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Gender inequality in STEM fields remains pervasive and undermines the ability for talented individuals to excel. Despite advances, women still encounter obstacles in pursuing academic careers and reaching leadership positions. This commentary discusses the "scissor-shaped curve" and examines effective strategies to fix it, including data-driven initiatives that we have implemented at our university.
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Academia , Equidad de Género , Humanos , Femenino , Liderazgo , UniversidadesRESUMEN
The vasculature is a key regulator of leukocyte trafficking into the central nervous system (CNS) during inflammatory diseases including multiple sclerosis (MS). However, the impact of endothelial-derived factors on CNS immune responses remains unknown. Bioactive lipids, in particular oxysterols downstream of Cholesterol-25-hydroxylase (Ch25h), promote neuroinflammation but their functions in the CNS are not well-understood. Using floxed-reporter Ch25h knock-in mice, we trace Ch25h expression to CNS endothelial cells (ECs) and myeloid cells and demonstrate that Ch25h ablation specifically from ECs attenuates experimental autoimmune encephalomyelitis (EAE). Mechanistically, inflamed Ch25h-deficient CNS ECs display altered lipid metabolism favoring polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) expansion, which suppresses encephalitogenic T lymphocyte proliferation. Additionally, endothelial Ch25h-deficiency combined with immature neutrophil mobilization into the blood circulation nearly completely protects mice from EAE. Our findings reveal a central role for CNS endothelial Ch25h in promoting neuroinflammation by inhibiting the expansion of immunosuppressive myeloid cell populations.
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Encefalomielitis Autoinmune Experimental , Oxiesteroles , Ratones , Animales , Células Endoteliales/metabolismo , Oxiesteroles/metabolismo , Enfermedades Neuroinflamatorias , Sistema Nervioso Central/metabolismo , Ratones Endogámicos C57BLRESUMEN
Cholesterol is an essential structural component of all membranes of mammalian cells where it plays a fundamental role not only in cellular architecture, but also, for example, in signaling pathway transduction, endocytosis process, receptor functioning and recycling, or cytoskeleton remodeling. Consequently, intracellular cholesterol concentrations are tightly regulated by complex processes, including cholesterol synthesis, uptake from circulating lipoproteins, lipid transfer to these lipoproteins, esterification, and metabolization into oxysterols that are intermediates for bile acids. Oxysterols have been considered for long time as sterol waste products, but a large body of evidence has clearly demonstrated that they play key roles in central nervous system functioning, immune cell response, cell death, or migration and are involved in age-related diseases, cancers, autoimmunity, or neurological disorders. Among all the existing oxysterols, this review summarizes basic as well as recent knowledge on 25-hydroxycholesterol which is mainly produced during inflammatory or infectious situations and that in turn contributes to immune response, central nervous system disorders, atherosclerosis, macular degeneration, or cancer development. Effects of its metabolite 7α,25-dihydroxycholesterol are also presented and discussed.
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Hidroxicolesteroles , Oxiesteroles , Animales , Hidroxicolesteroles/metabolismo , Colesterol/metabolismo , Transporte Biológico , Lipoproteínas/metabolismo , Mamíferos/metabolismoRESUMEN
Disruption of gut barrier function and intestinal immune cell homeostasis are increasingly considered critical players in pathogenesis of extra-intestinal inflammatory diseases, including multiple sclerosis (MS) and its prototypical animal model, the experimental autoimmune encephalomyelitis (EAE). Breakdown of epithelial barriers increases intestinal permeability and systemic dissemination of microbiota-derived molecules. However, whether the gut-vascular barrier (GVB) is altered during EAE has not been reported. Here, we demonstrate that endothelial cell proliferation and vessel permeability increase before EAE clinical onset, leading to vascular remodeling and expansion of intestinal villi capillary bed during disease symptomatic phase in an antigen-independent manner. Concomitant to onset of angiogenesis observed prior to neurological symptoms, we identify an increase of intestinal perivascular immune cells characterized by the surface marker lymphatic vessel endothelial hyaluronic acid receptor 1 (LYVE-1). LYVE-1+ is expressed more frequently on B cells that show high levels of CD73 and have proangiogenic properties. B cell depletion was sufficient to mitigate enteric blood endothelial cell proliferation following immunization for EAE. In conclusion, we propose that altered intestinal vasculature driven by a specialized LYVE-1+ B cell subset promotes angiogenesis and that loss of GVB function is implicated in EAE development and autoimmunity.
