Brain, Vol. 124, No. 7, 1396-1402,
July 2001
© 2001 Oxford University Press
T1 hypointense lesions in secondary progressive multiple sclerosis: effect of interferon beta-1b treatment
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1 MR-MS centre, VU Medical Centre, Amsterdam, the Netherlands, 2 Neuroimaging Research Unit, Department of Neuroscience, Scientific Institute San Raffaele, University of Milan, 3 Department of Neurology, La Sapienza, Rome, Italy, 4 Department of Neuroradiology, Klinikum Grosshadern, Munich, 5 Institut for Röntgendiagnostik, Universität Würzburg, Germany, 6 NMR Research Group, Institute of Neurology, London, UK and 7 Department of Neurology, University Hospitals, Kantonsspittal, Basel, Switzerland
Correspondence to:
Dr F. Barkhof, MS-MRI Centre and Department of Radiology, VU Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands E-mail: f.barkhof{at}azvu.nl
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Abstract |
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Recently, the clinical efficacy of interferon ß-1b (IFNß-1b) was demonstrated for secondary progressive (SP) multiple sclerosis in a European multicentre study. We evaluated the effect of IFNß-1b treatment on the rate of development of hypointense T1 MRI lesions, a putative marker of axonal damage. Unenhanced T1-weighted images were obtained in a subgroup of 95 multiple sclerosis patients from five centres at 6-month intervals; this subgroup was similar to the total study population for all demographic, clinical and MRI parameters. An experienced observer blinded to the clinical data and treatment allocation measured volumes. The median baseline lesion load for hypointense T1 lesions was 5.1 cm3 for placebo-treated and 4.9 cm3 for IFNß-1b-treated patients (P = 0.56). Placebo-treated patients showed an increase in T1 lesion load by a median of 14% per year (P = 0.0002 compared with baseline); this was reduced to 7.7% per year in the IFNß-1b-treated patients (P = 0.003 versus placebo). In the IFNß-1b arm there was a statistically significant correlation between absolute change in Expanded Disability Status Scale scores and T1 lesion load by month 36 (r = 0.38, P = 0.0015). In patients with SP multiple sclerosis, IFNß-1b treatment reduces the development of hypointense T1 lesions, suggesting that reduced axonal damage in lesions may play a part in the beneficial effect that is observed clinically.
multiple sclerosis; interferon beta; MRI; black holes; magnetization transfer
EDSS = Expanded Disability Status Scale; IFNß-1b = interferon ß-1b; RR = relapsing–remitting; SP = secondary progressive
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Introduction |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionAppendix IAcknowledgementsReferences |
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Several types of interferon ß have been shown to be partially effective in the treatment of relapsing–remitting (RR) multiple sclerosis (Paty and Li, 1993
; Multiple Sclerosis Collaborative Research Group, 1996; Li and Paty, 1999). Recently, efficacy of interferon ß-1b (IFNß-1b) was also demonstrated for secondary progressive (SP) multiple sclerosis in a European multicentre study (European Study Group on interferon beta-1b in secondary progressive multiple sclerosis, 1998), which showed delayed development of sustained progression, a lower relapse rate and reduced MRI evidence of disease. Frequent MRI showed a continuously reduced rate of development of active lesions, and the T2 lesion load measured in annual scans of all patients was reduced compared with baseline (Miller et al., 1999), a result quite similar to that found for RR patients (Paty and Li, 1993; Li and Paty, 1999). The mechanisms that lead to relapse and MRI lesion activity may be similar in RR and SP patients, and the congruent results of interferon treatment in the two subtypes may therefore not come as a surprise. With regard to the development of disability, RR patients predominantly suffer from incomplete recovery from relapses, while SP patients, by definition, also suffer from chronic progression independently of relapses. In SP patients, the development of disability is likely to result from more pronounced progressive axonal loss, either in lesions or in the form of widespread non-focal disease.
