RESUMEN
Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the CNS caused by the JC virus, which infects white and grey matter cells and leads to irreversible demyelination and neuroaxonal damage. Brain MRI, in addition to the clinical presentation and demonstration of JC virus DNA either in the CSF or by histopathology, is an important tool in the detection of PML. In clinical practice, standard MRI pulse sequences are utilized for screening, diagnosis and monitoring of PML, but validated imaging-based outcome measures for use in prospective, interventional clinical trials for PML have yet to be established. We review the existing literature regarding the use of MRI and PET in PML and discuss the implications of PML histopathology for neuroradiology. MRI not only demonstrates the localization and extent of PML lesions, but also mirrors the tissue destruction, ongoing viral spread, and resulting inflammation. Finally, we explore the potential for imaging measures to serve as an outcome in PML clinical trials and provide recommendations for current and future imaging outcome measure development in this area.
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Virus JC , Leucoencefalopatía Multifocal Progresiva , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Humanos , Virus JC/genética , Leucoencefalopatía Multifocal Progresiva/diagnóstico por imagen , Leucoencefalopatía Multifocal Progresiva/tratamiento farmacológico , Imagen por Resonancia Magnética , Estudios ProspectivosRESUMEN
OBJECTIVE: The early detection of MRI findings suggestive of immune reconstitution inflammatory syndrome (IRIS) in natalizumab-associated progressive multifocal leukoencephalopathy (PML) is of crucial clinical relevance in terms of treatment decision-making and clinical outcome. The aim of this study was to investigate the earliest imaging characteristics of PML-IRIS manifestation in natalizumab-treated patients with multiple sclerosis and describe an imaging pattern that might aid in the early and specific diagnosis. METHODS: This was a retrospective study assessing brain MRI of 26 patients with natalizumab-associated PML presenting with lesions suggestive of PML-IRIS during follow-up. MRI findings were evaluated considering the imaging findings such as mass effect, swelling, contrast enhancement, new perivascular T2 lesions and signs suggestive of meningeal inflammation. RESULTS: Contrast enhancement was the most common imaging sign suggestive of PML-IRIS, seen in 92.3% of the patients (with patchy and/or punctuate pattern in 70.8% and 45.8% respectively), followed by new T2 lesions with a perivascular distribution pattern (34.6%). In those patients with contrast enhancement, the enhancement was present in the lesion periphery in 95.8% of the patients. Contrast-enhancing lesions with a perivascular distribution pattern outside of the PML lesion were observed in 33.3% of the patients. The most common overall pattern was contrast enhancement in the border of the PML lesion with either a patchy or punctuate appearance in 88.5% of all patients. CONCLUSIONS: Contrast enhancement is the most common earliest sign of natalizumab-associated PML-IRIS with a frequent imaging pattern of contrast-enhancing lesions with either a patchy or punctuate appearance in the border of the PML lesion.
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Síndrome Inflamatorio de Reconstitución Inmune/inducido químicamente , Síndrome Inflamatorio de Reconstitución Inmune/diagnóstico por imagen , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Leucoencefalopatía Multifocal Progresiva/diagnóstico por imagen , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab/efectos adversos , Natalizumab/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/complicaciones , Leucoencefalopatía Multifocal Progresiva/complicaciones , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/diagnóstico por imagen , Neuroimagen , Estudios RetrospectivosRESUMEN
BACKGROUND: In natalizumab-treated multiple sclerosis (MS) patients, magnetic resonance imaging (MRI) is considered as a sensitive tool in detecting both MS disease activity and progressive multifocal leukoencephalopathy (PML). OBJECTIVE: To investigate the performance of neuroradiologists using brain MRI in detecting new MS lesions and asymptomatic PML lesions and in differentiating between MS and PML lesions in natalizumab-treated MS patients. The secondary aim was to investigate interrater variability. METHODS: In this retrospective diagnostic study, four blinded neuroradiologists assessed reference and follow-up brain MRI scans of 48 natalizumab-treated MS patients with new asymptomatic PML lesions (n = 21) or new MS lesions (n = 20) or no new lesions (n = 7). Sensitivity and specificity for detection of new lesions in general (MS and PML lesions), MS and PML lesion differentiation, and PML detection were determined. Interrater agreement was calculated. RESULTS: Overall sensitivity and specificity for the detection of new lesions, regardless of the nature of the lesions, were 77.4% and 89.3%, respectively; for PML-MS lesion differentiation, 74.2% and 84.7%, respectively; and for asymptomatic PML lesion detection, 59.5% and 91.7%, respectively. Interrater agreement for the tested categories was fair to moderate. CONCLUSION: The diagnostic performance of trained neuroradiologists using brain MRI in pharmacovigilance of natalizumab-treated MS patients is moderately good. Interrater agreement among trained readers is fair to moderate.
