Multiplehttp://msj.sagepub.com/ Sclerosis Journal Identical lesion morphology in primary progressive and relapsing−remitting MS −an ultrahigh field MRI study Joseph Kuchling, Caren Ramien, Ivan Bozin, Jan Dörr, Lutz Harms, Berit Rosche, Thoralf Niendorf, Friedemann Paul, Tim Sinnecker and Jens Wuerfel Mult Scler published online 29 April 2014 DOI: 10.1177/1352458514531084 The online version of this article can be found at: http://msj.sagepub.com/content/early/2014/04/28/1352458514531084
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On behalf of: European Committee for Treatment and Research in Multiple Sclerosis
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Latin American Committee on Treatment and Research of Multiple Sclerosis
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531084
research-article2014
MSJ0010.1177/1352458514531084Multiple Sclerosis JournalJ Kuchling, C Ramien,
MULTIPLE SCLEROSIS MSJ JOURNAL
Research Paper
Identical lesion morphology in primary progressive and relapsing–remitting MS – an ultrahigh field MRI study
Multiple Sclerosis Journal 1–6 DOI: 10.1177/ 1352458514531084 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Joseph Kuchling, Caren Ramien, Ivan Bozin, Jan Dörr, Lutz Harms, Berit Rosche, Thoralf Niendorf, Friedemann Paul, Tim Sinnecker* and Jens Wuerfel*
Abstract: Potential differences between primary progressive (PP) and relapsing–remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g. perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI. Keywords: MRI, primary progressive multiple sclerosis, PPMS, relapsing–remitting multiple sclerosis, RRMS, ultrahigh field MRI, 7 T MRI Date received: 22 November 2013; revised: 16 March 2014; accepted: 17 March 2014
Introduction Primary progressive (PP) multiple sclerosis (MS) is often characterized by a more severe long-term disability, pronounced spinal cord damage, and only minor gender differences compared to relapsing–remitting (RR) MS.1 Previous studies suggest differences in magnetic resonance imaging (MRI) and histopathology between MS disease courses.1 In general, PPMS lesions seemed to be smaller,2 and blood–brain barrier breakdown was detectable with lower frequency.3 In addition, differences in magnetization transfer ratio, MR spectroscopy, and spinal cord diffusion tensor imaging have been described.4 Pathophysiological differences, between both MS subtypes,1 may explain the current lack of effective immunomodulatory or disease-modifying therapies in PPMS.5 Due to increased signal-to-noise ratio and susceptibility effects at 7 Tesla (T), ultrahigh field MRI often visualizes a small central vein and a hypointense rim at the edge of MS lesions,6–10 both of which can be used as novel markers to distinguish RRMS from neuromyelitis optica (NMO),8 Susac syndrome,9 and non-specific white matter lesions.6,7 Furthermore, the depiction of cortical lesions is a hallmark of ultrahigh field MRI.11
However, 7 T MRI data on PPMS are still scarce with only few cases being published so far suggesting no substantial differences in intra-lesional vein count between PPMS and RRMS patients.6,7 The aim of this study was to compare lesion count and morphology at 7 T MRI in PPMS and matching RRMS patients. Methods Study participants Nine PPMS patients and nine age- and gendermatched RRMS patients were investigated (Table 1). The study was approved by the local ethics committee. All participants gave written informed consent.
MRI data acquisition Images were acquired using a 7 T whole body MR system (Magnetom; Siemens, Erlangen, Germany), applying a 24-channel receive head RF coil (Nova Medical, Wilmington, MA, USA). The imaging protocol included a two-dimensional axial T2*w fast low angle shot (FLASH) (echo time [TE] 25 ms, repetition time
Correspondence to: Friedemann Paul NeuroCure Clinical Research Center, Charité Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. [email protected] Joseph Kuchling Caren Ramien Ivan Bozin NeuroCure Clinical Research Center, Charité – Universitaetsmedizin Berlin, Germany Tim Sinnecker NeuroCure Clinical Research Center, Charité - Universitaetsmedizin Berlin, Germany/Asklepios Fachklinikum Teupitz, Germany Jan Dörr NeuroCure Clinical Research Center/Clinical and Experimental MS Research Center, Charité – Universitaetsmedizin Berlin, Berlin, Germany Lutz Harms Berit Rosche Clinical and Experimental MS Research Center/Charité – Universitaetsmedizin Berlin, Berlin, Germany Thoralf Niendorf Berlin Ultrahigh Field Facility (BUFF)/ Experimental and Clinical Research Center, Charité – Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin, Germany Friedemann Paul NeuroCure Clinical Research Center/Clinical and Experimental MS Research Center/Experimental and Clinical Research Center, Charité – Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin, Germany Jens Wuerfel NeuroCure Clinical Research Center/BUFF, Max Delbrueck Center for Molecular Medicine, Berlin, Germany/ Experimental and Clinical Research Center, Charité – Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin/ Institute of Neuroradiology, University Medicine Goettingen, Germany *equally contributing senior authors.
