A three-year, multi-parametric MRI study in patients at presentation with CIS
To define the extent of overall brain damage in patients with clinically isolated syndromes (CIS) suggestive of multiple sclerosis (MS) and to identify non-conventional magnetic resonance (MR) metrics predictive of evolution to definite MS.
Brain conventional and magnetization transfer (MT) MRI scans were obtained from 208 CIS patients and 55 matched healthy controls, recruited in four centres. Patients were assessed clinically at the time of MRI acquisition and after a median period of 3.1 years from disease onset. The following measures were derived: T2, T1 and gadolinium (Gd)- enhancing lesion volumes (LV), normalized brain volume (NBV), MTR histogram-derived quantities of the normal-appearing white matter (NAWM) and grey matter (GM).
During the follow-up, 43 % of the patients converted to definite MS. At baseline, a significant inter-centre heterogeneity was detected for T2 LV (p = 0.003), T1 LV (p = 0.006), NBV (p < 0.001) and MTR histogram-derived metrics (p < 0.001). Pooled average MTR values differed between CIS patients and controls for NAWM (p = 0.003) and GM (p = 0.01). Gdactivity and positivity of International Panel (IP) criteria for disease dissemination in space (DIS), but not NAWM and GM MTR and NBV, were associated with evolution to definite MS. The final multivariable model retained only MRI IP criteria for DIS (p = 0.05; HR = 1.66, 95 % CI = 1.00–2.77) as an independent predictor of evolution to definite MS.
Although irreversible tissue injury is present from the earliest clinical stages of MS, macroscopic focal lesions but not "diffuse" brain damage measured by MTR are associated to an increased risk of subsequent development of definite MS in CIS patients.
Key wordsMRI clinically isolated syndrome multiple sclerosis magnetization transfer predictors disease evolution
- 5.Barkhof F, Rocca M, Francis G, van Waesberghe JHTM, Uitfrhaag BMJ, Hommes OR, Hartung HP, Durelli L, Edan G, Fernandez O, Seeldrayers P, Soelberg Sorensen P, Margrie S, Rovaris M, Comi G, Filippi M for the ETOMS Study Group (2003) Validation of diagnostic magnetic resonance imaging criteria for multiple sclerosis and response to interferon beta1a. Ann Neurol 53:718–724PubMedCrossRefGoogle Scholar
- 11.Caramia F, Pantano P, Di Legge S, Piattella MC, Lenzi D, Paolillo A, Nucciarelli W, Lenzi GL, Bozzao L, Pozzilli C (2002) A longitudinal study of MR diffusion changes in normal appearing white matter of patients with early multiple sclerosis. Magn Reson Imaging 20:383–388PubMedCrossRefGoogle Scholar
- 12.CHAMPS Study Group (2002) MRI predictors of early conversion to clinically definite MS in the CHAMPS placebo group. Neurology 59:998–1005Google Scholar
- 14.Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung HP, Seeldrayers P, Soelberg Sorensen P, Rovaris M, Martinelli V, Hommes OR and the ETOMS Study Group (2001) Effect of early interferon treatment on conversion to definite multiple sclerosis: a randomized study. Lancet 357:1576–1582PubMedCrossRefGoogle Scholar
- 15.Dalton CM, Brex PA, Jenkins R, Fox NC, Miszkiel KA, Crum WR, O’Riordan JI, Plant GT, Thompson AJ, Miller DH (2002) Progressive ventricular enlargement in patients with clinically isolated syndromes is associated with the early development of multiple sclerosis. J Neurol Neurosurg Psychiatry 73:141–147PubMedCrossRefGoogle Scholar
- 16.Dalton CM, Chard DT, Davies GR, Miszkiel KA, Altmann DR, Fernando K, Plant GT, Thompson AJ, Miller DH (2004) Early development of multiple sclerosis is associated with progressive grey matter atrophy in patients presenting with clinically isolated syndromes. Brain 127:1101–1107PubMedCrossRefGoogle Scholar
- 22.Filippi M, Rovaris M, Inglese M, Barkhof F, De Stefano N, Smith S, Comi G, and the ETOMS Study Group (2004) Interferon beta-1a for brain tissue loss in patients at presentation with syndromes suggestive of multiple sclerosis: a randomized, double-blind, placebo-controlled trial. Lancet 364:1489–1496PubMedCrossRefGoogle Scholar
- 23.Gallo A, Rovaris M, Riva R, Ghezzi A, Benedetti B, Martinelli V, Falini A, Comi G, Filippi M (2005) Diffusion- tensor magnetic resonance imaging detects normal-appearing white matter damage unrelated to short-term disease activity in patients at the earliest clinical stage of multiple sclerosis. Arch Neurol 62:803–808PubMedCrossRefGoogle Scholar
- 27.Kappos L, Polman CH, Freedman MS, Edan G, Hartung HP, Miller DH, Montalban X, Barkhof F, Bauer L, Jakobs P, Pohl C, Sandbrink R (2006) Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes. Neurology 67:1242–1249PubMedCrossRefGoogle Scholar
- 28.Korteweg T, Tintore M, Uitdehaag B, Rovira A, Frederiksen J, Miller D, Fernando K, Filippi M, Agosta F, Rocca MA, Fazekas F, Enziger C, Matthews P, Parry A, Polman C, Montalban X, Barkhof F (2006) MRI criteria for dissemination in space in patients with clinically isolated syndromes: a multicentre follow-up study. Lancet Neurol 5:221–227PubMedCrossRefGoogle Scholar
- 30.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 50:121–127PubMedCrossRefGoogle Scholar
- 36.Morrissey SP, Miller DH, Kendall BE, Kingsley DP, Kelly MA, Francis DA, MacManus DG, McDonald WI (1993) The significance of brain magnetic resonance imaging abnormalities at presentation with clinically isolated syndromes suggestive of multiple sclerosis. A 5-year follow-up study. Brain 116:135–146PubMedCrossRefGoogle Scholar
- 39.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, Wolinski JS (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the "McDonald Criteria". Ann Neurol 58:840–846PubMedCrossRefGoogle Scholar
- 45.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
- 49.van Waesberghe JH, Kamphorst W, DeGroot CJ, van Walderveen MA, Castelijns JA, Ravid R, Lycklama a Nijeholt GJ, van der Valk P, Polman CH, Thompson AJ, Barkhof F (1999) Axonal loss in multiple sclerosis lesions: magnetic resonance imaging insights into substrates of disability. Ann Neurol 46:747–754PubMedCrossRefGoogle Scholar