Publications by authors named "Luanne M Metz"

81 Publications

Cannabinoids and bladder symptoms in multiple sclerosis.

Mult Scler Relat Disord 2021 Jun 23;54:103105. Epub 2021 Jun 23.

Dept of Clinical Neurosciences, Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary.

Background: Research on the health benefits of cannabis has been limited because use remains restricted or illegal in most countries. Medical cannabis has been legal in Canada since 2001 and recreational use became legal in October 2018. While there are data that support a biological mechanism by which cannabinoids can impact various other symptoms of MS, the evidence of effectiveness of cannabis as a treatment for bladder symptoms remains unsettled. We conducted an exploratory study to describe the current trends of cannabis product consumption among people with MS (PwMS) and their association with perceived benefits on MS symptoms.

Methods: A cross-sectional survey study of PwMS, recruited from the MS Clinic in Calgary, Alberta, Canada was undertaken. Logistic regression analyses were performed to assess the associations between cannabis consumption and improvement in bladder function symptoms.

Results: There were 775 respondents out of 2899 PwMS contacted by email. Among respondents, 734 reported cannabis use in the past 3 months. There were 275 (37.5%) respondents who reported cannabis use in the prior 3 months, and 73.8% of these reported at least weekly use of cannabis. Among all users, 78.1% reported a primary medical or therapeutic indication for consumption. The most common modes of cannabis consumption were oral-edible (69.0%) and smoked (57.1%), while 59.3% used more than one mode of consumption and 2.6% used five different modes. The most common reasons for cannabis use were for sleep (58.3%), pain (51.5%), relaxation (44.4%), muscle spasms (40.2%), anxiety (33.8%) and depression (22.9%). Among the 19 participants who reported bladder symptoms as a main reason for cannabis use, 89.5% reported "better" bladder symptoms when using cannabis. Cannabis consumption in the past 3 months was associated with a two-fold increased odds of reporting improvement in urinary frequency, urinary urgency, bladder leakage and wetness, pad use and bladder emptying.

Conclusions: Cannabis is commonly used in this survey study of personal cannabis use among PwMS. Patterns of use, dosing, frequency and mode of delivery are diverse among survey respondents. This pilot study provides some initial glimpses into real world therapeutic use of cannabinoids among PwMS for bladder symptoms.
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http://dx.doi.org/10.1016/j.msard.2021.103105DOI Listing
June 2021

Nonlesional diffusely abnormal appearing white matter in clinically isolated syndrome: Prevalence, association with clinical and MRI features, and risk for conversion to multiple sclerosis.

J Neuroimaging 2021 Sep 15;31(5):981-994. Epub 2021 Jun 15.

Department of Radiology, University of British Columbia, Vancouver, British Columbia, Canada.

Background And Purpose: While diffusely abnormal white matter (DAWM) is a nonlesional MRI abnormality identified in ∼25% of patients with multiple sclerosis (MS), it has yet to be investigated in patients at an earlier disease stage, namely clinically isolated syndrome (CIS). The goals of this study were to (1) determine the prevalence of DAWM in patients with a CIS suggestive of MS, (2) evaluate the association between DAWM and demographic, clinical, and MRI features, and (3) evaluate the prognostic significance of DAWM on conversion from CIS to MS.

Methods: One hundred and forty-two CIS participants were categorized into DAWM and non-DAWM groups at baseline and followed for up to 24 months or until MS diagnosis. The primary outcome was conversion to MS (2005 McDonald criteria) within 6 months.

Results: DAWM was present in 27.5% of participants, and was positively associated with brainstem symptom onset, receiving corticosteroids, dissemination in space, and T lesion volume. DAWM was associated with an increased risk of conversion to MS over 6 months after adjustment for age and disability (hazard ratio [HR] = 2.24, p = 0.004). This association remained at a trend-level after adjustment for high-risk imaging features (HR = 1.68, p = 0.10).

Conclusions: DAWM is present in a similar proportion of patients with CIS and clinically definite MS, and it is associated with increased risk of conversion to MS over 6 months.
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http://dx.doi.org/10.1111/jon.12900DOI Listing
September 2021

Repurposing Domperidone in Secondary Progressive Multiple Sclerosis: A Simon 2-Stage Phase 2 Futility Trial.

Neurology 2021 05 23;96(18):e2313-e2322. Epub 2021 Mar 23.

From the Departments of Clinical Neurosciences (M.W.K., K.S., S.K., J.K., G.C., V.W.Y., L.M.M.) and Community Health Sciences (M.W.K.), University of Calgary, Alberta, Canada; and Department of Biostatistics (G.R.C.), University of Alabama at Birmingham.

Objective: To assess whether treatment with the generic drug domperidone can reduce the progression of disability in secondary progressive multiple sclerosis (SPMS), we conducted a phase 2 futility trial following the Simon 2-stage design.

Methods: We enrolled patients in an open-label, Simon 2-stage, single-center, phase 2, single-arm futility trial at the Calgary Multiple Sclerosis Clinic if they met the following criteria: age of 18 to 60 years, SPMS, screening Expanded Disability Status Scale score of 4.0 to 6.5, and screening timed 25-ft walk (T25FW) of ≥9 seconds. Patients received domperidone 10 mg 4 times daily for 1 year. The primary outcome was worsening of disability, defined as worsening of the T25FW performance by ≥20% at 12 months compared to baseline. This trial is registered with ClinicalTrials.gov (NCT02308137).

Results: Between February 13, 2015, and January 3, 2020, 110 patients were screened, 81 received treatment, and 64 completed follow-up, of whom 62 were analyzed. The study did not meet its primary endpoint: 22 of 62 (35%) patients experienced significant worsening of disability, which is close to the expected proportion of 40% and above the predefined futility threshold. Patients with higher prolactin levels during the study had a significantly lower risk of disability progression, which may warrant further investigation. Domperidone treatment was reasonably well tolerated, but adverse events occurred in 84% and serious adverse events in 15% of patients.

