Brain, Vol. 123, No. 11, 2256-2263,
November 2000
© 2000 Oxford University Press
The effect of interferon beta-1b treatment on MRI measures of cerebral atrophy in secondary progressive multiple sclerosis
Correspondence to:
D. H. Miller, NMR Research Unit, Institute of Neurology, National Hospital, Queen Square, London WC1N 3BG, UK
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Abstract |
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The recently completed European trial of interferon beta-1b (IFNß-1b) in patients with secondary progressive multiple sclerosis (SP multiple sclerosis) has given an opportunity to assess the impact of treatment on cerebral atrophy using serial MRI. Unenhanced T1-weighted brain imaging was acquired in a subgroup of 95 patients from five of the European centres; imaging was performed at 6-month intervals from month 0 to month 36. A blinded observer measured cerebral volume on four contiguous 5 mm cerebral hemisphere slices at each time point, using an algorithm with a high level of reproducibility and automation. There was a significant and progressive reduction in cerebral volume in both placebo and treated groups, with a mean reduction of 3.9 and 2.9%, respectively, by month 36 (P = 0.34 between groups). Exploratory subgroup analyses indicated that patients without gadolinium (Gd) enhancement at the baseline had a greater reduction of cerebral volume in the placebo group (mean reduction at month 36: placebo 5.1%, IFNß-1b 1.8%, P < 0.05) whereas those with Gd-enhancing lesions showed a trend to greater reduction of cerebral volume if the patient was on IFNß-1b (placebo 2.6%, IFNß-1b 3.7%; P > 0.05). These results are consistent with ongoing tissue loss in both arms of this study of secondary progressive multiple sclerosis. This finding is concordant with previous observations that disease progression, although delayed, is not halted by IFNß. The different pattern seen in patients with and without baseline gadolinium enhancement suggests that part of the cerebral volume reduction observed in IFNß-treated patients may be due to the anti-inflammatory/antioedematous effect of the drug. Longer periods of observation and larger groups of patients may be needed to detect the effects of treatment on cerebral atrophy in this population of patients with advanced disease
cerebral atrophy; interferon beta-1b; secondary progressive multiple sclerosis; multiple sclerosis; MRI
EDSS = expanded disability status scale; IFNß-1b = interferon beta-1b; RR = relapsing–remitting; SP = secondary progressive
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Introduction |
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The recently published trial of interferon beta-1b (IFNß-1b) in secondary progressive (SP) multiple sclerosis demonstrated a highly significant effect of treatment on the primary clinical outcome—delay of confirmed disability progression—as well as on relapse-related parameters (European Study Group, 1998
). However, the treatment effect on the primary MRI outcomes was considerably greater: a reduction in monthly gadolinium-enhancing lesion activity of up to 80% was found on treatment, in association with complete stabilization of T2 lesion volume in the treated group after 3 years (Miller et al., 1999). This disparity between the magnitude of the treatment effect on MRI and clinical indices has also been noted in a number of other recent phase III studies in earlier relapsing–remitting (RR) multiple sclerosis (IFNß Study Group, 1995, PRISMS Study Group, 1998). Consequently, appropriate concerns have been raised about the utility of such MRI indices as outcome measures in multiple sclerosis treatment trials (Miller et al., 1998).
The limited nature of the correlation between clinical progression, assessed with the Expanded Disability Status Scale (EDSS) and the change in T2 lesion volume, has also been reported in a number of recent studies (Paty et al., 1993; Molyneux et al., 1998). This is likely to reflect the low pathological specificity of standard T2-weighted imaging for the more destructive pathological elements of demyelination and axonal loss, and makes caution advisable in the interpretation of T2 lesion volume findings in isolation.
Several novel MRI techniques have been developed recently that offer the prospect of selectively monitoring different aspects of the disease process. The European IFNß-1b trial in SP multiple sclerosis has provided the opportunity to apply a number of these MRI tools in a large phase III study. In particular, serial measurements of cerebral volume have been performed in a subgroup of patients in this study, giving an opportunity to study the effect of IFNß-1b treatment on tissue loss in patients with SP multiple sclerosis. The present paper reports the results of this analysis.
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Methods |
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Seven hundred and eighteen patients with SP multiple sclerosis were recruited from 32 European centres into a randomized, double-blind, placebo-controlled trial of IFNß-1b planned to occupy 3 years. The trial design, the major clinical endpoints and the core MRI protocol have been described elsewhere (Polman et al., 1995
; European Study Group 1998). In addition to the annual imaging, a subgroup of 95 patients from five of the 32 European centres underwent T1-weighted brain imaging at intervals of 6 months; from these images an assessment of tissue loss was performed using methods described below.
