DOI:10.2214/AJR.05.2212
AJR 2007; 188:697-702
© American Roentgen Ray Society
Sensitivity of Immediate and Delayed Gadolinium-Enhanced MRI After Injection of 0.5 M and 1.0 M Gadolinium Chelates for Detecting Multiple Sclerosis Lesions
Ender Uysal1,
Sukru Mehmet Erturk1,
Hakan Yildirim1,
Feray Seleker2 and
Muzaffer Basak1
1 Department of Radiology, Sisli Etfal Hospital, Etfal Sok, Istanbul 80220,
Turkey.
2 Department of Neurology, Sisli Etfal Hospital, Istanbul 80220, Turkey.
Received December 22, 2005;
accepted after revision June 7, 2006.
Address correspondence to E. Uysal
(enderuysaltr{at}yahoo.com).
Abstract
OBJECTIVE. The purpose of our study was to compare the efficacy of
cranial MR images obtained immediately after, 5 minutes after, and 10 minutes
after the injection of 0.5-mol/L (Magnevist) and 1.0-mol/L (Gadovist)
gadolinium chelates in the detection of active multiple sclerosis (MS)
lesions.
MATERIALS AND METHODS. Thirty patients with MS were examined with
MRI first with 0.5-mol/L and then, after 24-48 hours, with 1.0-mol/L
gadolinium chelates. T1-weighted spin-echo images with magnetization transfer
were obtained immediately, 5 minutes, and 10 minutes after the injection of
the contrast material. Three radiologists evaluated the gadolinium-enhanced
T1-weighted images on a remote MR console (Advantage Windows) in six separate
sessions and counted the number of enhancing lesions in consensus.
RESULTS. Significantly fewer enhancing lesions were seen on MR
images immediately after the injection of 0.5- and 1.0-mol/L gadolinium
chelates (n = 18 and n = 36, respectively; p <
0.05) than at 5 minutes (n = 32 and n = 54; p <
0.05) and 10 minutes (n = 34 and n =55; p <
0.05) after the injection (p < 0.05). Likewise, significantly
fewer patients with at least one enhancing lesion after the injection of 0.5-
and 1.0-mol/L gadolinium chelates (n = 10 and n = 16;
p < 0.05) were found immediately after injection than were found 5
minutes (n = 18 and n = 24; p < 0.05) and 10
minutes (n = 18 and n = 24; p < 0.05) after
injection (p < 0.01).
CONCLUSION. The use of 1.0-mol/L gadolinium chelate enables us to
detect an increased number of enhancing lesions and patients with active
disease. A delay of 5 minutes after the injection of the gadolinium chelate
might be sufficient to detect active lesions in patients with MS.
Keywords: contrast media • multiple sclerosis • neuroradiology
Introduction
Gadolinium-enhanced brain MRI has become the most sensitive tool for
confirming the diagnosis of multiple sclerosis (MS) and for monitoring MS
treatment trials [1]. In
longitudinal clinical studies, the presence of at least one enhancing (i.e.,
active) lesion at screening is an established entry criterion for therapy
[2,
3]. Hence, to show one or no
enhancing lesions is an important clinical and research goal
[4].
The sensitivity of gadolinium-enhanced MRI may be improved by means of
magnetization transfer or by increasing the concentration of gadolinium in the
tissues by increasing the injected volume of 0.5-mol/L gadolinium chelates or
by increasing the delay between injection and the imaging sequences
[1,
5,
6].
Although the use of magnetization transfer has become commonplace for
patients with MS, the optimal gadolinium dose and the optimal scan timing are
still controversial. Furthermore, a new MRI contrast agent with double
gadolinium concentration (molarity) has recently been introduced into clinical
practice and deserves to be investigated in this context.
In this study, our aim was to compare the ability of cranial MR images
obtained immediately, 5 minutes, and 10 minutes after the injection of
0.5-mol/L (Magnevist [gadopentetate dimeglumine], Schering) and 1.0-mol/L
(Gadovist [gadobutrol], Schering) gadolinium chelates in the detection of
active MS lesions. To our knowledge, ours is the first study to compare 0.5-
and 1.0-mol/L gadolinium chelates in the clinical setting of MS.
Materials and Methods
Patients
Thirty patients (21 women, nine men; mean age, 32.24 years) who had
clinically proven MS and who were classified as relapsing-remitting according
to the criteria of McDonald et al.
[6] were included in the study.
