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Enhancing Magnetic Resonance Imaging Lesions and Cerebral Atrophy in Patients With Relapsing Multiple Sclerosis
T. P. Leist, PhD, MD;
M. I. Gobbini, MD;
J. A. Frank, MD;
H. F. McFarland, MD
Arch Neurol. 2001;58:57-60.
ABSTRACT
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Objective To examine the relation between the frequency of enhancing magnetic
resonance imaging lesions and their characteristics of enhancement and atrophy
in patients with early relapsing multiple sclerosis.
Design Analysis of number of enhancing lesions, ventricular volumes and diameters,
and lesion characteristics on monthly magnetic resonance imaging scans during
natural history follow-up.
Setting A clinical research institution.
Patients Sixteen patients with confirmed early relapsing multiple sclerosis.
Main Outcome Measure Cerebral atrophy as measured by ventricular enlargement.
Results Numbers of enhancing lesions correlated well with an increase of ventricular
size. This correlation was strongest for patients with a high proportion of
concentric ring–enhancing lesions with central contrast pallor.
Conclusions Inflammatory events, especially those within lesions with associated
blood-brain barrier breakdown, affect the ensuing loss of brain parenchyma.
Patients with a high proportion of lesions with central contrast pallor, which
is likely associated with more extensive tissue damage, have a higher rate
of atrophic changes.
INTRODUCTION
PATIENTS WITH multiple sclerosis exhibit a varying degree of cerebral
atrophy.1, 2, 3 Little
is known about the underlying mechanisms and individual disease characteristics
that affect the rate at which brain parenchyma decreases.4, 5
Loss of neurons,6 oligodendrocytes, the formation
of glial scars, and the effects of therapeutics, such as corticosteroids,7 may contribute to reduction of brain matter and atrophy.8 Magnetic resonance imaging (MRI) has had a major impact
on the understanding and management of multiple sclerosis.9, 10
Blood-brain barrier breakdown is a consistent early feature of new lesion
development in patients with relapsing and secondary progressive multiple
sclerosis, which usually correlates with active inflammation and myelin breakdown.
On the MRI scan, these lesions are visualized by T1-weighted, contrast-enhanced
images.11 Characteristics of enhancing lesions
vary greatly, with individual patients often having predominant types regarding
size, location, or ring enhancement (Figure
1).12 T2-weighted brain imaging remains
the standard diagnostic tool; however, it is limited by poor pathological
specificity.13, 14
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Figure 1. A, Concentric ring–enhancing
lesion with central pallor. B, Lesion with homogeneous contrast uptake.
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To assess the impact of ongoing disease activity on atrophy development,
we correlated the increase of ventricular volume and diameter with the cumulative
number of contrast-enhancing lesions and their characteristics on serial monthly
MRI scans. In contrast to the spinal cord, most supratentorial lesions do
not affect primary efferent pathways. Their effects on neurologic function
may be, therefore, less readily assessable. Disability as a function of ventricular
enlargement or cumulative lesion count was, therefore, not a primary objective
of this study. Contrast enhancement is a transient feature of some acute lesions.
In general, lesions do not remain enhancing for more than 2 to 4 weeks and
the volume of enhancement varies with time after the onset of blood-brain
barrier breakdown.15 Since MRI scans were performed
monthly, we elected to account for the number and the characteristics of the
lesions rather than the volume of enhancement.
PATIENTS AND METHODS
Patients were enrolled in clinical research protocols approved by the
Institutional Review Board; provided signed and informed consent; and were
followed up monthly in the Neuroimmunology Clinic, National Institute of Neurological
Disorders and Stroke, Bethesda, Md. Sixteen patients were identified according
to the following inclusion criteria: (1) relapsing remitting course of disease;
(2) a diagnosis within 2 years of the first scan; (3) at least 2 gadolinium-enhancing
lesions during the first 3 monthly MRI scans; (4) a natural history follow-up
of at least 16 months (mean ± SD, 23.0 ± 11.7 months); and (5)
no treatment with immunomodulatory medication other than methylprednisolone
sodium succinate, 1 g/d given intravenously for 3 to 5 days, for acute exacerbations.
Five individuals did not have clinically significant exacerbations during
the study period. The remaining patients had between 1 and 3 attacks per year
requiring treatment with corticosteroids (Figure 2). The mean ± SD age of the cohort (9 women and 7
men) at the time of diagnosis was 29.7 ± 6.4 years. Four normal volunteers
(2 women and 2 men [mean ± SD age, 34.7 ± 10.9 years]) were
followed up for up to 5 years (mean ± SD follow-up, 3.8 ± 3.2
years) with unenhanced MRI scans.
