RESUMEN
BACKGROUND: Mirror movements (MM) are commonly caused by a defect of interhemispheric pathways also affected in multiple sclerosis (MS), particularly the corpus callosum. We investigated the prevalence of MM in MS in relation to functional and morphological callosal fiber integrity by transcranial magnetic stimulation (TMS), magnetic resonance imaging (MRI), as well as fatigue. METHODS: In 21 patients with relapsing-remitting MS and 19 healthy controls, MM were assessed and graded (Woods and Teuber scale: MM 1-4) using a bedside test. Fatigue was evaluated using the Fatigue Scale for Motor and Cognitive Functions (FSMC) questionnaire. TMS measured ipsilateral silent period latency and duration. MRI assessed callosal atrophy by measuring the normalized corpus callosum area (nCCA), corpus callosum index (CCI), and lesion volume. RESULTS: MS patients had significantly more often and pronounced MM compared to healthy controls (p = 0.0002) and nCCA was significantly lower (p = 0.045) in MRI studies. Patients with higher MM scores (MM > 1 vs. MM 0/1) showed significantly more fatigue (higher FSMC sum score, p = 0.04, motor score, p = 0.01). In TMS and MRI studies, no significant differences were found between patients with MM 0/1 and those with MM > 1 (ipsilateral silent period measurements, CCA, CCI and lesion volume). CONCLUSIONS: MM are common in MS and can easily be detected through bedside testing. As MM are associated with fatigue, they might indicate fatigue in MS. It is possible that other cerebral structures, in addition to the corpus callosum, may contribute to the origin of MM in MS.
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Cuerpo Calloso , Imagen por Resonancia Magnética , Estimulación Magnética Transcraneal , Humanos , Femenino , Masculino , Adulto , Cuerpo Calloso/diagnóstico por imagen , Cuerpo Calloso/patología , Estimulación Magnética Transcraneal/métodos , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/patología , Fatiga/diagnóstico por imagen , Fatiga/fisiopatología , Fatiga/etiología , Fatiga/epidemiologíaRESUMEN
BACKGROUND AND OBJECTIVES: Slow-burning inflammation at the edge, and chronic demyelination at the core, of established multiple sclerosis (MS) lesions are potential mediators of disease progression. However, their relative contribution to progressive axonal damage has not been explored. Therefore, in this study, we investigated the comparative contribution of slow-burning inflammation and chronic demyelination to axonal attrition within MS lesions by measuring progressive tissue rarefaction. In addition, we use the visual system as a model to investigate the effect of chronic demyelination on the acceleration of axonal death in a sub-group of patients with unilateral optic neuritis. METHODS: Pre- and post-gadolinium 3D-T1, 3D FLAIR, diffusion tensor images, Optical Coherence tomography and multifocal visual evoked potentials were acquired from 52 relapsing-remitting MS patients who completed at least 5 years follow-up. Lesion expansion was measured using custom software, and the rate of tissue rarefication inside lesion core was assessed by measuring increase of normalized mean diffusivity (nMD). Axonal loss was also examined in eyes with severe optic nerve demyelination. RESULTS: Among the 361 lesions analyzed, 104 were expanding (a minimum of 4 % expansion per year) and 257 were stable. Expanding lesions showed a significantly higher rate of progressive tissue rarefication inside lesion (1.12 % per year) core compared to stable lesions (0.21 % per year, p = 0.01). The magnitude of nMD change was significantly correlated with the rate of lesion expansion (r = 0.4, p < 0.001). Analysis of retinal ganglion cells in eyes with severe optic nerve demyelination (Inter-eye latency delay of >10 ms) revealed a similar rate of axonal loss (0.19 %) to the degree of tissue rarefaction observed in stable lesions (0.21 %). DISCUSSION: The results of the study suggest that the slow-burning inflammation at the lesion's edge (as measured by lesion expansion), is likely to have a greater impact on tissue damage (as measured by nMD change), when compared to stable chronically demyelinated lesions. The similar modest degree of tissue damage was also observed in chronically demyelinated fibers of the optic nerve.
