Journal of Neurology

, Volume 257, Issue 10, pp 1602–1611 | Cite as

The radiologically isolated syndrome: take action when the unexpected is uncovered?

  • Johann Sellner
  • Lucas Schirmer
  • Bernhard Hemmer
  • Mark Mühlau
Review

Abstract

The increasing diagnostic application of magnetic resonance imaging (MRI) in neurology has resulted in an increase in accidental disclosure of asymptomatic brain pathologies with potential clinical significance. Here, we discuss the incidental detection of multiple sclerosis (MS) typical central nervous system (CNS) lesions fulfilling MRI criteria for dissemination in space (radiologically isolated syndrome, RIS) and its diagnostic, prognostic and therapeutic implications. Three recent studies, including a total of 136 RIS cases which were followed for up to 10 years, indicate that a subgroup of such patients will develop MS. MRI-based dissemination in time (DIT) was determined in more than two-thirds and clinically isolated syndrome (CIS) occurred in almost one-third of the patients. Presence of Gadolinium (Gd)-enhancing lesions was identified as potential predictor for MRI-based DIT in one study, and pathological visual evoked potential (VEP) examinations at baseline and Gd-enhancement at the second MRI scan for CIS (clinical DIT) in another study. In the lack of established management guidelines, we propose a pragmatic diagnostic and therapeutic approach for patients with RIS. Individual concepts are required and both “wait” as well as “follow” strategies are justifiable. Further prospective studies are required to elucidate potential biomarkers for narrowing down the high-risk cohort and exploring further characteristics of this disease stage.

Keywords

Multiple sclerosis Clinically isolated syndrome Prognosis Magnetic resonance imaging Immunomodulation 

Notes

Acknowledgments

This study was supported by a KKF grant from the Medical Faculty of the Technische Universität München to JS.

Conflict of interest statement

JS and LS have nothing to disclose. BH has received honoraria for lecturing, travel expenses for attending meetings, and received research support from Bayer Schering, Biogen Idec, Merck Serono, and Teva Pharmaceutical. MM has received travel expenses for attending meetings from Bayer and research support from Merck Serono.

