Publications by authors named "Gregg Blevins"

34 Publications

Cross-sectional analysis of peripheral blood mononuclear cells in lymphopenic and non-lymphopenic relapsing-remitting multiple sclerosis patients treated with dimethyl fumarate.

Mult Scler Relat Disord 2021 Jul 7;52:103003. Epub 2021 May 7.

Division of Neurology, Department of Medicine, University of Alberta, Alberta Canada T6G 2M8, Edmonton, Canada. Electronic address:

Background: Relapsing-remitting multiple sclerosis (RRMS) is an autoimmune disorder of the central nervous system. Dimethyl Fumarate is a disease-modifying medication used to treat RRMS patients that can induce lymphopenia. We aimed to immunophenotype peripheral blood mononuclear cells (PBMC) in RRMS patients cross-sectionally and examine the characteristics and modifications of lymphopenia over time.

Methods: Characterization of PBMC was done by multiparametric flow cytometry. Patients had been on treatment for up to 4 years and were grouped into lymphopenic (DMF-L) and non-lymphopenic (DMF-N) patients.

Results: Lymphopenia affected the cell population changes over time, with other patient characteristics (gender, age, and previous treatment status) also having significant effects. In both lymphopenic and non-lymphopenic patients, PBMC percentages were reduced over time. While overall T and B cells frequencies were not affected, males, older patients and untreated patients had significant changes in B cell subpopulations over time. CD4 to CD8T cell ratio increased significantly in lymphopenic patients over time. CD4CD8T cell population was similarly reduced in both lymphopenic and non-lymphopenic patients, over time. While the monocyte and NK overall populations were not changed, non-classical monocyte subpopulation decreased over time in lymphopenic patients. We also found CD56CD16 and CD56CD16 NK cells frequencies changed over time in lymphopenic patients. Immune populations showed correlations with clinical outcomes measured by EDSS and relapse rate. Analysis of the overall immunophenotype showed that, while groups divided by other patient characteristics showed differences, the lymphopenia status overrode these differences, resulting in similar immunophenotype within DMF-L.

Conclusions: Our data provide evidence that under the same therapy, lymphopenia affects how the immunophenotype changes over time and can override the differences associated with other patient characteristics and possibly mask other significant changes in the immune profile of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2021.103003DOI Listing
July 2021

Sarcoidosis: a prospective observational cohort from Northern Alberta.

Sarcoidosis Vasc Diffuse Lung Dis 2020 16;37(4):e2020014. Epub 2020 Dec 16.

Emeritus, Division of Preventive Medicine, University of Alberta.

Introduction: Sarcoidosis is a multi-system disease reported to occur with a higher incidence in Alberta than many other health jurisdictions within and outside of Canada. The reasons for this higher incidence are currently not known. Exposure to beryllium can result in a clinically and radiologically identical disease to sarcoidosis. The purpose of our study was to identify patterns with potential occupational or environmental exposures to beryllium amongst individuals with sarcoidosis in Alberta through a tertiary referral center.

Methods: A prospective observational study was carried out at the University of Alberta Hospital. Patients with confirmed sarcoidosis (stages 0-4) were recruited from subspecialty clinics (Respirology, Cardiology, Neurology and Occupational Health). A predetermined list of industries thought to involve potentially relevant exposures for the development of sarcoidosis was used to capture current and previous exposure history. Results were entered into a database and where possible verified by comparing with existing electronic medical records (including histories, physical examination, diagnostic imaging and physiology).

Results: A total of 45 patients were recruited, 25 men and 20 women. Of these, 84% of participants reported working in or being exposed to an industry/environment suspected of contributing to development of sarcoidosis over their lifetime. The most frequently reported exposures were within farming and agriculture (27%), oil and gas (20%), metalworking and handling animals (18%).

Conclusions: Amongst this cohort, a high proportion reported working with a potentially relevant exposure. Individuals being assessed for sarcoidosis should have their most responsible physician elicit a detailed work and environmental history. .
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.36141/svdld.v37i4.8522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883513PMC
June 2021

The Clinical Conundrum of Managing Ischemic Stroke in Patients with Immune Thrombocytopenia.

Can J Neurol Sci 2021 01 10;48(1):38-46. Epub 2020 Jul 10.

Department of Medicine, Division of Neurology, University of Alberta, Edmonton, Canada.

Guidelines are lacking for management of acute ischemic stroke and stroke prevention in patients with immune thrombocytopenia (ITP). Our aim is to highlight the dilemma inherent in managing patients with both significant bleeding and thrombotic risk factors. In this review, we present two patients with history of ITP who presented with acute ischemic stroke and received tissue plasminogen activator (tPA) and endovascular thrombectomy (EVT), a rare management strategy in this patient population. In addition, we identified 27 case reports of ischemic stroke in patients with ITP; none of them received tPA or EVT. Furthermore, there are 92 patients with significant thrombocytopenia with no available data regarding the cause of thrombocytopenia, who were acutely treated with tPA or EVT. Conclusive evidence cannot be determined based on these limited number of cases. Future multicenter prospective cohort studies in patients with ITP are needed to provide better evidence-based treatment plans. At present, treatment of acute ischemic stroke in patients with ITP requires close collaboration between hematology and vascular neurology experts to find a balance between the benefit and risk of hemorrhagic complications.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2020.138DOI Listing
January 2021

AMPA-R Limbic Encephalitis Associated with Systemic Lupus Erythematosus.

Can J Neurol Sci 2020 09 13;47(5):709-710. Epub 2020 Apr 13.

Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2020.70DOI Listing
September 2020

Five year iron changes in relapsing-remitting multiple sclerosis deep gray matter compared to healthy controls.

Mult Scler Relat Disord 2019 Aug 31;33:107-115. Epub 2019 May 31.