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Axones , Progresión de la Enfermedad , Esclerosis Múltiple Recurrente-Remitente , Neuritis Óptica , Tomografía de Coherencia Óptica , Humanos , Femenino , Adulto , Masculino , Axones/patología , Neuritis Óptica/patología , Neuritis Óptica/fisiopatología , Neuritis Óptica/diagnóstico por imagen , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Inflamación/patología , Potenciales Evocados Visuales/fisiología , Imagen de Difusión Tensora , Enfermedades Desmielinizantes/patología , Enfermedades Desmielinizantes/diagnóstico por imagen , Imagen por Resonancia Magnética , Enfermedad CrónicaRESUMEN
BACKGROUND: Sleep disturbance in MS is common and can significantly impair overall quality of life. The ketogenic diet (KD) associates with improved sleep quality in people living with epilepsy and may have similar benefits when used within MS; however, the impact of a KD on sleep in this population remains poorly defined. METHODS: Forty-five patients with relapsing MS enrolled into a 6-month KD intervention trial and completed self-reported assessments of sleep quality and sleep disorder symptoms prior to diet initiation and while on diet, using the Epworth Sleepiness Scale (ESS) and Sleep Disorders Symptom Checklist-25 (SDS). Participants who did not complete sleep assessments at baseline and 6-months were excluded from analysis. In addition to sleep metrics, data collection included anthropometrics and MS-related fatigue scores. RESULTS: Thirty-nine of 45 (87 %) participants completed the required sleep assessments. There was a mean reduction in ESS score of 1.90 (95 % CI [-2.85, -0.94], p < 0.001). Total SDS score decreased at 6-months on KD (-4.4, 95 % CI [-7.1, -1.7], p = 0.002), with improvements noted in insomnia (-1.55, 95 % CI [-2.66, -0.43], p = 0.008), obstructive sleep apnea (-0.91, 95 % CI [-1.57, -0.25], p = 0.008), and restless leg syndrome screening scores (-1.00, 95 % CI [-1.95, -0.051], p = 0.04). Sleep duration was unchanged on KD. CONCLUSION: KD associates with improvements in daytime sleepiness, independent of sleep duration, and common comorbid sleep disorders in people living with relapsing MS. The findings herein support the benefits of KD on sleep quality and highlight the potential role of dietary therapeutics for sleep disorders in neurological disease. TRIAL REGISTRATION INFORMATION: Registered on Clinicaltrials.gov under registration number NCT03718247, posted on Oct 24, 2018. First patient enrollment date: Nov 1, 2018. Link: https://clinicaltrials.gov/ct2/show/NCT03718247?term=NCT03718247&draw=2&rank=1.
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Dieta Cetogénica , Esclerosis Múltiple Recurrente-Remitente , Calidad del Sueño , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Dieta Cetogénica/métodos , Esclerosis Múltiple Recurrente-Remitente/dietoterapia , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Calidad de Vida , Autoinforme , Trastornos del Sueño-Vigilia/dietoterapiaRESUMEN
Motor fatigue in Multiple Sclerosis (MS) is due to reduced motor cortex (M1) output and altered sensorimotor network (SMN) modulation. Natalizumab, a disease-modifying therapy, reduces neuroinflammation and improves fatigue. However, some patients treated with natalizumab experience fatigue recurrence ('wearing-off') before subsequent infusions. Wearing-off provides a valuable window into MS-related motor fatigue mechanisms in a controlled, clinically stable, setting. This study investigates whether wearing-off is associated with worsening motor fatigue and its neurophysiological mechanisms and assesses natalizumab's effect on MS-related fatigue. Forty-five relapsing-remitting MS patients with wearing-off symptoms were evaluated pre- and post-natalizumab infusion. Assessments included evaluating disability levels, depressive symptoms, and the impact of fatigue symptoms on cognitive, physical, and psychosocial functioning. The motor fatigue index was computed through the number of blocks completed during a fatiguing task and peripheral, central, and supraspinal fatigue (M1 output) were evaluated by measuring the superimposed twitches evoked by peripheral nerve and transcranial magnetic stimulation of M1. Transcranial magnetic stimulation-electroencephalography assessed M1 effective connectivity by measuring TMS-evoked potentials (TEPs) within the SMN before- and after the task. We found that wearing-off was associated with increased motor fatigue index, increased central and supraspinal fatigue, and diminished task-related modulation of TEPs compared to post-natalizumab infusion. Wearing-off was also associated with worsened fatigue impact and depression symptom scores. We conclude that the wearing-off phenomenon is associated with worsening motor fatigue due to altered M1 output and modulation of the SMN. Motor fatigue in MS may reflect reversible, inflammation-related changes in the SMN that natalizumab can modulate. Our findings apply primarily to MS patients receiving natalizumab, emphasizing the need for further research on other treatments with wearing-off.
