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Background: Multiple sclerosis (MS), a chronic autoimmune disorder marked by demyelination in the central nervous system, is exceptionally uncommon in China, and remains poorly understood in terms of its peripheral blood manifestations. Methods: We conducted a cohort study comprising 39 MS patients and 40 normal controls (NC). High-dimensional mass cytometry, protein arrays, and targeted metabolomics were utilized to profile immune subsets, proteins, and metabolites in blood. Differences in multi-omics signatures were scrutinized across varying MS subtypes. Results: Immune profiling demonstrated an elevation in various B cell subsets and monocytes, alongside a reduction in dendritic cells among MS patients. Proteomic data revealed a downregulation in neurotrophic and tissue repair proteins. Metabolomic assessment showed a noted decrease in anti-inflammatory molecules and sphingolipids. Integrated analysis identified distinct molecular patterns distinguishing MS from controls. Additionally, multi-omics differences among different MS subtypes were uncovered. Notably, hippuric acid levels was consistently lower in MS subgroups with greater disease severity. Conclusion: This study represents the pioneering exploration of multi-omics in Chinese MS patients, presenting a comprehensive view of the peripheral blood changes in MS. Our study underscores the robust capability of multi-omics assessments in identifying peripheral blood biomarkers that delineate the varied clinical presentation, and facilitates future development of biomarkers and targeted therapeutic interventions in MS.
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The potential of combining serum neurofilament light chain (sNfL) and glial fibrillary acidic protein (sGFAP) levels to predict disability worsening in multiple sclerosis (MS) remains underexplored. We aimed to investigate whether sNfL and sGFAP values identify distinct subgroups of patients according to the risk of disability worsening and their response to disease-modifying treatments (DMTs). This multicentre study, conducted across thirteen European hospitals, spanned from July 15, 1994, to August 18, 2022, with follow-up until September 26, 2023. We enrolled MS patients who had serum samples collected within 12 months from disease onset and before initiating DMTs. Multivariable regression models were used to estimate the risk of relapse-associated worsening (RAW), progression independent of relapse activity (PIRA), and Expanded Disability Status Scale (EDSS) score of 3. Of the 725 patients included, median age was 34.2 years (IQR, 27.6-42.4), and 509 patients (70.2%) were female. Median follow-up duration was 6.43 years (IQR, 4.65-9.81). Higher sNfL values associated with an elevated risk of RAW (HR of 1.45; 95% CI 1.19-1.76; P < 0.001), PIRA (HR of 1.43; 95% CI 1.13-1.81; P = 0.003), and reaching an EDSS of 3 (HR of 1.55; 95% CI 1.29-1.85; P < 0.001). Moreover, higher sGFAP levels were linked to a higher risk of achieving an EDSS score of 3 (HR of 1.36; 95% CI 1.06-1.74; P = 0.02) and, in patients with low sNfL values, to PIRA (HR of 1.86; 95% CI 1.01-3.45; P = 0.04). We further examined the combined effect of sNfL and sGFAP levels. Patients with low sNfL and sGFAP values (NLGL) exhibited a low risk of all outcomes and served as reference. Untreated patients with high sNfL levels showed a higher risk of RAW, PIRA, and reaching an EDSS of 3. Injectable or oral DMTs reduced the risk of RAW in these patients but failed to mitigate the risk of PIRA and reaching an EDSS of 3. Conversely, high-efficacy DMTs counteracted the heightened risk of these outcomes, except for the risk of PIRA in patients with high sNfL and sGFAP levels. Patients with low sNfL and high sGFAP values (NLGH) showed an increased risk of PIRA and achieving an EDSS of 3, which remained unchanged with either high-efficacy or other DMTs. In conclusion, evaluating sNfL and sGFAP levels at disease onset in MS may identify distinct phenotypes associated with diverse immunological pathways of disability acquisition and therapeutic response.
