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Longitudinal Brain Volume Measurement in Multiple Sclerosis
Rate of Brain Atrophy Is Independent of the Disease Subtype
Nynke F. Kalkers, MD, PhD;
Najim Ameziane, MSci;
Joost C. J. Bot, MD;
Arjan Minneboo, MD;
Chris H. Polman, MD, PhD;
Frederik Barkhof, MD, PhD
Arch Neurol. 2002;59:1572-1576.
ABSTRACT
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Background In multiple sclerosis (MS), brain atrophy depicted by magnetic resonance
imaging reflects overall tissue loss, including axonal loss.
Objective To determine the course of atrophy by studying the rate of development
of brain atrophy in patients who have different subtypes of MS.
Methods Eighty-three patients with MS (42 with relapsing-remitting, 21 with
secondary progressive, and 20 with primary progressive) were studied longitudinally,
with an interval of 2 to 4 years. Magnetic resonance imaging included T1-
and T2-weighted images to obtain 2 brain volume measurements: (1) the parenchymal
fraction as a marker of global brain atrophy and (2) the ventricular fraction
as a marker of central atrophy. The annualized rate of global and central
brain atrophy was compared between those with different subtypes of MS and
related to clinical characteristics, including sex, age, disease duration,
and disability.
Results There was a significant decrease of the parenchymal fraction (-0.7%
per year; SEM, 0.11% per year) and a significant increase of ventricular fraction
(3.7% per year; SEM, 0.54% per year) in the total group. Significant tissue
loss was also seen in all 3 subtypes of MS; the decrease in parenchymal fraction
was not different between subtypes, whereas the increase in ventricular fraction
tended to be larger in patients with secondary progressive MS compared with
patients with primary progressive MS. Marginal associations were found between
clinical determinants and the rate of brain atrophy. Annualized increase in
the ventricular fraction was correlated with age (r
= -0.26) and duration of symptoms (r = -0.22):
younger patients (mainly patients with relapsing-remitting MS who have a limited
disability) displayed a larger increase in ventricular fraction compared with
older patients.
Conclusions The rate of development of brain atrophy is largely independent of the
course of the disease and other clinical characteristics. The relentless loss
of tissue occurring in MS is not restricted to later (progressive) phases
of the disease, thereby stressing the need for early neuroprotective treatment
in MS.
INTRODUCTION
BRAIN VOLUME measurement on magnetic resonance images (MRIs) in multiple
sclerosis (MS) has been proposed as a surrogate marker for axonal loss, the
presumed underlying pathologic process leading to irreversible disability
in MS. Axonal loss occurs not only inside but also outside focal lesions,
perhaps explaining why measures of focal lesion load on MRI may fail to show
good correlations with disability. Evidence from pathology and spectroscopy
studies (demonstrating a decrease in the neuronal marker N-acetyl-aspartate in lesions and normal-appearing white matter of
MS) indicate that axonal injury is substantial in MS.1-3
Speculations have been made as to the origin of brain atrophy; Simon4 suggests a linkage between gadolinium-enhancing lesions
on T1-weighted imaging with atrophy, whereas Saindane et al5
could not confirm this finding. The diffuse pathologic process may result
from local degeneration and subsequent contraction due to gliosis.6 Axonal loss may be caused by wallerian degeneration,
by diffuse low-grade inflammation, or by primary neurodegeneration.
Earlier studies showed that brain atrophy measurement has a somewhat
better correlation with disability measurements like the Expanded Disability
Status Scale (EDSS) or the MS Functional Composite than the assessment of
focal lesion volume.7-9
Moreover, correlations between brain atrophy and neuropsychological functioning
have been found.10-11
Even though brain atrophy has been widely recognized as a potential
surrogate for axonal damage, there is only a very small number of studies
that have addressed the natural course of atrophy in MS. Most studies so far
included patients with relapsing-remitting (RR) or secondary-progressive (SP)
MS, reflecting the fact that these studies were incorporated in the analysis
of large drug trials, in which restricted enrollment criteria were applied.7, 12-15
So far, only 2 studies16-17 reported
on the rate of cerebral atrophy in patients with primary progressive (PP)
MS. Moreover, different automated segmentation techniques were used in the
different studies, which hampers a meaningful comparison of the rate of atrophy
between subgroups.
In this study we analyzed, in a larger cohort of patients with MS, not
selected for disease type or EDSS score, the rate in brain volume over time
using 2 markers for atrophy: (1) the parenchymal fraction (PF) defined as
whole-brain parenchymal volume/intracranial volume (as a measure of global
atrophy), and (2) the ventricular fraction (VF) defined as ventricular volume/intracranial
volume (as a measure of central atrophy). Analyses were performed for different
clinical subtypes. Moreover, annualized rates of brain atrophy were correlated
to several clinical characteristics, including sex, age, baseline EDSS, annualized
change in EDSS score ( EDSS), and duration of symptoms.