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BACKGROUND: Diagnosis of primary diffuse large B-cell lymphoma of the central nervous system (PCNSL) is challenging and often delayed. MRI imaging, CSF cytology and flow cytometry have a low sensitivity and even brain biopsies can be misleading. We report three cases of PCNSL with various clinical presentation and radiological findings where the diagnosis was suggested by novel CSF biomarkers and subsequently confirmed by brain biopsy or autopsy. CASE PRESENTATIONS: The first case is a 79-year-old man with severe neurocognitive dysfunction and static ataxia evolving over 5 months. Brain MRI revealed a nodular ventriculitis. An open brain biopsy was inconclusive. The second case is a 60-year-old woman with progressive sensory symptoms in all four limbs, evolving over 1 year. Brain and spinal MRI revealed asymmetric T2 hyperintensities of the corpus callosum, corona radiata and corticospinal tracts. The third case is a 72-year-old man recently diagnosed with primary vitreoretinal lymphoma of the right eye. A follow-up brain MRI performed 4 months after symptom onset revealed a T2 hyperintense fronto-sagittal lesion, with gadolinium uptake and perilesional edema. In all three cases, CSF flow cytometry and cytology were negative. Mutation analysis on the CSF (either by digital PCR or by next generation sequencing) identified the MYD88 L265P hotspot mutation in all three cases. A B-cell clonality study, performed in case 1 and 2, identified a monoclonal rearrangement of the immunoglobulin light chain lambda (IGL) and kappa (IGK) gene. CSF CXCL-13 and IL-10 levels were high in all three cases, and IL-10/IL-6 ratio was high in two. Diagnosis of PCNSL was later confirmed by autopsy in case 1, and by brain biopsy in case 2 and 3. CONCLUSIONS: Taken together, 5 CSF biomarkers (IL-10, IL-10/IL-6 ratio, CXCL13, MYD88 mutation and monoclonal IG gene rearrangements) were strongly indicative of a PCNSL. Using innovative CSF biomarkers can be sensitive and complementary to traditional CSF analysis and brain biopsy in the diagnosis of PCNSL, potentially allowing for earlier diagnosis and treatment.
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Linfoma de Células B Grandes Difuso , Humanos , Masculino , Anciano , Linfoma de Células B Grandes Difuso/líquido cefalorraquídeo , Linfoma de Células B Grandes Difuso/diagnóstico , Persona de Mediana Edad , Femenino , Neoplasias del Sistema Nervioso Central/líquido cefalorraquídeo , Neoplasias del Sistema Nervioso Central/diagnóstico por imagen , Neoplasias del Sistema Nervioso Central/diagnóstico , Neoplasias del Sistema Nervioso Central/patología , Biomarcadores de Tumor/líquido cefalorraquídeo , Encéfalo/patología , Encéfalo/diagnóstico por imagen , Imagen por Resonancia MagnéticaRESUMEN
Myelin Oligodendrocyte Glycoprotein Antibody Associated Disease (MOGAD) is an autoimmune disease responsible for demyelination of the central nervous system that can occur in adults or children. Overlapping phenotypes between MOGAD, multiple sclerosis (MS) and neuromyelitis optica spectrum disease (NMOSD) have been described. The diagnostic criteria for MOGAD were proposed by a panel of international experts and published in 2023. Defining clinical, biological and imaging characteristics specific to this entity helps to improve diagnostic specificity. In this article, we present the clinical characteristics suggestive of MOGAD and discuss the importance of the antibody detection method and therapeutic management.
