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Short-term evolution of new multiple sclerosis lesions enhancing on standard and triple dose gadolinium-enhanced brain MRI scans
Journal of the Neurological Sciences 164 (1999) 148–152
Short-term evolution of new multiple sclerosis lesions enhancing on standard and triple dose gadolinium-enhanced brain MRI scans Marco Rovaris a , Giovanna Mastronardo a , Francesca Prandini b , Stefano Bastianello c , d a, Giancarlo Comi , Massimo Filippi * a
Neuroimaging Research Unit, Department of Neuroscience, Ospedale San Raffaele, via Olgettina 60, 20132 Milan, Italy b Department of Radiology, Spedali Civili, University of Brescia, Brescia, Italy c Department of Neuroradiology, Universita` ‘ La Sapienza’, Rome, Italy d Clinical Trials Unit, Department of Neuroscience, Ospedale San Raffaele, Milan, Italy Received 19 May 1998; received in revised form 16 December 1998; accepted 11 February 1999
Abstract We compared the short-term magnetic resonance imaging (MRI) evolution of new multiple sclerosis (MS) lesions enhancing after single dose (SD) (0.1 mmol / kg) or triple dose (TD) (0.3 mmol / kg) gadolinium–DTPA (Gd) to explore possible differences in the pathological substrates of acute MS lesions. Brain MRI scans were obtained at baseline and every 4 weeks for a 3-month period in 18 relapsing-remitting MS patients. At each time point, using two separate sessions, we obtained dual echo and T1-weighted scans before and after SD and TD of Gd. New enhancing lesions detected at month 1 and 2 were entered into the analysis. The presence of corresponding hypointense lesions on unenhanced T1-weighted scans and hyperintense lesions on T2 / proton density (PD)-weighted images was assessed on the same scan and on the scans performed 1 month before and 1 month after the new lesion development. Persistence of enhancement was evaluated on the SD and TD scans obtained 1 month after new lesion appearance. One-hundred and sixty lesions were studied. Of these, 97 lesions were enhancing after both SD and TD (group A) and 63 lesions only after TD (group B). Thirty (31%) of the lesions enhancing after both SD and TD and ten (16%) of the lesions enhancing only after TD had corresponding T1-weighted lesions (P50.03). Of these lesions, 87% in group A and 40% in group B (P50.003) were not hypointense on the previous scans. No differences were found in the frequencies of corresponding T2 / PD-weighted abnormalities (92% in Group A vs. 87% in Group B lesions). Of these hyperintense areas, 62% in group A and 56% in group B were not present on the previous scans. On follow-up scans, 52% of the lesions enhancing after SD and TD and 70% of the lesions enhancing only after TD did not show enhancement after the injection of both the doses of Gd (P50.02). The frequencies of corresponding T2 / PD and T1-weighted abnormalities were higher in Group A than in Group B lesions, but the differences were not statistically significant. Our findings suggest that the pathological process is less severe in MS lesions enhancing only after TD injection than in those enhancing after the SD. 1999 Elsevier Science B.V. All rights reserved. Keywords: Multiple sclerosis; Magnetic resonance imaging; Gadolinium enhancement; Lesion evolution
1. Introduction Although gadolinium–DTPA (Gd) enhancement on magnetic resonance imaging (MRI) scans from patients with multiple sclerosis (MS) reflects the presence of *Corresponding author. Tel.: 139-2-26433032; fax: 139-2-26433031. E-mail address: [email protected] (M. Filippi)
blood–brain barrier (BBB) damage and inflammation [1], the pathological characteristics of newly-formed lesions at the time of their appearance and their evolution over time are variable [2]. More than 80% of the new enhancing lesions have a corresponding area of high signal on T2 / proton density (PD)-weighted images [3], which usually persists at follow-up, but with significant fluctuations in size [4]. The presence of acute oedema or demyelination,
0022-510X / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00054-4
M. Rovaris et al. / Journal of the Neurological Sciences 164 (1999) 148 – 152
which usually accompany the first stages of lesion formation, may also result in hypointense areas on unenhanced T1-weighted images [2]. These hypointense areas persist on follow-up scans in about 30% of the cases [2,5], probably when reparative mechanisms are not effective. Persistent T1 hypointense lesions (‘black holes’) have low magnetization transfer ratio (MTR) values [6] and correspond to MS lesions where the matrix disorganization is severe [7]. Enhanced MRI is the most sensitive measure of shortterm MS activity and it is widely used to monitor disease evolution, both natural and modified by treatments [8]. Several methods have been proposed to increase the sensitivity of Gd-enhanced MRI [9]. Among these, the use of a triple dose (TD) of Gd detected about 70–80% more lesions than the standard dose (SD) in cross-sectional [10] and longitudinal MRI studies [11]. Although it is likely that TD enhancing lesions are those with more subtle BBB abnormalities, the MRI characteristics on T2 / PD and unenhanced T1-weighted scans preceding and following the appearance of such lesions have not yet been investigated. These aspects are the topics of the present longitudinal study, which aims at exploring the possible differences in the pathological substrates underlying SD and TD enhancing lesions.
