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Fluid-Attenuated Inversion Recovery Magnetic Resonance Imaging Detects Cortical and Juxtacortical Multiple Sclerosis Lesions
Rohit Bakshi, MD;
Suzie Ariyaratana, BS;
Ralph H. B. Benedict, PhD;
Lawrence Jacobs, MD
Arch Neurol. 2001;58:742-748.
ABSTRACT
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Background Autopsy studies showed cortical and juxtacortical multiple sclerosis
(MS) plaques. Fluid-attenuated inversion recovery (FLAIR) is an advanced magnetic
resonance imaging sequence that reveals tissue T2 prolongation with cerebrospinal
fluid suppression, allowing detection of superficial brain lesions.
Objectives To assess FLAIR, T1-weighted, and T2-weighted images for detecting lesions
in or near the cerebral cortex in patients with MS and to explore the relation
between cortical lesions and cortical atrophy.
Design, Setting, and Patients Cross-sectional study in a university MS clinic of 84 patients with
MS and 66 age-matched healthy controls receiving 1.5-T fast FLAIR, T2-weighted,
and T1-weighted images.
Main Outcome Measures Regional cortical atrophy was rated vs controls. Cortical and juxtacortical
lesions were ovoid hyperintensities involving the cortex and/or gray-white
junction.
Results A total of 810 cortical and juxtacortical lesions were seen by FLAIR
in patients (mean, 9.6 per patient), most commonly in the superior frontal
lobe. Cortical and juxtacortical lesions were identified in 72 patients and
6 controls. Fourteen percent of cortical and juxtacortical lesions were seen
on T1-weighted images and 26% were seen on T2-weighted images. More cortical
and juxtacortical lesions were present in secondary progressive disease than
relapsing-remitting disease. The total number of cortical and juxtacortical
lesions correlated significantly with disease duration and the regional number
correlated with the degree of regional atrophy. After taking into account
noncortical (white matter) lesions, only the cortical and juxtacortical lesion
count predicted atrophy in that region.
Conclusions FLAIR can detect many cortical and juxtacortical lesions in MS, which
were appreciated previously in autopsy studies but usually missed by magnetic
resonance imaging during life. Cortical and juxtacortical plaque formation
may contribute to cortical atrophy in MS.
INTRODUCTION
MULTIPLE sclerosis (MS) is commonly thought of as a multifocal disease
of white matter of the central nervous system, but a growing body of evidence
suggests that it is a more widespread, global disease of the brain.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13
Tissue abnormalities have been detected pathologically8
and by magnetic resonance imaging (MRI)4, 5, 14, 15
in grossly normal-appearing white matter distant from acute and chronic MS
lesions. In addition, the MS disease process appears to extend to the cortical
and subcortical gray matter.10, 11, 12, 13, 16
Tissue destruction and brain degeneration, including irreversible focal
damage in white matter,17 widespread axonal
loss,8 and brain atrophy,6, 7
appear to be an integral part of the MS disease process. Brain atrophy appears
to be common,6, 7, 18
occurs early in the disease process,6, 18
and results from white matter damage or involvement of both gray and white
matter.2
Fluid-attenuated inversion recovery (FLAIR) is an MRI technique that
shows areas of tissue T2 prolongation as bright while suppressing (darkening)
cerebrospinal fluid (CSF) signal, thus clearly revealing lesions in proximity
to CSF, such as cerebral cortical lesions.19, 20, 21
FLAIR was initially limited by a long acquisition time, but now it can be
performed rapidly using the fast spin-echo method22
that has improved the MRI diagnosis of various brain disorders compared with
previously used conventional MRI sequences.23, 24, 25, 26, 27, 28, 29, 30
FLAIR has been superior to T2-weighted images (T2WIs) for detecting MS brain
lesions, including those in or adjacent to the cerebral cortical gray matter.9, 31, 32, 33, 34, 35
In the present study, we assessed the value of FLAIR MRI for detecting MS
lesions in or near the cerebral cortical gray matter in a relatively large
series of patients with MS compared with age-matched controls. We compared
the sensitivity of FLAIR MRI relative to T1-weighted images (T1WIs) and T2WIs
in detecting these lesions and hypothesized that MS cortical gray matter lesions
were related to cortical atrophy.
