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Cited by 339Multiple Sclerosis Research StudiesPolyomavirus and related diseasesDementia and Cognitive Impairment Research

Radiologically isolated syndrome: 5-year risk for an initial clinical event

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Okuda, Darin T., Siva, Aksel, Kantarci, Orhun, Inglese, Matilde, Katz, Ilana, Tutuncu, Melih, Keegan, B. Mark, Donlon, Stacy +15 more·2014·PLoS ONE
DOI 10.1371/journal.pone.0090509PMC PMC3943959
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Abstract

OBJECTIVE: To report the 5-year risk and to identify risk factors for the development of a seminal acute or progressive clinical event in a multi-national cohort of asymptomatic subjects meeting 2009 RIS Criteria. METHODS: Retrospectively identified RIS subjects from 22 databases within 5 countries were evaluated. Time to the first clinical event related to demyelination (acute or 12-month progression of neurological deficits) was compared across different groups by univariate and multivariate analyses utilizing a Cox regression model. RESULTS: Data were available in 451 RIS subjects (F: 354 (78.5%)). The mean age at from the time of the first brain MRI revealing anomalies suggestive of MS was 37.2 years (y) (median: 37.1 y, range: 11-74 y) with mean clinical follow-up time of 4.4 y (median: 2.8 y, range: 0.01-21.1 y). Clinical events were identified in 34% (standard error=3%) of individuals within a 5-year period from the first brain MRI study. Of those who developed symptoms, 9.6% fulfilled criteria for primary progressive MS. In the multivariate model, age [hazard ratio (HR): 0.98 (95% CI: 0.96-0.99); p=0.03], sex (male) [HR: 1.93 (1.24-2.99); p=0.004], and lesions within the cervical or thoracic spinal cord [HR: 3.08 (2.06-4.62); p=<0.001] were identified as significant predictors for the development of a first clinical event. INTERPRETATION: These data provide supportive evidence that a meaningful number of RIS subjects evolve to a first clinical symptom. An age <37 y, male sex, and spinal cord involvement appear to be the most important independent predictors of symptom onset.

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  • Factors predicting increased risk of subsequent MS diagnosis in RIS are similar to those predicting MS diagnosis after a CIS: younger age, higher cerebral lesion load, asymptomatic infratentorial or spinal cord lesions, gadolinium-enhancing lesions, presence of CSF OCBs, and abnormal VEP.

    “The factors predicting increased risk of subsequent MS diagnosis are similar to those predicting MS diagnosis after a CIS: younger age, higher cerebral lesion load, asymptomatic infratentorial or spinal cord lesions, gadolinium-enhancing lesions, presence of CSF OCBs, and abnormal VEP. 87,89”

    From Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria (2018) · cites this paper as [87]

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  • Younger age, male gender and gadolinium-enhancing, cortical or spinal cord lesions may be associated with an increased risk of developing MS in RIS patients.

    “Younger age, male gender and gadolinium-enhancing, cortical or spinal cord lesions may be associated with an increased risk of developing MS.29- 31”

    From Diagnosis of multiple sclerosis: progress and challenges (2017) · cites this paper as [29]

    The Results identify younger age, male sex, and cervical or thoracic spinal cord lesions as predictors of a first clinical event in RIS. However, Table 4 shows no association for juxtacortical lesions, and the Discussion explicitly says baseline contrast enhancement was not predictive. The paper therefore does not support the cortical-lesion and gadolinium-enhancement parts of the claim. (LLM, conf=0.91)

    Experimental — accuracy not yet measured

  • RIS conversion to MS is most often with a relapsing-remitting course but occasionally with a primary progressive course.

    “Approximately one-third of RIS cases are diagnosed with MS within five years of presentation, most often with a relapsingremitting course 83,86 but occasionally with a primary progressive course. 87,88”

    From Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria (2018) · cites this paper as [87]

  • A third of RIS patients will develop clinical symptoms in the first 5 years of follow up (either a relapse or progressive symptoms).

