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Triple dose of gadolinium-DTPA increases the sensitivity of spinal cord MRI in detecting enhancing lesions in multiple sclerosis
Journal of the Neurological Sciences 158 (1998) 221–225
Triple dose of gadolinium-DTPA increases the sensitivity of spinal cord MRI in detecting enhancing lesions in multiple sclerosis a, a b b c Tarek A. Yousry *, Gunter Fesl , Ernst Walther , Raymond Voltz , Massimo Filippi a
Departments of Neuroradiology, Neurology Klinikum Grosshadern, University of Munich, Munich, Germany b Neurology Klinikum Grosshadern, University of Munich, Munich, Germany c MS Biosignal Analysis Centre, Department of Neurology, Scientific Institute Ospedale San Raffaele, University of Milan, Milan, Italy Received 24 July 1997; received in revised form 23 December 1997; accepted 29 December 1997
Abstract We compared the sensitivity of single and triple dose Gd-DTPA magnetic resonance imaging (MRI) in detecting enhancing lesions in the spinal cord of 13 patients with multiple sclerosis (MS). We detected two enhancing lesions in two of 13 (15%) patients when the single dose of Gd-DTPA was used and 12 lesions in five of 13 (38%) patients when the triple dose of Gd-DTPA was used. These results suggest that: (1) the use of triple dose increases the sensitivity of spinal cord MRI when studying relapsing–remitting or secondary progressive MS patients, (2) triple dose Gd-DTPA enhanced of the spinal cord MRI might be useful in monitoring disease activity in patients with MS. 1998 Elsevier Science B.V. All rights reserved. Keywords: Magnetic resonance; Comparative studies; Multiple sclerosis; Spinal cord; Contrast enhancement; Gadolinium-DTPA; Triple dose
1. Introduction Because spinal cord lesions are among the most disabling features of multiple sclerosis (MS), considerable attention has been devoted to optimizing evaluation of the spinal cord by magnetic resonance imaging (MRI) in these patients. Previous studies [3,6] have shown that by using multiarray receiver coils and fast spin echo (FSE) sequences it is frequently possible to detect MS lesions in spinal cord. However, no correlation was found between clinical disability and the extent of spinal cord damage [6]. On the other hand, it has also been demonstrated that, although spinal cord enhancement occurs significantly less often than brain enhancement [1,9,10], enhancing spinal cord lesions are usually symptomatic [1,9].
*Correspondence author: Tel.: 149 89 70953250; fax: 149 89 70958822. 0022-510X / 98 / $19.00 1998 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00114-2
In a previous study it has been demonstrated that using a triple dose of Gd-DTPA markedly increases the sensitivity of enhanced MRI in detecting active brain lesions [4]. Based on these results, we performed the study reported here to evaluate the role of triple dose Gd-DTPA in imaging the spinal cord in patients with MS.
2. Patients and methods
2.1. Patients Thirteen consecutive outpatients (five men and eight women) with clinically definite MS entered the study. Nine had relapsing–remitting and four had secondary progressive MS. Patients who had experienced an acute relapse or who had taken corticosteroids during the preceding 3 months were excluded from the study. The patients’ mean age was 34.4 years (SD59.3), the median duration of the
T. A. Yousry et al. / Journal of the Neurological Sciences 158 (1998) 221 – 225
222
disease was 4 years (range51–14 years), and the median Expanded Disability Status Scale (EDSS) score [7] was 2.0 (range50–7.0). Written informed consent to participate in the study was obtained from all 13 patients.