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Multiple Sclerosis Journal Table 1. Cohort description.
n Female Age (years)
n mean ± SD (range)
Time since diagnosis (months) Time since first symptoms (months) EDSS
mean ± SD (range) MWU mean ± SD (range) MWU median (range) MWU
PPMS
RRMS
9 3 46 ± 7 (35–55)
9 3 45 ± 5 (35–51)
57 ± 69 (2–201)
97 ± 67 (6–175) p = 0.19 117 ± 73 (23–187) p = 0.49 2.0 (1.5–4.5) p < 0.001
96 ± 68 (17–201) 5.5 (3.5–8.0)
PPMS = primary progressive multiple sclerosis. RRMS = relapsing–remitting multiple sclerosis. MWU = Mann–Whitney U test. EDSS = Expanded Disability Status Scale.
[TR] 1820 ms, acquisition time 12.11 minutes, spatial resolution 0.5 × 0.5 × 2 mm3; supratentorial brain coverage). Slightly modified sequence parameters were applied in three subjects due to technical limitations.
Image analysis Visual analysis was performed using OsiriX (OsiriX Foundation, Geneva, Switzerland, version 4.0) and its integrated region of interest (ROI) function. Images were analyzed by two experienced observers (JK, TS) blinded to clinical data in consensus reading. In general, a lesion was defined as a T2*w hyperintense signal alteration extending over at least 2 mm. Lesions (Figure 1) were characterized by their morphology (central vein, hypointense rim), appearance (ovoid, circular, trapezoid, complex-shaped, or confluent), and maximum diameter. In detail, veins that are both (i) continuously displayed within the lesion and (ii) passing through the inner third of the lesion were defined as ‘central’ veins. White matter lesions (WML) with a distance of less than 5 mm from the ventricles were defined periventricular, and periventricular lesions neighboring the ventricles were named ‘lesions adjacent to ventricles’. Lesions with a maximum distance to the cortex of 2 mm were considered subcortical, and lesions with direct contact with cortical gray matter were defined juxtacortical. Lesions within the corpus callosum were named callosal lesions. WML meeting none of the criteria above were defined as other WML. Cortical gray matter lesions (GML) were separated into leukocortical (type I), purely intracortical (type II), and subpial (type III) lesions.12
To determine intra-rater reliability, MRI data of 10 representative cases (7 MS patients and 3 healthy controls) were re-evaluated by TS and JK in consensus reading after two months. An additional evaluation of the same 10 representative cases was performed by an independent blinded rater (CR) to assess inter-rater reliability. Intra- and inter-rater reliability were calculated using intra-class-correlation (ICC) as a two-waymixed test for average measures. We observed a high ICC for lesion count (0.993), central vein count (0.975), hypointense rim count (0.854), and lesion size (0.964), indicating good intra-rater reliability. Interrater reliability indicated by ICC was equally sufficient (lesion count 0.968, central vein count 0.969, hypointense rim count 0.769, and lesion size 0.977).
Statistical analysis Differences were assessed using nonparametric Mann–Whitney U test (MWU). All statistics were calculated using IBM SPSS Statistics (version 20, IBM, Somers, NY, USA); p values < 0.05 were considered significant. Results Details on demographic and clinical data of the study participants are presented in Table 1. We observed no differences between PPMS (n = 362 lesions) and RRMS (n = 490 lesions) regarding lesion count, shape, location, or spatial distribution. However, lesion diameter was significantly higher in RRMS, as outlined in Table 2. The majority of both RRMS (n = 394, 69%) and PPMS lesions (n=277, 79%, p=0.863) was characterized by a central vein, commonly considered to be typical of
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RRMS lesions with a hypointense rim (i) and subpial (type III) gray matter lesion (j). Key: T = Tesla, PPMS = primary progressive multiple sclerosis, RRMS = relapsing-remitting multiple sclerosis, FLASH = fast low angle shot.
Figure 1. Comparison of PPMS and RRMS brain lesion appearance at 7 T. (a) Axial 7 T T2* weighted MR image of a PPMS patient exhibiting periventricular lesions and hypointense rims. (b, c) Typical shaped MS lesions of PPMS patients with a perivascular localization. (d) A PPMS lesion with a hypointense rim. (e) A subpial (type III) gray matter lesion in a representative PPMS patient. (f) Comparative axial 7 T T2* weighted FLASH image of an RRMS patient. (g, h) Lesions of RRMS patients exhibit a comparable perivascular localization.
J Kuchling, C Ramien, et al.
