Diffusely abnormal white matter in clinically isolated syndrome is associated with parenchymal loss and elevated neurofilament levels.

We characterized the frequency of diffusely abnormal white matter (DAWM) across a broad spectrum of multiple sclerosis (MS) participants. 35% of clinically isolated syndrome (CIS), 57% of relapsing remitting and 64% of secondary progressive MS participants demonstrated DAWM. CIS with DAWM had decreased cortical thickness, higher lesion load and a higher concentration of serum neurofilament light chain compared to CIS without DAWM. DAWM may be useful in identifying CIS patients with greater injury to their brains. Larger and longitudinal studies are warranted.

FLAIR2 improves LesionTOADS automatic segmentation of multiple sclerosis lesions in non-homogenized, multi-center, 2D clinical magnetic resonance images.

BACKGROUND: Accurate segmentation of MS lesions on MRI is difficult and, if performed manually, time consuming. Automatic segmentations rely strongly on the image contrast and signal-to-noise ratio. Literature examining segmentation tool performances in real-world multi-site data acquisition settings is scarce. OBJECTIVE: FLAIR2, a combination of T2-weighted and fluid attenuated inversion recovery (FLAIR) images, improves tissue contrast while suppressing CSF. We compared the use of FLAIR and FLAIR2 in LesionTOADS, OASIS and the lesion segmentation toolbox (LST) when applied to non-homogenized, multi-center 2D-imaging data. METHODS: Lesions were segmented on 47 MS patient data sets obtained from 34 sites using LesionTOADS, OASIS and LST, and compared to a semi-automatically generated reference. The performance of FLAIR and FLAIR2 was assessed using the relative lesion volume difference (LVD), Dice coefficient (DSC), sensitivity (SEN) and symmetric surface distance (SSD). Performance improvements related to lesion volumes (LVs) were evaluated for all tools. For comparison, LesionTOADS was also used to segment lesions from 3 T single-center MR data of 40 clinically isolated syndrome (CIS) patients. RESULTS: Compared to FLAIR, the use of FLAIR2 in LesionTOADS led to improvements of 31.6% (LVD), 14.0% (DSC), 25.1% (SEN), and 47.0% (SSD) in the multi-center study. DSC and SSD significantly improved for larger LVs, while LVD and SEN were enhanced independent of LV. OASIS showed little difference between FLAIR and FLAIR2, likely due to its inherent use of T2w and FLAIR. LST replicated the benefits of FLAIR2 only in part, indicating that further optimization, particularly at low LVs is needed. In the CIS study, LesionTOADS did not benefit from the use of FLAIR2 as the segmentation performance for both FLAIR and FLAIR2 was heterogeneous. CONCLUSIONS: In this real-world, multi-center experiment, FLAIR2 outperformed FLAIR in its ability to segment MS lesions with LesionTOADS. The computation of FLAIR2 enhanced lesion detection, at minimally increased computational time or cost, even retrospectively. Further work is needed to determine how LesionTOADS and other tools, such as LST, can optimally benefit from the improved FLAIR2 contrast.

Gadolinium Deposition in Deep Brain Structures: Relationship with Dose and Ionization of Linear Gadolinium-Based Contrast Agents.

BACKGROUND AND PURPOSE: Dose-dependent association between hyperintensity in deep brain structures on unenhanced T1WIs and gadolinium-based contrast agent administrations has been demonstrated with subsequent histopathological confirmation of gadolinium deposition. Our aim was to determine whether greater exposure to linear gadolinium-based contrast agent administration is associated with higher signal intensity in deep brain structures on unenhanced T1-weighted MR imaging. Secondary objective was to compare signal intensity differences between ionic and nonionic linear gadolinium-based contrast agents. MATERIALS AND METHODS: Subjects with secondary-progressive MS originally enrolled in a multicenter clinical trial were studied retrospectively. Eighty subjects (high-exposure cohort) received 9 linear gadolinium-based contrast agent administrations (30 nonionic/50 ionic) between week -4 and year 1 and a tenth administration by year 2. One hundred fifteen subjects (low-exposure cohort) received 2 administrations (40 nonionic/75 ionic) between week -4 and year 1 and a third administration by year 2. Signal intensities were measured on unenhanced T1WIs by placing sample-points on the dentate nucleus, globus pallidus, caudate, thalamus, pons, and white matter, and they were normalized using the following ratios: dentate/pons, globus pallidus/white matter, caudate/white matter, and thalamus/white matter. RESULTS: Between week -4 and year 1, subjects in the high-exposure cohort showed increased signal intensity ratios in all regions (P < .01), while the low-exposure cohort showed only an increase in the dentate nucleus (P = .003). Between years 1 and 2, when both cohorts received only 1 additional gadolinium-based contrast agent, no significant changes were observed. In the high-exposure cohort, significantly higher changes in signal intensity ratios were observed in subjects receiving linear nonionic than in those receiving linear ionic gadolinium-based contrast agents. CONCLUSIONS: Hyperintensity in deep brain structures from gadolinium deposition is related to the number of doses and the type of linear gadolinium-based contrast agent (nonionic greater than ionic) administration.