Department of Biomedical Engineering, University of Alberta, 1070 Research Transition Facility, 8308-114 Street, Edmonton T6G 2V2, Alberta, Canada.

Background: Relapsing-Remitting MS (RRMS) Deep Grey Matter (DGM) 5 year changes were examined using MRI measures of volume, transverse relaxation rate (R2*) and quantitative magnetic susceptibility (QS). By applying Discriminative Analysis of Regional Evolution (DARE), R2* and QS changes from iron and non-iron sources were separated.

Methods: 25 RRMS and 25 age-matched control subjects were studied at baseline and 5-year follow-up. Bulk DGM mean R2* and QS of the caudate nucleus, putamen, thalamus and globus pallidus were analyzed using mixed factorial analysis (α = 0.05) with sex as a covariate, while DARE employed non-parametric analysis to study regional changes. Regression/correlation analysis was performed with disease duration and MS Severity Score (MSSS).

Results: No significant change in Extended Disability Status Score was found over 5 years (baseline = 2.4 ± 1.2; follow-up = 2.8 ± 1.3). Significant time effects were found for R2* in the caudate (Q = 0.000008; η = 0.36), putamen (Q = 0.0000007; η = 0.43), and globus pallidus (Q = 0.0000007; η = 0.43), while significant longitudinal effects were only found for QS in the putamen (Q = 0.002; η = 0.22). Significant bulk interaction was only found for thalamus volume (Q = 0.02; η = 0.20). Iron decrease was the only detected significant effect using DARE, and the highest significant DARE effect size was mean thalamus R2* iron decrease (Q = 0.002; η = 0.26). No significant correlations or regressions were demonstrated with clinical measures.

Conclusions: Thalamic atrophy was the only bulk effect that demonstrated different rates of changes over 5 years compared to age-matched controls. DARE Iron decrease in regions of the caudate, putamen, and thalamus were prominent features in stable RRMS over 5 years.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.msard.2019.05.028DOI Listing
August 2019

Human pegivirus-1 associated leukoencephalitis: Clinical and molecular features.

Ann Neurol 2018 11 8;84(5):781-787. Epub 2018 Nov 8.

Department of Medicine, University of Alberta, Edmonton, AB, Canada.

Etiologic diagnosis is uncertain in 35% to 50% of patients with encephalitis, despite its substantial global prevalence and disease burden. We report on 2 adult female patients with fatal leukoencephalitis associated with human pegivirus-1 (HPgV-1) brain infection. Neuroimaging showed inflammatory changes in cerebral white matter. Brain-derived HPgV-1 RNA sequences clustered phylogenetically with other pegiviruses despite an 87-nucleotide deletion in the viral nonstructural (NS)2 gene. Neuropathology disclosed lymphocyte infiltration and gliosis predominantly in brain white matter. HPgV-1 NS5A antigen was detected in lymphocytes as well as in astrocytes and oligodendrocytes. HPgV-1 neuroadaptation should be considered in the differential diagnosis of progressive leukoencephalitis in humans. Ann Neurol 2018;84:789-795.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ana.25343DOI Listing
November 2018

Discriminative analysis of regional evolution of iron and myelin/calcium in deep gray matter of multiple sclerosis and healthy subjects.

J Magn Reson Imaging 2018 Mar 14. Epub 2018 Mar 14.

Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada.

Background: Combined R2* and quantitative susceptibility (QS) has been previously used in cross-sectional multiple sclerosis (MS) studies to distinguish deep gray matter (DGM) iron accumulation and demyelination.

Purpose: We propose and apply discriminative analysis of regional evolution (DARE) to define specific changes in MS and healthy DGM.

Study Type: Longitudinal (baseline and 2-year follow-up) retrospective study.

Subjects: Twenty-seven relapsing-remitting MS (RRMS), 17 progressive MS (PMS), and corresponding age-matched healthy subjects.

Field Strength/sequence: 4.7T 10-echo gradient-echo acquisition.

Assessment: Automatically segmented caudate nucleus (CN), thalamus (TH), putamen (PU), globus pallidus, red nucleus (RN), substantia nigra, and dentate nucleus were retrospectively analyzed to quantify regional volumes, bulk mean R2*, and bulk mean QS. DARE utilized combined R2* and QS localized changes to compute spatial extent, mean intensity, and total changes of DGM iron and myelin/calcium over 2 years.

Statistical Tests: We used mixed factorial analysis for bulk analysis, nonparametric tests for DARE (α = 0.05), and multiple regression analysis using backward elimination of DGM structures (α = 0.05, P = 0.1) to regress bulk and DARE measures with the follow-up Multiple Sclerosis Severity Score (MSSS). False detection rate correction was applied to all tests.

Results: Bulk analysis only detected significant (Q ≤ 0.05) interaction effects in RRMS CN QS (η = 0.45; Q = 0.004) and PU volume (η = 0.38; Q = 0.034). DARE demonstrated significant group differences in all RRMS structures, and in all PMS structures except the RN. The largest RRMS effect size was CN total R2* iron decrease (r = 0.74; Q = 0.00002), and TH mean QS myelin/calcium decrease for PMS (r = 0.70; Q = 0.002). DARE iron increase using total QS demonstrated the highest correlation with MSSS (r = 0.68; Q = 0.0005).

Data Conclusion: DARE enabled discriminative assessment of specific DGM changes over 2 years, where iron and myelin/calcium changes were the primary drivers in RRMS and PMS compared to age-matched controls, respectively. Specific DARE measures of MS DGM correlated with follow-up MSSS, and may reflect complex disease pathology.

Level Of Evidence: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmri.26004DOI Listing
March 2018

Characterization of lymphopenia in patients with MS treated with dimethyl fumarate and fingolimod.

Neurol Neuroimmunol Neuroinflamm 2018 Mar 28;5(2):e432. Epub 2017 Dec 28.

Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Canada.

