Multiplehttp://msj.sagepub.com/ Sclerosis Journal
Diagnostic value of brain chronic black holes on T1-weighted MR images in clinically isolated syndromes Raquel Mitjana, Mar Tintoré, Maria A Rocca, Cristina Auger, Frederik Barkhof, Massimo Filippi, Chris Polman, Franz Fazekas, Elena Huerga, Xavier Montalban and Àlex Rovira Mult Scler published online 27 February 2014 DOI: 10.1177/1352458514526083 The online version of this article can be found at: http://msj.sagepub.com/content/early/2014/02/27/1352458514526083
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
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526083 research-article2014
MSJ0010.1177/1352458514526083Multiple Sclerosis JournalMitjana et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Research Paper
Diagnostic value of brain chronic black holes on T1-weighted MR images in clinically isolated syndromes
Multiple Sclerosis Journal 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458514526083 msj.sagepub.com
Raquel Mitjana1, Mar Tintoré1, Maria A Rocca2, Cristina Auger1, Frederik Barkhof 3, Massimo Filippi2, Chris Polman3, Franz Fazekas4, Elena Huerga1, Xavier Montalban1 and Àlex Rovira1
Abstract Background: Non-enhancing black holes (neBHs) are more common in multiple sclerosis (MS) patients with longer disease durations and progressive disease subtypes. Objective: Our aim was to analyse the added value of neBHs in patients with clinically isolated syndromes (CISs) for predicting conversion to clinically definite MS (CDMS). Methods: Patients were classified based on the presence or absence of neBHs and on the number of Barkhof–Tintoré (B-T) criteria fulfilled. Dissemination in space (DIS) was defined as the presence of at least three of the four B-T criteria. Dissemination in time (DIT)1 was defined by simultaneous presence of enhancing and non-enhancing lesions. DIT2 was defined by simultaneous presence of neBHs and T2 lesions not apparent on T1-weighted images. Results: Focal T2-hyperintense brain lesions were identified in 87.7% of the 520 CIS patients, and 41.4% of them presented at least one neBH. Patients meeting DIS, DIT1, and DIT2 had a significantly higher rate of conversion to CDMS. After adjusting for DIS, only patients who fulfilled DIT1 preserved a significant increase in CDMS conversion. Conclusions: Non-enhancing black holes in CIS patients are associated with a higher risk of conversion to CDMS. However, the predictive value of this finding is lost when added to the DIS criteria. Keywords Clinically isolated syndrome, magnetic resonance imaging, diagnosis Date received: 12 November 2013; revised: 3 February 2014; accepted: 7 February 2014
Introduction According to the McDonald criteria, a diagnosis of multiple sclerosis (MS) in patients who present for the first time with a clinically isolated syndrome (CIS) can be established using brain magnetic resonance imaging (MRI) if this examination demonstrates demyelinating lesions disseminated in space (DIS) and time (DIT).1,2 To demonstrate DIS, brain MRI must fulfil the classic Barkhof–Tintoré (B-T) criteria3,4 (2005 McDonald criteria) or the Swanton criteria (MAGNIMS criteria) included in the recently proposed 2010 version of the McDonald criteria.5,6 As recent data from a collaborative MAGNIMS study have suggested,7 the 2010 version of the McDonald criteria establishes that a single brain MRI scan may suffice to demonstrate DIT, even when it is performed at any time following the onset of symptoms. This suggestion is based on the concept that simultaneous presence of
asymptomatic gadolinium-enhancing and non-enhancing lesions is sufficient to demonstrate DIT because these findings indicate that the lesions are in different stages of 1MR
Unit (IDI), Department of Radiology, and Department of Neurology-Neuroimmunology, CEM-CAT, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain. 2Neuroimaging Research Unit, Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. 3Department Neurology, VU University Medical Centre, Amsterdam, The Netherlands. 4Department of Neurology, Medical University of Graz, Austria. Corresponding author: Àlex Rovira, MR Unit, Department of Radiology, Hospital Vall d’Hebron, Passeig Vall d’Hebron 119-129, Barcelona, 08035, Spain. Email: [email protected]
Downloaded from msj.sagepub.com at UNIV OF TENNESSEE on September 15, 2014
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Multiple Sclerosis Journal
evolution and therefore evolved at different times. Some studies have also shown that non-enhancing black holes (neBHs) correlate pathologically with more severe demyelination and axonal loss, indicating areas of irreversible tissue damage.8 These lesions have been associated with brain atrophy, and disability, in patients with MS,8 but there are no data regarding their prevalence in patients with CIS, or their diagnostic value for predicting early conversion to clinically definite MS (CDMS). Although not all enhancing lesions evolve uniformly into either neBH or isointense lesions on T1-weighted sequences,9 their formation is more common in patients with longer disease durations and progressive disease subtypes. For that reason their presence in patients with CIS could indicate a more advanced disease course and be considered as an alternative criteria for demonstrating DIT. Therefore, the purpose of this study is to determine the prevalence of neBHs in a large population of patients with CIS, and to analyse their added value for predicting conversion to CDMS as an alternative criterion for demonstrating DIT.
