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Cerebral Microbleeds in Multiple Sclerosis Evaluated on Susceptibility-weighted Images and Quantitative Susceptibility Maps: A Case-Control Study. - Radiology
Purpose To assess cerebral microbleed (CMB) prevalence in patients with multiple sclerosis (MS) and clinically isolated syndrome (CIS) and associations with clinical outcomes. Materials and Methods CMBs are associated with aging and neurodegenerative disorders. The prevalence of CMBs has not previously been well established. In this study, 445 patients with MS (266 with relapsing-remitting MS, 138 with secondary progressive MS, and 41 with primary progressive MS), 45 patients with CIS, 51 patients with other neurological diseases, and 177 healthy control subjects (HCs) underwent 3-T magnetic resonance (MR) imaging and clinical examinations. A subset of 168 patients with MS and 50 HCs underwent neuropsychological testing. Number of CMBs was assessed on susceptibility-weighted minimum intensity projections by using the Microbleed Anatomic Rating Scale; volume was calculated by using quantitative susceptibility maps. Differences between groups were analyzed with the Ï‡(2) test, Fisher exact test, Student t test, and analysis of variance; associations of CMBs with clinical and other MR imaging outcomes were explored with correlation and regression analyses. Because CMB frequency increases with age, prevalence was investigated in participants at least 50 years of age and younger than 50 years. Results Significantly more patients with MS than HCs had CMBs (19.8% vs 7.4%, respectively; P = .01) in the group at least 50 years old. A trend toward greater presence of CMBs was found in patients with MS (P = .016) and patients with CIS who were younger than 50 years (P = .039) compared with HCs. In regression analysis adjusted for age, hypertension, and normalized brain volume, increased number of CMBs was significantly associated with increased physical disability in the MS population (R(2) = 0.23, P < .0001). In correlation analysis, increased number of CMBs was significantly associated with deteriorated auditory and verbal learning and memory (P = .006) and visual information processing speed trends (P = .049) in patients with MS. Conclusion Monitoring CMBs may be relevant in patients with MS and CIS at higher risk for developing cognitive and physical disability. (Â©) RSNA, 2016 Online supplemental material is available for this article.
Is no evidence of disease activity an achievable goal in MS patients on intramuscular interferon beta-1a treatment over long-term follow-up? - Multiple sclerosis (Houndmills, Basingstoke, England)
No evidence of disease activity (NEDA) has been proposed as a new treatment goal in multiple sclerosis (MS). NEDA-3 status is defined as the absence of magnetic resonance imaging (MRI; new/enlarging/enhancing lesions and increased whole brain volume loss in NEDA-4) and clinical disease activity.To investigate the persistence of NEDA status over long-term follow-up in MS patients treated with weekly intramuscular interferon beta-1a.We included 192 patients after the first demyelinating event suggestive of MS, that is, clinically isolated syndrome (CIS) and 162 relapsing-remitting MS (RRMS) patients.NEDA-3 status was observed in 40.1% of CIS and 20.4% of RRMS patients after 1 year. After 4 years, 10.1% of CIS patients had NEDA-3 status. After 10 years, none of the RRMS patients had NEDA-3 status. Only 4.6% of CIS and 1.0% of RRMS patients maintained NEDA-4 status after 4 years. Loss of NEDA-3 status after the first year was associated with a higher risk of disability progression (hazard ratio (HR)â€‰=â€‰2.3-4.0; pâ€‰=â€‰0.005-0.03) over 6 years.Despite intramuscular interferon beta-1a treatment, loss of NEDA status occurred in the vast majority of individuals. Loss of NEDA status during the first year was associated with disability progression over long-term follow-up; however, specificity for individual patient was low.Â© The Author(s), 2016.
