751647 research-article2018 MSJ0010.1177/1352458517751647Multiple Sclerosis JournalMHJ Hagens, J Burggraaff MULTIPLE SCLEROSIS MSJ JOURNAL Original Research Paper Impact of 3 Tesla MRI on interobserver Multiple Sclerosis Journal 2019, Vol. 25(3) 352­–360 agreement in clinically isolated syndrome: A DOI: 10.1177/ https://doi.org/10.1177/1352458517751647 1352458518751647 https://doi.org/10.1177/1352458517751647 MAGNIMS multicentre study © The Author(s), 2018. Article reuse guidelines: Marloes HJ Hagens, Jessica Burggraaff, Iris D Kilsdonk, sagepub.com/journals- permissions Serena Ruggieri, Sara Collorone, Rosa Cortese, Niamh Cawley, Emilia Sbardella, Michaela Andelova, Michael Amann, Johanna M Lieb, Patrizia Pantano, Birgit I Lissenberg-Witte, Joep Killestein, Celia Oreja-Guevara, Jens Wuerfel, Olga Ciccarelli, Claudio Gasperini, Carsten Lukas, Alex Rovira, Frederik Barkhof and Mike P Wattjes; For the MAGNIMS Study Group Abstract Correspondence to: MHJ Hagens Background: Compared to 1.5 T, 3 T magnetic resonance imaging (MRI) increases signal-to-noise ratio Department of Neurology, leading to improved image quality. However, its clinical relevance in clinically isolated syndrome sug- MS Center Amsterdam, VU University Medical Center, gestive of multiple sclerosis remains uncertain. De Boelelaan 1117 (ZH 0A 65), 1081 HV Amsterdam, Objectives: The purpose of this study was to investigate how 3 T MRI affects the agreement between The Netherlands. raters on lesion detection and diagnosis. m.hagens1@vumc.nl Methods: We selected 30 patients and 10 healthy controls from our ongoing prospective multicentre Marloes Hendrika Johanna Hagens cohort. All subjects received baseline 1.5 and 3 T brain and spinal cord MRI. Patients also received Jessica Burggraaff Joep Killestein follow-up brain MRI at 3–6 months. Four experienced neuroradiologists and four less-experienced rat- Department of Neurology, ers scored the number of lesions per anatomical region and determined dissemination in space and time MS Center Amsterdam, VU University Medical Center, (McDonald 2010). Amsterdam, The Netherlands Results: In controls, the mean number of lesions per rater was 0.16 at 1.5 T and 0.38 at 3 T (p = 0.005). Iris D Kilsdonk Department of Radiology For patients, this was 4.18 and 4.40, respectively (p = 0.657). Inter-rater agreement on involvement per and Nuclear Medicine, anatomical region and dissemination in space and time was moderate to good for both field strengths. MS Center Amsterdam, VU University Medical 3 T slightly improved agreement between experienced raters, but slightly decreased agreement between Center, Amsterdam, The Netherlands/Department less-experienced raters. of Radiology and Nuclear Conclusion: Overall, the interobserver agreement was moderate to good. 3 T appears to improve the read- Medicine, Onze Lieve Vrouwen Gasthuis, ing for experienced readers, underlining the benefit of additional training. Amsterdam, The Netherlands Serena Ruggieri Department of Neurology and Psychiatry, Sapienza University of Rome, Keywords: Multiple sclerosis, clinically isolated syndrome, magnetic resonance imaging, interobserver Rome, Italy/Department of variation, multicentre study Neurosciences, San Camillo- Forlanini Hospital, Rome, Italy Date received: 3 July 2017; revised: 20 October 2017; accepted: 29 November 2017 Sara Collorone Department of Neurology and Psychiatry, Sapienza Introduction University of Rome, Rome, Italy/NMR Research Unit, Magnetic resonance imaging (MRI) plays a pivotal clinical decision making, such as initiation of dis- Queen Square Multiple role in the diagnosis and monitoring of multiple ease-modifying therapy in early stage of the dis- Sclerosis Centre, UCL Institute of Neurology, sclerosis (MS).1,2 After clinically isolated syndrome ease. Moreover, precise lesion detection is important London, UK (CIS), which is commonly the first manifestation of in identifying patients with an increased risk of Rosa Cortese NMR Research Unit, Queen MS, 56%–82% of patients with brain MRI abnor- long-term disability, mainly patients with a high Square Multiple Sclerosis malities will develop clinically definite MS within lesion load, gadolinium enhancing lesions and Centre, UCL Institute of Neurology, London, UK; the next 20 years.3,4 For patients with a normal brain infratentorial lesions.5–7 In addition, adequate moni- Department of Basic Medical MRI, this is much