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13 (2.7%) 3.38±5.63 0–15.38 p = 0.436
29 (5.9%) 7.33±13.39 0–41.03 p = 0.436
3 (0.6%) 0.78±1.32 0–3.45 p = 0.796
5 (1.4%) 0.62±1.29 0–3.61
type II
35 (7.1%) 6.57±4.66 0–12.79 p = 0.730
30 (8.3%) 7.66±10.96 0–33.33
occipital
WML
311 (85.9%) 90.29±8.99 77.11–100 459 (93.7%) 81.38±33.17 0–100 p = 0.931 ovoid
300 (82.9%) 76.49±12.70 50.00–88.73 412 (84.0%) 73.54±28.29 0–92.59 p = 0.546
deep GML
8 (2.2%) 1.46±2.53 0–5.88 2 (0.4%) 0.18±0.54 0–1.61 p = 0.436 type III/IV
22 (6.1%) 3.92±5.18 0–14.46 13 (2.7%) 3.17±7.56 0–23.08 p = 0.436
juxtacortical
46 (12.7%) 15.66±15.62 0–50.00 94 (19.2%) 16.12±10.57 0–29.17 p = 0.605 trapezoid
20 (5.5%) 4.89±4.35 0–11.76 23 (4.7%) 3.40±3.44 0–10.31 p = 0.489
subcortical
59 (16.3%) 11.03±7.84 0–22.54 65 (13.3%) 12.40±7.77 0–25.00 p = 0.931 circular
16 (4.4%) 8.51±15.95 0–50.00 17 (3.5%) 5.14±6.67 0–20.83 p = 0.863
19 (3.9%) 3.77±3.81 0–12.82 p = 0.863
14 (3.9%) 6.60±10.53 0–33.33
complex
238 (48.6%) 39.20±27.38 0–65.52 p = 0.730
147 (40.6%) 51.26±23.26 27.71–100
periventricular
oWML
52 (14.4%) 10.67±7.37 0–18.31 51 (10.4%) 11.47±8.94 0–29.17 p = 0.863 lesion diameter
N/A 5.0±2.0mm 2.10–15.15mm N/A 5.8±2.7mm 2.00–23.66mm p < 0.001
adjacent to ventricles
103 (28.45%) 37.42±19.59 10.00–66.67 179 (36.53%) 30.86±22.31 0–58.62 p = 0.489 confluent
12 (3.3%) 3.50±5.17 0–11.76 19 (3.9%) 3.04±3.56 0–10.34 p = 1.000
11 (2.2%) 2.12±1.81 0–4.17 p = 0.605
7 (1.9%) 1.68±2.59 0–5.88
callosal
Key: p values are related to differences between PPMS and RRMS patients (Mann–Whitney U test); percentage is related to total lesion count. PPMS = primary progressive multiple sclerosis, RRMS = relapsing–remitting multiple sclerosis, TLC = total lesion count, WML = white matter lesions, oWML= other white matter lesions, GML = gray matter lesions, N/A = not applicable.
99 (20.2%) 21.13±23.52 0–74.07 p = 0.796
394 (80.4%) 68.87±28.34 0–88.89 p = 0.863
16 (4.4%) 3.71±3.32 0–10.00
97 (26.8%) 23.23±22.89 0–66.67
43 (11.9%) 8.25±8.53 0–22.89
PPMS No. (ratio of TLC) Mean+SD Range RRMS No. (ratio of TLC) Mean+SD Range
277 (76.5%) 78.90±12.23 63.38–100
type I
cortical GML
hypointense rim
central vein
35 (7.1%) 6.63±6.16 0–18.52 p = 0.436
136 (27.8%) 22.36±11.95 0–32.56 p = 0.222
282 (57.6%) 53.15±23.84 0–91.67 p = 0.730
490 (100%) 54.44±40.72 0–124 p = 0.387
14 (3.9%) 2.97±3.01 0–6.80
116 (32.0%) 31.60±18.30 0–66.67
No. (ratio of TLC) Mean+SD Range
194 (53.6%) 56.32±26.98 0–100.00
temporal
parietal
362 (100%) 40.22±38.42 2–103
frontal
PPMS No. (ratio of TLC) Mean+SD Range RRMS
TLC
Table 2. Lesion location, frequency, distribution, appearance, diameter, and ultrahigh field MRI characteristics of PPMS and RRMS patients at 7 T.
Multiple Sclerosis Journal
MS (Figure 1, Table 2).6–9 A strong hypointense rim on T2*w FLASH images was likewise detectable at the edge of a similar proportion of lesions in RRMS (n = 99, 21%) and PPMS (n = 97, 23%, p = 0.796, Figure 1). However, we observed a high inter-individual variability in hypointense signal alterations at the edges of MS lesions.
Gray matter damage Forty-three cortical GML were visualized in 6/9 (67%) PPMS patients and 29 cortical lesions were depicted in 5/9 (56%) RRMS patients (Table 2). Importantly, subpial lesions considered typical of MS were detectable in both, RRMS (n = 13) and PPMS (n = 22) patients. Further statistical testing revealed no significant group differences, neither in total cortical GML count (p = 0.436), nor in leukocortical (p = 0.436), intracortical (p = 0.796), and subpial lesion count (p = 0.436). Discussion In this ultrahigh field MRI study, we analyzed the frequency, morphology, and distribution of focal white and gray matter pathology in patients with PPMS versus RRMS without observing significant differences.
