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A Longitudinal Study of Callosal Atrophy and Interhemispheric Dysfunction in Relapsing-Remitting Multiple Sclerosis
J. Pelletier, MD, PhD;
L. Suchet, MD;
T. Witjas, MD;
M. Habib, MD;
C. R. G. Guttmann, MD, PhD;
G. Salamon, MD;
O. Lyon-Caen, MD;
A. Ali Chérif, MD
Arch Neurol. 2001;58:105-111.
ABSTRACT
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Objectives To determine if callosal atrophy and interhemispheric dysfunction can
be detected in the early stages of relapsing-remitting multiple sclerosis
(MS) and to evaluate their progression in relation to the disability and evolution
of lesions seen on magnetic resonance imaging during a 5-year period.
Methods We compared 30 patients who had clinically definite early-onset replasing-remitting
MS and mild disability with control subjects. Regional and segmental callosal
size and extent of white matter abnormalities on magnetic resonance imaging,
as well as performance on tasks exploring interhemispheric transfer of motor,
auditory, and sensory information were assessed. Patients with MS were evaluated
at baseline and after 5 years. Physical disability was determined at both
times using the Expanded Disability Status Scale score.
Results Patients with MS were seen with significant callosal atrophy and functional
impairment of interhemispheric transfer at baseline that worsened during the
5-year study. A significant correlation was found between the magnitude of
disability and the severity of morphological and functional callosal involvement
at baseline. This association persisted at year 5. Baseline clinical characteristics
such as age and prestudy relapse rate were unrelated to callosal size or interhemispheric
performance. However, the number of baseline T2-weighted lesions was correlated
with callosal involvement and this relation persisted at year 5.
Conclusion Patients who had relapsing-remitting MS in the early stages of the disease
and mild disability had significant callosal involvement that progressed over
time. The relationship between disability, T2-weighted lesions load, and degree
of morphological and functional callosal impairment confirm the potential
value of using callosal dysfunction as a surrogate marker of disease progression
in MS.
INTRODUCTION
CLINICAL AND magnetic resonance imaging (MRI) features that are predictive
of disease progression in the early stages of relapsing-remitting (RR) multiple
sclerosis (MS) remain uncertain. It was recently shown that T2-weighted brain
lesion (T2 lesion) volume in patients with clinically isolated symptoms suggestive
of MS was predictive of clinical disease progression.1, 2
However, neuronal involvement and axonal loss have been demonstrated in early
RR MS by magnetic resonance spectroscopy and histopathological studies.3, 4, 5, 6 Some
studies have shown strong correlations between disability and spinal cord,7 cerebellar,8 and cerebral
atrophy9, 10, 11 in
MS. In particular, Simon et al11 recently reported
that patients with RR MS and moderate disability have measurable amounts of
cerebral atrophy that progress yearly and that the course of cerebral atrophy
was influenced by prior inflammatory activity of MS evaluated by the presence
of gadolinium-enhancing brain lesions as seen on MRI. Cerebral atrophy observed
in patients with MS could reflect an irreversible process based on axonal
loss already present at an early stage of MS.3, 12
However, if brain atrophy increases more rapidly in patients with high levels
of disability, the progression of atrophy seems unrelated to clinical variables
such as relapse rate or changes in the Expanded Disability Status Scale (EDSS)
score.13 Finally, in early MS, the relationship
between indexes of atrophy and level of disability, as well as their predictive
value for clinical disease progression, remains uncertain. Nevertheless, whole-brain
atrophy, as estimated by brain parenchymal fraction measurements on MRI, could
represent a sensitive index for axonal loss and for evaluating the potential
effects of treatments.13 In particular, using
this approach, a recent report suggested a protective impact of interferon ß-1a
on the progression of cerebral atrophy.13 Another
valuable method to evaluate axonal loss could be provided by studying callosal
anatomy and interhemispheric function.