What Have We Learned from Perfusion MRI in Multiple Sclerosis?

Using MR imaging, perfusion can be assessed either by dynamic susceptibility contrast MR imaging or arterial spin-labeling. Alterations of cerebral perfusion have repeatedly been described in multiple sclerosis compared with healthy controls. Acute lesions exhibit relative hyperperfusion in comparison with normal-appearing white matter, a finding mostly attributed to inflammation in this stage of lesion development. In contrast, normal-appearing white and gray matter of patients with MS has been mostly found to be hypoperfused compared with controls, and correlations with cognitive impairment as well as fatigue in multiple sclerosis have been described. Mitochondrial failure, axonal degeneration, and vascular dysfunction have been hypothesized to underlie the perfusion MR imaging findings. Clinically, perfusion MR imaging could allow earlier detection of the acute focal inflammatory changes underlying relapses and new lesions, and could constitute a marker for cognitive dysfunction in MS. Nevertheless, the clinical relevance and pathogenesis of the brain perfusion changes in MS remain to be clarified.

FLAIR2: A Combination of FLAIR and T2 for Improved MS Lesion Detection.

BACKGROUND AND PURPOSE: FLAIR and double inversion recovery are important MR imaging scans for MS. The suppression of signal from CSF in FLAIR and the additional suppression of WM signal in double inversion recovery improve contrast between lesions, WM and GM, albeit at a reduced SNR. However, whether the acquisition of double inversion recovery is necessary is still debated. Here, we present an approach that allows obtaining CSF-suppressed images with improved contrast between lesions, WM and GM without strongly penalizing SNR. MATERIALS AND METHODS: 3D T2-weighted and 3D-FLAIR data acquired from September 2014 to April 2015 in healthy volunteers (23.4 ± 2.4 years of age; female/male ratio, 3:2) and patients (44.1 ± 14.0 years of age; female/male ratio, 4:5) with MS were coregistered and multiplied (FLAIR(2)). SNR and contrast-to-noise measurements were performed for focal lesions and GM and WM. Furthermore, data from 24 subjects with relapsing-remitting and progressive MS were analyzed retrospectively (52.7 ± 8.1 years of age; female/male ratio, 14:10). RESULTS: The GM-WM contrast-to-noise ratio was by 133% higher in FLAIR(2) than in FLAIR and improved between lesions and WM by 31%, 93%, and 158% compared with T2, DIR, and FLAIR, respectively. Cortical and juxtacortical lesions were more conspicuous in FLAIR(2). Furthermore, the 3D nature of FLAIR(2) allowed reliable visualization of callosal and infratentorial lesions. CONCLUSIONS: We present a simple approach for obtaining CSF suppression with an improved contrast-to-noise ratio compared with conventional FLAIR and double inversion recovery without the acquisition of additional data. FLAIR(2) can be computed retrospectively if T2 and FLAIR scans are available.

Progressive multiple sclerosis exhibits decreasing glutamate and glutamine over two years.