The finding that a central vein is often visible in PPMS and RRMS lesions is in line with previous ultrahigh field MRI studies and ex vivo histological reports,6,7,13 suggesting that perivascular inflammation plays a key role in both, RRMS and PPMS. In general, the perivascular localization and the expression of a hypointense rim at the edge of the lesion is considered typical of MS,6,9 and may thus serve as a biomarker to differentiate MS plaques from nonspecific WML,6,7 in addition to facilitating the distinction from NMO and Susac syndrome,8,9 diseases with overlapping clinical presentation but clearly distinct etiology.
An additional key point of this study was the detection of cortical pathology in MS that has proven to be superior at 7 T in comparison to GML detection at lower field strengths.11 In alignment with a previous study at 1.5 T,14 we found that cortical gray matter damage is equally common in PPMS and RRMS. Likewise, we did not observe any differences between RRMS and PPMS when exclusively looking at subpial cortical demyelination, which is considered specific of MS.15
One important limitation of this qualitative rather than quantitative study is the low sample size.
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J Kuchling, C Ramien, et al. Hence, this study was focused on lesion morphology. Findings on lesion count, size and distribution should be understood as exploratory in nature. Furthermore, due to technical limitations, this study was only focused on supratentorial brain damage. One should also note that our age-matched RRMS group is characterized by a more benign disease course, which could have influenced the outcome of this study. Nevertheless, given that subpial demyelination, the existence of a central vein within brain lesions and the expression of a hypointense rim are considered typical of MS and are equally detectable in both, PPMS and RRMS, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, share the same lesion morphology at ultrahigh field MRI. Acknowledgements We thank our technicians and study nurses Antje Els, Susan Pikol, Cynthia Kraut, and Gritt Stoffels for invaluable support. Conflict of interest JK, CR, and IB have nothing to disclose. JD receives research grants from Novartis and Bayer, has received travel support from Novartis and Merck-Serono, honoraria for consultancy from Bayer and Teva, and speaker honoraria from Bayer, Teva, Genzyme, and Novartis. LH has received speaker honoraria from Biogen Idec, Bayer, Novartis, and Merck-Serono. He serves on the advisory board for Biogen Idec, Genzyme, and Novartis and has received travel grants from Bayer, Merck-Serono, Teva, and Biogen Idec. BR has participated in meetings sponsored by Bayer Healthcare, Merck Serono, Biogen Idec, Novartis, Ovamed, and Teva Pharmaceuticals and has also received lecture and research fees from these companies. TN is founder of MRI.TOOLS GmbH, Berlin, Germany, and received speaker honoraria from Siemens Healthcare, Erlangen, Germany. FP has received speaker honoraria, travel grants, and research grants from Teva, Sanofi, Bayer, MerckSerono, Biogen Idec, and Novartis. FP is supported by the German Research Foundation (Exc 257) and has received travel reimbursement from the Guthy Jackson Charitable Foundation. He is supported by the German ministry for education and research (BMBF/KKNMS). TS received a travel grant from Bayer and Genzyme. JW serves for the Novartis advisory board, received a Novartis research grant, and speaker honoraria from Bayer. He is supported by the German ministry for education and research (BMBF/KKNMS).
Funding This work was supported by the German Research Foundation (DFG Exc 257).
References 1. Antel J, Antel S, Caramanos Z, et al. Primary progressive multiple sclerosis: part of the MS disease spectrum or separate disease entity? Acta Neuropathol (Berl) 2012; 123: 627–638. 2. Thompson AJ, Kermode AG, MacManus DG, et al. Patterns of disease activity in multiple sclerosis: clinical and magnetic resonance imaging study. BMJ 1990; 300: 631–634. 3. Thompson AJ, Kermode AG, Wicks D, et al. Major differences in the dynamics of primary and secondary progressive multiple sclerosis. Ann Neurol 1991; 29: 53–62. 4. Rocca MA, Absinta M and Filippi M. The role of advanced magnetic resonance imaging techniques in primary progressive MS. J Neurol 2011; 259: 611–621. 5. Stuve O and Paul F. Progressive multiple sclerosis: desperately seeking remedy. Lancet Neurol 2013; 13: 70181–70189. 6. Tallantyre EC, Dixon JE, Donaldson I, et al. Ultrahigh-field imaging distinguishes MS lesions from asymptomatic white matter lesions. Neurology 2011; 76: 534–539. 7. Mistry N, Dixon J, Tallantyre E, et al. Central veins in brain lesions visualized with high-field magnetic resonance imaging – a pathologically specific diagnostic biomarker for inflammatory demyelination in the brain. JAMA Neurol 2013; 70: 623–628 8. Sinnecker T, Dörr J, Pfueller CF, et al. Distinct lesion morphology at 7-T MRI differentiates neuromyelitis optica from multiple sclerosis. Neurology 2012; 79: 708–714. 9. Wuerfel J, Sinnecker T, Ringelstein EB, et al. Lesion morphology at 7 Tesla MRI differentiates Susac syndrome from multiple sclerosis. Mult Scler 2012; 18: 1592–1599. 10. Pitt D, Boster A, Pei W, et al. Imaging cortical lesions in multiple sclerosis with ultra-high-field magnetic resonance imaging. Arch Neurol 2010; 67: 812–818 11. Sinnecker T, Mittelstaedt P, Dörr J, et al. Multiple sclerosis lesions and irreversible brain tissue damage – a comparative ultrahigh-field strength magnetic resonance imaging study. Arch Neurol 2012; 69: 739–745. 12. Peterson JW, Bö L, Mörk S, et al. Transected neurites, apoptotic neurons, and reduced
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Multiple Sclerosis Journal inflammation in cortical multiple sclerosis lesions. Ann Neurol 2001; 50: 389–400. Visit SAGE journals online http://msj.sagepub.com
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1 3. Lassmann H. The pathologic substrate of magnetic resonance alterations in multiple sclerosis. Neuroimaging Clin N Am 2008; 18: 563–576.