lower, approximately 20%.3,4 toring of CIS and MS patients requires an accurate Sciences, Neurosciences and Sense Organs, University of An early accurate diagnosis is highly relevant in detection of new lesions.1,2 Bari, Bari, Italy 352 journals.sagepub.com/home/msj MHJ Hagens, J Burggraaff et al. Niamh Cawley The current McDonald 2010 diagnostic criteria for MS Recruitment of subjects Olga Ciccarelli do not define MRI acquisition parameters such as mag- Patients with CIS suggestive of MS, as defined by NMR Research Unit, Queen Square Multiple Sclerosis netic field strength, spatial resolution and the selection the International Panel on MS diagnosis,8 were Centre, UCL Institute of of pulse sequences.8 Mainly due to the improved sig- recruited from the outpatient clinics of the six par- Neurology, London, UK nal-to noise ratio leading to an improvement of image ticipating centres between July 2013 and September Emilia Sbardella Department of Neurology quality, brain imaging at higher magnetic field strengths 2015. Patients were recruited within 6 months after and Psychiatry, Sapienza offers new possibilities with respect to the diagnosis the first clinical episode suggestive of demyelina- University of Rome, Rome, Italy and follow-up of neuroinflammatory disease.9–11 tion. All subjects were aged 18 to 59 years at base- Michaela Andelova Current expert panel guidelines recommend 3 T brain line. Exclusion criteria were a history of vascular, Department of Neurology, imaging,1,2 as the improved signal-to-noise ratio results malignant or other immunological disease and University Hospital Basel, Basel, Switzerland in an increased lesion detection in anatomical regions MRI-related contra-indications, such as claustro- Michael Amann relevant for dissemination in space (DIS), especially in phobia and a previous allergic reaction to a gadolin- Department of Neurology, the (juxta)cortical, periventricular and infratentorial ium-based contrast agent. University Hospital Basel, Basel, Switzerland/Medical region.12,13 However, the clinical relevance of high Image Analysis Center field strength MRI is uncertain. In particular, the ques- Thirty patients and ten healthy controls were selected (MIAC), Basel, Switzerland/ Division of Neuroradiology, tion remains, whether the use of 3 T leads to an earlier for this project. Subjects were randomly selected per Department of Radiology, diagnosis of MS. A previous prospective single-centre site, for the patients based on availability of com- University Hospital Basel, Basel, Switzerland and single-vendor study with 40 CIS patients demon- pleted follow-up visits. Johanna M Lieb strated an increased lesion detection on brain scans, but Division of Neuroradiology, Department of Radiology, as such this did not lead to an earlier diagnosis of MS University Hospital Basel, according to the McDonald 2005 and Swanton crite- Neurological examination Basel, Switzerland ria.14,15 Moreover, when retrospectively applying the At baseline, a medical history was taken and the Patrizia Pantano Department of Neurology 2010 revised McDonald criteria to this dataset, this out- Expanded Disability Status Scale (EDSS) was and Psychiatry, Sapienza come did not change.16 assessed by a trained physician. At follow-up visits, University of Rome, Rome, Italy/Istituto Neurologico possible new symptoms leading to diagnosis of clini- Mediterraneo, Neuromed, The purpose of this prospective multicentre, multi- cally definite MS were registered and the EDSS Pozzilli, Italy vendor and multi-rater study in patients presenting assessment was repeated. Birgit I Lissenberg-Witte Department of Epidemiology with a CIS was to evaluate the effect of 3 T MRI on and Biostatistics, VU interobserver agreement on lesions detection and sub- University Medical Centre, Amsterdam, The Netherlands sequently fulfilment of the criteria for DIS and dis- MRI acquisition Celia Oreja-Guevara semination in time (DIT). Additionally, we evaluated All patients received baseline MRI scans of the brain Department of Neurology, the effect of the raters’ experience on the interobserver and spinal cord at both 1.5 and 3 T separated by 24– Hospital Clínico San Carlos, Madrid, Spain agreement for both the lesion detection and the 72 hours (see Figure 1 for the illustration of the scan- Jens Wuerfel McDonald diagnostic criteria. ning protocol and study design). For both magnetic Medical Image Analysis Center (MIAC), Basel, field strengths, a multisequence scanner optimized Switzerland/NeuroCure, acquisition protocol was used (detailed information is Charité – Berlin University of Medicine, Berlin, Germany/ Materials and methods given in Supplementary Table 1). In summary, brain Department of Biomedical This study is part of a MAGNIMS (Magnetic imaging included isotropic three-dimensional (3D) Engineering, University Hospital Basel, Basel, Resonance Imaging in MS, http://www.magnims.eu) T1 and 3D fluid-attenuated inversion recovery Switzerland prospective multicentre, multi-vendor project con- (FLAIR), as well as axial 3 mm two-dimensional (2D) Claudio Gasperini ducted at the following MS Centres: VU University T2, proton density (PD) and post-contrast T1 spin- Department of Neurosciences, San Camillo- Medical Center Amsterdam, University Hospital of echo (SE) sequences. From the 3D sequences, 3 mm Forlanini Hospital, Rome, Basel, St. Josef Hospital Bochum, UCL Institute of axial reconstructions were made following the same Italy Neurology London, Hospital Clínico San Carlos repositioning compared to the 2D sequences. Spinal Carsten Lukas Department of Diagnostic Madrid and Sapienza University of Rome. cord imaging included post-contrast sagittal 3 mm T1 and Interventional Radiology SE and PD/T2. According to the MAGNIMS guide- and Nuclear Medicine, St. Josef Hospital, Ruhr At each centre, the study design was approved by the lines on MS diagnosis and monitoring, axial spinal University, Bochum, local institutional review board. Written informed cord imaging was not included due to the substantial Germany consent was obtained from all participants. increase in scan duration. Alex Rovira Department of Radiology, Hospital Universitari Vall For the CIS patients, two visits were used for this analy- In healthy controls, the same protocol was used d’Hebron, Barcelona, Spain Frederik Barkhof sis: the baseline visit and the first follow-up 3 to 6 months without the administration of intravenous contrast. Department of Radiology later (Figure 1). As at this interval, no change on MRI For the patients’ follow-up, the brain MRI protocol and Nuclear Medicine, MS Center Amsterdam, scans is to be expected for healthy controls; only base- was repeated without the administration of intrave- VU University Medical line visits were scheduled for the control group. nous contrast. Center, Amsterdam, The journals.sagepub.com/home/msj 353 Multiple Sclerosis Journal 25(3) Netherlands/Institutes of Neurology and Healthcare Engineering, UCL Institute of Neurology, London, UK Mike P Wattjes Department of Radiology and Nuclear Medicine, MS Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands Figure 1. Study protocol. DIR: double inversion recovery; EDSS: Expanded Disability Status Scale; FLAIR: fluid-attenuated inversion recovery; FU: follow-up; PD: proton density; SDMT: standard digit modalities test; SE: spin-echo; T: Tesla. categorized according to the anatomical region Imaging analysis (periventricular, juxtacortical, infratentorial and All scans were centrally collected and checked for spinal cord). In CIS patients but not in healthy con- completeness. The scans were rated independently trol subjects (no contrast administered), the number by eight raters during a central reading session: four of enhancing lesions per region was reported. experienced raters (C.L., neuroradiologist for 8 years; Subsequently, the presence of DIS and DIT accord- A.R., neuroradiologist for 26 years; M.P.W., neurora- ing to the McDonald 2010 criteria was determined. diologist for 9 years; F.B., neuroradiologist for For follow-up scans, new lesions per region were 19 years) and four MS researchers or radiology resi- scored and again fulfilment of the criteria for DIS dents considered as less-experienced raters (I.D.K., and DIT was determined. S.R., S.C., R.C.). For this central reading, the full scan protocol, as described in Figure 1, was availa- ble. For each subject, the 1.5 and 3 T scans were pre- sented separately with approximately a 20-hour time Statistical analysis interval. The order of presentation was randomized The difference in lesion detection between 1.5 and 3 T between sessions, but the same for all the eight raters. was tested using generalized estimating equations Localization of symptoms at onset was presented for (GEEs) with a logit link function and an exchangea- each patient, as per McDonald 