SUBJECTS AND METHODS
SUBJECTS
Eighty-three patients with MS (42 with RR, 21 with SP, and 20 with PP
MS18) underwent an MRI scan and EDSS examination
at baseline and after an interval of 2 to 4 years. Patients were recruited
from natural history studies ongoing in our center. Data were retrospectively
analyzed for this study. Twenty-two patients were receiving interferon-beta
1a treatment at the time of follow-up examination.
MAGNETIC RESONANCE IMAGING
Magnetic resonance imaging was performed at 1.0 T (Magnetom Impact;
Siemens AG, Erlangen, Germany) and consisted of axial T1-weighted (repetition
time, 620 milliseconds; echo time, 15 milliseconds; and number of excitations,
2) and T2-weighted (repetition time, 2500 milliseconds; echo time, 45 and
90 milliseconds; and number of excitations, 1) spin-echo MRIs. A slice thickness
of 5 mm, with a 0.5-mm gap, and a pixel size of 0.98 x 0.98 mm was used
to obtain 21 slices covering the whole brain.
MRI ANALYSIS
All MRIs were analyzed on a computer workstation (Sun, Mountainview,
Calif) using home-developed semiautomated seed growing software (Show_Images)
based on a local threshold determined by a Canny edge-detection filter, which
is designed to detect strong intensity gradients. When this failed, manual
adjustment of the threshold was performed. Parenchymal and ventricular volumes
were measured on T1-weighted MRIs and intracranial volume was measured on
the corresponding slices of the heavily T2-weighted MRIs. Parenchymal volume
consisted of combined supratentorial and infratentorial parenchymal volume
(whole-brain parenchyma); MRIs below the level of the cerebellum, consisting
of only medulla oblongata or spinal cord, were not considered. Ventricular
measurement included all 4 ventricles (including the choroid plexus). The
fourth ventricle was measured until the slice below the foramen of Luschka
(the Bochdalek flower basket). To correct for differences in skull size, 2
ratios were calculated (1) the PF or whole-brain parenchymal volume/intracranial
volume, and (2) the VF or ventricular volume/intracranial volume. The PF was
used as a marker of overall brain volume; the VF was used as a marker for
central atrophy. Intrarater reliability of measurements was calculated, being
2% (SD, 1.7%) for PF19 and 5% (SD, 3.5%) for
VF. All data were analyzed by a single, blinded rater (N.F.K.) and are presented
as annualized percentages (annualized PF and annualized VF).
STATISTICAL ANALYSES
Baseline data, annualized EDSS, annualized PF, and annualized VF
were calculated for the total group and for each subtype of MS separately.
When variables were not normally distributed (baseline VF and annualized VF),
nonparametric analyses were used. Wilcoxon rank sum test was performed for
the comparison of brain atrophy measurements between baseline and follow-up.
The Kruskal-Wallis test was applied to analyze differences between the subtypes
for baseline PF and VF and annualized PF and VF. Spearman rank
correlation coefficients were calculated to analyze the relation between clinical
characteristics (sex, age, duration of symptoms, baseline EDSS score, and
annualized EDSS score) and the rate of annualized brain atrophy markers.
Models for multiple linear regression analysis were created, using annualized PF
or annualized VF as dependent variables, to analyze the influence of
clinical characteristics (in which subtype of MS, sex, age, duration of symptoms,
baseline EDSS score, and the interval between the 2 time points were used
as predictors). To account for a possible effect of interferon-beta 1a treatment
on the rate of brain atrophy analyses were repeated when patients who were
receiving treatment were excluded. The Kruskal-Wallis test was repeated after
dividing the patients into quartiles of age, to analyze whether group differences
could be found post hoc. P<.05 was considered
a trend; P<.01 was considered statistically significant
in this exploratory analysis. All values are given as mean (SD).
RESULTS
Forty-nine women (59%) and 34 men (41%) were studied. These patients
had a mean age of 39.8 (10.5) years, a mean duration of symptoms of 6.4 (6.4)
years, and a median EDSS score of 2.0 (range, 0-7.5). The mean interval between
baseline and follow-up was 2 years 11 months. From 4 patients (3.3%), no EDSS
score at follow-up was available; for analysis, in which annualized EDSS
was used as a determinant, these patients were excluded. Patient characteristics
and brain atrophy measurements are listed in Table 1 for the total group and 3 major disease subtypes.