Autopsy and MRI studies indicate that atrophy of corpus callosum (CC)
is a common finding in patients with MS.14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24
Demyelinating lesions of callosal or subcallosal areas found in most patients
with MS could explain CC atrophy.17, 20
However, some studies demonstrated dysfunction of interhemispheric transfer
in patients with MS, particularly on verbal dichotic listening tasks showing
a left-ear dichotic suppression.18, 22, 25, 26, 27
Functional impairment of interhemispheric transfer in MS has also been correlated
to the degree of callosal atrophy and to the severity and diffusion of white
matter changes identified by MRI.18, 22, 23
Moreover, it has been recently shown that even in cases where high-resolution
MRI had failed to demonstrate cerebral demyelination, interhemispheric dysfunction
and, to a lesser degree, callosal atrophy may be present.22
This unexpected result could be interpreted as witnessing infraradiological
involvement of callosal fibers that could be therefore viewed as an early
marker of axonal and neuronal damage.
To determine the potential value of callosal atrophy and interhemispheric
transfer impairment as a sensitive marker of MS progression, we conducted
a 5-year prospective study in a group of patients with RR MS enrolled at the
early stage of MS who had mild disability based on EDSS scores. The aims of
this study were to (1) assess whether callosal atrophy and interhemispheric
impairment could be detected in patients with RR MS early in the disease,
(2) determine if functional and morphological callosal impairments progress
during a 5-year period, (3) evaluate the potential relationship between functional
and morphological callosal measures and disability, and (4) determine the
influence of T2 lesions on callosal involvement as seen on MRI.
PATIENTS AND METHODS
PATIENTS
Of the 90 patients with MS who were initially examined and enrolled
in our original study,22 30 were still available
and were considered suitable for our 5-year follow-up study. Inclusion criteria
were (1) clinically definite RR MS as determined by the criteria of Poser
et al28 with a clinically documented MS duration
of less than 3 years at baseline, (2) no long-term treatment for MS during
the follow-up period, (3) clinical remission at the time of evaluation, (4)
no major signs of cerebellar, motor, or sensitive involvement of the upper
limbs at baseline examination, and (5) hemispheric white matter hyperintensities
on T2-weighted MRI consistent with the diagnosis of MS29
at baseline MRI. All patients' disabilities were scored using the EDSS30 at both times by the same evaluating neurologist
(J.P.).
CONTROL SUBJECTS
Twenty-five sex-, age-, and handedness-matched normal subjects without
known neurological disorders or history of alcoholism or other drug abuse
were recruited as controls and underwent neuropsychological testing. This
group had a mean age of 29 years (age range, 20-40 years). Normal callosal
morphology was defined by a previous study of 53 healthy volunteers who had
undergone the same MRI procedure as used for this study.31
NEUROPSYCHOLOGICAL TESTING
Interhemispheric transfer of auditory (verbal dichotic listening task),
sensory (crossed tactile finger localization), and motor (finger-tapping task)
information was evaluated in all patients and controls at baseline and 5 years
later for the group with MS only. The detailed procedure has been previously
described.22 Twenty-eight patients had normal
brainstem auditory evoked potentials. For the remaining 2 patients, it was
verified individually that abnormal brainstem auditory evoked potentials could
not account for the asymmetry in dichotic listening performance. Data analyses
were based on functional transfer (FT) indexes (mean difference in errors
between the 2 ears for verbal dichotic listening task; mean difference in
errors between intermanual and monomanual conditions for sensory transfer
task, and mean ratio between monomanual and bimanual conditions for motor
transfer task).22
MAGNETIC RESONANCE IMAGING
The design of this study was performed in 1991 and we used the same
MRI unit (Magneton; Siemens, Erlangen, Germany) operating at a field strength
of 1.5 T at baseline and at year 5. The image resolution was 0.89 mm in-plane
for 5-mm-thick sections (acquisition matrix, 256 x 256 pixels; field
of view, 23 cm) and imaging was done in the axial and sagittal planes. The
axial section thickness was 5 mm and computed tomographic scans were performed
on patients using a T2 sequence with a repetition time of 2700 milliseconds
and an echo-delay time of 20 to 90 milliseconds. All patients were also evaluated
by T1-weighted sagittal partial saturation images using a repetition time
of 600 milliseconds and an echo-delay time of 20 milliseconds (slice thickness,
5 mm).