Conclusions: Domperidone treatment could not reject futility in reducing disability progression in SPMS. The Simon 2-stage trial model may be a useful model for phase 2 studies in progressive MS.

Trial Registration Information: ClinicalTrials.gov Identifier: NCT02308137.

Classification Of Evidence: This study provides Class III evidence that in individuals with SPMS participating in a futility trial, domperidone treatment could not reject futility in reducing disability progression at 12 months.
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http://dx.doi.org/10.1212/WNL.0000000000011863DOI Listing
May 2021

Multiple Sclerosis Clinic Utilization is Associated with Fewer Emergency Department Visits.

Can J Neurol Sci 2021 May 24:1-5. Epub 2021 May 24.

Department of Clinical Neurosciences, University of Calgary, Cumming School of Medicine, Calgary, Alberta, Canada.

Objective: Alberta is a Canadian province with a high prevalence of multiple sclerosis (MS). In this ecological study, we examined group differences in health care utilization among persons with MS (pwMS) living within different regions of the province.

Methods: pwMS were identified from provincial administrative databases spanning 2002-2011. Utilization of health care services was determined for a 2-year period (April 2010-March 2012). Residential postal codes placed patients into their provincial health care zones. As data were provided to the investigators in an aggregated form, tests of statistical significance and confounding were not performed.

Results: In total, 11,721 pwMS were identified. During the 2-year observation period, 96.2% of pwMS accessed a family physician and 57.1% accessed a neurologist. Nearly all (99.0%) pwMS who received neurologist care in Calgary visited an MS clinic, in contrast to Edmonton where a larger proportion (34.8%) received solely community neurologist care. More pwMS living in Edmonton accessed the ED (41.1%) compared to Calgary (35.7%), and the rate of visits per pwMS was higher in Edmonton (1.07/pwMS) than in Calgary (0.81/pwMS). The frequency of inpatient admissions was similar.

Conclusions: Over 2 years, most pwMS accessed primary care and over half saw a neurologist. Despite a similar frequency of inpatient admissions, the frequency of ED visits by pwMS was higher in Edmonton compared to Calgary, where more patients received MS clinic care. Although this exploratory study is subject to several limitations, our findings suggest that specialized MS clinics may reduce costly ED visits.
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http://dx.doi.org/10.1017/cjn.2021.118DOI Listing
May 2021

Advanced Analysis of Diffusion Tensor Imaging Along With Machine Learning Provides New Sensitive Measures of Tissue Pathology and Intra-Lesion Activity in Multiple Sclerosis.

Front Neurosci 2021 7;15:634063. Epub 2021 May 7.

Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada.

Tissue pathology in multiple sclerosis (MS) is highly complex, requiring multi-dimensional analysis. In this study, our goal was to test the feasibility of obtaining high angular resolution diffusion imaging (HARDI) metrics through single-shell modeling of diffusion tensor imaging (DTI) data, and investigate how advanced measures from single-shell HARDI and DTI tractography perform relative to classical DTI metrics in assessing MS pathology. We examined 52 relapsing-remitting MS patients who had 3T anatomical brain MRI and DTI. Single-shell HARDI modeling yielded 5 sub-voxel-based metrics, totalling 11 diffusion measures including 4 DTI and 2 tractography metrics. Based on machine learning of 3-dimensional regions of interest, we evaluated the importance of the measures through several tissue classification tasks. These included two within-subject comparisons: lesion versus normal appearing white matter (NAWM); and lesion core versus shell. Further, by stratifying patients as having high (above 75% ) and low (below 25% ) number of MS lesions, we also performed 2 classifications between subjects for lesions and NAWM respectively. Results showed that in lesion-NAWM analysis, HARDI orientation distribution function (ODF) energy, DTI fractional anisotropy (FA), and HARDI orientation dispersion index were the top three metrics, which together achieved 65.2% accuracy and 0.71 area under the receiver operating characteristic curve (AUROC). In core-shell analysis, DTI mean diffusivity (MD), radial diffusivity, and FA were the top three metrics, and MD dominated the classification, which achieved 59.3% accuracy and 0.59 AUROC alone. Between patients, FA was the leading feature in lesion comparisons, while ODF energy was the best in NAWM separation. Collectively, single-shell modeling of common diffusion data can provide robust orientation measures of lesion and NAWM pathology, and DTI metrics are most sensitive to intra-lesion abnormality. Combined analysis of both advanced and classical diffusion measures may be critical for improved understanding of MS pathology.
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http://dx.doi.org/10.3389/fnins.2021.634063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8138061PMC
May 2021

Multimodal peripheral fluid biomarker analysis in clinically isolated syndrome and early multiple sclerosis.

Mult Scler Relat Disord 2021 May 3;50:102809. Epub 2021 Feb 3.

Departments of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada; Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.

Background: Increasing evidence suggests that various inflammatory, immunological and metabolic pathways are altered in the clinically isolated syndrome (CIS) of multiple sclerosis (MS). Moreover, recent diagnostic criteria have made possible the very early diagnosis of MS. We evaluated multiple fluid biomarkers in people with early MS and CIS.

Methods: We measured blood levels of cytokines, matrix metalloproteinases (MMPs), serum metabolomics and immune cell immunophenotyping in participants in the Trial of Minocycline in a Clinically Isolated Syndrome of Multiple Sclerosis.