MRI acquisition
The brain MRI protocol comprised an unenhanced T1-weighted spin-echo (SE) sequence with the following parameters: TR (repetition time) = 500–700 ms; TE (echo time) 5–25 ms; field of view 25 cm; 28 axial oblique, contiguous, interleaved 5 mm slices; matrix 256 x 256; 1 or 2 excitations. This protocol was performed at baseline and then at intervals of 6 months until month 36; repositioning was performed with a protocol based on standardized anatomical landmarks (Gallagher et al., 1997).
MRI analysis
Measurement of cerebral volume was performed by a single blinded observer using an automated algorithm that first extracted the brain from the skull and CSF spaces, and then quantified the volume of the extracted image. Details of the algorithm have been described fully (Losseff et al., 1996). This approach was highly reproducible, with a mean scan–rescan coefficient of variation of <1%. The analysis process required an observer to select four contiguous slices, with the most caudal at the level of the velum interpositum cerebri, as this was found to be the most reproducible method covering the region of interest. Next, the algorithm was applied slice by slice, with subsequent review of the effectiveness of the extraction process. In a small percentage of slices, the extraction was incomplete, resulting in residual small islands of skull, and these non-brain regions were manually deleted where necessary.
Following extraction and editing, the volume of the extracted brain in the four slices was calculated with in-house software (Calc-Vol; L. Wang, Institute of Neurology, University College London, London, UK). Progressive atrophy was expressed as change in millilitres per year.
For the serial MRI studies of each patient, each study was compared against the baseline image to ensure that repositioning was adequate. When this was not the case, that image was excluded from the analysis.
Statistical analysis
Comparison between baseline cerebral volumes as defined (i.e. the four contiguous slices rostral to the velum interpositum) in the placebo and treated groups was performed using the Wilcoxon rank sum test. The significance of any within-group change in cerebral volume from baseline was assessed using a paired t-test for both the placebo and the treated patients. This analysis was performed for both absolute and percentage change in the MRI variables. Statistical analyses included all data available at a given time, with missing data maintained as missing. In addition, cerebral volumes at individual last visits (last scan available) were evaluated for all patients who had data available at least once during treatment.
Non-parametric analysis of covariance with stratification adjustment for centre and covariance adjustment for baseline cerebral volume was used to assess the significance of any treatment effect on cerebral volume at each time point. Post hoc analysis was performed by stratifying patients into those with and those without gadolinium enhancement at the baseline and subsequently repeating the analysis. However, since sample sizes are small in the subgroups of patients with and without gadolinium enhancement at the baseline, consideration of centres might not be appropriate. Thus, non-parametric analyses of covariance with adjustment for baseline cerebral volume alone were used to explore associations between treatment and percentage change from baseline in cerebral volume. In addition, a repeated measures analysis of variance was performed to further investigate the significance of any treatment effect over the whole study duration.
The strength of the relationship between the MRI data and two clinical variables—(i) EDSS and (ii) a composite neuropsychological change score (Rao et al., 1991)—was assessed with Goodman–Kruskal correlation coefficients. The composite neuropsychological change score measured sustained attention and concentration, verbal learning and delayed recall, visuospatial learning and delayed recall, and semantic retrieval (Rao et al., 1991). The relationship between cerebral volume and the primary MRI variables from the study (T2 lesion volume and new lesion activity) was also assessed with Goodman–Kruskal correlation coefficients.
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Results |
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Patients (Table 1
)The placebo and treated groups were well matched for baseline cerebral volume as defined (307 and 308 cm3 in placebo and treated groups, respectively; P = 0.90), and for age, duration of multiple sclerosis, number of enhancing lesions, T2 lesion volume, and EDSS change and number of relapses in the 2 years before the study. The time since evidence of progressive deterioration and diagnosis of SP multiple sclerosis was longer and EDSS scores were higher in the placebo group (P < 0.01), and the proportion of patients with higher EDSS scores was significantly greater in the placebo than the IFNß-1b group (P < 0.05); none of these group differences was seen in the study cohort as a whole (European Study Group, 1998
). In the present subgroup, 43.5% of the patients on placebo were female compared with 53.1% of the patients on IFNß-1b; this is in contrast to the study cohort as a whole, in which approximately 60% of patients in both groups were female.