References

  1. 1.
    Barkhof F, Filippi M, Miller DH, Scheltens P, Campi A, Polman CH, Comi G, Ader HJ, Losseff N, Valk J (1997) Comparison of MRI criteria at first presentation to predict conversion to clinically definite multiple sclerosis. Brain 120:2059–2069CrossRefPubMedGoogle Scholar
  2. 2.
    Benedict RH, Fazekas F (2009) Benign or not benign MS. A role for routine neuropsychological assessment? Neurology 73:494–495CrossRefPubMedGoogle Scholar
  3. 3.
    Bot JC, Barkhof F, Polman CH, Lycklama a Nijeholt GJ, de Groot V, Bergers E, Ader HJ, Castelijns JA (2004) Spinal cord abnormalities in recently diagnosed MS patients: added value of spinal MRI examination. Neurology 62:226–233PubMedGoogle Scholar
  4. 4.
    Bourdette D, Simon J (2009) The radiologically isolated syndrome: is it very early multiple sclerosis? Neurology 72:780–781CrossRefPubMedGoogle Scholar
  5. 5.
    Brex PA, Miszkiel KA, O’Riordan JI, Plant GT, Moseley IF, Thompson AJ, Miller DH (2001) Assessing the risk of early multiple sclerosis in patients with clinically isolated syndromes: the role of a follow up MRI. J Neurol Neurosurg Psychiatry 70:390–393CrossRefPubMedGoogle Scholar
  6. 6.
    Butler MA, Bennett TL (2003) In search of a conceptualization of multiple sclerosis: a historical perspective. Neuropsychol Rev 13:93–112CrossRefPubMedGoogle Scholar
  7. 7.
    Castaigne P, Lhermitte F, Escourolle R, Hauw JJ, Gray F, Lyon-Caen O (1981) Les scleroses en plaques asymptomatiques. Rev Neurol (Paris) 137:729–739Google Scholar
  8. 8.
    Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomised study. Lancet 357:1576–1582CrossRefPubMedGoogle Scholar
  9. 9.
    Compston A, Coles A (2008) Multiple sclerosis. Lancet 372:1502–1517CrossRefPubMedGoogle Scholar
  10. 10.
    Confavreux C, Vukusic S (2008) The clinical epidemiology of multiple sclerosis. Neuroimaging Clin N Am 18:589–622CrossRefPubMedGoogle Scholar
  11. 11.
    Engell T (1989) A clinical patho-anatomical study of clinically silent multiple sclerosis. Acta Neurol Scand 79:428–430CrossRefPubMedGoogle Scholar
  12. 12.
    Ergun U, Ozer G, Sekercan S, Artan E, Kudiaki C, Ucler S, Coskun O, Inan L (2009) Headaches in the different phases of relapsing-remitting multiple sclerosis: a tendency for stabbing headaches during relapses. Neurologist 15:212–216CrossRefPubMedGoogle Scholar
  13. 13.
    Feuillet L, Reuter F, Audoin B, Malikova I, Barrau K, Cherif AA, Pelletier J (2007) Early cognitive impairment in patients with clinically isolated syndrome suggestive of multiple sclerosis. Mult Scler 13:124–127CrossRefPubMedGoogle Scholar
  14. 14.
    Fisniku LK, Brex PA, Altmann DR, Miszkiel KA, Benton CE, Lanyon R, Thompson AJ, Miller DH (2008) Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis. Brain 131:808–817CrossRefPubMedGoogle Scholar
  15. 15.
    Frischer JM, Bramow S, Dal-Bianco A, Lucchinetti CF, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Lassmann H (2009) The relation between inflammation and neurodegeneration in multiple sclerosis brains. Brain 132:1175–1189CrossRefPubMedGoogle Scholar
  16. 16.
    Gilbert JJ, Sadler M (1983) Unsuspected multiple sclerosis. Arch Neurol 40:533–536PubMedGoogle Scholar
  17. 17.
    Hakiki B, Goretti B, Portaccio E, Zipoli V, Amato MP (2008) ‘Subclinical MS’: follow-up of four cases. Eur J Neurol 15:858–861CrossRefPubMedGoogle Scholar
  18. 18.
    Hemmer B, Nessler S, Zhou D, Kieseier B, Hartung HP (2006) Immunopathogenesis and immunotherapy of multiple sclerosis. Nat Clin Pract Neurol 2:201–211CrossRefPubMedGoogle Scholar
  19. 19.
    Hutchinson M (2009) Predicting and preventing the future: actively managing multiple sclerosis. Pract Neurol 9:133–143, (discussion 144)Google Scholar
  20. 20.
    Jacobi C, Hahnel S, Martinez-Torres F, Rieger S, Juttler E, Heiland S, Jarius S, Meyding-Lamade U, Storch-Hagenlocher B, Wildemann B (2008) Prospective combined brain and spinal cord MRI in clinically isolated syndromes and possible early multiple sclerosis: impact on dissemination in space and time. Eur J Neurol 15:1359–1364CrossRefPubMedGoogle Scholar
  21. 21.
    Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, Simonian NA, Slasor PJ, Sandrock AW (2000) Intramuscular interferon beta-1a therapy initiated during a first demyelinating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 343:898–904CrossRefPubMedGoogle Scholar
  22. 22.
    Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Radu EW, Metzig C, Bauer L, Lanius V, Sandbrink R, Pohl C (2009) Long-term effect of early treatment with interferon beta-1b after a first clinical event suggestive of multiple sclerosis: 5-year active treatment extension of the phase 3 BENEFIT trial. Lancet Neurol 8:987–997CrossRefPubMedGoogle Scholar
  23. 23.
    Kobelt G, Berg J, Lindgren P, Kerrigan J, Russell N, Nixon R (2006) Costs and quality of life of multiple sclerosis in the United Kingdom. Eur J Health Econ 7 S2:S96–104Google Scholar
  24. 24.
    Kurne A, Isikay IC, Karlioguz K, Kalyoncu U, Aydin OF, Calguneri M, Karabudak R (2008) A clinically isolated syndrome: a challenging entity: multiple sclerosis or collagen tissue disorders: clues for differentiation. J Neurol 255:1625–1635CrossRefPubMedGoogle Scholar
  25. 25.
    Lebrun C, Bensa C, Debouverie M, De Seze J, Wiertlievski S, Brochet B, Clavelou P, Brassat D, Labauge P, Roullet E (2008) Unexpected multiple sclerosis: follow-up of 30 patients with magnetic resonance imaging and clinical conversion profile. J Neurol Neurosurg Psychiatry 79:195–198CrossRefPubMedGoogle Scholar
  26. 26.
    Lebrun C, Bensa C, Debouverie M, Wiertlevski S, Brassat D, de Seze J, Rumbach L, Pelletier J, Labauge P, Brochet B, Tourbah A, Clavelou P (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 66:841–846CrossRefPubMedGoogle Scholar
  27. 27.
    Lyoo IK, Seol HY, Byun HS, Renshaw PF (1996) Unsuspected multiple sclerosis in patients with psychiatric disorders: a magnetic resonance imaging study. J Neuropsychiatry Clin Neurosci 8:54–59PubMedGoogle Scholar
  28. 28.
    McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, McFarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, van den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127CrossRefPubMedGoogle Scholar
  29. 29.
    Miller D, Barkhof F, Montalban X, Thompson A, Filippi M (2005) Clinically isolated syndromes suggestive of multiple sclerosis, part I: natural history, pathogenesis, diagnosis, and prognosis. Lancet Neurol 4:281–288CrossRefPubMedGoogle Scholar
  30. 30.
    Miller D, McDonald I, Smith K (2006) The diagnosis of multiple sclerosis. In: Compston A (ed) McAlpine’s multiple sclerosis. Churchill Livingstone Elsevier, Cambridge, pp 347–388Google Scholar
  31. 31.
    Miller DH, Weinshenker BG, Filippi M, Banwell BL, Cohen JA, Freedman MS, Galetta SL, Hutchinson M, Johnson RT, Kappos L, Kira J, Lublin FD, McFarland HF, Montalban X, Panitch H, Richert JR, Reingold SC, Polman CH (2008) Differential diagnosis of suspected multiple sclerosis: a consensus approach. Mult Scler 14:1157–1174CrossRefPubMedGoogle Scholar
  32. 32.
    Morris Z, Whiteley WN, Longstreth WT Jr, Weber F, Lee YC, Tsushima Y, Alphs H, Ladd SC, Warlow C, Wardlaw JM, Al-Shahi Salman R (2009) Incidental findings on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 339:b3016CrossRefPubMedGoogle Scholar
  33. 33.
    Mowry EM, Pesic M, Grimes B, Deen S, Bacchetti P, Waubant E (2009) Demyelinating events in early multiple sclerosis have inherent severity and recovery. Neurology 72:602–608CrossRefPubMedGoogle Scholar
  34. 34.
    Neema M, Goldberg-Zimring D, Guss ZD, Healy BC, Guttmann CR, Houtchens MK, Weiner HL, Horsfield MA, Hackney DB, Alsop DC, Bakshi R (2009) 3 T MRI relaxometry detects T2 prolongation in the cerebral normal-appearing white matter in multiple sclerosis. Neuroimage 46:633–641CrossRefPubMedGoogle Scholar
  35. 35.
    Okuda DT (2009) Unanticipated demyelinating pathology of the CNS. Nat Rev Neurol 5:591–597CrossRefPubMedGoogle Scholar
  36. 36.
    Okuda DT, Mowry EM, Beheshtian A, Waubant E, Baranzini SE, Goodin DS, Hauser SL, Pelletier D (2009) Incidental MRI anomalies suggestive of multiple sclerosis: the radiologically isolated syndrome. Neurology 72:800–805CrossRefPubMedGoogle Scholar
  37. 37.
    Pittock SJ, McClelland RL, Mayr WT, Jorgensen NW, Weinshenker BG, Noseworthy J, Rodriguez M (2004) Clinical implications of benign multiple sclerosis: a 20-year population-based follow-up study. Ann Neurol 56:303–306CrossRefPubMedGoogle Scholar
  38. 38.
    Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 58:840–846CrossRefPubMedGoogle Scholar
  39. 39.
    Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, Johnson KP, Sibley WA, Silberberg DH, Tourtellotte WW (1983) New diagnostic criteria for multiple sclerosis: guidelines for research protocols. Ann Neurol 13:227–231CrossRefPubMedGoogle Scholar