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Figure 2. Correlation of mean ventricular
diameter increases per month with mean monthly new gadolinium-enhancing lesions
on monthly magnetic resonance imaging scans. The mean monthly number of new
lesions was calculated by dividing the cumulative number of new monthly lesions
by the length of follow-up. The mean monthly increase of ventricular diameter
was calculated as the difference between the mean diameter measured on the
last 3 scans and the mean diameter measured on the first 3 scans, divided
by the length of follow-up. Shaded symbols indicate values for patients with
a high percentage of concentric ring–enhancing lesions; and unshaded
symbols, values for patients with a low percentage of concentric ring–enhancing
lesions. Patients had 0 (squares), 1 (diamonds), 2 (triangles), or 3 (circles)
courses of methylprednisolone sodium succinate per year during follow-up.
The shaded left-pointing triangles indicate normal volunteers. A correlation
analysis was performed (linear regression, R2 = 0.65
[95% confidence interval, 0.20-0.87], z= 2.68, P=
.007).
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Magnetic resonance imaging was performed on a 1.5-T MRI unit (General
Electric, Milwaukee, Wis) with a quadrature head coil. Unenhanced and gadopentate
dimeglumine (Magnevist; Berlex Laboratories, Wayne, NJ), 0.1 mmol/kg, enhanced
T1-weighted sequences were analyzed (echo time, 20 ms; and repetition time,
600 ms) for this study. Reproducible head positioning was attempted by application
of vitamin E–containing capsules in the external acoustic meatus and
over the lateral canthus of the orbit. Depending on when enrolled, patients
and volunteers underwent imaging with either a 5-mm (n = 9) or a 3-mm (n =
7) slice thickness. Measurement of third ventricular width and the diameter
of the lateral ventricles was performed on all scans. Images with 3-mm section
thicknesses were evaluated with computer analysis of ventricular volume after
3-dimensional reconstruction and with linear measurements to cross validate
the 2 methods.
Reconstruction and coregistration of scans with 3-mm section thicknesses
were performed with image processing software (MEDx; Sensor Systems Inc, Sterling,
Va). A graded caliper with a 0.1-mm scale was used for linear measurements
on film copies. The predominant head position on monthly scans was identified,
and scans with nonconforming head positions were not included in the analysis.
Third ventricular width was determined, and diameters of the left and right
lateral ventricles were measured at the level of the interventricular foramen.
The percentage of ventricular enlargement was calculated with equal weighing
of measurements for the third ventricle and the mean of the lateral ventricles
as follows: percentage of ventricular enlargement = {(Vti/Vt0) + [(Vri/Vr0) + (Vli/Vl0)
x 0.5] x 100} - 100, with Vt being the measurement for the
third ventricle; i, month of study; 0, baseline; and Vr and Vl, the width
of the right and left lateral ventricles at the level of the interventricular
foramen, respectively.
Linear regression of the values obtained for linear and volume measurements
yielded R2 = 0.84 and P= .009. Good correlation
between the 2 measures could also be seen for longitudinal data in 4 individuals
(Figure 3).
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Figure 3. Correlation of ventricular volume
and diameter increase with cumulative number of new contrast-enhancing lesions
(found by magnetic resonance imaging [MRI]) on monthly scans for 4 patients
(A, patient 1; B, patient 2; C, patient 3; and D, patient 4). Upper panel,
Correlation of ventricular volumes calculated on coregistered MRI scans with
a slice thickness of 3 mm, as described in the "Patients and Methods" section
(shaded squares), with cumulative number of new enhancing lesions (unshaded
squares) on monthly MRI scans. Lower panel, Correlation between measurements
for ventricular diameters (percentage enlargement [caliper]) and volumes (percentage
enlargement coregistration).
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For regression analysis, the t test, and nonparametric
analysis, statistical software (StatView 4.5, Macintosh version; SAS Institute
Inc, Cary, NC) was used.
Characteristics of enhancing lesions were analyzed on the initial MRI
scans. Enhancing lesions on at least 3 monthly MRI scans (a minimum of 25
consecutive lesions) were studied. Patients were grouped according to the
percentage of concentric ring–enhancing lesions exhibiting central contrast
pallor.
RESULTS
The cumulative number of enhancing lesions and enlargement of the ventricles
were compared longitudinally based on the mean monthly changes between patients
(Figure 2) and among individual
patients (Figure 3). To elucidate
an association between the number of enhancing lesions and atrophy, the numbers
of mean monthly lesions and mean monthly changes in ventricular measures were
studied. A correlation analysis was performed on data from a natural history
follow-up of at least 16 months (Figure 2) (linear regression, R2 = 0.65, P = .007). The correlation between enhancing lesions and
atrophy was also maintained when patients were stratified according to corticosteroid
use.
