Multiple Sclerosis: Traboulsee A

Simon JH, Li D, Traboulsee A, Coyle PK, Arnold DL, Barkhof F, Frank JA, Grossman R, Paty DW, Radue EW, Wolinsky JS. · Department of Radiology, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA. · AJNR Am J Neuroradiol. · Pubmed #16484429 links to  free full text

This publication has no abstract.

Traboulsee A, Li DK. · Department of Medicine, Division of Neurology, University of British Columbia, 2211 Wesbrook Mall, Room s199, Vancouver, British Columbia V6T 2B5, Canada. · Neuroimaging Clin N Am. · Pubmed #19068407 No free full text.

Abstract: Conventional MR imaging refers to techniques that are readily available and widely used in the diagnosis and monitoring of individuals with multiple sclerosis (MS). MR imaging is helpful in establishing an early diagnosis of MS after a single clinical event consistent with demyelination. A standardized imaging protocol is invaluable for diagnosis and monitoring disease evolution and response to treatment over time. The characteristic lesions of MS are varied and not always evident at the earliest stages of the disease. Furthermore, MR imaging is highly sensitive for detecting these lesions but remains pathologically nonspecific. Careful communication among clinicians and radiologists will optimize the interpretation of important abnormalities on MR imaging.

Traboulsee A. · Department of Medicine, Division of Neurology, MS/MRI Research Group, University of British Columbia, Vancouver, British Columbia, Canada. · J Neurol Sci. · Pubmed #17346748 No free full text.

Abstract: MRI is extremely sensitive for detecting new inflammatory activity in the central nervous system of patients with multiple sclerosis (MS) that is often clinically silent. Each new lesion often leaves a permanent MS plaque, which is composed of varying degrees of demyelination, axonal loss, and gliosis. New large lesions have a greater risk of evolving into permanent T1-weighted hypointense lesions (black holes) that pathologically contain the greatest axonal loss and correlate more strongly with clinical disability than with overall lesion load on T2-weighted images. There is also an association between the severity of the total T2 lesion burden with cerebral atrophy and with diffuse changes in the normal-appearing brain tissue as determined by magnetization transfer imaging and magnetic resonance spectroscopy. To maintain normal clinical functioning, the brain may compensate by recruiting increased regions of cortex, as demonstrated by functional MRI (fMRI) studies. The degree of increased fMRI activation is proportional to the severity of T2 lesion load, up to a critical limit at which it appears that these compensatory mechanisms may fail. Therefore, new inflammatory activity, as detected by MRI, carries a risk of significant early pathologic damage and delayed yet permanent clinical disability.

Li DK, Li MJ, Traboulsee A, Zhao G, Riddehough A, Paty D. · Department of Radiology, University of British Columbia Hospital, Vancouver, Canada. · Adv Neurol. · Pubmed #16400836 No free full text.

Abstract: Because the changes on MRI likely reflect various aspects of the underlying pathology of multiple sclerosis, MRI outcome measures have become an important component of most MS clinical trials, providing objective, supportive evidence for the clinical endpoints. Although there is currently insufficient evidence to support any single or combination of MRI measures as a fully validated surrogate, it is now generally accepted that if the aim of a new therapy is to prevent relapses, new Gd-enhancing and T2 lesions can be considered an appropriate surrogate outcome measure of relapses, and MRI activity outcomes can be recommended as the primary measure of treatment efficacy.

Traboulsee A, Zhao G, Li DK. · Division of Neurology, Department of Medicine, The University of British Columbia, S199-2211 Westbrook Mall, Vancouver, British Columbia V6T 2B5, Canada. · Neurol Clin. · Pubmed #15661091 No free full text.

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Traboulsee A. · Division of Neurology, University of British Columbia, s195-2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada. · J Neurol. · Pubmed #15549354 No free full text.

Abstract: Magnetic resonance imaging (MRI) is an extremely sensitive diagnostic tool that provides us with highly detailed images of the living human brain. Since it was first applied to multiple sclerosis (MS) in clinical trials in the 1980s, MRI has become established as a reliable, sensitive and reproducible technique for studying the pathophysiology of this complex disease. It has provided a variety of surrogate measures for clinical trials, and continues to offer new methods for the detection and monitoring of the physical and chemical changes in the brains of living patients. The unique sensitivity of conventional MRI measures for detecting MS pathology has made MRI an attractive tool for optimising treatment in clinical practice for individual patients.