2010 criteria sympto- ble correlation structure. Repeated measures for each matic brainstem or spinal cord lesions are excluded subject were defined as the scores of the different from demonstration of DIS.8 Besides location of observers. onset, the raters were blinded for clinical information such as age, gender and centre. Inter-rater agreement on number of lesions detected per region was calculated with Conger’s kappa. For all baseline scans, the number of inflammatory Agreement on involvement per anatomical region, lesions larger than 3 mm in size were scored and independent of the number of lesions scored in 354 journals.sagepub.com/home/msj MHJ Hagens, J Burggraaff et al. Table 1. Demographics of clinically isolated syndrome (median 3, IQR = 1–6) (p = 0.732), see Figure 2. patients and healthy controls. Only very few enhancing juxtacortical and Characteristics Patients Controls infratentorial lesions at baseline and new infraten- (n = 30) (n = 10) torial lesions at follow-up were identified leading to the exclusion of these regions at these time Age, mean ± SD (years) 34.5 ± 7.0 38.7 ± 9.3 points from further analyses. Gender, male/female (n) 11/19 2/8 EDSS, median and range 2.0 (0–6) The mean number of cases per rater diagnosed as MS Location presenting based on radiological criteria was at baseline 1.63 at symptoms (n): 1.5 T (median 2, IQR = 1–2) and 2.25 at 3 T (median 2, Optic nerve 12 IQR = 2–2), and at follow-up 4.63 at 1.5 T (median 5, Cerebral hemisphere 3 IQR = 3.25–5.75) and 6.38 at 3 T (median 6, IQR = 6– 6). Full statistical analysis will be presented based on Infratentorial 4 a consensus score after completion of our ongoing Spinal cord 11 cohort study. EDSS: Expanded Disability Status Scale; SD: standard deviation. Inter-rater agreement on lesion detection Inter-rater agreement on involvement per anatomical region for all the raters was moderate to good on both that region, was calculated with Cohen’s kappa. This 1.5 and 3 T, with kappa scores (κ) varying from 0.49 statistical analysis was also used to determine agree- to 0.84, see Figure 3. The agreement was highest for ment on the fulfilment of the criteria for DIS, DIT baseline infratentorial lesions (3 T: κ 0.84, 1.5 T: κ and MS. Values of 0.41 to 0.60 were considered as 0.76) and lowest for baseline juxtacortical lesions moderate agreement, 0.61 to 0.80 as substantial (3 T: κ 0.53, 1.5 T: κ 0.49). Agreement on presence of agreement and >0.81 as good agreement.17 spinal cord lesions was lower at 1.5 T compared to 3 T Calculations were performed using SPSS 22.0 (3 T: κ 0.76, 1.5 T: κ 0.66). Agreement on enhancing (Windows) and ‘R’ version 3.1.1. lesions was substantial for periventricular lesions (3 T: κ 0.70, 1.5 T: κ 0.80) and moderate for spinal cord lesions (3 T: κ 0.57, 1.5 T: κ 0.59). Overall, agree- Results ment on involvement of regions was higher at base- line compared to follow-up. Patient characteristics Detailed demographic information of the study sub- As can be expected, inter-rater agreement dropped for jects is given in Table 1. The mean age for patients the category ‘exact number of lesions scored per was 34.5 ± 7.0 years, 64% was female. The median region’, see Figure 3. Agreement on enhancing lesions EDSS at baseline was 2.0 (range 0–6). Most CIS was not affected, as there was no more than one patients presented with an optic neuritis (n = 12) or enhancing lesion in any anatomical region. spinal cord syndrome (n = 11). Patients were scanned with a median of 90 days (interquartile range When looking at the kappa scores for involvement per (IQR) = 29–123) after onset of the symptoms. anatomical region for the groups by experience, agreement on involvement per anatomical region was In healthy controls, the mean age was 38.7 ± 9.3 years, overall higher at 3 T for the experienced raters and 80% were female. overall higher at 1.5 T for the less-experienced raters, see Figure 4. Lesion detection and diagnosis In healthy controls, no spinal cord lesions were Inter-rater agreement on diagnosis scored. The mean total number of brain lesions In CIS patients, the inter-rater agreement for DIS, DIT scored per rater per subject was 0.38 at 3 T (median and diagnosis of MS at baseline was also moderate to 0, IQR = 0–0.8) and 0.16 at 1.5 T (median 0, good, with κ scores varying from 0.51 to 1.00, see IQR = 0–0) (p = 0.005). In the patient group, the Figure 5. The remarkable κ of 1.00 for DIT at 1.5 T at mean overall number of lesions at baseline was baseline for both experienced and less-experienced 4.40 at 3 T (median 3, IQR = 1–7) and 4.14 at 1.5 T raters is due to full agreement on non-symptomatic journals.sagepub.com/home/msj 355 Multiple Sclerosis Journal 25(3) Figure 2. 