2. Materials and methods From a cohort of MS patients participating in a multicentre, longitudinal study evaluating the sensitivities of SD and TD brain MRI for detecting enhancing lesions [11], 18 patients with relapsing–remitting [12] MS (13 women and five men) were selected for the present study. These patients did not receive any steroid treatment at the study entry or during the follow-up period. Their mean age was 33.5 years (standard deviation (S.D.)55.9 years), median disease duration was 7.0 years (range 2–13 years) and median expanded disability status scale (EDSS) [13] was 1.0 (range: 0.0–3.5). All the patients signed a written informed consent before entering the study. Brain MRI scans were performed using 1.5 Tesla machines. Every 28 (65) days the patients underwent, at an interval of 12–24 h, two MRI sessions consisting of unenhanced and enhanced conventional spin echo (CSE) T1-weighted scans (TR5560–768 ms, TE515 ms, 24 axial contiguous interleaved 5-mm thick slices, image matrix52563256, FOV525 cm). The dose of Gd administered was standard (e.g. 0.1 mmol / kg) in one session and triple (e.g. 0.3 mmol / kg) in the other. The sequence of dose administration was randomised and post-injection imaging delay was 20 min for both the doses. In each monthly session, unenhanced dual echo CSE images (TR5 2000 ms, TE550 / 80 ms) were also acquired, using the same parameters as for T1-weighted scans. The duration of follow-up was 3 months (i.e. each patient underwent a
149
baseline plus three follow-up MRI scans). Patients were accurately repositioned in the scanner following ad-hoc EC guidelines [14]. For each patient and each Gd dose, the four monthly scans were evaluated side-by-side by two experienced observers (MR, GM) working together and the numbers of total and new (i.e. not visible on the previous scan) enhancing lesions were identified. During the identification of enhancing lesions, the observers were blinded to the Gd dosage used, to avoid any potential bias in the subsequent analysis. New enhancing lesions on the first and second follow-up MRI scans (i.e. the new lesions for which at least one follow-up scan was available after their appearance) were entered into the analysis. The proportions of such lesions with corresponding hypointense signal on unenhanced T1-weighted and hyperintense signal on T2 / PD-weighted scans were evaluated on the same MRI scan and on the scans obtained 1 month before and 1 month after, thus assessing the number of both total and new (i.e. not present on the previous scans) corresponding abnormalities on unenhanced T1- and T2 / PD-weighted images. Any persistence of enhancement was evaluated on the SD and TD scans obtained 1 month after new lesion appearance. The numbers of total and new enhancing lesions on SD and TD scans were compared using the Mann–Whitney test. The proportions of corresponding unenhanced abnormalities for SD and TD enhancing lesions were compared using the chi-square test.
3. Results Seventy-two MRI scans were evaluated. One month and 2 month MRI scans revealed 160 new enhancing lesions, which were entered into the present analysis. Ninety-seven lesions were enhancing after both SD and TD (Group A). Of these, 89 (92%) had T2 / PD-weighted and 30 (31%) had T1-weighted corresponding lesions. New lesions accounted for 55 / 89 (62%) T2 / PD-weighted and 26 / 30 (87%) T1-weighted abnormalities (Table 1). Fifty (52%) of these new lesions were not enhancing 1 month later. Of the 47 persistently enhancing lesions, 33 (70%) were enhancing on SD and TD scans and 14 (30%) only on TD scans. On the follow-up scans, corresponding T2 / PD-weighted and T1-weighted lesions were visible in 94 / 97 (97%) and 19 / 97 (20%) lesions, respectively (Table 2). Sixty-three lesions were enhancing only after TD (Group B). Of these, 55 (87%) had T2 / PD-weighted and 10 (16%) had T1-weighted corresponding lesions (P50.03 vs. Group A lesions) (Table 1). New lesions accounted for 31 (56%) T2 / PD-weighted and four (40%) T1-weighted lesions (P50.003 vs. Group A lesions). Forty-four (70%) of these new lesions were not enhancing 1 month later. Nineteen lesions were still enhancing (P50.02 vs. Group
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Table 1 MRI findings on dual-echo and unenhanced T1-weighted scans for new enhancing lesions
Corresponding T2 / PD lesions New corresponding T2 / PD lesions Corresponding T1 lesions New corresponding T1 lesions c
Group A lesions a
Group B lesions b
89 / 97 (92%) 55 / 89 (62%) 30 / 97 (31%) 26 / 30 (87%)
55 / 63 (87%) 31 / 55 (56%) 10 / 55 (16%)* 4 / 10 (40%)**
a
Lesions enhancing after both SD and TD. Lesions enhancing only after TD. c Not visible on the previous MRI scans. * P50.03 and, ** P50.003 vs. Group A lesions (chi-square test). b
A lesions). Of these, 10 (53%) enhanced on SD and TD scans and nine (47%) only on TD scans. Corresponding T2 / PD-weighted and T1-weighted lesions were visible in 58 / 63 and 11 / 63 lesions, respectively (Table 2).