Because of differences in size, a low percentage loss of brain volume
may be leveraged into a large percentage increase of ventricular and other
fluid-filled spaces. For 2 patients (patients 1 and 2) (Figure 3), fractional brain volumes were available16
and were compared with ventricular changes. These 2 patients had reductions
of 1.7% and 1.9% of the fractional brain volumes per year, respectively. When
expressed based on the nonparenchymal volume, the total fluid-filled volume
increased by 1.1% and 1.3% per months during the study period, respectively.
Lesion characteristics vary between patients, with some individuals
exhibiting more concentric ring–enhancing lesions with central contrast
pallor. These latter areas are thought to arise in zones of fulminate tissue
destruction or glial scars. Seven of the 16 patients in the study cohort had
greater than 1 in 7 lesions with central pallor. In the other 9 individuals,
less than 1 in 10 lesions had this characteristic. Patients with high numbers
of lesions with central contrast pallor had the strongest correlation between
atrophy and cumulative lesion load (Figure
3). The presence of concentric ring–enhancing lesions with
central pallor in itself strongly correlated with ensuing ventricular enlargement
and loss of brain parenchyma (Figure 4).
However, this group of patients had received the most corticosteroid treatments
(Figure 2).
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Figure 4. Comparison of atrophy in patients
with a low ( 15%) or a high (>15%) proportion of concentric ring–enhancing
lesions with central pallor. The 2 groups were significantly (P=
.004) different. Shaded diamonds indicate mean of measurements; unshaded diamonds,
individual measurements.
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COMMENT
Focal inflammatory events leading to demyelination and repair are hallmark
characteristics of multiple sclerosis. Serial MRI studies have added much
to our understanding of the natural history and pathophysiological features
of this disease. Many short-term MRI changes are readily reversible, but several
MRI variables, such as a reduced N-acetylaspartate
level,17 low magnetization transfer ratios,18 and T1 hypointensity, are more persistent.12, 19 To gain further insight into whether
short-term inflammatory events lead to irreversible damage and associated
loss of brain parenchyma, we studied the correlation between atrophy, cumulative
number, and the characteristics of gadolinium-enhancing lesions. To control
for the variability of atrophy rate as a function of disease duration, only
patients with a long-term natural history of MRI follow-up, starting within
2 years of the clinical diagnosis, were included in this analysis. Ventricular
enlargement was assessed using image processing software or measurement of
ventricular diameters.
In patients with ongoing inflammatory activity and blood-brain barrier
breakdown, the results presented in this study favor a strong relation between
cumulative lesion load and atrophy (Figure
2 and Figure 3). Since
month to month ventricular changes are incremental, it is not possible to
temporally link enhancing lesions, regional edema in the area of inflammatory
lesions with resulting ventricular changes, and ensuing atrophy. The cumulative
number of enhancing lesions varies greatly between patients.20
Similarly, individual patients exhibit varying degrees of cerebral atrophy.2 The correlation between ventricular enlargement and
cumulative enhancing lesion load was particularly strong for patients with
more concentric ring–enhancing lesions with central pallor (Figure 1 and Figure 4). This group of patients also had the highest rate of clinical
relapses and, therefore, the greatest number of corticosteroid treatments
(Figure 2). Concentric ring–enhancing
lesions with central contrast pallor are thought to arise either in previously
damaged areas with avascular glial scars and peripheral neovascularization
or from a fulminate local inflammation with destruction of parenchyma and
passing microvasculature and peripheral angiogenesis. Rapid ventricular enlargement
in this high-risk group of patients is probably multifactorial, especially
in view of the high corticosteroid use.7
The results of this study also indicate that enhancing lesions and atrophy
can have predictive value, especially in patients with early disease. Patients
with recurring enhancing disease activity on an MRI scan are at high risk
for the development of cerebral atrophy, and may profit from early immunomodulatory
intervention with medications such as interferon. The presence of many concentric
ring–enhancing lesions seems to correlate with a more aggressive course
of the disease.
AUTHOR INFORMATION
Accepted for publication May 8, 2000.
From the Neuroimmunology Branch, National Institute of Neurological
Disorders and Stroke (Drs Leist, Gobbini, and McFarland), and Laboratory of
Diagnostic Radiology Research, Clinical Center (Dr Frank), National Institutes
of Health, Bethesda, Md.
Corresponding author: T. P. Leist, PhD, MD, Neuroimmunology Branch,
National Institute of Neurological Disorders and Stroke, National Institutes
of Health, 9000 Rockville Pike, Bldg 10, Room 5B16, Bethesda, MD 20892.
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