None of the patients were under steroid treatment for at least 3 months before
the study. Approval was obtained from our institutional review board, and
informed consent was obtained from each patient before entering the study.
View larger version (174K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 1A —35-year-old man with multiple sclerosis. Axial fast spin-echo
T2-weighted image (TR/TE, 4,800/102; inversion time, 2 milliseconds) shows
plaque lesion at left side of pons near tectum.
|
|
View larger version (168K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 1B —35-year-old man with multiple sclerosis. Ten minutes after IV
administration of 0.5-mol/L contrast medium (0.1 mmol/kg), no contrast
enhancement attributable to this lesion is detectable on magnetization
transfer contrast-enhanced T1-weighted image (560/15; inversion time, 1
millisecond).
|
|
MRI Technique
Brain MR images were obtained with a 1.5-T unit (Signa Excite 2.0, GE
Healthcare) using a standard head coil. Axial spin-echo T1-weighted images
with a magnetization transfer pulse (TR/TE, 560/15; number of excitations, 1;
5-mm-thick slices with 0.5-mm gap; 256 x 192 matrix; 24-cm field of
view) were obtained before and after the injection of 0.1 mL of 0.5-mol/L
gadolinium chelate (0.1 mmol of gadolinium) per kilogram of body weight. In
each patient, contrast-enhanced images were obtained immediately after, 5
minutes after, and 10 minutes after the manual injection of contrast material
through an antecubital vein. Twenty-four to 48 hours (mean ± SD, 39.9
± 7.0 hours) after the first MR examination, all patients underwent a
second MR examination with the same protocol as the first but after the
injection of 0.1 mL of 1.0 mol/L gadolinium chelate (0.2 mmol of gadolinium)
per kilogram of body weight. Thus, a total of six cranial MRI sets were
obtained for each patient.
View larger version (164K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 1D —35-year-old man with multiple sclerosis. However, 5 (D) and
10 (E) minutes after administration of 1.0-mol/L contrast medium (0.2
mmol/kg), enhancement is clearly visible in this lesion.
|
|
View larger version (164K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 1E —35-year-old man with multiple sclerosis. However, 5 (D) and
10 (E) minutes after administration of 1.0-mol/L contrast medium (0.2
mmol/kg), enhancement is clearly visible in this lesion.
|
|
Axial T2-weighted fast spin-echo (4,800/102; number of excitations, 2;
5-mm-thick slices with 0.5-mm gap; 256 x 192 matrix; 24-cm field of
view) and FLAIR sequences (8,800/102; number of excitations, 2; 5-mm-thick
slices with 0.5-mm gap; 256 x 192 matrix; 24-cm field of view) were also
obtained at the first session to achieve a complete MR examination for
clinical purposes.
Safety Assessment
Blood urea and creatinine levels were evaluated in all patients as part of
the clinical management of MS patients in our neurology clinic; no abnormality
was detected. Furthermore, all patients were asked whether they had renal
disease before the MR examination and were asked about any discomfort or side
effects related to contrast administration at the end of the each scanning
session. The patients were called back to our clinic 1 day after study and the
questions were posed by the same observers. Both contrast agents were well
tolerated by all patients and no adverse reaction was detected.
Image Analysis
Three radiologists evaluated the gadolinium-enhanced T1-weighted images and
the unenhanced T1- and T2-weighted images on a remote MR console (Advantage
Windows, GE Healthcare) in six separate sessions and counted the number of
enhancing lesions in consensus. An enhancing lesion was defined as a
well-demarcated area of unequivocally increased signal intensity as compared
with normal-appearing white matter. We tried to detect false enhancement,
enhancing vessels, and flow artifacts by evaluating unenhanced and
contrast-enhanced images together on the remote MR console. An equal number of
MRI sets were randomly assigned to the reviewing sessions, so that in each
session the radiologists evaluated 30 image sets obtained with different
gadolinium chelates and different scanning times. The radiologists were
blinded to patients' identity, the molarity of the gadolinium chelate, and the
timing of MRI. The reviewing sessions were 2 weeks apart to avoid a learning
bias.
Statistical Analysis
The number of enhancing lesions on MR images obtained with different time
delays after the injection of 0.5- or 1.0-mol/L gadolinium chelate were
compared using Friedman and Dunn post hoc tests. The number of the patients
who had at least one enhancing lesion was compared between the image sets with
different scanning times using the McNemar test.