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Natalizumab , Estimulación Magnética Transcraneal , Humanos , Natalizumab/uso terapéutico , Natalizumab/efectos adversos , Femenino , Masculino , Adulto , Fatiga/etiología , Corteza Motora/fisiopatología , Corteza Motora/efectos de los fármacos , Persona de Mediana Edad , Potenciales Evocados Motores/efectos de los fármacos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Factores Inmunológicos/uso terapéutico , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/administración & dosificación , Fatiga Muscular/efectos de los fármacos , ElectroencefalografíaRESUMEN
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/patologíaRESUMEN
AIM AND RATIONALE: Problems with manual dexterity and cognition impact the everyday performance of people with multiple sclerosis (PwMS). Accumulated findings point to the relationship between deficits in manual dexterity and auditory domains of cognition with a lack of evidence on visuospatial and verbal aspects of cognitive functioning. Therefore, this study explores the relationship between manual dexterity and cognition in a cohort of PwMS. METHOD: This cross-sectional study collected data from 63 PwMS aged 22 to 55 through a convenient sampling method. Participants were diagnosed with relapsing-remitting multiple sclerosis (RRMS). Cognition was measured using a multi-domain computerized cognitive testing, NeuroTrax, and manual dexterity was measured using a 9-hole peg assessment. Spearman correlation was used to identify the correlation among cognition subtests as well as with manual dexterity. Linear regression analysis was also conducted to identify whether manual dexterity predicts cognitive functioning. RESULTS: A significant negative correlation was found between 9-hole peg scores and global cognitive scores (GCS), r = -0.34, p = 006. The manual dexterity scores were also shown to predict GCS, R2= 0.165, p = 0.001. CONCLUSION: Manual dexterity was found to not only predict cognitive dysfunction but was also associated with multiple cognitive domains. Understanding the relationship between manual dexterity and cognition and the inferred progression of deficits can assist clinicians to provide interventions at earlier stages of disease progression to potentially increase daily functioning and quality of life (QoL).
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Esclerosis Múltiple Recurrente-Remitente , Humanos , Masculino , Femenino , Adulto , Estudios Transversales , Persona de Mediana Edad , Adulto Joven , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Pruebas Neuropsicológicas , Disfunción Cognitiva/etiología , Disfunción Cognitiva/fisiopatología , Cognición/fisiología , Destreza Motora/fisiología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/fisiopatologíaRESUMEN
BACKGROUND: Multiple sclerosis (MS) causes sleep disturbances in up to 70 % of individuals. These problems are linked to fatigue, mood and cognitive performance, thereby affecting the quality of life in people with MS (PwMS). The frequent and debilitating side effects of sleep medications prompt the exploration of alternative therapies. Physical activity has shown benefits in improving sleep, reducing fatigue, and enhancing quality of life. Combined with a controlled exercise program tailored for PwMS, the study aims to analyze the impact of moderate physical exercise on sleep quality, cognitive function, quality of life, mood, and fatigue. METHODS: A single-center prospective cohort study was designed to assess the impact of a 12-week physical exercise program on patients with relapsing-remitting multiple sclerosis. Changes in sleep and activity parameters are evaluated using an actigraph and cognitive, quality of life, fatigue and mood changes are assessed through specific questionnaires before, during, and after the exercise program application. RESULTS: 23 patients completed the study (women = 84.6 %) Mean age was 37.2 years (SD 7.5). The mean EDSS score was 1.9, and 80.8 % were diagnosed within the last six years. Significant improvements were noted in sleep efficiency between baseline and final measurements (χ2 = 27.5; p.adj = 0.004), sleep latency (χ2 = 275; p.adj = 0.000), sleep duration (χ2 = 251; p.adj = 0.001) and in the number of awakenings (χ2 = 269.5; p.adj = 0.000), with a decreased in total time in bed from 8.5 h to 7.35 h post-intervention. Regarding activity variables, an increase in caloric expenditure and an increase in the time participants engaged in light activity were observed. We found significant improvements in fatigue, quality of life and mood. Concerning neuropsychological exploration results, improvements were observed in all studied parameters, with statistically significant improvement in Verbal SRT (χ2 = 43; p = 0.022). CONCLUSION: Our study showed a positive impact of a 12-week physical exercise program on sleep performance, cognition and mood in PwMS. The observed improvements underscore the potential of tailored exercise interventions in promoting a more comprehensive and holistic care paradigm for PwMS.
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Ejercicio Físico , Fatiga , Esclerosis Múltiple Recurrente-Remitente , Calidad de Vida , Calidad del Sueño , Humanos , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/psicología , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Femenino , Masculino , Adulto , Estudios Prospectivos , Ejercicio Físico/fisiología , Terapia por Ejercicio/métodos , Actigrafía , Encuestas y Cuestionarios , Afecto/fisiología , Cognición/fisiología , Persona de Mediana EdadRESUMEN
BACKGROUND: Comorbidities, particularly vascular comorbidities, have been shown to exacerbate the progression of disability in multiple sclerosis (MS). Metabolic syndrome (MetS) is a cluster of conditions including abdominal obesity, insulin resistance, atherogenic dyslipidemia, and vascular dysfunction, which contribute to vascular morbidity and chronic inflammation. OBJECTIVE: To describe the characteristics of MetS in a cohort of MS patients and evaluate its relationship with the MS phenotype. METHODS: A monocentric cohort study was conducted on MS patients, collecting demographic, clinical, radiological, and therapeutic data, as well as metabolic data including waist circumference, blood pressure, serum triglycerides, high-density lipoprotein cholesterol, and fasting blood glucose. RESULTS: Among the 84 patients included in the study, 27% were diagnosed with MetS. MetS was found to be associated with secondary progressive MS (SPMS). Patients with SPMS had a higher prevalence of MetS compared to those with relapsing-remitting MS (RRMS), even after adjusting for disease duration. While MetS was associated with Expanded Disability Status Scale (EDSS) progression in the 3-year period according to univariate analysis, it did not show a significant association with disease activity. CONCLUSION: This study provides evidence supporting the connection between MetS and the progression of disability in MS, independent of disease relapse activity.