14. Calabrese M, Rocca MA, Atzori M, et al. Cortical lesions in primary progressive multiple sclerosis: a 2-year longitudinal MR study. Neurology 2009; 72: 1330–1336. 15. Fischer MT, Wimmer I, Hoftberger R, et al. Diseasespecific molecular events in cortical multiple sclerosis lesions. Brain 2013; 136: 1799–1815.
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Published by: http://www.sagepublications.com
On behalf of: European Committee for Treatment and Research in Multiple Sclerosis
Americas Committee for Treatment and Research in Multiple Sclerosis
Pan-Asian Committee for Treatment and Research in Multiple Sclerosis
Latin American Committee on Treatment and Research of Multiple Sclerosis
Additional services and information for Multiple Sclerosis Journal can be found at: Email Alerts: http://msj.sagepub.com/cgi/alerts Subscriptions: http://msj.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Downloaded from msj.sagepub.com at OhioLink on November 14, 2014
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>> OnlineFirst Version of Record - Apr 29, 2014 What is This?
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531084
research-article2014
MSJ0010.1177/1352458514531084Multiple Sclerosis JournalJ Kuchling, C Ramien,
MULTIPLE SCLEROSIS MSJ JOURNAL
Research Paper
Identical lesion morphology in primary progressive and relapsing–remitting MS – an ultrahigh field MRI study
Multiple Sclerosis Journal 1–6 DOI: 10.1177/ 1352458514531084 © The Author(s), 2014. Reprints and permissions: http://www.sagepub.co.uk/ journalsPermissions.nav
Joseph Kuchling, Caren Ramien, Ivan Bozin, Jan Dörr, Lutz Harms, Berit Rosche, Thoralf Niendorf, Friedemann Paul, Tim Sinnecker* and Jens Wuerfel*
Abstract: Potential differences between primary progressive (PP) and relapsing–remitting (RR) multiple sclerosis (MS) have been controversially discussed. In this study, we compared lesion morphology and distribution in patients with PPMS and RRMS (nine in each group) using 7 T MRI. We found that gray and white matter lesions in PPMS and RRMS patients did not differ in their respective morphological characteristics (e.g. perivascular p = 0.863, hypointense rim p = 0.796, cortical lesion count p = 0.436). Although limited by a small sample size, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, exhibit identical lesion morphology under ultrahigh field MRI. Keywords: MRI, primary progressive multiple sclerosis, PPMS, relapsing–remitting multiple sclerosis, RRMS, ultrahigh field MRI, 7 T MRI Date received: 22 November 2013; revised: 16 March 2014; accepted: 17 March 2014
Introduction Primary progressive (PP) multiple sclerosis (MS) is often characterized by a more severe long-term disability, pronounced spinal cord damage, and only minor gender differences compared to relapsing–remitting (RR) MS.1 Previous studies suggest differences in magnetic resonance imaging (MRI) and histopathology between MS disease courses.1 In general, PPMS lesions seemed to be smaller,2 and blood–brain barrier breakdown was detectable with lower frequency.3 In addition, differences in magnetization transfer ratio, MR spectroscopy, and spinal cord diffusion tensor imaging have been described.4 Pathophysiological differences, between both MS subtypes,1 may explain the current lack of effective immunomodulatory or disease-modifying therapies in PPMS.5 Due to increased signal-to-noise ratio and susceptibility effects at 7 Tesla (T), ultrahigh field MRI often visualizes a small central vein and a hypointense rim at the edge of MS lesions,6–10 both of which can be used as novel markers to distinguish RRMS from neuromyelitis optica (NMO),8 Susac syndrome,9 and non-specific white matter lesions.6,7 Furthermore, the depiction of cortical lesions is a hallmark of ultrahigh field MRI.11
However, 7 T MRI data on PPMS are still scarce with only few cases being published so far suggesting no substantial differences in intra-lesional vein count between PPMS and RRMS patients.6,7 The aim of this study was to compare lesion count and morphology at 7 T MRI in PPMS and matching RRMS patients. Methods Study participants Nine PPMS patients and nine age- and gendermatched RRMS patients were investigated (Table 1). The study was approved by the local ethics committee. All participants gave written informed consent.