Results: When compared with healthy controls, people with early MS/CIS had higher levels of eotaxin, MCP-3, IL-1 receptor antagonist, IL-1β, IL-9 and IP-10, as well as MMPs 1, 8 and 9. In metabolomics analysis, the alanine, aspartate and glutamate metabolism and the synthesis and degradation of ketone bodies pathways were altered compared to healthy controls. There were no differences in lymphocyte subpopulation numbers. Out of all these biomarkers, only MMP-1 was able to differentiate between early MS and CIS, and was found to correlate with lesion volume and gadolinium enhancing lesions on MRI.

Conclusion: The immunological and metabolic profile of CIS and early MS is remarkably similar, supporting that these are a continuum of a common underlying pathophysiological process.
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http://dx.doi.org/10.1016/j.msard.2021.102809DOI Listing
May 2021

Multiple sclerosis-related fatigue: the role of impaired corticospinal responses and heightened exercise fatigability.

J Neurophysiol 2020 10 2;124(4):1131-1143. Epub 2020 Sep 2.

Neuromuscular Fatigue Laboratory, Faculty of Kinesiology, University of Calgary, Calgary, Alberta, Canada.

It is unclear whether motor fatigability and perceived fatigue share a common pathophysiology in people with multiple sclerosis (PwMS). This cross-sectional investigation explored the relationship between the mechanisms of motor fatigability from cycling and fatigue severity in PwMS. Thirteen highly fatigued (HF) and thirteen nonfatigued (LF) PwMS and thirteen healthy controls (CON) completed a step test until volitional exhaustion on an innovative cycle ergometer. Neuromuscular evaluations involving femoral nerve electrical stimulation and transcranial magnetic stimulation were performed every 3 min throughout cycling. One-way ANOVA at baseline and exhaustion uncovered evidence of consistently smaller motor evoked potential (MEP) amplitudes ( = 0.011) and prolonged MEP latencies ( = 0.041) in HF as well as a greater decline in maximal voluntary contraction force (HF: 63 ± 13%; LF: 75 ± 13%; CON: 73 ± 11% of pre;  = 0.037) and potentiated twitch force (HF: 35 ± 13%; LF: 50 ± 16%; CON: 47 ± 17% of pre;  = 0.049) in HF at volitional exhaustion. Hierarchical regression determined that fatigue severity on the Fatigue Severity Scale was predicted by prolonged MEP latencies (change in  = 0.389), elevated peripheral muscle fatigability (change in  = 0.183), and depressive symptoms (change in  = 0.213). These findings indicate that MS-related fatigue is distinguished by disrupted corticospinal responsiveness, which could suggest progressive pathology, but fatigability from whole body exercise and depressive symptoms also influence perceptions of fatigue in PwMS. The etiology of fatigability from whole body exercise was examined for the first time to accurately elucidate the relationship between fatigue and fatigability in multiple sclerosis (MS). Compromised corticospinal responsiveness predicted fatigue severity, providing a novel, objective indicator of fatigue in MS. Although the impaired corticomotor transmission did not aggravate muscle activation in this group of people with multiple sclerosis (PwMS) of lower disability, heightened muscle fatigability was seen to contribute to perceptions of fatigue in PwMS.
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http://dx.doi.org/10.1152/jn.00165.2020DOI Listing
October 2020

Long noncoding RNAs associated with phenotypic severity in multiple sclerosis.

Mult Scler Relat Disord 2019 Nov 19;36:101407. Epub 2019 Sep 19.

Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada; Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Canada; Alberta Children's Hospital Research Institute, University of Calgary, Calgary, Alberta, Canada. Electronic address:

Introduction: Multiple sclerosis (MS) is a disease that causes progressive neurological disability. Treatments are available that are protective against MS relapses and it is thought that reduction of early neuroinflammation may improve long term prognosis. At present there is no biomarker that can predict which patients may have a more severe disease course, and potentially benefit from more aggressive therapy. Long noncoding RNAs (lncRNAs) are emerging as potential disease biomarkers that could be of interest in prognostication of MS.

Methods: We identified a discovery cohort of 20 patients, ten of which had a mild MS phenotype and ten with severe MS phenotype according to the Age-Related MS Severity Scale (ARMSS). RNAseq was performed on RNA extracted from whole blood and bioinformatic analysis restricted to lncRNAs. Our goal was to select the most significant lncRNAs and quantify these using custom digital droplet RT-qPCR assays in a validation cohort of 44 participants (with mild or severe MS).

Results: Eight lncRNA candidates were identified from the discovery cohort. Of these, four lncRNAs remained significantly differentially expressed in the validation cohort (ENSG00000260302, ENSG00000270972, ENSG00000272512 and ENSG00000223387). Little is known about the precise roles of these lncRNAs but based on expression data they appear to be important to immune function and are of potential biological significance to MS pathogenesis.

Conclusions: This study is the first to investigate possible lncRNA biomarkers to differentiate phenotypic severity in MS. Although the findings are preliminary based on our small sample size, they are sufficient to identify hypotheses for future investigation, and give guidance regarding the design of future studies.
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http://dx.doi.org/10.1016/j.msard.2019.101407DOI Listing
November 2019

Biomarkers of intestinal barrier function in multiple sclerosis are associated with disease activity.

Mult Scler 2020 10 18;26(11):1340-1350. Epub 2019 Jul 18.

Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada/Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.

Background: Recent evidence suggests a role for the gut-brain axis in the pathophysiology of multiple sclerosis (MS).

Materials And Methods: We studied biomarkers of intestinal permeability in 126 people with MS (57 relapsing-remitting multiple sclerosis (RRMS) and 69 progressive MS) and in a group of healthy controls for comparison. Serum/plasma concentrations of zonulin (a regulator of enterocyte tight junctions), tight junction proteins (ZO-1 and occludin), intestinal fatty acid binding protein (IFABP)/ileal bile acid binding protein (IBABP), D-lactate, and lipopolysaccharide (LPS) binding protein were measured.

