RESUMEN
OBJECTIVE: In a previous pilot monocentric study, we investigated the relation between human leukocyte antigen (HLA) genotype and multiple sclerosis (MS) disease progression over 2 years. HLA-A*02 allele was correlated with better outcomes, whereas HLA-B*07 and HLA-B*44 were correlated with worse outcomes. The objective of this extension study was to further investigate the possible association of HLA genotype with disease status and progression in MS as measured by sensitive and complex clinical and imaging parameters. METHODS: Hundred and forty-six MS patients underwent HLA typing. Over a 4-year period of follow-up, we performed three clinical and magnetic resonance imaging (MRI) assessments per patient, which respectively included Expanded Disability Status Scale, Multiple Sclerosis Severity Scale, Timed-25-Foot-Walk, 9-Hole Peg Test, Symbol Digit Modalities Test, Brief Visual Memory Test, California Verbal Learning Test-II, and whole-brain atrophy, fluid-attenuated inversion recovery (FLAIR) lesion volume change and number of new FLAIR lesions using icobrain. We then compared the clinical and MRI outcomes between predefined HLA patient groups. RESULTS: Results of this larger study with a longer follow-up are in line with what we have previously shown. HLA-A*02 allele is associated with potentially better MS outcomes, whereas HLA-B*07, HLA-B*44, HLA-B*08, and HLA-DQB1*06 with a potential negative effect. Results for HLA-DRB1*15 are inconclusive. CONCLUSION: In the era of MS treatment abundance, HLA genotype might serve as an early biomarker for MS outcomes to inform individualized treatment decisions.
Asunto(s)
Cadenas beta de HLA-DQ/genética , Antígenos de Histocompatibilidad Clase I/genética , Esclerosis Múltiple Crónica Progresiva/genética , Esclerosis Múltiple Recurrente-Remitente/genética , Adolescente , Adulto , Anciano , Progresión de la Enfermedad , Femenino , Genotipo , Antígeno HLA-A2/genética , Antígeno HLA-B44/genética , Antígeno HLA-B7/genética , Antígeno HLA-B8/genética , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Crónica Progresiva/fisiopatología , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/fisiopatología , Pronóstico , Adulto JovenRESUMEN
PURPOSE OF REVIEW: This review discusses demyelinating events of the nervous system that have been associated with new immunomodulatory treatments, in particular monoclonal antibodies (mAbs). RECENT FINDINGS: Natalizumab, a mAb targeting the alpha-4 integrins, which is efficient in relapsing-remitting multiple sclerosis, has been associated with progressive multifocal leukoencephalopathy (PML). We will review the putative mechanisms linking natalizumab with JC virus, the agent of PML. Efalizumab, a mAb targeting a member of the integrin family, CD11a, was approved for the treatment of psoriasis, but had to be withdrawn in 2009 because of the occurrence of three cases of PML. Rituximab, an anti-CD20 mAb, is used in different neoplastic and autoimmune diseases and may soon enter the pharmacopeia of multiple sclerosis. It has been suggested that rituximab is a risk factor for PML; however, evidence of such a link is unclear. Antitumor necrosis factor-alpha agents are used in several autoimmune diseases. Several cases of demyelinating events of the nervous system have been reported, prompting a heightened surveillance of treated patients. Recent data are reassuring, suggesting that the incidence of such events is relatively low. SUMMARY: Neurologists must become familiar with neurological complications of new immunomodulatory treatments, a field situated at the interface of neurology, immunology and infection.
Asunto(s)
Anticuerpos Monoclonales/efectos adversos , Enfermedades Desmielinizantes/inducido químicamente , Enfermedades Desmielinizantes/tratamiento farmacológico , Enfermedad Iatrogénica/prevención & control , Factores Inmunológicos/efectos adversos , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Animales , Anticuerpos Monoclonales Humanizados , Anticuerpos Monoclonales de Origen Murino , Enfermedades Desmielinizantes/fisiopatología , Humanos , Leucoencefalopatía Multifocal Progresiva/inmunología , Leucoencefalopatía Multifocal Progresiva/fisiopatología , Natalizumab , Sistema Nervioso/efectos de los fármacos , Sistema Nervioso/inmunología , Sistema Nervioso/fisiopatología , Medición de Riesgo/normas , Rituximab , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
We describe a patient presenting with a first generalized convulsion after alcohol consumption, in whom the early postictal finding of a rapidly regressive cortical visual impairment suggested the presence of a posterior reversible encephalopathy. This was confirmed radiologically, and probably represented the key factor in the seizure etiology.