Objective: Lymphopenia is a common occurrence of disease-modifying therapies (DMTs) for relapsing-remitting MS (RRMS). The aim of this study was to dissect the prevalence of various lymphocyte subsets in patients with RRMS treated with 2 DMTs commonly associated with lymphopenia, dimethyl fumarate (DMF), and fingolimod (FTY).

Methods: Multicolor flow cytometry and multiplex assays were used to identify up to 50 lymphocyte subpopulations and to examine the expression of multiple cytokines in selected patients. We compared patients untreated (NT) or treated with FTY or DMF who did (DMF-L) or did not (DMF-N) develop lymphopenia.

Results: All FTY patients developed lymphopenia in both T-cell and B-cell compartments. CD41 T cells were more affected by this treatment than CD81 cells. In the B-cell compartment, the CD271IgD2 subpopulation was reduced. T cells but not B cells were significantly reduced in DMF-L. However, within the B cells, CD271 cells were significantly lower. Both CD41 and CD81 subpopulations were reduced in DMF-L. Within the remaining CD41 and CD81 compartments, there was an expansion of the naive subpopulation and a reduction of the effector memory subpopulation. Unactivated lymphocyte from DMF-L patients had significantly higher levels of interferon-γ, interleukin (IL)-12, IL-2, IL-4, IL-6, and IL-1β compared with DMF-N. In plasma, TNFβ was significantly higher in DMF-N and DMF-L compared with NT, whereas CCL17 was significantly higher in DMF-L compared with NT and DMF-N.

Conclusions: This study shows that different treatments can target different lymphocyte compartments and suggests that lymphopenia can induce compensatory mechanisms to maintain immune homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/NXI.0000000000000432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746425PMC
March 2018

Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

N Engl J Med 2017 06;376(22):2122-2133

From the Cumming School of Medicine and the Hotchkiss Brain Institute, Calgary, AB (L.M.M., G.C., J.G., M.Y., M.D.H., V.W.Y.), the University of British Columbia, Vancouver (D.K.B.L., A.L.T., A.R.), the University of Montreal, Montreal (P.D.), Western University, London, ON (M.K.), Fraser Health MS Clinic, Burnaby, BC (G.V.), the University of Ottawa and the Ottawa Hospital Research Institute, Ottawa (M.S.F.), Dalhousie University, Halifax, NS (V.B.), the University of Alberta, Edmonton (G.B.), the University of Manitoba, Winnipeg (J.J.M.), Clinique Neuro Rive-Sud, Greenfield Park, QC (F.G.), the University of Toronto, Toronto (L.L.), and CHA-Hôpital Enfant-Jésus, Quebec, QC (M.T.) - all in Canada; and Tufts University, Boston (M.E.).

Background: On the basis of encouraging preliminary results, we conducted a randomized, controlled trial to determine whether minocycline reduces the risk of conversion from a first demyelinating event (also known as a clinically isolated syndrome) to multiple sclerosis.

Methods: During the period from January 2009 through July 2013, we randomly assigned participants who had had their first demyelinating symptoms within the previous 180 days to receive either 100 mg of minocycline, administered orally twice daily, or placebo. Administration of minocycline or placebo was continued until a diagnosis of multiple sclerosis was established or until 24 months after randomization, whichever came first. The primary outcome was conversion to multiple sclerosis (diagnosed on the basis of the 2005 McDonald criteria) within 6 months after randomization. Secondary outcomes included conversion to multiple sclerosis within 24 months after randomization and changes on magnetic resonance imaging (MRI) at 6 months and 24 months (change in lesion volume on T-weighted MRI, cumulative number of new lesions enhanced on T-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T-weighted MRI plus new and newly enlarged lesions on T-weighted MRI]).

Results: A total of 142 eligible participants underwent randomization at 12 Canadian multiple sclerosis clinics; 72 participants were assigned to the minocycline group and 70 to the placebo group. The mean age of the participants was 35.8 years, and 68.3% were women. The unadjusted risk of conversion to multiple sclerosis within 6 months after randomization was 61.0% in the placebo group and 33.4% in the minocycline group, a difference of 27.6 percentage points (95% confidence interval [CI], 11.4 to 43.9; P=0.001). After adjustment for the number of enhancing lesions at baseline, the difference in the risk of conversion to multiple sclerosis within 6 months after randomization was 18.5 percentage points (95% CI, 3.7 to 33.3; P=0.01); the unadjusted risk difference was not significant at the 24-month secondary outcome time point (P=0.06). All secondary MRI outcomes favored minocycline over placebo at 6 months but not at 24 months. Trial withdrawals and adverse events of rash, dizziness, and dental discoloration were more frequent among participants who received minocycline than among those who received placebo.

Conclusions: The risk of conversion from a clinically isolated syndrome to multiple sclerosis was significantly lower with minocycline than with placebo over 6 months but not over 24 months. (Funded by the Multiple Sclerosis Society of Canada; ClinicalTrials.gov number, NCT00666887 .).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1056/NEJMoa1608889DOI Listing
June 2017

Progressive iron accumulation across multiple sclerosis phenotypes revealed by sparse classification of deep gray matter.

J Magn Reson Imaging 2017 11 16;46(5):1464-1473. Epub 2017 Mar 16.

Department of Biomedical Engineering, University of Alberta, Edmonton, AB, Canada.

Purpose: To create an automated framework for localized analysis of deep gray matter (DGM) iron accumulation and demyelination using sparse classification by combining quantitative susceptibility (QS) and transverse relaxation rate (R2*) maps, for evaluation of DGM in multiple sclerosis (MS) phenotypes relative to healthy controls.