MRI data acquisition Images were acquired using a 7 T whole body MR system (Magnetom; Siemens, Erlangen, Germany), applying a 24-channel receive head RF coil (Nova Medical, Wilmington, MA, USA). The imaging protocol included a two-dimensional axial T2*w fast low angle shot (FLASH) (echo time [TE] 25 ms, repetition time
Correspondence to: Friedemann Paul NeuroCure Clinical Research Center, Charité Universitaetsmedizin Berlin, Charitéplatz 1, 10117 Berlin, Germany. [email protected] Joseph Kuchling Caren Ramien Ivan Bozin NeuroCure Clinical Research Center, Charité – Universitaetsmedizin Berlin, Germany Tim Sinnecker NeuroCure Clinical Research Center, Charité - Universitaetsmedizin Berlin, Germany/Asklepios Fachklinikum Teupitz, Germany Jan Dörr NeuroCure Clinical Research Center/Clinical and Experimental MS Research Center, Charité – Universitaetsmedizin Berlin, Berlin, Germany Lutz Harms Berit Rosche Clinical and Experimental MS Research Center/Charité – Universitaetsmedizin Berlin, Berlin, Germany Thoralf Niendorf Berlin Ultrahigh Field Facility (BUFF)/ Experimental and Clinical Research Center, Charité – Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin, Germany Friedemann Paul NeuroCure Clinical Research Center/Clinical and Experimental MS Research Center/Experimental and Clinical Research Center, Charité – Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin, Germany Jens Wuerfel NeuroCure Clinical Research Center/BUFF, Max Delbrueck Center for Molecular Medicine, Berlin, Germany/ Experimental and Clinical Research Center, Charité – Universitaetsmedizin Berlin and Max Delbrueck Center for Molecular Medicine, Berlin/ Institute of Neuroradiology, University Medicine Goettingen, Germany *equally contributing senior authors.
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Multiple Sclerosis Journal Table 1. Cohort description.
n Female Age (years)
n mean ± SD (range)
Time since diagnosis (months) Time since first symptoms (months) EDSS
mean ± SD (range) MWU mean ± SD (range) MWU median (range) MWU
PPMS
RRMS
9 3 46 ± 7 (35–55)
9 3 45 ± 5 (35–51)
57 ± 69 (2–201)
97 ± 67 (6–175) p = 0.19 117 ± 73 (23–187) p = 0.49 2.0 (1.5–4.5) p < 0.001
96 ± 68 (17–201) 5.5 (3.5–8.0)
PPMS = primary progressive multiple sclerosis. RRMS = relapsing–remitting multiple sclerosis. MWU = Mann–Whitney U test. EDSS = Expanded Disability Status Scale.
[TR] 1820 ms, acquisition time 12.11 minutes, spatial resolution 0.5 × 0.5 × 2 mm3; supratentorial brain coverage). Slightly modified sequence parameters were applied in three subjects due to technical limitations.
Image analysis Visual analysis was performed using OsiriX (OsiriX Foundation, Geneva, Switzerland, version 4.0) and its integrated region of interest (ROI) function. Images were analyzed by two experienced observers (JK, TS) blinded to clinical data in consensus reading. In general, a lesion was defined as a T2*w hyperintense signal alteration extending over at least 2 mm. Lesions (Figure 1) were characterized by their morphology (central vein, hypointense rim), appearance (ovoid, circular, trapezoid, complex-shaped, or confluent), and maximum diameter. In detail, veins that are both (i) continuously displayed within the lesion and (ii) passing through the inner third of the lesion were defined as ‘central’ veins. White matter lesions (WML) with a distance of less than 5 mm from the ventricles were defined periventricular, and periventricular lesions neighboring the ventricles were named ‘lesions adjacent to ventricles’. Lesions with a maximum distance to the cortex of 2 mm were considered subcortical, and lesions with direct contact with cortical gray matter were defined juxtacortical. Lesions within the corpus callosum were named callosal lesions. WML meeting none of the criteria above were defined as other WML. Cortical gray matter lesions (GML) were separated into leukocortical (type I), purely intracortical (type II), and subpial (type III) lesions.12
To determine intra-rater reliability, MRI data of 10 representative cases (7 MS patients and 3 healthy controls) were re-evaluated by TS and JK in consensus reading after two months. An additional evaluation of the same 10 representative cases was performed by an independent blinded rater (CR) to assess inter-rater reliability. Intra- and inter-rater reliability were calculated using intra-class-correlation (ICC) as a two-waymixed test for average measures. We observed a high ICC for lesion count (0.993), central vein count (0.975), hypointense rim count (0.854), and lesion size (0.964), indicating good intra-rater reliability. Interrater reliability indicated by ICC was equally sufficient (lesion count 0.968, central vein count 0.969, hypointense rim count 0.769, and lesion size 0.977).