4. Discussion The number of enhancing MS lesions visible on postcontrast MRI scans may be increased by using a TD of Gd, as confirmed by several cross-sectional and longitudinal studies [9–11]. Since it has been demonstrated [1,2] that the pathological substrate of Gd enhancement is an increased BBB permeability, associated with inflammation [15], there are two possible explanations for the higher sensitivity of TD MRI. The first is that the time course of BBB leakage for some lesions is such that they might be detectable with SD scanning for only a part of the inflammatory episode. The second is that there are lesions where the BBB permeability is too low for enhancement ever to be seen with SD contrast administration. In a recent study [16], we found that MS lesions enhancing only after TD of Gd have higher MTR values than those lesions enhancing after both SD and TD. These Table 2 MRI findings on follow-up scans for Group A and B enhancing lesions
No enhancement Enhancement after SD and TD Enhancement after TD Corresponding T2 / PD lesions Corresponding T1 lesions a
Group A lesions a
Group B lesions b
50 / 97 (52%) 33 / 97 (34%) 14 / 97 (14%) 94 / 97 (97%) 19 / 97 (20%)
44 / 63 (70%)* 10 / 63 (16%) 9 / 63 (14%) 58 / 63 (92%) 11 / 63 (17%)
Lesions enhancing after both SD and TD. Lesions enhancing only after TD. * P50.02 vs. Group A lesions (chi-square test). b
findings suggest that the former lesions have a less severe tissue disorganization. It has been reported [17] that the effect of beta-interferon (IFN) 1a on MRI activity is more pronounced on TD than on SD enhancing lesion numbers and volumes. This suggests that the effect of the drug may be inversely related to the degree of lesion BBB disruption. The present study was undertaken to obtain new insights into the different pathological substrates of MS lesions enhancing after either SD or TD injection, by comparing their short-term evolution on serial unenhanced and enhanced MRI scans. Our results confirm that enhancing lesions form a heterogeneous population, since there is a substantial proportion of lesions which enhance only after the injection of a high dose of Gd [10]. The lesions enhancing only after TD of Gd are probably characterized by milder pathological changes than lesions enhancing on SD scans, as suggested by several findings in the present study. Visible enhancement in MS lesions depends upon the local concentration of Gd, which is in turn dependent on the vascular concentration of Gd, the BBB permeability and the volume fraction of the leakage space [18]. Because in this study we obtained enhanced scans 20 min after the contrast injection, such a short post-contrast delay means that the local concentration of Gd is less influenced by the leakage space [18] and this suggests that the lesions visible only after TD were those with a less damaged BBB. The persistence of enhancement at 1 month follow-up was also less frequent in the group of lesions enhancing after TD, suggesting that the duration of the BBB disruption is shorter in these lesions than in those enhancing after SD. Since on follow-up scans only few lesions changed their enhancement from SD to TD or vice versa, this also suggests that TD enhancement is a feature of a group of lesions with a low-grade of BBB opening and inflammation, which seems to be independent of the lesions’ age. In other words, TD enhancement rarely reflects the beginning or the end of a more severe pathological process which might be seen on SD scans. Moreover, in a longitudinal study with weekly MRI scanning, Lai et al. [19] demon-
M. Rovaris et al. / Journal of the Neurological Sciences 164 (1999) 148 – 152
strated that, although the majority of the MS lesions enhance between 4 and 8 weeks, few lesions can enhance for shorter periods. From these data [19] it seems unlikely that a substantial proportion of the additional lesions seen with TD are transiently enhancing. This suggests the need for using higher doses of Gd if a complete picture of MS activity is to be obtained. Corresponding hypointense lesions on unenhanced T1weighted images are less frequently visible for lesions enhancing after TD than for lesions enhancing also after SD. This suggests that the balance between damaging and reparative mechanisms, which are known to occur in the early stages of MS lesion formation [2] is more favourable in the lesions enhancing after TD. However, since these are acute hypointensities, which subsequently may disappear [5] this difference could also be related to variable amounts of transient oedema in the two populations of lesions. Several studies [7,20] indicate that hypointense lesions on unenhanced T1-weighted images represent areas where the white matter disruption is severe. This is possibly due to the presence of demyelination and / or axonal loss, and suggests that the extent of T1-weighted abnormalities on brain MRI scans is the best predictor of clinical disability and disease evolution