Results: Zonulin concentrations were significantly higher when a concurrent magnetic resonance imaging (MRI) confirmed the presence of blood-brain barrier (BBB) disruption (Gad+ RRMS) and were correlated with tight junction proteins. IBABP and D-lactate were elevated in people with RRMS compared to controls, but did not discriminate between Gad+ and Gad- subgroups. Baseline zonulin concentrations were associated with 1-year disease progression in progressive MS.

Conclusions: People with MS have altered biomarkers of intestinal barrier integrity. Zonulin concentrations are associated with 1-year disease progression in progressive MS and closely mirror BBB breakdown in RRMS. Zonulin may mediate breakdown of both the intestinal barrier and the BBB in gut dysbiosis through the regulation of tight junctions. This could explain how the gut-brain axis modulates neuroinflammation in MS.
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http://dx.doi.org/10.1177/1352458519863133DOI Listing
October 2020

Clinically Isolated Syndrome and Early Relapsing Multiple Sclerosis.

Authors:
Luanne M Metz

Continuum (Minneap Minn) 2019 Jun;25(3):670-688

Purpose Of Review: This article reviews management of clinically isolated syndrome and early relapsing-remitting multiple sclerosis (MS). It provides a general approach to patient management and determination of prognosis, reviews first-line disease-modifying therapies, and provides an approach to treatment selection.

Recent Findings: Revision of the MS diagnostic criteria allows an earlier MS diagnosis, which reduces diagnostic uncertainty and often allows additional treatment options. Identification of factors that influence disease activity and progression highlights the importance of counseling patients about behavior modifications that, along with disease-modifying therapy, may improve long-term outcomes. Recommended lifestyle modifications include smoking cessation, vitamin D supplementation, a healthy diet, maintaining a healthy weight, remaining active, and management of cardiovascular risk factors. Identifying individuals at high risk for future disability allows them to make informed decisions about the use of highly effective, higher-risk disease-modifying therapies.

Summary: Patients with clinically isolated syndrome, even those with only dissemination in space but not dissemination in time, and patients with relapsing-remitting MS and disease activity within the prior 2 years, are at high risk of disease activity within the next 2 years. Lifestyle modification suggestions and disease-modifying therapy should be considered. Treatment decisions should be made in collaboration with patients using the shared decision-making approach.
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http://dx.doi.org/10.1212/CON.0000000000000729DOI Listing
June 2019

Focus on the gut-brain axis: Multiple sclerosis, the intestinal barrier and the microbiome.

World J Gastroenterol 2018 Oct;24(37):4217-4223

Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary T2N 2T9, Canada.

The brain-gut axis serves as the bidirectional connection between the gut microbiome, the intestinal barrier and the immune system that might be relevant for the pathophysiology of inflammatory demyelinating diseases. People with multiple sclerosis have been shown to have an altered microbiome, increased intestinal permeability and changes in bile acid metabolism. Experimental evidence suggests that these changes can lead to profound alterations of peripheral and central nervous system immune regulation. Besides being of pathophysiological interest, the brain-gut axis could also open new avenues of therapeutic targets. Modification of the microbiome, the use of probiotics, fecal microbiota transplantation, supplementation with bile acids and intestinal barrier enhancers are all promising candidates. Hopefully, pre-clinical studies and clinical trials will soon yield significant results.
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http://dx.doi.org/10.3748/wjg.v24.i37.4217DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175760PMC
October 2018

Ischemic Strokes in a Man with Congenital Afibrinogenemia.

Can J Neurol Sci 2018 09 18;45(5):590-592. Epub 2018 Jul 18.

4Department of Clinical Neurosciences,University of Calgary (LMM)Calgary, Alberta,Canada.

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http://dx.doi.org/10.1017/cjn.2018.57DOI Listing
September 2018

Effective treatment of progressive MS remains elusive.

Lancet 2018 03 23;391(10127):1239-1240. Epub 2018 Mar 23.

Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, AB T2N 2T9, Canada.

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http://dx.doi.org/10.1016/S0140-6736(18)30426-4DOI Listing
March 2018

Discriminative ability of quality of life measures in multiple sclerosis.

Health Qual Life Outcomes 2017 Dec 21;15(1):246. Epub 2017 Dec 21.

Department of Internal Medicine, University of Manitoba, GF533, 820 Sherbrook Street, Winnipeg, MB, R3A 1R9, Canada.

Background: Though many people with multiple sclerosis (MS) have comorbidities, the use of generic and disease-specific health related quality of life (HRQOL) scales to discriminate the effects of comorbidity has not been established. The utility of these scales to discriminate differences between persons with varying levels of disability is also unknown.

Methods: Using online questionnaires, a convenience sample of Albertans with MS was recruited between July 2011 and March 2013. Participants completed demographic questions, a validated comorbidity questionnaire, a self-reported disability scale, and the following HRQOL scales: the Short Form (SF)-36, SF-6D, Health Utilities Index-Mark III (HUI-III), and Multiple Sclerosis Quality of Life-54 (MSQOL-54). The ability of each HRQOL scale to distinguish between comorbidity groups was assessed using a one-way analysis of covariance, adjusting for age, sex, disease course, and disability level.

Results: Five hundred sixty three participants completed all relevant questionnaires. All HRQOL measures distinguished between persons with or without depression, while none were able to distinguish between participants with or without hypertension, thyroid disease, irritable bowel syndrome, or osteoporosis. The SF-36 physical scale, SF-6D, HUI-III, and MSQOL-54 physical scales were able to distinguish between all disability groups, though the HUI-III was better able to distinguish between individuals with moderate versus severe disability.