Asunto(s)
Hipoxia Encefálica/diagnóstico , Convulsiones/complicaciones , Convulsiones/diagnóstico , Trastornos de la Visión/etiología , Anciano , Edema Encefálico/diagnóstico , Diagnóstico Diferencial , Femenino , Humanos , Imagen por Resonancia Magnética , Trastornos de la Visión/diagnósticoAsunto(s)
Anemia Hemolítica Autoinmune/inducido químicamente , Inmunosupresores/efectos adversos , Esclerosis Múltiple/tratamiento farmacológico , Glicoles de Propileno/efectos adversos , Esfingosina/análogos & derivados , Clorhidrato de Fingolimod , Humanos , Esfingosina/efectos adversos , Adulto JovenRESUMEN
This is one of the first studies to compare the frequencies of different human leucocyte antigen (HLA) class I and II alleles and haplotype HLA-DRB1*15-DQB1*06 in a cohort of 119 patients with multiple sclerosis (MS) and a cohort of 124 healthy controls in Belgium. An association with MS was found for the HLA-DRB1*15 (odds ratio [OR] 2.60 [95% confidence interval (CI) 1.51-4.50]) and HLA-DQB1*06 (OR 1.97 [95% CI 1.18-3.29]) alleles, and for haplotype DRB1*15-DQB1*06 (OR 2.63 [95% CI 1.52-4.56]). The HLA-B*07 allele also tended to be more frequent in MS patients (OR 1.46 [95% CI 0.80-2.65]) and more frequent among MS patients with than in those without the HLA-DRB1*15 allele (26/54 [48.1%] versus 6/65 [9.2%]; p value <0.0001). Other alleles were underrepresented in MS patients, such as the HLA-DRB1*07 (OR 0.39 [95% CI 0.21-0.73]) and HLA-A*02 (OR 0.56 [95% CI 0.34-0.94]), showing a protective role against the disease. The HLA-B*44 (OR 0.58 [95% CI 0.31-1.09]) and HLA-DRB1*04 (OR 0.75 [95% CI 0.42-1.34]) alleles tended to be less frequent in MS patients. Altogether, the significant results observed in this population are in line with those from other countries and confirm that propensity to MS can be due to a complex presence of various HLA class I and class II alleles.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase I/genética , Esclerosis Múltiple/genética , Adulto , Bélgica , Femenino , Frecuencia de los Genes , Haplotipos , Humanos , Masculino , Persona de Mediana EdadRESUMEN
OBJECTIVE: The identification of a biomarker with prognostic value is an unmet need in multiple sclerosis (MS). The objective of this study was to investigate a possible association of HLA genotype with disease status and progression in MS, based on comprehensive and sensitive clinical and magnetic resonance imaging (MRI) parameters to measure disease effects. METHOD: A total of 118 MS patients (79 females, 39 males) underwent HLA typing. Patient MS status was assessed at two time points in a 2-year interval, based on clinical scores (including EDSS, MSSS, T25FW, 9-HPT, SDMT, BVMT, CVLT-II) and MRI evaluations. Quantitative brain MRI values were obtained for whole brain atrophy, FLAIR lesion volume change and number of new lesions using MSmetrix. Predefined HLA patient groups were compared as of disease status and progression. Global assessment was achieved by an overall t-statistic and assessment per measurement by a Welch test and/or Mann Whitney U test. The effects of multiple covariates, including age, gender and disease duration as well as scan parameters, were also evaluated using a regression analysis. RESULTS: The HLA-A*02 allele was associated with better outcomes in terms of MSSS, EDSS and new lesion count (Welch test p-value<0.05). The HLA-B*07 and HLA-B*44 alleles showed a global negative effect on disease status, although none of the measurements reached significance (p-value<0.05). Results for the HLA-DRB1*15, HLA-DQB1*06 and HLA-B*08 alleles were inconclusive. The influence of the confounding variables on the statistical analysis was limited.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Antígenos HLA-B/genética , Esclerosis Múltiple/genética , Adulto , Anciano , Evaluación de la Discapacidad , Progresión de la Enfermedad , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Estudios Longitudinales , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/diagnóstico por imagen , Proyectos Piloto , Adulto JovenRESUMEN
INTRODUCTION: There is emerging evidence that brain atrophy is a part of the pathophysiology of Multiple Sclerosis (MS) and correlates with several clinical outcomes of the disease, both physical and cognitive. Consequently, brain atrophy is becoming an important parameter in patients' follow-up. Since in clinical practice both 1.5Tesla (T) and 3T magnetic resonance imaging (MRI) systems are used for MS patients follow-up, questions arise regarding compatibility and a possible need for standardization. METHODS: Therefore, in this study 18 MS patients were scanned on the same day on a 1.5T and a 3T scanner. For each scanner, a 3D T1 and a 3D FLAIR were acquired. As no atrophy is expected within 1 day, these datasets can be used to evaluate the median percentage error of the brain volume measurement for gray matter (GM) volume and parenchymal volume (PV) between 1.5T and 3T scanners. The results are obtained with MSmetrix, which is developed especially for use in the MS clinical care path, and compared to Siena (FSL), a widely used software for research purposes. RESULTS: The MSmetrix median percentage error of the brain volume measurement between a 1.5T and a 3T scanner is 0.52% for GM and 0.35% for PV. For Siena this error equals 2.99%. When data of the same scanner are compared, the error is in the order of 0.06-0.08% for both MSmetrix and Siena. CONCLUSIONS: MSmetrix appears robust on both the 1.5T and 3T systems and the measurement error becomes an order of magnitude higher between scanners with different field strength.