La maladie du spectre des anticorps anti-MOG (glycoprotéine de myéline oligodendrocytaire) (myelin oligodendrocyte glycoprotein antibody-associated disease, MOGAD) est une maladie autoimmune responsable d'une démyélinisation du système nerveux central pouvant survenir chez les adultes ou les enfants. Des phénotypes de chevauchement entre MOGAD, sclérose en plaques et maladie du spectre de la neuromyélite optique ont été décrits. Les critères diagnostiques de MOGAD ont été proposés par un panel d'experts internationaux et publiés en 2023. Ils permettent de définir des caractéristiques cliniques, biologiques et d'imagerie propres à cette entité, afin d'améliorer la spécificité diagnostique. Nous présentons dans cet article les caractéristiques cliniques en faveur de MOGAD, discutons de l'importance de la méthode de détection des anticorps et terminons par une mise au point sur la prise en charge thérapeutique.
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Autoanticuerpos , Esclerosis Múltiple , Glicoproteína Mielina-Oligodendrócito , Neuromielitis Óptica , Humanos , Glicoproteína Mielina-Oligodendrócito/inmunología , Neuromielitis Óptica/diagnóstico , Neuromielitis Óptica/inmunología , Autoanticuerpos/inmunología , Autoanticuerpos/sangre , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/inmunología , Adulto , Niño , Enfermedades Autoinmunes/diagnóstico , Enfermedades Autoinmunes/inmunologíaRESUMEN
The management of multiple sclerosis (MS) has undergone a veritable revolution in recent years, with the arrival of highly effective treatments. In some cases, therapeutic discussions even precede the first clinical signs of the disease. The aim of this review is to present the therapeutic arsenal of progression-preventing treatments available in 2024 for MS, with anti-CD20 antibodies taking pride of place, also available for certain progressive forms of MS. The use of these immunosuppressants requires in-depth knowledge of their mechanisms of action, in order to understand their risks, such as the occurrence of opportunistic infections.
La prise en charge de la sclérose en plaques (SEP) a subi une véritable révolution ces dernières années avec l'arrivée de traitements à haute efficacité. La discussion thérapeutique précède même, dans certains cas, l'apparition des premiers signes cliniques de la maladie. Cet article a pour but de présenter l'arsenal des traitements de fond de la SEP disponibles en 2024. Parmi eux, les anticorps monoclonaux anti-lymphocytes B (anti-CD20) occupent une grande place. Ces derniers sont validés dans la forme poussée-rémission mais aussi pour les formes progressives de la SEP. L'utilisation de ces traitements nécessite une connaissance approfondie de leurs mécanismes d'actions afin de comprendre leurs risques tels que la survenue d'infections opportunistes.
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Inmunosupresores , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/terapia , Esclerosis Múltiple/tratamiento farmacológico , Inmunosupresores/uso terapéutico , Progresión de la EnfermedadRESUMEN
Aging in multiple sclerosis (MS) leads to altered clinical manifestations, where the pathophysiology shifts towards compartmentalized inflammation that drives clinical progression independent of relapse activity. Consequently, the effectiveness of disease-modifying therapies (DMTs) diminishes in older patients, coinciding with an elevated risk of adverse events. This raises the question of whether MS therapies should be discontinued after a certain age, which is often proposed for patients over 55 years. Studies on treatment discontinuation have shown a slight increase in disease activity, yet without significant disability progression. This suggests that the decision to stop DMTs should be discussed with older patients, considering existing comorbidities. Following the cessation of therapy, meticulous monitoring is essential.
L'avancée en âge modifie la présentation clinique de la sclérose en plaques (SEP). La physiopathologie évolue progressivement au profit d'une inflammation restreinte au système nerveux central entraînant une progression clinique indépendante des poussées. Cette évolution est associée à une baisse d'efficacité des traitements de la SEP, alors qu'en parallèle le risque de complications augmente. Se pose donc la question d'un arrêt des thérapies de la SEP après un certain âge, souvent proposé à 55 ans. Bien que les premières études suggèrent une légère reprise d'activité à l'arrêt des traitements, celle-ci n'est pas associée à une progression du handicap. L'arrêt du traitement chez les patients les plus âgés devrait donc être envisagé en prenant en compte les comorbidités. Par la suite, une surveillance méticuleuse est indispensable.
