Neuroradiology Original Research

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1 MRI of Multiple Sclerosis Lesions Neuroradiology Original Research Ender Uysal 1 Sukru Mehmet Erturk 1 Hakan Yildirim 1 Feray Seleker 2 Muzaffer Basak 1 Uysal E, Erturk SM, Yildirim H, et al. Keywords: contrast media, multiple sclerosis, neuroradiology DOI: /AJR Received December 22, 2005; accepted after revision June 7, Department of Radiology, Sisli Etfal Hospital, Etfal Sok, Istanbul 80220, Turkey. Address correspondence to E. Uysal (enderuysaltr@yahoo.com). 2 Department of Neurology, Sisli Etfal Hospital, Istanbul 80220, Turkey. AJR 2007; 188: X/07/ 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 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 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. adolinium-enhanced brain MRI G 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, 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 AJR:188, March

2 A C Fig year-old man with multiple sclerosis. A, 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. B, 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). C, Immediately after administration of 1.0-mol/L contrast medium (0.2 mmol/kg), focal contrast enhancement (arrowhead) is barely detectable. (Fig. 1 continues on next page) B institutional review board, and informed consent was obtained from each patient before entering the study. 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 698 AJR:188, March 2007

3 MRI of Multiple Sclerosis Lesions Fig. 1 (continued) 35-year-old man with multiple sclerosis. D and E, 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. gap; 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. Axial T2-weighted fast spin-echo (4,800/102; number of excitations, 2; 5-mm-thick slices with 0.5-mm gap; 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; 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 D 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 gadoliniumenhanced 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 E AJR:188, March

4 A C Fig year-old woman with multiple sclerosis (MS). A, Millimetric MS plaque lesions are seen in subcortical white matter and at periventricular region on axial fast spin-echo T2-weighted image. B, 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. C, Immediately after administration of 1.0-mol/L contrast medium (0.2 mmol/kg), there is also no contrast enhancement. (Fig. 2 continues on next page) B 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. 700 AJR:188, March 2007

5 MRI of Multiple Sclerosis Lesions 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). 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). D Fig. 2 (continued) 27-year-old woman with multiple sclerosis (MS). D and E, 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. 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. 1 and 2). 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 E AJR:188, March

6 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 1. 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: 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: Sardanelli F, Losacco C, Iozzelli A, et al. 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