MRI ANALYSIS
Quantification of CC morphology was carried out from the T1-weighted
midsagittal MRI. Global and segmental morphology of the CC was assessed with
automated measurements based on a manual midsagittal outline of the CC. The
midcallosal area was partitioned into the following 6 subregions: 3 anterior
(A1, A2, and A3) and 3 posterior (P1, P2, and P3) regions.22, 31
The extent of T2 white matter lesions was assessed on axial sections using
a semiquantitative method with a 5-point grading scale (total lesion index).32 Regional distribution of lesions within and outside
of the CC was analyzed for an anterior (A3 + A2), middle (A1 + P1), and posterior
(P2 + P3) region using the same 5-point scale. Each axial image was subdivided
into these 3 regions by projecting the boundaries calculated on the midsagittal
image (Figure 1). Magnetic resonance
imaging scans were graded independently by 2 blinded physicians (L.S. and
T.W.). Interrater agreement was high (0.87 for lesion grading; 0.96 for CC
measurements).
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Mode of partition of callosal area and regional distribution of magentic
resonance imaging lesions. The central point represents the center of gravity
(mathematically calculated for each subject).
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STATISTICAL ANALYSIS
Analysis of variance (ANOVA) was performed to characterize the overall
relationship between callosal functional performances and morphological measures
on both data series (at baseline and at year 5). Multiple stepwise regression
analysis was computed to assess the relationship between FT impairment, CC
atrophy, and baseline and 5-year measures. Patients' and controls' FT scores,
as well as global and segmental callosal morphology measures of patients with
MS and controls were compared using the t test. Spearman
rank correlation coefficients were calculated to characterize the relationship
between clinical, functional, and MRI measures. The t
tests were used to compare baseline and year 5 changes for callosal morphology
and functional performances. All statistical analyses were performed on a
Macintosh personal computer (Apple Computer Inc, Cupertino, Calf) using StatWorks
(version 1.1, 1985; MacIntosh Inc, Apple Computer Inc) and CLR ANOVA (1992;
Midvision Software, Abacus Concept Inc, Berkeley, Calif) softwares.
RESULTS
BASELINE CHARACTERISTICS
Demographic and clinical characteristics of the MS population are summarized
in Table 1. As determined by the
inclusion criteria, patients were at the early stage of MS (mean disease duration,
2.4 years) with a low EDSS score (mean EDSS score, 2.1).
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Table 1. Demographic and Clinical Characteristics of Population With
Multiple Sclerosis (MS)*
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Functional Interhemispheric Transfer Assessment
As previously reported, patients with MS were significantly impaired
compared with controls for all modalities explored (left ear extinction, hands-tactile
condition, and increased time in bimanual tapping [Table 2]).
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Table 2. Performance of Patients With Multiple Sclerosis (MS) and Controls
on Functional Tasks of Interhemispheric Transfer at Baseline and Year 5*
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Callosal Morphology on MRI
The comparison of mean callosal areas between the population with MS
and the controls showed significant atrophy in the group with MS for global
callosal area, as well as for all 6 subregions (P<.001)
(Table 3). We found no significant
effect or interaction of gender and hand preference on callosal area measurements
in patients with MS.