Asunto(s)
Encéfalo/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Factores Inmunológicos/uso terapéutico , Leucoencefalopatía Multifocal Progresiva/diagnóstico por imagen , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Natalizumab/uso terapéutico , Infecciones Oportunistas/diagnóstico por imagen , Farmacovigilancia , Adulto , Diagnóstico Diferencial , Femenino , Humanos , Huésped Inmunocomprometido , Factores Inmunológicos/efectos adversos , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Leucoencefalopatía Multifocal Progresiva/inmunología , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/inmunología , Natalizumab/efectos adversos , Variaciones Dependientes del Observador , Infecciones Oportunistas/inducido químicamente , Infecciones Oportunistas/inmunología , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de Riesgo , Factores de Tiempo , Resultado del TratamientoRESUMEN
Natalizumab, a highly effective therapy for relapsing-remitting multiple sclerosis, is associated with a risk of progressive multifocal leukoencephalopathy (PML). The objective of this analysis was to examine factors predicting survival in a large natalizumab-associated PML global population. Patients with natalizumab-associated PML identified through postmarketing surveillance were followed up for up to 24 months using a structured questionnaire completed by treating physicians. Demographic and clinical characteristics, JC viral load, magnetic resonance imaging (MRI) results, and Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were compared in survivors and nonsurvivors. Kaplan-Meier analysis was used to model survival function. Among the 336 patients included in this analysis, 76 % survived, with mean follow-up time from PML diagnosis of 16.1 months for survivors; mean time from diagnosis to death was 4.7 months for nonsurvivors. Survivors were significantly younger at diagnosis, had significantly lower EDSS scores and higher KPS scores prior to PML diagnosis, and had significantly lower cerebrospinal fluid JC viral load at the time of diagnosis. Patients with less extensive disease on MRI at diagnosis had a higher survival rate than those with widespread disease. Survivors generally had less functional disability pre-PML, at PML diagnosis, and in subsequent months. In survivors, functional disability appeared to stabilize approximately 6 months post-PML diagnosis. In this analysis, younger age at diagnosis, less functional disability prior to PML diagnosis, lower JC viral load at diagnosis, and more localized brain involvement by MRI at the time of diagnosis appeared to predict improved survival in natalizumab-associated PML.
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Factores Inmunológicos/efectos adversos , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Leucoencefalopatía Multifocal Progresiva/mortalidad , Natalizumab/efectos adversos , Adolescente , Adulto , Anciano , Encéfalo/patología , Femenino , Humanos , Virus JC , Estimación de Kaplan-Meier , Leucoencefalopatía Multifocal Progresiva/virología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Sobrevivientes/estadística & datos numéricos , Carga Viral , Adulto JovenRESUMEN
OBJECTIVE: To investigate the MRI manifestation pattern of asymptomatic natalizumab-associated progressive multifocal leukoencephalopathy (PML) in patients with multiple sclerosis (MS). METHODS: 18 patients with MS with natalizumab-associated PML lesions on MRI were included. In 6 patients, the PML lesions were identified on MRI prospectively and in 12 patients PML lesions were identified retrospectively. MRI sequences were analysed for PML lesion distribution, appearance, grey matter/white matter involvement and possible signs of inflammation. Lesion probability maps were created to demonstrate lesion distribution pattern. RESULTS: The frontal lobe was involved in 14 patients (77.8%) and the parietal lobe in 4 patients (22.2%). Most patients presented with focal lesions (13 patients, 72.2%) involving one single lobe (12 patients, 66.7%). The cortical grey matter was affected in 15 patients (83.3%) and 13 patients (72.2%) presented with a combination of cortical grey and white matter involvement. Signs of inflammation were detected in 7 patients (38.8%). Among patients with available diffusion-weighted imaging, 6 patients (40%) did not show high-signal-intensity lesions. A classical imaging pattern including unilateral and unilobar focal lesions in the frontal lobe affecting the cortical grey matter or the cortical grey and adjacent white matter was observed in 8 patients (44.4%). CONCLUSIONS: Asymptomatic natalizumab-associated PML manifestations on MRI show a rather localised disease, frequently located in the frontal lobes, affecting the cortical grey matter and adjacent juxtacortical white matter. Awareness of this lesion pattern facilitates an earlier diagnosis of natalizumab-associated PML in an asymptomatic stage associated with a more favourable prognosis.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Encéfalo/patología , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Enfermedades Asintomáticas , Encéfalo/efectos de los fármacos , Femenino , Humanos , Leucoencefalopatía Multifocal Progresiva/patología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple , Natalizumab , NeuroimagenRESUMEN