The number of enhancing lesions and the number of patients who had at least
one enhancing lesion were compared between the image sets obtained after the
administration of 0.5-mol/L gadolinium chelate and the corresponding image
sets obtained after the administration of 1.0-mol/L gadolinium chelate using
Wilcoxon's matched pairs and McNemar tests, respectively.
Results
The number (n = 18) of enhancing lesions on MR images obtained
immediately after the injection of 0.5-mol/L gadolinium chelate was
significantly less than those obtained 5 minutes (n = 32) and 10
minutes (n = 34) after the injection (p < 0.05).
Likewise, the number of enhancing lesions on MR images obtained immediately
after the injection of 1.0-mol/L gadolinium chelate was significantly less
than those obtained 5 minutes (n = 54) and 10 minutes (n =
55) after the injection (p < 0.05). In both gadolinium chelate
groups, the number of enhancing lesions did not differ significantly between
the images obtained 5 and 10 minutes after the injection.
View larger version (160K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 2A —27-year-old woman with multiple sclerosis (MS). Millimetric MS
plaque lesions are seen in subcortical white matter and at periventricular
region on axial fast spin-echo T2-weighted image.
|
|
View larger version (162K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 2B —27-year-old woman with multiple sclerosis (MS). Ten minutes after IV
administration of 0.5-mol/L contrast medium (0.1 mmol/kg), no contrast
enhancement attributable to a white matter lesion is detectable on
magnetization transfer contrast-enhanced T1-weighted image.
|
|
The number of patients with at least one enhancing lesion (n = 10)
was significantly less on the MR images obtained immediately after the
injection of 0.5-mol/L gadolinium chelate than on those obtained 5 minutes
(n = 18) and 10 minutes (n = 18) after the injection
(p < 0.01). Likewise, the number of patients with at least one
enhancing lesion (n = 16) was significantly less on the MR images
obtained immediately after the injection of 1.0-mol/L gadolinium chelate than
on those obtained 5 minutes (n = 24) and 10 minutes (n = 24)
after the injection (p < 0.01).
View larger version (171K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 2D —27-year-old woman with multiple sclerosis (MS). However, 5
(D) and 10 (E) minutes after administration of 1.0-mol/L
contrast medium (0.2 mmol/kg), one enhancing lesion (arrowhead) is
detectable in frontal left lobe. Note that enhancement is more prominent on
latest image.
|
|
View larger version (168K):
[in this window]
[in a new window]
[as a PowerPoint slide]
|
Fig. 2E —27-year-old woman with multiple sclerosis (MS). However, 5
(D) and 10 (E) minutes after administration of 1.0-mol/L
contrast medium (0.2 mmol/kg), one enhancing lesion (arrowhead) is
detectable in frontal left lobe. Note that enhancement is more prominent on
latest image.
|
|
Significantly fewer enhancing lesions were seen on MR images obtained
immediately, 5 minutes, and 10 minutes after the injection of 0.5-mol/L
gadolinium chelate than at corresponding times after the injection of
1.0-mol/L gadolinium chelate (p < 0.05), and significantly fewer
patients had at least one enhancing lesion on MR images obtained after the
injection of 0.5-mol/L gadolinium chelate than on those obtained at
corresponding times after the injection of 1.0-mol/L gadolinium chelate
(p < 0.05).
Discussion
Our results show that the use of a 1.0-mol/L gadolinium chelate
significantly increases the sensitivity of contrast-enhanced MRI in detecting
active lesions in patients with MS compared with the use of a 0.5-mol/L
gadolinium chelate. On MR images obtained immediately, 5 minutes, and 10
minutes after the injection of gadolinium chelate, we detected more active
lesions with the 1.0-mol/L gadolinium chelate (Figs.
1A,
1B,
1C,
1D,
1E and
2A,
2B,
2C,
2D,
2E). Furthermore, for every
scanning time, we detected significantly more patients who had at least one
enhancing lesion with the 1.0-mol/L gadolinium chelate. More critically, in
our study the clinical management has been changed in six patients who had no
enhancing lesions after the administration of 0.5-mol/L gadolinium chelate but
at least one enhancing lesion after the administration of 1.0-mol/L gadolinium
chelate.
Gadovist is a hydrophilic, electrically neutral macrocyclic contrast agent.