in patients with MS [21,22]. However, it is well known that, when there is Gd enhancement, also oedematous lesions can be hypointense on unenhanced T1-weighted scans [5]. This may contribute to a reversible hypointensity in acute lesions. In this study, we indeed found that, at follow-up, there was no significant difference between SD and TD enhancing lesions in the proportions of persistently hypointense areas. This finding is in keeping with previous studies [16,23] showing a marked recovery of MTR in newly-formed enhancing lesions and suggests that the most likely pathological substrates of these changes are resolution of pre-existing edema and remyelination. It also confirms that, when the extent of ‘black holes’ has to be used to monitor long-term disease evolution [22], contrast should be administered to exclude transient abnormalities. In summary, our data suggest that in MS lesions enhancing only after the injection of a TD of Gd the degree of pathological changes are less severe than in those enhancing after the standard dose. Further longitudinal MRI studies comparing SD and TD with longer follow-up periods are needed to confirm the pathological heterogeneity of enhancing lesions and to determine whether this has an impact on the overall disease evolution.
Acknowledgements This study was generously supported by a grant from the ‘Associazione Italiana Sclerosi Multipla’ (AISM). We thank Dr Jack C. Sipe (Scripps Clinic, Division of
151
Neurology and The Scripps Research Institute, La Jolla, California, USA) for his assistance in manuscript revision.
References [1] Kermode AG, Thompson AJ, Tofts PS, MacManus DG, Kendall BE, Kingsley DPE, Moseley IF, Rudge P, McDonald WI. Breakdown of the blood–brain barrier precedes symptoms and other MRI signs of new lesions in multiple sclerosis. Pathogenetic and clinical implications. Brain 1990;113:1477–89. [2] McDonald WI, Miller DH, Barnes D. The pathological evolution of multiple sclerosis. Neuropathol Appl Neurobiol 1992;18:319–34. [3] Miller DH, Barkhof F, Nauta JJP. Gadolinium enhancement increased the sensitivity of MRI in detecting disease activity in MS. Brain 1993;116:1077–94. [4] Stone LA, Albert PS, Smith ME, DeCarli C, Armstrong MR, McFarlin DE, Frank JA, McFarland HF. Changes in the amount of diseased white matter over time in patients with relapsing–remitting multiple sclerosis. Neurology 1995;45:1808–14. [5] van Waesberghe JHTM, van Walderveen MAA, Castelijns JA, Scheltens P, Lycklama a` Nijeholt GJ, Polman CH, Barkhof F. Patterns of lesion development in multiple sclerosis: longitudinal observations with T1-weighted spin-echo and magnetization MR. Am J Neuroradiol 1998;19:675–83. [6] Loevner LA, Grossman RI, McGowan JC, Ramer KN, Cohen JA. Characterization of multiple sclerosis plaques with T 1 -weighted MR and quantitative magnetization transfer. Am J Neuroradiol 1995;16:1473–9. [7] van Walderveen MAA, Kamphorst W, Scheltens P, van Waesberghe JHTM, Ravid R, Valk J, Polman Ch, Barkhof F. Histopathologic correlate of hypointense lesions on T1-weighted spin-echo MRI in multiple sclerosis. Neurology 1998;50:1282–8. [8] Filippi M, Miller DH. MRI in the differential diagnosis and monitoring the treatment of multiple sclerosis. Curr Opin Neurol 1996;9:176–86. [9] Silver NC, Good CD, Barker GJ, MacManus DG, Thompson AJ, Moseley IF, McDonald WI, Miller DH. Sensitivity of contrast enhanced MRI in multiple sclerosis. Effects of gadolinium dose, magnetization transfer contrast and delayed imaging. Brain 1997;120:1149–61. [10] 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 MS. Neurology 1996;46:379–84. [11] Filippi M, Rovaris M, Capra R, Gasperini C, Yousry TA, Sormani MP, Prandini F, Horsfield MA, Martinelli V, Bastianello S, Kuhne I, Pozzilli C, Comi G. 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. Brain 1998;121:2011–20. [12] Lublin FD, Reingold SC. The National Multiple Sclerosis Society (USA) Advisory Committee on Clinical Trials of New Agents in Multiple Sclerosis: Defining the clinical course of multiple sclerosis: results of an international survey. Neurology 1996;46:907–11. [13] Kurtzke JF. Rating neurological impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 1983;33:1444– 52. [14] Miller DH, Barkhof F, Berry I, Kappos L, Scotti G, Thompson AJ. Magnetic resonance imaging in monitoring the treatment of multiple sclerosis: Concerted Action Guidelines. J Neurol Neurosurg Psychiatry 1991;54:683–8. [15] Katz D, Taubenberger JK, Cannella B, McFarlin DE, Raine CS,