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Table 3. Comparison of Midsagittal Corpus Callosum Area in Patients
With Multiple Sclerosis (MS) and Controls at Baseline and Year 5*
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Correlations Between MRI and Neuropsychological Measures
The global ANOVA performed on the baseline results showed a significant
interaction between performance on FT tasks for all modalities explored and
EDSS score (F = 4.25, P<.01). A significant interaction
was also found between CC morphology and EDSS score (F = 5.89, P<.001) and between T2 MRI lesion grading and EDSS score (F = 4.39, P<.01). The stepwise regression confirmed that the EDSS
score was predominantly linked to dichotic listening (F = 10.625) and sensory
tranfer tests (F = 9.34) for interhemispheric tranfer, to A3 and P3 areas
for callosal morphology (F = 12.6), and to total index for MRI white matter
lesions. A significant correlation was found between the magnitude of relative
left ear impairment and all callosal measurements carried out (Table 4). Similarly, significant correlations were noted between
severity of transfer impairment for tactile and motor tasks and callosal atrophy
except for the splenium. As we previously reported, each FT was predominantly
associated with atrophy of one part of the CC (anterior region for motor transfer,
middle region for tactile localization task, and posterior region for dichotic
listening test) (Table 4). Correlation
between regional grading of T2 MRI white matter abnormalities and functional
impairment of interhemispheric transfer tests demonstrated a global relation
between the dichotic listening task score or the sensory transfer test score
and each callosal measure (P<.01). In contrast,
a preferential relationship between the motor transfer test and lesions localized
in the middle and anterior regions was found (Table 5). Results of correlation analysis between callosal atrophy
and MRI lesion load showed an association between the total lesion index and
all measurements of callosal areas. More interestingly, regional analysis
of MRI lesions demonstrated a preferential relationship between lesion indexes
for the anterior, middle, and posterior regions of callosal and subcallosal
areas and atrophy of the anterior, middle, and posterior callosal subregions
(Table 6).
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Table 4. Correlation Between Functional Performances and Callosal Areas
at Baseline and Year 5*
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Table 5. Correlation Between Functional Performances and Magnetic Resonance
Imaging (MRI) Lesions at Baseline and Year 5*
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Table 6. Correlation Between Callosal Areas and Magnetic Resonance
Imaging (MRI) Lesions at Baseline and Year 5*
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Correlations Between Functional, MRI, and Clinical Measures
There were no significant correlations between baseline CC measures
and FT and age (P = .09) or prestudy relapse rate
(P = .12). However, baseline EDSS scores were correlated
with baseline total callosal atrophy (P<.04),
FT impairment (P<.01), and extent of T2 lesions
(P = .02) (Table
7).
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Table 7. Correlation Between Callosal Areas, Functional Performances,
Magnetic Resonance Imaging Lesions, and Expanded Disability Status Scale (EDSS)
Score at Baseline and Year 5*
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FOLLOW-UP ANALYSIS
At year 5, the RR course of MS persisted in 23 patients with MS (80%)
and no difference was found between baseline and year 5 for annual relapse
rate. Patients who had relapses were treated with corticosteroids. Seven patients
were on a secondary progressive course of the disease at year 5, but none
of them was being treated with immunosuppressive drugs or serial infusions
of corticosteroids during the study.
CC Atrophy and FT Impairment Progression in Patients With MS
A significant progression of CC atrophy and FT impairment was noted
between baseline and follow-up evaluation (Table 2 and Table 3).
During the 5-year study, patients with MS had a significant increase of CC
atrophy for each measure explored (P = .001 for total
area, P<.02 for anterior subregions, and P<.01 for posterior subregions) and they presented a
significant progression of impairment on the dichotic listening task (P = .005), sensory transfer test (P
= .003), and motor transfer task (P = .01).
Correlations Between Clinical, MRI, and Neuropsychological Measures
No significant correlations were found between baseline CC and FT and
age (P = .09) or prestudy relapse rate (P = .12). Because of the semiquantitative method used to assess T2
MRI lesions, it was impossible to compare change in T2 white matter extent
between baseline and year 5. Global ANOVA performed at follow-up showed a
persistent significant interaction between performance on dichotic listening
and sensory tasks and EDSS score (F = 3.82, P<.01),
but no significant interaction was found for motor transfer test (F = 1.28, P = .12). A significant interaction was also found between
CC morphology and EDSS scores (F = 4.21, P = .006)
and between T2 MRI lesion grading and EDSS score (F = 4.02, P = .002). Multiple regression analysis showed no relationship between
CC or FT and 5-year relapse rate or the number of corticosteroid courses used
during the study. A significant relationship persisted at year 5 between CC
atrophy and FT impairment except for the same subregions than baseline results
(splenium for sensory and motor transfer tests and midanterior subregion for
dichotic listening test) (Table 4).