1.5 and 3 T MRI scans of two CIS patients. 1. 3DFLAIR brain scans of one CIS patient presenting with optic neuritis: (a) baseline scan on 3 T with no brain lesions, (b) follow-up scan on 3 T showing two new T2 lesions in the corpus callosum, (c) follow-up scan on 1.5 T on which only one of the new lesion can be identified. 2. Baseline (a) 3 and (b) 1.5 T 3DFLAIR brain scans of one CIS patient presenting with a spinal cord syndrome. All raters identified additional periventricular and juxtacortical lesions on 3 T MRI leading to dissemination in space, while only three experienced raters on 1.5 T. enhancing lesions, and therefore DIT, in two patients. field strength.8 However, recent MAGNIMS guide- At 3 T part of the raters identified a non-symptomatic lines recommend the use of 3 T brain MRI based on an enhancing lesion in another six patients, leading to a improved signal-to-noise ratio resulting in higher drop in inter-rater agreement on DIT and the diagnosis lesion detection.1,2 Nonetheless, to date the extent of of MS at 3 T. and the clinical relevance of a higher detection rate using higher magnetic field strength with respect to At follow-up, 3 T slightly improved the inter-rater diagnostic and prognostic purposes remains unclear. agreement for the experienced raters on DIS, DIT and This multicentre, multi-vendor and multi-rater study MS, while the agreement between less-experienced provides important information on the lesion detection raters slightly decreased on all criteria. Overall, the rates and interobserver variation with respect to MS inter-rater agreement on the diagnosis of MS at follow- lesion detection for diagnostic purposes in patients pre- up was substantial (κ 0.61–0.80) at both field strengths senting with CIS suggestive of MS. Overall, inter-rater agreement on involvement per anatomical region was moderate to good, which was not substantially influ- Discussion enced by field strength. With respect to the lesion loca- The McDonald criteria for the diagnosis of MS do not tion, the agreement was the lowest for juxtacortical define important MRI acquisition parameters such as lesions at baseline. When comparing this to the 356 journals.sagepub.com/home/msj MHJ Hagens, J Burggraaff et al. Figure 3. Agreement on lesions per anatomical region per field strength. Agreement between the eight raters on the involvement of an anatomical region, calculated with Cohen’s kappa scores, and on the exact number of lesions per anatomical regions, calculated with weighted Conger’s kappa scores. The horizontal lines indicate the cut-off values of 0.41 for moderate agreement, 0.61 for substantial agreement and 0.81 for good agreement. BL: baseline; E: enhancement; FU: follow-up; IT: infratentorial; JC: juxtacortical; PV: periventricular; SC: spinal cord. In contrast to a previous single-centre and single- vendor study,15 we used 3D brain imaging with 3-mm-thick axial reconstructions on both field strengths. Moreover, we also studied spinal cord imaging at both field strengths. Previous studies have shown that the identification of a spinal cord lesion does not only facilitate the fulfilment of the MRI criteria for diagnosis of MS, but is also predic- tive for conversion to clinically definite MS in CIS patients.18,19 However, spinal cord MRI is challeng- ing – especially at 3 T – due to various possible arte- facts due to patient motion, swallowing, respiration and pulsation of the cerebrospinal fluid and blood vessels.20 In addition, it has not conclusively been Figure 4. Effect of experience on agreement on demonstrated that 3 T leads to higher lesion detec- involvement per anatomical region per field strength. Calculated by subtracting Cohen’s kappa for 3 T by tion levels compared to lower field strength.21 Cohen’s kappa for 1.5 T. Contrary to this, agreement on spinal cord lesions BL: baseline; E: enhancement; FU: follow-up; IT: infratentorial; was highest at 3 T for both the experienced and less- JC: Juxtacortical; PV: periventricular; SC: spinal cord; T: Tesla. experienced raters. When demonstrating the effect of the experience of agreement on the exact number of