Statistical analysis Differences were assessed using nonparametric Mann–Whitney U test (MWU). All statistics were calculated using IBM SPSS Statistics (version 20, IBM, Somers, NY, USA); p values < 0.05 were considered significant. Results Details on demographic and clinical data of the study participants are presented in Table 1. We observed no differences between PPMS (n = 362 lesions) and RRMS (n = 490 lesions) regarding lesion count, shape, location, or spatial distribution. However, lesion diameter was significantly higher in RRMS, as outlined in Table 2. The majority of both RRMS (n = 394, 69%) and PPMS lesions (n=277, 79%, p=0.863) was characterized by a central vein, commonly considered to be typical of
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RRMS lesions with a hypointense rim (i) and subpial (type III) gray matter lesion (j). Key: T = Tesla, PPMS = primary progressive multiple sclerosis, RRMS = relapsing-remitting multiple sclerosis, FLASH = fast low angle shot.
Figure 1. Comparison of PPMS and RRMS brain lesion appearance at 7 T. (a) Axial 7 T T2* weighted MR image of a PPMS patient exhibiting periventricular lesions and hypointense rims. (b, c) Typical shaped MS lesions of PPMS patients with a perivascular localization. (d) A PPMS lesion with a hypointense rim. (e) A subpial (type III) gray matter lesion in a representative PPMS patient. (f) Comparative axial 7 T T2* weighted FLASH image of an RRMS patient. (g, h) Lesions of RRMS patients exhibit a comparable perivascular localization.
J Kuchling, C Ramien, et al.
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13 (2.7%) 3.38±5.63 0–15.38 p = 0.436
29 (5.9%) 7.33±13.39 0–41.03 p = 0.436
3 (0.6%) 0.78±1.32 0–3.45 p = 0.796
5 (1.4%) 0.62±1.29 0–3.61
type II
35 (7.1%) 6.57±4.66 0–12.79 p = 0.730
30 (8.3%) 7.66±10.96 0–33.33
occipital
WML
311 (85.9%) 90.29±8.99 77.11–100 459 (93.7%) 81.38±33.17 0–100 p = 0.931 ovoid
300 (82.9%) 76.49±12.70 50.00–88.73 412 (84.0%) 73.54±28.29 0–92.59 p = 0.546
deep GML
8 (2.2%) 1.46±2.53 0–5.88 2 (0.4%) 0.18±0.54 0–1.61 p = 0.436 type III/IV
22 (6.1%) 3.92±5.18 0–14.46 13 (2.7%) 3.17±7.56 0–23.08 p = 0.436
juxtacortical
46 (12.7%) 15.66±15.62 0–50.00 94 (19.2%) 16.12±10.57 0–29.17 p = 0.605 trapezoid
20 (5.5%) 4.89±4.35 0–11.76 23 (4.7%) 3.40±3.44 0–10.31 p = 0.489
subcortical
59 (16.3%) 11.03±7.84 0–22.54 65 (13.3%) 12.40±7.77 0–25.00 p = 0.931 circular
16 (4.4%) 8.51±15.95 0–50.00 17 (3.5%) 5.14±6.67 0–20.83 p = 0.863
19 (3.9%) 3.77±3.81 0–12.82 p = 0.863
14 (3.9%) 6.60±10.53 0–33.33
complex
238 (48.6%) 39.20±27.38 0–65.52 p = 0.730
147 (40.6%) 51.26±23.26 27.71–100
periventricular
oWML
52 (14.4%) 10.67±7.37 0–18.31 51 (10.4%) 11.47±8.94 0–29.17 p = 0.863 lesion diameter
N/A 5.0±2.0mm 2.10–15.15mm N/A 5.8±2.7mm 2.00–23.66mm p < 0.001
adjacent to ventricles
103 (28.45%) 37.42±19.59 10.00–66.67 179 (36.53%) 30.86±22.31 0–58.62 p = 0.489 confluent
12 (3.3%) 3.50±5.17 0–11.76 19 (3.9%) 3.04±3.56 0–10.34 p = 1.000
11 (2.2%) 2.12±1.81 0–4.17 p = 0.605
7 (1.9%) 1.68±2.59 0–5.88
callosal
Key: p values are related to differences between PPMS and RRMS patients (Mann–Whitney U test); percentage is related to total lesion count. PPMS = primary progressive multiple sclerosis, RRMS = relapsing–remitting multiple sclerosis, TLC = total lesion count, WML = white matter lesions, oWML= other white matter lesions, GML = gray matter lesions, N/A = not applicable.
99 (20.2%) 21.13±23.52 0–74.07 p = 0.796
394 (80.4%) 68.87±28.34 0–88.89 p = 0.863
16 (4.4%) 3.71±3.32 0–10.00
97 (26.8%) 23.23±22.89 0–66.67
43 (11.9%) 8.25±8.53 0–22.89
PPMS No. (ratio of TLC) Mean+SD Range RRMS No. (ratio of TLC) Mean+SD Range
277 (76.5%) 78.90±12.23 63.38–100
type I
cortical GML
hypointense rim
central vein
35 (7.1%) 6.63±6.16 0–18.52 p = 0.436
136 (27.8%) 22.36±11.95 0–32.56 p = 0.222
282 (57.6%) 53.15±23.84 0–91.67 p = 0.730
490 (100%) 54.44±40.72 0–124 p = 0.387
14 (3.9%) 2.97±3.01 0–6.80
116 (32.0%) 31.60±18.30 0–66.67
No. (ratio of TLC) Mean+SD Range
194 (53.6%) 56.32±26.98 0–100.00
temporal
parietal
362 (100%) 40.22±38.42 2–103
frontal
PPMS No. (ratio of TLC) Mean+SD Range RRMS
TLC
Table 2. Lesion location, frequency, distribution, appearance, diameter, and ultrahigh field MRI characteristics of PPMS and RRMS patients at 7 T.