    “A third of RIS patients will develop clinical symptoms in the first 5 years of follow up (either a relapse or progressive symptoms).29”

    From Diagnosis of multiple sclerosis: progress and challenges (2017) · cites this paper as [29]

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Research works printed but not linked: 27

  1. [1]Okuda DT, Mowry EM, Beheshtian A, Waubant E, Baranzini SE, et al (2009) Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 72: 800– 805. 19073949
  2. [2]Lebrun C, Bensa C, Debouverie M, De Seze J, Wiertlievski S, et al (2008) Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile. J Neurol Neurosurg Psychiatry 79: 195– 198. 18202208
  3. [3]Siva A, Saip S, Altintas A, Jacob A, Keegan BM, et al (2009) Multiple sclerosis risk in radiologically uncovered asymptomatic possible inflammatory-demyelinating disease. Mult Scler 15: 918– 927. 19667020
  4. [4]Lebrun C, Blanc F, Brassat D, Zephir H, de Seze J, et al (2010) Cognitive function in radiologically isolated syndrome. Mult Scler 16: 919– 925. 20610492
  5. [5]De Stefano N, Stromillo ML, Rossi F, Battaglini M, Giorgio A, et al (2011) Improving the characterization of radiologically isolated syndrome suggestive of multiple sclerosis. PLoS One 6: e19452. 21559385 PMC3084867
  6. [6]Gabelic T, Radmilovic M, Posavec V, Skvorc A, Boskovic M, et al.. (2012) Differences in oligoclonal bands and visual evoked potentials in patients with radiologically and clinically isolated syndrome. Acta Neurol Belg. 22740024
  7. [7]Giorgio A, Stromillo ML, Rossi F, Battaglini M, Hakiki B, et al (2011) Cortical lesions in radiologically isolated syndrome. Neurology 77: 1896– 1899. 22076541
  8. [8]Gabelic T, Ramasamy DP, Weinstock-Guttman B, Hagemeier J, Kennedy C, et al.. (2013) Prevalence of Radiologically Isolated Syndrome and White Matter Signal Abnormalities in Healthy Relatives of Multiple Sclerosis Patients. AJNR Am J Neuroradiol. PMC7966501 23886745
  9. [9]Stromillo ML, Giorgio A., Rossi F., Battaglini M., Hakiki B., Malentacchi G., Santangelo M., Gasperini C., Bartolozzi M.L., Portaccio E., Amato M.P., De Stefano, N. (2013) Brain metabolic changes suggestive of axonal damage in radiologically isolated syndrome. Neurology. 23635962
  10. [10]Lebrun C, Bensa C, Debouverie M, Wiertlevski S, Brassat D, et al (2009) Association between clinical conversion to multiple sclerosis in radiologically isolated syndrome and magnetic resonance imaging, cerebrospinal fluid, and visual evoked potential: follow-up of 70 patients. Arch Neurol 66: 841– 846. 19597085
  11. [11]Lebrun C, Le Page E, Kantarci O, Siva A, Pelletier D, et al (2012) Impact of pregnancy on conversion to clinically isolated syndrome in a radiologically isolated syndrome cohort. Mult Scler 18: 1297– 1302. 22300971
  12. [12]Okuda DT, Mowry EM, Cree BA, Crabtree EC, Goodin DS, et al (2011) Asymptomatic spinal cord lesions predict disease progression in radiologically isolated syndrome. Neurology 76: 686– 692. 21270417 PMC3053327
  13. [13]Kruit MC, van Buchem MA, Launer LJ, Terwindt GM, Ferrari MD (2010) Migraine is associated with an increased risk of deep white matter lesions, subclinical posterior circulation infarcts and brain iron accumulation: the population-based MRI CAMERA study. Cephalalgia 30: 129– 136. 19515125 PMC3241741
  14. [14]Liu S, Kullnat J, Bourdette D, Simon J, Kraemer DF, et al (2013) Prevalence of brain magnetic resonance imaging meeting Barkhof and McDonald criteria for dissemination in space among headache patients. Mult Scler 19: 1101– 1105. 23380650
  15. [16]Vernooij MW, Ikram MA, Tanghe HL, Vincent AJ, Hofman A, et al (2007) Incidental findings on brain MRI in the general population. N Engl J Med 357: 1821– 1828. 17978290
  16. [17]Koch-Henriksen N, Sorensen PS (2010) The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 9: 520– 532. 20398859
  17. [18]Scalfari A, Neuhaus A, Daumer M, Ebers GC, Muraro PA (2011) Age and disability accumulation in multiple sclerosis. Neurology 77: 1246– 1252. 21917763 PMC3179646
  18. [19]Confavreux C, Vukusic S, Adeleine P (2003) Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process. Brain 126: 770– 782. 12615637
  19. [20]Tutuncu M, Tang J, Zeid NA, Kale N, Crusan DJ, et al (2013) Onset of progressive phase is an age-dependent clinical milestone in multiple sclerosis. Mult Scler 19: 188– 198. 22736750 PMC4029334
  20. [21]Cohen AB, Neema M, Arora A, Dell'oglio E, Benedict RH, et al (2012) The relationships among MRI-defined spinal cord involvement, brain involvement, and disability in multiple sclerosis. J Neuroimaging 22: 122– 128. 21447024 PMC3128174
  21. [22]Oh J, Saidha S, Chen M, Smith SA, Prince J, et al.. (2013) Spinal cord quantitative MRI discriminates between disability levels in multiple sclerosis. Neurology. PMC3589285 23325903
  22. [24]Sombekke MH, Wattjes MP, Balk LJ, Nielsen JM, Vrenken H, et al (2013) Spinal cord lesions in patients with clinically isolated syndrome: A powerful tool in diagnosis and prognosis. Neurology 80: 69– 75. 23243070
  23. [25]Tintore M, Rovira A, Arrambide G, Mitjana R, Rio J, et al (2010) Brainstem lesions in clinically isolated syndromes. Neurology 75: 1933– 1938. 21098409
  24. [26]Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, et al (2000) Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343: 898– 904. 11006365
  25. [27]Comi G, Martinelli V, Rodegher M, Moiola L, Bajenaru O, et al (2009) Effect of glatiramer acetate on conversion to clinically definite multiple sclerosis in patients with clinically isolated syndrome (PreCISe study): a randomised, double-blind, placebo-controlled trial. Lancet 374: 1503– 1511. 19815268
  26. [28]Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, et al (2006) Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 67: 1242– 1249. 16914693
  27. [29]McDonnell GV, Cabrera-Gomez J, Calne DB, Li DK, Oger J (2003) Clinical presentation of primary progressive multiple sclerosis 10 years after the incidental finding of typical magnetic resonance imaging brain lesions: the subclinical stage of primary progressive multiple sclerosis may last 10 years. Mult Scler 9: 204– 209. 12708816