lesions per region, the raters on the variability of lesion detection, the largest decrease in agreement was understandably overall the inter-rater agreement for the less-experi- in the periventricular region, as this is the region where enced raters is higher for the 1.5 T scans, while the most lesions were identified. more experienced raters agree more at 3 T. This journals.sagepub.com/home/msj 357 Multiple Sclerosis Journal 25(3) Figure 5. Agreement on the diagnosis per field strength dependent on experience of the raters. Calculated using Cohen’s kappa scores. The horizontal lines indicate the cut-off values 0.41 for moderate agreement, 0.61 for substantial agreement and 0.81 for good agreement. DIS: dissemination in space; DIT: dissemination in time; MS: diagnosis of multiple sclerosis. could be explained by an effect of training. Most As a future perspective, the introduction of ultra- probably, a correct interpretation of high field high-field MRI creates new possibilities and chal- strength MRI requires more experience as smaller lenges. Given the strong effect of tissue relaxation details become visible, including more incidental times, in particular on clinically recommended lesions in healthy controls. sequences (such as FLAIR, conventional T2 and optionally double inversion recovery), and the dif- ferent appearances of cortical grey matter and white Even though all eight raters were well familiar with matter structures, the reading of 7 T images in the the McDonald 2010 criteria, applying these criteria context of MS is likely to be even more challeng- consistently to all the scans appeared to be more ing.26–32 7 T is now exclusively used in research and challenging than anticipated. A good working its future role in clinical practice remains uncertain. knowledge of these complex criteria was not with- Possibly, the effect of training will be even stronger out doubt even for the experienced neuroradiolo- for ultra-high-field MRI. gists. The difficulty of applying the diagnostic criteria for MS has previously also been demon- In conclusion, this study demonstrates a moderate to strated when using the McDonald 2001 criteria.22 good interobserver agreement on lesion detection, For the 2010 revision of the diagnostic criteria, DIS and DIT, which was not substantially influenced most questions arose on how to exclude the sympto- by field strength. Furthermore, interobserver agree- matic brainstem and spinal cord lesions in the crite- ment at 3 T was lower for less-experienced raters ria for DIS. In the current criteria, symptomatic compared to experienced raters, indicating correct lesions localized in the brainstem or spinal cord are interpretation of high field strength MRI may require to be excluded from lesion count. However, it is more training. unclear as to whether only the one symptomatic lesion or all the lesions in the symptomatic area should be excluded when scoring DIS. Moreover, Acknowledgements it can be quite difficult, if not impossible, to MAGNIMS steering committee members: F Barkhof identify the particular lesion causing the clinical (MS Centre Amsterdam, VU University Medical symptoms. These doubts ask for a simplification of Centre, Amsterdam, The Netherlands and Institutes of the McDonald 2010 criteria, as recently proposed Neurology and Healthcare Engineering, UCL Institute by the MAGNIMS study group.23 This is supported of Neurology, London, UK), O Ciccarelli and T by recent studies indicating that including the symp- Yousry (Queen Square Multiple Sclerosis Centre, tomatic lesion in the criteria for DIS, does not lead UCL Institute of Neurology, London, UK), N De to a decrease in specificity and even increases the Stefano (University of Siena, Siena, Italy), C Enzinger sensitivity of these diagnostic criteria.24,25 (Department of Neurology, Medical University of 358 journals.sagepub.com/home/msj MHJ Hagens, J Burggraaff et al. Graz, Graz, Austria), M Filippi and M A Rocca (San Multiple Sclerosis Journal and Radiology and serves Raffaele Scientific Institute, Vita-Salute San Raffaele as a consultant for Bayer Schering Pharma, Sanofi- University, Milan, Italy), J L Frederiksen (Glostrup Aventis, Genzyme, Biogen, Teva, Novartis, Roche, Hospital and University of Copenhagen, Copenhagen, Synthon BV and Jansen Research. M.P.W. serves on Denmark), C Gasperini (San Camillo-Forlanini the editorial boards of Neuroradiology, Journal of