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Of the 95 patients recruited into the cerebral atrophy protocol, 65 had cerebral volume measured at month 36. The dropouts reflect a combination of (i) patients who dropped out of the entire study, or just the imaging protocol (n =20), and (ii) MRI studies that were rejected due to inadequate repositioning (n = 10).
Cerebral volume
The changes in cerebral volume over the study duration according to treatment effect are given in Table 2 and Fig. 1. In the placebo group, a significant 0.89% mean reduction in cerebral volume was apparent at 6 months compared with baseline (P = 0.0005) and further reductions were seen throughout the study, such that by month 36 there was a mean reduction in cerebral volume of 3.86% compared with baseline.
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In the treated group, a significant mean reduction in cerebral volume of 1.39% was seen at 6 months compared with baseline (P < 0.0001), and further reductions were identified at subsequent time points, such that by month 36 there was a mean reduction in cerebral volume of 2.91% compared with baseline.
There was no significant effect of treatment on the progression of cerebral volume loss at any of the 6-monthly time points, although there was a trend towards greater reduction in cerebral volume at 6 months in the treated group (P = 0.09). Furthermore, the repeated measures analysis of variance did not show a significant treatment effect on cerebral volume (P = 0.14).
Post hoc analysis was performed by stratifying patients into those with and those without gadolinium enhancement at baseline and subsequently repeating the analysis (Tables 3 and 4, Figs 2 and 3). In the inactive group (no enhancement at baseline), there was a greater loss of cerebral volume at each time point in the placebo than in the treatment group (Fig. 2). The mean reductions in cerebral volume in this group at 36 months were 5.1 and 1.8% for the placebo and treated subgroups, respectively (P = 0.0026); significance was not reached at earlier time points. In the group with one or more enhancing lesions at baseline, there was a greater loss of cerebral volume in the treated than in the placebo subgroup at all time points (Fig. 3); the mean reductions at month 36 were 3.7% in the treated subgroup and 2.6% in the placebo subgroup (P = 0.34).
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Clinical/MRI correlations
Patients with confirmed EDSS progression had a higher rate of atrophy than those without progression in both treatment groups. In those with confirmed progression, mean percentage reductions in cerebral volume from baseline to month 36 were 4.95 and 3.31% in the placebo and treated groups, respectively. In contrast, for patients without progression, mean percentage changes were 2.97 and 2.56% for the placebo and treated groups, respectively. There was a significant but low correlation at baseline between EDSS and cerebral volume for the group as a whole (r = –0.18, P = 0.018). No longitudinal relationship was identified between the change in EDSS and the change in cerebral volume. However, a significant relationship between cerebral volume and the composite neuropsychological score at baseline was identified for the group as a whole (r = 0.25, P = 0.007). This correlation was significant in the placebo group (r = 0.30, P = 0.005) but not in the treated group (r = 0.15, P =0.18). A significant relationship between percentage change in cerebral volume and the composite neuropsychological change score was also identified for the group as a whole (r = 0.23, P < 0.005), which was also significant in the placebo group (r = 0.32, P = 0.002) but not in the treated group (r = 0.14, P = 0.31).
There was no difference in the rate of cerebral atrophy between patients who had one or more courses of steroids during the study and those who did not (data not shown).
A modest correlation, approaching statistical significance, was found over the study duration between percentage change in T2 lesion volume and cerebral volume (r = –0.12, P =0.098) and between enhancing lesion activity (measured for months 1–6 and 19–24) and percentage change in cerebral volume (r = –0.15, P = 0.059).
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Discussion |
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This study documents a decrease in cerebral volume in both treatment groups over a period of 3 years; in contrast to the effect observed on the clinical parameters, and to a much greater extent the effect on the established MRI parameters (European Study Group 1999; Miller et al., 1999
), there was no statistically significant effect of treatment on the development of atrophy. A number of factors might have contributed to these results.
First, it might be queried whether unblinding of the MRI analyst could have influenced the results. This is most unlikely. The analyst was blinded to the treatment status of the patients and did not have access to their other imaging data, such as T2-weighted and gadolinium-enhanced images, from which the observation of an apparent treatment effect might have led to unblinding. The analyst was unblinded to the date of the MRI studies; in fact, this was necessary in order to check for repositioning against the baseline study. However, knowledge of the scan date should not have affected the results since the technique is almost fully automated and is thus not potentially subject to operator-dependent measurement bias. The average rate of ~1% loss of cerebral tissue per year also accords well with that reported in other studies (Losseff et al., 1996; Fox et al., 2000).
