proteína 1 Similar a Quitinasa-3/líquido cefalorraquídeo

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INTRODUCTION: Ocrelizumab (OCR) and Fingolimod (FGL) are two high-efficacy treatments in multiple sclerosis which, besides their strong anti-inflammatory activity, may limit neurodegeneration. AIM: To compare the effect of OCR and FGL on clinical and MRI endpoints. METHODS: 95 relapsing-remitting patients (57 OCR, 38 FGL) clinically followed for 36 months underwent a 3-Tesla MRI at baseline and after 24 months. The annualized relapse rate, EDSS, new cortical/white matter lesions and regional cortical and deep grey matter volume loss were evaluated. RESULTS: OCR reduced the relapse rate from 0.48 to 0.04, FGL from 0.32 to 0.05 (both p < 0.001). Compared to FGL, OCR-group experienced fewer new white matter lesions (12% vs 32%, p = 0.005), no differences in new cortical lesions, lower deep grey matter volume loss (- 0.12% vs - 0.66%; p = 0.002, Cohen's d = 0.54), lower global cortical thickness change (- 0.45% vs - 0.70%; p = 0.036; d = 0.42) and reduced cortical thinning/volume loss in several regions of interests, including those of parietal gyrus (d-range = 0.65-0.71), frontal gyrus (d-range = 0.47-0.60), cingulate (d-range = 0.41-0.72), insula (d = 0.36), cerebellum (cortex d = 0.72, white matter d = 0.44), putamen (d = 0.35) and thalamus (d = 0.31). The effect on some regional thickness changes was confirmed in patients without focal lesions. CONCLUSIONS: When compared with FGL, patients receiving OCR showed greater suppression of focal MRI lesions accumulation and lower cortical and deep grey matter volume loss.

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Anticuerpos Monoclonales Humanizados , Clorhidrato de Fingolimod , Sustancia Gris , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente , Humanos , Femenino , Masculino , Adulto , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Sustancia Gris/efectos de los fármacos , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Anticuerpos Monoclonales Humanizados/uso terapéutico , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/patología , Persona de Mediana Edad , Clorhidrato de Fingolimod/farmacología , Clorhidrato de Fingolimod/uso terapéutico , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/patología , Corteza Cerebral/efectos de los fármacos , Moduladores de los Receptores de fosfatos y esfingosina 1/farmacología , Factores Inmunológicos/farmacología , Factores Inmunológicos/administración & dosificación , Estudios de Seguimiento

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Importance: Multiple sclerosis (MS) misdiagnosis remains an important issue in clinical practice. Objective: To quantify the performance of cortical lesions (CLs) and central vein sign (CVS) in distinguishing MS from other conditions showing brain lesions on magnetic resonance imaging (MRI). Design, Setting, and Participants: This was a retrospective, cross-sectional multicenter study, with clinical and MRI data acquired between January 2010 and May 2020. Centralized MRI analysis was conducted between July 2020 and December 2022 by 2 raters blinded to participants' diagnosis. Participants were recruited from 14 European centers and from a multicenter pan-European cohort. Eligible participants had a diagnosis of MS, clinically isolated syndrome (CIS), or non-MS conditions; availability of a brain 3-T MRI scan with at least 1 sequence suitable for CL and CVS assessment; presence of T2-hyperintense white matter lesions (WMLs). A total of 1051 individuals were included with either MS/CIS (n = 599; 386 [64.4%] female; mean [SD] age, 41.5 [12.3] years) or non-MS conditions (including other neuroinflammatory disorders, cerebrovascular disease, migraine, and incidental WMLs in healthy control individuals; n = 452; 302 [66.8%] female; mean [SD] age, 49.2 [14.5] years). Five individuals were excluded due to missing clinical or demographic information (n = 3) or unclear diagnosis (n = 2). Exposures: MS/CIS vs non-MS conditions. Main Outcomes and Measures: Area under the receiver operating characteristic curves (AUCs) were used to explore the diagnostic performance of CLs and the CVS in isolation and in combination; sensitivity, specificity, and accuracy were calculated for various cutoffs. The diagnostic importance of CLs and CVS compared to conventional MRI features (ie, presence of infratentorial, periventricular, and juxtacortical WMLs) was ranked with a random forest model. Results: The presence of CLs and the previously proposed 40% CVS rule had a sensitivity, specificity, and accuracy for MS of 59.0% (95% CI, 55.1-62.8), 93.6% (95% CI, 91.4-95.6), and 73.9% (95% CI, 71.6-76.3) and 78.7% (95% CI, 75.5-82.0), 86.0% (95% CI, 82.1-89.5), and 81.5% (95% CI, 78.9-83.7), respectively. The diagnostic performance of the CVS (AUC, 0.89 [95% CI, 0.86-0.91]) was superior to that of CLs (AUC, 0.77 [95% CI, 0.75-0.80]; P < .001), and was increased when combining the 2 imaging markers (AUC, 0.92 [95% CI, 0.90-0.94]; P = .04); in the random forest model, both CVS and CLs outperformed the presence of infratentorial, periventricular, and juxtacortical WMLs in supporting MS differential diagnosis. Conclusions and Relevance: The findings in this study suggest that CVS and CLs may be valuable tools to increase the accuracy of MS diagnosis.