SUBJECTS AND METHODS
PATIENTS AND CONTROLS
Subjects were patients from a university-affiliated MS clinic and age-matched
healthy controls who underwent the same scanning protocol at a single MRI
center during a 2-year period. Patients had clinically definite MS36 and were 18 to 60 years of age. Exclusion criteria
were as follows: (1) other major neurologic or systemic diseases, (2) active
substance abuse, (3) pregnancy, (4) poor-quality MRI scans, and (5) primary
progressive clinical course.37 Eighty-four
consecutive patients with MS (mean ± SD age, 43 ± 9 years) and
66 age-matched healthy controls (mean ± SD age, 40 ± 10 years)
were included. The MS clinical courses were categorized37
as relapsing-remitting (RR) in 58 patients or secondary progressive (SP) in
26 patients. The mean ± SD duration of MS disease was 10 ± 8.4
years. Neurologic disability was rated by the Expanded Disability Status Scale
(EDSS). The EDSS scores ranged from 0 to 8 in the patients with MS (mean ±
SD, 3.4 ± 1.9). Control subjects, ages 18 to 60 years, in whom MS was
excluded clinically were obtained consecutively from a normative MRI database
that was compiled by our published method.24
MRI PROTOCOL
All subjects were studied on the same 1.5-T MRI scanner using axial
5-mm interleaved (contiguous, no slice gap) FLAIR, T1-weighted, and T2-weighted
acquisitions that generated images with approximately a 1 x 1-mm in-plane
resolution. Fast spin-echo FLAIR was performed as previously detailed38 as follows: repetition time [TR]/echo time [TE]/number
of excitations, 8000/150/2; delay time, 2200 milliseconds; echo train length
(number of echoes), 20; and scan time, approximately 2 minutes. Multisection
imaging technique was used with a section selective inversion pulse. The inversion
pulse section was as wide as the imaging section (ie, 5 mm). A presaturation
band was placed caudal to the image volume. Fast spin-echo T2WIs (TR/TE/excitations,
2300/120/2; echo train length, 18; scan time, approximately 2.5 minutes) and
conventional spin-echo T1WIs (TR/TE/excitations, 400/10/2; scan time, approximately
4 minutes) were also acquired.
MRI ANALYSIS
Two observers masked to clinical details visually assessed the MRIs
by consensus. Cortical lesions were defined as hyperintensities compared with
normal cortical gray matter that involved or abutted the parenchyma of the
cerebral cortex (cortical or juxtacortical). These included lesions that were
in the cortex and those in the subcortical U fibers (corticomedullary junction).
No effort was made to define lesions as either purely cortical vs adjacent
to the cortex, since this was not thought to be feasible by analysis of images.
The lesions are referred to as "cortical lesions" throughout the remaining
text. Only intra-axial hyperintensities were included (hyperintensities of
leptomeningeal and sulcal vessels or cerebrospinal fluid pulsation were excluded).
Cortical lesions were assigned to 1 of 6 regions: superior frontal, inferior
frontal, superior parietal, inferior parietal, occipital, and temporal. The
conspicuousness of cortical lesions on FLAIR images was compared with T1WIs
and T2WIs. The total number of hyperintensities in brain parenchyma was also
counted by analyzing all axial FLAIR brain slices. Standard fissures were
used to separate the various lobes, including the central (rolandic), lateral
(sylvian), and parieto-occipital sulci. The third ventricle demarcated superior
vs inferior frontal and parietal lobes. All axial slices showing the region
were analyzed.
Regional cortical atrophy was assessed semiquantitatively on noncontrast
T1WIs according to the previously described visual rating method39, 40, 41, 42, 43
in these same 6 regions in each hemisphere by ordinally rating the enlargement
of subarachnoid spaces in comparison to the age-matched controls. Magnetic
resonance atrophy in each patient was rated side by side against a single
randomly chosen age- and sex-matched control scan. Each control scan was compared
with at least 1 patient with MS. Since there were more patients than controls,
some of the controls' scans were used twice and then discarded. The degree
of atrophy was ordinally rated as normal, grade 1 (mild; <10%), grade 2
(moderate; 10%-25%), or grade 3 (severe; >25%), according to the percentage
of volume loss of parenchyma or percentage of ventricular size increase. Total
cortical atrophy was the median of all ordinal ratings. The validity of this
atrophy rating method is supported by our demonstration that the degree of
atrophy measured by this technique in patients with MS correlates significantly
with positron emission tomography cortical hypometabolism,39
physical disability,43 depression,42 quality of life,41
and cognitive impairment44 in patients with
MS. Regarding the reliability of this atrophy rating method, the intraobserver
agreement of this magnetic resonance analysis technique is generally very
good (mean  , 0.9; range, 0.8-1.0); the interobserver agreement is generally
moderate to very good (mean , 0.8; range, 0.6-1.0). Details regarding
the reliability and validity of this atrophy rating scale were part of a separate
publication.43 Regions were collapsed across
homologous regions in both hemispheres by adding the number of lesions or
calculating the median of atrophy ratings. Atrophy ratings were performed
before and without knowledge of the FLAIR findings.