Materials And Methods: R2*/QS maps were computed using a 4.7T 10-echo gradient echo acquisition from 16 clinically isolated syndrome (CIS), 41 relapsing-remitting (RR), 40 secondary-progressive (SP), 13 primary-progressive (PP) MS patients, and 75 controls. Sparse classification for R2*/QS maps of segmented caudate nucleus (CN), putamen (PU), thalamus (TH), and globus pallidus (GP) structures produced localized maps of iron/myelin in MS patients relative to controls. Paired t-tests, with age as a covariate, were used to test for statistical significance (P ≤ 0.05).

Results: In addition to DGM structures found significantly different in patients compared to controls using whole region analysis, singular sparse analysis found significant results in RRMS PU R2* (P = 0.03), TH R2* (P = 0.04), CN QS (P = 0.04); in SPMS CN R2* (P = 0.04), GP R2* (P = 0.05); and in PPMS CN R2* (P = 0.04), TH QS (P = 0.04). All sparse regions were found to conform to an iron accumulation pattern of changes in R2*/QS, while none conformed to demyelination. Intersection of sparse R2*/QS regions also resulted in RRMS CN R2* becoming significant, while RRMS R2* TH and PPMS QS TH becoming insignificant. Common iron-associated volumes in MS patients and their effect size progressively increased with advanced phenotypes.

Conclusion: A localized technique for identifying sparse regions indicative of iron or myelin in the DGM was developed. Progressive iron accumulation with advanced MS phenotypes was demonstrated, as indicated by iron-associated sparsity and effect size.

Level Of Evidence: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2017;46:1464-1473.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmri.25682DOI Listing
November 2017

Recovery of accurate T from historical 1.5 tesla proton density and T-weighted images: Application to 7-year T changes in multiple sclerosis brain.

Magn Reson Imaging 2017 Apr 14;37:21-26. Epub 2016 Nov 14.

Department of Biomedical Engineering, University of Alberta, Edmonton, Canada. Electronic address:

Objective: To determine accurate quantitative transverse relaxation times (T) using retrospective clinical images and apply it to examine 7-year changes in multiple sclerosis (MS) brain.

Methods: A method for T mapping from retrospective proton density (PD) and T-weighted fast spin echo images was recently introduced, but requires measurement of flip angles. We examined whether 1.5T flip angle variation in brain can be predicted, thus enabling T analysis of historical PD and T-weighted images without a concurrent flip angle map. After method validation in healthy volunteers, retrospective longitudinal T analysis was performed in 14 MS subjects over seven years. Changes in patient T values were compared with brain atrophy, T lesion load and disability score in MS.

Results: Similar flip angle maps across volunteers enabled retrospective T from PD and T-weighted images even when different refocusing angles were used. Over seven years, significant T changes of 2-4% were observed when using T modelling and the 7-year effect size for globus pallidus T was 0.56, which was more significant than brain atrophy. No significant T results were found when using exponential fit, which cannot account for refocusing angle variation. Moreover, change is T in globus pallidus and internal capsule correlated with MS disability score over time when using T modelling.

Conclusions: Accurate quantitative T can be extracted from standard clinical 1.5T MRI exams that include PD and T-weighted imaging even when no flip angle map is available. This method was applied retrospectively to examine seven year changes in MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.mri.2016.11.007DOI Listing
April 2017

Multifocal inflammatory demyelination in a patient with rheumatoid arthritis and treatment complications.

J Neurol Sci 2016 Aug 16;367:305-7. Epub 2016 Jun 16.

Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Rheumatoid arthritis (RA) and multiple sclerosis (MS) are both autoimmune diseases that share similar pathogenesis, but the development of MS in RA patients without the treatment of anti-tumor necrosis factor-alpha is rarely reported, which might be attributed to the use of other medications with potential immunosuppressive effects in the treatment of RA. Since MS can be clinically silent and autopsy examination of the central nervous system in RA patients is rarely described, the association of MS with RA may be possibly under-recognized. We report an autopsy case revealing multifocal inflammatory demyelination in a RA patient who had a prolonged use of methotrexate and hydroxychloroquine resulting in hydroxychloroquine-induced myopathies and heart failure. The neuropathological features of this case are consistent with MS, although there are some altered inflammatory demyelinating features such as relatively smaller lesions and less infiltration of inflammatory cells, particularly T-cells. Our present case, in combination with literature review, suggests that the RA treatment especially with hydroxychloroquine and methotrexate is likely to alter the characteristics of inflammatory demyelination and disease course.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2016.06.034DOI Listing
August 2016

Medical Tourism for CCSVI Procedures in People with Multiple Sclerosis: An Observational Study.

Can J Neurol Sci 2016 May 4;43(3):360-7. Epub 2016 Feb 4.

9Departments of Medicine,Medical Genetics, and Pediatrics,University of Alberta,Edmonton,Alberta,Canada.

Background: Many Canadians with multiple sclerosis (MS) have recently travelled internationally to have procedures for a putative condition called chronic cerebrospinal venous insufficiency (CCSVI). Here, we describe where and when they went and describe the baseline characteristics of persons with MS who participated in this non-evidence-based medical tourism for CCSVI procedures.

Methods: We conducted a longitudinal observational study that used online questionnaires to collect patient-reported information about the safety, experiences, and outcomes following procedures for CCSVI. A convenience sample of all Albertans with MS was recruited between July 2011 and March 2013.

Results: In total, 868 individuals enrolled; 704 were included in this cross-sectional, baseline analysis. Of these, 128 (18.2%) participants retrospectively reported having procedures for CCSVI between April 2010 and September 2012. The proportion of participants reporting CCSVI procedures declined from 80 (62.5%) in 2010, to 40 (31.1%) in 2011, and 8 (6.3%) in 2012. In multivariable logistic regression analysis, CCSVI procedures were independently associated with longer disease duration, secondary progressive clinical course, and greater disability status.

