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Introduction
MRI has been formally included in the diagnostic work-up of patients with a suspicion of multiple sclerosis (MS) in 2001, to demonstrate disease dissemination in space (DIS) and time (DIT) and to exclude alternative diagnoses.1 Over time, these criteria have been modified to simplify their use and to clarify specific aspects (eg, spinal cord findings).2
One aspect marginally analysed in the diagnostic work-up of patients with clinically isolated syndrome (CIS) is the role of intracortical lesions (ICLs), which are a prominent feature of MS and contribute to disability and cognitive impairment.2 A single-centre study3 showed that inclusion of ICL for the evaluation of DIS in CIS increased the accuracy of MRI diagnostic criteria, with an improvement of specificity.3
The aim of this study was to compare revised McDonald-20101 and Filippi-20103 criteria with respect to development of clinically definite MS (CDMS) in a multicentric cohort of patients with CIS.
Methods
Institutional review board approval and written informed consent were obtained.
Subjects
Consecutive patients with CIS suggestive of MS were prospectively recruited from 2008 to 2013 from five European centres within the MAGNIMS network (http://www.magnims.eu/) (see online supplementary file 1, Supplementary Methods).
Inclusion criteria were a typical CIS syndrome, exclusion of alternative diagnoses and previous events, a baseline brain (including double inversion recovery (DIR)) and spinal cord MRI scan acquired ≤3 months from CIS onset, a follow-up brain scan acquired ≤12 months from CIS onset and a clinical follow-up ≥3 years or until CDMS conversion (defined as occurrence of a second relapse ≥1 month after the first attack) if ≤3 years.
MRI acquisition and analysis
Using 1.5 (two centres) or 3.0 Tesla (three centres) scanners, brain (including DIR) and spinal cord sequences for lesion identification were acquired. Online supplementary material shows parameters and examples of MRI sequences acquired.
Main baseline demographic, clinical and MRI findings from the final sample of patients with CIS
All images were assessed by consensus of two experienced observers (PP and MAR, 9 and 20 years of experience) blinded to patients’ identity (see Supplementary Methods).
DIS and DIT criteria
On baseline MRI scans, DIS for revised McDonald-2010 criteria was defined by ≥1 subclinical lesion in ≥2 among juxtacortical (JC); periventricular, posterior fossa (PF); and spinal cord regions. According to Filippi-2010 criteria, DIS was defined by ≥2 of ≥1 ICL, ≥1 PF lesion, ≥1 spinal cord or ≥1 gadolinium (Gd)-enhancing lesion.
DIT was defined as the simultaneous presence of asymptomatic Gd-enhancing and non-enhancing lesions or a new T2/Gd-enhancing lesion on the follow-up MRI. The fulfilment of DIS+DIT for both criteria was also evaluated.
Statistical analysis
The performance of the MRI criteria was assessed using CDMS at 3 years as the outcome. The risk of development of CDMS was assessed using OR, adjusted for centre. Sensitivity, specificity, accuracy, positive and negative predictive values, and positive and negative likelihood ratios were calculated.
Comparisons between revised McDonald-2010 and Filippi-2010 criteria were performed using DeLong approach for correlated data.
Results
From 171 screened subjects, the final cohort included 86 patients with CIS, with a median follow-up of 46.1 months (range 2.2–78.7 months). Online supplementary file 1 (Supplementary Results) summarises the study flow chart. Table 1 reports baseline characteristics from the 86 patients with CIS patients who were analysed.
At follow-up, 57 (66.3%) patients with CIS developed CDMS (median time to conversion 10.3 months), 63 (73.3%) developed new lesions and 36 (41.9%) patients started a disease-modifying drug (34 of them developed CDMS).
Online supplementary file 1 summarises performances of the different MRI criteria in predicting CDMS conversion.
Both DIS from revised McDonald-2010 (OR 6.22, 95% CI 1.50 to 32.21, p=0.016) and Filippi-2010 (OR 5.67, 95% CI 1.81 to 19.39, p=0.004) criteria predicted CDMS conversion.
The sensitivity of DIS criteria was high (revised McDonald-2010, 0.91; Filippi-2010, 0.82). Filippi-2010 criteria gained in specificity (0.54) compared with revised McDonald-2010 (0.34) (p=0.18, McNemar’s exact test).
The accuracy to correctly classify patients with CIS according to CDMS conversion was high for both revised McDonald-2010 (0.72) and Filippi-2010 criteria (0.73).
In the direct comparison, no difference was found for area under the curve (AUC) from revised McDonald-2010 (AUC 0.63, 95% CI 0.53 to 0.72) versus Filippi-2010 (AUC 0.68, 95% CI 0.57 to 0.79) criteria (p=0.41).
For both criteria, DIS+DIT was associated with CDMS development (OR 5.14, 95% CI 1.73 to 16.37, p=0.004 for revised McDonald-2010 criteria; OR 5.14, 95% CI 1.77 to 16.24, p=0.003 for Filippi-2010 criteria). The sensitivity, specificity and accuracy for DIS+DIT were similar for the two sets of criteria. When considering DIS+DIT, no difference was found in the comparison between the two sets of criteria (AUC 0.70 for both, p=0.99).