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OBJECTIVES: Clinically isolated syndrome (CIS) is a preclinical phase of multiple sclerosis (MS). The progression rate of CIS to clinical definite MS (CDMS) varies significantly across different populations, and identifying predictors of progression is crucial for early diagnosis and treatment. We aimed to investigate predictors of progression from CIS to CDMS in a Chinese cohort. METHODS: A single-center cohort study was conducted with newly diagnosed patients with CIS in China between 2018 and 2021. All patients underwent a comprehensive clinical evaluation, including neurological examination, magnetic resonance imaging, and laboratory tests. Follow-up assessments were conducted at regular intervals to monitor disease progression. Progression to CDMS was defined according to the 2017 McDonald criteria. Age, sex, Expanded Disability Status Scale (EDSS) score, number of patients with magnetic resonance imaging gadolinium-enhancing (Gd+) lesions, T2 lesions and Gd+ lesions count, CSF cell count, CSF total protein, CSF and serum neurofilament light chain (NfL), progranulin (PGRN) and Th17-related cytokines (IL-6, IL-17, IL-21, IL-22, IL-23 and TGF-ß) were measured for association with risk of progression to CDMS. RESULTS: A total of 96 CIS patients were recruited in the study. During the at least 24 months follow-up period, 57 (59.38â¯%) CIS patients progressed to CDMS, while 39 (40.62â¯%) patients without progression remained stable as CIS. Multivariate analysis revealed that younger age at onset (OR= 43.43, 95â¯% CI= 1.76-1071.68, p<0.021), higher CSF elevated protein (OR=58.64, 95â¯% CI=2.72-1264.51, p=0.009), higher CSF NfL levels (OR= 97.00, 95â¯% CI= 4.68-2012.99, p=0.003) and higher CSF IL-23 levels (OR= 412.02, 95â¯% CI=6.56-25869.60, p=0.004) were associated with high risk of progression to CDMS. CONCLUSION: Younger age at onset, elevated CSF NfL, IL-23 and protein levels might be progression predictors of CIS to CDMS in Chinese population.
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Enfermedades Desmielinizantes , Progresión de la Enfermedad , Esclerosis Múltiple , Humanos , Masculino , Femenino , Adulto , Esclerosis Múltiple/líquido cefalorraquídeo , China/epidemiología , Estudios Prospectivos , Persona de Mediana Edad , Adulto Joven , Imagen por Resonancia Magnética , Estudios de Cohortes , Citocinas/sangre , Citocinas/líquido cefalorraquídeoRESUMEN
Multiple sclerosis (MS) is a neurological disorder characterized by immune dysregulation. It begins with a first clinical manifestation, a clinically isolated syndrome (CIS), which evolves to definite MS in case of further clinical and/or neuroradiological episodes. Here we evaluated the diagnostic value of transcriptional alterations in MS and CIS blood by machine learning (ML). Deep sequencing of more than 200 blood RNA samples comprising CIS, MS and healthy subjects, generated transcriptomes that were analyzed by the binary classification workflow to distinguish MS from healthy subjects and the Time-To-Event pipeline to predict CIS conversion to MS along time. To identify optimal classifiers, we performed algorithm benchmarking by nested cross-validation with the train set in both pipelines and then tested models generated with the train set on an independent dataset for final validation. The binary classification model identified a blood transcriptional signature classifying definite MS from healthy subjects with 97% accuracy, indicating that MS is associated with a clear predictive transcriptional signature in blood cells. When analyzing CIS data with ML survival models, prediction power of CIS conversion to MS was about 72% when using paraclinical data and 74.3% when using blood transcriptomes, indicating that blood-based classifiers obtained at the first clinical event can efficiently predict risk of developing MS. Coupling blood transcriptomics with ML approaches enables retrieval of predictive signatures of CIS conversion and MS state, thus introducing early non-invasive approaches to MS diagnosis.