To gain further insight into the biological mechanisms underlying the slowing of progression in SP patients on IFNß-1b therapy, we evaluated the development of hypointense MRI lesions under treatment. In comparison with RR multiple sclerosis, hypointense T1 lesions are more prevalent in SP patients and correlate better with disability than hyperintense T2 lesions (Truyen et al., 1996). Data from post-mortem studies (van Waesberghe et al., 1999) and in vivo magnetic resonance spectroscopy (van Walderveen et al., 1999) indicate that lesion hypointensity is strongly correlated with axonal density, and it is thus well suited to address the rate of development of axonal loss in multiple sclerosis. In this paper we report the effect of IFNß-1b treatment on the rate of development of hypointense lesions in SP multiple sclerosis.
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Material and methods |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionAppendix IAcknowledgementsReferences |
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This study was performed in a subgroup of 95 multiple sclerosis patients participating in a large European, multicentre, randomized, double-blind, placebo-controlled trial (Polman et al., 1995
; European Study Group on interferon beta-1b in secondary progressive multiple sclerosis, 1998). In brief, patients with SP multiple sclerosis were randomized to receive IFNß-1b (Betaferon; Schering, Berlin, Germany) 8 MIU, subcutaneously on alternate days, or placebo injections. The study was approved by the Ethical Committees of the participating centres, and all patients gave informed consent. The full study included 718 patients, all of whom underwent yearly conventional T2-weighted imaging; in a subset of 125 patients from seven centres, frequent gadolinium-enhanced images were also obtained (Miller et al., 1999). In five of those centres (Amsterdam, Milan, Munich, Würzburg and London), additional unenhanced T1-weighted images were obtained at 6-month intervals to assess the development of hypointense lesions. Clinical disability was measured at 3-month intervals using the Expanded Disability Status Scale (EDSS) score by the assessing physician, who was blinded to treatment-related activities (Polman et al., 1995). The T2-weighted and gadolinium-enhanced MRI results have been reported previously (Miller et al., 1999), and we used the existing database to assess whether our subset differed from the full study with regard to T2 lesion load or active lesions.
MR imaging protocol and image analysis
The data used for this study comprised unenhanced T1-weighted images obtained before the administration of gadolinium. All five centres operated at 1.5 T. T1-weighted images were obtained using a spin-echo sequence with a repetition time between 400 and 600 ms and echo time between 5 and 25 ms, using 5 mm slices and 1 mm in-plane resolution. To obtain a contiguous data set of 24 slices, two interleaved series of 12 slices each were acquired. On these T1-weighted images, hypointense lesions were marked using a mouse-controlled cursor on the electronic data by a single experienced observer. Lesion hypointensity was defined as a signal clearly lower than the surrounding white matter, but not necessarily lower than the grey matter. Identification of lesions was done by checking, for each lesion that was visible on a T2-weighted image, whether it was hypointense on the corresponding T1-weighted image. The observer marked all scans of a given patient consecutively in order to reduce observer variability, but without knowledge of clinical data and treatment allocation. The marked lesions were then quantified by another observer on the electronic MRI data using home-developed software based on seeding and local thresholding, and the result was multiplied by the interslice distance to obtain volumetric data; the intra-observer variation for the quantification is 5% (Truyen et al., 1996). These observers were fully blinded to the clinical data and treatment allocation.
Statistical analysis
Data were entered into a database by an independent contract research organization (independent from the sponsor) and checked for consistency. Therefore, even though the analyses were performed after unblinding of the study, the analyses were performed in a strictly blinded fashion. Statistical analyses were performed for both absolute and percentage changes in hypointense lesion load compared with baseline. Analyses include all patients with data available at baseline and at least once during treatment. All data available at any given point in time were evaluated with missing data maintained as missing. In additional analyses, missing data were imputed by linear interpolation; because these yielded the same results, only data without replacement are presented in this report. Furthermore, changes in hypointense lesion load at individual last visits (last scan available) were evaluated.
Comparisons of baseline data between groups were performed using the Wilcoxon rank-sum test and Fisher's exact test. To assess changes in hypointense lesion load from baseline within treatment groups, the paired t test was used. Comparisons between groups were performed using non-parametric analysis of covariance with stratification adjustment for centre and covariance adjustment for baseline lesion load. To assess the association between T1 hypointense lesion load and EDSS, non-parametric (Goodman–Kruskal) correlation coefficients were calculated; because we assumed that changes in data for month 6 may have been confounded by temporary hypointense lesions (and minor fluctuations in EDSS), assessments were correlated from month 12 onwards.