2.2. Spinal cord MRI All MRI scans were performed using a 1.5 Tesla superconducting system (Vision, Siemens, Erlangen, Germany). The receiver coil array consisted of six separate coils, although only four of the elements were active. T1-weighted images (FSE TR5642 ms, TE512 ms, 3-mm contiguous axial slices, echo train length515, FOV56553 500 (phase encode 3 read-out), raw data matrix55123 512, number of signal averages52, acquisition time54 min and 46 s) were obtained before and 5–7 min after injection of the single dose (0.1 mmol / kg) of Gd-DTPA (Schering, Berlin, Germany) as well as before and after 5–7 min after injection of the triple dose (0.3 mmol / kg). The time interval between imaging with the single dose and imaging with the triple dose was 24 h. Before the single dose of Gd-DTPA was injected, T2-weighted FSE sequences were obtained (TR53817 ms, TE5112 ms, echo train length515, FOV56553500 (phase encode 3 read-out), raw data matrix55123512, number of signal averages51, acquisition time52 min and 13 s).
2.3. MRI evaluation Two of us (TAY and MF), unaware of the Gd-DTPA dosage used, evaluated by consensus and in a random order the numbers of enhancing spinal cord lesions present on scans obtained with single or with triple doses of Gd-DTPA. T2-weighted scans were always used as references to confirm the presence of enhancing lesions.
3. Results We detected two enhancing lesions in two of 13 (15%) patients when the single dose of Gd-DTPA was used and 12 lesions in five of 13 (38%) patients when the triple dose of Gd-DTPA was used (Table 1, Figs. 1 and 2). The scans Table 1 Spinal cord lesions and locations seen on Gd-DTPA enhanced MRI a Patient b
Single dose scans
Triple dose scans
1 2 3 4 5
0 1-C5 0 0 1-C7
1-T2 1-C5 1-C5 6-C4, C5, C6, T1, T1 3-C7, T8, T10
a
Only patients with at least one enhancing lesion in one of the two sequences are included in the table. b These patients were selected out of a total of 13 patients. C, cervical; T, thoracic.
obtained before administering the triple dose, never revealed an indication of remaining enhancement from the previous single dose examination. Of the 12 lesions detected with the triple dose of Gd-DTPA, eight were located in the cervical and four in the thoracic spinal cord.
4. Discussion In this study, we compared the sensitivity of MRI single and triple doses of Gd-DTPA for revealing enhancing lesions within the spinal cord of MS patients. We found that the use of triple doses led to enhancement of six times as many lesions as single doses and detection of lesions in more than twice as many patients. These results are in line with those of previous studies [2,4] that compared the enhancement of brain lesions with a single and triple dose of Gd-DTPA. In one of these studies [4], performed in patients with relapsing–remitting or secondary progressive MS, the number of enhancing lesions seen on the triple dose scans was 66% higher than on single dose scans. Neither of these studies, nor our study, indicated a change in threshold by the previous administration of a single dose of Gd-DTPA. A time interval of 24 h can be considered sufficiently long enough to minimize any remaining effect from the previous examination. Due to the possible activity of the disease, new lesions could appear when using a longer time interval. Other strategies that have been used to increase MRI sensitivity in detecting MS lesions within the brain include magnetization transfer (MT) pulse T1-weighted sequences [8] and high-resolution magnetization prepared rapid acquisition gradient-echo (MP RAGE) [5] sequences. However, the gain in sensitivity for these techniques was only 18% [8] and 25% [5] in patients with relapsing–remitting and secondary progressive MS. In addition, these techniques might prove challenging to optimize and standardize for imaging the spinal cord. The results of previous studies that evaluated the role of contrast enhancement in detecting spinal cord lesions were disappointing [1,9,10]. In a longitudinal study, ten patients with relapsing–remitting MS underwent monthly single dose Gd-DTPA imaging of the spinal cord by MRI over one year and only 19 enhancing lesions were detected [9]. In another study, ten patients underwent single dose GdDTPA imaging every 2 weeks for 3 months and only three cervical lesions were detected in the 60 scans [1]. In the last study, 19 enhancing spinal cord lesions were detected in 79 scans of 29 patients who underwent serial imaging [10]. The results of this study, which demonstrate a high gain in sensitivity when using triple doses of Gd-DTPA in relapsing–remitting or secondary progressive MS patients, have two major implications. First, if our results are
T. A. Yousry et al. / Journal of the Neurological Sciences 158 (1998) 221 – 225
223
Fig. 1. Single dose Gd-DTPA enhanced MRI revealed no enhancing lesions in the spinal cord of a 27-year-old woman (patient 1, Table 1) (A). With a triple dose of Gd-DTPA, at least one lesion can be detected at the level of T2 (B).