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Aprendizaje Automático , Esclerosis Múltiple , Transcriptoma , Humanos , Esclerosis Múltiple/sangre , Esclerosis Múltiple/genética , Esclerosis Múltiple/diagnóstico , Transcriptoma/genética , Masculino , Femenino , Adulto , Persona de Mediana Edad , Enfermedades Desmielinizantes/genética , Enfermedades Desmielinizantes/sangre , Enfermedades Desmielinizantes/diagnóstico , Algoritmos , Perfilación de la Expresión Génica/métodosRESUMEN
Aortitis is a rare disease entity of unknown prevalence. Primary aortitis mainly affects the thoracic aorta. They are most often diagnosed on imaging by grade III 18-FDG uptake of the aortic wall on PET, or by circumferential thickening>2.2mm on CT or MRI with late-stage contrast. More rarely, aortitis is histologically proven, as in some cases of clinically isolated aortitis discovered after planned aortic aneurysm surgery or during aortic dissection surgery. The most common histological types are granulomatous/giant cell or lymphoplasmacytic. Clinical signs associated with aortitis are often non-specific: asthenia, fever, dry cough, chest, back, lumbar or abdominal pain. Aortitis can be divided into different etiological categories: primary aortitis, which includes vasculitis with a preferential or exclusive tropism for the aortic wall, aortitis secondary to systemic or iatrogenic diseases, and infectious aortitis. The main etiologies of primary aortitis are giant cell arteritis (GCA), Takayasu arteritis (TA) or clinically isolated aortitis. Aortitis secondary to systemic diseases is seen in atrophying polychondritis, systemic lupus and inflammatory rheumatic diseases such as spondyloarthropathy and rheumatoid arthritis. In both ACG and AT, aortitis is a negative factor, characterized by a higher risk of relapse, cardiovascular complications and increased mortality. The management of aortitis is insufficiently codified, and relies on the control of cardiovascular risk factors, with particular monitoring of blood pressure and LDL cholesterol, and on corticosteroid therapy and immunosuppressive drugs, the use of which will depend on the disease associated with the aortitis, the initial severity and comorbidities.
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BACKGROUND: Studies on the capability of cerebrospinal fluid neurofilament light chain (cNfL) to predict multiple sclerosis (MS) conversion in clinically isolated syndromes have yielded varying results. OBJECTIVES: To expand our understanding of cNfL in optic neuritis (ON) and investigate whether incorporating cNfL into the 2017 McDonald criteria could accelerate the diagnosis of MS in patients with ON. METHODS: cNfL was measured in diagnostic samples from 74 patients with verified ON. MS was diagnosed using the 2017 McDonald criteria with a minimum observation time of two years from ON onset. RESULTS: 20.5% of 44 MS-converters did not fulfil the 2017 McDonald criteria at ON onset. A doubling of cNfL was associated with 207% (74%-514%) higher odds of MS (p = 0.00042, adjusted for age). Fulfilment of ≥ 1 MRI criterion for dissemination in space (DIS) and presence of brain contrast-enhancing lesions were associated with higher cNfL. Furthermore, cNfL correlated with inter-eye differences in retinal nerve fiber layer (RNFL) thickness (Spearman's ρ = 0.46, p = 8 × 10-5). Incorporating cNfL ≥ 906 pg/mL as a substitute for either dissemination in time or one MRI criterion for DIS increased the sensitivity (90.9% vs. 79.6%) and accuracy (91.9% vs. 87.8%), but also reduced the specificity (93.3% vs. 100%) of the 2017 McDonald criteria. CONCLUSION: cNfL was related to MS diagnostic parameters and the degree of RNFL swelling. Clinical use of cNfL may aid in identification of ON patients with increased risk of MS until larger studies have elaborated on the potential loss of specificity if used diagnostically.