Conclusions: Disease-specific measures would discriminate better between those with and without comorbidities than generic-specific measures and the HUI-III would discriminate best between persons with differing severities of disability. Generic or disease-specific measures may be useful in future studies examining the effects of comorbidity in MS and the effects of treatment of comorbidities in MS.
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http://dx.doi.org/10.1186/s12955-017-0828-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5740906PMC
December 2017

Unexpected additive effects of minocycline and hydroxychloroquine in models of multiple sclerosis: Prospective combination treatment for progressive disease?

Mult Scler 2018 10 31;24(12):1543-1556. Epub 2017 Aug 31.

Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada.

Background: Most multiple sclerosis (MS) patients succumb to a progressive phenotype. Continued lymphocyte activity in the brain, microglia-mediated injury, iron deposition, and oxidative stress are characteristics of progressive MS.

Objective: As minocycline and hydroxychloroquine have been shown to inhibit microglia, we evaluated their effects on other outcomes relevant for progression.

Methods: Medications were evaluated in culture and in mice with acute and chronic experimental autoimmune encephalomyelitis (EAE).

Results: Both medications individually reduced iron neurotoxicity and a combination effect was not observed. Hydroxyl radical scavenging activity was manifested by minocycline only. Minocycline reduced T-cell proliferation more prominently than hydroxychloroquine; an aggregate effect occurred at low but not high concentrations. B-cell proliferation was mitigated to a greater extent by hydroxychloroquine and an additive effect was not evident. In EAE, suboptimal doses of minocycline and hydroxychloroquine individually delayed onset of clinical signs, while their combination suppressed clinical manifestations until treatment was stopped. In Biozzi ABH mice, a model of progressive MS, the chronic phase was beneficially altered using the combination.

Conclusion: While minocycline and hydroxychloroquine did not manifest additive effects in most culture assays, their combination at suboptimal doses in EAE unexpectedly exceeded their individual activity. Minocycline and hydroxychloroquine combined are candidate treatments for progressive MS.
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http://dx.doi.org/10.1177/1352458517728811DOI Listing
October 2018

Trial of Minocycline in Clinically Isolated Syndrome of Multiple Sclerosis.

N Engl J Med 2017 08;377(8):789

Tufts University, Boston, MA.

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http://dx.doi.org/10.1056/NEJMc1708486DOI Listing
August 2017

Hospitalization is associated with subsequent disability in multiple sclerosis.

Mult Scler Relat Disord 2017 May 24;14:23-28. Epub 2017 Mar 24.

Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Canada; Department of Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Canada. Electronic address:

Background: Although an increasing amount of research has evaluated interactions between MS and comorbid chronic disease, few data exist regarding the interactions between MS and acute illness. As compared to age and sex-matched persons without MS, persons with MS experience higher rates of hospitalization and critical illness, and higher mortality rates and health care utilization following critical illness. We aimed to determine whether acute illness requiring hospitalization is associated with progression of multiple sclerosis (MS).

Methods: We conducted this population-based, retrospective cohort study by linking data from the regional MS Clinic in Calgary, Canada with the Canadian Discharge Abstract Database to identify non-obstetric hospitalizations. We included individuals with a confirmed diagnosis of MS, at least one recorded Expanded Disability Status Scale (EDSS) measurement, and known age of symptom onset of age 10 years or older. Using data from 2009 to 2014, we used generalized linear models with generalized estimating equations to establish the association within individuals between hospitalization and the time course of MS-related disability (as measured by the EDSS), adjusting for sex, age, disease course at onset, and use of disease-modifying therapies.

Results: We included 2104 individuals with MS in the analysis, who had a median of 4 EDSS measurements each. Of these 491 (23.3%) had at least one hospitalization. Most subjects were female, with a relapsing disease course at onset, and a mean (SD) age at symptom onset of 33.0 (10.0) years. The underlying rate of disability progression averaged 0.9 EDSS points per decade. Following hospitalization, there was a step increase in EDSS, averaging 0.23 points, equivalent to 2.5 years of time-related disease progression. Hospitalization did not alter the subsequent temporal rate of disability progression. The findings did not differ in those hospitalized for MS versus other reasons.

Conclusions: Acute illness requiring hospitalization is associated with a worsening of MS-related disability.
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http://dx.doi.org/10.1016/j.msard.2017.03.009DOI Listing
May 2017

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

Gestational bisphenol-A exposure lowers the threshold for autoimmunity in a model of multiple sclerosis.

Proc Natl Acad Sci U S A 2017 05 24;114(19):4999-5004. Epub 2017 Apr 24.

Hotchkiss Brain Institute and the Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada;

Environmental and hormonal factors are implicated in dysimmunity in multiple sclerosis. We investigated whether bisphenol-A, a prominent contaminant with endocrine-disrupting capabilities, altered susceptibility in an inflammatory model of multiple sclerosis. We found that gestational, but not adult, exposure to bisphenol-A increased the development of experimental autoimmune encephalomyelitis in adulthood in male, but not female, mice when a suboptimal disease-inducing immunization was used. Gestational bisphenol-A in male mice primed macrophages in adulthood and raised granulocyte-colony stimulating factor and neutrophil counts/activity postsuboptimal immunization. Neutralizing granulocyte-colony stimulating factor blocked susceptibility to disease in bisphenol-A mice. Early life exposure to bisphenol-A may represent an environmental consideration in multiple sclerosis.
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http://dx.doi.org/10.1073/pnas.1620774114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5441731PMC
May 2017

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

Cholesterol and markers of cholesterol turnover in multiple sclerosis: relationship with disease outcomes.

Mult Scler Relat Disord 2016 Jan 19;5:53-65. Epub 2015 Oct 19.