The T1 relaxivity of Gadovist is 5.6 L/mmol per second in plasma at 39°C
and 20 MHz. Magnevist, a standard extracellular paramagnetic MR contrast
agent, has a T1 relaxivity of 4.8 L/mmol second in plasma at 39°C and 20
Hz. Elimination of gadobutrol occurred predominantly via the renal route, and
12 hours after administration, 92.5%, 98.0%, and 96.6% of the dose had already
been recovered from the urine for the low, medium, and high doses,
respectively [7]. Approximately
80% of the dose was excreted in the urine within 6 hours and 93% within 24
hours after injection of a 0.1 mmol/kg dose of Magnevist
[8].
Enhanced MRI is the most sensitive measure of short-term MS activity and is
widely used to monitor disease evolution, both natural and modified by
treatment [4]. Thus,
optimization of image timing, sequences, and contrast dose is essential.
Increasing the delay between injection and scanning time (20-30 minutes after
injection) to make use of the cumulative effect of gadolinium in the
extracellular space is an efficient technique, but it is time-consuming
[9] and hard to apply in a busy
clinical setting. In our study, the last contrast-enhanced scan was started 10
minutes after the gadolinium injection. We found significantly more enhancing
lesions and more patients with at least one enhancing lesion on MR images
obtained 5 and 10 minutes after the injection of gadolinium than on those
obtained immediately after injection with both gadolinium chelate
concentrations. No difference was seen in the number of lesions or the number
of patients with at least one lesion between the 5- and 10-minute
postinjection groups.
Visible enhancement of MS lesions depends on the local concentration of
gadolinium, which in turn depends on the vascular concentration of gadolinium,
the permeability of the blood-brain barrier, and the size of the leakage space
[10]. Thus, increasing the
dose of contrast material is another method for identifying more enhancing
lesions on brain MR images in MS patients. Previous longitudinal studies have
emphasized that triple-dose gadolinium-enhanced MRI maximizes the harvest of
enhancing lesions in MS patients
[11,
12]; and its use, in
combination with other strategies such as delayed scanning and a magnetization
transfer pulse, can lead to increased sensitivity of about 130% over standard
techniques [13]. But the
clinical use of triple-dose gadolinium is limited by cost-benefit
considerations. Another shortcoming of the triple dose is the increased
procedure time. Furthermore, several studies have documented that a double
dose of gadopentetate dimeglumine is as sensitive as a triple dose
[14,
15].
Although the gadolinium dose (0.2 mmol/kg) we used in the 1.0-mol/L
gadolinium chelate group was double the standard dose of 0.1 mmol per kilogram
of body weight, the 0.5-mol/L gadolinium chelate group received a standard
single dose of gadolinium. Few studies have compared the number of enhanced
lesions seen with single and double doses of gadolinium. Our results differ
from those of a recent study in which three subsequent single doses of
gadolinium chelate were administered in 10 patients with MS, with imaging
delays of 5, 13, and 21 minutes after injection
[16]. The authors reported no
significant difference in the number of enhancing lesions between the single
dose and the fractionated double dose.
In contrast to that study, we found significantly more enhancing lesions
using 1.0-mol/L gadolinium chelate (i.e., a double dose of gadolinium) than
using 0.5-mol/L gadolinium chelate (i.e., a single dose). A possible
explanation of this discrepancy is that we used not a fractionated but a
single injection of both 0.5- and 1.0-mol/L gadolinium chelates. The
relatively small sample size (n = 10) of the study of Sardanelli et
al. [16] might also have
contributed to this discrepancy.
Our study has some limitations. Higher relaxivity of 1.0-mol/L gadolinium
chelate has been reported in some studies
[7]. However, because we did
not use a double dose of 0.5-mol/L gadolinium chelate, we could not evaluate a
possible difference in relaxivity after the administration of 1.0-mol/L
gadolinium chelate and a double dose of 0.5-mol/L gadolinium chelate, which
contain equal total amounts of gadolinium. We were not able to randomize
patients in this study. Thus, there might be potential residual gadolinium in
the system just before the administration of Gadovist. However, 93% of the
gadolinium is excreted within 24 hours after injection.
Furthermore, we used the magnetization transfer technique, and lesions may
show high signal intensity even on unenhanced T1-weighted images. Thus, we
asked our reviewers to mark the lesions that showed a definite signal
enhancement on contrast-enhanced T1-weighted MR images compared with
unenhanced T1-weighted images regardless of the signal intensity of lesions on
unenhanced images. Another limitation is our relatively small sample size.
Finally, we did not acquire images 20 or 30 minutes after injection; in our
opinion, this approach is not feasible in the busy clinical setting of our
institution.