Patients and methods Within a European multicentre collaborative research network dedicated to MRI research in MS (MAGnetic Resonance Imaging in MS [MAGNIMS] http://www.magnims.eu/), brain MRI results and clinical data were retrospectively collected from four European centres, in which these data had been prospectively obtained from CIS patients following local standards. Each centre was asked to identify patients who met the following inclusion criteria: 1) CIS suggestive of central nervous system demyelination involving the optic nerve, brainstem, spinal cord, or other topography, not attributable to other diseases; 2) age 16–50 years; 3) clinical assessment within 3 months of CIS onset; 4) brain MRI obtained within 6 months of first attack; and 5) clinical follow-up of at least 24 months after CIS onset or until development of CDMS,10 if this occurred within the first 2 years.
Clinical data Each centre provided the following clinical information: age at CIS onset, gender, topography and date of CIS (and second event if applicable), and dates of brain MRI scans and last follow-up visit. The diagnosis of CDMS was established by an experienced neurologist at each centre, based on clinical information alone, according to the Poser criteria10 (i.e. symptomatic and objective evidence of a second neurological episode attributable to demyelination of >24 h duration, >4 weeks after the initial attack). Alternative diagnoses were ruled out by appropriate tests according to the local protocols.
Ethics approval for the CIS studies at each centre was obtained from the local institutional review boards. As the present study was based on retrospective analysis of existing data, no additional approval was required.
Brain MRI data All MRI scans were performed on 1.5-T systems and included transverse T2-weighted dual-echo sequences and contrast-enhanced transverse T1-weighted sequences covering the whole brain, with slice thickness of 3–5 mm. MRI scans were assessed by an experienced neuroradiologist blinded to the clinical data, who determined the number and topography (periventricular, subcortical, juxtacortical, or infratentorial) of high-intensity lesions suggestive of demyelinating plaques on T2-weighted images. DIS was defined according to the 2005 McDonald diagnostic criteria as the presence of at least three of the four B-T criteria (at least three of the following four features: 1) one gadolinium-enhancing lesion or nine T2 hyperintense lesions if gadolinium-enhancing lesions are not present, 2) at least one infratentorial lesion, 3) at least one juxtacortical lesion and 4) at least three periventricular lesions). DIT1 was defined as the presence of simultaneous enhancing and non-enhancing lesions on post-contrast T1-weighted scans. The number of neBHs was determined on contrastenhanced T1-weighted images. NeBH was defined as an area of unequivocal low signal intensity compared with normal-appearing white matter that did not show contrast uptake and was concordant with a hyperintense lesion seen on T2-weighted imaging.11 DIT2 was defined as the simultaneous presence of neBH and and T2 lesion not apparent (isointense) on contrast-enhanced T1-weighted images. DIT2 was analysed in two ways: a) in the overall cohort of patients (DIT2) and b) in the subgroup of patients without gadoliniumenhancing lesions (DIT2a). This was done to investigate the possible added value of neBH as an alternative marker of DIT in patients who do not meet the classic DIT criterion (simultaneous presence of enhancing and nonenhancing lesions). A 12-month follow-up MRI scan was available in a subset of patients from a single centre (n=214, 41.1%). Persistent neBH was defined as persistence of neBHs seen in the first MRI scan on this follow-up scan. All MRI assessments were performed by a single rater blinded to clinical data.
