вход по аккаунту


Correlations between monthly enhanced MRI Lesion rate and changes in T2 Lesion volume in multiple sclerosis.

код для вставкиСкачать
Correlations between Monthlv Enhanced
MRI Lesion Rate and Chaiges in T2
Lesion Volume in Multiple Sclerosis
P. D. Molyneux, MRCP,* M. Filippi, MD,? F. Barkhof, MD,$ C. Gasperini, MD,S T. A. Yousry, MD,"
L. Truyen, MD,$ H. M. Lai, MRCP,* M. A. Rocca, MD,? I. F. Moseley, FRCP,* and D. H. Miller, FRCP*
Magnetic resonance imaging (MRI) provides a powerful tool for assessing disease activity in multiple sclerosis (MS), and
its role as a surrogate marker for monitoring treatment eficacy is now becoming established. The most commonly used
MRI parameters in treatment trials are (1) monthly gadolinium-enhanced MRI, with the number of active lesions serving
as the outcome measure, and (2) annual lesion load quantification, in which change in MS lesion volume provides the
MRI endpoint. We evaluated clinicallMRI correlations and the relationship between these two markers of disease activity
in 73 patients with clinically definite MS. Quantification of T2 lesion load was performed at study entry and exit, with
a median study duration of 11 months (range, 9 to 14 months). Monthly postgadolinium T1-weighted images were
acquired between these time points. Lesion load at study entry was significantly correlated with the baseline Expanded
Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated. The number of
enhancing lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated
with the subsequent enhancing lesion activity over the study period. A significant correlation was found between change
in lesion load and disease activity on the monthly scans. Our results suggest that annual lesion load quantification
provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of
disease evolution in phase I11 treatment trials.
Molyneux I'D, Filippi M, Barkhof F, Gasperini C, Yousry TA, Truyen L, Lai HM, Rocca MA, Moseley IF,
Miller DH. Correlations between monthly enhanced MRI lesion rate and changes in T2 lesion
volume in multiple sclerosis. Ann Neurol 1998;43:332-339
The application of serial brain MRI in multiple sclerosis (MS) has provided powerful insights into the evolution of disease over time. The high sensitivity of
MRI to disease activity in MS has led to its use as a
surrogate marker of treatment effect in clinical trials.'-'
In this context, the most established MRI parameters
are serial monthly gadolinium-enhanced imaging and
yearly T2-weighted lesion load quantification.
Definitive (phase 111) treatment trials rely on clinical
assessment as the primary outcome, with changes in
the lesion volume on yearly TZweighted images serving as a surrogate marker. This approach has been used
to assess treatment efficacy in several
and was
used to provide support for the efficacy of interferon
p-1b in patients with relapsing-remitting MS.4 However, this and other studies have demonstrated a poor
relationship between clinical and MRI markers of disease progression such as T 2 lesion load, and this urges
caution against interpreting such MRI findings in isolation. The lack of pathological specificity of increased
signal with this sequence may in part explain the clinical/MRI discrepancy. Increased signal on T2-weighted
images results from increased water content and relaxation time, which may result from edema, inflammation, gliosis, axonal loss, and remyelination.8 Accumulation of lesion load, therefore, reflects a range of
different pathological processes, and it is as yet unclear
what such changes represent in functional terms.
Exploratory (phase 11) screening trials use monthly
enhanced imaging, with disease activity assessed by gadolinium enhancement serving as the primary outcome
measure. The pathology underlying gadolinium enhancement is well defined, representing blood-brain
barrier breakdown with inflammation and active demyelination.92'o Monthly enhanced imaging is undoubtedly a sensitive marker of disease activity and can
From the "NMR Research Group, Institute of Neurology, Queen
Square, London, United Kingdom; t M S Biosignal Analysis Centre,
Department of Neurology, Ospedale San Raffaele, Milan, Italy;
tMS-MRI Centre and Department of Diagnostic Radiology, Academic Hospital of the Vrije Universiteit, Amsterdam, The Netherlands; $Department of Neurology, University of Rome, Italy; and
IlDepartment of Neuroradiology, Klinikum Grosshadern, Munich,
Received Jun 25, 1997, and in revised form Oct 15. Accepted for
publication Oct 15, 1997.
Address correspondence to Prof Miller, N M R Research Unit, Institute of Neurology, The National Hospital, Queen Square, London,
UK W C l N 3BG.