Conclusions: Although all types of people with MS pursued procedures for CCSVI, a major driver of participation was greater disability. This highlights that those with the greatest disability are the most vulnerable to unproven experimental procedures. Participation in CCSVI procedures waned over time possibly reflecting unmet expectations of treated patients, decreased media attention, or that individuals who wanted procedures had them soon after the CCSVI hypothesis was widely publicized.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/cjn.2015.350DOI Listing
May 2016

Neuroinflammation Preceding and Accompanying Primary Central Nervous System Lymphoma: Case Study and Literature Review.

World Neurosurg 2016 Apr 24;88:692.e1-692.e8. Epub 2015 Dec 24.

Division of Neurology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada.

Background: Primary central nervous system lymphoma (PCNSL) is an aggressive lymphoma confined to the CNS. Although the pathogenesis of PCNSL in immunocompetent individuals remains unclear, there have been several case studies demonstrating the "sentinel" inflammatory lesions months before the manifestation of PCNSL. However, the pathologic relationship between the inflammatory lesions and subsequent PCNSL is still unknown.

Case Description: We present the case of a 44-year-old immunocompetent woman who developed several cerebral and cerebellar lesions on magnetic resonance imaging (MRI). A partial resection of the cerebellar contrast-enhancing lesion showed active inflammation with large destructive process but no evidence of B-cell lymphoma. Her disease was in a relapsing-remitting course for 28 months and progressed with new MRI findings of more contrast-enhancing lesions. She died at 33 months after the initial presentation. Postmortem examination revealed B-cell PCNSL with extensive involvement but sparing a few brain regions, including the previous resection site, with only an inflammatory destructive process.

Conclusions: PCNSL may be preceded and accompanied by an inflammatory process that is pathologically distinct from PCNSL. Our case study, in combination with a review of previously published similar cases, supports the hypothesis that the "sentinel" inflammatory lesions may be the first immune response against PCNSL.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.wneu.2015.11.099DOI Listing
April 2016

Rapid Multifocal Neurologic Decline in an Immunocompromised Patient.

JAMA Neurol 2016 Feb;73(2):226-31

Department of Radiology and Diagnostic Imaging, University of Alberta, Edmonton, Alberta, Canada.

A man in his early 70s with a diagnosis of chronic lymphocytic leukemia and being treated with prednisone, fludarabine, cyclophosphamide, and rituximab presented with progressive multifocal neurologic decline. The patient died 2 months after the onset of this decline despite extensive clinical and laboratory investigation and a trial of methylprednisolone therapy. The approach to the immunosuppressed patient with progressive neurologic decline, neuropathologic findings, and final diagnosis are discussed.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/jamaneurol.2015.2658DOI Listing
February 2016

Spin echo transverse relaxation and atrophy in multiple sclerosis deep gray matter: A two-year longitudinal study.

Mult Scler 2016 08 26;22(9):1133-43. Epub 2015 Oct 26.

Department of Biomedical Engineering, University of Alberta, Canada

Background: Deep gray matter (DGM) is affected in relapsing-remitting multiple sclerosis (RRMS) and may be studied using short-term longitudinal MRI.

Objective: To investigate two-year changes in spin-echo transverse relaxation rate (R2) and atrophy in DGM, and its relationship with disease severity in RRMS patients.

Methods: Twenty six RRMS patients and 26 matched controls were imaged at 4.7 T. Multiecho spin-echo R2 maps and atrophy measurements were obtained in DGM at baseline and two-year follow-up. Differences between MRI measures and correlations to disease severity were examined.

Results: After two years, mean R2 values in the globus pallidus and pulvinar increased by ~4% (p<0.001) in patients and <1.7% in controls. Two-year changes in R2 showed significant correlation to disease severity in the globus pallidus, pulvinar, substantia nigra, and thalamus. Multiple regression of the two-year R2 difference using these four DGM structures as variables, yielded high correlation with disease severity (r=0.83, p<0.001). Two-year changes in volume and R2 showed significant correlation only for the globus pallidus in multiple sclerosis (MS) (p<0.05).

Conclusions: Two-year difference R2 measurements in DGM correlate to disease severity in MS. R2 mapping and atrophy measurements over two years can be used to identify changes in DGM in MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458515614091DOI Listing
August 2016

Subcortical gray matter segmentation and voxel-based analysis using transverse relaxation and quantitative susceptibility mapping with application to multiple sclerosis.

J Magn Reson Imaging 2015 Dec 18;42(6):1601-10. Epub 2015 May 18.

Biomedical Engineering, University of Alberta, Edmonton, Canada.

Purpose: To investigate subcortical gray matter segmentation using transverse relaxation rate (R2 *) and quantitative susceptibility mapping (QSM) and apply it to voxel-based analysis in multiple sclerosis (MS).

Materials And Methods: Voxel-based variation in R2 * and QSM within deep gray matter was examined and compared to standard whole-structure analysis using 37 MS subjects and 37 matched controls. Deep gray matter nuclei (caudate, putamen, globus pallidus, and thalamus) were automatically segmented and morphed onto a custom atlas based on QSM and standard T1 -weighted images. Segmentation accuracy and scan-rescan reliability were tested.

Results: When considering only significant regions as returned by the multivariate voxel-based analysis, increased R2 * and QSM was found in MS subjects compared to controls in portions of all four nuclei studied (P < 0.002). For R2 *, regional analysis yielded at least 66-fold improved P-value significance in all nuclei over standard whole-structure analysis, while for QSM only thalamus benefited, with 5-fold improvement in significance. Improved segmentation over standard methods, particularly for globus pallidus (2.8 times higher Dice score), was achieved by incorporating high-contrast QSM into the atlas. Voxel-based reliability was highest for QSM (<1% variation).

Conclusion: Automatic segmentation of iron-rich deep gray matter can be improved by incorporating QSM. Voxel-based evaluation yielded increased R2 * and QSM in MS subjects in all four nuclei studied with R2 *, benefiting the most from localized analysis over whole-structure measures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmri.24951DOI Listing
December 2015

Decision-making under explicit risk is impaired in multiple sclerosis: relationships with ventricular width and disease disability.