Department of Neuroscience, Centre de recherche du CHU de Québec - Université Laval, Québec, Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec, Canada. Electronic address:

Multiple sclerosis (MS) is a chronic central nervous system disease that is associated with progressive loss of myelin and subsequent axonal degeneration. Cholesterol is an essential component of mammalian cellular and myelin membranes. In this systematic review, we examined the relationship between levels of cholesterol and markers of cholesterol turnover in circulation and/or cerebrospinal fluid (CSF) and disease outcomes in adults with clinically isolated syndrome (CIS) or confirmed MS. Studies suggest that elevated levels of circulating low density lipoprotein cholesterol (LDL), total cholesterol, and particularly, apolipoprotein B and oxidized LDL are associated with adverse clinical and MRI outcomes in MS. These relationships were observed as early as CIS. The studies also suggest that oxysterols, cholesterol precursors, and apolipoprotein E may be markers of specific disease processes in MS, but more research is required to elucidate these processes and relationships. Taken together, the data indicate that cholesterol and markers of cholesterol turnover have potential to be used clinically as biomarkers of disease activity and may even be implicated in the pathogenesis of MS.
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http://dx.doi.org/10.1016/j.msard.2015.10.005DOI Listing
January 2016

Multi-scale MRI spectrum detects differences in myelin integrity between MS lesion types.

Mult Scler 2016 10 11;22(12):1569-1577. Epub 2016 Jan 11.

Department of Anatomy & Neurosciences, VU University Medical Center, Amsterdam, The Netherlands.

Background: Lesions with different extents of myelin pathology are found at autopsy in multiple sclerosis (MS), but the differences are not discernible in magnetic resonance imaging (MRI).

Objective: To determine whether analysis of the local spectrum in MRI is sensitive to lesion differences in myelin integrity.

Methods: We imaged fresh brain slices from 21 MS patients using 1.5T scanners. White matter lesions were identified in T2-weighted MRI, matched to corresponding specimens, and then classified into five categories in histology: pre-active (intact myelin); active, chronic active, chronic inactive (complete demyelination); and remyelinated lesions. Voxel-based frequency spectrum was calculated using T2-weighted MRI to characterize lesion structure (image texture).

Results: MRI texture heterogeneity resulting from all spectral scales was greater in completely demyelinated lesions than in myelin-preserved lesions (p = 0.02) and normal-appearing white matter (p < 0.01). Moreover, the spectral distribution pattern over low-frequency scales differentiated demyelinated lesions from remyelinated and pre-active lesions (p < 0.01), where different lesion types also showed distinct texture scales.

Conclusion: Using multi-scale spectral analysis, it may be possible for standard MRI to evaluate myelin integrity in MS lesions. This can be critical for monitoring disease activity and assessing remyelination therapies for MS patients.
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http://dx.doi.org/10.1177/1352458515624771DOI Listing
October 2016

1,25-Dihydroxyvitamin D3 Protects against Immune-Mediated Killing of Neurons in Culture and in Experimental Autoimmune Encephalomyelitis.

PLoS One 2015 17;10(12):e0144084. Epub 2015 Dec 17.

Hotchkiss Brain Institute and the Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Canada.

Several studies have reported that low vitamin D levels are associated with an increased risk of developing multiple sclerosis (MS). As MS is an inflammatory disorder with degeneration of axons and neurons, we examined whether the biologically active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), could protect against the T cell-mediated killing of human neurons in culture, and the axonal loss seen in mice with experimental autoimmune encephalomyelitis (EAE). Human neurons were exposed to activated human T lymphocytes and the loss of neurons was documented 24 hours later by counting the number of microtubule-associated protein-2 positive cells. Mice with EAE were harvested for counts of axonal profiles in the spinal cord. 1,25D3 was exposed to T cells in culture or administered to mice from peak EAE clinical severity when axonal loss was already evolving. Activated T lymphocytes killed human neurons prominently within 24 hours but toxicity was significantly attenuated when T cells were exposed to 1,25D3 prior to the co-culture. In EAE, 1,25D3 treatment initiated from peak clinical severity reduced the extent of clinical disability and mitigated the progressive loss of axons. The reduction of axonal and neuronal loss by 1,25D3 in the context of an inflammatory assault to the central nervous system is a potential contributor to the putative benefits of vitamin D in MS.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0144084PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4683031PMC
June 2016

Canadian Expert Panel Recommendations for MRI Use in MS Diagnosis and Monitoring.

Can J Neurol Sci 2015 May 21;42(3):159-67. Epub 2015 Apr 21.

19Department of Radiology/Division of Neurology,University of British Columbia,Vancouver,British Columbia,Canada.

Background: A definitive diagnosis of multiple sclerosis (MS), as distinct from a clinically isolated syndrome, requires one of two conditions: a second clinical attack or particular magnetic resonance imaging (MRI) findings as defined by the McDonald criteria. MRI is also important after a diagnosis is made as a means of monitoring subclinical disease activity. While a standardized protocol for diagnostic and follow-up MRI has been developed by the Consortium of Multiple Sclerosis Centres, acceptance and implementation in Canada have been suboptimal.

Methods: To improve diagnosis, monitoring, and management of a clinically isolated syndrome and MS, a Canadian expert panel created consensus recommendations about the appropriate application of the 2010 McDonald criteria in routine practice, strategies to improve adherence to the standardized Consortium of Multiple Sclerosis Centres MRI protocol, and methods for ensuring effective communication among health care practitioners, in particular referring physicians, neurologists, and radiologists.

Results: This article presents eight consensus statements developed by the expert panel, along with the rationale underlying the recommendations and commentaries on how to prioritize resource use within the Canadian healthcare system.