Hospital, Rome, Italy), L Kappos (University of Neuroimaging, European Radiology, Frontiers of Basel, Basel, Switzerland), J Palace (University of Neurology and serves as a consultant for Roche, Oxford Hospitals Trust, Oxford, UK), A Rovira and J Novartis and Biogen. Sastre-Garriga (Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, Barcelona, Funding Spain), H Vrenken (MS Centre Amsterdam, VU The author(s) disclosed receipt of the following finan- Medical Centre, Amsterdam, The Netherlands). cial support for the research, authorship and/or publi- cation of this article: This research has been supported Declaration of Conflicting Interests by a programme grant (14-358e) from the Dutch MS The author(s) declared the following potential con- Research Foundation (Voorschoten, The Netherlands). flicts of interest with respect to the research, author- The study in London was supported by the National ship and/or publication of this article: M.H.J.H., Institute for Health Research University College J.B., I.D.K., S.R., R.C., N.C., E.S., M.An., M.Am., London Hospitals Biomedical Research Centre. J.M.L. and B.I.L-W. have nothing to disclose. S.C. received meeting compensations from Novartis. P.P. has received founding for travel from Novartis, Genzyme and Bracco and speaker honoraria from References Biogen. J.K. has accepted speaker and consultancy 1. Wattjes MP, Rovira A, Miller D, et al. Evidence- fees from Merck-Serono, Teva, Biogen, Genzyme, based guidelines: MAGNIMS consensus guidelines Roche and Novartis. C.O-G received honoraria as on the use of MRI in multiple sclerosis – Establishing speaker from Biogen Idec, Bayer Schering, Merck- disease prognosis and monitoring patients. Nat Rev Neurol 2015; 11: 597–606. Serono, Teva, Genzyme and Novartis. J.W. is CEO of MIAC AG, has received research grants from the 2. Rovira A, Wattjes MP, Tintore M, et al. Evidence- German Ministries of Science and Economy, the based guidelines: MAGNIMS consensus guidelines European Union and from Novartis. He received on the use of MRI in multiple sclerosis-clinical speaker honoraria from Bayer, Biogen, Genzyme implementation in the diagnostic process. Nat Rev Sanofi, Novartis and Teva, and he served for advi- Neurol 2015; 11: 471–482. sory boards for Novartis, Biogen, Genzyme and 3. Beck RW, Trobe JD, Moke PS, et al. High- and low- Roche. O.C. is an Associate Editor of Neurology, risk profiles for the development of multiple sclerosis and she serves as consultant for Novartis, Roche, within 10 years after optic neuritis: Experience of the Genzyme and Teva, and payments are made to the optic neuritis treatment trial. Arch Ophthalmol 2003; institution. C.G. received fees as speaker for 121: 944–949. Bayer Schering Pharma, Sanofi-Aventis, Genzyme, 4. Fisniku LK, Brex PA, Altmann DR, et al. Disability Biogen, Teva, Novartis and Merck-Serono and and T2 MRI lesions: A 20-year follow-up of patients received a grant for research by Teva. C.L. holds an with relapse onset of multiple sclerosis. Brain 2008; endowed professorship supported by the Novartis 131: 808–817. foundation, has received consulting and speaker’s 5. Minneboo A, Barkhof F, Polman CH, et al. honoraria from Biogen Idec, Bayer Schering, Infratentorial lesions predict long-term disability in Novartis, Sanofi, Genzyme and TEVA and has patients with initial findings suggestive of multiple received research scientific grant support from sclerosis. Arch Neurol 2004; 61: 217–221. Merck-Serono and Novartis. A.R. serves on scien- tific advisory boards for Biogen Idec, Novartis, 6. Tintore M, Rovira A, Rio J, et al. Defining high, medium and low impact prognostic factors for Genzyme and OLEA Medical, and on the editorial developing multiple sclerosis. Brain 2015; 138: board of the American Journal of Neuroradiology 1863–1874. and Neuroradiology, has received speaker honoraria from Bayer, Genzyme, Sanofi-Aventis, Bracco, 7. Tintore M, Rovira A, Arrambide G, et al. Brainstem Merck-Serono, Teva Pharmaceutical Industries Ltd, lesions in clinically isolated syndromes. Neurology Stendhal, Novartis and Biogen Idec and has research 2010; 75: 1933–1938. agreements with Siemens AG. F.B. serves on the 8. Polman CH, Reingold SC, Banwell B, et al. editorial boards of Brain, Neurology, Neuroradiology, Diagnostic criteria for multiple sclerosis: 2010 journals.sagepub.com/home/msj 359 Multiple Sclerosis Journal 25(3) revisions to the McDonald criteria. Ann Neurol 2011; 21. Stankiewicz JM, Neema M, Alsop DC, et al. Spinal 69: 292–302. cord lesions and clinical status in multiple sclerosis: A 1.5 T and 3 T MRI study. J Neurol Sci 2009; 279: 9. Wattjes MP and Barkhof F. High field MRI in the 99–105. diagnosis of multiple sclerosis: High field-high yield? Neuroradiology 2009; 51: 279–292. 