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Progresión de la Enfermedad , Síndrome Metabólico , Esclerosis Múltiple , Fenotipo , Humanos , Masculino , Femenino , Síndrome Metabólico/epidemiología , Síndrome Metabólico/complicaciones , Adulto , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/complicaciones , Estudios de Cohortes , Esclerosis Múltiple Crónica Progresiva/epidemiología , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/sangre , Comorbilidad , PrevalenciaRESUMEN
Studying the relationship between cerebral oxygen utilization and cognitive impairment is essential to understanding neuronal functional changes in the disease progression of multiple sclerosis (MS). This study explores the potential of using venous susceptibility in internal cerebral veins (ICVs) as an imaging biomarker for cognitive impairment in relapsing-remitting MS (RRMS) patients. Quantitative susceptibility mapping derived from fully flow-compensated MRI phase data was employed to directly measure venous blood oxygen saturation levels (SvO2) in the ICVs. Results revealed a significant reduction in the susceptibility of ICVs (212.4 ± 30.8 ppb vs 239.4 ± 25.9 ppb) and a significant increase of SvO2 (74.5 ± 1.89% vs 72.4 ± 2.23%) in patients with RRMS compared with age- and sex-matched healthy controls. Both the susceptibility of ICVs (r = 0.508, p = 0.031) and the SvO2 (r = -0.498, p = 0.036) exhibited a moderate correlation with cognitive decline in these patients assessed by the Paced Auditory Serial Addition Test, while no significant correlation was observed with clinical disability measured by the Expanded Disability Status Scale. The findings suggest that venous susceptibility in ICVs has the potential to serve as a specific indicator of oxygen metabolism and cognitive function in RRMS. .
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Venas Cerebrales , Disfunción Cognitiva , Imagen por Resonancia Magnética , Oxígeno , Humanos , Masculino , Femenino , Adulto , Disfunción Cognitiva/etiología , Disfunción Cognitiva/metabolismo , Venas Cerebrales/diagnóstico por imagen , Venas Cerebrales/metabolismo , Oxígeno/metabolismo , Oxígeno/sangre , Imagen por Resonancia Magnética/métodos , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/metabolismo , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/psicología , Circulación Cerebrovascular/fisiología , Consumo de Oxígeno , Saturación de OxígenoRESUMEN
BACKGROUND: Prior research has established a link between thalamic pathology and cognitive impairment (CI) in people with multiple sclerosis (pwMS). However, the translation of these findings to pwMS in everyday clinical settings has been insufficient. OBJECTIVE: To assess which global and/or thalamic imaging biomarkers can be used to identify pwMS at risk for CI and cognitive worsening (CW) in a real-world setting. METHODS: This was an international, multi-center (11 centers), longitudinal, retrospective, real-word study of people with relapsing-remitting MS (pwRRMS). Brain MRI exams acquired at baseline and follow-up were collected. Cognitive status was evaluated using the Symbol Digit Modalities Test (SDMT). Thalamic volume (TV) measurement was performed on T2-FLAIR, as well as on T1-WI, when available. Thalamic dysconnectivity, T2-lesion volume (T2-LV), and volumes of gray matter (GM), whole brain (WB) and lateral ventricles (LVV) were also assessed. RESULTS: 332 pwMS were followed for an average of 2.8 years. At baseline, T2-LV, LVV, TV and thalamic dysconnectivity on T2-FLAIR (p < 0.016), and WB, GM and TV volumes on T1-WI (p < 0.039) were significantly worse in 90 (27.1 %) CI vs. 242 (62.9 %) non-CI pwRRMS. Greater SDMT decline over the follow-up was associated with lower baseline TV on T2-FLAIR (standardized ß = 0.203, p = 0.002) and greater thalamic dysconnectivity (standardized ß = -0.14, p = 0.028) in a linear regression model. CONCLUSIONS: PwRRMS with thalamic atrophy and worse thalamic dysconnectivity present more frequently with CI and experience greater CW over mid-term follow-up in a real-world setting.