In conclusion, the use of 1.0-mol/L gadolinium chelate enables us to detect
more enhancing lesions and more patients with active disease. A delay of 5
minutes after injection of gadolinium chelate may be sufficient to detect
active lesions in patients with MS.
References
- Gavra MM, Voumvourakis C, Gouliamos AD, Sfagos C, Vlahos LJ. Brain
MR post-gadolinium contrast in multiple sclerosis: the role of magnetization
transfer and image subtraction in detecting more enhancing lesions.
Neuroradiology 2004;46
: 205-210[CrossRef][Medline]
- Miller DH, Barkhof F, Albert PS, et al. Guidelines for the use of
magnetic resonance techniques to monitor the treatment of multiple sclerosis.
Ann Neurol 1996;39
: 6-16[CrossRef][Medline]
- Sardanelli F, Losacco C, Iozzelli A, et al. Evaluation of
Gd-enhancement in brain MR of multiple sclerosis: image subtraction with and
without magnetization transfer. Eur Radiol2002; 12:2077
-2082[Medline]
- Molyneux PD, Miller DH. Magnetic resonance imaging techniques to
monitor phase III treatment trials. In: Filippi M, Grossman RI, Comi G, eds.
Magnetic resonance techniques in clinical trials in multiple
sclerosis. Milan, Italy: Springer-Verlag, 1999:49
-73
- McFarland HF, Frank JA. The application of magnetic resonance
imaging to phase II trials in multiple sclerosis. In: Filippi M, Grossman RI,
Comi G, eds. Magnetic resonance techniques in clinical trials in
multiple sclerosis. Milan, Italy: Springer-Verlag,1999
: 37-48
- McDonald WI, Compston A, Edan G, et al. Recommended diagnostic
criteria for multiple sclerosis: guidelines from the International Panel on
the diagnosis of multiple sclerosis. Ann Neurol2001; 50:121
-127[CrossRef][Medline]
- Goyen M, Lauenstein TC, Herborn CU, Debatin JF, Bosk S, Ruehm SG.
0.5 M Gd chelate (Magnevist) versus 1.0 M Gd chelate (Gadovist):
dose-independent effect on image quality of pelvic three-dimensional
MR-angiography. J Magn Reson Imaging2001; 14:602
-607[CrossRef][Medline]
- Magnevist monograph. Berlin, Germany: Schering AG,1993
- Filippi M, Capra R, Campi A, et al. Triple dose of gadolinium-DTPA
and delayed MRI in patients with benign multiple sclerosis. J
Neurol Neurosurg Psychiatry 1996;60
: 526-530[Abstract]
- Tofts PS, Kermode AG. Measurement of the blood-brain barrier
permeability and leakage space using dynamic MR imaging. 1. Fundamental
concepts. Magn Reson Med 1991;17
: 357-367[Medline]
- Filippi M, Rovaris M, Capra R, et al. A multi-centre longitudinal
study comparing the sensitivity of monthly MRI after standard and triple dose
gadolinium-DTPA for monitoring disease activity in multiple sclerosis:
implications for phase II clinical trials. Brain1998; 121(Pt 10):2011
-2020[Abstract/Free Full Text]
- Wolansky LJ, Bardini JA, Cook SD, Zimmer AE, Sheffet A, Lee HJ.
Triple-dose versus single-dose gadoteridol in multiple sclerosis patients.
J Neuroimaging 1994;4
: 141-145[Medline]
- Silver NC, Good CD, Barker GJ, et al. Sensitivity of contrast
enhanced MRI in multiple sclerosis: effects of gadolinium dose, magnetization
transfer contrast and delayed imaging. Brain1997; 120(Pt 7):1149
-1161[Abstract/Free Full Text]
- Gasperini C, Paolillo A, Rovaris M, et al. A comparison of the
sensitivity of MRI after double- and triple-dose Gd-DTPA for detecting
enhancing lesions in multiple sclerosis. Magn Reson
Imaging 2000; 18:761
-763[CrossRef][Medline]
- Stecco A, Migazzo E, Saponaro A, et al. Gadolinium dose
optimisation in patients with multiple sclerosis: intra- and inter-individual
comparisons. Eur J Radiol 2006;57
: 37-42; Epub 2005 Jul
22[CrossRef][Medline]
- Sardanelli F, Iozzelli A, Losacco C, Murialdo A, Filippi M. Three
subsequent single doses of gadolinium chelate for brain MR imaging in multiple
sclerosis. Am J Neuroradiol 2003;24
: 658-662[Abstract/Free Full Text]
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
Top
Abstract
Introduction