22. Korteweg T, Uitdehaag BM, Knol DL, et al. Interobserver agreement on the radiological criteria 10. Kilsdonk ID, de Graaf WL, Barkhof F, et al. of the International Panel on the diagnosis of multiple Inflammation high-field magnetic resonance imaging. sclerosis. Eur Radiol 2007; 17: 67–71. Neuroimaging Clin N Am 2012; 22: 135–157, ix. 23. Filippi M, Rocca MA, Ciccarelli O, et al. MRI criteria 11. Filippi M, Evangelou N, Kangarlu A, et al. Ultra- for the diagnosis of multiple sclerosis: MAGNIMS high-field MR imaging in multiple sclerosis. J Neurol consensus guidelines. Lancet Neurol 2016; 15: Neurosurg Psychiatry 2014; 85: 60–66. 292–303. 12. Wattjes MP, Lutterbey GG, Harzheim M, et al. 24. Brownlee WJ, Swanton JK, Miszkiel KA, et al. Higher sensitivity in the detection of inflammatory Should the symptomatic region be included in brain lesions in patients with clinically isolated dissemination in space in MRI criteria for MS? syndromes suggestive of multiple sclerosis using high Neurology 2016; 87: 680–683. field MRI: An intraindividual comparison of 1.5 T with 3.0 T. Eur Radiol 2006; 16: 2067–2073. 25. Tintore M, Otero-Romero S, Rio J, et al. Contribution of the symptomatic lesion in establishing MS 13. Simon B, Schmidt S, Lukas C, et al. Improved in vivo diagnosis and prognosis. Neurology 2016; 87: detection of cortical lesions in multiple sclerosis using 1368–1374. double inversion recovery MR imaging at 3 Tesla. Eur Radiol 2010; 20: 1675–1683. 26. De Graaf WL, Kilsdonk ID, Lopez-Soriano A, et al. Clinical application of multi-contrast 7-T 14. Wattjes MP, Harzheim M, Kuhl CK, et al. Does MR imaging in multiple sclerosis: Increased lesion high-field MR imaging have an influence on the detection compared to 3 T confined to grey matter. classification of patients with clinically isolated Eur Radiol 2013; 23: 528–540. syndromes according to current diagnostic MR imaging criteria for multiple sclerosis? AJNR Am J 27. De Graaf WL, Zwanenburg JJ, Visser F, et al. Lesion Neuroradiol 2006; 27: 1794–1798. detection at seven Tesla in multiple sclerosis using magnetisation prepared 3D-FLAIR and 3D-DIR. Eur 15. Wattjes MP, Harzheim M, Lutterbey GG, et al. Does Radiol 2012; 22: 221–231. high field MRI allow an earlier diagnosis of multiple sclerosis? J Neurol 2008; 255: 1159–1163. 28. Kilsdonk ID, Jonkman LE, Klaver R, et al. Increased cortical grey matter lesion detection in multiple 16. Kilsdonk ID, Barkhof F and Wattjes MP. 2010 sclerosis with 7 T MRI: A post-mortem verification revisions to McDonald criteria for diagnosis of study. Brain 2016; 139: 1472–1481. multiple sclerosis: Impact of 3-Tesla magnetic resonance imaging. Ann Neurol 2011; 70: 182–183. 29. Mistry N, Tallantyre EC, Dixon JE, et al. Focal multiple sclerosis lesions abound in ‘normal 17. Landis JR and Koch GG. The measurement of appearing white matter’. Mult Scler 2011; 17: observer agreement for categorical data. Biometrics 1313–1323. 1977; 33: 159–174. 30. Tallantyre EC, Dixon JE, Donaldson I, et al. Ultra- 18. Sombekke MH, Wattjes MP, Balk LJ, et al. Spinal high-field imaging distinguishes MS lesions from cord lesions in patients with clinically isolated asymptomatic white matter lesions. Neurology 2011; syndrome: A powerful tool in diagnosis and 76: 534–539. prognosis. Neurology 2013; 80: 69–75. 31. Kilsdonk ID, Wattjes MP, Lopez-Soriano A, et al. 19. Bot JC, Barkhof F, Polman CH, et al. Spinal cord Improved differentiation between MS and vascular abnormalities in recently diagnosed MS patients: brain lesions using FLAIR* at 7 Tesla. Eur Radiol Added value of spinal MRI examination. Neurology 2014; 24: 841–849. 2004; 62: 226–233. Visit SAGE journals online 32. Sinnecker T, Kuchling J, Dusek P, et al. Ultrahigh journals.sagepub.com/ 20. Bot JC and Barkhof F. Spinal-cord MRI in multiple field MRI in clinical neuroimmunology: A potential home/msj sclerosis: Conventional and nonconventional MR contribution to improved diagnostics and personalised SAGE journals techniques. Neuroimaging Clin N Am 2009; 19: 81–99. disease management. EPMA J 2015; 6: 16. 360 journals.sagepub.com/home/msj