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Results |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionAppendix IAcknowledgementsReferences |
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For seven patients no valid T1 data were available and for three others the baseline value was missing, leaving 85 valid cases for analysis, 41 on placebo, 44 on IFNß-1b. Table 1
shows that the demographics and baseline descriptive findings of those patients were similar to those of the total study population, indicating that no major selection bias had occurred. Also, none of the baseline descriptive data differed between placebo and verum at the 5% significance level. For T2 lesion load, there was a median increase of 4.19 cm3 (17.5%) at month 36 in the placebo group, whereas the IFNß-1b group showed a median decrease of 0.35 (4.0%) at month 36 (P < 0.0001 between groups). At month 36, the median cumulative number of new or enlarged lesions on T2-weighted images was 7 in the placebo group and 1 in the IFNß-1b group (P = 0.038). Similarly, highly significant differences favouring the IFNß-1b group were seen in the numbers of enhancing lesions during the monthly scanning blocks for months 1–6 and 19–24 (P < 0.0005 between groups for both periods). All these data are consistent with the analysis performed on the full data set (European Study Group on interferon beta-1b in secondary progressive multiple sclerosis, 1998).
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The median baseline lesion load for hypointense T1 lesions was 5.1 cm3 for the placebo group and 4.9 cm3 for the IFNß-1b patients (P = 0.56). Both arms showed a linear increase in lesion load across time (Table 2
). In the placebo-treated patients, this increase was significant from month 6 onwards; by month 36 they had increased their T1 lesion load by a median value of 2.43 cm3, corresponding to a median change from baseline of 41.8% (P = 0.0002 compared with baseline), with an average an increase of 14% per annum (Fig. 1). The IFNß-1b patients also showed a linear increase from baseline, which became statistically significant at month 18 for the first time, and by month 36 the median increase in lesion load was 0.76 cm3, corresponding to a median change from baseline of 23.2% (P = 0.006), with an average increase of 7.7% per annum. The rate of increase in T1 hypointense lesion load was significantly slower in the IFNß-1b treated patients than in the placebo-treated group (P = 0.0003). This was also true when individual last-scan data were analysed (P = 0.0001, adjusted value for treatment effect between groups).
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The correlations between absolute change in T1 lesion load and EDSS are reported in Table 3
. For the whole group, there was a positive correlation (r = 0.28 at month 36, P = 0.007). Within the individual arms, the correlations were weak in the placebo arm, whereas statistically significant correlations were found in the IFNß-1b arm from month 12 onwards (r = 0.38 at month 36, P = 0.002). In the same subgroup of patients, no significant correlations were detected between EDSS and T2 lesion load (not tabulated), with a maximum correlation of 0.16 for the IFNß-1b arm after 3 years (P = 0.19).
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Discussion |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionAppendix IAcknowledgementsReferences |
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Traditionally, MRI measures used in treatment trials include the number of active (e.g. gadolinium-enhancing or new T2) lesions and changes in T2 lesion load. The behaviour of these MRI measures has been fairly well established, and they provide high statistical power in detecting anti-inflammatory treatment effects (Sormani et al., 1999
; Molyneux et al., 2000a). MRI-monitored interferon-beta studies have systematically shown dramatic treatment effects on active lesions and T2 lesion load, typically with a dose–effect relationship (Paty and Li, 1993; Multiple Sclerosis Collaborative Research Group, 1996; Li and Paty, 1999; Miller et al., 1999). On the basis of these and other results, an ad hoc committee of the National Multiple Sclerosis Society of the USA decided to advocate the use of MRI measures as a primary outcome measure in exploratory (phase II) trials (Miller et al., 1996). However, given the uncertain relationship between changes in MRI and clinical parameters over time, it also recommended that MRI should only be used as a secondary outcome measure in definitive (phase III) trials (Miller et al., 1996).
