Subtraction MR images in a multiple sclerosis multicenter clinical trial setting

Radiology. 2009 Feb;250(2):506-14. doi: 10.1148/radiol.2501080480. Epub 2008 Nov 26.


Purpose: To explore the applicability of subtraction magnetic resonance (MR) images to (a) detect active multiple sclerosis (MS) lesions, (b) directly quantify lesion load change, and (c) detect treatment effects (distinguish treatment arms) in a placebo-controlled multicenter clinical trial by comparing the subtraction scheme with a conventional pair-wise comparison of nonregistered MR images.

Materials and methods: Forty-six pairs of MR studies in 40 patients (31 women; mean age, 31.9 years) from a multicenter clinical trial were used. The clinical trial was approved by local ethics review boards, and all subjects gave written informed consent. Active MS lesions were scored by two independent raters, and lesion load measurements were conducted by using semiautomated software. Lesion counts were evaluated by using the Wilcoxon signed rank test, interrater agreement was evaluated by using the intraclass correlation coefficient (ICC), and treatment (interferon beta-1b) effect was evaluated by using the Mann-Whitney U test.

Results: When subtraction images were used, there was a 1.7-fold increase in the detection of positive active lesions, as compared with native image pairs, and significantly greater interobserver agreement (ICC = 0.98 vs 0.91, P < .001). Subtraction images also allowed direct quantification of positive disease activity, a measure that provided sufficient power to distinguish treatment arms (P = .012) compared with the standard measurement of total lesion load change on native images (P = .455).

Conclusion: MR image subtraction enabled detection of higher numbers of active MS lesions with greater interobserver agreement and exhibited increased power to distinguish treatment arms, as compared with a conventional pair-wise comparison of nonregistered MR images.

Publication types

  • Multicenter Study
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Artifacts
  • Brain / pathology*
  • Female
  • Humans
  • Immunologic Factors / therapeutic use*
  • Interferon-beta / therapeutic use*
  • Magnetic Resonance Imaging / methods*
  • Male
  • Middle Aged
  • Multiple Sclerosis / drug therapy*
  • Multiple Sclerosis / pathology*
  • Placebos
  • Statistics, Nonparametric
  • Subtraction Technique
  • Treatment Outcome


  • Immunologic Factors
  • Placebos
  • Interferon-beta