OBJECTIVE: Natalizumab is an effective treatment for patients with multiple sclerosis (MS) that is associated with a risk of progressive multifocal leukoencephalopathy (PML). Recommendations were published in 2006 to improve early diagnosis of PML using magnetic resonance imaging (MRI). However, due to the small number of MS patients initially diagnosed with PML, the imaging criteria could only be derived from PML lesions in patients with human immunodeficiency virus. Therefore, there is an urgent need to assess the MRI characteristics of PML in MS patients to update the existing recommendations. METHODS: In this retrospective review, the first 40 natalizumab-treated MS patients diagnosed with PML in the postmarketing setting were identified, of whom 22 (10 with clinically diagnosed immune reconstitution inflammatory syndrome) fulfilled the inclusion criteria for this study. Magnetic resonance images were analyzed according to predefined criteria by 5 independent readers. RESULTS: The most frequent lesion pattern in early scans from PML patients was that of large (>3 cm, 15 of 18), subcortical (18 of 18), T2 or fluid-attenuated inversion recovery hyperintense (18 of 18), T1-hypointense (17 of 18), and diffusion-hyperintense (15 of 15) lesions, with a sharp border toward the gray matter and an ill-defined border toward the white matter (18 of 18) on T2-weighted images. We could detect contrast enhancement in 41% (7 of 17) of the cases on the first scan at clinical presentation. INTERPRETATION: Attention to characteristic MRI patterns, especially the presence of contrast enhancement, and the subcortical location may have utility in screening and early diagnosis of PML in natalizumab-treated MS patients.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Encéfalo/patología , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Leucoencefalopatía Multifocal Progresiva/patología , Imagen por Resonancia Magnética , Adulto , Femenino , Estudios de Seguimiento , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/tratamiento farmacológico , Natalizumab , Vigilancia de Productos Comercializados , Estudios Retrospectivos , Factores de TiempoRESUMEN
Natalizumab is a monoclonal antibody against α4-integrin approved for the treatment of multiple sclerosis (MS) due to a positive effect on clinical and magnetic resonance imaging (MRI) outcome measures. However, one relatively rare but serious side effect of this drug is a higher risk of developing progressive multifocal leukoencephalopathy (PML). Since the FDA approval, more than 300 natalizumab-associated PML cases have been documented among more than 100,000 treated MS patients. MRI is a crucial tool in the surveillance of patients treated with natalizumab in order to detect possible signs of PML in the asymptomatic stage. Although classical imaging characteristics of PML are well established, MRI findings in natalizumab-associated PML, particularly in early disease stages, show rather new and heterogeneous imaging findings including different patterns of inflammation with contrast enhancement. This review provides a comprehensive overview of the heterogeneous imaging findings in natalizumab-associated PML in the context of the underlying pathophysiology, histopathology, and the diagnostic procedure. We describe the MRI patterns of PML lesion evolution and complications including immune reconstitution inflammatory syndrome (IRIS). Finally, we present guidelines to differentiate MRI findings in PML from inflammatory demyelinating lesions, to facilitate the early diagnosis of PML in patients treated with natalizumab.
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Anticuerpos Monoclonales Humanizados/efectos adversos , Encéfalo/patología , Factores Inmunológicos/efectos adversos , Leucoencefalopatía Multifocal Progresiva/patología , Imagen por Resonancia Magnética , Neuroimagen/métodos , Animales , Encéfalo/efectos de los fármacos , Encéfalo/virología , Enfermedades Desmielinizantes/patología , Diagnóstico Diferencial , Diagnóstico Precoz , Humanos , Síndrome Inflamatorio de Reconstitución Inmune/inducido químicamente , Síndrome Inflamatorio de Reconstitución Inmune/patología , Síndrome Inflamatorio de Reconstitución Inmune/virología , Leucoencefalopatía Multifocal Progresiva/inducido químicamente , Leucoencefalopatía Multifocal Progresiva/virología , Natalizumab , Valor Predictivo de las PruebasRESUMEN
We describe the acute presentation and the long-term evolution of recurrent tumefactive lesions (TLs) in a patient with relapsing-remitting multiple sclerosis. Five TLs occurred on three different occasions over a period of 12 years and these were followed by 73 serial magnetic resonance images (MRI). TL evolution was described by means of magnetization transfer imaging (MTI) and cerebrospinal fluid tissue specific imaging (TSI) over the follow-up period. During the study period, the patient had three clinical relapses with only minimal disability progression. MTI demonstrated that only the peripheral portion of each TL reverted to pre-lesional MT ratios within six months' post-enhancement. Recurring TLs may present a similar pattern of evolution that may be associated with a long-term favourable clinical outcome.