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M. Rovaris et al. / Journal of the Neurological Sciences 164 (1999) 148 – 152 McFarland HF. Correlation between magnetic resonance imaging findings and lesion development in multiple sclerosis. Ann Neurol 1993;34:661–9. Filippi M, Rocca MA, Rizzo G, Horsfield MA, Rovaris M, Minicucci L, Colombo B, Comi G. Magnetization transfer ratios in multiple sclerosis lesions enhancing after different doses of gadolinium. Neurology 1998;50:1289–93. Filippi M, Rovaris M, Capra R, Gasperini C, Martinelli V, Sormani MP, Bastianello S, Comi G. Serial standard- and triple-dose MRI to monitor the effect of interferon b-1a on multiple sclerosis activity (Abstract). Neurology 1998;50(Suppl 4):A323. Tofts PS, Kermode AG. Measurement of the blood–brain barrier permeability and leakage space using dynamic MR imaging. I. Fundamental concepts. Magn Reson Med 1991;17:357–67. Lai M, Hodgson T, Gawne-Cain M, Webb S, MacManus DG, McDonald WI, Thompson AJ, Miller DH. A preliminary study into the sensitivity of disease activity detection by serial weekly magnetic resonance imaging in multiple sclerosis. J Neurol Neurosurg Psychiatry 1996;60:339–41.
[20] Bruck W, Bitsch A, Kolenda H, Bruck Y, Stiefel M, Lassmann H. Inflammatory central nervous system demyelination: correlation of magnetic resonance imaging findings with lesion pathology. Ann Neurol 1997;42:783–93. [21] van Walderveen MAA, Barkhof F, Hommes OR, Polman CH, Tobi H, Frequin STFM, Valk J. Correlating MRI and clinical disease activity in multiple sclerosis: relevance of hypointense lesions on short TR / short TE (T 1 -weighted) spin-echo images. Neurology 1995;45:1684–90. [22] Truyen L, van Waesberghe JHTM, van Walderveen MAA, van ` HJA, Barkhof F. Oosten BW, Polman CH, Hommes OR, Ader Accumulation of hypointense lesions (‘black holes’) on T1 spinecho MRI correlates with disease progression in multiple sclerosis. Neurology 1997;47:1469–76. [23] Lai HM, Davie CA, Gass A, Barker GJ, Webb S, Tofts PS, Thompson AJ, McDonald WI, Miller DH. Serial magnetisation transfer ratios in gadolinium-enhancing lesions in multiple sclerosis. J Neurol 1997;244:308–11.
Short-term evolution of new multiple sclerosis lesions enhancing on standard and triple dose gadolinium-enhanced brain MRI scans Marco Rovaris a , Giovanna Mastronardo a , Francesca Prandini b , Stefano Bastianello c , d a, Giancarlo Comi , Massimo Filippi * a
Neuroimaging Research Unit, Department of Neuroscience, Ospedale San Raffaele, via Olgettina 60, 20132 Milan, Italy b Department of Radiology, Spedali Civili, University of Brescia, Brescia, Italy c Department of Neuroradiology, Universita` ‘ La Sapienza’, Rome, Italy d Clinical Trials Unit, Department of Neuroscience, Ospedale San Raffaele, Milan, Italy Received 19 May 1998; received in revised form 16 December 1998; accepted 11 February 1999
Abstract We compared the short-term magnetic resonance imaging (MRI) evolution of new multiple sclerosis (MS) lesions enhancing after single dose (SD) (0.1 mmol / kg) or triple dose (TD) (0.3 mmol / kg) gadolinium–DTPA (Gd) to explore possible differences in the pathological substrates of acute MS lesions. Brain MRI scans were obtained at baseline and every 4 weeks for a 3-month period in 18 relapsing-remitting MS patients. At each time point, using two separate sessions, we obtained dual echo and T1-weighted scans before and after SD and TD of Gd. New enhancing lesions detected at month 1 and 2 were entered into the analysis. The presence of corresponding hypointense lesions on unenhanced T1-weighted scans and hyperintense lesions on T2 / proton density (PD)-weighted images was assessed on the same scan and on the scans performed 1 month before and 1 month after the new lesion development. Persistence of enhancement was evaluated on the SD and TD scans obtained 1 month after new lesion appearance. One-hundred and sixty lesions were studied. Of these, 97 lesions were enhancing after both SD and TD (group A) and 63 lesions only after TD (group B). Thirty (31%) of the lesions enhancing after both SD and TD and ten (16%) of the lesions enhancing only after TD had corresponding T1-weighted lesions (P50.03). Of these lesions, 87% in group A and 40% in group B (P50.003) were not hypointense on the previous scans. No differences were found in the frequencies of corresponding T2 / PD-weighted abnormalities (92% in Group A vs. 87% in Group B lesions). Of these hyperintense areas, 62% in group A and 56% in group B were not present on the previous scans. On follow-up scans, 52% of the lesions enhancing after SD and TD and 70% of the lesions enhancing only after TD did not show enhancement after the injection of both the doses of Gd (P50.02). The frequencies of corresponding T2 / PD and T1-weighted abnormalities were higher in Group A than in Group B lesions, but the differences were not statistically significant. Our findings suggest that the pathological process is less severe in MS lesions enhancing only after TD injection than in those enhancing after the SD. 1999 Elsevier Science B.V. All rights reserved. Keywords: Multiple sclerosis; Magnetic resonance imaging; Gadolinium enhancement; Lesion evolution
1. Introduction Although gadolinium–DTPA (Gd) enhancement on magnetic resonance imaging (MRI) scans from patients with multiple sclerosis (MS) reflects the presence of *Corresponding author. Tel.: 139-2-26433032; fax: 139-2-26433031. E-mail address: [email protected] (M. Filippi)