There are many problems in detecting a relationship between MRI measures and clinical status. Apart from problems with clinical scales, the location of lesions and the duration of follow-up, the lack of histopathological specificity beyond the inflammatory stage (identified by gadolinium enhancement) is a major weakness of MRI. On T2-weighted images, almost any alteration in brain tissue composition will lead to increased signal, including oedema, partial demyelination, gliosis and axonal loss. There is evidence that even remyelinated lesions may return high signal on these T2-weighted images ('t Hart et al., 1998; van Walderveen et al., 1998). This could explain the poor correlation with clinical disability, which is likely to be determined mainly by axonal loss. There are several magnetic resonance techniques with improved histopathological specificity, including magnetic resonance spectroscopy, magnetization transfer and T1 hypointensity. In this study we evaluated the effect of IFNß-1b treatment on T1 hypointensity as a marker of matrix destruction and axonal loss in progressive multiple sclerosis (van Walderveen et al., 1998, 1999; van Waesberghe et al., 1999).
The subset of patients presented here is comparable with the full data set (European Study Group on interferon beta-1b in secondary progressive multiple sclerosis, 1998), indicating that no significant selection bias occurred and that the treatment arms were well matched. Valid T1 data were available for the vast majority of patients. The T1 lesion load at baseline was slightly higher than in an earlier study on the natural history of multiple sclerosis (Truyen et al., 1996), in which a median volume of 3.0 cm3 was reported for SP multiple sclerosis patients, who progressed to 4.15 cm3 after an average of 3.5 years. The increase of 12% per annum in that natural course study is similar to the increase in lesion load in the placebo arm of the present study (42% over 3 years). The finding of an expected pattern of behaviour in the placebo arm is an essential element in the interpretation of randomized controlled trials (Li and Paty, 1999).
In studies of SP multiple sclerosis, the increase in T1 hypointense lesion load may seem large with respect to the increase in T2 lesion load (Truyen et al., 1996); in our study the median increase in T1 hypointense lesion load was 2.43 cm3, while the T2 hyperintense lesion load increased by a median of 4.19 cm3. This may reflect three phenomena. First, the net change in lesion load is derived from an increase by new lesions and shrinkage by others (Lee et al., 1998), a phenomenon that is much less plausible for T1 hypointense lesions. Secondly, progressive damage in pre-existing lesions has been demonstrated (Rocca et al., 1999), suggesting that ongoing axonal damage may occur in pre-existing lesions, especially in patients with SP multiple sclerosis, which may eventually lead to hypointensity on T1-weighted SE images. Lastly, the relatively small lesion load at baseline compared with the T2-hyperintense lesion load may influence the increase in T1 hypointense lesion load, expressed as a percentage. The latter phenomenon may also explain the findings in patients with RR multiple sclerosis, with a yearly increase of 14.5% per year (Simon et al., 2000), the low lesion load at baseline (median 0.64 cm3) providing a small denominator.
In the IFNß-1b-treated arm, the increase in T1 lesion load was significantly lower than in the placebo arm (P = 0.0003), with a 45% reduction in the increase in T1 hypointense lesion load. This is the first parallel-design controlled study to demonstrate a therapeutic effect on this MRI parameter in SP multiple sclerosis patients. An effect on the development of hypointense lesions has also been noted in a phase II trial of interferon alpha-1a in RR multiple sclerosis, in which patients served as their own controls (Gasperini et al., 1999). In this phase II study, a lower percentage of new lesions on T2-weighted images with persistent hypointensity on T1-weighted images was suggested (Paolillo et al., 1999a). A phase III trial with interferon alpha-1a failed to find a significant treatment effect, even though a clear trend was suggested (Simon et al., 2000).
Both post-mortem MRI data (van Waesberghe et al., 1999) and in vivo magnetic resonance spectroscopy data (van Walderveen et al., 1999; Brex et al., 2000) indicate that the degree of T1 hypointensity relates to the amount of axonal damage (resulting in widening of extracellular space, with more free, slowly relaxing water). The smaller increase in T1 hypointense lesion load in the IFNß-1b group in our SP multiple sclerosis study indicates less progression of axonal loss in lesions. As axonal loss is the most likely correlate of clinical progression, our findings are comparable with the moderate clinical effect of 40% reduction in time to progression (12 months delay after a median time on study of 18 months (European Study Group on interferon beta-1b in secondary progressive multiple sclerosis, 1998). The causality between these two measures is suggested by the finding of positive correlation coefficients in the IFNß-1b arm; the absence of similar correlations in the placebo arm could be explained by more relapse-related changes in disability. The fact that even in the IFNß-1b arm the correlations are still modest indicates that other mechanisms leading to disability (e.g. diffuse disease leading to atrophy) may still be at play.