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Encéfalo/patología , Esclerosis Múltiple Recurrente-Remitente/patología , Adulto , Anticuerpos Monoclonales Humanizados/uso terapéutico , Daclizumab , Progresión de la Enfermedad , Acetato de Glatiramer , Humanos , Inmunoglobulina G/uso terapéutico , Factores Inmunológicos/uso terapéutico , Interferón beta-1a , Interferón beta/uso terapéutico , Estudios Longitudinales , Imagen por Resonancia Magnética , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Proteína Básica de Mielina/uso terapéutico , Fragmentos de Péptidos/uso terapéutico , Péptidos/uso terapéuticoRESUMEN
Objective: In the pivotal DEFINE and CONFIRM trials for dimethyl fumarate (DMF), patterns of brain volume changes were different, potentially due to low sample sizes and because MRIs were analyzed at two different reading centers. We evaluated effects of DMF on brain volume change in patients with multiple sclerosis (MS) through reanalysis of pooled images from DEFINE/CONFIRM trials in one reading center. Methods: MRIs from DEFINE/CONFIRM at weeks 0, 24, 48, and 96 from patients randomized to twice-daily DMF or placebo (PBO) were reanalyzed at the Cleveland Clinic to measure brain parenchymal fraction (BPF). To account for pseudoatrophy, brain volume estimates were re-baselined to calculate changes for weeks 48-96. Results: Across studies, 301 and 314 patients receiving DMF and PBO, respectively, had analyzable MRIs. In weeks 0-48, mean ± SE percentage change in BPF was -0.44 ± 0.04 vs. -0.34 ± 0.04% in DMF vs. PBO, respectively, whereas in weeks 48-96, mean ± SE percentage change in BPF was -0.27 ± 0.03 vs. -0.41 ± 0.04% in DMF vs. PBO, respectively. The mixed-effect model for repeated measures showed similar results: in weeks 48-96, estimated change (95% confidence interval) in BPF was -0.0021 (-0.0027, -0.0016) for DMF vs. -0.0033 (-0.0039, -0.0028) for PBO (35.9% reduction; p = 0.0025). Conclusions: The lower rate of whole brain volume loss with DMF in this pooled BPF analysis in the second year vs. PBO is consistent with its effects on relapses, disability, and MRI lesions. Brain volume changes in the first year may be explained by pseudoatrophy effects also described in other MS clinical trials.
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BACKGROUND: Cerebrospinal fluid tissue specific imaging (CSF-TSI), a newly implemented magnetic resonance imaging (MRI) technique, allows visualization of a subset of chronic black holes (cBHs) with MRI characteristics suggestive of the presence of CSF-like fluid, and representing lesions with extensive tissue destruction. OBJECTIVE: To investigate the relationship between lesions in CSF-TSI and disease measures in patients with multiple sclerosis (MS). METHODS: Twenty-six patients with MS were imaged at 3.0 T, obtaining T(1)-weighted (T(1)-w) and T(2)-w spin echo (SE), T(1) volumetric images and CSF-TSI images. We measured: (i) lesion volume (LV) in T(1)-w (cBH-LV) and T(2)-w SE images, and in CSF-TSI; (ii) brain parenchyma fraction (BPF). Differences between patients with and without CSF-TSI lesions were analyzed and association between clinical and MRI metrics were investigated. RESULTS: cBHs were seen in 92% of the patients while lesions in CSF-TSI were seen in 40%. Patients with CSF-TSI lesions were older, with longer disease duration, higher disability scores, larger cBH-LV and T(2)-LV, and lower BPF than patients without CSF-TSI lesions (≤0.047). Partial correlation analysis correcting for T(2)-LV, cBH-LV and BPF showed an association (p < 0.0001, r = 0.753) between CSF-TSI LV and disability score. CONCLUSIONS: CSF-TSI lesions characterize patients with more advanced disease and probably contribute to the progress of disability.
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Encéfalo/patología , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple Recurrente-Remitente/patología , Algoritmos , Líquido Cefalorraquídeo , Evaluación de la Discapacidad , Humanos , Interpretación de Imagen Asistida por Computador/métodos , Sensibilidad y EspecificidadRESUMEN
Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear.