Copyright 0 1998 by the American Neurological Association
readily detect new lesions that are not expressed clinically as relapses. However, the time expenditure and
costs of such a protocol render it difficult to apply to
all patients in the context of large cohort definitive
treatment trials.
T h e relationship between disease activity demonstrated on monthly enhanced imaging and annual T2
lesion load change has not previously been defined. If
such a relationship is identified, this would confirm
that changes in MRI disease burden are due, at least in
part, to ongoing blood-brain barrier breakdown and
inflammation. This would support the use of annual
lesion volume assessment in treatment trials.
T h e purpose of the present study is to establish the
extent of such a relationship. In view of the possibility
that immunomodulatory treatment might have a differential effect o n the two MRI parameters, patients on
such treatment were excluded from this study. Furthermore, the dynamics of disease activity in primary progressive MS have been shown to be fundamentally different from other MS subgroups," and this study was
therefore restricted to patients with relapsing-remitting
MS (RRMS) and secondary progressive MS (SPMS).
Patients and Methods
Seventy-three patients (52 women and 21 men) with clinically definite MS12 were selected from five European centers
(12 from Amsterdam, 36 from London, 6 from Milan, 9
from Munich, and 10 from Rome). The cohort consisted of
46 patients with RRMS, as defined by a history of relapses
and remissions without gradual deterioration, and 27 patients with SPMS, as defined by an initial relapsing and remitting course with subsequent progressive deterioration for
at least 6 months, with or without superimposed relapses.
The median age at entry was 33 years (range, 15-61 years),
and median disease duration was 5 years (range, 1-28 years).
Patients were either involved in natural history studies (45
patients) or formed the placebo arms of treatment trials (28
patients). To be included, patients had to have had serial
monthly gadolinium-enhanced T1-weighted images for at
least 9 months with a T2-weighted scan coinciding with the
first and last enhanced scan (study entry and exit). Full neurological history and examination at study entry and exit
were performed in all cases, with disability assessed using
Kurtzke's Expanded Disability Status Scale (EDSS).13 Details
of any relapses over the study duration were also available in
all cases. Patients taking immunosuppressive drugs other
than infrequent short courses of corticosteroids during relapses were excluded. No patients with RRMS entered the
secondary progressive phase during the study.
Serial T2-weighted conventional spin echo (CSE) or fast
spin-echo (FSE) MR images were acquired at study entry
and exit. T1-weighted imaging 5 to 15 minutes after injection of gadolinium was also performed monthly throughout
the study period. Conventional dose gadolinium-DPTA (0.1
mmollkg) was given in 64 of 73 patients, the other 9 patients (Munich cohort) received 0.2 mmol1kg. Gadoliniumenhanced images were not performed within 1 week of corticosteroid treatment (because of the transient suppressive
effect of corticosteroids on enhancement). In London, all
MRI was performed with a Signa GE 1.5-Tesla scanner with
either CSE (18 patients, SE 2,000/34 at entry and exit, SE
640114 for enhanced scans, 5-mm contiguous axial slices) or
FSE (18 patients, SE 3,500/18 at entry and exit, SE 579/19
or 570/13 for enhanced scans, 4-mm contiguous axial slices).
In Amsterdam, CSE images were obtained on a 0.6-Tesla
Technicare (Teslacon 11) machine (SE 2,755/60 at entry and
exit, SE 400/28 or 450128 for enhanced scans, 5-mm axial
slices with an interslice gap of 1.25 mm). In Milan, a Siemens 1.5-Tesla machine was used to obtain CSE images (SE
2,000/50 at entry and exit, SE 768115 for enhanced scans,
5-mm contiguous axial slices). In Rome, a Toshiba 0.5-Tesla
machine was used to obtain CSE images (SE 2,500/30 at
entry and exit, SE 400118 for enhanced scans, 5-mm axial
slices with an interslice gap of 1.0 mm). In Munich, images
were obtained on a Magneton scanner at 1.0 Tesla (SE
3,000140 at entry and exit, SE 600128 for enhanced scans,
5-mm contiguous axial slices). Scanners were not changed or
upgraded over the study duration, and image acquisition parameters were not modified between entry and exit.
Lesion volume quantification was performed by four experienced observers (P.M., L.T., M.L., M.A.R.) blinded to
the clinical data, using two semiautomated local intensitybased segmentation techniques (the seed growing method in
Amsterdam'* and c o n t ~ u r i n g ' ~at~ 'all
~ other centers). Intraobserver variability with these approaches is about 3%.