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Patient Characteristics and Values on Brain Atrophy Markers for Baseline
and Follow-up in the Total Group and Subtypes of Multiple Sclerosis (MS)*
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CROSS-SECTIONAL DATA AT BASELINE
At baseline, patients with RR MS showed the highest PF (P<.05 vs patients with SP MS and P<.01
vs patients with PP MS), and the lowest VF (P<.05
vs patients with SP MS). Patients with SP or PP MS did not differ with regard
to baseline PF and VF. Patients with RR MS differed significantly from patients
with SP or PP MS on the baseline EDSS score.
COURSE OF ATROPHY DURING FOLLOW-UP: TOTAL GROUP AND SUBTYPES
Baseline measurements of brain atrophy markers differed significantly
from follow-up; this was seen for both the total group and the subtypes (P<.001 for all comparisons, except P<.01 for VF in patients with PP MS). For the whole group, annualized PF
was -0.7% (SEM, 0.11%), and annualized VF was 3.7% (SEM, 0.54%).
Annualized PF, annualized VF, and an annualized EDSS
score were largest in the group with SP MS and smallest in the group with
PP MS. Statistical analysis revealed that annualized PF did not significantly
differ between the subtypes; however, annualized VF showed a trend
for significance in difference between patients with PP and SP MS, with patients
who have SP MS showing the largest increase in VF per year (P = .02). No difference on annualized VF was found between patients
with RR and PP MS and patients with SP MS. An annualized EDSS score
did not differ significantly between the 3 subtypes of MS.
RELATION BETWEEN CLINICAL DETERMINANTS AND RATE OF BRAIN ATROPHY
In the total group, no correlations were found between annualized PF
and clinical characteristics. A trend was observed in the correlation between
age and the duration of symptoms and annualized VF (r = -0.26 with age, and r = -0.22
with duration of symptoms). No correlation was found between the baseline
EDSS score or the annualized EDSS score with annualized markers of
brain atrophy. When multiple linear regression analysis was performed using
the stepwise method, a minor influence of age was found on annualized VF
(adjusted r2 = 0.076), whereas subtype
of MS, duration of symptoms, baseline EDSS score, and interval between the
2 time points were excluded from the model. To further analyze the influence
of age on annualized VF, the total group was divided into quartiles
according to age (median, 39.5 years). Post hoc comparison of annualized VF
between the lowest quartile (the youngest group aged <31.1 years; consisting
mainly of patients with RR MS and patients with low EDSS scores) and the highest
quartile (the oldest group aged >47.8 years; consisting mainly of patients
with PP MS and patients with moderate to high EDSS scores) showed a significant
difference, with the youngest group having a larger increase of VF (6.5%)
per year than the oldest group (2.5%) per year.
INFLUENCE OF INTERFERON-BETA 1a TREATMENT ON THE RATE OF BRAIN ATROPHY
Twenty-two patients (26.5%) were receiving interferon beta treatment
at follow-up. Data were reanalyzed for patients receiving treatment and those
who were not, showing no significant difference in baseline data, follow-up
data, and annualized values on PF and VF. Both groups showed an annualized PF
of -0.7%, whereas the group who was not receiving interferon-beta 1a
treatment showed an annualized VF of 3.5% vs 4.4% for the group receiving
interferon-beta 1a. The group with RR MS included the largest group of patients
receiving interferon-beta 1a treatment at follow-up (n = 16). The annualized PF
was –0.7 % for the group who was not receiving interferon-beta 1a treatment
and -0.6 % for those receiving interferon beta treatment; the annualized VF
was 3.9% vs 4.4%, respectively. These differences were not statistically significant
(both r = 0.07). The trend in difference between
patients with PP and SP MS on annualized VF was no longer present after
excluding the interferon-beta 1a–treated patients.
COMMENT
In this study, the rate of global brain atrophy and central atrophy
per year was calculated for 83 patients with MS, representing all 3 major
disease subtypes. The rate of global brain atrophy was 0.7% (SEM, 0.11%) per
year in the total group, while central atrophy increased by 3.7% (SEM, 0.54%)
per year. The first major observation from this study is the fact that no
significant difference in the rate of global brain atrophy between the subtypes
of MS (including patients with PP MS) was found. So far, only 1 small study
reported longitudinal brain atrophy data for different types of MS.17 In that study, Fox et al17
found a decrease in overall brain volume similar to our findings (0.8%). They
used an image registration technique in a small group of patients with MS
(n = 26) and found the largest decrease (0.9% per year) of brain volume in
patients with PP MS (n = 9) and the smallest decrease (0.6% per year) in patients
with SP MS (n = 6). However, as in our study, these differences were not statistically
significant. Other studies reporting on the percentage of decrease of brain
volume reported values ranging from 0.6%20
to 1.6% per year21 for patients with RR MS,
and from 1.0%22 to 1.7%23
for patients with SP MS. One large longitudinal study was performed in patients
with PP MS (n = 137), reporting a median decrease in overall brain volume
of 0.95% per year.16 However, different intervals
and different techniques have been used for these different studies. In some
studies a few slices of the brain were measured,16, 22-23
whereas in other studies, the whole brain was included13-15;
a correction for skull size was not always applied. A limitation of our study
is the fact that we did not include longitudinal follow-up of healthy control
subjects. In an earlier cross-sectional study,8
we did find a difference between PF and VF for all 3 subtypes of MS (including
patients with RR MS) compared with healthy controls (P<.001
for PF and P<.01 for VF) using the same technique.