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Atrofia , Disfunción Cognitiva , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente , Tálamo , Humanos , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Femenino , Masculino , Adulto , Tálamo/patología , Tálamo/diagnóstico por imagen , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/diagnóstico por imagen , Atrofia/patología , Persona de Mediana Edad , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Estudios LongitudinalesRESUMEN
BACKGROUND: Research work has shown that hippocampal subfields are atrophic to varying extents in multiple sclerosis (MS) patients. However, studies examining the functional implications of subfield-specific hippocampal damage in early MS are limited. We aim to gain insights into the relationship between hippocampal atrophy and memory function by investigating the correlation between global and regional hippocampal atrophy and memory performance in early MS patients. METHODS: From the Italian Neuroimaging Network Initiative (INNI) dataset, we selected 3D-T1-weighted brain MRIs of 219 early relapsing remitting (RR)MS and 246 healthy controls (HC) to identify hippocampal atrophic areas. At the time of MRI, patients underwent Selective-Reminding-Test (SRT) and Spatial-Recall-Test (SPART) and were classified as mildly (MMI-MS: n.110) or severely (SMI-MS: n:109) memory impaired, according to recently proposed cognitive phenotypes. RESULTS: Early RRMS showed lower hippocampal volumes compared to HC (p < 0.001), while these did not differ between MMI-MS and SMI-MS. In MMI-MS, lower hippocampal volumes correlated with worse memory tests (r = 0.23-0.37, p ≤ 0.01). Atrophic voxels were diffuse in the hippocampus but more prevalent in cornu ammonis (CA, 79%) than in tail (21%). In MMI-MS, decreased subfield volumes correlated with decreases in memory, particularly in the right CA1 (SRT-recall: r = 0.38; SPART: r = 0.34, p < 0.01). No correlations were found in the SMI-MS group. CONCLUSION: Hippocampal atrophy spreads from CA to tail from early disease stages. Subfield hippocampal atrophy is associated with memory impairment in MMI-MS, while this correlation is lost in SMI-MS. This plays in favor of a limited capacity for an adaptive functional reorganization of the hippocampi in MS patients.
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Atrofia , Hipocampo , Imagen por Resonancia Magnética , Trastornos de la Memoria , Esclerosis Múltiple Recurrente-Remitente , Humanos , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Masculino , Hipocampo/patología , Hipocampo/diagnóstico por imagen , Femenino , Atrofia/patología , Adulto , Trastornos de la Memoria/etiología , Trastornos de la Memoria/patología , Trastornos de la Memoria/diagnóstico por imagen , Persona de Mediana Edad , Pruebas NeuropsicológicasRESUMEN
INTRODUCTION: Fatigue is a highly prevalent debilitating symptom among patients with multiple sclerosis (PwMS), which markedly affects the quality of life. The present study aimed to evaluate the effect of extended-release fampridine on fatigue in PwMS. METHODS: This was a randomized, double-blind clinical trial on 77 PwMS with a complaint of fatigue, aged over 18 years old, randomized to extended-release fampridine (n = 44) or placebo (n = 35) for 12 weeks. Fatigue and motor function were assessed at baseline and end point. RESULTS: A total of 88 patients were recruited, of whom 77 were analyzed. 80.5% were female, with a median age of 38. 87% were diagnosed with relapsing-remitting MS (RRMS) with a median disease duration of 96 months. Fingolimod (37.7%) was considered the most frequently used DMT, followed by ani-CD20s (32.5%). The total median MFIS score was 43.5 and 37 in the fampridine and placebo groups which were not significantly different (p > 0.05). After 12 weeks, the total MFIS improved in both groups compared to the baseline, which was significant in the active group (p = 0.04). However, the final end point total MFIS was still comparable between the two groups (p = 0.11). CONCLUSION: The present study revealed a positive short-term effect of extended-release fampridine on MFIS in PwMS. However, this effect was not significantly superior to the placebo.