The number of new and persistently gadolinium-enhancing
lesions were identified on all monthly scans by experienced
observers (IFM, FB, MF).
Statistical Methods
The relapse rate, change in EDSS, and absolute and percentage change in lesion load over the study duration for each
patient were adjusted for the length of study. Adjusted annual values for all the parameters were entered into the analysis. The new enhancing and total (new and persistently enhancing) lesion rates were adjusted for the study duration
and for missing data points to provide monthly enhancing
lesion rates for each patient (lesions/month/patient). Because
most of the data were not normally distributed, medians
rather than means were used to describe the data. Site by site
differences between MRI outcome measures were assessed using the Kruskal-Wallis test. Differences in clinical characteristics between patients with RRMS and SPMS were assessed
by means of the Mann-Whitney test. All clinical and MRI
correlations were evaluated using Spearman's rank correlation
coefficient (SRCC). To reflect the large number of statistical
comparisons, a significance level of p 5 0.01 was considered
significant, a p value between 0.01 and 0.05 was considered
a trend, and values greater than 0.05 were considered not
Molyneux et al: Enhancing Lesion Rate and Change in Lesion Load in MS
Clinical Characteristics
Seventy-three patients were observed for a median duration of 11 months (range, 9-14 months). The clinical characteristics over the study duration are given in
Table 1. There were significant differences between the
two clinical subgroups in terms of age, disease duration
at entry, and EDSS a t entry to the study. Relapse rates
during the study period were also significantly different
between the two subgroups. However, there was no
significant difference between the two groups in terms
of change in EDSS (exit minus entry) during the
study. There was an increase in EDSS during the study
duration in 29 of the 73 patients, a decrease in EDSS
in 14, and no change in EDSS in 30 patients. Only 19
patients changed EDSS by a whole point or more during the study.
MRI Characteristics
All patients had serial monthly enhanced MRI for at
least 9 months. A total of 761 scans were acquired, and
only 19 time points were missed within the continuous
series of scans (12 in SPMS and 7 in RRMS patients).
There were no significant site-by-site differences in
terms of baseline lesion load ( p = 0.08), change in
lesion load ( p = 0.6), or enhancing lesion rates ( p =
0.09). The MRI characteristics are given in Table 1.
Baseline lesion loads and changes in lesion load over
the study duration were not significantly different between the two subgroups. For the group as a whole,
the median change in lesion load was +1.5 cm3
(range, -5.6 to 18.8 cm3), with a median increase of
8.9% (range, -21.6 to +190%). Lesion loads increased in 52 patients (33 in RRMS and 19 in SPMS
subgroup) and decreased in 2 1 patients (13 in RRMS
and 8 in SPMS subgroup). Although the median new
and enhancing lesion rates were substantially higher in
the RRMS compared with SPMS patients, no statistically significant difference between the two subgroups
was found (possibly due to the high interpatient variability). Sixty-three patients had at least one enhancing
lesion over the study duration; in 10 patients (4 with
RRMS and 6 with SPMS) there were no enhancing
lesions on any of the serial scans.
Clinical/MRI Correlcttionsf o r Baseline MRI Data
There was a significant correlation between EDSS and
lesion load at study entry (SRCC = 0.31, p = 0.007),
although this was not statistically significant for the individual subgroups (Table 2). Furthermore, the baseline lesion load was also predictive for the change in
EDSS over the study duration in the RRMS group
(SRCC = 0.44, p = 0.002) but not for the SPMS
subgroup (SRCC = 0.10, p = 0.6). The number of
enhancing lesions at study entry was predictive of subsequent relapse rate over the study duration for the
group as a whole (SRCC = 0.47, p < 0.001) and for
the SPMS group (SRCC = 0 . 5 6 , ~= 0.002), but this
was only a trend in the RRMS subgroup (SRCC =
0.35, p = 0.02).
