MR Susceptibility Separation for Quantifying Lesion Paramagnetic and Diamagnetic Evolution in Relapsing-Remitting Multiple Sclerosis.

BACKGROUND: Multiple sclerosis (MS) lesion evolution may involve changes in diamagnetic myelin and paramagnetic iron. Conventional quantitative susceptibility mapping (QSM) can provide net susceptibility distribution, but not the discrete paramagnetic and diamagnetic components. PURPOSE: To apply susceptibility separation (χ separation) to follow lesion evolution in MS with comparison to R2*/R2 '/QSM. STUDY TYPE: Longitudinal, prospective. SUBJECTS: Twenty relapsing-remitting MS subjects (mean age: 42.5 ± 9.4 years, 13 females; mean years of symptoms: 4.3 ± 1.4 years). FIELD STRENGTH/SEQUENCE: Three-dimensional multiple echo gradient echo (QSM and R2* mapping), two-dimensional dual echo fast spin echo (R2 mapping), T2-weighted fluid attenuated inversion recovery, and T1-weighted magnetization prepared gradient echo sequences at 3 T. ASSESSMENT: Data were analyzed from two scans separated by a mean interval of 14.4 ± 2.0 months. White matter lesions on fluid-attenuated inversion recovery were defined by an automatic pipeline, then manually refined (by ZZ/AHW, 3/25 years' experience in MRI), and verified by a radiologist (MN, 25 years' experience in MS). Susceptibility separation yielded the paramagnetic and diamagnetic susceptibility content of each voxel. Lesions were classified into four groups based on the variation of QSM/R2* or separated into positive/negative components from χ separation. STATISTICAL TESTS: Two-sample paired t tests for assessment of longitudinal differences. Spearman correlation coefficients to assess associations between χ separation and R2*/R2 '/QSM. Significant level: P < 0.005. RESULTS: A total of 183 lesions were quantified. Categorizing lesions into groups based on χ separation demonstrated significant annual changes in QSM//R2*/R2 '. When lesions were grouped based on changes in QSM and R2*, both changing in unison yielded a significant dominant paramagnetic variation and both opposing yielded a dominant diamagnetic variation. Significant Spearman correlation coefficients were found between susceptibility-sensitive MRI indices and χ separation. DATA CONCLUSION: Susceptibility separation changes in MS lesions may distinguish and quantify paramagnetic and diamagnetic evolution, potentially providing additional insight compared to R2* and QSM alone. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Canadian Consensus Guidelines for the Diagnosis and Treatment of Autoimmune Encephalitis in Adults.

Autoimmune encephalitis is increasingly recognized as a neurologic cause of acute mental status changes with similar prevalence to infectious encephalitis. Despite rising awareness, approaches to diagnosis remain inconsistent and evidence for optimal treatment is limited. The following Canadian guidelines represent a consensus and evidence (where available) based approach to both the diagnosis and treatment of adult patients with autoimmune encephalitis. The guidelines were developed using a modified RAND process and included input from specialists in autoimmune neurology, neuropsychiatry and infectious diseases. These guidelines are targeted at front line clinicians and were created to provide a pragmatic and practical approach to managing such patients in the acute setting.

High-resolution diffusion tensor imaging and T2 mapping detect regional changes within the hippocampus in multiple sclerosis.

Hippocampus demyelinating lesions in multiple sclerosis (MS) have been frequently observed in ex vivo histopathological studies; however, they are difficult to image and quantify in vivo. Diffusion tensor imaging (DTI) and T2 mapping could potentially detect such regional in vivo changes if acquired with sufficient spatial resolution. The goal here was to evaluate whether there are focal hippocampal abnormalities in 43 MS patients (35 relapsing-remitting, eight secondary progressive) with and without cognitive impairment (CI) versus 43 controls using high-resolution 1 mm isotropic DTI, as well as complementary methods of T2-weighted and T2 mapping at 3 T. Abnormal hippocampus regions were identified voxel-by-voxel by using mean diffusivity (MD)/T2 thresholds and avoiding voxels attributed to cerebrospinal fluid. When compared with controls, averaged left/right whole hippocampus MD was higher in both MS groups, while lower fractional anisotropy (FA) and volume, and higher T2 relaxometry and T2-weighted signal values, were only significant in CI MS. The hippocampal MD and T2 images/maps were not uniformly affected and focal regions of elevated MD/T2 were evident in MS patients. Both CI and not CI MS groups showed greater proportional areas of the hippocampus with elevated MD, whereas only the CI group showed a greater proportional area of elevated T2 relaxation times or T2-weighted signal. Higher T2 relaxometry and T2-weighted signal values of elevated regions correlated with greater disability and whole hippocampus FA negatively correlated with physical fatigue. High-resolution hippocampus DTI and T2 mapping with less partial volume effects showed whole hippocampus abnormalities with regional elevations of MD/T2 in MS, which could be interpreted as potentially from demyelination, neuron loss, and/or inflammation, and which overall were more extensive in the hippocampus of patients with larger total brain lesion volumes and CI.