confirmed by longitudinal studies, triple dose Gd-DTPA imaging of the spinal cord by MRI might be useful in monitoring phase II clinical trials. Secondly, the higher rate at which lesions are detected using a triple dose of
Gd-DTPA suggests that the permeability of MS lesions in the spinal cord changes only moderately, which would explain the low sensitivity of conventional enhanced MRI for detecting MS lesions in the spinal cord [1,9,10].
224
T. A. Yousry et al. / Journal of the Neurological Sciences 158 (1998) 221 – 225
Fig. 2. In a 54-year-old woman (patient 5, Table 1), no enhancing lesions were detected at the midthoracic level using a single dose of Gd-DTPA (A). Only after triple dosing was a lesion recognizable at that level (B).
Acknowledgements Presented at the annual meeting of the International Society of Magnetic Resonance in Medicine, Vancouver
1997. This work derives in part from the collaboration made possible by the EC funded (ERBCHRXCT 940684) European Magnetic Resonance Network in Multiple Sclerosis (MAGNIMS).
T. A. Yousry et al. / Journal of the Neurological Sciences 158 (1998) 221 – 225
References [1] Capra R, Marciano N, Vignolo LA, Chiesa A, Gasparotti R. Gadolinium-pentetic acid magnetic resonance imaging in patients with relapsing–remitting multiple sclerosis. Arch Neurol 1992;49:687–9. [2] Filippi M, Capra R, Campi A, Colombo B, Prandini F, Marciano N, Gasparotti R, Comi G. Triple dose of gadolinium-DTPA and delayed scanning in benign multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;60:526–30. [3] Filippi M, Yousry TA, Alkadhi H, Stehling M, Horsfield MA, Voltz R. Spinal cord MRI in multiple sclerosis using multi-coil arrays: a comparison between fast spin-echo and fast-FLAIR. J Neurol Neurosurg Psychiatry 1996;61:632–5. [4] Filippi M, Yousry T, Campi A, Kandziora C, Colombo B, Voltz R, Martinelli V, Spuler S, Bressi S, Scotti G, Comi G. Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with multiple sclerosis. Neurology 1996;46:379–84. [5] Filippi M, Yousry T, Horsfield MA, Alkadhi H, Rovaris M, Campi A, Voltz R, Comi G. A high resolution 3-D T1-weighted gradient-
[6]
[7]
[8]
[9]
[10]
225
echo sequence improves the detection of disease activity in multiple sclerosis. Ann Neurol 1996;40:901–7. Kidd D, Thorpe JW, Thompson AJ, Kendall BE, Moseley IF, MacManus DG, McDonald WI, Miller DH. Spinal cord MRI using multi-array coils and fast spin echo. II. Findings in multiple sclerosis. Neurology 1993;43:2632–7. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444– 52. Metha RC, Pike BG, Enzmann R. Improved detection of enhancing and non-enhancing lesions of multiple sclerosis with magnetization transfer. Am J Neuroradiol 1995;16:1771–8. Thorpe JW, Kidd D, Moseley IF, Kenndall BE, Thompson AJ, MacManus DG, McDonald WI, Miller DH. Serial gadoliniumenhanced MRI of the brain and spinal cord in early relapsing– remitting multiple sclerosis. Neurology 1996;46:373–8. Wiebe S, Lee DH, Karlik SJ, Hopkins M, Vandervoort MK, Womg CJ, Hewitt L, Rice GP, Ebers GC, Noseworthy JH. Serial cranial and spinal cord magnetic resonance imaging in multiple sclerosis. Ann Neurol 1992;32:643–50.