Statistical analysis All data were entered in a database by a single person and checked for accuracy and consistency by confirmation of the validity of all entries.
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3
Mitjana et al. Table 1. Demographic data and clinical characteristics of the cohort.
Table 2. Presence of non-enhancing black holes and number of Barkhof–Tintoré criteria fulfilled.
Characteristics
Number (%) of patients N=520
Number of patients
Number (%) of patients with neBHs
Age at onset, mean, y Male/female, n Patients from each centre Milan (Italy) Barcelona (Spain) Amsterdam (The Netherlands) Graz (Austria) Patients with each presenting clinical syndrome Optic neuritis Brainstem syndrome Spinal cord syndrome Other
31 161/359
Number of Barkhof–Tintoré criteria fulfilled 0 1 2 3 4 0–2 3–4 Any
117 59 58 104 182 234 286 520
3 (2.6) 11 (18.6) 17 (29.3) 41 (39.4) 117 (64.3) 31 (13.2) 158 (55.2) 189 (36.3)
234 (41.2) 214 (45.0) 63 (12.1) 9 (1.7) 173 (33.3) 153 (29.4) 138 (26.5) 56 (10.8)
Descriptive results are expressed as the mean or quartiles, and as the minimum and maximum for continuous variables (age and times) and percentages for categorical data. Kaplan–Meier analysis was used to estimate cumulative survival probabilities and to build survival plots. To assess the association between presence of neBHs and time to conversion to CDMS, univariate analysis and multivariate analysis (considering number of B-T criteria and presence/absence of contrast-enhancing lesions) using Cox proportional hazard regression was performed. Proportional hazard assumption was checked graphically from survival plots. All analyses were carried out with appropriate parameterization using the entire data set. Statistical analyses were done with SPSS (version 13.0 for windows, SPSS Inc., Chicago, IL, USA).
Results Clinical and demographic characteristics The study included 520 patients with CIS, 359 (69%) women and 161 (31%) men, with a mean age at onset of 31 years (range 16–50 years). Of these, 173 (33.3%) presented with optic neuritis, 153 (29.4%) with brainstem symptoms, 138 (26.5%) with spinal cord syndrome, and the remaining 56 (10.8%) had other presentations involving hemispheric, polyregional, or undetermined topography. Median clinical follow-up time was 38.8 months (range 3.1–150.3; Q1–Q3 26.4–74.7) (Table 1).
Baseline MRI In 64 patients (12.3%), brain MRI findings were normal, whereas 456 patients (87.7%) showed focal brain lesions of the type seen in MS. DIS was fulfilled in 286/520 patients (55%), and DIT1 was fulfilled in 184/520 patients (35.3%).
neBH: non-enhancing black holes.
NeBHs were identified in 189/520 patients (36.3%) (mean number per patient 3.19; range 1–23). In all 189 patients, neBHs and isointense lesions were simultaneously present on contrast-enhanced T1-weighted images, thereby fulfilling the DIT2a criteria. The proportion of patients presenting neBHs was similar among the different forms of CIS. The number of patients showing neBHs varied from 13.2% in those not fulfilling DIS to 55.2% in those fulfilling DIS (Table 2). In the subset of patients who did not show gadoliniumenhancing lesions (n=336), DIT2a was satisfied in 106 patients (31.5%). At 12 months’ follow-up, MRI scans were available in 214/520 (41.1%) patients; 62 of them (29.0%) had neBHs, which were persistent in 52 (83.9%) patients.
Conversion to CDMS Univariate analysis Conversion in the total cohort. A confirmed second clinical attack occurred in 232 patients (44.6%), with a median conversion time of 13.2 months (range 1.1–106.7; Q1–Q3 6.9–25.0). The univariate analysis is shown in Table 3. Conversion in patients fulfilling DIS. Of the patients who met the DIS criteria (n=286), 172 (60.1%) converted to CDMS, compared with 60 of the 234 patients (25.6%) who did not fulfil DIS (HR 3.28; CI 2.45–4.44; p
Diagnostic value of brain chronic black holes on T1-weighted MR images in clinically isolated syndromes Raquel Mitjana, Mar Tintoré, Maria A Rocca, Cristina Auger, Frederik Barkhof, Massimo Filippi, Chris Polman, Franz Fazekas, Elena Huerga, Xavier Montalban and Àlex Rovira Mult Scler published online 27 February 2014 DOI: 10.1177/1352458514526083 The online version of this article can be found at: http://msj.sagepub.com/content/early/2014/02/27/1352458514526083
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 UNIV OF TENNESSEE on September 15, 2014
Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Feb 27, 2014 What is This?