Kappos L, Traboulsee A, Constantinescu C, Erälinna JP, Forrestal F, Jongen P, Pollard J, Sandberg-Wollheim M, Sindic C, Stubinski B, Uitdehaag B, Li D. · University of Basel, Basel, Switzerland. · Neurology. · Pubmed #17000959 No free full text.

Abstract: OBJECTIVE: To conduct systematic long-term follow-up (LTFU) of patients in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study to provide up to 8 years of safety, clinical and MRI outcomes on subcutaneous (s.c.) interferon (IFN) beta-1a in relapsing-remitting multiple sclerosis (RRMS). METHODS: The original cohort of 560 patients was randomized to IFNbeta-1a, 44 or 22 microg three times weekly (TIW) or to placebo; after 2 years, patients on placebo were rerandomized to active treatment and the blinded study continued for a further 4 years. The LTFU visit was scheduled 7 to 8 years after baseline. RESULTS: LTFU was attended by 68.2% of the original PRISMS study cohort (382/560 patients). 72.0% (275/382) were still receiving IFNbeta-1a s.c. TIW. Patients originally randomized to IFNbeta-1a 44 microg s.c. TIW showed lower Expanded Disability Status Scale progression, relapse rate and T2 burden of disease up to 8 years compared with those in the late treatment group. Brain parenchymal volume did not show differences by treatment group. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated. CONCLUSIONS: Despite the limitations inherent in any long-term study (for example, potential differences between returning and nonreturning patients), these results indicate that patients with relapsing-remitting multiple sclerosis can experience sustained benefit over many years from early interferon beta-1a subcutaneous therapy three times weekly compared with patients whose treatment is delayed. This effect was more apparent in the patients receiving the higher dose.

Vavasour IM, Laule C, Li DK, Oger J, Moore GR, Traboulsee A, MacKay AL. · Department of Radiology, University of British Columbia, Vancouver, BC, Canada. · J Neurol Sci. · Pubmed #18822435 No free full text.

Abstract: Multiple sclerosis (MS) is characterised by focal areas that undergo cycles of demyelination and remyelination. Although conventional magnetic resonance imaging is very effective in localising areas of damage, these techniques are not pathology specific. A newer technique, T(2) relaxation, can separate water from brain into three compartments: (1) a long T(2) component (>2 s) arising from CSF, (2) an intermediate T(2) component (~80 ms) attributed to intra- and extra-cellular water and (3) a short T(2) component (~20 ms) assigned to water trapped in between the myelin bilayers (termed myelin water). Histological evidence shows that myelin water is a specific marker of myelination. The goal of this work was to follow changes in total water content (WC) and myelin water fraction (MWF) in evolving MS lesions over one year. Multi-echo T(2) relaxation data was collected and used to measure water content and myelin water fraction from three new MS lesions in two patients. WC increased in the three large (>1 cm(3)) lesions at lesion appearance and remained elevated in the central core. Two lesions showed low MWF in the core suggesting demyelination upon first appearance. At later time points, one lesion showed a decrease in volume of low MWF, reflecting remyelination whereas the volume of low MWF in the other lesion core remained constant. This work provides evidence that MWF and WC can monitor demyelination and remyelination in MS.

Traboulsee A, Al-Sabbagh A, Bennett R, Chang P, Li DK, Anonymous00349, Anonymous00350. · Division of Neurology, Medicine, University of British Columbia, Vancouver, BC, Canada. · BMC Neurol. · Pubmed #18426595 links to  free full text