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Enfermedades Desmielinizantes , Esclerosis Múltiple , Humanos , Femenino , Adulto , Persona de Mediana Edad , Masculino , Esclerosis Múltiple/diagnóstico , Estudios Retrospectivos , Estudios Transversales , Encéfalo/patología , Venas/patología , Enfermedades Desmielinizantes/patología , Imagen por Resonancia Magnética/métodos

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BACKGROUND: Cognitive phenotyping may be useful for predicting rehabilitation response in multiple sclerosis. OBJECTIVE: To evaluate the association between cognitive phenotype(s) and response to restorative cognitive rehabilitation (RRCR). METHODS: In a post hoc retrospective analysis of the RRCR study including 51 multiple sclerosis patients, we evaluated both impairment within specific cognitive domains as well as overall global impairment severity to investigate their relationship to improvement following rehabilitation. RESULTS: Greater improvement in executive function was predicted by impairment within this domain as well as by having fewer impaired cognitive domains overall. Similar results were observed for visuospatial memory. CONCLUSIONS: Patients most likely to benefit from restorative cognitive rehabilitation may exhibit impairment within the domain of interest yet lower cognitive burden overall.

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Trastornos del Conocimiento , Disfunción Cognitiva , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/psicología , Trastornos del Conocimiento/psicología , Estudios Retrospectivos , Entrenamiento Cognitivo , Disfunción Cognitiva/psicología , Pruebas Neuropsicológicas , Cognición

RESUMEN

BACKGROUND: COVID-19 vaccines have been recommended to people with multiple sclerosis (pwMS) and, to ensure durable immunity, a third booster dose has been administered in several countries. Data about potential risks associated with the third booster dose in pwMS, such as vaccine-triggered disease exacerbations, are still scarce. OBJECTIVE: To investigate whether the administration of a third booster dose of mRNA COVID-19 vaccines was associated with an increased risk of short-term disease reactivation in a large cohort of pwMS. METHODS: We retrospectively selected 1265 pwMS who received a third booster dose of an mRNA COVID-19 vaccine. Demographic and clinical data were collected, including the presence, number and characteristics of relapses in the 60 days prior to and after the third booster dose. RESULTS: In the selected cohort, the relapse rate in the two months after administration of the third booster dose of mRNA COVID-19 vaccines did not increase when compared with the prior two months. Indeed, the percentage of pwMS experiencing relapses in the 60 days following the administration of the third booster dose was 2.1%, similar to the percentage recorded in 60 days prior to vaccination, which was 1.9%. CONCLUSIONS: The third booster dose of mRNA COVID-19 vaccines appeared to be safe for pwMS.