Downloaded from msj.sagepub.com at UNIV OF TENNESSEE on September 15, 2014
526083 research-article2014
MSJ0010.1177/1352458514526083Multiple Sclerosis JournalMitjana et al.
MULTIPLE SCLEROSIS MSJ JOURNAL
Research Paper
Diagnostic value of brain chronic black holes on T1-weighted MR images in clinically isolated syndromes
Multiple Sclerosis Journal 1–7 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1352458514526083 msj.sagepub.com
Raquel Mitjana1, Mar Tintoré1, Maria A Rocca2, Cristina Auger1, Frederik Barkhof 3, Massimo Filippi2, Chris Polman3, Franz Fazekas4, Elena Huerga1, Xavier Montalban1 and Àlex Rovira1
Abstract Background: Non-enhancing black holes (neBHs) are more common in multiple sclerosis (MS) patients with longer disease durations and progressive disease subtypes. Objective: Our aim was to analyse the added value of neBHs in patients with clinically isolated syndromes (CISs) for predicting conversion to clinically definite MS (CDMS). Methods: Patients were classified based on the presence or absence of neBHs and on the number of Barkhof–Tintoré (B-T) criteria fulfilled. Dissemination in space (DIS) was defined as the presence of at least three of the four B-T criteria. Dissemination in time (DIT)1 was defined by simultaneous presence of enhancing and non-enhancing lesions. DIT2 was defined by simultaneous presence of neBHs and T2 lesions not apparent on T1-weighted images. Results: Focal T2-hyperintense brain lesions were identified in 87.7% of the 520 CIS patients, and 41.4% of them presented at least one neBH. Patients meeting DIS, DIT1, and DIT2 had a significantly higher rate of conversion to CDMS. After adjusting for DIS, only patients who fulfilled DIT1 preserved a significant increase in CDMS conversion. Conclusions: Non-enhancing black holes in CIS patients are associated with a higher risk of conversion to CDMS. However, the predictive value of this finding is lost when added to the DIS criteria. Keywords Clinically isolated syndrome, magnetic resonance imaging, diagnosis Date received: 12 November 2013; revised: 3 February 2014; accepted: 7 February 2014
Introduction According to the McDonald criteria, a diagnosis of multiple sclerosis (MS) in patients who present for the first time with a clinically isolated syndrome (CIS) can be established using brain magnetic resonance imaging (MRI) if this examination demonstrates demyelinating lesions disseminated in space (DIS) and time (DIT).1,2 To demonstrate DIS, brain MRI must fulfil the classic Barkhof–Tintoré (B-T) criteria3,4 (2005 McDonald criteria) or the Swanton criteria (MAGNIMS criteria) included in the recently proposed 2010 version of the McDonald criteria.5,6 As recent data from a collaborative MAGNIMS study have suggested,7 the 2010 version of the McDonald criteria establishes that a single brain MRI scan may suffice to demonstrate DIT, even when it is performed at any time following the onset of symptoms. This suggestion is based on the concept that simultaneous presence of
asymptomatic gadolinium-enhancing and non-enhancing lesions is sufficient to demonstrate DIT because these findings indicate that the lesions are in different stages of 1MR
Unit (IDI), Department of Radiology, and Department of Neurology-Neuroimmunology, CEM-CAT, Hospital Vall d’Hebron, Autonomous University of Barcelona, Barcelona, Spain. 2Neuroimaging Research Unit, Department of Neurology, Institute of Experimental Neurology, Division of Neuroscience, San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Milan, Italy. 3Department Neurology, VU University Medical Centre, Amsterdam, The Netherlands. 4Department of Neurology, Medical University of Graz, Austria. Corresponding author: Àlex Rovira, MR Unit, Department of Radiology, Hospital Vall d’Hebron, Passeig Vall d’Hebron 119-129, Barcelona, 08035, Spain. Email: [email protected]
Downloaded from msj.sagepub.com at UNIV OF TENNESSEE on September 15, 2014
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Multiple Sclerosis Journal
evolution and therefore evolved at different times. Some studies have also shown that non-enhancing black holes (neBHs) correlate pathologically with more severe demyelination and axonal loss, indicating areas of irreversible tissue damage.8 These lesions have been associated with brain atrophy, and disability, in patients with MS,8 but there are no data regarding their prevalence in patients with CIS, or their diagnostic value for predicting early conversion to clinically definite MS (CDMS). Although not all enhancing lesions evolve uniformly into either neBH or isointense lesions on T1-weighted sequences,9 their formation is more common in patients with longer disease durations and progressive disease subtypes. For that reason their presence in patients with CIS could indicate a more advanced disease course and be considered as an alternative criteria for demonstrating DIT. Therefore, the purpose of this study is to determine the prevalence of neBHs in a large population of patients with CIS, and to analyse their added value for predicting conversion to CDMS as an alternative criterion for demonstrating DIT.