blood–brain barrier (BBB) damage and inflammation [1], the pathological characteristics of newly-formed lesions at the time of their appearance and their evolution over time are variable [2]. More than 80% of the new enhancing lesions have a corresponding area of high signal on T2 / proton density (PD)-weighted images [3], which usually persists at follow-up, but with significant fluctuations in size [4]. The presence of acute oedema or demyelination,
0022-510X / 99 / $ – see front matter 1999 Elsevier Science B.V. All rights reserved. PII: S0022-510X( 99 )00054-4
M. Rovaris et al. / Journal of the Neurological Sciences 164 (1999) 148 – 152
which usually accompany the first stages of lesion formation, may also result in hypointense areas on unenhanced T1-weighted images [2]. These hypointense areas persist on follow-up scans in about 30% of the cases [2,5], probably when reparative mechanisms are not effective. Persistent T1 hypointense lesions (‘black holes’) have low magnetization transfer ratio (MTR) values [6] and correspond to MS lesions where the matrix disorganization is severe [7]. Enhanced MRI is the most sensitive measure of shortterm MS activity and it is widely used to monitor disease evolution, both natural and modified by treatments [8]. Several methods have been proposed to increase the sensitivity of Gd-enhanced MRI [9]. Among these, the use of a triple dose (TD) of Gd detected about 70–80% more lesions than the standard dose (SD) in cross-sectional [10] and longitudinal MRI studies [11]. Although it is likely that TD enhancing lesions are those with more subtle BBB abnormalities, the MRI characteristics on T2 / PD and unenhanced T1-weighted scans preceding and following the appearance of such lesions have not yet been investigated. These aspects are the topics of the present longitudinal study, which aims at exploring the possible differences in the pathological substrates underlying SD and TD enhancing lesions.
2. Materials and methods From a cohort of MS patients participating in a multicentre, longitudinal study evaluating the sensitivities of SD and TD brain MRI for detecting enhancing lesions [11], 18 patients with relapsing–remitting [12] MS (13 women and five men) were selected for the present study. These patients did not receive any steroid treatment at the study entry or during the follow-up period. Their mean age was 33.5 years (standard deviation (S.D.)55.9 years), median disease duration was 7.0 years (range 2–13 years) and median expanded disability status scale (EDSS) [13] was 1.0 (range: 0.0–3.5). All the patients signed a written informed consent before entering the study. Brain MRI scans were performed using 1.5 Tesla machines. Every 28 (65) days the patients underwent, at an interval of 12–24 h, two MRI sessions consisting of unenhanced and enhanced conventional spin echo (CSE) T1-weighted scans (TR5560–768 ms, TE515 ms, 24 axial contiguous interleaved 5-mm thick slices, image matrix52563256, FOV525 cm). The dose of Gd administered was standard (e.g. 0.1 mmol / kg) in one session and triple (e.g. 0.3 mmol / kg) in the other. The sequence of dose administration was randomised and post-injection imaging delay was 20 min for both the doses. In each monthly session, unenhanced dual echo CSE images (TR5 2000 ms, TE550 / 80 ms) were also acquired, using the same parameters as for T1-weighted scans. The duration of follow-up was 3 months (i.e. each patient underwent a
149
baseline plus three follow-up MRI scans). Patients were accurately repositioned in the scanner following ad-hoc EC guidelines [14]. For each patient and each Gd dose, the four monthly scans were evaluated side-by-side by two experienced observers (MR, GM) working together and the numbers of total and new (i.e. not visible on the previous scan) enhancing lesions were identified. During the identification of enhancing lesions, the observers were blinded to the Gd dosage used, to avoid any potential bias in the subsequent analysis. New enhancing lesions on the first and second follow-up MRI scans (i.e. the new lesions for which at least one follow-up scan was available after their appearance) were entered into the analysis. The proportions of such lesions with corresponding hypointense signal on unenhanced T1-weighted and hyperintense signal on T2 / PD-weighted scans were evaluated on the same MRI scan and on the scans obtained 1 month before and 1 month after, thus assessing the number of both total and new (i.e. not present on the previous scans) corresponding abnormalities on unenhanced T1- and T2 / PD-weighted images. Any persistence of enhancement was evaluated on the SD and TD scans obtained 1 month after new lesion appearance. The numbers of total and new enhancing lesions on SD and TD scans were compared using the Mann–Whitney test. The proportions of corresponding unenhanced abnormalities for SD and TD enhancing lesions were compared using the chi-square test.