STATISTICAL ANALYSIS
Correlation of number of lesions with age, disease duration, EDSS score,
and regional cortical atrophy scores was assessed across all 84 patients with
MS by the Spearman rank correlation test. Group differences (RR vs SP) were
assessed by the Mann-Whitney test. Linear stepwise regression (F probability
to enter = 0.05, F to remove = 0.10) was used to compare the amount of predictive
variance in atrophy accounted for by cortical vs white matter lesions. To
account for the number of statistical tests, P<.01
was considered significant for all univariate comparisons. This was believed
to be an adequate correction because the study is exploratory.
RESULTS
Results are presented in Table 1, Table 2, and Table 3 and in Figure 1, Figure 2, Figure 3, and Figure 4.
Cortical lesions were typically seen on FLAIR as focal oval or ovoid hyperintensities
(Figure 1, Figure 2, and Figure 3)
or occasionally linear lesions (not shown). Most were confined to cortex (Figure 1, Figure 2, and Figure 3)
but some extended into subcortical white matter (Figure 1 and Figure 4).
As shown in Table 1, a total of
810 FLAIR cortical lesions were seen in patients with MS (mean, 9.6 per patient;
range, 0-94). Lesions were present in all cortical regions, most commonly
in superior frontal cortex (Figure 1, Figure 2, and Figure 3). Cortical lesions represented 26% of the total number
of brain lesions seen on FLAIR images. Thirty-two percent of cortical lesions
(n = 258) were 5 mm in diameter or smaller (Figure 1), 48% (n = 389) were 6 to 10 mm (Figure 1 and Figure 3),
and 20% (n = 163) were greater than 10 mm (Figure 2). At least 1 cortical lesion was seen in 86% of patients
with MS (n = 72). Cortical lesions were poorly shown by T1WIs and T2WIs (Figure 1, Figure 2, Figure 3, and Figure 4); 14% of cortical lesions were seen
as a hypointensity on T1WIs (Figure 1)
and 26% were seen as hyperintensity on T2WIs (Figure 1). Thus, 74% to 86% of cortical lesions were missed by conventional
MRI. Only 6 total cortical hyperintensities were seen on FLAIR images of controls
(mean, 0.1 per patient; range, 0-1). Disease duration correlated positively
with the number of regional cortical lesions in the superior frontal (
= 0.3; P<.005) and temporal ( = 0.34; P<.001) lobes and total cortical lesions ( = 0.33, P<.001) but not with inferior frontal, superior parietal,
inferior parietal, or occipital number of cortical lesions (P>.16 for all). Cortical lesion counts did not reliably correlate with
EDSS score; small nonsignificant correlation coefficients were obtained except
in the case of the temporal lobes ( = 0.33; P<.001),
where a weak association was revealed. As shown in Table 2, patients with SP disease had significantly more cortical
lesions than patients with RR disease in superior parietal and temporal cortex
(P<.01) but not in other cortical regions. Total
cortical lesions did not differ between patients with RR and SP disease. As
shown in Table 3, cortical lesions
were associated with regional cortical atrophy in the same region. In the
superior frontal, superior parietal, temporal, and occipital cortex, the number
of regional cortical lesions correlated positively and significantly with
regional cortical atrophy (P<.001 for all). This
effect was not seen in the inferior frontal and parietal regions, where there
were also lower lesion counts. In each of the regions yielding a reliable
lesion count–to-atrophy association, regression analyses were conducted
to test whether cortical lesions account for more variance in atrophy than
can be accounted for by that region's white matter lesions. When superior
frontal atrophy was regressed on superior frontal cortical and white matter
lesion counts, the cortical lesions accounted for the most variance, and the
white matter lesions were not retained in the final model. The same results
were obtained in the models for the other cortical regions.
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Table 1. Frequency and Distribution of Lesions on FLAIR Scans in 84
Patients With Multiple Sclerosis*
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Table 2. Association Between Cortical Lesions on FLAIR Images and Clinical
Course in 84 Patients With Multiple Sclerosis*
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Table 3. Association Between Cortical Lesions on FLAIR Images and Regional
Atrophy in 84 Patients With Multiple Sclerosis*
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Figure 1. A 33-year-old patient with relapsing-remitting
multiple sclerosis. A, T1-weighted image; B, T2-weighted image; and C, fluid-attenuated
inversion recovery (FLAIR) image. Multiple lesions are seen in the axial FLAIR
image involving the dorsal frontal cortex and gray-white junction. Several
but not all are detected on the T2-weighted image, and 2 of the lesions show
definite hypointensity on the T1-weighted image (arrows). The lesions are
most crisply shown by FLAIR. Lesions range in diameter from 2 (open arrow)
to 7 mm (curved arrow).