CLinicaL/MRI Correlations for LongitudinaL
MRI Data
Significant correlations (Figs 1 and 2; see also Table 2)
were identified between relapse rate and both new and
total enhancing lesion rate over the study duration for
the group as a whole (SRCC = 0.52, p < 0.001 and
SRCC = 0.51, p < 0.001, respectively), and this relationship was particularly strong in the SPMS subgroup (SRCC = 0.73, p < 0.001 for both new and
total enhancing lesion rate). No significant correlation
Table 1. Clinical and MRI Characteristics of Patients
All Patients
Median (Range)
Age (yr)
Disease duration (yr)
EDSS at entry
EDSS at exit
Change in EDSS per yearb
Yearly relapse rate
T2 lesion load at entry (cm’)
Change in lesion load ( ~ r n ~ ) ~
Percentage change in lesion loadb
New enhancing lesion rateC
Total enhancing lesion rated
3.5 (0-8)
4 (0-8)
0 (-2.04.0)
1.3 (0-6.7)
14.7 (1.4-97.2)
+1.5 (-5.6-18.8)
+8.7 (-21.6-190)
1.0 (0-13.5)
1.4 (0-17.0)
RRMS (n = 46)
Median (Range)
0 (-2.0-4.0)
2.0 (0-5.5)
12.7 (1.4-72.8)
+1.3 (-4.4-18.8)
+10.4 (-19.6-190)
1.2 (0-13.5)
1.6 (0-14.5)
SPMS (n = 27)
Median (Range)
(0-1 1.7)
0.8 (0-17.0)
“Significance levels for differences between the subgroups: significance level set a t p 5 0.01; trend, 0.01 < p
‘Annualized change, adjusted for length of study in each patient.
‘New enhancing lesion rare represents number of new enhancing lesions per month.
dToral enhancing lesion rate represents rhe number of new and persistently enhancing lesions per month.
Annals of Neurology
Vol 43
No 3
March 1998
Test, p Value”
0.0 10
< 0.05; not significant (NS) p
Table 2. Cross-Sectional and Longitudinal Correlations between Clinical and MRI Measures of Disease Activiy
EDSS at entry vs baseline lesion
load (an3)
Change in EDSS vs baseline
lesion load
Annual relapse rate vs number
of enhancing lesions at entry
EDSS change vs change in lesion load (cm3)
EDSS change vs percentage
change in lesion load
Annual relapse rate vs change in
lesion load (an3)
Annual relapse rate vs new enhancing lesion rate
Annual relapse rate vs total enhancing lesion rate
EDSS change vs new enhancing
lesion rate
All Patients (n = 73)
SRCC ( p value")
RRMS Patients (n
SRCC ( p value")
0.31 (0.007)
0.34 (0.02)
0.17 (NS)
0.30 (0.01)
0.44 (0.002)
0.10 INS)
0.47 (<O.OOl)
0.35 (0.02)
0.56 (0.002)
0.09 (NS)
0.28 (NS)
-0.15 (NS)
0.09 (NS)
0.18 (NS)
-0.14 (NS)
0.10 (NS)
0.06 (NS)
0.21 (NS)
0.52 (<O.OOl)
0.33 (0.02)
0.73 (<0.001)
0.51 (<O.OOl)
0.32 (0.03)
0.73 (<0.001)
0.15 (NS)
0.15 (NS)
0.26 (NS)
"Significance levels: significance level set at p
0.01; trend, 0.01
< p < 0.05;
not significant (NS) p
." . . ... .
.". .
..... .
SPMS Patients (n
SRCC ( p value")
New lesion rate over study period (new lesions/rnonth/patient)
was demonstrated between new enhancing lesion rate
and change in EDSS. There was also no significant
correlation between change in lesion load over the
study duration and relapse rate. Furthermore, no significant correlation was demonstrated in either subgroup between either absolute or percentage change in
lesion load and change in EDSS. Comparing the
change in EDSS between the 52 patients with an increase in lesion load and the 21 patients whose lesion
loads decreased, no significant difference was found.
Correlations between the MRI Parameters
There was a strong relationship (Table 3 and Figs 3
and 4) between both new and total enhancing lesion
rate over the study duration and change in lesion load
for the data as a whole (SRCC = 0.53, p < 0.001 and
SRCC = 0.50, p < 0.001, respectively), and this was
Fig 1. Scatterplot of annual relapse
rate against new enhancing lesion rate
in RRMS subgroup (SRCC = 0.33,
p = 002)
particularly apparent in the RRMS subgroup
(SRCC = 0.60, p < 0.001 and SRCC = 0.58, p <
0.001, respectively). However, the number of enhancing lesions at study entry did not predict subsequent
change in lesion load, and only modest correlations
were found between enhancing lesion activity in the
first 3 months of the study and change in lesion load
over the study duration, In contrast, enhancing lesion
activity in the last 3 months and at study exit alone
correlated substantially better with change in lesion
load, to a level similar to values for enhancing lesion
rates over the entire study duration (see Table 3 ) .