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Esclerosis Múltiple , Humanos , Esclerosis Múltiple/tratamiento farmacológico , Progresión de la Enfermedad , Factores de Edad , Persona de Mediana Edad , Privación de TratamientoRESUMEN
OBJECTIVE: Intrathecal Immunoglobulin M synthesis (IgMIntrathecal Fraction (IF) + ) and spinal MRI lesions are both strong independent predictors of higher disease activity and severity in multiple sclerosis (MS). We investigated whether IgMIF + is associated with spinal cord manifestation and higher neuroaxonal damage in early MS. METHODS: In 122 patients with a first demyelinating event associations between (1) spinal versus (vs) non-spinal clinical syndrome (2) spinal vs cerebral T2-weighted (T2w) and (3) contrast-enhancing (CE) lesion counts with IgGIF + (vs IgGIF - ) or IgMIF + (vs IgMIF - ) were investigated by logistic regression adjusted for age and sex, respectively. For serum neurofilament light chain (sNfL) analysis patients were categorized for presence or absence of oligoclonal IgG bands (OCGB), IgGIF and IgMIF (>0% vs 0%, respectively): (1) OCGB- /IgGIF - /IgMIF - ; (2) OCGB+ /IgGIF - /IgMIF - ; (3) OCGB+ /IgGIF + /IgMIF - ; and (4) OCGB+ /IgGIF + /IgMIF + . Associations between categories 2 to 4 vs category 1 with sNfL concentrations were analyzed by robust linear regression, adjusted for sex and MRI parameters. RESULTS: Patients with a spinal syndrome had a 8.36-fold higher odds of IgMIF + (95%CI 3.03-23.03; p < 0.01). Each spinal T2w lesion (odds Ratio 1.39; 1.02-1.90; p = 0.037) and CE lesion (OR 2.73; 1.22-6.09; p = 0.014) was associated with an increased risk of IgMIF + (but not of IgGIF + ); this was not the case for cerebral lesions. OCGB+ /IgGIF + /IgMIF + category patients showed highest sNfL levels (estimate:1.80; 0.55-3.06; p < 0.01). INTERPRETATION: Intrathecal IgM synthesis is strongly associated with spinal manifestation and independently more pronounced neuroaxonal injury in early MS, suggesting a distinct clinical phenotype and pathophysiology. ANN NEUROL 2022;91:814-820.
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Esclerosis Múltiple , Bandas Oligoclonales , Humanos , Inmunoglobulina G , Inmunoglobulina M , Esclerosis Múltiple/patología , Médula Espinal/diagnóstico por imagen , Médula Espinal/patologíaRESUMEN
BACKGROUND: Detecting new and enlarged lesions in multiple sclerosis (MS) patients is needed to determine their disease activity. LeMan-PV is a software embedded in the scanner reconstruction system of one vendor, which automatically assesses new and enlarged white matter lesions (NELs) in the follow-up of MS patients; however, multicenter validation studies are lacking. PURPOSE: To assess the accuracy of LeMan-PV for the longitudinal detection NEL white-matter MS lesions in a multicenter clinical setting. STUDY TYPE: Retrospective, longitudinal. SUBJECTS: A total of 206 patients with a definitive MS diagnosis and at least two follow-up MRI studies from five centers participating in the Swiss Multiple Sclerosis Cohort study. Mean age at first follow-up = 45.2 years (range: 36.9-52.8 years); 70 males. FIELD STRENGTH/SEQUENCE: Fluid attenuated inversion recovery (FLAIR) and T1-weighted magnetization prepared rapid gradient echo (T1-MPRAGE) sequences at 1.5 T and 3 T. ASSESSMENT: The study included 313 MRI pairs of datasets. Data were analyzed with LeMan-PV and compared with a manual "reference standard" provided by a neuroradiologist. A second rater (neurologist) performed the same analysis in a subset of MRI pairs to evaluate the rating-accuracy. The Sensitivity (Se), Specificity (Sp), Accuracy (Acc), F1-score, lesion-wise False-Positive-Rate (aFPR), and other measures were used to assess LeMan-PV performance for the detection of NEL at 1.5 T and 3 T. The performance was also evaluated in the subgroup of 123 MRI pairs at 3 T. STATISTICAL TESTS: Intraclass correlation coefficient (ICC) and Cohen's kappa (CK) were used to evaluate the agreement between readers. RESULTS: The interreader agreement was high for detecting new lesions (ICC = 0.97, Pvalue < 10-20 , CK = 0.82, P value = 0) and good (ICC = 0.75, P value < 10-12 , CK = 0.68, P value = 0) for detecting enlarged lesions. Across all centers, scanner field strengths (1.5 T, 3 T), and for NEL, LeMan-PV achieved: Acc = 61%, Se = 65%, Sp = 60%, F1-score = 0.44, aFPR = 1.31. When both follow-ups were acquired at 3 T, LeMan-PV accuracy was higher (Acc = 66%, Se = 66%, Sp = 66%, F1-score = 0.28, aFPR = 3.03). DATA CONCLUSION: In this multicenter study using clinical data settings acquired at 1.5 T and 3 T, and variations in MRI protocols, LeMan-PV showed similar sensitivity in detecting NEL with respect to other recent 3 T multicentric studies based on neural networks. While LeMan-PV performance is not optimal, its main advantage is that it provides automated clinical decision support integrated into the radiological-routine flow. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 2.