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Barrera Hematoencefálica/efectos de los fármacos , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/metabolismo , Inhibidores de Fosfodiesterasa 4 , Inhibidores de Fosfodiesterasa/uso terapéutico , Rolipram/uso terapéutico , Biomarcadores/metabolismo , Barrera Hematoencefálica/patología , Proliferación Celular/efectos de los fármacos , Medios de Contraste , Humanos , Inmunofenotipificación , Inflamación/diagnóstico , Inflamación/tratamiento farmacológico , Inflamación/patología , Imagen por Resonancia Magnética , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/inmunología , Inhibidores de Fosfodiesterasa/efectos adversos , Rolipram/efectos adversos , Linfocitos T/patología , Factores de Tiempo , Insuficiencia del TratamientoRESUMEN
BACKGROUND/PURPOSE: Contrast-enhancing lesions (CEL) on magnetic resonance imaging (MRI) are believed to represent inflammatory disease activity in multiple sclerosis (MS), but their relationship to subsequent long-term disability and progression is unclear, particularly at longer time periods such as 8-10 years. METHODS: Between 1989 and 1994, 111 MS patients were seen at the National Institutes of Health for clinical evaluations and 3 monthly contrast-enhanced MRI scans. Of these, 94 patients were re-evaluated a mean of 8 years later (range 6.1-10.5 years) with a single MRI scan and clinical evaluation. CEL number and volume were determined at baseline and follow-up. The number of relapses was ascertained over the follow-up period and annualized relapse rates were calculated. Other MRI parameters, such as T2 hyperintensity volume, T1 volume, and brain parenchymal fraction, were also calculated. RESULTS: While there was no direct correlation between CEL number or volume at baseline and disability status at follow-up, CEL measures at baseline did correlate with number of relapses observed in the subsequent years, and the number of relapses in turn correlated with subsequent disability as well as transition to progressive MS. CONCLUSION: While number and volume of CEL at baseline do not directly correlate with disability in the longer term in MS, our data suggest that 1 route to disability involves relapses as a mediator variable in the causal sequence of MS progression from CEL to disability. Further studies using relapse as a mediator variable in a larger data set may be warranted.
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Evaluación de la Discapacidad , Aumento de la Imagen , Imagen por Resonancia Magnética/métodos , Esclerosis Múltiple Crónica Progresiva/diagnóstico por imagen , Esclerosis Múltiple Recurrente-Remitente/diagnóstico por imagen , Adulto , Encéfalo/diagnóstico por imagen , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Estudios Longitudinales , Masculino , Persona de Mediana Edad , Examen Neurológico , Estadística como AsuntoRESUMEN
BACKGROUND: Chronic, hypointense black holes (BHs) are recognized as a sign of permanent damage in patients with multiple sclerosis. Although the effects of interferon beta-1b in reducing the formation of new BHs are established, it is not clear whether the drug may reduce BH duration after these lesions are formed. OBJECTIVE: To analyze the effects of interferon beta-1b in reducing the duration of T1 BHs in patients with multiple sclerosis. DESIGN: Patients were clinically assessed and imaged monthly over a 36-month natural history phase and 36-month therapy phase. Numbers of contrast-enhanced lesions and newly formed BHs were counted on each scan. Each BH was counted until it was no longer seen. SETTING: Outpatient service of the Neuroimmunology Branch at the National Institutes of Health, Bethesda, Md. PATIENTS: Six patients with relapsing-remitting multiple sclerosis were included. One patient did not form any BHs during the therapy phase. Analyses were performed on the remaining 5 individuals. INTERVENTIONS: Interferon beta-1b at the dosage of 8 million international units every other day. MAIN OUTCOME MEASURES: Number and duration (in months) of newly formed BHs. RESULTS: Rate of BH accumulation decreased with treatment (P = .01), but Kaplan-Meier models revealed that the duration of BHs did not shorten (chi2(1) = 2.47, P = .12). CONCLUSIONS: Interferon beta-1b reduces the frequency of new BH formation but does not appear to decrease their duration in time. Analyses with larger patient cohorts are needed to confirm these preliminary findings.