BACKGROUND: Few biomarkers of progressive multiple sclerosis (MS) are sensitive to change within the two-year time frame of a clinical trial. OBJECTIVE: To identify biomarkers of MS disease progression with magnetic resonance spectroscopy (MRS) in secondary progressive MS (SPMS). METHODS: Forty-seven SPMS subjects were scanned at baseline and annually for two years. Concentrations of N-acetylaspartate, total creatine, total choline, myo-inositol, glutamate, glutamine, and the sum glutamate+glutamine were measured in a single white matter voxel. RESULTS: Glutamate and glutamine were the only metabolites to show an effect with time: with annual declines of (95% confidence interval): glutamate -4.2% (-6.2% to -2.2%, p < 10(-4)), glutamine -7.3% (-11.8% to -2.9%, p = 0.003), and glutamate+glutamine -5.2% (-7.6% to -2.8%, p < 10(-4)). Metabolite rates of change were more apparent than changes in clinical scores or brain atrophy measures. CONCLUSIONS: The high rates of change of both glutamate and glutamine over two years suggest they are promising new biomarkers of MS disease progression.

Dehydration affects spinal cord cross-sectional area measurement on MRI in healthy subjects.

STUDY DESIGN: This was a prospective cohort observational study. OBJECTIVE: To determine the effect of dehydration and rehydration on spinal cord cross-sectional area (CSA) measurement on magnetic resonance imaging (MRI). SETTING: MRI Research Centre, University of British Columbia, Canada. METHODS: Ten healthy subjects (aged 21-32 years) were scanned on a 3T MRI scanner at four time points: (1) baseline, (2) rescan after 1 h, (3) the next day after fasting for a minimum of 14 h and (4) after rehydration with 1.5 l of water over the course of 1 h. Two independent, established semi-automatic CSA measurement techniques (one based on two-dimensional (2D) edge detection, the other on three-dimensional (3D) surface fitting) were applied to a 3D T1-weighted scan of each subject at each time point, with the operator blinded to scan order. The percentage change in CSA from baseline to each subsequent time point was calculated. One-tailed paired t-tests were used to assess the significance of the changes from baseline. RESULTS: A decrease in CSA following dehydration was detected by both measurement methods, with a mean change of -0.654% (s.d.=0.778, P<0.05) and -0.650% (s.d.=1.071, P<0.05) for the first and second methods, respectively. CONCLUSION: Dehydration can confound CSA measurements on MRI. The magnitude of the effect is significant relative to short-term pathological changes that have been observed in diseases such as multiple sclerosis.

Application and a proposed modification of the 2010 McDonald criteria for the diagnosis of multiple sclerosis in a Canadian cohort of patients with clinically isolated syndromes.

BACKGROUND: The 2005 and 2010 McDonald criteria utilize magnetic resonance imaging (MRI) to provide evidence of disease dissemination in space (DIS) and time (DIT) for the diagnosis of multiple sclerosis (MS) in patients who have clinically isolated syndromes (CIS). METHODS: Data from 109 CIS patients not satisfying the 2005 criteria at entry into a randomized controlled minocycline trial were analyzed to determine the proportion who would have been diagnosed with MS at screening based on 2010 criteria. The impact of including symptomatic, as well as asymptomatic, MRI lesions to confirm DIT was also explored. RESULTS: Thirty percent (33/109) of patients, retrospectively, met the 2010 criteria for a diagnosis of MS at baseline. When both symptomatic and asymptomatic lesions were used to confirm DIT, three additional patients met the 2010 criteria. There was a significant 10.1% increase in the proportion of patients who met the 2010 DIS criteria, compared with the 2005 DIS criteria; however, two patients satisfied the 2005 DIS but not 2010 DIS criteria. CONCLUSION: Using 2010 McDonald criteria, 30% of the CIS patients could be diagnosed with MS using a single MRI scan. Inclusion of symptomatic lesions in the DIT criteria further increases this proportion to 33%.

Evaluation of safety monitoring guidelines based on MRI lesion activity in multiple sclerosis.