Triple dose of gadolinium-DTPA increases the sensitivity of spinal cord MRI in detecting enhancing lesions in multiple sclerosis a, a b b c Tarek A. Yousry *, Gunter Fesl , Ernst Walther , Raymond Voltz , Massimo Filippi a
Departments of Neuroradiology, Neurology Klinikum Grosshadern, University of Munich, Munich, Germany b Neurology Klinikum Grosshadern, University of Munich, Munich, Germany c MS Biosignal Analysis Centre, Department of Neurology, Scientific Institute Ospedale San Raffaele, University of Milan, Milan, Italy Received 24 July 1997; received in revised form 23 December 1997; accepted 29 December 1997
Abstract We compared the sensitivity of single and triple dose Gd-DTPA magnetic resonance imaging (MRI) in detecting enhancing lesions in the spinal cord of 13 patients with multiple sclerosis (MS). We detected two enhancing lesions in two of 13 (15%) patients when the single dose of Gd-DTPA was used and 12 lesions in five of 13 (38%) patients when the triple dose of Gd-DTPA was used. These results suggest that: (1) the use of triple dose increases the sensitivity of spinal cord MRI when studying relapsing–remitting or secondary progressive MS patients, (2) triple dose Gd-DTPA enhanced of the spinal cord MRI might be useful in monitoring disease activity in patients with MS. 1998 Elsevier Science B.V. All rights reserved. Keywords: Magnetic resonance; Comparative studies; Multiple sclerosis; Spinal cord; Contrast enhancement; Gadolinium-DTPA; Triple dose
1. Introduction Because spinal cord lesions are among the most disabling features of multiple sclerosis (MS), considerable attention has been devoted to optimizing evaluation of the spinal cord by magnetic resonance imaging (MRI) in these patients. Previous studies [3,6] have shown that by using multiarray receiver coils and fast spin echo (FSE) sequences it is frequently possible to detect MS lesions in spinal cord. However, no correlation was found between clinical disability and the extent of spinal cord damage [6]. On the other hand, it has also been demonstrated that, although spinal cord enhancement occurs significantly less often than brain enhancement [1,9,10], enhancing spinal cord lesions are usually symptomatic [1,9].
*Correspondence author: Tel.: 149 89 70953250; fax: 149 89 70958822. 0022-510X / 98 / $19.00 1998 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 98 )00114-2
In a previous study it has been demonstrated that using a triple dose of Gd-DTPA markedly increases the sensitivity of enhanced MRI in detecting active brain lesions [4]. Based on these results, we performed the study reported here to evaluate the role of triple dose Gd-DTPA in imaging the spinal cord in patients with MS.
2. Patients and methods
2.1. Patients Thirteen consecutive outpatients (five men and eight women) with clinically definite MS entered the study. Nine had relapsing–remitting and four had secondary progressive MS. Patients who had experienced an acute relapse or who had taken corticosteroids during the preceding 3 months were excluded from the study. The patients’ mean age was 34.4 years (SD59.3), the median duration of the
T. A. Yousry et al. / Journal of the Neurological Sciences 158 (1998) 221 – 225
222
disease was 4 years (range51–14 years), and the median Expanded Disability Status Scale (EDSS) score [7] was 2.0 (range50–7.0). Written informed consent to participate in the study was obtained from all 13 patients.
2.2. Spinal cord MRI All MRI scans were performed using a 1.5 Tesla superconducting system (Vision, Siemens, Erlangen, Germany). The receiver coil array consisted of six separate coils, although only four of the elements were active. T1-weighted images (FSE TR5642 ms, TE512 ms, 3-mm contiguous axial slices, echo train length515, FOV56553 500 (phase encode 3 read-out), raw data matrix55123 512, number of signal averages52, acquisition time54 min and 46 s) were obtained before and 5–7 min after injection of the single dose (0.1 mmol / kg) of Gd-DTPA (Schering, Berlin, Germany) as well as before and after 5–7 min after injection of the triple dose (0.3 mmol / kg). The time interval between imaging with the single dose and imaging with the triple dose was 24 h. Before the single dose of Gd-DTPA was injected, T2-weighted FSE sequences were obtained (TR53817 ms, TE5112 ms, echo train length515, FOV56553500 (phase encode 3 read-out), raw data matrix55123512, number of signal averages51, acquisition time52 min and 13 s).