Internal Jugular Vein Cross-Sectional Area and Cerebrospinal Fluid Pulsatility in the Aqueduct of Sylvius: A Comparative Study between Healthy Subjects and Multiple Sclerosis Patients. - PloS one
Constricted cerebral venous outflow has been linked with increased cerebrospinal fluid (CSF) pulsatility in the aqueduct of Sylvius in multiple sclerosis (MS) patients and healthy individuals. This study investigates the relationship between CSF pulsatility and internal jugular vein (IJV) cross-sectional area (CSA) in these two groups, something previously unknown.65 relapsing-remitting MS patients (50.8% female; mean age = 43.8 years) and 74 healthy controls (HCs) (54.1% female; mean age = 43.9 years) were investigated. CSF flow quantification was performed on cine phase-contrast MRI, while IJV-CSA was calculated using magnetic resonance venography. Statistical analysis involved correlation, and partial least squares correlation analysis (PLSCA).PLSCA revealed a significant difference (p<0.001; effect size = 1.072) between MS patients and HCs in the positive relationship between CSF pulsatility and IJV-CSA at C5-T1, something not detected at C2-C4. Controlling for age and cardiovascular risk factors, statistical trends were identified in HCs between: increased net positive CSF flow (NPF) and increased IJV-CSA at C5-C6 (left: r = 0.374, p = 0.016; right: r = 0.364, p = 0.019) and C4 (left: r = 0.361, p = 0.020); and increased net negative CSF flow and increased left IJV-CSA at C5-C6 (r = -0.348, p = 0.026) and C4 (r = -0.324, p = 0.039), whereas in MS patients a trend was only identified between increased NPF and increased left IJV-CSA at C5-C6 (r = 0.351, p = 0.021). Overall, correlations were weaker in MS patients (p = 0.015).In healthy adults, increased CSF pulsatility is associated with increased IJV-CSA in the lower cervix (independent of age and cardiovascular risk factors), suggesting a biomechanical link between the two. This relationship is altered in MS patients.
Combining clinical and magnetic resonance imaging markers enhances prediction of 12-year disability in multiple sclerosis. - Multiple sclerosis (Houndmills, Basingstoke, England)
Disease progression and treatment efficacy vary among individuals with multiple sclerosis. Reliable predictors of individual disease outcomes are lacking.To examine the accuracy of the early prediction of 12-year disability outcomes using clinical and magnetic resonance imaging (MRI) parameters.A total of 177 patients from the original Avonex-Steroids-Azathioprine study were included. Participants underwent 3-month clinical follow-ups. Cox models were used to model the associations between clinical and MRI markers at baseline or after 12â€‰months with sustained disability progression (SDP) over the 12-year observation period.At baseline, T2 lesion number, T1 and T2 lesion volumes, corpus callosum (CC), and thalamic fraction were the best predictors of SDP (hazard ratio (HR)â€‰=â€‰1.7-4.6; pâ€‰â©½â€‰0.001-0.012). At 12â€‰months, Expanded Disability Status Scale (EDSS) and its change, number of new or enlarging T2 lesions, and CC volume % change were the best predictors of SDP over the follow-up (HRâ€‰=â€‰1.7-3.5; pâ€‰â©½â€‰0.001-0.017). A composite score was generated from a subset of the best predictors of SDP. Scores of â©¾4 had greater specificity (90%-100%) and were associated with greater cumulative risk of SDP (HRâ€‰=â€‰3.2-21.6; pâ€‰<â€‰0.001) compared to the individual predictors.The combination of established MRI and clinical indices with MRI volumetric predictors improves the prediction of SDP over long-term follow-up and may provide valuable information for therapeutic decisions.Â© The Author(s), 2016.
Long-Term Neurocognitive, Psychosocial, and Magnetic Resonance Imaging Outcomes in Pediatric-Onset Acute Disseminated Encephalomyelitis. - Pediatric neurology
Acute disseminated encephalomyelitis (ADEM) is a demyelinating disorder that is usually self-limited. Recent studies have suggested ongoing neurological deficits and neurocognitive impairment in these patients. Little information on the correlation of clinical and neuroimaging markers in ADEM is available. We examined potential clinical factors (e.g., age of onset, acute symptom duration, magnetic resonance imaging [MRI] lesions) and their relation to neurocognitive and psychosocial outcomes.This is a retrospective chart review of consecutive pediatric patients diagnosed with ADEM between 2006 and 2012. Patients were evaluated with standard neurological assessment, MRI of the brain, and neuropsychological evaluation.Twenty-three patients with ADEM with average age at neuropsychological assessment of 10.1Â years (Â±3.50) were included. Five (22.7%) patients were impaired on three or more neurocognitive measures. Psychosocial problems were reported in 20%-40% of patients. Earlier age of onset was correlated with poorer sustained attention and psychosocial problems, whereas acute symptom duration and Expanded Disability Status Scale were not. MRI outcomes were correlated with psychosocial outcomes but not neuropsychological findings.Our findings suggest lingering cognitive and psychosocial deficits in children with a history of ADEM. Clinical features and MRI findings correlated more strongly with psychosocial outcomes than cognitive functioning. Further studies are needed to confirm relationships and other possible contributing factors to lingering deficits.Copyright Â© 2016 Elsevier Inc. All rights reserved.