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4-Aminopiridina , Fatiga , Esclerosis Múltiple , Humanos , Femenino , Masculino , 4-Aminopiridina/uso terapéutico , 4-Aminopiridina/administración & dosificación , Adulto , Método Doble Ciego , Persona de Mediana Edad , Fatiga/tratamiento farmacológico , Fatiga/etiología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/tratamiento farmacológico , Bloqueadores de los Canales de Potasio/uso terapéutico , Bloqueadores de los Canales de Potasio/administración & dosificación , Resultado del Tratamiento , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/complicacionesAsunto(s)
Anticuerpos Antivirales , Virus JC , Leucoencefalopatía Multifocal Progresiva , Esclerosis Múltiple , Natalizumab , Humanos , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Leucoencefalopatía Multifocal Progresiva/etiología , Leucoencefalopatía Multifocal Progresiva/diagnóstico , Leucoencefalopatía Multifocal Progresiva/inmunología , Natalizumab/efectos adversos , Natalizumab/uso terapéutico , Virus JC/inmunología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/complicaciones , Resultado Fatal , Anticuerpos Antivirales/sangre , Factores Inmunológicos/efectos adversos , Factores Inmunológicos/uso terapéutico , Femenino , Adulto , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The time to diagnosis of multiple sclerosis (MS) is of great importance for early treatment, thereby reducing the disability and burden of the disease. The purpose of this study was to determine the time from the onset of clinical symptoms to the diagnosis of MS and to evaluate the factors associated with a late diagnosis in Iranian MS patients. METHODS: The present cross-sectional study was conducted on patients with MS who were registered in the National MS Registry System of Iran (NMSRI). RESULTS: Overall, 23291 MS patients registered in 18 provinces of Iran were included in this study. The mean (standard deviation) interval between the onset of the disease and diagnosis of MS was 13.42 (32.40) months, and the median was one month. The diagnostic interval of 41.6% of patients was less than one month, and 14.8% of them had a one-month time to diagnosis. Patients with an age of onset below 18 years and those diagnosed after the age of 50 years had a longer time to diagnosis (P<0.001). Patients with primary progressive MS (PPMS) had the longest time to diagnose and those with relapsing-remitting MS (RRMS) had the shortest time (P<0.001). The results of negative binominal regression showed that the average rate of delay in diagnosis in women was 12% less than that in men. The average delay in diagnosis in patients with a positive family history of MS was 23% more than that in others. The rate of delay in the diagnosis of patients with PPMS and secondary progressive MS was 2.22 and 1.66 times higher, respectively, compared with RRMS. CONCLUSION: The findings of the present study revealed that more than half of the MS patients were diagnosed within a one-month interval from the symptom onset, which is an acceptable period. More attention should be paid to patients' access to medical facilities and MS specialists.
Asunto(s)
Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Masculino , Humanos , Femenino , Adolescente , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/complicaciones , Estudios Transversales , Irán , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Esclerosis Múltiple Crónica Progresiva/epidemiología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/epidemiología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Sistema de RegistrosRESUMEN
Multiple Sclerosis (MS) is an autoimmune disease affecting the central nervous system, characterised by neuroinflammation and neurodegeneration. Fatigue and depression are common, debilitating, and intertwined symptoms in people with relapsing-remitting MS (pwRRMS). An increased understanding of brain changes and mechanisms underlying fatigue and depression in RRMS could lead to more effective interventions and enhancement of quality of life. To elucidate the relationship between depression and fatigue and brain connectivity in pwRRMS we conducted a systematic review. Searched databases were PubMed, Web-of-Science and Scopus. Inclusion criteria were: studied participants with RRMS (n ≥ 20; ≥ 18 years old) and differentiated between MS subtypes; published between 2001-01-01 and 2023-01-18; used fatigue and depression assessments validated for MS; included brain structural, functional magnetic resonance imaging (fMRI) or diffusion MRI (dMRI). Sixty studies met the criteria: 18 dMRI (15 fatigue, 5 depression) and 22 fMRI (20 fatigue, 5 depression) studies. The literature was heterogeneous; half of studies reported no correlation between brain connectivity measures and fatigue or depression. Positive findings showed that abnormal cortico-limbic structural and functional connectivity was associated with depression. Fatigue was linked to connectivity measures in cortico-thalamic-basal-ganglial networks. Additionally, both depression and fatigue were related to altered cingulum structural connectivity, and functional connectivity involving thalamus, cerebellum, frontal lobe, ventral tegmental area, striatum, default mode and attention networks, and supramarginal, precentral, and postcentral gyri. Qualitative analysis suggests structural and functional connectivity changes, possibly due to axonal and/or myelin loss, in the cortico-thalamic-basal-ganglial and cortico-limbic network may underlie fatigue and depression in pwRRMS, respectively, but the overall results were inconclusive, possibly explained by heterogeneity and limited number of studies. This highlights the need for further studies including advanced MRI to detect more subtle brain changes in association with depression and fatigue. Future studies using optimised imaging protocols and validated depression and fatigue measures are required to clarify the substrates underlying these symptoms in pwRRMS.
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Esclerosis Múltiple Recurrente-Remitente , Humanos , Encéfalo/patología , Depresión/diagnóstico por imagen , Fatiga , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/patología , Calidad de Vida , AdultoRESUMEN
Cognitive fatigue is a major symptom of Multiple Sclerosis (MS), from the early stages of the disease. This study aims to detect if brain microstructure is altered early in the disease course and is associated with cognitive fatigue in people with MS (pwMS) compared to matched healthy controls (HC). Recently diagnosed pwMS (N = 18, age < 45 years old) with either a Relapsing-Remitting or a Clinically Isolated Syndrome course of the disease, and HC (N = 19) matched for sex, age and education were analyzed. Quantitative multiparameter maps (MTsat, PD, R1 and R2*) of pwMS and HC were calculated. Parameters were extracted within the normal appearing white matter, cortical grey matter and deep grey matter (NAWM, NACGM and NADGM, respectively). Bayesian T-test for independent samples assessed between-group differences in brain microstructure while associations between score at a cognitive fatigue scale and each parameter in each tissue class were investigated with Generalized Linear Mixed Models. Patients exhibited lower MTsat and R1 values within NAWM and NACGM, and higher R1 values in NADGM compared to HC. Cognitive fatigue was associated with PD measured in every tissue class and to MTsat in NAWM, regardless of group. Disease-specific negative correlations were found in pwMS in NAWM (R1, R2*) and NACGM (R1). These findings suggest that brain microstructure within normal appearing tissues is already altered in the very early stages of the disease. Moreover, additional microstructure alterations (e.g. diffuse and widespread demyelination or axonal degeneration) in pwMS may lead to disease-specific complaint of cognitive fatigue.