For the 52 patients whose lesion load increased and
21 patients whose lesion load decreased, the median
new lesion rates were, respectively, 1.9 and 0.3 lesions/
month/patient, and this difference was significant ( p =
Molyneux et al: Enhancing Lesion Rate and Change in Lesion Load in MS
a 1
m o
..- .
Fig 2. Scatterplot of annual relapse
Table 3. Correlations between MRI Parameters
Number of enhancing lesions at entry
vs new enhancing lesion rate over
study duration
Baseline lesion load vs change in lesion load (cm3)
Number of enhancing lesions at entry
vs change in lesion load (cm3)
New enhancing lesion rate in first 3
months of study vs change in lesion load (cm3)
New enhancing lesion rate in last 3
months of study vs change in lesion load (cm3)
New enhancing lesion rate at study
exit vs change in lesion load (cm3)
New enhancing lesion rate over entire
study duration vs change in lesion
load (cm3)
Total enhancing lesion rate over entire study duration vs change in
lesion load (cm’)
“Significance levels: significance level set at p
All Patients (n = 73)
SRCC ( p Value”)
RRMS Patients (n
SRCC ( p Value”)
0.60 (<O.OOl)
0.46 (0.002)
0.78 (<0.001)
0.17 (NS)
0.19 (NS)
0.17 (NS)
0.20 (NS)
0.19 (NS)
0.23 (NS)
0.37 (0.001)
0.43 (0.003)
0.28 (NS)
0.54 (<0.001)
0.54 (0.001)
0.53 (0.001)
0.53 (<0.001)
0.48 (0.001)
0.64 (<0.001)
0.53 (<0.001)
0.60 (<0.001)
0.46 (0.02)
0.50 (<O.OOl)
0.58 (<0.001)
0.44 (0.02)
0.01; trend, 0.01
< p < 0.05; not significant (NS) p
The number of enhancing lesions at study entry was
predictive of subsequent enhancing lesion activity
(SRCC = 0.60, p < 0.001), and this relationship was
particularly apparent in the SPMS subgroup (SRCC =
0.78, p < 0.001).
This study demonstrates the existence of a moderate
relationship between enhancing lesion rate and change
in T 2 lesion load over the study duration in patients
with W S and SPMS. Whereas several previous studies have demonstrated the sensitivity of these MRI parameters to disease activity and evol~tion,”-~’we are
not aware of previous work that has directly compared
Annals of Neurology
Vol 43
No 3
March 1998
SPMS Patients (n = 27)
( p Value”)
2 0.05.
enhancing lesion rates with changes in annual lesion load. The results of this study provide evidence
that serial lesion load quantification is sensitive to
gadolinium-enhancing disease activity over relatively
short periods. This supports the current practice of
performing annual lesion load quantification as a surrogate marker of disease progression in definitive treatment trials.’”
The degree of this correlation might be lessened by
several factors. First, a proportion of newly enhancing
lesions are not apparent on T2-weighted
and therefore will not be reflected as a change in lesion
volume. Such lesions may reflect reactivation of established confluent lesions particularly in periventricular
New lesion rate over study period (new lesionshonthlpatient)
areas where any subtle change in appearance on T2weighted images is obscured in large regions of abnorma1 signal. 19,22-24 The larger lesion volumes in the patients with SPMS in this study might explain why the
correlations were weaker in this subgroup.
Second, a proportion of new or enlarging T 2 lesions
in both RRMS and SPMS is not visible on enhanced
T1-weighted images with conventional doses of gadolinium.'
Therefore, T2-weighted lesion load can
potentially increase in the absence of gadolinium enhancement. Recently described strategies to optimize
the sensitivity to gadolinium e n h a n ~ e m e n t may
further diminish the number of new T2 lesions not
demonstrating enhancement, improving the strength of
this relationship.