Secondly, it is possible that methodological limitations may have prevented the identification of a genuine treatment effect. This seems unlikely since the technique adopted to measure cerebral volume has an extremely high level of reproducibility, with a scan–rescan variability of <1% (Losseff et al., 1996). Furthermore, the high level of automation reduced the risk of operator-dependent measurement error and measurement drift over time. The almost linear reduction in cerebral volume in the placebo group also suggests that it was detecting genuine change over time. This supports an earlier study in which significant change in cerebral volume was also demonstrated over 18 months in a smaller cohort of multiple sclerosis patients (Losseff et al., 1996).
Thirdly, the study may have been inadequately powered to detect a treatment effect. Specific power calculations were not performed before the study, as there were insufficient natural history data obtained with these new techniques to allow the estimation of sample size. Furthermore, whereas 95 patients were recruited into the atrophy protocol, only 65 patients had cerebral their volume measured at month 36.
Fourthly, a genuine treatment effect (i.e. a slowing of the rate of progressive tissue loss) may have been obscured by the effect of acute inflammatory lesions at baseline. Among the patients with no enhancing lesions at baseline (in whom relatively few enhancing lesions occurred at follow-up even in the placebo group), there was less cerebral volume reduction in the treated than in the placebo group at each time point, and the overall loss of volume in the treated group was less than half of that seen in the placebo group. In contrast, among the patients with at least one enhancing lesion at baseline there was a trend for the treated group to develop more volume loss than the placebo group. This may well reflect the fact that IFNß-1b treatment is associated with resolution of oedema and inflammation in acute multiple sclerosis lesions (Miller et al., 1999), resulting in a loss of volume that is not solely due to ongoing tissue loss (i.e. demyelination or axonal loss). The profound effect of IFNß-1b in reducing the duration of gadolinium enhancement has been reported recently (Miller et al., 1999), indicating that IFNß-1b treatment facilitates a more rapid resolution of blood–brain barrier breakdown and inflammation. This resolution of oedema and acute inflammatory infiltrate due to treatment could have resulted in an apparently greater loss of cerebral volume in the treated than in the untreated group. This may have masked a genuine effect of treatment in slowing the rate of ongoing tissue loss in the cohort as a whole. Such an effect may also have contributed to the apparent uncoupling of the relationship between the change in cerebral volume and the neuropsychological change score in the treated cohort. Furthermore, ongoing enhancing activity in the placebo group, which was considerable in those who had enhancing lesions at baseline, may well have masked the true extent of atrophy due to progressive tissue loss in this cohort.
Notwithstanding the above caveats, it is likely that most of the anti-oedema effect of treatment would occur within the first few weeks and months, and it is clear that cerebral atrophy continued to accrue in both treatment arms throughout the whole study period. This is in contrast to the dramatic and sustained effect of treatment on the well-established conventional MRI indices of disease activity (gadolinium enhancement) and progression (T2 lesion volume). It is, however, noteworthy that, in terms of magnitude, the results of treatment on cerebral tissue loss more closely matched the major clinical outcome measure of disability progression. Thus, disability continued to accrue in the treated group, albeit to a significantly lesser extent than in the placebo group, and the results of the current study suggest a trend towards a modest treatment effect on cerebral atrophy, although the lower sample size in this analysis might explain why a significant treatment effect was seen only with the clinical endpoints. However, it seems clear that any effect of treatment on the rate of cerebral tissue loss in this population of patients would be modest.
What mechanisms might account for such an ongoing loss of cerebral tissue in the treated group despite marked concurrent reduction in acute inflammatory lesions? One possibility is that diffuse tissue atrophy develops in multiple sclerosis by mechanisms that are not yet understood but which are independent of focal inflammatory lesion activity. An alternative explanation is that atrophy is a consequence of earlier inflammatory activity. Recent work has supported the notion that the acute inflammatory process may result in an inevitable pathological cascade, with demyelination and axonal loss as the end result (Coles et al., 1999; Paollilo et al., 1999, Simon et al., 1999). Treatment aimed at preventing the formation of further new lesions may have little effect on this process, once established. That atrophy can occur in the face of minimal inflammatory multiple sclerosis lesion activity is also suggested by studies in primary progressive multiple sclerosis, in which gadolinium enhancement is relatively infrequent, but substantial atrophy nonetheless occurs in the brain (Filippi et al., 1999; Stevenson et al., 2000; Tortorella et al., 2000). It is therefore possible that IFNß-1b will have a greater effect in slowing the progression of atrophy if given earlier in the disease course. It is of interest that IFNß-1a has been reported to slow the progression of atrophy in a group of patients with RR multiple sclerosis and minimal disability, although this effect was only marginally significant and then only in the second year of treatment (Rudick et al., 1999). Also, the cohort studied was larger than in the present study, increasing the likelihood of demonstrating statistical significance, and the methods for quantifying atrophy were not the same as in the current study. Further work is therefore needed both to elucidate the mechanisms by which atrophy develops at different stages of the disease and to determine whether the effect of IFNß treatment on atrophy progression at the various stages of the disease is indeed different.