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Esclerosis Múltiple , Proteínas de Neurofilamentos , Neuritis Óptica , Humanos , Neuritis Óptica/líquido cefalorraquídeo , Neuritis Óptica/diagnóstico , Masculino , Femenino , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/diagnóstico , Adulto , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Persona de Mediana Edad , Biomarcadores/líquido cefalorraquídeo , Imagen por Resonancia Magnética , Progresión de la EnfermedadRESUMEN
Multiple sclerosis (MS) treatment intervention with immunomodulating therapy at early disease stage improves short term clinical outcomes. The objective of this study is to describe the long-term outcomes and healthcare utilization of patients with clinically isolated syndrome (CIS) included in the Betaferon®/Betaseron® in Newly Emerging MS for Initial Treatment (BENEFIT) randomized, parallel group trial. In BENEFIT patients were assigned to "early" IFNB-1b treatment or placebo ("delayed" treatment). After 2 years or conversion to clinically definite multiple sclerosis (CDMS), all patients were offered IFNB-1b and were reassessed 15 years later. Of 468 patients, 261 (55.8%) were enrolled into BENEFIT 15 (161 [55.1%] from the early, 100 [56.8%] from the delayed treatment arm). In the full BENEFIT analysis set, risk of conversion to CDMS remained lower in the early treatment group ( - 30.5%; hazard ratio 0.695 [95% CI, 0.547-0.883]; p = 0.0029) with a 15.7% lower risk of relapse than in the delayed treatment group (p = 0.1008). Overall, 25 patients (9.6%; 9.9% early, 9.0% delayed) converted to secondary progressive multiple sclerosis. Disability remained low and stable with no significant difference between groups in Expanded Disability Status Scale score or MRI metrics. Paced Auditory Serial Addition Task-3 scores were better in the early treatment group (p = 0.0036 for treatment effect over 15 years). 66.3% of patients were still employed at Year 15 versus 74.7% at baseline. In conclusion, results 15 years from initial randomization support long-term benefits of early treatment with IFNB-1b.
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Interferon beta-1b , Esclerosis Múltiple , Humanos , Interferon beta-1b/uso terapéutico , Interferon beta-1b/farmacología , Masculino , Femenino , Adulto , Estudios de Seguimiento , Esclerosis Múltiple/tratamiento farmacológico , Enfermedades Desmielinizantes/tratamiento farmacológico , Resultado del Tratamiento , Persona de Mediana Edad , Progresión de la Enfermedad , Adulto Joven , Método Doble CiegoRESUMEN
BACKGROUND: Conventional magnetic resonance imaging (MRI) does not account for all disability in multiple sclerosis. OBJECTIVE: The objective was to assess the ability of graph metrics from diffusion-based structural connectomes to explain motor function beyond conventional MRI in early demyelinating clinically isolated syndrome (CIS). METHODS: A total of 73 people with CIS underwent conventional MRI, diffusion-weighted imaging and clinical assessment within 3 months from onset. A total of 28 healthy controls underwent MRI. Structural connectomes were produced. Differences between patients and controls were explored; clinical associations were assessed in patients. Linear regression models were compared to establish relevance of graph metrics over conventional MRI. RESULTS: Local efficiency (p = 0.045), clustering (p = 0.034) and transitivity (p = 0.036) were reduced in patients. Higher assortativity was associated with higher Expanded Disability Status Scale (EDSS) (ß = 74.9, p = 0.026) scores. Faster timed 25-foot walk (T25FW) was associated with higher assortativity (ß = 5.39, p = 0.026), local efficiency (ß = 27.1, p = 0.041) and clustering (ß = 36.1, p = 0.032) and lower small-worldness (ß = -3.27, p = 0.015). Adding graph metrics to conventional MRI improved EDSS (p = 0.045, ΔR2 = 4) and T25FW (p < 0.001, ΔR2 = 13.6) prediction. CONCLUSION: Graph metrics are relevant early in demyelination. They show differences between patients and controls and have relationships with clinical outcomes. Segregation (local efficiency, clustering, transitivity) was particularly relevant. Combining graph metrics with conventional MRI better explained disability.