Multiple Sclerosis Journal
MS (Figure 1, Table 2).6–9 A strong hypointense rim on T2*w FLASH images was likewise detectable at the edge of a similar proportion of lesions in RRMS (n = 99, 21%) and PPMS (n = 97, 23%, p = 0.796, Figure 1). However, we observed a high inter-individual variability in hypointense signal alterations at the edges of MS lesions.
Gray matter damage Forty-three cortical GML were visualized in 6/9 (67%) PPMS patients and 29 cortical lesions were depicted in 5/9 (56%) RRMS patients (Table 2). Importantly, subpial lesions considered typical of MS were detectable in both, RRMS (n = 13) and PPMS (n = 22) patients. Further statistical testing revealed no significant group differences, neither in total cortical GML count (p = 0.436), nor in leukocortical (p = 0.436), intracortical (p = 0.796), and subpial lesion count (p = 0.436). Discussion In this ultrahigh field MRI study, we analyzed the frequency, morphology, and distribution of focal white and gray matter pathology in patients with PPMS versus RRMS without observing significant differences.
The finding that a central vein is often visible in PPMS and RRMS lesions is in line with previous ultrahigh field MRI studies and ex vivo histological reports,6,7,13 suggesting that perivascular inflammation plays a key role in both, RRMS and PPMS. In general, the perivascular localization and the expression of a hypointense rim at the edge of the lesion is considered typical of MS,6,9 and may thus serve as a biomarker to differentiate MS plaques from nonspecific WML,6,7 in addition to facilitating the distinction from NMO and Susac syndrome,8,9 diseases with overlapping clinical presentation but clearly distinct etiology.
An additional key point of this study was the detection of cortical pathology in MS that has proven to be superior at 7 T in comparison to GML detection at lower field strengths.11 In alignment with a previous study at 1.5 T,14 we found that cortical gray matter damage is equally common in PPMS and RRMS. Likewise, we did not observe any differences between RRMS and PPMS when exclusively looking at subpial cortical demyelination, which is considered specific of MS.15
One important limitation of this qualitative rather than quantitative study is the low sample size.
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J Kuchling, C Ramien, et al. Hence, this study was focused on lesion morphology. Findings on lesion count, size and distribution should be understood as exploratory in nature. Furthermore, due to technical limitations, this study was only focused on supratentorial brain damage. One should also note that our age-matched RRMS group is characterized by a more benign disease course, which could have influenced the outcome of this study. Nevertheless, given that subpial demyelination, the existence of a central vein within brain lesions and the expression of a hypointense rim are considered typical of MS and are equally detectable in both, PPMS and RRMS, our study results suggest that PPMS and RRMS, despite differences in disease course and clinical characteristics, share the same lesion morphology at ultrahigh field MRI. Acknowledgements We thank our technicians and study nurses Antje Els, Susan Pikol, Cynthia Kraut, and Gritt Stoffels for invaluable support. Conflict of interest JK, CR, and IB have nothing to disclose. JD receives research grants from Novartis and Bayer, has received travel support from Novartis and Merck-Serono, honoraria for consultancy from Bayer and Teva, and speaker honoraria from Bayer, Teva, Genzyme, and Novartis. LH has received speaker honoraria from Biogen Idec, Bayer, Novartis, and Merck-Serono. He serves on the advisory board for Biogen Idec, Genzyme, and Novartis and has received travel grants from Bayer, Merck-Serono, Teva, and Biogen Idec. BR has participated in meetings sponsored by Bayer Healthcare, Merck Serono, Biogen Idec, Novartis, Ovamed, and Teva Pharmaceuticals and has also received lecture and research fees from these companies. TN is founder of MRI.TOOLS GmbH, Berlin, Germany, and received speaker honoraria from Siemens Healthcare, Erlangen, Germany. FP has received speaker honoraria, travel grants, and research grants from Teva, Sanofi, Bayer, MerckSerono, Biogen Idec, and Novartis. FP is supported by the German Research Foundation (Exc 257) and has received travel reimbursement from the Guthy Jackson Charitable Foundation. He is supported by the German ministry for education and research (BMBF/KKNMS). TS received a travel grant from Bayer and Genzyme. JW serves for the Novartis advisory board, received a Novartis research grant, and speaker honoraria from Bayer. He is supported by the German ministry for education and research (BMBF/KKNMS).
Funding This work was supported by the German Research Foundation (DFG Exc 257).
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