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European Study Group on Interferon beta-1b in Secondary Progressive Multiple Sclerosis (MRI)*
*Corresponding author: D. H. Miller, Queen Square NMR Research Group, London
Contributors
Investigators (principal investigators in bold)
Aberdeen: R. Knight, J. E. C. Hern, O. J. Robb, J. Moore
Amsterdam: C. Polman, J. Valk, F. Barkhof, J. H. van Waesberghe, T. Schweigmann, L. Pfennings
Barcelona: J. Montalbán, A. Rovira, S. Pedraza, C. Jacas
Basel: L. Kappos, E. W. Radü, A. Plohmann
Belfast: S. Hawkins, K. E. Bell, C. S. McKinstry
Berlin: H. Altenkirch, K. Baum, K. M. Einhäupl, P. Marx,
R. Lehmann, H. Bauer
Birmingham: D. Francis, E. B. Rolfe
Bordeaux: B. Brochet, V. Dousset, S. Auriacombe
Cardiff: C. M. Wiles, S. F. S. Halpin, M. D. Hourihan
Dublin: M. Hutchinson, D. McErlaine, T. Burke
Düsseldorf: G. Stoll, T. Kahn
Erfurt: H. W. Kölmel, R. Kachel, H. Schulz
Florence: L. Amaducci (died 1998), L. Massacesi, C. Fonda,
L. Bracco
Göttingen: S. Poser, A. Riegel, B. Welskop
Groningen: J. Minderhoud, J. De Keyser, H. van Woerden,
T. de Jong, J. M. Spikman
Helsinki: J. Wikström, O. Salonen
Huddinge: S. Fredrikson, B. Isberg
Leuven: G. Wilms, P. Demaerel
London: D. Miller, D. W. Langdon
Lyon: C. Confavreux, J.-C. Froment
Masku: M. Panelius, P. Sonninen, H. Oivanen, J. Ruutiainen,
P. Hämäläinen
Melsbroek: M. D'Hooghe, L. Vleugels
Milan: G. Comi, M. Filippi, M. Rovaris, M. Falautano
Munich: R. Hohlfeld, T. A. Yousry, C. Becker, F. Stadie,
P. Eppmann
Newcastle: N. Cartlidge, A. Coulthard, P. English, C. Skilbeck
Osnabrück: P. Haller, A.W. Frank, L. Wetzig
Paris: O. Lyon-Caen, E. Cabanis, M.-T. Iba-Zizen, N. Benoît
Rennes: G. Edan, M. Carsin, Y. Rolland
Rome: C. Fieschi, S. Bastianello, E. Giugni
Sheffield: S. J. L. Howell, T. J. Hodgson, C. A. J. Romanowski
Toulouse: M. Clanet, I. Berry, D. Ibarrolla, O. Martin,
C. Pigois-Gayo, S. Petit
Vienna: H. Kollegger, L. Deecke, S. Trattnig, E. Knauder
Würzburg: R. Gold, H.-P. Hartung, D. Hahn, W. Kenn, T. Pabst, R. Lütkewitte
Queen Square MRI Central Evaluation Unit (London)
G. J. Barker, P. Brex, J. Cook, A. Fletcher, C. Fogg, D. Galetti, H. Gallagher, M. Gawne-Cain, B. Gomez-Anson, S. Gregory,
E. Gunn, T. Holmes, L. Livingstone, M. Lowis, D. G. MacManus, R. Maunder, B. McNulty, C. Middleditch, D. H. Miller,
P. D. Molyneux, I. F. Moseley, C. Noctor, J. O'Riordan,
T. Pearce, P. Robinson, A. Stepney, V. Stevenson, P. Tofts, N. Tubridy,
L. Wang, I. Walsh
Writing Committee
D. H. Miller, P. D. Molyneux, G. J. Barker, D. G. MacManus,
I. F. Moseley, K. Wagner
Berlin (Schering AG): K. Beckmann, (statistician) C. Christel
Richmond (Berlex Laboratories): L. Bedell, (statistician)
Steering Committee
Amsterdam: C. H. Polman
Basle: L. Kappos
Berlin (Schering AG): F. Dahlke, M. Ghazi, K. Wagner
London: A. J. Thompson
Rome: C. Pozzilli
Independent Advisory Board
Bethesda: H. McFarland (Chairman)
Vancouver: J. Petkau (statistical adviser)
Rennes: O. Sabouraud
Würzburg: K. Toyka
Data entry and statistical analyses
Parexel, Berlin
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Received March 27, 2000. Revised June 30, 2000. Accepted July 10, 2000.