OBJECTIVE: We evaluate variants of a commonly used data safety monitoring guideline in clinical trials in multiple sclerosis (MS) that flags patients who, at a follow-up visit, have 5 or more contrast-enhancing lesions (CELs) above their baseline count. METHODS: We apply the guideline to a relapsing cohort and a secondary progressive cohort. We assess the number of patients that meet the guideline and describe the characteristics of these patients; we also examine the value of the guideline in predicting relapse occurrence in the 28 days following that MRI. These analyses were repeated for thresholds varying from 1 to 10 CELs above baseline. RESULTS: Between 4% and 6% of patients met the threshold of 5 in both cohorts; patients with higher baseline counts and higher T2 lesion burden were more apt to meet the threshold. After adjustment for other covariates, the odds ratio (OR) of relapse associated with meeting the threshold is significant (p < 0.05) or near significant (0.05 ≤ p < 0.10) for thresholds between 5 and 8 for the relapsing cohort, but not for the secondary progressive cohort. Across thresholds, the adjusted OR is consistently greater than 1, and there is an increasing trend as the threshold increases from 1 to 7. CONCLUSIONS: A guideline based on crossing a threshold CEL count above baseline may be valuable in monitoring patient safety. Further study should be conducted using different datasets to assess the generalizability of these results.

The impact of intensity variations in T1-hypointense lesions on clinical correlations in multiple sclerosis.

BACKGROUND: The correlations between T1-hypointense lesion ('black hole') volume and clinical measures have varied widely across previous studies. The degree of hypointensity in black holes is associated with the severity of tissue damage, but the impact on the correlation with disability is unknown. OBJECTIVES: To determine how variations in the intensity level used for lesion classification can impact clinical correlation, specifically with the Expanded Disability Status Scale (EDSS), and whether using a restricted range can improve correlation. METHODS: A highly automated image analysis procedure was applied to the scans of 24 multiple sclerosis (MS) patients with well-distributed EDSS scores to compute their black hole volumes at nine different levels of intensity relative to the reference intensities sampled in normal-appearing white matter (NAWM) and cerebrospinal fluid (CSF). Two methods of volume computation were used. RESULTS: The black hole volume-EDSS Spearman correlations ranged between 0.49-0.73 (first method) and 0.54-0.74 (second method). The strongest correlations were observed by only including the voxels with maximum intensities at 30-40% of the CSF to NAWM range. CONCLUSIONS: Intensity variations can have a large impact on black hole-EDSS correlation. Restricting the measurement to a subset of the darkest voxels may yield stronger correlations.

Proton MRS of large multiple sclerosis lesions reveals subtle changes in metabolite T(1) and area.

The T(1) values of metabolites were measured in eight subjects with clinically definite multiple sclerosis (MS) having at least one large brain lesion (2.6 ± 0.7 mL) and in eight age- and sex-matched healthy controls. MRS examinations were conducted at 1.5 T using point-resolved spectroscopy (PRESS) (TE = 30 ms, TR = 530, 750, 1200, 1500, 3500, 5000 ms). Spectra were acquired from a voxel placed in the largest lesion in the subject with MS, and in a corresponding voxel (same size and region) in normal white matter (NWM) in the matched control, and were fitted using LCModel. As there are regional variations in metabolite and water T(1) and metabolite signal areas, careful placement of the control voxel was necessary to measure subtle differences between the lesions and NWM. The T(1) and T(1)-corrected signal areas of creatine were the same in MS lesions as in controls. The T(1) values of choline were significantly shorter in MS lesions located in occipital and parietal, but not in frontal, white matter. N-Acetylaspartate (NAA) and myoinositol T(1) values in MS lesions were similar to those in NWM; however, the area of myoinositol correlated directly with lesion water T(1), and the area of NAA correlated inversely with lesion water T(1). MR spectra acquired at short TR require T(1) correction of choline for accurate quantification. Careful voxel placement in controls to match lesion location in subjects with MS enables a clearer view of the subtle changes in lesions.

Two-year study of cervical cord volume and myelin water in primary progressive multiple sclerosis.