Moreover, all patients in this study were examined in parallel using the same
equipment.
New in this study is the inclusion of longitudinal measurement of central
atrophy in different subtypes of MS. We found a median increase in VF of 3.7%
for the total group. A trend for a difference between patients with PP or
SP MS, with patients with SP MS having the largest increase in annualized VF,
was found. This trend was no longer present after the removal of patients
who were receiving interferon-beta 1a treatment at follow-up. This may be
caused by the fact that the subgroups were of limited size. Moreover, we did
not consider the duration in treatment history. A study comparing patients
with the clinically isolated syndrome with healthy controls already showed
significant ventricular enlargement in those with the clinically isolated
syndrome.24 So far, only 1 study measured central
atrophy longitudinally in a large group of patients with RR MS; Simon et al14 reported an increase in third ventricle width of
4.5 % and an increase in lateral ventricle width of 5.5% per year.
The second major observation in this study is the fact that most of
the variance in central atrophy could not be explained by subtype of MS or
other clinical determinants. Only for VF was a minor percentage of the variance
explained by age. Interestingly, the larger increase was seen in the younger
group, consisting mainly of patients with RR and of patients having EDSS scores
below 2.0.
Apart from age as a (minor) predictor for atrophy, no other clinical
characteristics (such as the duration of symptoms or annualized EDSS)
predicted the variance in the rate of global or central brain atrophy. The
absence of a correlation between change in EDSS score and rate of global or
central brain atrophy, might be caused by the fact that most patients had
EDSS scores in the lower range, where minor loss in brain volume could easily
be limited to symptoms and signs (eg, small changes in cognitive function)
that are not picked up by the EDSS. Unfortunately, assessments of the MS functional
composite (that is more strongly related to brain atrophy measurement) were
excluded from the study at that time.25-26
Other studies20, 22-23
also failed to show a correlation between EDSS score and the rate of
brain volume loss over time, although others did find a correlation between
the changes of brain volume and the change in EDSS score7
and cognitive deterioration.27 However, for
these studies, in which a correlation was found, brain volumes were used without
correction for skull size. Ge et al15 found
no correlation between the change in brain volume (corrected for skull size)
and the change in EDSS score in 27 patients with RR MS, whereas they did find
this correlation in 9 patients with SP MS.15
A potential confounder might be that about one fourth of our group was
receiving interferon-beta 1a treatment at time of follow-up. However, we found
no significant difference for both global and central brain atrophy between
the group receiving treatment and the group not receiving treatment. This
can be explained by the small sample size of the group using interferon-beta
1a, and by the fact that the duration of treatment was not similar for all
patients.
Our main observations—the rate of brain atrophy being independent
from clinical course (including both patients with RR MS and patients with
PP MS) and the rate of central atrophy being larger in younger patients—suggest
that MS should be considered a disease in which neurodegeneration is an early
feature, thereby stressing the need for the study of early (neuroprotective)
treatment in MS.
AUTHOR INFORMATION
Accepted for publication May 30, 2002.
Author contributions: Study concept and design (Drs Kalkers, Polman, and Barkhof); acquisition of data (Drs Kalkers, Bot, Minneboo, Barkhof, and Mr Ameziane);
analysis and interpretation of data (Drs Kalkers, Minneboo,
Polman, Barkhof, and Mr Ameziane); drafting of the manuscript (Drs Kalkers, Bot, Polman, Barkhof, and Mr Ameziane); critical
revision of the manuscript for important intellectual content (Drs Polman, Barkhof, and Mr Ameziane); statistical expertise (Drs Kalkers and Barkhof); obtained funding (Dr Barkhof); administrative, technical, and material support (Drs Kalkers, Bot, Minneboo, Barkhof, and Mr Ameziane);
study supervision (Drs Barkhof and Polman).
Corresponding author: Nynke F. Kalkers, MD, PhD, Department of Neurology,
Vrije Universiteit Medical Center, De Boelelaan 1117, PO Box 7057, 1007 MB
Amsterdam, the Netherlands (e-mail: nf.kalkers{at}vumc.nl).
From the Departments of Neurology (Drs Kalkers and Polman) and Radiology
(Mr Ameziane and Drs Bot, Minneboo, and Barkhof), Vrije Universiteit Medical
Center, Amsterdam, the Netherlands.
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