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R. Zivadinov, L. Locatelli, D. Cookfair, B. Srinivasaraghavan, A. Bertolotto, M. Ukmar, A. Bratina, C. Maggiore, A. Bosco, A. Grop, et al. I nterferon beta-1a slows progression of brain atrophy in relapsing-remitting multiple sclerosis predominantly by reducing gray matter atrophy Multiple Sclerosis, May 1, 2007; 13(4): 490 - 501. [Abstract] [PDF]
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J H Simon Brain atrophy in multiple sclerosis: what we know and would like to know Multiple Sclerosis, November 1, 2006; 12(6): 679 - 687. [Abstract] [PDF]
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L. Kappos, A. Traboulsee, C. Constantinescu, J. -P. Eralinna, F. Forrestal, P. Jongen, J. Pollard, M. Sandberg-Wollheim, C. Sindic, B. Stubinski, et al. Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS. Neurology, September 26, 2006; 67(6): 944 - 953. [Abstract] [Full Text] [PDF]
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 J T H Van Asseldonk, L H Van den Berg, S Kalmijn, R M Van den Berg-Vos, C H Polman, J H J Wokke, and H Franssen Axon loss is an important determinant of weakness in multifocal motor neuropathy. J. Neurol. Neurosurg. Psychiatry, June 1, 2006; 77(6): 743 - 747. [Abstract] [Full Text] [PDF]
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Y. Ge Multiple Sclerosis: The Role of MR Imaging AJNR Am. J. Neuroradiol., June 1, 2006; 27(6): 1165 - 1176. [Abstract] [Full Text] [PDF]
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S. J. Pittock, B. G. Weinshenker, J. H. Noseworthy, C. F. Lucchinetti, M. Keegan, D. M. Wingerchuk, J. Carter, E. Shuster, and M. Rodriguez Not every patient with multiple sclerosis should be treated at time of diagnosis. Arch Neurol, April 1, 2006; 63(4): 611 - 614. [Full Text] [PDF]
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E. M. Frohman, E. Havrdova, F. Lublin, F. Barkhof, A. Achiron, M. K. Sharief, O. Stuve, M. K. Racke, L. Steinman, H. Weiner, et al. Most patients with multiple sclerosis or a clinically isolated demyelinating syndrome should be treated at the time of diagnosis. Arch Neurol, April 1, 2006; 63(4): 614 - 619. [Full Text] [PDF]
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C. M. Dalton, K. A. Miszkiel, P. W. O'Connor, G. T. Plant, G.P.A. Rice, and D. H. Miller Ventricular enlargement in MS: One-year change at various stages of disease Neurology, March 14, 2006; 66(5): 693 - 698. [Abstract] [Full Text] [PDF]
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N. D. Richert, T. Howard, J. A. Frank, R. Stone, J. Ostuni, J. Ohayon, C. Bash, and H. F. McFarland Relationship between inflammatory lesions and cerebral atrophy in multiple sclerosis Neurology, February 28, 2006; 66(4): 551 - 556. [Abstract] [Full Text] [PDF]
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H. Krapf, S. P. Morrissey, O. Zenker, T. Zwingers, R. Gonsette, H. -P. Hartung, and the MIMS Study Group Effect of mitoxantrone on MRI in progressive MS: Results of the MIMS trial Neurology, September 13, 2005; 65(5): 690 - 695. [Abstract] [Full Text] [PDF]
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S. B. Coutts, M. D. Hill, J. E. Simon, C. -H. Sohn, J. N. Scott, A. M. Demchuk, and for the VISION Study Group Silent ischemia in minor stroke and TIA patients identified on MR imaging Neurology, August 23, 2005; 65(4): 513 - 517. [Abstract] [Full Text] [PDF]
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R. J Fox, E. Fisher, J. Tkach, J.-C. Lee, J. A Cohen, and R. A Rudick Brain atrophy and magnetization transfer ratio following methylprednisolone in multiple sclerosis: short-term changes and long-term implications Multiple Sclerosis, April 1, 2005; 11(2): 140 - 145. [Abstract] [PDF]
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M. Tiberio, D. T. Chard, D. R. Altmann, G. Davies, C. M. Griffin, W. Rashid, J. Sastre-Garriga, A. J. Thompson, and D. H. Miller Gray and white matter volume changes in early RRMS: A 2-year longitudinal study Neurology, March 22, 2005; 64(6): 1001 - 1007. [Abstract] [Full Text] [PDF]