Abstract: BACKGROUND: The EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study was an international, randomized, open-label, assessor-blinded, parallel-group study assessing the efficacy and tolerability of interferon (IFN) beta-1a, 44 mcg subcutaneously (sc) three times weekly (tiw), and IFN beta-1a, 30 mcg intramuscularly (im) once weekly (qw), in patients with relapsing-remitting multiple sclerosis (RRMS). The aim of this analysis was to assess whether reductions in T2 burden of disease (BOD) were greater for patients receiving IFN beta-1a, 44 mcg sc tiw, than for those treated with IFN beta-1a, 30 mcg im qw, and to assess the impact of neutralizing antibodies (NAbs). METHODS: A post-hoc analysis was performed on magnetic resonance imaging (MRI) data collected prospectively from the EVIDENCE study. The analysis included all patients with evaluable T2 MRI scans at the start of dosing and at week 48, and those who received at least one drug dose (n = 553). Lesions were identified by a radiologist blinded to treatment codes and the total volume of T2 lesions (BOD) was reported in mm3. RESULTS: Both median percentage decreases and absolute reduction in BOD were greater in the IFN beta-1a, 44 mcg sc tiw, treatment group. The adjusted mean treatment difference in percentage change in BOD from baseline to week 48 showed a significant treatment benefit for patients treated with IFN beta-1a, 44 mcg sc tiw, over those treated with IFN beta-1a, 30 mcg im qw (-4.6%; standard error: 2.6%; p = 0.002). The presence of NAbs reduced the effect of IFN beta-1a 44, mcg sc tiw, on BOD, but BOD changes were still similar to those seen with IFN beta-1a, 30 mcg im qw. CONCLUSION: Patients with RRMS treated with IFN beta-1a, 44 mcg sc tiw, had greater reduction in T2 BOD after 48 weeks than those treated with IFN beta-1a, 30 mcg im qw, which is consistent with other clinical and MRI outcome measures in the EVIDENCE study. In patients testing positive for NAbs (NAb+) to IFN beta-1a 44 mcg sc tiw, changes in BOD were smaller than in NAb negative (NAb-) patients, but similar to those receiving IFN beta-1a, 30 mcg im qw.

Zhao Y, Traboulsee A, Petkau AJ, Li D. · Department of Medicine, University of British Columbia, Vancouver, BC, Canada. · Neurology. · Pubmed #18003938 No free full text.

Abstract: BACKGROUND: Contrast enhancing lesions (CEL) is a common endpoint in multiple sclerosis (MS) clinical trials. To minimize sample size or placebo exposure, a crossover design without a concurrent control group is attractive. Natural regression may confound this strategy. We assessed the degree of regression in monthly new gadolinium activity in relapsing-remitting (RR) placebo patients. METHODS: A post hoc analysis was performed on 65 RRMS placebo patients in the Prevention of Relapses and disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) trial. Patients were originally selected for relapses but not preselected for MRI activity. Eleven MRI scans were taken at screening, baseline, and months 1 through 9. Monthly new CEL rates were examined using a random effects Poisson model. Patients were analyzed as a single group and by screening CEL count level subgroups: no, low, and high (0, 1 to 3, >3 CEL). RESULTS: A total of 32, 19, and 14 patients had no, low, and high CEL counts at screening. The monthly new CEL rates (95% CI) of all patients at baseline, months 1 to 3, 4 to 6, and 7 to 9 were 2.0 (1.3, 2.9), 1.8 (1.3, 2.5), 1.4 (1.0, 2.0), and 1.2 (0.8, 1.7). Compared to baseline, the rate decreased by 10%, 27%, and 39%. The monthly rate of the no subgroup remained stable. The rates for both the low and high subgroups decreased by 4%, 29%, and 48% at months 1 to 3, 4 to 6, and 7 to 9 compared to baseline. CONCLUSIONS: Placebo relapsing-remitting multiple sclerosis patients experience a decline of new gadolinium activity over 9 months. A crossover design without a concurrent comparison group may overestimate the treatment effect.

Ishaq O, Hamarneh G, Tam R, Traboulsee A. · Medical Image Analysis Lab, School of Computing Science, Simon Fraser University, Burnaby, Canada. · Conf Proc IEEE Eng Med Biol Soc. · Pubmed #18002404 No free full text.

Abstract: The corpus callosum (CC) is an anatomical structure which connects the two brain hemispheres. Neurological diseases can cause atrophy of the CC resulting in a change in its size and shape. The measurement and analysis of this change is one of the goals of clinical research. We perform statistical analysis of the shape of the CC extracted from MR brain scans of a group of multiple sclerosis patients undergoing a longitudinal (serial) study. In contrast to the classical boundary-based, global shape variability measures, e.g. principal component analysis (PCA) of CC boundary vertices, we perform a deformation-specific PCA for analyzing the global and regional shape of the CC. This deformation-specific PCA is based on a medial-based shape representation. The adopted shape representation describes shape variability in terms of intuitive deformations (e.g. bending, stretching and thickness). We present qualitative and quantitative results for 412 MR images of the CC. We show that our method is successful in identifying and quantifying the effect of each type of deformation on the shape variability of the CC. In addition to analyzing the spatial shape variability in the CC, we explore shape changes as the disease progresses. Our method allows the exploration of the shape variability quantitatively (e.g. the amount of variance explained by a particular principal mode of shape variation) as well as in a qualitative visual manner (e.g. by visualizing, say, the 2nd principal mode of shape variation due to bending at the 4th sub-region of the CC) which is useful for developing an intuitive understanding of the effects of MS on the CC shape.