Results did not change after removing the two patients without CDMS who started treatment during follow-up (data not shown).
Discussion
By evaluating a multicentric cohort of patients with CIS, we found that, compared with revised McDonald-2010, Filippi-2010 criteria, which include ICL assessment, had a better specificity, preserving accuracy and sensitivity, thus increasing our confidence for an early correct identification of those patients with CIS who will develop MS. Our results confirm those of a previous single-centre study,3 thus urging the inclusion of ICL assessment in the diagnostic work-up of patients with CIS since ICLs have been demonstrated in up to 40% of patients with CIS,3 but not in patients with other neurological conditions, including neuromyelitis optica and migraine.
ICL imaging is technically challenging, appropriate standardised sequence are lacking and training and expert guidelines for their assessment are need.4 Therefore, the recent MAGNIMS guidelines of MRI diagnostic criteria,5 which are currently being tested within the network, proposed to combine ICLs and JC lesions to increase their applicability in clinical practice.
Given the increased risk of misdiagnosis with an oversimplification of diagnostic criteria,1 features distinctive for MS compared with other diseases with similar characteristics should be considered. Based on current and previous findings,3 while the presence of ICLs supports a diagnosis of MS, their absence, particularly in patients with atypical clinical/neuroradiological findings, could be listed among possible imaging ‘red flags’ for an alternative diagnosis.
Further longitudinal studies with larger cohorts of patients including also MS mimickers are needed to confirm the relevance of ICLs in MS diagnosis, also considering that our cohort was recruited in highly specialised centres and that DIR sequences are not routinely acquired in all patients with CIS, thus possibly resulting in the selection of patients at higher risk to CDMS evolution.
Footnotes
Contributors PP: drafting/revising the manuscript and MRI data analysis. MAR: drafting/revising the manuscript, MRI data analysis and interpretation of the data. SM: patients’ recruitment. AM: drafting/revising the manuscript and statistical analysis. XM: patients’ recruitment and drafting/revising the manuscript. JD: patients’ recruitment. AD: patients’ recruitment. FZ: patients’ recruitment and revising the manuscript. MC: patients’ recruitment. JS-G: patients’ recruitment and drafting/revising the manuscript. ID-B: patients’ recruitment. AR: patients’ recruitment and drafting/revising the manuscript. MF: drafting/revising the manuscript, study concept and analysis and interpretation of the data. MF also acted as study supervisor. All the authors gave their approval to the current version of the manuscript.
Funding This study was partially supported by a grant from the Ministry of Science, Republic of Serbia (project number 175031).
Competing interests PP has received speakers honoraria from Biogen Idec, Novartis and ExceMED. MAR has received speakers honoraria from Biogen Idec, Novartis, Genzyme, Sanofi-Aventis, Teva and Merk Serono and receives research support from the Italian Ministry of Health and Fondazione Italiana Sclerosi Multipla. XM has received speaking honoraria and travel expenses for participation in scientific meetings, has been a steering committee member of clinical trials or participated in advisory boards of clinical trials in the past years with Actelion, Bayer, Biogen, Celgene, Genzyme, Merck, Novartis, Oryzon Genomics, Roche, Sanofi-Genzyme and Teva Pharmaceutical. FZ received funds for consultation or research/symposia from Novartis, Merck Serono, Teva, Ono, Octapharma, Biogen, Genzyme and Sanofi Aventis. MC received funds for consultation or research/symposia from Novartis, Merck Serono, Teva, Biogen, Genzyme and Sanofi Aventis. JS-G has received compensation in the last 12 months for participating on advisory boards, speaking, travel expenses for scientific meetings or research support from Genzyme, Novartis, Biogen, Excemed and Merck. AR serves on scientific advisory boards for Biogen Idec, Novartis, Sanofi-Genzyme, and OLEA Medical; has received speaker honoraria from ExceMED Bayer, Genzyme, Sanofi-Aventis, Bracco, Merck-Serono, Teva Pharmaceutical Industries Ltd, OLEA Medical, Stendhal, Novartis and Biogen Idec; and has research agreements with Siemens AG and Icometrix.MF is Editor-in-Chief of the Journal of Neurology; serves on a scientific advisory board for Teva Pharmaceutical Industries; has received compensation for consulting services and/or speaking activities from Biogen Idec, Merk-Serono, Novartis, and Teva Pharmaceutical Industries; and receives research support from Biogen Idec, Teva Pharmaceutical Industries, Novartis, Italian Ministry of Health, Fondazione Italiana Sclerosi Multipla (FISM), Cure PSP, Alzheimer’s Drug Discovery Foundation (ADDF), the Jacques and Gloria Gossweiler Foundation (Switzerland), and ARiSLA (Fondazione Italiana di Ricerca per la SLA).
Patient consent Obtained.
Ethics approval Each participating centre.
Provenance and peer review Not commissioned; externally peer reviewed.