BACKGROUND: Spinal cord involvement in multiple sclerosis (MS) is common and an important element in disability. Previous studies demonstrated smaller cervical cord area at the C2 level in MS compared to controls, and a decrease in cord area over 12 months, most marked in primary progressive MS (PPMS). A subset of subjects participating in a multicentre, double-blind, placebo-controlled clinical trial evaluating the efficacy of glatiramer acetate in PPMS (PROMiSe trial) were followed for 2 years. METHODS: 24 PPMS subjects, randomized to placebo (n = 9) and glatiramer acetate (n = 15), and 24 matched controls were studied. Cervical cord volume (CCV) at C2-3 was determined using a 3D inversion recovery (IR)-prepared spoiled-gradient echo sequence. Myelin water fraction (MWF) at C2-3 was obtained using a 32-echo IR-prepared relaxation sequence. Scans were repeated at baseline, years 1 and 2. RESULTS: Baseline CCV was significantly smaller for PPMS than controls [median (interquartile range) 951 (829-1043) vs. 1072 (1040-1129) mm(3), p = 0.0004] and MWF trended to be lower in PPMS cord [median (interquartile range) 0.225 (0.187-0.267) vs. 0.253 (0.235-0.266), p = 0.12]. Baseline CCV correlated with baseline Expanded Disability Status Scale, disease duration, brain white and grey matter volume. In PPMS, CCV was significantly decreased at year 1 (-0.83%, p = 0.04) and year 2 (-1.65%, p = 0.02). Baseline MWF correlated with baseline CCV and brain white and grey matter volume. MWF was significantly decreased from baseline for PPMS at year 2 (-10.5%, p = 0.01). Treatment effect was not detected on change in CCV nor MWF. CONCLUSIONS: Metrics at the level of the cord, including volume and MWF at C2-3, were lower in PPMS than controls and changed over 2 years only in PPMS.

Does MRI lesion activity regress in secondary progressive multiple sclerosis?

BACKGROUND: The rate of new contrast-enhancing lesions (CELs) on monthly magnetic resonance imaging (MRI) scans has been shown to decrease over a 9-month period in placebo-treated patients with relapsing-remitting (RR) multiple sclerosis (RRMS). OBJECTIVE: We examined this phenomenon in placebo-treated secondary progressive MS (SPMS) patients. METHODS: Patients were chosen from two clinical trials. Monthly scans were taken at screening, baseline and months 1-9 for Cohort-1 and months 1-6 for Cohort-2. We examined the monthly new CEL rates according to initial CEL level: 0, 1-3, >3 CELs at screening, and presence and absence of pre-study relapses. RESULTS: Respectively, 59, 21 and 14 of the 94 Cohort-1 patients, and 36, 17 and 9 of the 62 Cohort-2 patients had 0, 1-3 and >3 initial CELs. For Cohort-1, the monthly new CEL rates did not change during follow-up, regardless of initial CEL level. For Cohort-2, the monthly rate was unchanged in the 0 initial CEL subgroup, but decreased 33% (95% confidence interval: 8%, 52%) from months 1-3 to months 4-6 in the other two subgroups. For the combined cohorts, a decreasing rate was observed in the 12 patients with >3 initial CELs and pre-study relapses. CONCLUSIONS: The short-term trend of new CEL activity in placebo-treated SPMS patients may vary across cohorts.

Absolute metabolite concentrations calibrated using the total water signal in brain (1)H MRS.

Magnetic resonance spectroscopy (MRS) has been coupled with a multi-echo imaging sequence to determine the relaxation corrected signal areas of the metabolites and the tissue water. Stimulated echo acquisition mode (STEAM) spectra (TE/TM/TR 30/13.7/5000 ms) acquired from gray and white matter voxels in 43 healthy volunteers were fit using LCModel. Corresponding water signals, measured using a multi-echo T(2) imaging sequence, were fit with a Non-Negative Least Squares algorithm. Using this approach the water area could be T(1) and T(2) corrected for all three water compartments: cerebrospinal fluid (CSF), intra- and extra-cellular water, and myelin water. The image-based water measurement is an improvement over spectroscopy methods because it can be more sensitive to water changes in diseased tissue. Metabolite areas were also corrected for relaxation losses. In occipital gray matter, the concentrations of Cho, Cr, and N-acetyl aspartate (NAA) were 1.27 (0.06), 8.9 (0.3), and 9.3 (0.3) mmol/L tissue, respectively and in parietal white matter they were 1.90 (0.05), 7.9 (0.2), and 9.8 (0.2) mmol/L tissue. The Cho and Cr concentrations were different in occipital gray compared to parietal white matter (p < 0.0001 and <0.005, respectively).

Longitudinal changes in myelin water fraction in two MS patients with active disease.

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.

MR relaxation in multiple sclerosis.