Traboulsee A, Dehmeshki J, Peters KR, Griffin CM, Brex PA, Silver N, Ciccarrelli O, Chard DT, Barker GJ, Thompson AJ, Miller DH. · NMR Research Unit, Institute of Neurology, University College London, Queen Square, London WC1N 3BG, UK. · Mult Scler. · Pubmed #14664468 No free full text.

Abstract: BACKGROUND: Magnetization transfer ratio (MTR) histogram analysis provides a global measure of disease burden in multiple sclerosis (MS). MTR abnormalities in normal appearing brain tissue (NABT) provide quantitative information on the extent of tissue damage undetected by conventional T2-weighted (T2W) magnetic resonance imaging (MRI). AIMS: 1) To compare the MTR histograms from NABT across a broad spectrum of relapse onset MS patients, including relapsing-remitting (RR) MS (including newly diagnosed and benign subgroups) and secondary progressive (SP) MS. 2) To determine the relationship between clinical disability and NABT MTR histograms. METHODS: 2D spin echo magnetization transfer imaging was performed on 70 RRMS and 25 SPMS patients and compared with 63 controls. MTR histograms were acquired for NABT after extracting lesions and cerebrospinal fluid (CSF). T2W images were used to measure the brain parenchymal fraction (BPF) and T2 lesion load. RESULTS: MS patients had a disease duration ranging from 0.5 to 37 years and an Expanded Disability Status Scale (EDSS) score ranging from 0 to 8.5. There was a significant decrease in NABT mean MTR (+/- standard deviation) compared with controls (33.07 pu +/- 1.06 versus 34.26 pu +/- 0.47; P < 0.001) with an effect size of 2.56. The reduction in NABT mean MTR varied among patient groups from 4.9% for SPMS, 3% for all RRMS, 2.7% for early RRMS and 2.5% for benign MS, compared with controls. NABT mean MTR correlated significantly with T2 lesion load (r = -0.82) and BPF (r = 0.58). EDSS score correlated with NABT mean MTR (r = -0.43), BPF (r = -0.33) and with T2 lesion load (r = 0.59). Multivariate analysis using NABT MTR peak height, T2 lesion load and BPF combined only accounted for 38% of the variance in the EDSS (r = 0.62; P < 0.001). Disease duration accounted for an additional 14% of variance in the EDSS (r = 0.72; P < 0.001). CONCLUSIONS: There is evidence of diffuse abnormalities in NABT in addition to global brain atrophy in relapse onset MS patients, including those with recently diagnosed RRMS and benign MS. The abnormalities are greatest in patients with the more disabling SPMS. Atrophy, NABT and lesion abnormalities are all partly correlated; the processes marked by these MR measures all contribute to disability in MS, providing complementary information relevant to the complex pathological processes that occur in MS.

Traboulsee A, Dehmeshki J, Brex PA, Dalton CM, Chard D, Barker GJ, Plant GT, Miller DH. · NMR Research Unit, Institute of Neurology, University College London, United Kingdom. · Neurology. · Pubmed #12105321 No free full text.

Abstract: Segmented normal-appearing brain tissue (NABT) was investigated in 40 patients with a recent onset and 13 patients with a remote onset of a clinically isolated syndrome (CIS) using magnetization transfer ratio (MTR) histograms. Abnormalities were present in patients with a high risk for MS (recent onset and T2-weighted lesions present) and in those with a low risk for relapse (recent onset without T2-weighted lesions). Similar mild NABT abnormality was present with CIS and no further disease activity 14 years later. NABT MTR abnormality in CIS may indicate susceptibility to demyelination but not to disease progression.

Paty D, Arnason B, Li D, Traboulsee A. · No affiliation provided · Lancet. · Pubmed #12781559 No free full text.

This publication has no abstract.