Asunto(s)
Encéfalo , Imagen por Resonancia Magnética , Esclerosis Múltiple , Humanos , Masculino , Femenino , Adulto , Esclerosis Múltiple/patología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Fatiga Mental/etiología , Fatiga Mental/diagnóstico por imagen , Fatiga Mental/patología , Sustancia Gris/diagnóstico por imagen , Sustancia Gris/patología , Disfunción Cognitiva/etiología , Disfunción Cognitiva/patología , Disfunción Cognitiva/fisiopatología , Disfunción Cognitiva/diagnóstico por imagen , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/patología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Adulto JovenRESUMEN
BACKGROUND: Multiple sclerosis (MS) is a rare but serious condition associated with significant morbidity. OBJECTIVE: This review provides a focused assessment of MS for emergency clinicians, including the presentation, evaluation, and emergency department (ED) management based on current evidence. DISCUSSION: MS is an autoimmune disorder targeting the central nervous system (CNS), characterized by clinical relapses and radiological lesions disseminated in time and location. Patients with MS most commonly present with long tract signs (e.g., myelopathy, asymmetric spastic paraplegia, urinary dysfunction, Lhermitte's sign), optic neuritis, or brainstem syndromes (bilateral internuclear ophthalmoplegia). Cortical syndromes or multifocal presentations are less common. Radiologically isolated syndrome and clinically isolated syndrome (CIS) may or may not progress to chronic forms of MS, including relapsing remitting MS, primary progressive MS, and secondary progressive MS. The foundation of outpatient management involves disease-modifying therapy, which is typically initiated with the first signs of disease onset. Management of CIS and acute flares of MS in the ED includes corticosteroid therapy, ideally after diagnostic testing with imaging and lumbar puncture for cerebrospinal fluid analysis. Emergency clinicians should evaluate whether patients with MS are presenting with new-onset debilitating neurological symptoms to avoid unnecessary testing and admissions, but failure to appropriately diagnose CIS or MS flare is associated with increased morbidity. CONCLUSIONS: An understanding of MS can assist emergency clinicians in better diagnosing and managing this neurologically devastating disease.
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Esclerosis Múltiple Crónica Progresiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Neuritis Óptica , Humanos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple Crónica Progresiva/complicaciones , Esclerosis Múltiple Crónica Progresiva/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Radiografía , Neuritis Óptica/diagnóstico , Imagen por Resonancia MagnéticaRESUMEN
INTRODUCTION: Cognitive impairment occurs from the earliest stages of multiple sclerosis (MS) and progresses over time. The introduction of disease modifying therapies (DMTs) has changed the prognosis for MS patients, offering a potential opportunity for improvement in the cognitive arena as well. MATERIAL AND METHODS: 41 patients with relapsing-remitting multiple sclerosis (MS) were recruited to the study. Thirty patients were available for final follow-up and were included in the analysis. Baseline (BL) brain MRI including volumetry and neuropsychological tests were performed. Blood samples were collected at BL and follow-up (FU) and were tested for: vascular endothelial growth factor (VEGF), soluble vascular cell adhesion molecule-1 (sVCAM1), soluble platelet-endothelial CAM-1 (sPECAM1), and soluble intercellular CAM-1 (sICAM-1). Patients were invited for a final neuropsychological follow-up after a median of 6 years. Disease activity (relapses, EDSS increase, new/active brain lesions on MRI) was analysed between BL and FU. RESULTS: The study group deteriorated in the Rey-Osterrieth Complex Figure (ROCF) test (p = 0.001), but improved significantly in three other tests, i.e. semantic fluency test (p = 0.013), California Verbal Learning Test (CVLT, p = 0.016), and Word Comprehension Test (WCT, p < 0.001). EDSS increase correlated negatively with semantic fluency and WCT scores (r = -0.579, p = 0.001 and r = -0.391, p = 0.033, respectively). Improvements in semantic fluency test and WCT correlated positively with baseline deep grey matter, grey matter, and cortical volumes (p < 0.05, r > 0). Higher EDSS on FU correlated significantly negatively with baseline left and right pallidum, right caudate, right putamen, right accumbens, and cortical volume (p < 0.05, r < 0). No significant relationship was found between the number of relapses and EDSS on FU or neuropsychological deteriorations. Improvements in WCT and CVLT correlated positively with baseline sPECAM1 and sVCAM1 results, respectively (r > 0, p < 0.05). Deterioration in ROCF test correlated significantly with higher levels of baseline VEGF and sVCAM1 (p < 0.05). CONCLUSIONS: Brain volume is an important predictor of future EDSS and cognitive functions outcome. MS patients have a potential for improving in neuropsychological tests over time. It remains to be established whether this is related to successful disease modification with immunotherapy. Baseline volumetric measures are stronger predictors of cognitive performance than relapse activity, which yet again highlights the importance of atrophy in MS prognosis.
