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. 2023 Aug 1;146(8):3431-3443.
doi: 10.1093/brain/awad073.

The radiologically isolated syndrome: revised diagnostic criteria

Christine Lebrun-Frénay  1 , Darin T Okuda  2 , Aksel Siva  3 , Cassandre Landes-Chateau  1 , Christina J Azevedo  4 , Lydiane Mondot  1 , Clarisse Carra-Dallière  5   6 , Helene Zephir  7 , Celine Louapre  8 , Françoise Durand-Dubief  9 , Emmanuelle Le Page  10 , Caroline Bensa  11 , Aurélie Ruet  12   13 , Jonathan Ciron  14   15 , David A Laplaud  16   17 , Olivier Casez  18   19 , Guillaume Mathey  20   21 , Jerome de Seze  22 , Burcu Zeydan  23 , Naila Makhani  24 , Melih Tutuncu  3 , Michael Levraut  1 , Mikael Cohen  1 , Eric Thouvenot  25   26 , Daniel Pelletier  4 , Orhun H Kantarci  27
Affiliations

The radiologically isolated syndrome: revised diagnostic criteria

Christine Lebrun-Frénay et al. Brain. .

Abstract

The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P < 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1-2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P < 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.

Keywords: MRI; diagnostic criteria; multiple sclerosis; prognosis; radiologically isolated syndrome.

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Conflict of interest statement

C.L.F. has participated in international meetings. Expert in academic boards and Speaker honoraria were either declined or donated to the URRIS research unit, University Cote d’Azur, Nice, France. She did not receive any financial compensation for her participation in the scientific committee of the French MS Society, the Revue Neurologique, OFSEP, ARSEP and ECTRIMS apart from travel expenses. D.T.O. received personal compensation for consulting and advisory services from Alexion, Biogen, Celgene/Bristol Myers Squibb, EMD Serono, Genentech, Genzyme, Janssen Pharmaceuticals, Novartis, Osmotica Pharmaceuticals, RVL Pharmaceuticals, Inc., TG Therapeutics, Viela Bio, Inc., and research support from Biogen and EMD Serono/Merck. Dr Okuda has issued national and international patents and pending patents related to developed technologies. D.T.O. also received royalties for intellectual property licensed by The Board of Regents of The University of Texas System. A.S. received research grants from The Turkish Multiple Sclerosis Society, The Scientific and Technological Research Council of Turkey & Istanbul University-Cerraphasa Research Support Funds. Received honoraria or consultancy fees for participating in advisory boards, giving educational lectures and/or travel and registration coverage for attending scientific congresses or symposia from F. Hoffmann-La Roche Ltd, Sanofi-Genzyme, Alexion, Merck-Serono, Novartis, Biogen Idec/Gen Pharma of Turkey and Abdi Ibrahim Ilaç, Turkey. C.J.A. has received grant support from the National Multiple Sclerosis Society and the National Institutes of Health (NIH). In the last 3 years, she has received honoraria or consulting fees from Biogen, Sanofi-Genzyme, Novartis, Genentech, Alexion Pharmaceuticals, Serono, and Horizon Therapeutics for participation on advisory boards and data safety monitoring committees. C.C.D. has received honoraria or consulting fees from Novartis, Sanofi and Merck in the last 3 years for participation on advisory boards and giving educational lectures. H.Z. has no competing interests regarding this study. Unrelated to this study, H.Z. received personal compensation for consulting, travel and registration coverage for attending scientific congresses from Alexion, BMS, Novartis, Biogen Idec, and Merck, and research grants from Roche. C.L. has received a research grant from the ARSEP foundation, Neuratris, and Biogen. In the last 3 years, she has received honoraria or consulting fees from Biogen, Sanofi-Genzyme, Novartis, Roche and Merck. C.B. has received consulting honoraria from Alexion, Sanofi, Merck, Biogen, BMS, Novartis, Roche and Teva. A.R. personal fees, non-financial support and research grants from Biogen; personal fees and non-financial support from Novartis; personal fees, non-financial support and research grants from Roche; personal fees from Merck; personal fees from Alexion; personal fees from Horizon therapeutics; research grants from Genzyme; outside the submitted work. J.C. has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Biogen, Novartis, Merck, Sanofi-Genzyme, Roche, BMS, Alexion, Horizon Therapeutics, none related to this study. D.A.L. has participated in advisory boards for Alexion, Merck, Novartis and Roche in the last 3 years. Apart from travel expenses, he did not receive any financial compensation for his participation in the scientific committee of OFSEP and ARSEP. B.Z. received grant support from the NIH (U54 AG044170) and the Eugene and Marcia Applebaum Award. N.M. has no financial conflicts related to this work and has received research funding from the NIH (award number K23NS101099), the National Multiple Sclerosis Society and the Charles H. Hood Foundation. E.T. has received honoraria, travel grants, or research grants from the following pharmaceutical companies: Actelion, Biogen, Genzyme, Merck Serono, Novartis, Roche, Teva pharma. D.P. has received consulting honoraria from F. Hoffmann-La Roche, Sanofi-Genzyme, and Novartis. All other authors report no competing interests.