2.3. MRI evaluation Two of us (TAY and MF), unaware of the Gd-DTPA dosage used, evaluated by consensus and in a random order the numbers of enhancing spinal cord lesions present on scans obtained with single or with triple doses of Gd-DTPA. T2-weighted scans were always used as references to confirm the presence of enhancing lesions.
3. Results We detected two enhancing lesions in two of 13 (15%) patients when the single dose of Gd-DTPA was used and 12 lesions in five of 13 (38%) patients when the triple dose of Gd-DTPA was used (Table 1, Figs. 1 and 2). The scans Table 1 Spinal cord lesions and locations seen on Gd-DTPA enhanced MRI a Patient b
Single dose scans
Triple dose scans
1 2 3 4 5
0 1-C5 0 0 1-C7
1-T2 1-C5 1-C5 6-C4, C5, C6, T1, T1 3-C7, T8, T10
a
Only patients with at least one enhancing lesion in one of the two sequences are included in the table. b These patients were selected out of a total of 13 patients. C, cervical; T, thoracic.
obtained before administering the triple dose, never revealed an indication of remaining enhancement from the previous single dose examination. Of the 12 lesions detected with the triple dose of Gd-DTPA, eight were located in the cervical and four in the thoracic spinal cord.
4. Discussion In this study, we compared the sensitivity of MRI single and triple doses of Gd-DTPA for revealing enhancing lesions within the spinal cord of MS patients. We found that the use of triple doses led to enhancement of six times as many lesions as single doses and detection of lesions in more than twice as many patients. These results are in line with those of previous studies [2,4] that compared the enhancement of brain lesions with a single and triple dose of Gd-DTPA. In one of these studies [4], performed in patients with relapsing–remitting or secondary progressive MS, the number of enhancing lesions seen on the triple dose scans was 66% higher than on single dose scans. Neither of these studies, nor our study, indicated a change in threshold by the previous administration of a single dose of Gd-DTPA. A time interval of 24 h can be considered sufficiently long enough to minimize any remaining effect from the previous examination. Due to the possible activity of the disease, new lesions could appear when using a longer time interval. Other strategies that have been used to increase MRI sensitivity in detecting MS lesions within the brain include magnetization transfer (MT) pulse T1-weighted sequences [8] and high-resolution magnetization prepared rapid acquisition gradient-echo (MP RAGE) [5] sequences. However, the gain in sensitivity for these techniques was only 18% [8] and 25% [5] in patients with relapsing–remitting and secondary progressive MS. In addition, these techniques might prove challenging to optimize and standardize for imaging the spinal cord. The results of previous studies that evaluated the role of contrast enhancement in detecting spinal cord lesions were disappointing [1,9,10]. In a longitudinal study, ten patients with relapsing–remitting MS underwent monthly single dose Gd-DTPA imaging of the spinal cord by MRI over one year and only 19 enhancing lesions were detected [9]. In another study, ten patients underwent single dose GdDTPA imaging every 2 weeks for 3 months and only three cervical lesions were detected in the 60 scans [1]. In the last study, 19 enhancing spinal cord lesions were detected in 79 scans of 29 patients who underwent serial imaging [10]. The results of this study, which demonstrate a high gain in sensitivity when using triple doses of Gd-DTPA in relapsing–remitting or secondary progressive MS patients, have two major implications. First, if our results are
T. A. Yousry et al. / Journal of the Neurological Sciences 158 (1998) 221 – 225
223
Fig. 1. Single dose Gd-DTPA enhanced MRI revealed no enhancing lesions in the spinal cord of a 27-year-old woman (patient 1, Table 1) (A). With a triple dose of Gd-DTPA, at least one lesion can be detected at the level of T2 (B).