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Esclerosis Múltiple , Sustancia Blanca , Masculino , Humanos , Adulto , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Estudios de Cohortes , Estudios Retrospectivos , Imagen por Resonancia Magnética/métodos , Encéfalo/diagnóstico por imagen , Encéfalo/patologíaRESUMEN
Cognitive disorders are present in 30 to 45% of relapsing-remitting forms of multiple sclerosis and in up to 50-75% of progressive forms. They bear a negative impact on the quality of life and predict an unfavorable disease progression. According to guidelines, screening based on objective measurement such as the Single Digit Modality Test (SDMT) should be performed at the time of diagnosis and then on an annual basis. Confirmation of diagnosis and management are performed in collaboration with neuropsychologists. Increased awareness from patients and healthcare professionals is important to ensure earlier management and prevent negative consequences on the patients professional and family life.
Les troubles cognitifs sont présents chez 30 à 45 % des patients souffrant d'une forme poussée-rémission de sclérose en plaques (SEP) et chez jusqu'à 50-75 % de ceux souffrant des formes progressives. Ces troubles cognitifs impactent négativement la qualité de vie et sont associés à une progression défavorable de la SEP elle-même. Les recommandations proposent un dépistage au moment du diagnostic, puis annuellement, à l'aide d'un test objectif tel que le Single Digit Modality Test (SDMT) ou équivalents. La confirmation du diagnostic et la prise en charge se font en collaboration avec les neuropsychologues. Une meilleure sensibilisation des patients et des professionnels de santé est nécessaire pour assurer une prise en charge plus précoce et limiter les conséquences négatives sur la vie professionnelle et familiale des patients.
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Trastornos del Conocimiento , Disfunción Cognitiva , Esclerosis Múltiple Recurrente-Remitente , Esclerosis Múltiple , Humanos , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico , Calidad de Vida , Esclerosis Múltiple Recurrente-Remitente/diagnóstico , Esclerosis Múltiple Recurrente-Remitente/psicología , Disfunción Cognitiva/diagnóstico , Disfunción Cognitiva/etiología , Trastornos del Conocimiento/diagnóstico , Pruebas NeuropsicológicasRESUMEN
BACKGROUND: Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system (CNS) commonly affecting young adults. There is increasing evidence that environmental factors are important in the development and course of MS. The metabolic syndrome (MetS) which comprises dyslipidemia has been associated with a worse outcome in MS disease. Furthermore, the lipid-lowering drug class of statins has been proposed to improve MS disease course. However, cholesterol is also rate-limiting for myelin biogenesis and promotes remyelination in MS animal models. Thus, the impact of circulating blood cholesterol levels during the disease remains debated and controversial. METHODS: We assessed the role of circulating cholesterol on the murine model of MS, the experimental autoimmune encephalomyelitis (EAE) disease using two different approaches: (1) the mouse model of familial hypercholesterolemia induced by low-density lipoprotein receptor (LDLr) deficiency, and (2) the use of the monoclonal anti-PCSK9 neutralizing antibody alirocumab, which reduces LDLr degradation and consequently lowers blood levels of cholesterol. RESULTS: Elevated blood cholesterol levels induced by LDLr deficiency did not worsen clinical symptoms of mice during EAE. In addition, we observed that the anti-PCSK9 antibody alirocumab did not influence EAE disease course, nor modulate the immune response in EAE. CONCLUSIONS: These findings suggest that blood cholesterol level has no direct role in neuro-inflammatory diseases and that the previously shown protective effects of statins in MS are not related to circulating cholesterol.
