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To investigate whether inclusion of lesions in the symptomatic region influences the performance of dissemination in space (DIS) criteria for a diagnosis of clinically definite multiple sclerosis (CDMS) in patients with a clinically isolated syndrome (CIS).
We studied 30 patients with CIS with brainstem/cerebellar and spinal cord syndromes who had MRI scans at the time of CIS and were followed up for the development of CDMS. We retrospectively applied the McDonald 2010 DIS criteria (excluding all lesions in the symptomatic region) to baseline MRI scans and 2 modified DIS criteria: (1) the inclusion of asymptomatic lesions in the symptomatic region in DIS, and (2) the inclusion of any lesion in the symptomatic region in DIS. The performance of the McDonald 2010 DIS criteria and the 2 modified criteria for the development of CDMS was compared.
The sensitivity, specificity, and accuracy of the DIS criteria was, respectively, 73%, 73%, and 73% for the McDonald 2010 criteria, 80%, 73%, and 77% when asymptomatic lesions in the symptomatic region were included, and 87%, 73%, and 80% when any lesion in the symptomatic region was included in DIS.
Including lesions in the symptomatic region in DIS increases the sensitivity of MRI criteria for diagnosing multiple sclerosis without compromising specificity. These findings may help inform future revisions of the diagnostic criteria for multiple sclerosis.
This study provides Class II evidence that for patients with CIS, including lesions in the symptomatic region as part of the criteria for DIS does not significantly increase the accuracy for predicting the development of CDMS. The study lacks the precision to detect an important change in accuracy.
A diagnosis of multiple sclerosis (MS) requires the demonstration of dissemination in space (DIS) and time (DIT). In people with a clinically isolated syndrome (CIS), the McDonald criteria1,2 allow the use of MRI to provide evidence of DIS and DIT rather than waiting for a second clinical attack.3 In patients with CIS, the McDonald criteria have an excellent sensitivity and specificity for the development of clinically definite MS (CDMS)4 and facilitate an earlier diagnosis of MS.5
In the 2010 revisions to the McDonald criteria, there was a major change in the requirements for DIS.6 The presence of one or more T2 hyperintense lesions in 2 of 4 anatomical regions typically affected in demyelination (periventricular, juxtacortical, infratentorial, spinal cord) provides MRI evidence for DIS.1 When the patient's symptoms are referable to the brainstem/cerebellum or spinal cord, then lesions in the symptomatic region are excluded.1,6 However, the criteria are ambiguous as to whether all lesions in the symptomatic region should be excluded or only the symptomatic lesion.7
The exclusion of lesions in the symptomatic region is not based on strong evidence, but rather a desire to maximize the specificity of MRI criteria by requiring lesions in 2 sites outside the symptomatic region to establish DIS. However, in previous diagnostic criteria for MS, whether clinical criteria3 or incorporating MRI,2 symptomatic lesions have always contributed to DIS. The exclusion of lesions in the symptomatic region may reduce the sensitivity of the McDonald 2010 criteria in patients with brainstem/cerebellar and spinal cord syndromes,8,9 leading to delays in the diagnosis and management of MS. We wanted to investigate whether inclusion of lesions in the symptomatic region influences the sensitivity and specificity of DIS criteria for a diagnosis CDMS.
All patients provided written informed consent and the study was approved by the institutional ethics committee.
Thirty patients with CIS with brainstem/cerebellar and spinal cord syndromes were included. The patients were part of a larger prospective CIS cohort study described in detail previously.5,6 Briefly, patients aged between 16 and 50 years with typical CIS syndromes and no history of previous neurologic symptoms were eligible. T2-weighted and postcontrast T1-weighted scans of the brain and spinal cord were done at baseline (within 3 months of CIS) and brain imaging was repeated after 3 months. All scans were reviewed by a single neuroradiologist, blinded to the patient's clinical status. Lesion number, location, and gadolinium enhancement were noted. Patients were seen again at scheduled follow-up over the first 5 to 8 years after CIS. CDMS was diagnosed using the Poser criteria (i.e., a second clinical attack with evidence of 2 separate lesions).3
We retrospectively applied 3 DIS criteria to the baseline MRI scans:
We defined DIT using the 2010 McDonald criteria1 (i.e., the presence of asymptomatic gadolinium-enhancing and nonenhancing lesions on a single scan or a new T2 lesion on the follow-up MRI) using the baseline and 3-month follow-up scans.