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Conectoma , Enfermedades Desmielinizantes , Humanos , Masculino , Femenino , Adulto , Enfermedades Desmielinizantes/diagnóstico por imagen , Enfermedades Desmielinizantes/fisiopatología , Persona de Mediana Edad , Imagen de Difusión por Resonancia Magnética , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/fisiopatología , Evaluación de la Discapacidad , Imagen por Resonancia Magnética , Adulto Joven , Encéfalo/diagnóstico por imagen , Encéfalo/fisiopatología , Encéfalo/patologíaRESUMEN
Multiple sclerosis (MS) is the most common demyelinating disease affecting the central nervous system. It has a wide range of manifestations and commonly affects the visual system. Many patients with MS report decreased vision, diplopia, nystagmus, and abnormal ocular motility. Nevertheless, bilateral horizontal gaze palsies are exceptionally rarely seen. We present the case of a 24-year-old female who came to our pediatric ophthalmology clinic complaining of bilateral horizontal gaze palsy, photophobia, and eye pain for 2 days. Although the patient had a family history of MS, there was no similar or previous complaint, with an unremarkable past medical and surgical history. During the examination, she was found to have a complete bilateral absence of horizontal saccade and pursuit, with slight limitations in vertical ones. There was no nystagmus or skew deviation, and the rest of the cranial nerves (CNs) were intact. Her ocular vital signs were normal, and her corrected visual acuity was 20/20 with full-color vision. The rest of the physical and neurological examinations were unremarkable. After referral to neurology, the magnetic resonance imaging showed multiple hyperintense lesions in deep white matter, pons, and midbrain. The correlation of imaging findings with clinical presentation confirmed the diagnosis of a clinically isolated syndrome. Extra-ocular motility (EOM) significantly improved after pulse steroid therapy and five sessions of plasma exchange, but the patient developed 35 prism diopter of acquired concomitant esotropia. She underwent a right medial rectus botulinum toxin injection which dramatically improved her condition, and became orthotropic during the last 2 months of follow-up after the injection.
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BACKGROUND: Although certain subsets patients with multiple sclerosis (MS), an immune-mediated disorder, are at higher risk of worse acute COVID-19 outcomes compared to the general population, it is not clear whether SARS-CoV-2 infection impacts long-term outcomes compared with MS patients without COVID-19 infection. OBJECTIVES: This study investigated MS disease activity and mortality 3.5 years post SARS-CoV-2 infection and compared with MS patients without COVID-19. METHODS: This retrospective study evaluated 1,633 patients with MS in the Montefiore Health System in the Bronx from January 2016 to July 2023. This health system serves a large minority population and was an epicenter for the early pandemic and subsequent surges of infection. Positive SARS-CoV-2 infection was determined by a positive polymerase-chain-reaction test. Primary outcomes were all-cause mortality, and optic neuritis post SARS-CoV-2 infection. Secondary outcomes included change in disease-modifying therapy (DMT), treatment with high-dose methylprednisolone, cerebellar deficits, relapse, and all-cause hospitalization post-infection. RESULTS: MS patients with COVID-19 had similar demographics but higher prevalence of pre-existing major comorbidities (hypertension, type-2 diabetes, chronic obstructive pulmonary disease, congestive heart failure, chronic kidney disease, and coronary artery disease), optic neuritis, and history of high dose steroid treatment for relapses compared to MS patients without COVID-19. MS patients with COVID-19 had greater risk of mortality (adjusted HR=4.34[1.67, 11.30], p < 0.005), greater risk of post infection optic neuritis (adjusted HR=2.97[1.58, 5.58], p < 0.005), higher incidence of methylprednisolone treatment for post infection acute relapse (12.65% vs. 2.54 %, p < 0.001), and more hospitalization (78.92% vs. 66.81 %, p < 0.01), compared to MS patients without COVID-19. CONCLUSIONS: MS patients who survived COVID-19 infection experienced worse long-term outcomes, as measured by treatment for relapse, hospitalization and mortality. Identifying risk factors for worse long-term outcomes may draw clinical attention to the need for careful follow-up of at-risk individuals post-SARS-CoV-2 infection.