The 45% reduction in development in T1 hypointense lesions is closer to the clinical effect size than the enormous effect seen on T2 lesion load; the latter even showed a slight decrease in lesion load in the IFNß-1b arm after 3 years (Miller et al., 1999). The overestimation of the treatment effect on T2 lesion load relates to an initial decrease in lesion load, which has been a consistent finding in previous interferon studies (Paty and Li, 1993; Li and Paty, 1999) . This probably reflects the resolution of oedematous and inflammatory changes caused by active lesions present at baseline, and the subsequent increase in T2 lesion load during the trial is too small to offset this initial dip. A similar phenomenon is not detectable for the development of T1 hypointensity using this 6-monthly analysis, even though monthly studies have noted that a percentage of lesions may become hypointense initially (van Waesberghe et al., 1998; Rovira et al., 1999). However, the vast majority of the temporary hypointense lesions revert to isointensity after 1 or 2 months, which probably explains why lesion load measurements of unenhanced and gadolinium-enhanced images (where acutely hypointense lesions are masked by their enhancement) show an extremely high correlation (O'Riordan et al., 1998). Therefore, in this study, with a low sampling rate (relative to the duration of enhancement and oedema of new multiple sclerosis lesions), we are confident that the increase in hypointense lesions measured in this study was not due to temporary hypointensity (with marked oedema), but rather to the development of chronic `black holes' (with axonal loss).
Previous studies in SP multiple sclerosis have shown a relationship between change in the T1 hypointense load and the rate of atrophy (Paolillo et al., 1999b). The fact that such measures are correlated indicates that both are (indirect) measures of axonal damage. On the other hand, the correlations are far from perfect, indicating that severe tissue damage in lesions (i.e. black holes) and overall cerebral tissue loss are not invariably linked. This partial independence may also account for the disparate effect of INFß-1b on a measure of cerebral volume in the same trial with SP multiple sclerosis patients (Molyneux et al., 2000b). In that study, a progressive decrease in cerebral volume was noted in both placebo- and interferon-treated patients, with no clear treatment effect. The partial effect on T1 hypointense lesions in the absence of a clear effect on cerebral volume loss indicates that, in this group of SP multiple sclerosis patients, axonal loss may progress to a certain extent. Similar uncoupling has been noted with other immunomodulatory drugs that have a clear effect on gadolinium enhancement, but no effect on T1 hypointense lesion load and atrophy (Coles et al. 1999; Filippi et al., 2000).
In conclusion, this is the first phase III trial to show a beneficial effect of IFNß-1b on the development of T1 hypointense lesion load, a marker of axonal loss in the lesions of SP multiple sclerosis.
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Appendix I |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionAppendix IAcknowledgementsReferences |
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List of investigators
Amsterdam: C. Polman, J. Valk, F. Barkhof, J. H. van Waesberghe and T. Schweigmann.
London: D. Miller, I. F. Mosely, P. Molyneux, P. Brex, D. MacManus.
Milan: G. Comi, M. Filippi and M. Rovaris.
Munich: R. Hohlfeld, T. A. Yousry, C. Becker, F. Stadie and P. Eppmann.
Würzburg: R. Gold, H.-P. Hartung, D. Hahn, W. Kenn and T. Pabst.
MRI Central Evaluation: Image Analysis Center, Amsterdam
F. Barkhof, J. H. T. M. van Waesberghe, J. Seebus, M. de Vos and L. Bergers.
Steering Committee
C. H. Polman, L. Kappos, A. J. Thompson, C. Pozzilli, F. Dahlke, M. Ghazi and K. Wagner (Schering AG).
Independent Advisory Board
H. McFarland (Chairman), J. Petkau (Statistical Advisor), O. Sabouraud and K. Toyka.
Statistician
K. Beckmann (Schering AG).
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Notes |
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* A full list of investigators is given in Appendix I
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Acknowledgements |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionAppendix IAcknowledgementsReferences |
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This study was sponsored by Schering AG, Berlin, Germany.
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References |
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TopAbstractIntroductionMaterial and methodsResultsDiscussionAppendix IAcknowledgementsReferences |
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Received March 6, 2000. Revised January 29, 2001. Accepted February 27, 2001.
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