BMC Neurol 2015 Apr 23;15:61. Epub 2015 Apr 23.

Department of Psychiatry, University of Alberta, 1E1.01 WCM Health Sciences Centre, Edmonton, Alberta, T6G 2R7, Canada.

Background: Decision-making is an essential function of everyday life. Decision-making under explicit risk requires developing advantageous decision strategies based on fixed outcomes (e.g., probabilities of winning or losing a bet). Decision-making and its neural substrates have been rarely studied in MS. We expected performance in decision-making under risk to be lowered in MS patients, and negatively correlated with disease-related disability, cognition, and ventricular width.

Methods: Three groups were included: 32 MS patients and 20 healthy controls were examined with conventional neuropsychological tests and the Game-of-Dice Task (GDT) assessing decision-making under explicit risk. Linear 2-D ventricular width was assessed on MS patients' clinical MRIs and compared to a third group, 20 non-MS neurological control patients.

Results: Compared to healthy controls, MS patients showed impaired GDT and neuropsychological performance, depending on the MS-subtype (relapsing-remitting (RR), n = 22; secondary progressive, n = 10) and disability severity among RR-MS patients. In MS patients, GDT performance correlated with processing speed, intercaudate ratio, and third ventricle ratio (p's < 0.05). Mediation analysis showed that the link between GDT performance and processing speed was fully explained by ventricular size.

Conclusion: Decision-making under explicit risk was reduced in MS patients, but only those with more pronounced disability. Independent of processing speed, decision-making under explicit risk correlates inversely with central atrophy in MS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s12883-015-0318-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4428249PMC
April 2015

Validation of quantitative susceptibility mapping with Perls' iron staining for subcortical gray matter.

Neuroimage 2015 Jan 8;105:486-92. Epub 2014 Nov 8.

Department of Biomedical Engineering, University of Alberta, Edmonton, Alberta, Canada, T6G 2V2. Electronic address:

Quantitative susceptibility mapping (QSM) measures bulk susceptibilities in the brain, which can arise from many sources. In iron-rich subcortical gray matter (GM), non-heme iron is a dominant susceptibility source. We evaluated the use of QSM for iron mapping in subcortical GM by direct comparison to tissue iron staining. We performed in situ or in vivo QSM at 4.7 T combined with Perls' ferric iron staining on the corresponding extracted subcortical GM regions. This histochemical process enabled examination of ferric iron in complete slices that could be related to susceptibility measurements. Correlation analyses were performed on an individual-by-individual basis and high linear correlations between susceptibility and Perls' iron stain were found for the three multiple sclerosis (MS) subjects studied (R(2) = 0.75, 0.62, 0.86). In addition, high linear correlations between susceptibility and transverse relaxation rate (R2*) were found (R(2) = 0.88, 0.88, 0.87) which matched in vivo healthy subjects (R(2) = 0.87). This work validates the accuracy of QSM for brain iron mapping and also confirms ferric iron as the dominant susceptibility source in subcortical GM, by demonstrating high linear correlation of QSM to Perls' ferric iron staining.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroimage.2014.11.010DOI Listing
January 2015

The regulation of reactive changes around multiple sclerosis lesions by phosphorylated signal transducer and activator of transcription.

J Neuropathol Exp Neurol 2013 Dec;72(12):1135-44

From the Departments of Laboratory Medicine and Pathology (JQL), and Medicine/Neurology (CP, GB, FG), University of Alberta, Edmonton, Alberta, Canada; and Departments of Clinical Neurosciences and Oncology, University of Calgary, Calgary, Alberta, Canada (VWY).

Activation of signal transducer and activator of transcription 3 (STAT3) by phosphorylation is thought to mediate anti-inflammatory responses to CNS injury. Several studies have reported an increase in phosphorylated STAT3 (pSTAT3) in peripheral T cells and monocytes from patients with multiple sclerosis (MS) during relapses, suggesting that pSTAT3 might represent an inflammatory marker. Here, we examined immunoreactivity for pSTAT3 in brain tissue samples from MS patients and controls. Phosphorylated STAT3 immunoreactivity was sparse within lesions, with no difference between active and inactive lesions. It was, however, significantly greater in white matter (WM) adjacent to active and inactive lesions; moreover, it was significantly greater in WM adjacent to active versus inactive lesions. Phosphorylated STAT3-positive cells were identified as astrocytes and macrophages/microglia. Phosphorylated STAT3 expression was also detected by Western blotting in WM of patients with MS. In comparison, pSTAT3 immunoreactivity was either rare or found focally in brain tissue samples from patients with other neurologic diseases. Our findings show that pSTAT3 does not correlate with inflammatory activity in MS lesions, but that it may play an important role in regulating reactive changes proximal to MS lesions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/NEN.0000000000000011DOI Listing
December 2013

Longitudinal MR imaging of iron in multiple sclerosis: an imaging marker of disease.

Radiology 2014 Jan 28;270(1):186-96. Epub 2013 Oct 28.

From the Department of Biomedical Engineering (A.J.W., R.M.L., P.S., A.H.W.), Division of Neurology (G.B.), and Department of Radiology and Diagnostic Imaging (D.J.E.), Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada T6G 2V2.

Purpose: To investigate the relationship between magnetic resonance (MR) imaging markers of iron content and disease severity in patients with multiple sclerosis (MS) over a 2-year period.

Materials And Methods: This prospective study was approved by the local ethics committee, and written informed consent was obtained from all participants. Seventeen patients with MS and 17 control subjects were examined twice, 2 years apart, by using phase imaging and transverse relaxation (R2*) mapping at 4.7 T. Quantitative differences in iron content in deep gray matter between patients and control subjects were evaluated with repeated-measures multivariate analysis of variance separately for R2* mapping and phase imaging. Multiple regression analysis was used to evaluate correlations of MR imaging measures, both 2-year-difference and single-time measurements, to baseline disease severity.