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Adyuvantes Inmunológicos/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/patología , Interferón beta/uso terapéutico , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/patología , Adulto , Distribución de Chi-Cuadrado , Humanos , Interferon beta-1b , Estudios Longitudinales , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Factores de Tiempo , Resultado del TratamientoRESUMEN
BACKGROUND AND PURPOSE: We investigated the impact of focal and diffuse corticospinal tracts damage on sensory-motor disability in multiple sclerosis (MS) patients. METHODS: Twenty-five MS patients underwent 3.0 Tesla (3T) magnetic resonance imaging with diffusion tensor imaging (DTI). The Expanded Disability Status Scale (EDSS) and the Timed 25-Foot Walk test (T25FW) quantified patient physical disability. Fractional anisotropy (FA) and mean diffusivity (MD) of the corticospinal tracts, whole brain and corticospinal tracts lesion volume were also computed. Spearman rank correlation analyses measured the associations between DTI-derived metrics and other measures of disease. Partial correlation analyses between DTI and disability measures were performed and corrected for lesion volumes as appropriate. RESULTS: Significant associations were seen between FA of the corticospinal tracts and EDSS (r = -.500, P = .0011), motor-EDSS (r = -.519, P = .008), and T25WF (r = -.637, P = .001) scores and MD of the corticospinal tracts and motor-EDSS (r = .469, P = .018) and T25WF (r = .428, P = .033) scores. When correcting for lesion volumes, only the association between FA of the corticospinal tracts and EDSS (r ≤ -.516, p ≤ .01) or motor-EDSS score (r ≤ -.516, p ≤ .01) persisted. CONCLUSIONS: DTI at 3T shows that the impact of diffuse corticospinal tracts disease on sensory-motor disability is greatly mediated by focal lesions in MS.
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Imagen de Difusión Tensora/métodos , Trastornos Neurológicos de la Marcha/diagnóstico , Interpretación de Imagen Asistida por Computador/métodos , Esclerosis Múltiple/patología , Enfermedades de la Médula Espinal/patología , Adulto , Evaluación de la Discapacidad , Femenino , Trastornos Neurológicos de la Marcha/etiología , Humanos , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/complicaciones , Tractos Piramidales , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , Enfermedades de la Médula Espinal/complicacionesRESUMEN
OBJECTIVE: As of 3 September 2013, 399 cases of natalizumab-associated progressive multifocal leukoencephalopathy (PML) were confirmed in multiple sclerosis (MS) patients. We evaluated outcomes of natalizumab-treated MS patients who were asymptomatic at PML diagnosis. METHODS: Analyses included data available as of 5 June 2013. Asymptomatic patients diagnosed with PML by magnetic resonance imaging (MRI) findings and JC virus DNA detection in the central nervous system were compared with patients presenting with symptoms at diagnosis. Demographics, MRI, and survival over 12 months were analyzed. Expanded Disability Status Scale (EDSS) and Karnofsky Performance Scale (KPS) scores were recorded pre-PML, at diagnosis, and at 6 and 12 months post-diagnosis. RESULTS: A total of 372 PML cases were analyzed; 30 patients were asymptomatic and 342 were symptomatic at PML diagnosis. Classifications of PML lesions on MRI in asymptomatic versus symptomatic patients were unilobar in 68% versus 37%, multilobar in 21% versus 24%, and widespread in 11% versus 40%. In both groups with unilobar lesions, frontal lobe lesions predominated. Prior to PML, mean EDSS and KPS scores were similar for asymptomatic and symptomatic patients. At diagnosis, mean EDSS score was significantly lower for asymptomatic patients (4.1; n = 11) than for symptomatic patients (5.4; n = 193; P = 0.038). Six months after PML diagnosis, asymptomatic patients had less functional disability than symptomatic patients. As of 5 June 2013, 96.7% of asymptomatic patients and 75.4% of symptomatic patients were alive. INTERPRETATION: PML patients asymptomatic at diagnosis had better survival and less functional disability than those who were symptomatic at diagnosis.
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OBJECTIVE: To report the development of CNS vasculitis in a patient with multiple sclerosis (MS) treated with daclizumab. METHODS: This report includes clinical, MRI, immunologic, and pathology data and CSF analysis. RESULTS: After completing a phase II daclizumab monotherapy study with an optimal response as evidenced by significant decrease in MRI disease activity and stable clinical examinations, the patient elected to continue daclizumab therapy outside of NIH study. Daclizumab was discontinued after 21 doses due to the onset of new clinical symptoms and evidence of a vascular pattern of contrast enhancement on brain and spine MRI. Because of continued clinical deterioration, stereotactic brain biopsy was performed, showing small-vessel CNS vasculitis. Treatment was initiated with IV methylprednisolone followed by a regimen of cyclophosphamide. Immunologic studies suggest that unexpected lack of expansion of CD56(bright) NK cells and predictable decline in FoxP3+ T-regs combined with a transient interruption in daclizumab dosing may have contributed to this serious side effect. CONCLUSIONS: Only safety data from larger phase III studies and potentially postmarketing experience will define the exact risk of daclizumab-induced immunopathologies. Nevertheless, our case provides plausible hypothesis and potential biomarker that may be used to screen susceptible patients and implement preventive safety measures during potentially vulnerable periods.
Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Inmunoglobulina G/uso terapéutico , Inmunosupresores/uso terapéutico , Esclerosis Múltiple/complicaciones , Vasculitis del Sistema Nervioso Central/tratamiento farmacológico , Vasculitis del Sistema Nervioso Central/etiología , Antiinflamatorios/uso terapéutico , Antígeno CD56/metabolismo , Ciclofosfamida/uso terapéutico , Daclizumab , Evaluación de la Discapacidad , Ensayo de Inmunoadsorción Enzimática/métodos , Femenino , Humanos , Células Asesinas Naturales/efectos de los fármacos , Células Asesinas Naturales/metabolismo , Imagen por Resonancia Magnética , Masculino , Metilprednisolona/uso terapéutico , Esclerosis Múltiple/líquido cefalorraquídeo , Esclerosis Múltiple/diagnóstico , Vasculitis del Sistema Nervioso Central/patologíaRESUMEN
Glial activation in the setting of central nervous system inflammation is a key feature of the multiple sclerosis (MS) pathology. Monitoring glial activation in subjects with MS, therefore, has the potential to be informative with respect to disease activity. The translocator protein 18 kDa (TSPO) is a promising biomarker of glial activation that can be imaged by positron emission tomography (PET). To characterize the in vivo TSPO expression in MS, we analyzed brain PET scans in subjects with MS and healthy volunteers in an observational study using [(11)C]PBR28, a newly developed translocator protein-specific radioligand. The [(11)C]PBR28 PET showed altered compartmental distribution of TSPO in the MS brain compared to healthy volunteers (p = 0.019). Focal increases in [(11)C]PBR28 binding corresponded to areas of active inflammation as evidenced by significantly greater binding in regions of gadolinium contrast enhancement compared to contralateral normal-appearing white matter (p = 0.0039). Furthermore, increase in [(11)C]PBR28 binding preceded the appearance of contrast enhancement on magnetic resonance imaging in some lesions, suggesting a role for early glial activation in MS lesion formation. Global [(11)C]PBR28 binding showed correlation with disease duration (p = 0.041), but not with measures of clinical disability. These results further define TSPO as an informative marker of glial activation in MS.
Asunto(s)
Esclerosis Múltiple/diagnóstico por imagen , Esclerosis Múltiple/patología , Neuroglía/patología , Receptores de GABA/biosíntesis , Acetamidas , Adulto , Anciano , Biomarcadores/análisis , Radioisótopos de Carbono , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Esclerosis Múltiple/inmunología , Neuroglía/inmunología , Neuroglía/metabolismo , Tomografía de Emisión de Positrones , Piridinas , RadiofármacosAsunto(s)
Inmunosupresores/uso terapéutico , Esclerosis Múltiple/diagnóstico , Esclerosis Múltiple/tratamiento farmacológico , Péptidos/uso terapéutico , Encéfalo/patología , Progresión de la Enfermedad , Estudios de Seguimiento , Acetato de Glatiramer , Humanos , Imagen por Resonancia Magnética , Reproducibilidad de los Resultados , Proyectos de Investigación , Tamaño de la Muestra , Terminología como AsuntoRESUMEN
OBJECTIVE: Maintenance therapy with anti-CD25 antibody has emerged as a potentially useful treatment for multiple sclerosis (MS). Constitutive CD25 expression on CD4+CD25+ regulatory T cells (Treg) suggests that anti-CD25 antibody treatment may potentially target a subset of T cells that exhibit immune suppressive properties. We examined changes to CD4+CD25+ Treg in patients with MS receiving maintenance anti-CD25 monoclonal antibody treatment to determine the effect of treatment on Treg and, consequently, on immunological tolerance. DESIGN: Peripheral blood and cerebrospinal fluid samples obtained from a before-and-after trial of anti-CD25 antibody monotherapy were examined to compare baseline and treatment differences in CD4+CD25+ Treg. SUBJECTS: A total of 15 subjects with MS. One subject was withdrawn owing to an adverse effect. RESULTS: Sustained reduction of the frequency of CD4+CD25+ Treg was observed during treatment. Anti-CD25 antibody treatment led to evidence of impaired in vivo Treg proliferation and impaired ex vivo Treg suppression. Inflammatory MS activity was substantially reduced with treatment despite reduction of circulating Treg, and there was no correlation between changes in the frequency of Treg and changes in brain inflammatory activity. However, new-onset inflammatory disease, notably dermatitis, was also observed in a number of subjects during treatment. CONCLUSION: The reduction in Treg did not negatively affect maintenance of central nervous system tolerance during anti-CD25 antibody treatment. The incidence of new-onset inflammatory disease outside of the central nervous system in a subset of patients, however, warrants further studies to examine the possibility of compartmental differences in the capacity to maintain tolerance in the setting of reduced CD4+CD25+ Treg.
Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Linfocitos T CD4-Positivos/efectos de los fármacos , Inmunoglobulina G/uso terapéutico , Inmunosupresores/uso terapéutico , Subunidad alfa del Receptor de Interleucina-2/inmunología , Esclerosis Múltiple/tratamiento farmacológico , Esclerosis Múltiple/inmunología , Linfocitos T Reguladores/efectos de los fármacos , Adulto , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados , Encéfalo/efectos de los fármacos , Encéfalo/inmunología , Encéfalo/patología , Recuento de Linfocito CD4 , Linfocitos T CD4-Positivos/inmunología , Daclizumab , Erupciones por Medicamentos/etiología , Erupciones por Medicamentos/inmunología , Femenino , Citometría de Flujo , Humanos , Inmunoglobulina G/efectos adversos , Inmunosupresores/efectos adversos , Infusiones Intravenosas , Cuidados a Largo Plazo , Activación de Linfocitos/efectos de los fármacos , Activación de Linfocitos/inmunología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Autotolerancia/efectos de los fármacos , Autotolerancia/inmunología , Linfocitos T Reguladores/inmunología , Adulto JovenRESUMEN
BACKGROUND: Several questions arise concerning the use of the anti-CD25 antibody daclizumab to treat multiple sclerosis (MS). OBJECTIVES: To answer the following 3 questions related to the efficacy of daclizumab therapy in patients with MS: Is the therapeutic effect of daclizumab dependent on combination with interferon beta? Is a higher dosage of daclizumab more efficacious in patients with persistent disease activity? Can biomarkers predict full vs partial therapeutic response to daclizumab? DESIGN: An open-label baseline vs treatment phase II clinical trial of daclizumab in patients having MS with inadequate response to interferon beta. Three months of interferon beta treatment at baseline were followed by 5.5 months of interferon beta-daclizumab combination therapy. If patients experienced more than 75% reduction of contrast-enhancing lesions (CELs) on brain magnetic resonance imaging at month 5.5 compared with baseline, daclizumab was continued as monotherapy for 10 months. Otherwise, the dosage of daclizumab was doubled. SETTING: Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, Bethesda, Maryland. PATIENTS: Fifteen patients with MS receiving standard preparations of interferon beta who experienced more than 1 MS exacerbation or whose clinical disability increased in the preceding 12 months and who had at least 2 CELs on baseline brain magnetic resonance images. INTERVENTION: Daclizumab (1 mg/kg) as an intravenous infusion every 4 weeks in combination with interferon beta (months 0-5.5) and as monotherapy (months 6.5-15.5). MAIN OUTCOME MEASURES: The primary outcome was the reduction of CELs among interferon beta monotherapy, interferon beta-daclizumab combination therapy, and daclizumab monotherapy. The secondary outcomes included immunologic biomarkers and changes in clinical disability. RESULTS: Overall, 5 of 15 patients (33%) experienced adverse effects of therapy. Two patients developed systemic adverse effects, and daclizumab therapy was discontinued. Although daclizumab monotherapy was efficacious in 9 of 13 patients with MS, interferon beta-daclizumab combination therapy was necessary to stabilize disease activity in the other 4 patients. Daclizumab therapy led to 72% inhibition of new CELs and significant improvement in clinical disability. Pilot biomarkers (increase in CD56bright natural killer cells and decrease in CD8+ T cells) were identified that can differentiate between full and partial daclizumab responders. CONCLUSIONS: Daclizumab monotherapy is effective in most patients who experienced persistent MS disease activity with interferon beta therapy. Interferon beta-daclizumab combination therapy or higher dosages of daclizumab may be necessary to achieve optimal therapeutic response in all patients. Biomarkers may identify patients with suboptimal response to daclizumab monotherapy. Administration among a large patient sample during a longer period is needed to fully define the safety and long-term efficacy of daclizumab as treatment for high-inflammatory MS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00001934.