These results confirmed that CC atrophy and FT impairment follow a progressive
and parallel evolution during the course of the disease. Correlation studies
showed that the extent of T2 MRI abnormalities continued to be associated
with FT impairment (Table 5) and
to a lesser degree with CC atrophy (Table
6). Moreover, the extent of MRI lesions at year 5 was correlated
with the final EDSS score and a significant correlation persisted between
CC atrophy and FT impairment and EDSS level evaluated at year 5 (Table 7). Finally, progression of disability
evaluated with EDSS was significantly related with progression of CC atrophy
and FT impairment and with T2 lesion load.
COMMENT
At first, our results confirmed that patients with MS are seen with
significant callosal atrophy compared with controls. As previously reported
in other studies,15, 17, 20, 21, 22, 23
callosal atrophy is frequently observed in MS, either in advanced disease
with a high level of disability or in patients with MS who have mild disability.
Since the patients with MS included in this study were at an early stage of
the RR MS phase and had a mild disability, callosal atrophy seems to be an
early morphological marker of CC involvement. These results are similar to
those reported recently by Simon et al.11 In
their longitudinal study of brain atrophy, patients with MS included had a
mild disability status (mean EDSS score±SD, 2.3 ± .82) and presented
at baseline a significant decrease of CC area and brain width, as well as
significant increases of third ventricle and lateral ventricle widths. A similar
result was obtained using the brain parenchymal fraction that measures whole-brain
atrophy.13 Moroever, our study provides further
evidence of impaired auditory, motor, and sensory interhemispheric transfer
and of a correlation between sensory interhemispheric transfer and regional
callosal atrophy. This result argues in favor of the concept of topographical
distribution of callosal fibers here demonstrated in vivo in a population
with MS. Functional and morphological involvement of CC could be explained
by demyelinating lesions of callosal or subcallosal areas and their possible
consequences of axonal loss and wallerian degeneration.15
The relationship between callosal atrophy and degree of white matter
lesions evaluated by MRI is unclear. Some previous studies have reported a
strong significant interaction of T2 lesions with CC atrophy,16, 22
with others finding only a weak relationship.17, 23
These conflicting results could be explained by the heterogeneity of methods
used to assess demyelinating lesions by MRI. Simon et al11
showed recently that the degree of CC atrophy was related to T2 lesion MRI
volume as well as to third and lateral ventricle atrophy. On the contrary,
they found no effect of gadolinium-enhancing lesions on callosal atrophy while
the number of enhancing lesions at baseline was predictive of progression
of third ventricle atrophy. In the light of this latter result, it is surprising
to consider that the presence of enhancing lesions reflected inflammatory
activity at the early stage of the RR MS but did not influence the degree
of callosal atrophy. In contrast, T2 abnormalities that characterized probably
more chronic demyelinating lesions with axonal loss were closely related to
the degree of CC atrophy. Accordingly, our results clearly showed that atrophy
of CC and FT impairment are both related to T2 MRI lesions and support the
hypothesis that demyelinating lesions of callosal and pericallosal regions
induce CC atrophy and interhemispheric impairment in patients with MS. The
fact that CC atrophy could be detected at early stage of MS and in patients
without MRI lesion could argue that CC atrophy represents an early marker
of atrophy in MS.22 However, further studies
of patients with MS seen at an early stage of MS with normal white matter
appearance on standard MRI are needed to prove that involvement of CC could
be related with early myelin and/or axonal loss. In this way, future studies
using proton magnetic resonance spectroscopy and new techniques such as magnetization
transfer MRI in patients with MS who have normal white matter appearance and
are seen with isolated syndromes suggestive of MS could document this hypothesis.3, 4, 8
The relationship between atrophy measures and disability in MS has been
evaluated in other studies, showing a significant link between cerebellar
dysfunction and cerebellar atrophy,8 and between
EDSS score and spinal cord atrophy.9, 32
Consistent with a recent report by Simon et al11
of a significant link between CC, third and lateral ventricle atrophy, and
EDSS score, we found a significant relationship between CC measures and EDSS
score at baseline. In the same way, the degree of FT impairment for all modalities
explored were correlated with the EDSS score. This significant interaction
between clinical, functional, and morphological measures and their relation
with T2 MRI lesions suggests that a destructive pathologic process is already
present at the early stage of RR MS.