Patients and methods Within a European multicentre collaborative research network dedicated to MRI research in MS (MAGnetic Resonance Imaging in MS [MAGNIMS] http://www.magnims.eu/), brain MRI results and clinical data were retrospectively collected from four European centres, in which these data had been prospectively obtained from CIS patients following local standards. Each centre was asked to identify patients who met the following inclusion criteria: 1) CIS suggestive of central nervous system demyelination involving the optic nerve, brainstem, spinal cord, or other topography, not attributable to other diseases; 2) age 16–50 years; 3) clinical assessment within 3 months of CIS onset; 4) brain MRI obtained within 6 months of first attack; and 5) clinical follow-up of at least 24 months after CIS onset or until development of CDMS,10 if this occurred within the first 2 years.
Clinical data Each centre provided the following clinical information: age at CIS onset, gender, topography and date of CIS (and second event if applicable), and dates of brain MRI scans and last follow-up visit. The diagnosis of CDMS was established by an experienced neurologist at each centre, based on clinical information alone, according to the Poser criteria10 (i.e. symptomatic and objective evidence of a second neurological episode attributable to demyelination of >24 h duration, >4 weeks after the initial attack). Alternative diagnoses were ruled out by appropriate tests according to the local protocols.
Ethics approval for the CIS studies at each centre was obtained from the local institutional review boards. As the present study was based on retrospective analysis of existing data, no additional approval was required.
Brain MRI data All MRI scans were performed on 1.5-T systems and included transverse T2-weighted dual-echo sequences and contrast-enhanced transverse T1-weighted sequences covering the whole brain, with slice thickness of 3–5 mm. MRI scans were assessed by an experienced neuroradiologist blinded to the clinical data, who determined the number and topography (periventricular, subcortical, juxtacortical, or infratentorial) of high-intensity lesions suggestive of demyelinating plaques on T2-weighted images. DIS was defined according to the 2005 McDonald diagnostic criteria as the presence of at least three of the four B-T criteria (at least three of the following four features: 1) one gadolinium-enhancing lesion or nine T2 hyperintense lesions if gadolinium-enhancing lesions are not present, 2) at least one infratentorial lesion, 3) at least one juxtacortical lesion and 4) at least three periventricular lesions). DIT1 was defined as the presence of simultaneous enhancing and non-enhancing lesions on post-contrast T1-weighted scans. The number of neBHs was determined on contrastenhanced T1-weighted images. NeBH was defined as an area of unequivocal low signal intensity compared with normal-appearing white matter that did not show contrast uptake and was concordant with a hyperintense lesion seen on T2-weighted imaging.11 DIT2 was defined as the simultaneous presence of neBH and and T2 lesion not apparent (isointense) on contrast-enhanced T1-weighted images. DIT2 was analysed in two ways: a) in the overall cohort of patients (DIT2) and b) in the subgroup of patients without gadoliniumenhancing lesions (DIT2a). This was done to investigate the possible added value of neBH as an alternative marker of DIT in patients who do not meet the classic DIT criterion (simultaneous presence of enhancing and nonenhancing lesions). A 12-month follow-up MRI scan was available in a subset of patients from a single centre (n=214, 41.1%). Persistent neBH was defined as persistence of neBHs seen in the first MRI scan on this follow-up scan. All MRI assessments were performed by a single rater blinded to clinical data.