3. Results Seventy-two MRI scans were evaluated. One month and 2 month MRI scans revealed 160 new enhancing lesions, which were entered into the present analysis. Ninety-seven lesions were enhancing after both SD and TD (Group A). Of these, 89 (92%) had T2 / PD-weighted and 30 (31%) had T1-weighted corresponding lesions. New lesions accounted for 55 / 89 (62%) T2 / PD-weighted and 26 / 30 (87%) T1-weighted abnormalities (Table 1). Fifty (52%) of these new lesions were not enhancing 1 month later. Of the 47 persistently enhancing lesions, 33 (70%) were enhancing on SD and TD scans and 14 (30%) only on TD scans. On the follow-up scans, corresponding T2 / PD-weighted and T1-weighted lesions were visible in 94 / 97 (97%) and 19 / 97 (20%) lesions, respectively (Table 2). Sixty-three lesions were enhancing only after TD (Group B). Of these, 55 (87%) had T2 / PD-weighted and 10 (16%) had T1-weighted corresponding lesions (P50.03 vs. Group A lesions) (Table 1). New lesions accounted for 31 (56%) T2 / PD-weighted and four (40%) T1-weighted lesions (P50.003 vs. Group A lesions). Forty-four (70%) of these new lesions were not enhancing 1 month later. Nineteen lesions were still enhancing (P50.02 vs. Group
150
M. Rovaris et al. / Journal of the Neurological Sciences 164 (1999) 148 – 152
Table 1 MRI findings on dual-echo and unenhanced T1-weighted scans for new enhancing lesions
Corresponding T2 / PD lesions New corresponding T2 / PD lesions Corresponding T1 lesions New corresponding T1 lesions c
Group A lesions a
Group B lesions b
89 / 97 (92%) 55 / 89 (62%) 30 / 97 (31%) 26 / 30 (87%)
55 / 63 (87%) 31 / 55 (56%) 10 / 55 (16%)* 4 / 10 (40%)**
a
Lesions enhancing after both SD and TD. Lesions enhancing only after TD. c Not visible on the previous MRI scans. * P50.03 and, ** P50.003 vs. Group A lesions (chi-square test). b
A lesions). Of these, 10 (53%) enhanced on SD and TD scans and nine (47%) only on TD scans. Corresponding T2 / PD-weighted and T1-weighted lesions were visible in 58 / 63 and 11 / 63 lesions, respectively (Table 2).