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M. Hardmeier, S. Wagenpfeil, P. Freitag, E. Fisher, R. A. Rudick, M. Kooijmans, M. Clanet, E. W. Radue, L. Kappos, and for the European IFNss-1a in Relapsing MS Dose Com Rate of brain atrophy in relapsing MS decreases during treatment with IFN{beta}-1a Neurology, January 25, 2005; 64(2): 236 - 240. [Abstract] [Full Text] [PDF]
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M. Filippi, M. A. Rocca, E. Pagani, G. Iannucci, M. P. Sormani, F. Fazekas, S. Ropele, O. R. Hommes, and G. Comi European Study on Intravenous Immunoglobulin in Multiple Sclerosis: Results of Magnetization Transfer Magnetic Resonance Imaging Analysis Arch Neurol, September 1, 2004; 61(9): 1409 - 1412. [Abstract] [Full Text] [PDF]
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F. M. Boneschi, M. Rovaris, G. Comi, and M. Filippi The use of magnetic resonance imaging in multiple sclerosis: lessons learned from clinical trials Multiple Sclerosis, August 1, 2004; 10(4): 341 - 347. [Abstract] [PDF]
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F G Maggs and J Palace The pathogenesis of multiple sclerosis: is it really a primary inflammatory process? Multiple Sclerosis, June 1, 2004; 10(3): 326 - 329. [Abstract] [PDF]
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L. Kappos Effect of drugs in secondary disease progression in patients with multiple sclerosis Multiple Sclerosis, June 1, 2004; 10(1_suppl): S46 - S55. [Abstract] [PDF]
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L. Kappos Effect of drugs in secondary disease progression in patients with multiple sclerosis Multiple Sclerosis, May 1, 2004; 10(3_suppl): S46 - S55. [Abstract] [PDF]
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J. A. Frank, N. Richert, C. Bash, L. Stone, P. A. Calabresi, B. Lewis, R. Stone, T. Howard, and H. F. McFarland Interferon-{beta}-1b slows progression of atrophy in RRMS: Three-year follow-up in NAb- and NAb+ patients Neurology, March 9, 2004; 62(5): 719 - 725. [Abstract] [Full Text] [PDF]
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X Lin, C R Tench, B Turner, L D Blumhardt, and C S Constantinescu Spinal cord atrophy and disability in multiple sclerosis over four years: application of a reproducible automated technique in monitoring disease progression in a cohort of the interferon {beta}-1a (Rebif) treatment trial J. Neurol. Neurosurg. Psychiatry, August 1, 2003; 74(8): 1090 - 1094. [Abstract] [Full Text] [PDF]
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M. Inglese, J.H.T.M. van Waesberghe, M. Rovaris, K. Beckmann, F. Barkhof, D. Hahn, L. Kappos, D.H. Miller, C. Polman, C. Pozzilli, et al. The effect of interferon {beta}-1b on quantities derived from MT MRI in secondary progressive MS Neurology, March 11, 2003; 60(5): 853 - 860. [Abstract] [Full Text] [PDF]
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B. Turner, X. Lin, G. Calmon, N. Roberts, and L. D Blumhardt C erebral atrophy and disability in relapsing-remitting and secondary progressive multiple sclerosis over four years Multiple Sclerosis, February 1, 2003; 9(1): 21 - 27. [Abstract] [PDF]
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S.M. Leary, D.H. Miller, V.L. Stevenson, P.A. Brex, D.T. Chard, and A.J. Thompson Interferon {beta}-1a in primary progressive MS: An exploratory, randomized, controlled trial Neurology, January 14, 2003; 60(1): 44 - 51. [Abstract] [Full Text] [PDF]
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E. Fisher, R. A. Rudick, J. H. Simon, G. Cutter, M. Baier, J. -C. Lee, D. Miller, B. Weinstock-Guttman, M. K. Mass, D. S. Dougherty, et al. Eight-year follow-up study of brain atrophy in patients with MS Neurology, November 12, 2002; 59(9): 1412 - 1420. [Abstract] [Full Text] [PDF]