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COVID-19 , Esclerosis Múltiple , Humanos , COVID-19/mortalidad , COVID-19/complicaciones , COVID-19/epidemiología , Masculino , Femenino , Persona de Mediana Edad , Esclerosis Múltiple/mortalidad , Esclerosis Múltiple/epidemiología , Esclerosis Múltiple/tratamiento farmacológico , Estudios Retrospectivos , Adulto , Comorbilidad , Neuritis Óptica/epidemiología , Población Urbana/estadística & datos numéricos , Hospitalización/estadística & datos numéricos , Ciudad de Nueva York/epidemiologíaRESUMEN
INTRODUCTION: Predicting the conversion of clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS) is critical to personalizing treatment planning and benefits for patients. The aim of this study is to develop an explainable machine learning (ML) model for predicting this conversion based on demographic, clinical, and imaging data. METHOD: The ML model, Extreme Gradient Boosting (XGBoost), was employed on the public dataset of 273 Mexican mestizo CIS patients with 10-year follow-up. The data was divided into a training set for cross-validation and feature selection, and a holdout test set for final testing. Feature importance was determined using the SHapley Additive Explanations library (SHAP). Then, two experiments were conducted to optimize the model's performance by selectively adding variables and selecting the most contributive variables for the final model. RESULTS: Nine variables including age, gender, schooling, motor symptoms, infratentorial and periventricular lesion at imaging, oligoclonal band in cerebrospinal fluid, lesion and symptoms types were significant. The model achieved an accuracy of 83.6 %, AUC of 91.8 %, sensitivity of 83.9 %, and specificity of 83.4 % in cross-validation. In the final testing, the model achieved an accuracy of 78.3 %, AUC of 85.8 %, sensitivity of 75 %, and specificity of 81.1 %. Finally, a web-based demo of the model was created for testing purposes. CONCLUSION: The model, focusing on feature selection and interpretability, effectively stratifies risk for treatment decisions and disability prevention in MS patients. It provides a numerical risk estimate for CDMS conversion, enhancing transparency in clinical decision-making and aiding in patient care.
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Enfermedades Desmielinizantes , Progresión de la Enfermedad , Aprendizaje Automático , Esclerosis Múltiple , Humanos , Femenino , Esclerosis Múltiple/diagnóstico , Masculino , Adulto , Enfermedades Desmielinizantes/diagnóstico , Enfermedades Desmielinizantes/diagnóstico por imagen , Persona de Mediana Edad , México , Estudios de Seguimiento , Imagen por Resonancia MagnéticaRESUMEN
Vitamin D deficiency is a risk factor for developing multiple sclerosis. The PrevANZ trial was conducted to determine if vitamin D3 supplementation can prevent recurrent disease activity in people with a first demyelinating event. As a sub-study of this trial, we investigated the effect of supplementation on peripheral immune cell gene expression. Participants were randomized to 1000, 5000 or 10,000 international units daily of vitamin D3 or placebo. Peripheral blood was collected at baseline and 12 weeks and sent for ribonucleic acid sequencing. Datasets from 55 participants were included. Gene expression was modulated by high dose supplementation. Antigen presentation and viral response pathways were upregulated. Oxidative phosphorylation and immune signaling pathways, including tumor necrosis factor-alpha and interleukin-17 signaling, were downregulated. Overall, vitamin D3 supplementation for 12 weeks modulated the peripheral immune cell transcriptome with induction of anti-inflammatory gene expression profiles. Our results support a dose-dependent effect of vitamin D3 supplementation on immune gene expression.