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Encefalomielitis Autoinmune Experimental , Inhibidores de Hidroximetilglutaril-CoA Reductasas , Hipercolesterolemia , Esclerosis Múltiple , Animales , Encefalomielitis Autoinmune Experimental/tratamiento farmacológico , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Hipercolesterolemia/metabolismo , Ratones , Enfermedades NeuroinflamatoriasRESUMEN
Type 1 regulatory T cells (Tr1 cells ) that produce interleukin 10 (IL-10) are instrumental in the prevention of tissue inflammation, autoimmunity and graft-versus-host disease. The transcription factor c-Maf is essential for the induction of IL-10 by Tr1 cells, but the molecular mechanisms that lead to the development of these cells remain unclear. Here we show that the ligand-activated transcription factor aryl hydrocarbon receptor (AhR), which was induced by IL-27, acted in synergy with c-Maf to promote the development of Tr1 cells. After T cell activation under Tr1-skewing conditions, the AhR bound to c-Maf and promoted transactivation of the Il10 and Il21 promoters, which resulted in the generation of Tr1 cells and the amelioration of experimental autoimmune encephalomyelitis. Manipulating AhR signaling could therefore be beneficial in the resolution of excessive inflammatory responses.
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Diferenciación Celular/inmunología , Regulación de la Expresión Génica , Proteína Oncogénica v-maf/inmunología , Receptores de Hidrocarburo de Aril/inmunología , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/inmunología , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Células Cultivadas , Interleucinas/farmacología , Ratones , Ratones Endogámicos C57BL , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
OBJECTIVE: We aimed to determine in relapsing multiple sclerosis (MS) whether intrathecal synthesis of immunoglobulin (Ig) M and IgG is associated with outcomes reflecting inflammatory activity and chronic worsening. METHODS: We compared cerebrospinal fluid analysis, clinical and magnetic resonance imaging data, and serum neurofilament light chain (sNfL) levels at baseline and follow-up in 530 patients with relapsing MS. Patients were categorized by the presence of oligoclonal IgG bands (OCGB) and intrathecal synthesis of IgG and IgM (intrathecal fraction [IF]: IgGIF and IgMIF ). Relationships with the time to first relapse, sNfL concentrations, T2-weighted (T2w) lesions, MS Severity Score (MSSS), and time to initiation of high-efficacy therapy were analyzed in covariate-adjusted statistical models. RESULTS: By categorical analysis, in patients with IgMIF the median time to first relapse was 28 months shorter and MSSS on average higher by 1.11 steps compared with patients without intrathecal immunoglobulin synthesis. Moreover, patients with IgMIF had higher sNfL concentrations, more new/enlarging T2w lesions, and higher total T2w lesion counts (all p ≤ 0.01). These associations were absent or equally smaller in patients who were positive for only OCGB or OCGB/IgGIF . Furthermore, quantitative analyses revealed that in patients with IgMIF ≥ median, the time to first relapse and to initiation of high-efficacy therapy was shorter by 32 and by 203 months, respectively (both p < 0.01), in comparison to patients with IgMIF < median. Dose-dependent associations were also found for IgMIF but not for IgGIF with magnetic resonance imaging-defined disease activity and sNfL. INTERPRETATION: This large study supports the value of intrathecal IgM synthesis as an independent biomarker of disease activity and severity in relapsing MS. ANN NEUROL 2021;90:477-489.