Results: R2* mapping using 2-year-difference measurements had the highest correlation to disease severity (r = 0.905, P < .001) compared with R2* mapping using single-time measurements (r = 0.560, P = .019) and phase imaging by using either single-time (r = 0.539, P = .026) or 2-year-difference (r = 0.644, P = .005) measurements. Significant increases in R2* occur during 2 years in the substantia nigra (P < .001) and globus pallidus (P = .035), which are both predictors of disease in regression analysis, in patients compared with control subjects. There were group differences in the substantia nigra, globus pallidus, pulvinar thalamus, thalamus, and caudate nucleus, compared with control subjects with R2* mapping (P < .05), and group differences in the caudate nucleus and pulvinar thalamus, compared with control subjects with phase imaging (P < .05).

Conclusion: There are significant changes in deep gray matter iron content in MS during 2 years measured with MR imaging, changes that are strongly related to physical disability. Longitudinal measurements may produce a higher correlation to disease severity compared with single-time measurements because baseline iron content of deep gray matter is variable among subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.13130474DOI Listing
January 2014

MS, MRI, and the 2010 McDonald criteria: a Canadian expert commentary.

Neurology 2012 Dec;79(23 Suppl 2):S1-15

Division of Neurology, St. Michael's Hospital, University of Toronto, Toronto, Canada.

Since the first development of diagnostic criteria for multiple sclerosis (MS), there have been regular revisions of disease definitions and diagnostic thresholds aimed at improving specificity while maintaining sensitivity. The central requirements for diagnosis of MS are dissemination in space (DIS) and dissemination in time (DIT) of lesions in the CNS, with the proviso that there should be no alternate diagnosis that better explains the clinical presentation. The most definitive diagnosis is the purely clinical one, with 2 separate attacks of symptoms (fulfilling DIT criteria) involving at least 2 different areas of the CNS (fulfilling DIS criteria). In patients who have had a first but not a second clinical attack, the McDonald criteria provide guidance on how paraclinical evidence can be used to support a diagnosis of MS. Recently, the McDonald criteria were revised and new definitions for DIS and DIT proposed. In response to that revision, a panel of Canadian MS neurologists and one neuroradiologist created this commentary regarding the clinical implications and applications of the 2010 McDonald criteria.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0b013e318277d144DOI Listing
December 2012

Multiple sclerosis: validation of MR imaging for quantification and detection of iron.

Radiology 2013 May 7;267(2):531-42. Epub 2013 Jan 7.

Department of Biomedical Engineering, University of Alberta, 1098 RTF, Edmonton, AB, Canada T6G 2V2.

Purpose: To investigate the relationship between iron staining and magnetic resonance (MR) imaging measurements in postmortem subjects with multiple sclerosis (MS).

Materials And Methods: Institutional ethical approval was obtained, and informed consent was obtained from the subjects and/or their families. Four MR imaging methods based on transverse relaxation (T2 weighting, R2 mapping, and R2* mapping) and phase imaging were performed by using a 4.7-T system in three in situ postmortem patients with MS less than 28 hours after death and in one in vivo patient 1 year before death. Iron staining with the Perls iron reaction was performed after brain extraction. Region-of-interest measurements from six subcortical gray matter structures were obtained from MR imaging and then correlated with corresponding locations on photographs of iron-stained pathologic slices by using a separate linear least-squares regression in each subject. Iron status of white matter lesions, as determined by staining, was compared with appearance on MR images.

Results: R2* mapping had the highest intrasubject correlations with iron in subcortical gray matter (R(2) = 0.857, 0.628, and 0.685; all P < .001), while R2 mapping (R(2) = 0.807, 0.615, 0.628, and 0.489; P < .001 and P = .001, .034, and .001, respectively), phase imaging (R(2) = 0.672, 0.441, 0.596, 0.548; all P ≤ .001), and T2-weighted imaging (R(2) = 0.463, 0.582, 0.650, and 0.551; all P < .001) had lower but still strong correlations. Within lesions, hypointense areas on phase images did not always represent iron. A hyperintense rim surrounding lesions on R2* maps was only present with iron staining, yet not all iron-staining lesions had R2* rim hyperintensity.

Conclusion: All four MR imaging methods had significant linear correlations with iron and could potentially be used to determine iron status of subcortical gray matter structures in MS, with R2* mapping being preferred. A reliable method of determining iron status within MS lesions was not established.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1148/radiol.12120863DOI Listing
May 2013

Cyclophosphamide-Induced Cardiomyopathy: A Case Report, Review, and Recommendations for Management.

J Investig Med High Impact Case Rep 2013 Jan-Mar;1(1):2324709613480346. Epub 2013 Jan 1.

University of Alberta, Edmonton, Alberta, Canada.

Cyclophosphamide is increasingly used to treat various types of cancers and autoimmune conditions. Higher doses of this drug may produce significant cardiac toxicity, including fatal hemorrhagic myocarditis. In this review, we present a case of cyclophosphamide-induced cardiomyopathy requiring mechanical circulatory support. We also describe the pathophysiology, clinical manifestations, and risk factors for this important clinical entity and propose early detection and management strategies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/2324709613480346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4528786PMC
October 2015

Susceptibility phase imaging with improved image contrast using moving window phase gradient fitting and minimal filtering.

J Magn Reson Imaging 2012 Dec 3;36(6):1460-9. Epub 2012 Aug 3.

Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

Purpose: To enhance image contrast in susceptibility phase imaging using a new method of background phase removal.

Materials And Methods: A background phase removal method is proposed that uses the spatial gradient of the raw phase image to perform a moving window third-order local polynomial estimation and correction of the raw phase image followed by minimal high pass filtering. The method is demonstrated in simulation, 10 healthy volunteers, and 5 multiple sclerosis patients in comparison to a standard phase filtering approach.