Inline dual-echo T2 quantification in brain using a fast mapping reconstruction technique.

T2 mapping from 2D proton density and T2-weighted images (PD-T2) using Bloch equation simulations can be time consuming and introduces a latency between image acquisition and T2 map production. A fast T2 mapping reconstruction method is investigated and compared with a previous modeling approach to reduce computation time and allow inline T2 maps on the MRI console. Brain PD-T2 images from five multiple sclerosis patients were used to compare T2 map reconstruction times between the new subtraction method and the Euclidean norm minimization technique. Bloch equation simulations were used to create the lookup table for decay curve matching in both cases. Agreement of the two techniques used Bland-Altman analysis for investigating individual subsets of data and all image points in the five volumes (meta-analysis). The subtraction method resulted in an average reduction of computation time for single slices from 134 s (minimization method) to 0.44 s. Comparing T2 values between the subtraction and minimization methods resulted in a confidence interval ranging from -0.06 to 0.06 ms (95% of values were within ± 0.06 ms between the techniques). Using identical reconstruction code based on the subtraction method, inline T2 maps were produced from PD-T2 images directly on the scanner console. The excellent agreement between the two methods permits the subtraction technique to be interchanged with the previous method, reducing computation time and allowing inline T2 map reconstruction based on Bloch simulations directly on the scanner.

Elevated ATP via enhanced miRNA-30b, 30c, and 30e downregulates the expression of CD73 in CD8+ T cells of HIV-infected individuals.

CD8+ T cells play a crucial role against chronic viral infections, however, their effector functions are influenced by the expression of co-stimulatory/inhibitory receptors. For example, CD73 works with CD39 to convert highly inflammatory ATP to adenosine. However, its expression on T cells in the context of viral infections has not been well defined. Here, we analyzed the expression of CD73 on human T cells in a cohort of 102 HIV-infected individuals including those on antiretroviral therapy (ART), ART-naïve, and long-term non-progressors who were not on ART. We found that the frequency of CD73+ T cells was markedly lower among T cell subsets (e.g. naïve, effector or memory) in the peripheral blood of all HIV-infected individuals. Notably, CD73 was decreased at the cell surface, intracellular and gene levels. Functionally, CD8+CD73+ T cells exhibited decreased cytokine expression (TNF-α, IFN-γ and IL-2) upon global or antigen-specific stimulation and impaired expression of cytolytic molecules at the gene and protein levels. In contrast, CD8+CD73+ T cells expressed elevated levels of homing receptors such as CCR7, α4ß7 integrin, which suggests a migratory advantage for these cells as observed in vitro. We also observed significant migration of CD73+CD8+ T cells into the cerebrospinal fluids of multiple sclerosis (MS) patients at the time of disease relapse. Moreover, we found that elevated levels of ATP in the plasma of HIV-infected individuals upregulates the expression of miRNA30b-e in T cells in vitro. In turn, inhibition of miRNAs (30b, 30c and 30e) resulted in significant upregulation of CD73 mRNA in CD8+ T cells. Therefore, we provide a novel mechanism for the downregulation of CD73 via ATP-induced upregulation of miRNA30b, 30c and 30e in HIV infection. Finally, these observations imply that ATP-mediated downregulation of CD73 mainly occurs via its receptor, P2X1/P2RX1. Our results may in part explain why HIV-infected individuals have reduced risk of developing MS considering the role of CD73 for efficient T cell entry into the central nervous system.