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Colecalciferol , Deficiencia de Vitamina D , Humanos , Colecalciferol/farmacología , Suplementos Dietéticos , Método Doble Ciego , Factores de Riesgo , Transcriptoma , Deficiencia de Vitamina D/tratamiento farmacológico , Deficiencia de Vitamina D/genéticaRESUMEN
The initial phase of multiple sclerosis (MS), often known as clinically isolated syndrome (CIS), is a critical period for identifying individuals at high risk of progressing to full-blown MS and initiating timely treatment. In this study, we aimed to evaluate the prognostic value of C-X-C motif chemokine ligand 13 (CXCL13) and interleukin-8 (IL-8) as potential markers for CIS patients' conversion to MS. Our study encompassed patients with CIS, those with relapsing-remitting MS (RRMS), and control subjects, with sample analysis conducted on both cerebrospinal fluid (CSF) and serum. Patients were categorized into four groups: CIS-CIS (no MS development within 2 years), CIS-RRMS (conversion to RRMS within 2 years), RRMS (already diagnosed), and a control group (CG) with noninflammatory central nervous system disorders. Results showed significantly elevated levels of CXCL13 in CSF across all patient groups compared with the CG (p < 0.0001, Kruskal-Wallis test). Although CXCL13 concentrations were slightly higher in the CIS-RRMS group, statistical significance was not reached. Similarly, significantly higher levels of IL-8 were detected in CSF samples from all patient groups compared with the CG (p < 0.0001, Kruskal-Wallis test). Receiver operating characteristic analysis in the CIS-RRMS group identified both CXCL13 (area under receiver operating characteristic curve = .959) and IL-8 (area under receiver operating characteristic curve = .939) in CSF as significant predictors of CIS to RRMS conversion. In conclusion, our study suggests a trend towards elevated CSF IL-8 and CSF CXCL13 levels in CIS patients progressing to RRMS. These findings emphasize the importance of identifying prognostic markers to guide appropriate treatment strategies for individuals in the early stages of MS.
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Quimiocina CXCL13 , Progresión de la Enfermedad , Interleucina-8 , Esclerosis Múltiple Recurrente-Remitente , Humanos , Quimiocina CXCL13/líquido cefalorraquídeo , Quimiocina CXCL13/sangre , Interleucina-8/líquido cefalorraquídeo , Interleucina-8/sangre , Femenino , Masculino , Adulto , Pronóstico , Esclerosis Múltiple Recurrente-Remitente/líquido cefalorraquídeo , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/sangre , Persona de Mediana Edad , Enfermedades Desmielinizantes/líquido cefalorraquídeo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/sangre , Esclerosis Múltiple/diagnóstico , Adulto JovenRESUMEN
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.
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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
INTRODUCTION: In Multiple Sclerosis (MS), patients´ characteristics and (bio)markers that reliably predict the individual disease prognosis at disease onset are lacking. Cohort studies allow a close follow-up of MS histories and a thorough phenotyping of patients. Therefore, a multicenter cohort study was initiated to implement a wide spectrum of data and (bio)markers in newly diagnosed patients. METHODS: ProVal-MS (Prospective study to validate a multidimensional decision score that predicts treatment outcome at 24 months in untreated patients with clinically isolated syndrome or early Relapsing-Remitting-MS) is a prospective cohort study in patients with clinically isolated syndrome (CIS) or Relapsing-Remitting (RR)-MS (McDonald 2017 criteria), diagnosed within the last two years, conducted at five academic centers in Southern Germany. The collection of clinical, laboratory, imaging, and paraclinical data as well as biosamples is harmonized across centers. The primary goal is to validate (discrimination and calibration) the previously published DIFUTURE MS-Treatment Decision score (MS-TDS). The score supports clinical decision-making regarding the options of early (within 6 months after study baseline) platform medication (Interferon beta, glatiramer acetate, dimethyl/diroximel fumarate, teriflunomide), or no immediate treatment (> 6 months after baseline) of patients with early RR-MS and CIS by predicting the probability of new or enlarging lesions in cerebral magnetic resonance images (MRIs) between 6 and 24 months. Further objectives are refining the MS-TDS score and providing data to identify new markers reflecting disease course and severity. The project also provides a technical evaluation of the ProVal-MS cohort within the IT-infrastructure of the DIFUTURE consortium (Data Integration for Future Medicine) and assesses the efficacy of the data sharing techniques developed. PERSPECTIVE: Clinical cohorts provide the infrastructure to discover and to validate relevant disease-specific findings. A successful validation of the MS-TDS will add a new clinical decision tool to the armamentarium of practicing MS neurologists from which newly diagnosed MS patients may take advantage. Trial registration ProVal-MS has been registered in the German Clinical Trials Register, `Deutsches Register Klinischer Studien` (DRKS)-ID: DRKS00014034, date of registration: 21 December 2018; https://drks.de/search/en/trial/DRKS00014034.