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Progresión de la Enfermedad , Inmunoglobulina M/líquido cefalorraquídeo , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/diagnóstico por imagen , Índice de Severidad de la Enfermedad , Adulto , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Inmunoglobulina M/biosíntesis , Imagen por Resonancia Magnética/tendencias , Masculino , Persona de Mediana Edad , Proteínas de Neurofilamentos/sangre , Proteínas de Neurofilamentos/líquido cefalorraquídeo , Punción Espinal/tendencias , Adulto JovenRESUMEN
Isolated chronic granulomatous meningitis remains a diagnostic challenge for the physician. Symptoms are often nonspecific and ancillary tests have low-sensitivity rates, which may delay targeted treatment and lead to increased morbidity and mortality. Here, we discuss the challenges in diagnosing and treating patients with chronic meningitis by reporting two cases of previously healthy patients who presented with granulomatous meningitis on brain biopsy.
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Enfermedades del Sistema Nervioso Central , Meningitis , Sarcoidosis , Tuberculosis Meníngea , Enfermedades del Sistema Nervioso Central/diagnóstico por imagen , Humanos , Meningitis/diagnóstico , Sarcoidosis/diagnóstico , Sarcoidosis/patología , Sarcoidosis/terapia , Tuberculosis Meníngea/diagnósticoRESUMEN
Microbiota-derived metabolites are important molecules connecting the gut to the brain. Over the last decade, several studies have highlighted the importance of gut-derived metabolites in the development of multiple sclerosis (MS). Indeed, microbiota-derived metabolites modulate the immune system and affect demyelination. Here, we discuss the current knowledge about microbiota-derived metabolites implications in MS and in different mouse models of neuroinflammation. We focus on the main families of microbial metabolites that play a role during neuroinflammation. A better understanding of the role of those metabolites may lead to new therapeutical avenues to treat neuroinflammatory diseases targeting the gut-brain axis.
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Microbioma Gastrointestinal , Microbiota , Esclerosis Múltiple , Animales , Encéfalo/metabolismo , Ratones , Esclerosis Múltiple/metabolismo , Enfermedades NeuroinflamatoriasRESUMEN
In multiple sclerosis (MS), a subset of chronic active white matter lesions are identifiable on magnetic resonance imaging by their paramagnetic rims, and increasing evidence supports their association with severity of clinical disease. We studied their potential role in differential diagnosis, screening an international multicenter clinical research-based sample of 438 individuals affected by different neurological conditions (MS, other inflammatory, infectious, and non-inflammatory conditions). Paramagnetic rim lesions, rare in other neurological conditions (52% of MS vs 7% of non-MS cases), yielded high specificity (93%) in differentiating MS from non-MS. Future prospective multicenter studies should validate their role as a diagnostic biomarker. ANN NEUROL 2020;88:1034-1042.
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Esclerosis Múltiple/diagnóstico por imagen , Adulto , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/epidemiología , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Neuroimagen , Prevalencia , Estudios Retrospectivos , Sensibilidad y Especificidad , Adulto JovenRESUMEN
BACKGROUND: The central vein sign (CVS) is an imaging biomarker able to differentiate multiple sclerosis (MS) from other conditions causing similar appearance lesions on magnetic resonance imaging (MRI), including cerebral small vessel disease (CSVD). However, the impact of vascular risk factors (VRFs) for CSVD on the percentage of CVS positive (CVS+) lesions in MS has never been evaluated. OBJECTIVE: To investigate the association between different VRFs and the percentage of CVS+ lesions in MS. METHODS: In 50 MS patients, 3T brain MRIs (including high-resolution 3-dimensional T2*-weighted images) were analyzed for the presence of the CVS and MRI markers of CSVD. A backward stepwise regression model was used to predict the combined predictive effect of VRF (i.e. age, hypertension, diabetes, obesity, ever-smoking, and hypercholesterolemia) and MRI markers of CSVD on the CVS. RESULTS: The median frequency of CVS+ lesions was 71% (range: 35%-100%). In univariate analysis, age (p < 0.0001), hypertension (p < 0.001), diabetes (p < 0.01), obesity (p < 0.01), smoking (p < 0.05), and the presence of enlarged-perivascular-spaces on MRI (p < 0.005) were all associated with a lower percentage of CVS+ lesions. The stepwise regression model showed that age and arterial hypertension were both associated with the percentage of CVS+ lesions in MS (adjusted R2 = 0.46; p < 0.0001 and p = 0.01, respectively). CONCLUSION: The proportion of CVS+ lesions significantly decreases in older and hypertensive MS patients. Although this study was conducted in patients with an already established MS diagnosis, the diagnostic yield of the previously proposed 35% CVS proportion-based diagnostic threshold appears to be not affected. Overall these results suggest that the presence of VRF for CSVD should be taken into account during the CVS assessment.