Asunto(s)

Vacunas contra la COVID-19 , COVID-19 , Esclerosis Múltiple , Humanos , Anticuerpos Antivirales , Enfermedad Crónica , COVID-19/prevención & control , Vacunas contra la COVID-19/efectos adversos , Esclerosis Múltiple/complicaciones , Recurrencia , Estudios Retrospectivos , Vacunación/efectos adversos , Inmunización Secundaria/efectos adversos , Vacunas de ARNm/efectos adversos

RESUMEN

Ocrelizumab is a recombinant humanized monoclonal antibody selectively targeting CD20-expressing B cells. The effect of ocrelizumab on primary progressive multiple sclerosis (PPMS) has been evaluated during phase 3 trials that enrolled patients under 55 years with a maximum Expanded Disability Status Scale (EDSS) of 6.5. However, little is known on older disabled patients with longer disease duration. We aimed to assess the clinical effectiveness of ocrelizumab in PPMS patients out of the ORATORIO eligibility criteria. This multicenter retrospective study collected data about the effectiveness of ocrelizumab in PPMS patients who received treatment between May 2017 and June 2022 in the Italian MS centers contributing to the Italian MS Registry who adhered to the Compassionate Use Program. The confirmed EDSS worsening (CEW) (defined as either a ≥ 1-point or ≥ 2-point increase in EDSS score from baseline that was confirmed at T12 and T24) was calculated. At the date of data extraction, out of 887 PPMS patients who had received ocrelizumab, 589 (mean age 49.7 ± 10.7 years, 242 (41.1%) females) were enrolled. The mean follow-up period was 41.3 ± 12.3 months. A total of 149 (25.3%) received ocrelizumab according to the ORATORIO criteria (ORATORIO group) and 440 (74.7%) outside the ORATORIO criteria (non-ORATORIO group). No differences in terms of cumulative probabilities of 12 and 24 months of CEW of ≤ 1 point were found between ORATORIO and non-ORATORIO groups. Cox regression analyses showed that age older than 65 years (HR 2.51, 25% CI 1.07-3.65; p = 0.01) was associated with higher risk of CEW at 24 months. Patients not responding to ORATORIO criteria for reimbursability may benefit from ocrelizumab treatment, as disease activity, disease duration, and EDSS seem to not impact the disability outcome. Our results may suggest to extend the possible use of this powerful agent in selected patients under the age of 65 years.

Asunto(s)

Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Femenino , Humanos , Adulto , Persona de Mediana Edad , Anciano , Masculino , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Estudios Retrospectivos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Factores Inmunológicos/farmacología

RESUMEN

BACKGROUND: Covid-19 pandemic impacted on management of people with Multiple Sclerosis (pwMS). Level of satisfaction of pwMS regarding the care received by the staff of Multiple Sclerosis Centers (MSCs) during the pandemic was not fully investigated. In a large patient-centered multicenter study, the therapeutic adherence and quality of care of MSCs was assessed. METHODS: In April-May 2021, an online survey was widespread by 16 Italian MSCs. Frequencies, percentages and/or means and standard deviations were calculated to describe the sample. ANOVAs were performed to evaluate the effect of sociodemographic and clinical variables on overall pwMS' rating of MSC assistance. RESULTS: 1670 pwMS completed the survey (67.3% women). During the pandemic, 88% did not change their disease modifying therapy schedule, and 89.1% reached their MSCs with no or little difficulties. Even if only 1.3% of participants underwent a tele-health follow-up visit with their MSC staff, the 80.1% believed that tele-health services should be improved regardless of pandemic. 92% of participants were satisfied of how their MSC took charge of their needs; ANOVAs revealed an effect of disease duration on pwMS' level of satisfaction on MSCs management during the pandemic. CONCLUSIONS: The results revealed an efficient MSCs response to Covid-19 pandemic and provided the basis for the implementing of tele-health services that would further improve the taking charge of patients, particularly those with longer disease, higher disability, and/or living far from their MSC.