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Optic neuritis is often an initial symptom in multiple sclerosis (MS) or clinically isolated syndrome (CIS), yet comprehensive studies using the 2017 McDonald criteria for MS are scarce. Patient records from our academic centre (2010-2018) were reviewed. Using the 2017 McDonald criteria, three groups were formed: MS optic neuritis (optic neuritis with confirmed MS), CIS optic neuritis (optic neuritis without confirmed MS) and suspected optic neuritis (sON). We compared clinical and paraclinical findings among the groups to identify predictors for CIS- or MS-optic neuritis. The study included 129 MS, 108 CIS, and 44 sON cases. The combination of visual impairment, dyschromatopsia, and retrobulbar pain was observed in 47% of MS patients, 42% of CIS patients, and 30% of sON patients. Dyschromatopsia was the strongest indicator of MS or CIS diagnosis in the backward regression model. 56% of MS patients had relative afferent pupillary defect, 61% optic nerve anomalies within magnetic resonance imaging, and 81% abnormal visual evoked potentials. Our results emphasize the challenges in diagnosing optic neuritis, as not all patients with objectively diagnosed MS exhibit the triad of typical symptoms. To address potentially missing clinical features, incorporating additional paraclinical findings is proposed.
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Enfermedades Desmielinizantes , Esclerosis Múltiple , Neuritis Óptica , Humanos , Potenciales Evocados Visuales , Neuritis Óptica/diagnóstico , Neuritis Óptica/patología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/patología , Enfermedades Desmielinizantes/diagnóstico , Nervio Óptico/diagnóstico por imagen , Nervio Óptico/patología , Imagen por Resonancia Magnética/métodosRESUMEN
Tumefactive demyelinating lesions (TDLs) can present as an isolated clinical incidence or could represent the initial presentation of multiple sclerosis. Radiological TDLs are characterized by large tumors like >2 cm space-occupying lesions with mass effect and perilesional edema. Diagnosis is based on MRI imaging and extensive work to exclude other causes and a biopsy of the lesion is often required. First-line treatments include pulsed methylprednisolone. We present a case of a refractory TDL treated successfully with therapeutic plasma exchange.
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INTRODUCTION: Body fluid markers could be helpful to predict the conversion into clinically definite multiple sclerosis (MS) in people with a first demyelinating event of the central nervous system (CNS). Consequently, biomarkers such as oligoclonal bands, which are integrated in the current MS diagnostic criteria, could assist early MS diagnosis. AREAS COVERED: This review examines existing knowledge on a broad spectrum of body fluid markers in people with a first CNS demyelinating event, explores their potential to predict conversion to MS, to assess MS disease activity, as well as their utility to differentiate MS from atypical demyelinating disorders such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein associated disease. EXPERT OPINION: This field of research has shown a dramatic increase of evidence, especially in the last decade. Some biomarkers are already established in clinical routine (e.g. oligoclonal bands) while others are currently implemented (e.g. kappa free light chains) or considered as breakthroughs (e.g. neurofilament light). Determination of biomarkers poses challenges for continuous monitoring, especially if exclusively detectable in cerebrospinal fluid. A handful of biomarkers are measurable in blood which holds a significant potential.
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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
The requirement to demonstrate dissemination in time (DIT) in order to diagnose multiple sclerosis (MS) has been enshrined in the literature since earliest efforts to establish diagnostic critera. However, various diagnostic criteria over the years, including the 2017 McDonald criteria, have inconsistently utilized this concept. This Viewpoint contends that current criteria for DIT are inadequate and sometimes inappropriate. It recommends continuing to consider DIT in the diagnosis of MS, but advocates utilizing all available information with high specificity for the disease, including the presence of large numbers of typical lesions, to make the diagnosis. This approach enables early initiation of disease-modifying treatment in situations with a favorable risk-benefit ratio.