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R Leigh, J Ostuni, D Pham, A Goldszal, B K Lewis, T Howard, N Richert, H McFarland, and J A Frank Estimating cerebral atrophy in multiple sclerosis patients from various MR pulse sequences Multiple Sclerosis, October 1, 2002; 8(5): 420 - 429. [Abstract] [PDF]
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R. J. Fox, E. Fisher, R. Rudick, B.O. Khatri, M.P. McQuillen, and D. S. Goodin Disease modifying therapies in multiple sclerosis Neurology, August 13, 2002; 59(3): 471 - 473. [Full Text] [PDF]
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C M Dalton, P A Brex, R Jenkins, N C Fox, K A Miszkiel, W R Crum, J I O'Riordan, G T Plant, A J Thompson, and D H Miller Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis J. Neurol. Neurosurg. Psychiatry, August 1, 2002; 73(2): 141 - 147. [Abstract] [Full Text] [PDF]
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D. H. Miller, F. Barkhof, J. A. Frank, G. J. M. Parker, and A. J. Thompson Measurement of atrophy in multiple sclerosis: pathological basis, methodological aspects and clinical relevance Brain, August 1, 2002; 125(8): 1676 - 1695. [Abstract] [Full Text] [PDF]
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D. L. Arnold and P.M. Matthews MRI in the diagnosis and management of multiple sclerosis Neurology, April 23, 2002; 58(90084): S23 - 31. [Abstract] [Full Text]
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C Gasperini, A Paolillo, E Giugni, S Galgani, F Bagnato, C Mainero, E Onesti, S Bastianello, and C Pozzilli MRI brain volume changes in relapsing-remitting multiple sclerosis patients treated with interferon beta-1a Multiple Sclerosis, April 1, 2002; 8(2): 119 - 123. [Abstract] [PDF]
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D. T. Chard, C. M. Griffin, G. J. M. Parker, R. Kapoor, A. J. Thompson, and D. H. Miller Brain atrophy in clinically early relapsing-remitting multiple sclerosis Brain, February 1, 2002; 125(2): 327 - 337. [Abstract] [Full Text] [PDF]
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P. D. Molyneux, G. J. Barker, F. Barkhof, K. Beckmann, F. Dahlke, M. Filippi, M. Ghazi, D. Hahn, D. MacManus, C. Polman, et al. Clinical-MRI correlations in a European trial of interferon beta-1b in secondary progressive MS Neurology, December 26, 2001; 57(12): 2191 - 2197. [Abstract] [Full Text] [PDF]
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M. Rovaris, G. Comi, M. A. Rocca, J. S. Wolinsky, and M. Filippi Short-term brain volume change in relapsing-remitting multiple sclerosis: Effect of glatiramer acetate and implications Brain, September 1, 2001; 124(9): 1803 - 1812. [Abstract] [Full Text] [PDF]
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F. Barkhof, J.-H. T. M. van Waesberghe, M. Filippi, T. Yousry, D. H. Miller, D. Hahn, A. J. Thompson, L. Kappos, P. Brex, C. Pozzilli, et al. T1 hypointense lesions in secondary progressive multiple sclerosis: effect of interferon beta-1b treatment Brain, July 1, 2001; 124(7): 1396 - 1402. [Abstract] [Full Text] [PDF]
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M A RON Imaging counterparts of cognitive decline in multiple sclerosis J. Neurol. Neurosurg. Psychiatry, June 1, 2001; 70(6): 721 - 721. [Full Text]
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D. H. Miller, A. J. Thompson, and L. Kappos MRI and assessment of treatment in multiple sclerosis Brain, May 1, 2001; 124(5): 1052 - 1053. [Full Text] [PDF]
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C Gasperini, M Rovaris, M P Sormani, S Bastianello, C Pozzilli, G Comi, and M Filippi Intra-observer, inter-observer and inter-scanner variations in brain MRI volume measurements in multiple sclerosis Multiple Sclerosis, February 1, 2001; 7(1): 27 - 31. [Abstract] [PDF]
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G. Ebers MRI: measure of efficacy Brain, November 1, 2000; 123(11): 2187 - 2188. [Full Text] [PDF]
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