Third, measurement errors in both identification of
enhancing lesions27 and measuring serial lesion l ~ a d ~ , ~
are likely to have attenuated the strength of the observed relationship." Even among experienced observers there are inevitable differences in interpretation of
gadolinium-enhanced scans; and in this study, several
observers were involved in lesion identification. Fur-
Fig 4. Scatterplot of change in lesion
load against new enhancing lesion rate
in SPMS subgroup (SRCC = 0.46
p = 0.02).
thermore, there are a number of well-recognized
sources of measurement error in serial lesion volume
quantification in both image a c q u i s i t i ~ n ~and
* ~post~~
processing (which usually requires significant operator
intervention). 16z28Lesion segmentation was performed
in this study using two similar semiautomated, local
thresholding approaches, with intraobserver variability
shown to be about 3% for a single scan. However, despite the multiple sources of measurement error, lesion
load quantification as performed in this study was responsive to disease activiry determined by gadolinium
enhancement on the monthly scans, supporting the use
of such segmentation techniques in longitudinal studies.
Finally, the natural history of evolving T 2 lesions is
also likely to be important. The area of increased signal
in new T2 lesions tends to be initially larger than the
*area of gadolinium enhancement on the corresponding
T1-weighted image.23,24The larger area of T 2 lesions
early in their evolution is likely to reflect increased signal from edema extending beyond the region of bloodbrain barrier b r e a k d o ~ n . Subsequent
~ ~ ~ ~ ' ~ ~T 2~ scans
typically show decreasing lesion size over a period of
Molyneux et al: Enhancing Lesion Rate and Change in Lesion Load in MS 337
months as edema reso1ves.23~24,32~33
A smaller T 2 abnormality generally persists, although MRI lesions may
The change in lesion load between
two time points is therefore a reflection of a dynamic
process of initial lesion enlargement and subsequent
shrinkage or disappearance occurring in multiple white
matter foci. Marked month-to-month fluctuations in
lesion load have indeed previously been demonstrated
in a study in which serial imaging was performed in
patients with RRMS.35 The amount of gadolinium enhancement in that study predicted a simultaneous increase in lesion load, suggesting that transient increases
in lesion load reflect periods of increased blood-brain
barrier breakdown. An important consequence of this
process is that the change in lesion load on annual
MRI may be influenced more by disease activity
shortly before the exit scan than earlier activity. This is
supported by our results. The correlations between enhancing lesion rate detected in the last 3 months of the
study and change in lesion load were almost as good as
that incorporating enhancing lesion activity over the
entire study duration. This suggests that changes in
lesion load on annual T2-weighted images may predominantly be a reflection of activity shortly before the
exit scan.
The implication of such a finding for definitive
treatment trials using annual lesion load assessment
alone is that a nonsustained treatment effect on disease
activity determined by gadolinium enhancement may
not be detected on annual MRI. This supports the use
of monthly enhanced imaging in at least a subgroup of
patients for 6 months after treatment has been initiated.’ The waxing and waning of new T 2 lesions may
also explain why lesion loads decreased in a few patients despite ongoing disease activity as measured on
the monthly enhanced scans (see Figs 3 and 4). If these
patients had developed a number of new lesions immediately before study entry, their initial T 2 lesion loads
may have been heavily influenced by such lesions and a
subsequent decrease in lesion load could be a reflection
of the evolution of these lesions. It is therefore possible
that lesion loads could decrease between two time
points despite ongoing activity.
Several other important clinical and MRI correlations were demonstrated in this study. The number of
enhancing lesions at study entiy predicted subsequent
relapse rate and also significantly correlated with subsequent activity on serial monthly imaging. MRI activity at a single time point can therefore predict both
future MRI and clinical activity. This study also confirms previous work’8331336
demonstrating a significant
longitudinal correlation between clinical exacerbations
and enhancing lesion rates. This correlation of MRI
activity with relapses provides support for short-term
MRI as a clinically relevant surrogate marker in screening new treatments.
338 Annals of Neurology
Vol 43
No 3
March 1998
A modest correlation between lesion load at st-udy
entry and baseline EDSS has been shown, and baseline
lesion load was also predictive of subsequent change in
EDSS in the RRMS subgroup. However, no significant
longitudinal correlations were found between progression of disability and either change in lesion load or
monthly enhancing activity. Therefore, whereas relapse
rate was predicted by MRI activity at a single time
point, neither of the MRI parameters used in this
study was predictive of progression of disability. This is
perhaps not surprising, given the relatively small numbers of patients, sample heterogeneity, and short duration of follow-up. Several smaller studies with a longer
period of follow-up have demonstrated significant longitudinal correlations between MRI activity and progression of disability,21937z38
albeit of a modest degree.