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Figure 2. A 40-year-old patient with relapsing-remitting
multiple sclerosis. A, T1-weighted image; B, T2-weighted image; and C, fluid-attenuated
inversion recovery (FLAIR) image. The patient has a large cortical-subcortical
lesion (12 mm in diameter) in the posterior frontal region that is seen on
all sequences. The lesion is most conspicuous on the FLAIR image.
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Figure 3. A 44-year-old patient with relapsing-remitting
multiple sclerosis. A, T1-weighted image; B, T2-weighted image; and C, fluid-attenuated
inversion recovery (FLAIR) image. An 8 x 8-mm lesion in the superior
frontal cortex and gray-white junction is seen on the FLAIR image (arrow)
but is poorly shown on the T1- and T2-weighted images.
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Figure 4. A 44-year-old patient with relapsing-remitting
multiple sclerosis. A, T1-weighted image; B, T2-weighted image; C, fluid-attenuated
inversion recovery (FLAIR) image. An 8 x 10-mm lesion involving the
superior temporal cortex with extension to subcortical white matter is seen
on the FLAIR image (arrow) but is poorly shown on the T1- and T2-weighted
images.
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COMMENT
This study indicates that lesions of the juxtacortical and cortical
region are common in MS and that FLAIR MRI is sensitive for detecting such
involvement. The neuropathologic characteristics, pathogenesis, and clinical
significance of these cortical lesions are incompletely understood. In a necropsy
study of 32 MS brains, Brownell and Hughes16
found numerous plaques in cerebral cortex, mostly in the frontal lobes. Twenty-one
percent of the hemisphere lesions were at the corticomedullary junction or
in the cortex. In a recent necropsy study10
of 12 MS brains, the 478 cortical lesions showed perivenular demyelination
and varying degrees of inflammation. Our MRI observations on the brain during
life were similar to previous ones at autopsy. We found 810 cortical lesions
of the brain, an average of 9.6 lesions per patient, and 86% of our patients
with MS have at least one such lesion. Cortical lesions accounted for 26%
of the total brain lesions, and 1 patient had 94 cortical lesions. Thus, cortical
involvement is common in MS, can represent a significant proportion of total
lesions, and can be detected during life by FLAIR MRI in a manner that seems
to correlate well with previous autopsy descriptions.
These cortical lesions may have clinical relevance. The number of cortical
lesions in the present study was significantly associated with longer disease
duration and progressive disease course, although the lesions also occurred
commonly in patients with RR disease. Cognitive dysfunction, such as memory
and information processing problems, is common in MS and may occur early in
the disease course.45, 46, 47, 48
One study32 found a relation between cortical
plaques detected by FLAIR and cognitive impairment in patients with MS. The
number of these lesions corresponded to impaired retention of information
in memory tasks.32 Cortical clinical syndromes
may occur in patients with MS.49, 50
Seizures, occurring in up to 5% of patients, were correlated pathologically
with corticomedullary lesions.50 Depression
and other mood disturbances are also common in patients with MS.42, 51, 52, 53, 54
Recent MRI studies implicated cortical gray matter atrophy in the pathogenesis
of primary depression55 and depression related
to MS.42
In the present study, T2WIs were insensitive relative to FLAIR for detecting
cortical involvement, probably due to 2 factors. The first factor accounting
for the poor sensitivity of T2WIs for identifying cortical hyperintensities
is partial volume averaging with sulcal subarachnoid CSF. Proton density images,
not obtained in the present study, show T2 prolongation and partially suppress
CSF and thus might offer greater sensitivity for cortical lesions than T2WIs.