Longitudinal studies of brain atrophy in MS are rare.9, 11, 13
Results of our longitudinal evaluation showed that CC atrophy and FT impairment
observed at baseline increased significantly at year 5 in the MS group. At
follow-up, a significant interaction also persisted between functional scores
on interhemispheric transfer and CC measures, and T2 lesion load was significantly
related with degree of FT impairment and CC atrophy. Moreover and as already
noted at baseline, the level of disability was linked to FT impairment and
CC atrophy at year 5. Because of the small number of patients included in
this study, it was impossible to compare FT and CC means in MS subgroups with
high and low levels of clinical disease activity. The lack of interaction
between callosal involvement and other clinical measures such as relapse rate,
confirm the poor value of these clinical variables as prognostic markers in
patients with RR MS.11, 13, 33
Moreover, because of the absence of relationship between treatment of relapses
and CC atrophy or FT impairment, corticosteroids do not seem to be a contributing
factor to callosal involvement. Finally, our results indicate that the major
factor influencing CC atrophy and FT impairment either at baseline or at follow-up
was T2 lesion load.
To further investigate the predictive value of callosal involvement
in MS, another possibly fruitful avenue would be to explore the relationship
between CC atrophy or FT impairment and neuropsychological dysfunctions. Although
clinically apparent callosal disconnection has been rarely reported,34 some prior studies demonstrated that global cognitive
dysfunction, as well as intellectual and memory disturbances were associated
with a significant increase of ventricular width.35, 36, 37
More recently, focal atrophy of the anterior part of the CC has been related
to verbal fluency impairment.19, 21
In particular, according to evidence showing that CC may play a key role in
between-hemisphere facilitation that maintains bilateral cerebral arousal,38 future studies should focus on the relationship between
attentional dysfunction, which is frequently reported in patients with MS,39, 40 and CC atrophy and MR abnormalities41 to determine the natural history of callosal involvement
in MS. Finally, the present results provide strong arguments for using anatomical
and functional callosal measurements as key indexes for future evaluations
of treatments susceptible of exerting a preventive effect on the natural history
of MS.42, 43, 44, 45
AUTHOR INFORMATION
Accepted for publication October 2, 2000.
This investigation was supported in part by grants from ARSEP (Association
pour la Recherche sur la Sclérose en Plaques), and PHRC1994-CA3844-UF-1628,
from the French National Ministry of Health, Paris, France.
From the Department of Neurology (Drs Pelletier, Suchet, Witjas, Habib,
and Ali Chérif) and Neuroradiology (Dr Salamon) University Hospital
of Marseilles, Marseilles, France, and Centre Hospitalo-Universitaire, Timone;
the Neurophysiology and Neuropsychology Unit, INSERM E 9926, University of
Marseilles, (Drs Pelletier, Habib, and Ali Chérif); the Federation
of Neurology, University Hospital La Salpétrière of Paris, Paris,
France (Dr Lyon-Caen); and the Department of Radiology, Brigham and Womens
Hospital, Harvard Medical School, Boston, Mass (Dr Guttmann).
Corresponding author: J. Pelletier, MD, PhD, Department of Neurology,
CHU Timone, F-13385 Marseilles 5, France (e-mail: jpelletier{at}ap-hm.fr).
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