Asunto(s)
Disfunción Cognitiva , Progresión de la Enfermedad , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente , Pruebas Neuropsicológicas , Humanos , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/psicología , Femenino , Masculino , Adulto , Estudios de Seguimiento , Disfunción Cognitiva/etiología , Persona de Mediana Edad , Pronóstico , Factor A de Crecimiento Endotelial Vascular/sangreRESUMEN
OBJECTIVES: The Fatigue Symptoms and Impacts Questionnaire-Relapsing Multiple Sclerosis (FSIQ-RMS) is a new content-valid, concise, and reliable 20-item patient-reported outcome measure to evaluate the symptoms and impacts of fatigue in patients with relapsing forms of multiple sclerosis. Analyses were performed to derive meaningful change thresholds (MCTs) on patient-reported outcomes as measured by FSIQ-RMS and generate receiver operating characteristic (ROC) curves to determine fatigue severity cut points at baseline and change in severity at post-baseline and supplement the anchor-based MCT results. METHODS: Analyses were based on data from the OPTIMUM trial (NCT02425644). An anchor-based approach using uncollapsed changes on the Patient Global Impression of Severity at week 108 were used to determine the MCT for only the FSIQ-RMS Symptoms domain; distribution-based MCT estimations were conducted using baseline FSIQ-RMS Impacts scores. ROC curves with calculation of area under the curve were used to identify the best cut point. RESULTS: Based on the evidence provided by the anchor-based analyses using the Patient Global Impression of Severity as an anchor for the FSIQ-RMS Symptoms domain, meaningful score changes for improvement and deterioration were -6.3 and 6.3, respectively. Meaningful score changes for the FSIQ-RMS Physical, Cognitive/Emotional, and Coping Impacts domains using distribution-based methods were 10.8, 8.4, and 9.8, respectively. These results are supported by the ROC analyses. CONCLUSIONS: Thresholds to support interpretation of the FSIQ-RMS, such as MCTs, can be used to determine and categorize patients who have experienced a meaningful change in their MS-related fatigue (eg, responder analyses) in future clinical research studies.
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Fatiga , Esclerosis Múltiple Recurrente-Remitente , Medición de Resultados Informados por el Paciente , Curva ROC , Índice de Severidad de la Enfermedad , Humanos , Fatiga/etiología , Femenino , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/complicaciones , Esclerosis Múltiple Recurrente-Remitente/psicología , Masculino , Adulto , Encuestas y Cuestionarios , Persona de Mediana Edad , Calidad de Vida , Reproducibilidad de los ResultadosRESUMEN
BACKGROUND: The heterogeneous nature of cognitive impairment in people with multiple sclerosis (PwMS) hampers understanding of the underlying mechanisms and developing patient-tailored interventions. We aim to identify and classify cognitive profiles in PwMS, comparing these to cognitive status (preserved versus impaired). METHODS: We included 1213 PwMS (72% female, age 45.4 ± 10.7 years, 83% relapsing-remitting MS). Cognitive test scores were converted to Z-scores compared to healthy controls for the functions: attention, inhibition, information processing speed (IPS), verbal fluency and verbal/visuospatial memory. Concerning cognitive status, impaired cognition (CI) was defined as performing at Z ≤ - 1.5 SD on ≥ 2 functions. Cognitive profiles were constructed using latent profile analysis on all cognitive functions. Cognitive profiles or status was classified using gradient boosting decision trees, providing the importance of each feature (demographics, clinical, cognitive and psychological functioning) for the overall classification. RESULTS: Six profiles were identified, showing variations in overall performance and specific deficits (attention, inhibition, IPS, verbal fluency, verbal memory and visuospatial memory). Across the profiles, IPS was the most impaired function (%CI most preserved profile, Profile 1 = 22.4%; %CI most impaired profile, Profile 6 = 76.6%). Cognitive impairment varied from 11.8% in Profile 1 to 95.3% in Profile 6. Of all cognitive functions, visuospatial memory was most important in classifying profiles and IPS the least (area under the curve (AUC) = 0.910). For cognitive status, IPS was the most important classifier (AUC = 0.997). CONCLUSIONS: This study demonstrated that cognitive heterogeneity in MS reflects a continuum of cognitive severity, distinguishable by distinct cognitive profiles, primarily explained by variations in visuospatial memory functioning.