The second factor is that gray matter lesions have higher relaxation times
than those of normal white matter, leading to poor resolution between gray
matter and lesions in the cortex compared with lesions and white matter.10 This results from the greater cellular density of
cortical lesions compared with those of white matter. This high cellular density
may not allow a sufficient expansion of the extracellular space to allow an
increase in T2 relaxation times in cortical lesions, as in white matter. In
the present study, we used a T2-weighted sequence that was optimized for fast
scanning time with an acceptable lesion contrast. A T2-weighted study with
a higher TR (stronger T2 weighting) might improve lesion detectability with
a trade-off of longer scanning time. We showed that T1WIs are also of lower
sensitivity than FLAIR for detecting cortical plaques that could relate to
the same cortical cellular density and partial volume averaging that affect
T2WIs. Also, the detection of MS plaques on T1WIs requires a marked increase
in lesional water content (eg, edema or tissue destruction) that does not
usually occur in gray matter plaques.10
The excellent demonstration of cortical lesions by FLAIR MRI probably
relates to its high sensitivity for detecting T2 prolongation in tissue and
the nulling of CSF in cortical sulci. Our data extend the results of previous
studies9, 31, 32, 33, 34, 35
that showed cortical lesions detected by FLAIR in patients with MS. One pilot
study9 of FLAIR detection of cortical plaques
in MS used an older (conventional spin-echo) FLAIR method on a low-field scanner
(0.5 T). Those authors found 60% more cortical lesions by FLAIR than by proton
density or T2WIs. Cortical lesions, representing 8% of the total, were rare
on FLAIR images of healthy controls. Another study35
found a higher number and volume of cortical and subcortical lesions than
on conventional sequences.
Cortical plaques may be seen on postcontrast T1WI studies in patients
with MS,10, 56 indicating that
some of these lesions have active blood-brain barrier disruption. A recent
large imaging study10 showed a total of 258
enhancing lesions in 172 patients with MS, 16% of which were cortical. However,
FLAIR imaging was not performed in that study. Further studies should compare
the relative sensitivities of FLAIR and contrast-enhanced T1WIs for detecting
cortical plaques.
No direct pathologic correlations of FLAIR findings were performed in
our study. However, previous pathologic studies indicated that the cortical
lesions reported herein represent direct pathologic involvement of the gray
matter or corticomedullary junction by demyelination and inflammation. Neuronal
loss and wallerian degeneration could also contribute to cortical hyperintensities
on FLAIR images.57, 58 Age-related
and ischemic changes may cause T2 prolongation as incidental findings in healthy
subjects, most commonly after the age of 50 years and usually in periventricular
subcortical white matter.59, 60
It could be argued that the cortical lesions seen on FLAIR images in our patients
with MS were false-positive results due to normal variants, age-related changes,
or other diseases. However, incidental cortical hyperintensities were not
seen on FLAIR images in healthy adults in the third to sixth decades of life
in a separate study61 and were rarely seen
in our age-matched controls (6 lesions in 60 subjects). None of our patients
with MS had major medical illnesses, such as hypertension, diabetes, or cardiopulmonary
diseases, that might have caused cortical lesions.
In our study, cortical lesions were associated with regional cortical
atrophy; in a given region, the number of FLAIR cortical lesions was significantly
related to the degree of enlargement of the cortical sulci. This relation
persisted after taking into account noncortical (white matter) lesions; only
the cortical lesions were retained in regression models predicting atrophy
in that region. Although not showing cause and effect, this finding indicates
that the cortical lesions are closely associated with cortical atrophy.
There is a potential problem with our method, since the MRI readers
were aware of the hypothesis that was to be tested. We were not able to blind
the readers since the patient's diagnosis of MS was obvious by the presence
of characteristic white matter plaques that could not be deleted from the
images and the normal scans were readily apparent. Our method of measuring
regional brain atrophy was qualitative and rater dependent. However, our atrophy
rating method showed good reliability and validity (see the "Subjects and
Methods" section).43
It is likely that improvements in our FLAIR protocol would have allowed
a more accurate appreciation and classification of the cortical and juxtacortical
lesions in the present study.31 For example,
multiplanar imaging and the use of thinner (ie, 3-mm) slices might allow a
differentiation of purely cortical vs purely subcortical lesions that we have
described. In the present study, we used a FLAIR protocol with a scanning
time of 2 minutes, which is applicable to routine clinical care. Thus, our
study demonstrates that cortical and juxtacortical lesions can be detected
by such a streamlined standard clinical protocol. Future studies using advanced
FLAIR protocols would be helpful to extend and confirm our findings.
AUTHOR INFORMATION
Accepted for publication November 17, 2000.
From the Departments of
Neurology (Drs Bakshi, Benedict, and Jacobs and Ms Ariyaratana),
Imaging Services (Dr Bakshi), Psychiatry (Dr Benedict), and Psychology
(Dr Benedict), Kaleida Health, State University of New York at Buffalo,
School of Medicine and Biomedical Sciences, Buffalo, NY.
Corresponding author: Rohit Bakshi, MD, Neuroscience Center, E-2,
Buffalo General Hospital, 100 High St, Buffalo, NY 14203 (e-mail: rbakshi{at}buffalo.edu).
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