This article provides an overview of relaxation times and their application to normal brain and brain and cord affected by multiple sclerosis. The goal is to provide readers with an intuitive understanding of what influences relaxation times, how relaxation times can be accurately measured, and how they provide specific information about the pathology of MS. The article summarizes significant results from relaxation time studies in the normal human brain and cord and from people who have multiple sclerosis. It also reports on studies that have compared relaxation time results with results from other MR techniques.

Dirty-appearing white matter in multiple sclerosis: preliminary observations of myelin phospholipid and axonal loss.

"Dirty-appearing white matter" (DAWM) in multiple sclerosis (MS) is defined as a region(s) with ill-defined borders of intermediate signal intensity between that of normal-appearing white matter (NAWM) and that of plaque on T(2)-weighted and proton density imaging. To delineate the histopathology of DAWM, four formalin-fixed cerebral hemisphere slices of three MS patients with DAWM were scanned with T(2)- weighted and proton density sequences. The myelin water fraction (MWF) was obtained by expressing the short T(2) component as a fraction of the total T(2) distribution. Hemispheric sections were then stained with Luxol fast blue (LFB) for myelin phospholipids, for myelin basic protein (MBP) and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) for myelin; Bielschowsky silver impregnation for axons; and for glial fibrillary acidic protein (GFAP) for astrocytes. Compared to NAWM, DAWM showed reduction in MWF, corresponding to a reduction of LFB staining. DAWM also showed reduced Bielschowsky staining. Quantitatively, the change in MWF in DAWM most consistently correlated with the change in LFB staining. The findings of this preliminary study suggest that DAWM is characterized by loss of myelin phospholipids, detected by the short T(2) component, and axonal reduction.

Reduction in magnetic resonance imaging T2 burden of disease in patients with relapsing-remitting multiple sclerosis: analysis of 48-week data from the EVIDENCE (EVidence of Interferon Dose-response: European North American Comparative Efficacy) study.

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.

Multi-parametric MR assessment of T(1) black holes in multiple sclerosis : evidence that myelin loss is not greater in hypointense versus isointense T(1) lesions.

BACKGROUND: Chronic T(1) hypointense lesions in multiple sclerosis (MS) are areas of severe tissue destruction. The purpose of this study was to compare total water content (WC),myelin water content (MWC), magnetization transfer ratio (MTR), T(1) relaxation time (T(1)), mean T(2) relaxation time (GMT(2)) between stable MS lesions that are hypointense and isointense on T(1)-weighted images. METHODS: Six MS patients were scanned five times over one year. WC, MWC, MTR, T(1) and GMT(2) were calculated for 15 isointense and 15 hypointense chronically stable T(1) lesions, as well as contralateral normal appearing white matter (NAWM). RESULTS: All MR measurements from both iso- and hypointense stable lesion types were significantly different from NAWM. WC, T(1) and GMT(2) were significantly higher and MTR significantly lower in hypointense T(1) lesions compared to isointense lesions. MWC was not significantly different between iso- and hypointense lesions. CONCLUSIONS: This work suggests that myelin loss occurs equally in both the chronic isointense and hypointense lesions but hypointense lesions are distinguished by increased extracellular water.

MRI T2 lesion burden in multiple sclerosis: a plateauing relationship with clinical disability.

BACKGROUND: Previous studies have shown only modest correlation between multiple sclerosis (MS) lesions on MRI and clinical disability. OBJECTIVE: To investigate the relationship between proton density/T2-weighted (T2) burden of disease (BOD) quantitatively measured on MRI scans and clinical determinants including disability. METHODS: Using the Sylvia Lawry Centre for Multiple Sclerosis Research (SLCMSR) database, the authors studied baseline T2 BOD data from a pooled subsample of 1,312 placebo MS patients from 11 randomized controlled trials. Univariate comparisons guided development of multiple regression models incorporating the most important clinical predictors. RESULTS: Significant, although weak to moderate, correlations were found between T2 BOD and age at disease onset, disease duration, disease course, disability (as measured by the Expanded Disability Status Scale [EDSS]), relapse rate, certain presenting symptoms, and gadolinium enhancement. An unexpected but key finding that persisted in the multiple regression analyses was a plateauing relationship between T2 BOD and disability for EDSS values above 4.5. CONCLUSIONS: This study confirmed the limited correlation between clinical manifestations and T2 burden of disease (BOD) but revealed an important plateauing relationship between T2 BOD and disability.