We calculated the sensitivity, specificity, and accuracy of the 3 DIS criteria (alone and in combination with DIT criteria) for the development of CDMS and 95% confidence intervals.6 We also calculated the times to diagnosis of MS based on clinical evidence alone (CDMS) or using the different MRI criteria (each requiring both DIS and DIT). The times to diagnosis of MS were not normally distributed and comparison was made using the 1-sample Wilcoxon signed rank test. All statistical analyses were done using SPSS version 21 (IBM Corp., Armonk, NY).
The baseline demographic characteristics were typical of patients with a CIS (table 1). Over a mean follow-up period of 7.3 years, 15 (50%) developed CDMS. None of the patients received disease-modifying treatment before developing CDMS.
Twenty-three patients (77%) had one or more T2 hyperintense lesions in the symptomatic region. Twenty-two patients (73%) had an identifiable symptomatic lesion based on the neurologic examination findings, the presence of gadolinium enhancement, or both. Eleven patients (37%) had at least one asymptomatic lesion. The figure shows a Kaplan-Meier survival curve with the time to diagnosis of CDMS based on the number of lesions in the symptomatic region.
All of the DIS criteria, alone or in combination with DIT criteria, had good sensitivity and specificity for the development of CDMS (table 2). The 2 modified criteria were more sensitive and more accurate than the McDonald 2010 DIS criteria, and all 3 DIS criteria had the same specificity. The inclusion of any lesion in the symptomatic region had the highest overall sensitivity and accuracy for the development of CDMS.
The mean time to MS diagnosis for various diagnostic criteria (requiring both DIS and DIT) was as follows:
Although using the modified DIS allowed a shorter time to diagnosis of MS compared with the time to CDMS (p < 0.001), the time to diagnosis was not significantly different when compared with the McDonald 2010 criteria.
We found that the inclusion of lesions in the symptomatic region in patients with clinically isolated brainstem/cerebellar and spinal cord syndromes increased the sensitivity and accuracy of DIS criteria for a diagnosis of CDMS without compromising specificity.
The Magnetic Resonance Imaging in Multiple Sclerosis Group has recently recommended revisions to the MRI criteria for DIS to include lesions in the symptomatic region.10 This study provides evidence to support that recommendation. We found that inclusion of both asymptomatic and symptomatic lesions in the symptomatic region increased the sensitivity of DIS criteria for the development of CDMS. However, we would favor modified DIS criteria that include any lesion in the symptomatic region, first because the sensitivity was higher and second because the criteria would be easier to apply in a clinical setting. Determining whether a lesion is symptomatic or asymptomatic is sometimes difficult and not always possible.
Some limitations need to be noted. First, patients included in this study had syndromes that were typical of a first demyelinating event, such as bilateral internuclear ophthalmoplegia and partial myelitis.11 The McDonald MRI criteria should only be applied to patients with typical CIS syndromes and care should be taken to exclude conditions that might mimic MS. Second, over a follow-up period of 7 years, half of the cohort developed CDMS. With longer follow-up, this number may increase, potentially influencing the performance of the MRI criteria, although more than half of patients with CIS who develop MS have a second clinical attack in the first 5 years of follow-up.10 Finally, we tested the 2 modified DIS criteria in a relatively small cohort of patients. Although we found an increase in sensitivity and accuracy using the modified DIS criteria, the confidence intervals are wide, reflecting the small size of the cohort. However, the results are encouraging and the criteria should be tested in a larger multicenter CIS cohort to inform future changes to the diagnostic criteria for MS.
Editorial, page 652
Dr. Brownlee contributed to study concept/design, analysis and interpretation of data, statistical analysis, and drafting the manuscript. Dr. Swanton contributed to acquisition of data and revision of the manuscript. Dr. Miszkiel contributed to acquisition of data and revision of the manuscript. Dr. Miller obtained funding and contributed to study concept/design and revision of the manuscript. Dr. Ciccarelli contributed to study concept/design, revision of the manuscript, and provided study supervision.
The study was supported by the United Kingdom MS Society (grant 995) and the Neurologic Foundation of New Zealand (grant 1207-CF). The Queen Square MS Centre is supported by the United Kingdom MS Society and the NIHR University College London Hospitals Biomedical Research Centre.
W. Brownlee, J. Swanton, and K. Miszkiel report no disclosures relevant to the manuscript. D. Miller has received honoraria through payments to UCL Institute of Neurology from Biogen Idec, Novartis, Bayer Schering, and Mitsubishi Pharma Europe. Dr. Miller receives royalties from the publication of McAlpine's Multiple Sclerosis, 4th edition. O. Ciccarelli is a consultant for Novartis, Biogen Idec, Genzyme, and General Electric, and all the payments are made to the UCL Institute of Neurology. She is an associate editor of Neurology®. Go to Neurology.org for full disclosures.