Results: Compared to standard phase filtering, the new method increased phase contrast with local background tissue in subcortical gray matter, cortical gray matter, and multiple sclerosis lesions by 67% ± 33%, 13% ± 7%, and 48% ± 19%, respectively (95% confidence interval). In addition, the new method removed more phase wraps in areas of rapidly changing background phase.

Conclusion: Local phase gradient fitting combined with minimal high pass filtering provides better tissue depiction and more accurate phase quantification than standard filtering.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jmri.23768DOI Listing
December 2012

Quantitative high-field imaging of sub-cortical gray matter in multiple sclerosis.

Mult Scler 2012 Apr 27;18(4):433-41. Epub 2011 Oct 27.

Department of Biomedical Engineering, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.

Background: In addition to neuronal injury, inflammatory, and demyelinating processes, evidence suggests multiple sclerosis (MS) is also associated with increased iron deposition in the basal ganglia. Magnetic resonance imaging (MRI), particularly at very high field strengths, is sensitive to iron accumulation and may enable visualization and quantification of iron associated with MS.

Objectives: To investigate the sub-cortical gray matter in patients with early-stage relapsing-remitting MS using multiple, and novel, quantitative MRI measures at very high field.

Methods: In total, 22 patients with relapsing-remitting MS and 22 control subjects were imaged at 4.7 Tesla. Transverse relaxation rates (R₂ and R₂*) and susceptibility phase were quantified in four basal ganglia nuclei, the thalamus, and the red nuclei. Parameters in patients with MS were compared with those in healthy subjects and correlated with clinical scores.

Results: Significant abnormalities were observed in most structures, most notably in the pulvinar sub-nucleus. Significant correlations with disability were observed in the pulvinar; marginally significant correlations were also observed in the thalamus and red nucleus. No significant correlations were observed with duration since index relapse.

Conclusions: Widespread abnormalities are present in the deep gray matter nuclei of patients recently diagnosed with MS; these abnormalities can be detected via multi-modal high-field MRI. Imaging metrics, particularly R₂*, relate to disease severity in the pulvinar and other gray matter regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458511428464DOI Listing
April 2012

Efficacy and safety of subcutaneous interferon β-1a in relapsing-remitting multiple sclerosis: further outcomes from the IMPROVE study.

J Neurol Sci 2012 Jan 31;312(1-2):97-101. Epub 2011 Aug 31.

Department of Neurological and Behavioral Sciences, University of Siena, Siena, Italy.

Background: The IMPROVE study demonstrated that the fetal bovine serum (FBS)- and human serum albumin (HSA)-free formulation of subcutaneous (sc) interferon (IFN) beta-1a had beneficial effects on the numbers of combined unique active magnetic resonance imaging (MRI) lesions in relapsing-remitting multiple sclerosis (RRMS). Here we report additional MRI endpoints (including post hoc analyses), and clinical efficacy, safety, and immunogenicity outcomes.

Methods: Patients with active RRMS were randomized (2:1) to IFN beta-1a, 44 mcg sc three times weekly (tiw) (n=120), or placebo (n=60), for 16 weeks (double-blind phase). All patients then received IFN beta-1a, 44 mcg sc tiw, for 24 weeks (rater-blind phase). Patients underwent MRI brain scans every 4 weeks.

Results: Compared with placebo, there was a 68% reduction in the mean cumulative number of new gadolinium-enhancing lesions with IFN beta-1a as early as week 4 (p<0.001), and a 53% reduction in the mean cumulative number of new T2 lesions as early as week 8 (p=0.025; post hoc analyses). During the 16-week double-blind phase, the relapse rate was 0.14 (95% confidence interval [CI] 0.09-0.23) with IFN beta-1a and 0.33 (95% CI 0.22-0.52) with placebo (p=0.010). Safety outcomes were consistent with those expected with IFN-beta treatment.

Conclusions: The FBS/HSA-free formulation of sc IFN beta-1a has a beneficial impact on MRI and efficacy outcomes as early as 4 weeks after treatment initiation in patients with RRMS and has a safety profile consistent with previous trials of sc IFN beta-1a.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jns.2011.08.013DOI Listing
January 2012

Rapid benefits of a new formulation of subcutaneous interferon beta-1a in relapsing-remitting multiple sclerosis.

Mult Scler 2010 Jul 3;16(7):888-92. Epub 2010 Mar 3.

Department of Neurological and Behavioral Sciences, University of Siena, Siena, Italy.

This study evaluated the efficacy of a new formulation of subcutaneous (sc) interferon (IFN)-beta1a in relapsing-remitting multiple sclerosis (RRMS). Patients (n = 180) were randomized (2 : 1) to IFN-beta1a or placebo for 16 weeks; all patients then received IFN-beta1a for 24 weeks. Monthly brain MRI was performed. At week 16, the mean number of combined unique active (CUA) lesions was lower with IFN-beta1a than with placebo (p < 0.001; 69% fewer lesions). The mean cumulative number of CUA lesions was already lower with IFN-beta1a by week 4 (post hoc analysis; p = 0.015). The new formulation of sc IFN-beta1a has rapid beneficial effects on MRI outcomes in RRMS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458510362442DOI Listing
July 2010

Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood--brain barrier disruption in multiple sclerosis.

Mult Scler 2009 Oct 23;15(10):1206-14. Epub 2009 Sep 23.

Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1352458509345903DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3085182PMC
October 2009

Effect of anti-CD25 antibody daclizumab in the inhibition of inflammation and stabilization of disease progression in multiple sclerosis.

Arch Neurol 2009 Apr;66(4):483-9

Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bldg 10, Room 5C103, 10 Center Dr, MSC 1400, Bethesda, MD 20892, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1001/archneurol.2009.50DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2742781PMC
April 2009
-->