confirmed by longitudinal studies, triple dose Gd-DTPA imaging of the spinal cord by MRI might be useful in monitoring phase II clinical trials. Secondly, the higher rate at which lesions are detected using a triple dose of
Gd-DTPA suggests that the permeability of MS lesions in the spinal cord changes only moderately, which would explain the low sensitivity of conventional enhanced MRI for detecting MS lesions in the spinal cord [1,9,10].
224
T. A. Yousry et al. / Journal of the Neurological Sciences 158 (1998) 221 – 225
Fig. 2. In a 54-year-old woman (patient 5, Table 1), no enhancing lesions were detected at the midthoracic level using a single dose of Gd-DTPA (A). Only after triple dosing was a lesion recognizable at that level (B).
Acknowledgements Presented at the annual meeting of the International Society of Magnetic Resonance in Medicine, Vancouver
1997. This work derives in part from the collaboration made possible by the EC funded (ERBCHRXCT 940684) European Magnetic Resonance Network in Multiple Sclerosis (MAGNIMS).
T. A. Yousry et al. / Journal of the Neurological Sciences 158 (1998) 221 – 225
References [1] Capra R, Marciano N, Vignolo LA, Chiesa A, Gasparotti R. Gadolinium-pentetic acid magnetic resonance imaging in patients with relapsing–remitting multiple sclerosis. Arch Neurol 1992;49:687–9. [2] Filippi M, Capra R, Campi A, Colombo B, Prandini F, Marciano N, Gasparotti R, Comi G. Triple dose of gadolinium-DTPA and delayed scanning in benign multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;60:526–30. [3] Filippi M, Yousry TA, Alkadhi H, Stehling M, Horsfield MA, Voltz R. Spinal cord MRI in multiple sclerosis using multi-coil arrays: a comparison between fast spin-echo and fast-FLAIR. J Neurol Neurosurg Psychiatry 1996;61:632–5. [4] Filippi M, Yousry T, Campi A, Kandziora C, Colombo B, Voltz R, Martinelli V, Spuler S, Bressi S, Scotti G, Comi G. Comparison of triple dose versus standard dose gadolinium-DTPA for detection of MRI enhancing lesions in patients with multiple sclerosis. Neurology 1996;46:379–84. [5] Filippi M, Yousry T, Horsfield MA, Alkadhi H, Rovaris M, Campi A, Voltz R, Comi G. A high resolution 3-D T1-weighted gradient-
[6]
[7]
[8]
[9]
[10]
225
echo sequence improves the detection of disease activity in multiple sclerosis. Ann Neurol 1996;40:901–7. Kidd D, Thorpe JW, Thompson AJ, Kendall BE, Moseley IF, MacManus DG, McDonald WI, Miller DH. Spinal cord MRI using multi-array coils and fast spin echo. II. Findings in multiple sclerosis. Neurology 1993;43:2632–7. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444– 52. Metha RC, Pike BG, Enzmann R. Improved detection of enhancing and non-enhancing lesions of multiple sclerosis with magnetization transfer. Am J Neuroradiol 1995;16:1771–8. Thorpe JW, Kidd D, Moseley IF, Kenndall BE, Thompson AJ, MacManus DG, McDonald WI, Miller DH. Serial gadoliniumenhanced MRI of the brain and spinal cord in early relapsing– remitting multiple sclerosis. Neurology 1996;46:373–8. Wiebe S, Lee DH, Karlik SJ, Hopkins M, Vandervoort MK, Womg CJ, Hewitt L, Rice GP, Ebers GC, Noseworthy JH. Serial cranial and spinal cord magnetic resonance imaging in multiple sclerosis. Ann Neurol 1992;32:643–50.