In conclusion, we have demonstrated that lesion
load changes in patients with RRMS and SPMS are
correlated with the rate of appearance of new enhancing lesions on monthly enhanced MRI. The existence
of this relationship suggests that accumulation of abnormal signal intensity on T 2 scans provides a measure
of the degree of disease activity over time. Yearly MRI
provides only a snapshot of a dynamic process of lesion
formation and evolution. This snapshot may be more
weighted toward activity near the end of the interval
between serial scans. This suggests that for definitive
treatment trials, monthly enhanced imaging immediately after initiation of therapy may be advisable in a
cohort of patients, to reduce the potential for a nonsustained treatment effect going undetected.
This work derives from the collaboration made possible by the
CEC funded programme (ERBCHRXCT940684) European Magnetic Resonance Network in Multiple Sclerosis (MAGNIMS), entitled “Development of Optimal Magnetic Resonance Techniques to Monitor Treatments for Preventing Disability in Multiple
1. Miller DH, Albert PS, Barkhof F, et al. Guidelines for the use
of magnetic resonance techniques in monitoring the treatment
of multiple sclerosis. Ann Neurol 1996;39:6-16
2. Zhao GJ, Li DKB, Wolinsky JS, et al. Clinical and magnetic
resonance imaging changes correlate in a clinical trial monitoring cyclosporine therapy for multiple sclerosis. J Neuroirnaging
1997;7: 1-7
3. Jacobs LD, Cookfair DL, Rudick RA, et al. Intramuscular interferon beta- 1a for disease progression in relapsing multiple
sclerosis. Ann Neurol 1996;39:285-294
4. Paty DW, Li DKB, UBC MS/MRI Study Group. Interferon
beta-lb is effective in relapsing-remitting multiple sclerosis.
MRI analysis results of a multicenter, randomised, douhleblind, placebo-controlled trial. Neurology 1993;43:662-667
5. Stone LA, Frank JA, Albert PS, et al. The effect of interferon-p
on blood-brain harrier disruptions demonstrated by contrastenhanced magnetic resonance imaging in multiple sclerosis.
Ann Neurol 1995;37:611-619
6. Edan G, Miller D, Clanet, et al. Therapeutic effect of niirox-
antrone combined with methylprednisolone in multiple
sclerosis: a randomised multicentre study of active disease using
MRI and clinical criteria. J Neurol Neurosurg Psychiatry 1997;
62: 112-1 18
Barkhof F, Filippi M, Miller DH, et al. Strategies for optimising MRI techniques aimed at monitoring disease activity in
multiple sclerosis treatment trials. J Neurol 1997;244:76-84
Barkhof F. MRI in the assessment of putative treatments for
multiple sclerosis. Imaging 1996;s:103-1 15
Nesbit GM, Forbes GS, Scheithauer BW, et al. Multiple
sclerosis: histopathologic and MR and/or CT correlation in 37
cases at biopsy and three cases at autopsy. Radiology 1991;180:
Rodriguez M, Scheirhauer BW, Forbes G, et al. Oligodendrocyte injury is an early event in lesions of multiple sclerosis.
Mayo Clin Proc 1993;68:627-636
Thompson AJ, Kermode AG, Wicks D , et al. Major differences
in the dynamics of primary and secondary progressive multiple
sclerosis. Ann Neurol 1991;29:53-62
Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiple sclerosis: guidelines for research protocols.
Ann Neurol 1983;13:227-231
Kurtzke JF. Rating neurologic impairment in multiple sclerosis:
an expanded disability status scale (EDSS). Neurology 1983;33:
van Walderveen MA, Barkhof F, Hommes OR, et al. Correlating MRI and clinical disease activity in multiple sclerosis: relevance of hypointense lesions on short-TWshort-TE (TIweighted) spin echo images. Neurology 1995;45:1684-1690
Plummer DL. Dispimage: a display and analysis tool for medical images. Riv Neuroradiol 1992;5:489-495
Grimaud J, Lai M, Thorpe J, et al. Quantification of MRI lesion load in MS: a comparison of three computer-assisted techniques. Magn Reson Imaging 1996;14:495-505
Thompson AJ, Miller DH, You1 B, et al. Serial gadoliniumenhanced MRI in relapsingiremitting multiple sclerosis of varying disease duration. Neurology 1992;42:60-63
Smith ME, Stone LA, Albert PS, et al. Clinical worsening in
multiple sclerosis is associated with increased frequency and area
of gadopentate dimeglumine-enhancing magnetic resonance
imaging lesions. Ann Neurol 1993;33:480-489
Capra R, Marciano N, Vignolo LA, et al. Gadolinium-pentitic
acid magnetic resonance imaging in patients with relapsingremitting multiple sclerosis. Arch Neurol 1992;49:687-689
Frank JA, Stone LA, Smith M, et al. Serial contrast-enhanced
magnetic resonance imaging in patients with early relapsingremitting multiple sclerosis: implications for treatment trials.