Asunto(s)
Encéfalo/diagnóstico por imagen , Imagen por Resonancia Magnética/instrumentación , Esclerosis Múltiple/diagnóstico por imagen , Adulto , Atrofia/diagnóstico por imagen , Femenino , Estudios de Seguimiento , Humanos , Interpretación de Imagen Asistida por Computador , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Estudios Prospectivos , Programas Informáticos , Adulto JovenRESUMEN
PURPOSE: Natalizumab (NTZ) is an effective treatment for relapsing-remitting multiple sclerosis (RRMS). Progressive multifocal leukoencephalopathy (PML) is a rare complication of NTZ treatment. In patients developing PML, NTZ cessation causes a reconstruction of cellular immunity, a rapid transition of cells through the blood-brain barrier, and significant inflammation in the central nervous system, leading to immune-reconstitution inflammatory syndrome (IRIS), with potentially poor outcomes. The occurrence of this syndrome is accelerated by plasmapheresis, the standard treatment for NTZ-PML, due to enhanced clearance of NTZ and thus rapid reconstitution of cellular immunity. IRIS can also occur after cessation of NTZ in the absence of PML. METHODS: We describe 4 patients who developed IRIS after NTZ cessation. FINDINGS: For the first patient, treatment was switched to fingolimod to avoid risk of developing PML. Despite plasmapheresis, corticosteroids, and other therapies, the outcome in this patient was fatal. For the 3 other patients, PML was detected early on magnetic resonance imaging, and IRIS after NTZ cessation was managed with a favorable outcome; 1 of these patients was managed without plasmapheresis or corticosteroid treatment. IMPLICATIONS: These cases demonstrate the need to consider and manage therapeutic strategies relative to the individual patient's risk for PML or IRIS. NTZ cessation to avoid PML risk can lead to severe IRIS without PML. On the other hand, if PML develops and is detected early, plasmapheresis may not be considered necessary and IRIS may be limited, with a favorable outcome. These 2 scenarios should be considered when managing NTZ MS patients.
Asunto(s)
Síndrome Inflamatorio de Reconstitución Inmune/inducido químicamente , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/efectos adversos , Adulto , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/uso terapéutico , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab/administración & dosificación , Adulto JovenRESUMEN
In young people, the most frequent cause of isolated monocular visual loss due to an optic neuropathy is optic neuritis. We present the case of a 27 year old woman who presented monocular visual loss, excruciating orbital pain and unusual temporal headache. The initial diagnosis of optic neuritis revealed later to be a posterior ischemic optic neuropathy (PION). In this case, PION was the first unique presentation of a non-traumatic carotid dissection, and it was followed 24h later by an ischemic stroke. Sudden monocular visual loss associated with a new-onset headache are clinical symptoms that should immediately prompt to a carotid dissection.
Asunto(s)
Neuritis Óptica/diagnóstico , Neuropatía Óptica Isquémica/diagnóstico , Adulto , Anticoagulantes/uso terapéutico , Isquemia Encefálica/complicaciones , Isquemia Encefálica/diagnóstico , Arterias Carótidas/patología , Angiografía Cerebral , Diagnóstico Diferencial , Ojo/patología , Humanos , Imagen por Resonancia Magnética , Masculino , Neuritis Óptica/etiología , Neuritis Óptica/patología , Neuropatía Óptica Isquémica/patología , Dolor/etiología , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/diagnóstico , Tomografía Computarizada por Rayos X , Trastornos de la Visión/etiologíaRESUMEN
Little is known on a putative effect of vitamin D on CD8+ T cells. Yet, these cells are involved in the immmunopathogenesis of MS. We assessed the cytokine profile of EBV-specific CD8+ T cells of 10 early MS patients and 10 healthy control subjects with or without 1,25(OH)(2)D(3) and found that, with 1,25(OH)(2)D(3), these cells secreted less IFN-γ and TNF-α and more IL-5 and TGF-ß. CD4+ T cell depletion or even culture with CD8+ T cells only did not abolish the immunomodulatory effect of 1,25(OH)(2)D(3) on CD8+ T cells, suggesting that 1,25(OH)(2)D(3) can act directly on CD8+ T cells.