Asunto(s)

COVID-19 , Esclerosis Múltiple , Humanos , Femenino , Masculino , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/terapia , Pandemias , Proteínas del Tejido Nervioso , Atención Dirigida al Paciente , Calidad de la Atención de Salud

RESUMEN

Growing evidence from cerebrospinal fluid samples and post-mortem brain tissue from individuals with multiple sclerosis (MS) and rodent models indicates that the meninges have a key role in the inflammatory and neurodegenerative mechanisms underlying progressive MS pathology. The subarachnoid space and associated perivascular spaces between the membranes of the meninges are the access points for entry of lymphocytes, monocytes and macrophages into the brain parenchyma, and the main route for diffusion of inflammatory and cytotoxic molecules from the cerebrospinal fluid into the brain tissue. In addition, the meningeal spaces act as an exit route for CNS-derived antigens, immune cells and metabolites. A number of studies have demonstrated an association between chronic meningeal inflammation and a more severe clinical course of MS, suggesting that the build-up of immune cell aggregates in the meninges represents a rational target for therapeutic intervention. Therefore, understanding the precise cell and molecular mechanisms, timing and anatomical features involved in the compartmentalization of inflammation within the meningeal spaces in MS is vital. Here, we present a detailed review and discussion of the cellular, molecular and radiological evidence for a role of meningeal inflammation in MS, alongside the clinical and therapeutic implications.

Asunto(s)

Esclerosis Múltiple , Humanos , Sustancia Gris/metabolismo , Sustancia Gris/patología , Corteza Cerebral/patología , Meninges/metabolismo , Meninges/patología , Inflamación , Progresión de la Enfermedad

RESUMEN

Fatigue is frequently reported by patients with multiple sclerosis, aquaporin-4-antibody neuromyelitis optica spectrum disorder and myelin-oligodendrocyte-glycoprotein antibody disease; thus they could share a similar pathophysiological mechanism. In this cross-sectional cohort study, we assessed the association of fatigue with resting-state functional MRI, diffusion and structural imaging measures across these three disorders. Sixteen patients with multiple sclerosis, 17 with aquaporin-4-antibody neuromyelitis optica spectrum disorder and 17 with myelin-oligodendrocyte-glycoprotein antibody disease assessed, outside of relapses, at the Oxford Neuromyelitis Optica Service underwent Modified Fatigue Impact Scale, Hospital Anxiety and Depression Scale and Expanded Disability Status Scale scoring. A 3T brain and spinal cord MRI was used to derive cortical, deep grey and white matter volumetrics, lesions volume, fractional anisotropy, brain functional connectivity metrics, cervical spinal cord cross-sectional area, spinal cord magnetic transfer ratio and average functional connectivity between the ventral and the dorsal horns of the cervical cord. Linear relationships between MRI measures and total-, cognitive- and physical-fatigue scores were assessed. All analyses were adjusted for correlated clinical regressors. No significant differences in baseline clinical characteristics, fatigue, depression and anxiety questionnaires and disability measures were seen across the three diseases, except for older age in patients with aquaporin-4-antibody neuromyelitis optica spectrum disorder (P = 0.0005). In the total cohort, median total-fatigue score was 35.5 (range 3-72), and 42% of patients were clinically fatigued. A positive correlation existed between the total-fatigue score and functional connectivity of the executive/fronto-temporal network in the in left middle temporal gyrus (P = 0.033) and between the physical-fatigue score and functional connectivity of the sensory-motor network (P = 0.032) in both pre- and post-central gyri. A negative relationship was found between the total-fatigue score and functional connectivity of the salience network (P = 0.023) and of the left fronto-parietal network (P = 0.026) in the right supramarginal gyrus and left superior parietal lobe. No clear relationship between fatigue subscores and the average functional connectivity of the spinal cord was found. Cognitive-fatigue scores were positively associated with white matter lesion volume (P = 0.018) and negatively associated with white matter fractional anisotropy (P = 0.032). Structural, diffusion and functional connectivity alterations were not influenced by the disease group. Functional and structural imaging metrics associated with fatigue relate to brain rather than spinal cord abnormalities. Salience and sensory-motor networks alterations in relation to fatigue might indicate a disconnection between the perception of the interior body state and activity and the actual behavioural responses and performances (reversible or irreversible). Future research should focus on functional rehabilitative strategies.