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Authors
Okuda, D. T., Siva, A., Kantarci, O., Inglese, M., Katz, I., Tutuncu, M., Keegan, B. M., Donlon, S., Hua, L. H., Vidal-Jordana, A., Montalban, X., Rovira, A., Tintoré, M., Amato, M. P., Brochet, B., de Seze, J., Brassat, D., Vermersch, P., De Stefano, N., Sormani, M. P., Pelletier, D., Lebrun, C., & on behalf of the Radiologically Isolated Syndrome Consortium (RISC) and Club Francophone de la Sclérose en Plaques (CFSEP)
Affiliations
  • The University of Texas Southwestern Medical Center (US)
  • Mayo Clinic (US)
  • Mount Sinai Hospital (US)
  • Barrow Neurological Institute (US)
  • Cleveland Clinic (US)
  • Vall d'Hebron Hospital Universitari (ES)
  • University of Florence (IT)
  • Centre Hospitalier Universitaire de Bordeaux (FR)
  • Hôpital Purpan (FR)
  • Hôpital Roger Salengro (FR)
  • University of Genoa (IT)
  • Yale University (US)
Corresponding author
Okuda, Darin T.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2014-03-05
Volume
9
Issue
3
Pages
e90509
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0090509
PMC
PMC3943959
OpenAlex
W2063158442
Cited by
339
References
2
Citations by year
2026: 24 · 2025: 27 · 2024: 21 · 2023: 26 · 2022: 21 · 2021: 34 · 2020: 29 · 2019: 19 · 2018: 36 · 2017: 33 · 2016: 33 · 2015: 28 · 2014: 8
FWCI
25.28
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by)
  • Florence Research (University of Florence) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
  • CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
  • univOAK (4 institutions : Université de Strasbourg, Université de Haute Alsace, INSA Strasbourg, Bibliothèque Nationale et Universitaire de Strasbourg) (submittedVersion, cc-by)
  • Use Siena air (University of Siena) (submittedVersion)
Funders
  • Biogen
  • Teva Pharmaceutical Industries
  • Acorda Therapeutics
  • IC Design Education Center
  • Ipsen
  • Allergan
Topics
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Health Sciences › Medicine › Oncology › Polyomavirus and related diseases
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
Keywords
radiologically isolated syndrome, multiple sclerosis, primary progressive multiple sclerosis, risk factors, age, sex differences, spinal cord lesions, demyelination, brain MRI
MeSH terms
Adolescent, Adult, Aged, Child, Demyelinating Diseases, Female, Humans, Magnetic Resonance Imaging, Male, Middle Aged, Multiple Sclerosis, Retrospective Studies, Risk Factors, Spinal Cord, Multivariate Analysis, Proportional Hazards Models, Disease Progression, Disease-Free Survival, Incidental Findings, Kaplan-Meier Estimate, Young Adult

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