A serial 10-year follow-up study of brain atrophy and disability progression in RRMS patients. - Multiple sclerosis (Houndmills, Basingstoke, England)
We explored the evolution of brain atrophy in relation to development of confirmed disability progression (CDP) on serial 1.5T magnetic resonance imaging (MRI) scans over a 10-year period in 181 patients with early relapsing-remitting multiple sclerosis (RRMS).At 10-year follow-up, they were divided into those with (100) or without (76) CDP (confirmed after 48â€‰weeks). Changes in whole brain (WB), cortical, gray matter (GM), white matter, and ventricular cerebrospinal fluid (vCSF) volumes were calculated on three-dimensional T1-weighted (3D-T1) scans between all available time points.In multiple sclerosis (MS) patients with CDP compared to those without, the greatest effect size percentage volume change from baseline to follow-up was detected for WB (dâ€‰=â€‰0.55, -7.5% vs -5.2%, pâ€‰<â€‰0.001), followed by vCSF (dâ€‰=â€‰0.51, +41.1% vs +25.7%, pâ€‰<â€‰0.001), cortical (dâ€‰=â€‰0.49, -7.7% vs -6.2%, pâ€‰=â€‰0.001), and GM (dâ€‰=â€‰0.40, -7.1% vs -5.8%, pâ€‰=â€‰0.006) volumes. Mixed-effects model analysis, adjusted for age, sex, and treatment change, showed significant interactions between CDP status and percentage changes for WB and vCSF (pâ€‰<â€‰0.001), cortical (pâ€‰=â€‰0.02), and GM (pâ€‰=â€‰0.04) volumes.WB and cortical atrophy, and enlargement of vCSF spaces are associated with development of CDP on serial yearly MRI assessments over a period of 10â€‰years.Â© The Author(s), 2016.
Randomised natalizumab discontinuation study: taper protocol may prevent disease reactivation. - Journal of neurology, neurosurgery, and psychiatry
To compare two modes of natalizumab cessation interventions: immediate versus tapered down, as measured by serial MRI and the occurrence of relapses during a 12-month period.Weighing progressive multifocal encephalopathy risk associated with â‰¥24â€…months of natalizumab therapy against the benefits of disease control, we initiated a natalizumab discontinuation study.A phase IV, 12-month, single-blinded randomised (MRI) study. Fifty relapsing patients with multiple sclerosis (MS) who had been on natalizumab therapy â‰¥24â€…months and were contemplating natalizumab discontinuation were enrolled. Participants were randomised to either the immediate discontinuation group (IDG) or the tapered group (TG). IDG discontinued natalizumab at once and initiated another disease modifying therapy (DMT) following the last natalizumab infusion, while the TG received two more natalizumab infusions, at 6 and 8â€…weeks (14â€…weeks from study entry) before initiating another DMT. Standardised MRI was performed at baseline, 6 and 12â€…months from the last natalizumab infusion.A higher rate of relapses in the IDG (n=28) compared to the TG (n=8) over 12â€…months from the last infusion (p=0.007) was observed, most relapses occurred within 3â€…months of discontinuation (20 vs 7 relapses, p=0.012). The IDG showed a higher number of new T2 lesions within 6-12â€…months of discontinuation (p=0.025), a higher mean absolute T2-LV change from 0 to 12â€…months (1.1 vs 0.1â€…mL, p=0.024) and a higher number of new T1-hypointense lesions over 0-12â€…months (p=0.005) as well as from baseline to 6â€…months (p=0.026) compared to the TG.Natalizumab discontinuation therapy was associated with development of new disease activity. Our tapered protocol showed benefits, as patients in the TG experienced less relapses and lower accumulation of MRI lesions compared to those in the IDG.Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/
Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS. - NeurologyÂ® neuroimmunology & neuroinflammation
Because dysregulated Epstein-Barr virus (EBV)-infected B cells may induce meningeal inflammation, which contributes to cortical pathology in multiple sclerosis (MS), we investigated associations between antibody responses to EBV and development of cortical pathology in MS.We included 539 patients with MS (369 with relapsing-remitting MS, 135 with secondary progressive MS, and 35 with primary progressive MS), 66 patients with clinically isolated syndrome (CIS), 63 patients with other neurologic diseases (OND), and 178 age- and sex-matched healthy controls (HC). All participants were scanned on 3T MRI. Serum samples were analyzed for IgG antibodies against EBV viral capsid antigen (VCA) and EBV nuclear antigen-1 (EBNA-1), and their quartiles were determined on the whole study sample. Differences between the study groups were assessed using analysis of covariance adjusted for multiple comparisons.More than 30% of patients with MS and CIS presented with the highest quartile of anti-EBV-VCA and -EBNA-1 status compared to â‰¤10% of HC (p < 0.001). The figures were 9 (14.3%) and 7 (12.3%) for patients with OND. Patients with MS with the highest quartile of anti-EBV-VCA showed significantly increased T2 lesion volume (p = 0.001), T1 lesion number (p = 0.002), and T1 lesion volume (p = 0.04) and decreased gray matter (p = 0.041) and cortical (p = 0.043) volumes compared to patients with MS with lower quartiles. No significant differences of MRI outcomes in patients with CIS, patients with OND, and HC with lower or highest quartiles of anti-EBV-VCA and -EBNA-1 were detected.Humoral response to anti-EBV-VCA and -EBNA-1 is associated with more advanced cortical atrophy, accumulation of chronic T1 black holes, and focal white matter lesions in patients with MS.