4. Discussion The number of enhancing MS lesions visible on postcontrast MRI scans may be increased by using a TD of Gd, as confirmed by several cross-sectional and longitudinal studies [9–11]. Since it has been demonstrated [1,2] that the pathological substrate of Gd enhancement is an increased BBB permeability, associated with inflammation [15], there are two possible explanations for the higher sensitivity of TD MRI. The first is that the time course of BBB leakage for some lesions is such that they might be detectable with SD scanning for only a part of the inflammatory episode. The second is that there are lesions where the BBB permeability is too low for enhancement ever to be seen with SD contrast administration. In a recent study [16], we found that MS lesions enhancing only after TD of Gd have higher MTR values than those lesions enhancing after both SD and TD. These Table 2 MRI findings on follow-up scans for Group A and B enhancing lesions
No enhancement Enhancement after SD and TD Enhancement after TD Corresponding T2 / PD lesions Corresponding T1 lesions a
Group A lesions a
Group B lesions b
50 / 97 (52%) 33 / 97 (34%) 14 / 97 (14%) 94 / 97 (97%) 19 / 97 (20%)
44 / 63 (70%)* 10 / 63 (16%) 9 / 63 (14%) 58 / 63 (92%) 11 / 63 (17%)
Lesions enhancing after both SD and TD. Lesions enhancing only after TD. * P50.02 vs. Group A lesions (chi-square test). b
findings suggest that the former lesions have a less severe tissue disorganization. It has been reported [17] that the effect of beta-interferon (IFN) 1a on MRI activity is more pronounced on TD than on SD enhancing lesion numbers and volumes. This suggests that the effect of the drug may be inversely related to the degree of lesion BBB disruption. The present study was undertaken to obtain new insights into the different pathological substrates of MS lesions enhancing after either SD or TD injection, by comparing their short-term evolution on serial unenhanced and enhanced MRI scans. Our results confirm that enhancing lesions form a heterogeneous population, since there is a substantial proportion of lesions which enhance only after the injection of a high dose of Gd [10]. The lesions enhancing only after TD of Gd are probably characterized by milder pathological changes than lesions enhancing on SD scans, as suggested by several findings in the present study. Visible enhancement in MS lesions depends upon the local concentration of Gd, which is in turn dependent on the vascular concentration of Gd, the BBB permeability and the volume fraction of the leakage space [18]. Because in this study we obtained enhanced scans 20 min after the contrast injection, such a short post-contrast delay means that the local concentration of Gd is less influenced by the leakage space [18] and this suggests that the lesions visible only after TD were those with a less damaged BBB. The persistence of enhancement at 1 month follow-up was also less frequent in the group of lesions enhancing after TD, suggesting that the duration of the BBB disruption is shorter in these lesions than in those enhancing after SD. Since on follow-up scans only few lesions changed their enhancement from SD to TD or vice versa, this also suggests that TD enhancement is a feature of a group of lesions with a low-grade of BBB opening and inflammation, which seems to be independent of the lesions’ age. In other words, TD enhancement rarely reflects the beginning or the end of a more severe pathological process which might be seen on SD scans. Moreover, in a longitudinal study with weekly MRI scanning, Lai et al. [19] demon-
M. Rovaris et al. / Journal of the Neurological Sciences 164 (1999) 148 – 152
strated that, although the majority of the MS lesions enhance between 4 and 8 weeks, few lesions can enhance for shorter periods. From these data [19] it seems unlikely that a substantial proportion of the additional lesions seen with TD are transiently enhancing. This suggests the need for using higher doses of Gd if a complete picture of MS activity is to be obtained. Corresponding hypointense lesions on unenhanced T1weighted images are less frequently visible for lesions enhancing after TD than for lesions enhancing also after SD. This suggests that the balance between damaging and reparative mechanisms, which are known to occur in the early stages of MS lesion formation [2] is more favourable in the lesions enhancing after TD. However, since these are acute hypointensities, which subsequently may disappear [5] this difference could also be related to variable amounts of transient oedema in the two populations of lesions. Several studies [7,20] indicate that hypointense lesions on unenhanced T1-weighted images represent areas where the white matter disruption is severe. This is possibly due to the presence of demyelination and / or axonal loss, and suggests that the extent of T1-weighted abnormalities on brain MRI scans is the best predictor of clinical disability and disease evolution in patients with MS [21,22]. However, it is well known that, when there is Gd enhancement, also oedematous lesions can be hypointense on unenhanced T1-weighted scans [5]. This may contribute to a reversible hypointensity in acute lesions. In this study, we indeed found that, at follow-up, there was no significant difference between SD and TD enhancing lesions in the proportions of persistently hypointense areas. This finding is in keeping with previous studies [16,23] showing a marked recovery of MTR in newly-formed enhancing lesions and suggests that the most likely pathological substrates of these changes are resolution of pre-existing edema and remyelination. It also confirms that, when the extent of ‘black holes’ has to be used to monitor long-term disease evolution [22], contrast should be administered to exclude transient abnormalities. In summary, our data suggest that in MS lesions enhancing only after the injection of a TD of Gd the degree of pathological changes are less severe than in those enhancing after the standard dose. Further longitudinal MRI studies comparing SD and TD with longer follow-up periods are needed to confirm the pathological heterogeneity of enhancing lesions and to determine whether this has an impact on the overall disease evolution.
Acknowledgements This study was generously supported by a grant from the ‘Associazione Italiana Sclerosi Multipla’ (AISM). We thank Dr Jack C. Sipe (Scripps Clinic, Division of
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Neurology and The Scripps Research Institute, La Jolla, California, USA) for his assistance in manuscript revision.
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