Conclusions: The expert panel calls on neurologists and radiologists in Canada to incorporate the McDonald criteria, the Consortium of Multiple Sclerosis Centres MRI protocol, and other guidance given in this consensus presentation into their practices. By improving communication and general awareness of best practices for MRI use in MS diagnosis and monitoring, we can improve patient care across Canada by providing timely diagnosis, informed management decisions, and better continuity of care.
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http://dx.doi.org/10.1017/cjn.2015.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416356PMC
May 2015

Prolactin in combination with interferon-β reduces disease severity in an animal model of multiple sclerosis.

J Neuroinflammation 2015 Mar 19;12:55. Epub 2015 Mar 19.

Hotchkiss Brain Institute and the Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, 3330 Hospital Drive NW, Calgary, AB, T2N 4N1, Canada.

Previous work has demonstrated that the hormone prolactin promotes oligodendrocyte precursor proliferation and remyelination following lysolecithin-induced demyelination of the mouse spinal cord. Prolactin, however, can elicit pro-inflammatory responses, and its use in the prototypical demyelinating and inflammatory condition, multiple sclerosis (MS), should thus be approached cautiously. Here, we sought to determine whether recombinant prolactin could alter the course of experimental autoimmune encephalomyelitis (EAE), an inflammatory animal model of MS. Consistent with previous literature, we found that prolactin activated leukocytes in vitro. Daily treatment with prolactin from around the time of onset of clinical signs, for 9 (days 9 to 17) or 25 (days 9 to 33) days did not increase clinical or histological signs of EAE over that of vehicle-treated mice. Instead, the combination of prolactin and a suboptimal dose of recombinant murine interferon-β resulted in (days 9 to 17 group) or trended towards (days 9 to 33 group), a greater amelioration of clinical signs of EAE, compared to either treatment alone or to vehicle controls. Histological analyses corroborated the clinical EAE data. These results suggest that prolactin may be beneficial when administered in combination with interferon-β in MS.
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http://dx.doi.org/10.1186/s12974-015-0278-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4367923PMC
March 2015

Predictors of chronic cerebrospinal venous insufficiency procedure use among older people with multiple sclerosis: a national case-control study.

BMC Health Serv Res 2015 Apr 16;15:161. Epub 2015 Apr 16.

Primary Health Care Research Unit, Faculty of Medicine, Memorial University, St. John's, NL, Canada.

Background: Following the initial reports of Chronic Cerebrospinal Venous Insufficiency (CCSVI) and the purported curative potential of venoplasty, (coined the 'liberation' procedure) Canadians living with multiple sclerosis (MS) began to travel abroad to receive the unregulated procedure, often placing them at odds with their health providers. The purpose of this study was to determine the factors influencing older MS patients' decision to undergo the procedure in order to develop more specific and targeted health information.

Methods: We performed secondary analysis of data collected as part of the 'Canadian Survey of Health Lifestyle and Aging with MS' from people over the age of 55 years with MS symptoms for 20 or more years. The survey consisted of self-reported information on impairments, disability, participation, demographics, personal and environmental factors. In order to compare respondents who underwent the procedure to those who did not and to develop a predictive model, we created a comparison group using a case-control algorithm, controlling for age, gender and education, and matching procedure cases to controls 1:3. We used multivariate stepwise least likelihood regression of 'a priori' variables to determine predictive factors.

Results: The prevalence of the 'liberation' procedure in our sample was 12.8% (95/743), substantially lower than reported in previous studies of complementary/alternative treatments in MS. The predictive model contained five factors; living alone (Odds ratio 0.24, 95%CI 0.09-0.63), diagnosis of anxiety (Odds ratio 0.29, 95%CI 0.10 - 0.84), rating of neurologist's helpfulness (Odds ratio 0.56, 95%CI 0.44 -0 .71), Body Mass Index (Odds ratio 0.93, 95%CI, 0.89 - 0.98) and perceived physical impact of MS (Odds ratio 1.02, 95%CI 1.01 - 1.04).

Conclusions: Predictive factors differed from previous studies of complementary/alternative treatment use likely due to both the invasiveness of the procedure and the advanced age of our study cohort. Our findings suggest that health professionals should target information on the risks and benefits of unregulated procedures to those patients who feel dissatisfied with their neurologist and they should include family members in discussions since they may be providing the logistical support to travel abroad and undergo the 'liberation' procedure. Our findings may be applicable to others with chronic disabling conditions who contemplate the user-pay unregulated invasive procedures available to them.
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http://dx.doi.org/10.1186/s12913-015-0835-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4424567PMC
April 2015

Long-term persistence with injectable therapy in relapsing-remitting multiple sclerosis: an 18-year observational cohort study.

PLoS One 2015 13;10(4):e0123824. Epub 2015 Apr 13.

Department of Clinical Neurosciences, Faculty of Medicine, University of Calgary; Calgary, Canada; Hotchkiss Brain Institute, Faculty of Medicine, University of Calgary, Calgary, Canada.