  40. 40.
    Putzki N, Pfriem A, Limmroth V, Yaldizli O, Tettenborn B, Diener HC, Katsarava Z (2009) Prevalence of migraine, tension-type headache and trigeminal neuralgia in multiple sclerosis. Eur J Neurol 16:262–267CrossRefPubMedGoogle Scholar
  41. 41.
    Ranjeva JP, Audoin B, Au Duong MV, Confort-Gouny S, Malikova I, Viout P, Soulier E, Pelletier J, Cozzone PJ (2006) Structural and functional surrogates of cognitive impairment at the very early stage of multiple sclerosis. J Neurol Sci 245:161–167CrossRefPubMedGoogle Scholar
  42. 42.
    Rocca MA, Ceccarelli A, Falini A, Colombo B, Tortorella P, Bernasconi L, Comi G, Scotti G, Filippi M (2006) Brain gray matter changes in migraine patients with T2-visible lesions: a 3-T MRI study. Stroke 37:1765–1770CrossRefPubMedGoogle Scholar
  43. 43.
    Schirmer L, Albert M, Buss A, Schulz-Schaeffer WJ, Antel JP, Brück W, Stadelmann C (2009) Substantial early, but non-progressive neuronal loss in MS spinal cord. Ann Neurol 66:698–704CrossRefPubMedGoogle Scholar
  44. 44.
    Sellner J, Greeve I, Findling O, Kamm CP, Minten C, Engelhardt B, Grandgirard D, Leib SL, Mattle HP (2008) Effect of interferon-beta and atorvastatin on Th1/Th2 cytokines in multiple sclerosis. Neurochem Int 53:17–21CrossRefPubMedGoogle Scholar
  45. 45.
    Sellner J, Greeve I, Leib SL, Mattle HP (2008) Atorvastatin does not alter interferon Beta-induced changes of serum matrix metalloproteinase 9 and tissue inhibitor of metalloproteinase 1 in patients with multiple sclerosis. Arch Neurol 65:672–674CrossRefPubMedGoogle Scholar
  46. 46.
    Simioni S, Ruffieux C, Bruggimann L, Annoni JM, Schluep M (2007) Cognition, mood and fatigue in patients in the early stage of multiple sclerosis. Swiss Med Wkly 137:496–501PubMedGoogle Scholar
  47. 47.
    Siva A, Saip S, Altintas A, Jacob A, Keegan B, Kantarci O (2009) Multiple sclerosis risk in radiologically uncovered asymptomatic possible inflammatory-demyelinating disease. Mult Scler 15:918–927CrossRefPubMedGoogle Scholar
  48. 48.
    Thrower BW (2007) Clinically isolated syndromes: predicting and delaying multiple sclerosis. Neurology 68:S12–S15CrossRefPubMedGoogle Scholar
  49. 49.
    Tienari PJ, Salonen O, Wikstrom J, Valanne L, Palo J (1992) Familial multiple sclerosis: MRI findings in clinically affected and unaffected siblings. J Neurol Neurosurg Psychiatry 55:883–886CrossRefPubMedGoogle Scholar
  50. 50.
    Tintore M (2008) Rationale for early intervention with immunomodulatory treatments. J Neurol 255 (Suppl 1):37–43Google Scholar
  51. 51.
    Tintore M, Rovira A, Martinez MJ, Rio J, Diaz-Villoslada P, Brieva L, Borras C, Grive E, Capellades J, Montalban X (2000) Isolated demyelinating syndromes: comparison of different MR imaging criteria to predict conversion to clinically definite multiple sclerosis. AJNR Am J Neuroradiol 21:702–706PubMedGoogle Scholar
  52. 52.
    Tintore M, Rovira A, Rio J, Nos C, Grive E, Sastre-Garriga J, Pericot I, Sanchez E, Comabella M, Montalban X (2003) New diagnostic criteria for multiple sclerosis: application in first demyelinating episode. Neurology 60:27–30PubMedGoogle Scholar
  53. 53.
    Tintore M, Rovira A, Rio J, Nos C, Grive E, Tellez N, Pelayo R, Comabella M, Sastre-Garriga J, Montalban X (2006) Baseline MRI predicts future attacks and disability in clinically isolated syndromes. Neurology 67:968–972CrossRefPubMedGoogle Scholar
  54. 54.
    Tintore M, Rovira A, Rio J, Tur C, Pelayo R, Nos C, Tellez N, Perkal H, Comabella M, Sastre-Garriga J, Montalban X (2008) Do oligoclonal bands add information to MRI in first attacks of multiple sclerosis? Neurology 70:1079–1083CrossRefPubMedGoogle Scholar
  55. 55.
    Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L (1998) Axonal transection in the lesions of multiple sclerosis. N Engl J Med 338:278–285CrossRefPubMedGoogle Scholar
  56. 56.
    Weiner HL (2009) The challenge of multiple sclerosis: how do we cure a chronic heterogeneous disease? Ann Neurol 65:239–248CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Johann Sellner
    • 1
  • Lucas Schirmer
    • 1
  • Bernhard Hemmer
    • 1
  • Mark Mühlau
    • 1
  1. 1.Neurologische Klinik und Poliklinik, Klinikum rechts der IsarTechnische Universität MünchenMunichGermany

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