Statistical analysis All data were entered in a database by a single person and checked for accuracy and consistency by confirmation of the validity of all entries.
Downloaded from msj.sagepub.com at UNIV OF TENNESSEE on September 15, 2014
3
Mitjana et al. Table 1. Demographic data and clinical characteristics of the cohort.
Table 2. Presence of non-enhancing black holes and number of Barkhof–Tintoré criteria fulfilled.
Characteristics
Number (%) of patients N=520
Number of patients
Number (%) of patients with neBHs
Age at onset, mean, y Male/female, n Patients from each centre Milan (Italy) Barcelona (Spain) Amsterdam (The Netherlands) Graz (Austria) Patients with each presenting clinical syndrome Optic neuritis Brainstem syndrome Spinal cord syndrome Other
31 161/359
Number of Barkhof–Tintoré criteria fulfilled 0 1 2 3 4 0–2 3–4 Any
117 59 58 104 182 234 286 520
3 (2.6) 11 (18.6) 17 (29.3) 41 (39.4) 117 (64.3) 31 (13.2) 158 (55.2) 189 (36.3)
234 (41.2) 214 (45.0) 63 (12.1) 9 (1.7) 173 (33.3) 153 (29.4) 138 (26.5) 56 (10.8)
Descriptive results are expressed as the mean or quartiles, and as the minimum and maximum for continuous variables (age and times) and percentages for categorical data. Kaplan–Meier analysis was used to estimate cumulative survival probabilities and to build survival plots. To assess the association between presence of neBHs and time to conversion to CDMS, univariate analysis and multivariate analysis (considering number of B-T criteria and presence/absence of contrast-enhancing lesions) using Cox proportional hazard regression was performed. Proportional hazard assumption was checked graphically from survival plots. All analyses were carried out with appropriate parameterization using the entire data set. Statistical analyses were done with SPSS (version 13.0 for windows, SPSS Inc., Chicago, IL, USA).
Results Clinical and demographic characteristics The study included 520 patients with CIS, 359 (69%) women and 161 (31%) men, with a mean age at onset of 31 years (range 16–50 years). Of these, 173 (33.3%) presented with optic neuritis, 153 (29.4%) with brainstem symptoms, 138 (26.5%) with spinal cord syndrome, and the remaining 56 (10.8%) had other presentations involving hemispheric, polyregional, or undetermined topography. Median clinical follow-up time was 38.8 months (range 3.1–150.3; Q1–Q3 26.4–74.7) (Table 1).
Baseline MRI In 64 patients (12.3%), brain MRI findings were normal, whereas 456 patients (87.7%) showed focal brain lesions of the type seen in MS. DIS was fulfilled in 286/520 patients (55%), and DIT1 was fulfilled in 184/520 patients (35.3%).
neBH: non-enhancing black holes.
NeBHs were identified in 189/520 patients (36.3%) (mean number per patient 3.19; range 1–23). In all 189 patients, neBHs and isointense lesions were simultaneously present on contrast-enhanced T1-weighted images, thereby fulfilling the DIT2a criteria. The proportion of patients presenting neBHs was similar among the different forms of CIS. The number of patients showing neBHs varied from 13.2% in those not fulfilling DIS to 55.2% in those fulfilling DIS (Table 2). In the subset of patients who did not show gadoliniumenhancing lesions (n=336), DIT2a was satisfied in 106 patients (31.5%). At 12 months’ follow-up, MRI scans were available in 214/520 (41.1%) patients; 62 of them (29.0%) had neBHs, which were persistent in 52 (83.9%) patients.
Conversion to CDMS Univariate analysis Conversion in the total cohort. A confirmed second clinical attack occurred in 232 patients (44.6%), with a median conversion time of 13.2 months (range 1.1–106.7; Q1–Q3 6.9–25.0). The univariate analysis is shown in Table 3. Conversion in patients fulfilling DIS. Of the patients who met the DIS criteria (n=286), 172 (60.1%) converted to CDMS, compared with 60 of the 234 patients (25.6%) who did not fulfil DIS (HR 3.28; CI 2.45–4.44; p