Disease modifying therapies (DMTs) reduce the frequency of relapses and accumulation of disability in multiple sclerosis (MS). Long-term persistence with treatment is important to optimize treatment benefit. This long-term, cohort study was conducted at the Calgary MS Clinic. All consenting adults with relapsing-remitting MS who started either glatiramer acetate (GA) or interferon-β 1a/1b (IFN-β) between January 1st, 1996 and July 1st, 2011 were included. Follow-up continued to February 1st, 2014. Time-to-discontinuation of the initial and subsequently-prescribed DMTs (switches) was analysed using Kaplan-Meier survival analyses. Group differences were compared using log-rank tests and multivariable Cox regression models. Analysis included 1471 participants; 906 were initially prescribed GA and 565 were initially prescribed IFN-β. Follow-up information was available for 87%; 29 (2%) were lost to follow-up and 160 (11%) moved from Southern Alberta while still using DMT. Median time-to-discontinuation of all injectable DMTs was 11.1 years. Participants with greater disability at treatment initiation, those who started treatment before age 30, and those who started between 2006 and 2011 were more likely to discontinue use of all injectable DMTs. Median time-to-discontinuation of the initial DMT was 8.6 years. Those initially prescribed GA remained on treatment longer. Of 610 participants who discontinued injectable DMT, 331 (54%) started an oral DMT, or a second-line DMT, or resumed injectable DMT after 90 days. Persistence with injectable DMTs was high in this long-term population-based study. Most participants who discontinued injectable DMT did not remain untreated. Further research is required to understand treatment outcomes and outcomes after stopping DMT.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0123824PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4395027PMC
March 2016

Serum NSE level and disability progression in multiple sclerosis.

J Neurol Sci 2015 Mar 11;350(1-2):46-50. Epub 2015 Feb 11.

Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

Background: Previous studies suggested that serum neuron specific enolase (NSE) may be a biomarker associated with progression in MS.

Methods: We measured serum NSE levels in 385 patients with multiple sclerosis (MS) (264 with relapsing-remitting (RR) MS, 86 with secondary progressive (SP) MS, and 35 with primary progressive (PP) MS), and compared levels between disease courses, between users and non-users of immunomodulatory treatment, and between patients with worsening or stable disability at one year follow-up (available in 161 patients). We also investigated the correlation between serum NSE and Expanded Disability Status Scale (EDSS) and MS Severity Score (MSSS) scores in the whole cohort and in subgroups, and built a multiple linear regression model to assess the influence of predictor variables on serum NSE.

Results: Age was the only independent predictor of serum NSE levels in the multiple linear regression model. In the subgroup of patients with PPMS, there was a moderate correlation between serum NSE and increasing MSSS (Pearson's r 0.35, p=0.04) and EDSS (Spearman's rho 0.37, p=0.03) scores.

Conclusion: Our data do not support the use of serum NSE as a prognostic biomarker in RRMS or SPMS. The correlations of serum NSE with EDSS and MSSS in the PPMS subgroup are interesting, but based on a small sample size and require replication in other cohorts.
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http://dx.doi.org/10.1016/j.jns.2015.02.009DOI Listing
March 2015

Validity of four screening scales for major depression in MS.

Mult Scler 2015 Jul 12;21(8):1064-71. Epub 2015 Jan 12.

Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada/Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

Background: There is a role for brief assessment instruments in detection and management of major depression in MS. However, candidate scales have rarely been validated against a validated diagnostic interview. In this study, we evaluated the performance of several candidate scales: Patient Health Questionnaire (PHQ)-9, PHQ-2, Center for Epidemiologic Studies Depression rating scale (CES-D), and Hospital Anxiety and Depression Scale (HADS-D) in relation to the Structured Clinical Interview for DSM-IV (SCID).

Methods: The sample was an unselected series of 152 patients attending a multiple sclerosis (MS) clinic. Participants completed the scales during a clinic visit or returned them by mail. The SCID was administered by telephone within two weeks. The diagnosis of major depressive episode, according to the SCID, was used as a reference standard. Receiver-operator curves (ROC) were fitted and indices of measurement accuracy were calculated.

Results: All of the scales performed well, each having an area under the ROC > 90%. For example, the PHQ-9 had 95% sensitivity and 88.3% specificity when scored with a cut-point of 11. This cut-point achieved a 56% positive predictive value for major depression.

Conclusions: While all of the scales performed well in terms of their sensitivity and specificity, the availability of the PHQ-9 in the public domain and its brevity may enhance the feasibility of its use.
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http://dx.doi.org/10.1177/1352458514559297DOI Listing
July 2015

The natural history of early versus late disability accumulation in primary progressive MS.

J Neurol Neurosurg Psychiatry 2015 Jun 4;86(6):615-21. Epub 2014 Aug 4.

Department of Clinical Neurosciences and Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

Background: Primary progressive multiple sclerosis (PPMS) is the least common MS disease course and carries the worst prognosis. In relapsing-remitting multiple sclerosis (RRMS) disability accumulation occurs in two distinct phases, but it is unclear whether this is also true for PPMS. Here we investigate factors associated with early and late disability accumulation in PPMS.

Methods: We used Kaplan-Meier survival analyses and Cox regression to investigate the influence of sex, age at disease onset and onset symptoms on time to, and age at, Expanded Disability Status Scale (EDSS) 4 and 6, as well as the time from EDSS 4 to 6 in patients with PPMS.

Results: We identified 500 patients with PPMS. The analyses on time to EDSS 4 included 358 patients, and those on time to EDSS 6 included 392 patients. The median times to EDSS 4 and EDSS 6 were 5 and 9 years. The analyses on age at EDSS 4 included 360 patients, and those on age at EDSS 6 included 402 patients. The median ages at EDSS 4 and EDSS 6 were 51 and 55 years. Older age at onset and bilateral motor onset symptoms were independently associated with a shorter time to both EDSS 4 and EDSS 6. Sex and other onset symptoms were not associated with time to, or age at, landmark disability. Only age at onset was significantly associated with the time from EDSS 4 to EDSS 6.

Conclusions: Age at disease onset is the most important predictor of disability accumulation in PPMS. Bilateral motor onset symptoms were associated with quicker disease progression. In contrast to RRMS, we found no evidence for distinct phases of disability accumulation in PPMS. Disability accumulation in PPMS appears to be affected by the same factors throughout its course.
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http://dx.doi.org/10.1136/jnnp-2014-307948DOI Listing
June 2015
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