Ann Neurol 1994;36:S86-90
Khoury SJ, Guttman CRG, Orav EJ, et al. Longitudinal MRI
in multiple sclerosis: correlation between disability and lesion
burden. Neurology 1994;44:2120-2124
Miller DH, Barkhof F, Nauta JJP. Gadolinium enhancement
increases the sensitivity of MRI in detecting disease activity in
multiple sclerosis. Brain 1993;16:1077-1094
Kermode AG, Tofts PS, Thompson AJ, et al. Heterogeneity of
blood-brain barrier changes in multiple sclerosis: an MRI study
with gadolinium-DPTA enhancement. Neurology 1990;40:
24. Harris JO, Frank JA, Patronas N, et al. Serial gadoliniumenhanced rnagnetic resonance imaging scans in patients with
early, relapsing-remitting multiple sclerosis: implications for
clinical trials and natural history. Ann Neurol 1991;29:548-
25. Silver NC, Good CD, Barker GJ, et al. Sensitivity of contrast
enhanced MRI in multiple sclerosis: effects of gadolinium dose,
magnetisation transfer contrast and delayed imaging. Brain
26. Filippi M, Yousry T, Campi A, et al. Comparison of triple dose
versus standard dose gadolinium-DPTA for detection of MRI
enhancing lesions in patients with MS. Neurology 1996:46;
27. Barkhof F, Filippi M, van Waesberghe JH, et al. Interobserver
variation in reporting gadolinium-enhanced MS lesions: consensus rules and effect of training. Proc Int SOCMagn Reson
Med 1997;1:640
28. Filippi M, Horsfield MA, Tofts PS, et al. Quantitative assessment of MRI lesion load in monitoring the evolution of multiple sclerosis. Brain 1995;118:1601-1612
29. Fleiss JL, ed. The design and analysis of clinical experiments.
New York: John Wiley & Sons, 1985
30. Gawne-Cain ML, Webb S, PS Tofts, et al. Lesion volume measurement in MS: how important is accurate repositioning? J
Magn Reson Imaging 1996;6:705-713
3 1. Willoughby EW, Grochowski E, Li DBK, et al. Serial magnetic
resonance scanning in multiple sclerosis: a second prospective
study in relapsing patients. Ann Neurol 1989;25:43-49
32. Isaac C, Li DKB, Genton M, et al. Multiple sclerosis: a serial
study using M N in relapsing patients. Neurology 1988;38:
33. Kermode AG, Thompson AJ, Tofts PS, et al. Breakdown of the
blood-brain barrier precedes symptoms and ocher MRI signs of
new lesions in multiple sclerosis. Brain 1990;113:1477-1489
34. McDonald WI, Miller DH, Barnes D. The pathological evolution of multiple sclerosis. Neuropathol Appl Neurobiol 1992;
35. Stone LA, Albert PS, Smith ME, et al. Changes in the amount
of diseased white matter over time in patients with relapsingremitting multiple sclerosis. Neurology 1995;45:1808-1814
36. Koudriavtesa T, Thompson AJ, Fiorelli M, et al. Gadoliniumenhanced MRI predicts clinical and MRI activity in relapsingremitting multiple sclerosis. J Neurol Neurosurg Psychiatry
37. Filippi M, Paty DW, Kappos L, et al. Correlations between
changes in disability and T2-weighted brain MRI activity in
multiple sclerosis: a follow-up study. Neurology 1995;45:255260
38. Losseff NA, Kingsley DPE, McDonald WI, et al. Clinical and
magnetic resonance predictors of disability in primary and secondary progressive multiple sclerosis. Multiple Sclerosis 1996;1:
Molyneux et al: Enhancing Lesion Rate a n d Change in Lesion Load in
MS 339
Без категории
Размер файла
732 Кб
correlation, volume, mri, lesions, change, rate, enhance, monthly, sclerosis, multiple
Пожаловаться на содержимое документа