Figures

Figure 1
Figure 1
Flow chart of the cohort.
Figure 2
Figure 2
Kaplan–Meier survival analysis with the end point of time to the first acute or progressive event. The graph compares the group with the current definition of 2009-RIS fulfilling three or four of four DIS criteria (green line) with Group 1 fulfilling one of four DIS criteria (blue line); Group 2 fulfilling two of four DIS criteria (orange line). There was a difference overall between the survival distributions of Group 1 (DIS 1), Group 2 (DIS 2) and 2009-RIS (DIS 3/4) (P = 0.0255). At 2 years, the risk of a clinical event was 13% [event-free survival 87% (95% CI: 43–73) for Group 1 (DIS 1)], 14% for Group 2 [event-free survival 86% (95% CI: 61–80) for Group 2 (DIS 2)] and 16% [event-free survival 84% (95% CI: 79–87) for 2009-RIS]. There was no difference between the survival distributions of Group 1 (DIS 1) and Group 2 (DIS 2) (P = 0.351). At 2 years, the clinical event-free survival was 87% (95% CI: 76–93) for Group 1 (DIS 1) and 86% (95% CI: 78–91) for Group 2 (DIS 2). At 5 years, the risk of a clinical event was 29% [event-free survival 71% (95% CI: 76–93) for Group 1 (DIS 1)], 28% for Group 2 [event-free survival 72% (95% CI: 78–91) for Group 2 (DIS 2)] and 45% [event-free survival 55% (95% CI: 48–62) for 2009-RIS]]. There was no difference between the survival distributions of Group 1 (DIS 1) and Group 2 (DIS 2) (P = 0.479). At 2 years, the clinical event-free survival was 87% (95% CI: 76–93) for Group 1 (DIS 1) and 86% (95% CI: 79–91) for Group 2 (DIS 2).
Figure 3
Figure 3
Kaplan–Meier survival analysis with the end point of time to the first acute or progressive event comparing the current definition of 2009-RIS fulfilling three or four of four DIS criteria (red line) with risk factors at the index scan. Subjects from Groups 1 and 2, fulfilling one or two of four DIS criteria and (presence of oligoclonal bands and presence of spinal cord lesions) (blue line); subjects from Groups 1 and 2, fulfilling one or two of four DIS criteria without (OCBs or spinal cord lesions) (green line); subjects from Groups 1 and 2, fulfilling one or two of four DIS criteria and (presence of OCBs or spinal cord lesions) (orange line). There was a difference between survival distributions of Groups 1 and 2 with OCB and spinal cord lesion, Groups 1 and 2 with OCB or spinal cord lesion, Groups 1 and 2 without OCB and spina cord lesion and RIS (P = 0.0319). At 2 years, the risk of the clinical event was 24% [event-free survival was 76% (95% CI: 51–89) for Groups 1 and 2 with OCB and spinal cord lesion], 18% [event-free survival was 82% (95% CI: 71–89) for Groups 1 and 2 with OCB or spinal cord lesion], 10% [event-free survival was 90% (95% CI: 78–95) for Groups 1 and 2 without OCB and spinal cord lesion] and 16% [event-free survival was 84% (95% CI: 79–87) for 2009-RIS]. At 5 years, the risk of the clinical event was 34% [event-free survival was 62% (95% CI: 35–80) for Groups 1 and 2 with OCB and spinal cord lesion], 24% [event-free survival was 76% (95% CI: 51–89) for Groups 1 and 2 with OCB or spinal cord lesion], 13% [event-free survival was 87% (95% CI: 74–94) for Groups 1 and 2 without OCB and spinal cord lesion] and 42% [event-free survival was 58% (95% CI: 50–64) for 2009-RIS].
Figure 4
Figure 4
Kaplan–Meier survival analysis with the end point of time to the first acute or progressive event comparing the current definition of subjects fulfilling 2023 RIS criteria. The orange line represents subjects who fulfilled 2023 RIS criteria or not (blue line); HR 2.24 (1.44–3.46), log-rank test P < 0.001.
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