Immunologic and MRI markers of the therapeutic effect of IFN-Î²-1a in relapsing-remitting MS. - NeurologyÂ® neuroimmunology & neuroinflammation
To assess potential roles of effector cells and immunologic markers in demyelinating CNS lesion formation, and their modulation by interferon Î²-1a (IFN-Î²-1a).Twenty-three patients with relapsing-remitting multiple sclerosis (RRMS) received IFN-Î²-1a for 6 months. Immunologic marker results were correlated with brain MRI lesion volumes, and volumes of normal-appearing brain tissue (NABT) with decreasing or increasing voxel-wise magnetization transfer ratio (VW-MTR), suggestive of demyelination and remyelination, respectively.Baseline expression of Th22 cell transcription factor aryl hydrocarbon receptor (AHR) and interleukin (IL)-17F, and percentages of IL-22-expressing CD4(+) and CD8(+) cells, were significantly higher in patients vs 15 healthy controls; IL-4 in CD4(+) cells was lower. Baseline percentage of IL-22-producing CD8(+) cells positively correlated with T2 lesion volumes, while percentage of IL-17A-producing CD8(+) cells positively correlated with T2 and T1 lesion volumes. IFN-Î²-1a induced reductions in transcription factor AHR, T-bet, and retinoic acid-related orphan nuclear hormone receptor C (RORc) gene expression, while it increased GATA3's expression in CD4(+) cells. Percentages of IL-22-, IL-17A-, and IL-17F-expressing T cells significantly decreased following treatment. Increased percentages of IL-10-expressing CD4(+) and CD8(+) cells correlated with greater NABT volume with increasing VW-MTR, while decreased percentage of IL-17F-expressing CD4(+) cells positively correlated with decreased NABT volume with decreasing VW-MTR.Findings indicate that IFN-Î²-1a suppresses Th22 and Th17 cell responses, which were associated with decreased MRI-detectable demyelination.This pilot study provides Class III evidence that reduced Th22 and Th17 responses are associated with decreased demyelination following IFN-Î²-1a treatment in patients with RRMS.
Immunological and short-term brain volume changes in relapsing forms of multiple sclerosis treated with interferon beta-1a subcutaneously three times weekly: an open-label two-arm trial. - BMC neurology
Brain volume atrophy is observed in relapsing-remitting multiple sclerosis (RRMS).Brain volume changes were evaluated in 23 patients with RRMS treated with interferon Î²-1a 44 Î¼g given subcutaneously (SC) three times a week (tiw) and 15 healthy controls. Percentages of whole brain and tissue-specific volume change were measured from baseline (0 months) to 3 months, from 3 to 6 months, and from baseline to 6 months using SIENAX Multi Time Point (SX-MTP) algorithms. Immunological status of patients was also determined and correlations between subsets of T cells and changes in brain volume were assessed.Interferon Î²-1a 44 Î¼g SC tiw in 23 patients with RRMS resulted in significant reductions in whole brain and gray matter tissue volume early in the treatment course (baseline to 3 months; mean change; -0.95%; P = 0.030, -1.52%; P = 0.004, respectively), suggesting a short-term treatment-induced pseudoatrophy effect. From baseline to 6 months, there were significant correlations observed between decreased T- cell expression of IL-17 F and decreased whole brain and brain tissue-specific volume.These findings are consistent with the interpretation of the pseudoatrophy effect as resolution of inflammation following treatment initiation with interferon Î²-1a 44 Î¼g SC tiw, rather than disease-related tissue loss.ClinicalTrials.gov; NCT01085318.
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