Diffusion imaging of fornix and interconnected limbic deep grey matter is linked to cognitive impairment in multiple sclerosis.

Diffusion tensor imaging (DTI) and volumetric magnetic resonance imaging (MRI) have shown white matter (WM) and deep grey matter (GM) abnormalities in the limbic system of multiple sclerosis (MS) participants. Structures like the fornix have been associated with cognitive impairment (CI) in MS, but the diffusion metrics are often biased by partial volume effects from cerebrospinal fluid (CSF) due to its small bundle size and intraventricular location. These errors in DTI parameter estimation worsen with atrophy in MS. The goal here was to evaluate DTI parameters and volumes of the fornix, as well as associated deep GM structures like the thalamus and hippocampus, with high-resolution fluid-attenuated inversion recovery (FLAIR)-DTI at 3T in 43 MS patients, with and without CI, versus 43 controls. The fornix, thalamus and hippocampus displayed atrophy and/or abnormal diffusion metrics, with the fornix showing the most extensive changes within the structures studied here, mainly in CI MS. The affected fornix volumes and diffusion metrics were associated with thalamic atrophy and atypical diffusion metrics in interconnected limbic GM, larger total lesion volume and global brain atrophy. Lower fractional anisotropy (FA) and higher mean and radial diffusivity in the fornix, lower hippocampus FA and lower thalamus volume were strongly correlated with CI in MS. Hippocampus FA and thalamus atrophy were negatively correlated with fatigue and longer time since MS symptoms onset, respectively. FLAIR-DTI and volumetric analyses provided methodologically superior evidence for microstructural abnormalities and extensive atrophy of the fornix and interconnected deep GM in MS that were associated with cognitive deficits.

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

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 CD8+T cell ratio increased significantly in lymphopenic patients over time. CD4-CD8-T 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 CD56-CD16+ and CD56-CD16- 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.

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

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.

Sarcoidosis: a prospective observational cohort from Northern 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. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (4): e2020014).

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

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 ±â€¯1.2; follow-up = 2.8 ±â€¯1.3). Significant time effects were found for R2* in the caudate (Q = 0.000008; η2 = 0.36), putamen (Q = 0.0000007; η2 = 0.43), and globus pallidus (Q = 0.0000007; η2 = 0.43), while significant longitudinal effects were only found for QS in the putamen (Q = 0.002; η2 = 0.22). Significant bulk interaction was only found for thalamus volume (Q = 0.02; η2 = 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; η2 = 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.

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

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.

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

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.

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

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-1ß compared with DMF-N. In plasma, TNFß 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.

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

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 T2-weighted MRI, cumulative number of new lesions enhanced on T1-weighted MRI ["enhancing lesions"], and cumulative combined number of unique lesions [new enhancing lesions on T1-weighted MRI plus new and newly enlarged lesions on T2-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 .).

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

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.

Recovery of accurate T2 from historical 1.5 tesla proton density and T2-weighted images: Application to 7-year T2 changes in multiple sclerosis brain.

OBJECTIVE: To determine accurate quantitative transverse relaxation times (T2) using retrospective clinical images and apply it to examine 7-year changes in multiple sclerosis (MS) brain. METHODS: A method for T2 mapping from retrospective proton density (PD) and T2-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 T2 analysis of historical PD and T2-weighted images without a concurrent flip angle map. After method validation in healthy volunteers, retrospective longitudinal T2 analysis was performed in 14 MS subjects over seven years. Changes in patient T2 values were compared with brain atrophy, T2 lesion load and disability score in MS. RESULTS: Similar flip angle maps across volunteers enabled retrospective T2 from PD and T2-weighted images even when different refocusing angles were used. Over seven years, significant T2 changes of 2-4% were observed when using T2 modelling and the 7-year effect size for globus pallidus T2 was 0.56, which was more significant than brain atrophy. No significant T2 results were found when using exponential fit, which cannot account for refocusing angle variation. Moreover, change is T2 in globus pallidus and internal capsule correlated with MS disability score over time when using T2 modelling. CONCLUSIONS: Accurate quantitative T2 can be extracted from standard clinical 1.5T MRI exams that include PD and T2-weighted imaging even when no flip angle map is available. This method was applied retrospectively to examine seven year changes in MS.

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

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.

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

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.