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Enfermedades de los Pequeños Vasos Cerebrales , Esclerosis Múltiple , Anciano , Encéfalo/diagnóstico por imagen , Humanos , Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/epidemiología , VenasRESUMEN
BACKGROUND: The central vein sign (CVS) has been shown to help in the differential diagnosis of multiple sclerosis (MS), but most prior studies are retrospective. OBJECTIVES: To prospectively assess the diagnostic predictive value of the CVS in diagnostically difficult cases. METHODS: In this prospective multicenter study, 51 patients with suspected MS who had clinical, imaging, or laboratory "red flags" (i.e. features atypical for MS) underwent 3T fluid-attenuated inversion recovery (FLAIR*) magnetic resonance imaging (MRI) for CVS assessment. After the diagnostic work-up, expert clinicians blinded to the results of the CVS assessment came to a clinical diagnosis. The value of the CVS to prospectively predict an MS diagnosis was assessed. RESULTS: Of the 39 patients who received a clinical diagnosis by the end of the study, 27 had MS and 12 received a non-MS diagnosis that included systemic lupus erythematosus, sarcoidosis, migraine, Sjögren disease, SPG4-spastic-paraparesis, neuromyelitis optica, and Susac syndrome. The percentage of perivenular lesions was higher in MS (median = 86%) compared to non-MS (median = 21%; p < 0.0001) patients. A 40% perivenular lesion cutoff was associated with 97% accuracy and a 96% positive/100% negative predictive value. CONCLUSION: The CVS detected on 3T FLAIR* images can accurately predict an MS diagnosis in patients suspected to have MS, but with atypical clinical, laboratory, and imaging features.
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Venas Cerebrales/diagnóstico por imagen , Imagen por Resonancia Magnética/normas , Esclerosis Múltiple/diagnóstico , Sustancia Blanca/diagnóstico por imagen , Adulto , Anciano , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Valor Predictivo de las Pruebas , Estudios Prospectivos , Adulto JovenRESUMEN
BACKGROUND: Diagnosing multiple sclerosis (MS) early is crucial to avoid future disability. However, potentially preventable delays in the diagnostic cascade from contact with a physician to definite diagnosis still occur and their causes are still unclear. OBJECTIVE: To identify the possible causes of delays in the diagnostic process. METHODS: We analyzed the data of the Swiss MS Registry. With logistic regression, we modeled the time from the first contact to the first consultation (contact-to-evaluation time, ⩽1 month/>1 month) and the evaluation-to-diagnosis time (⩽6 months/>6 months). Potential factors were health system characteristics, sociodemographic variables, first symptoms, and MS type. RESULTS: We included 522 participants. Mostly, general practitioners (67%) were contacted first, without delaying the diagnosis. In contrast, first symptoms and MS type were the major contributors to delays: gait problems were associated with longer contact-to-evaluation times, depression as a concomitant symptom with longer evaluation-to-diagnosis times, and having primary progressive MS prolonged both phases. In addition, living in mountainous areas was associated with longer contact-to-evaluation times, whereas diagnosis after 2000 was associated with faster diagnoses. CONCLUSION: For a quicker diagnosis, awareness of MS as a differential diagnosis of gait disorders and the co-occurrence of depression at onset should be raised, and these symptoms should be attentively followed.