Original ResearchFree Access

Accuracy of Unenhanced MRI in the Detection of New Brain Lesions in Multiple Sclerosis

Published Online:https://doi.org/10.1148/radiol.2019181568

Abstract

Background

Administration of a gadolinium-based contrast material is widely considered obligatory for follow-up imaging of patients with multiple sclerosis (MS). However, advances in MRI have substantially improved the sensitivity for detecting new or enlarged lesions in MS.

Purpose

To investigate whether the use of contrast material has an effect on the detection of new or enlarged MS lesions and, consequently, the assessment of interval progression.

Materials and Methods

In this retrospective study based on a local prospective observational cohort, 507 follow-up MR images obtained in 359 patients with MS (mean age, 38.2 years ± 10.3; 246 women, 113 men) were evaluated. With use of subtraction maps, nonenhanced images (double inversion recovery [DIR], fluid-attenuated inversion recovery [FLAIR]) and contrast material–enhanced (gadoterate meglumine, 0.1 mmol/kg) T1-weighted images were separately assessed for new or enlarged lesions in independent readings by two readers blinded to each other’s findings and to clinical information. Primary outcome was the percentage of new or enlarged lesions detected only on contrast-enhanced T1-weighted images and the assessment of interval progression. Interval progression was defined as at least one new or unequivocally enlarged lesion on follow-up MR images.

Results

Of 507 follow-up images, 264 showed interval progression, with a total of 1992 new or enlarged and 207 contrast-enhancing lesions. Four of these lesions (on three MR images) were retrospectively detected on only the nonenhanced images, corresponding to 1.9% (four of 207) of the enhancing and 0.2% (four of 1992) of all new or enlarged lesions. Nine enhancing lesions were not detected on FLAIR-based subtraction maps (nine of 1442, 0.6%). In none of the 507 images did the contrast-enhanced sequences reveal interval progression that was missed in the readouts of the nonenhanced sequences, with use of either DIR- or FLAIR-based subtraction maps. Interrater agreement was high for all three measures, with intraclass correlation coefficients of 0.91 with FLAIR, 0.94 with DIR, and 0.99 with contrast-enhanced T1-weighted imaging.

Conclusion

At 3.0 T, use of a gadolinium-based contrast agent at follow-up MRI did not change the diagnosis of interval disease progression in patients with multiple sclerosis.

© RSNA, 2019

See also the editorial by Saindane in this issue.

Summary

At 3.0 T, use of a gadolinium-based contrast material at follow-up MRI did not change the diagnosis of interval disease progression in patients with multiple sclerosis.

Key Points

  • ■ In more than 500 follow-up images, only four of 1996 new or enlarged multiple sclerosis lesions would have been missed with 3.0-T MRI without the administration of contrast material.

  • ■ With 3.0-T MRI, the assessment of interval progression did not differ between contrast-enhanced and nonenhanced images.

Introduction

Inflammatory lesions in multiple sclerosis (MS) are detected as focal areas of high signal intensity on T2-weighted MR images. By depicting newly occurring lesions, MRI reveals subclinical disease activity. Therefore, regular follow-up MRI is considered a mainstay of clinical care for patients with MS or clinically isolated syndromes.

Earlier studies have reported that the administration of contrast material is necessary to maximize sensitivity for detecting new lesions (1,2). However, these results date back more than 2 decades and were based on two-dimensional images obtained with 4–5-mm-thick sections at magnetic field strengths of 1.5 T and lower.

MRI units with higher field strengths have become widely available, especially for brain imaging. In addition, three-dimensional isotropic MRI sequences were introduced and were shown to outperform conventional two-dimensional sequences in lesion depiction (3,4); they are therefore part of recommended MRI standards in MS (5,6). Furthermore, the double inversion-recovery (DIR) sequence (7) was introduced. Although this sequence is best known for its ability to depict cortical lesions (8,9), it is also useful for depicting white matter lesions (10). Recently, longitudinal subtraction techniques have been developed that show new or enlarged lesions as bright spots while pre-existing lesions and normal-appearing brain parenchyma are canceled out. Such techniques substantially improve the sensitivity in the detection of new or enlarged lesions in MS at follow-up imaging (1113).

We hypothesized that the use of contrast material does not improve sensitivity in the detection of new or enlarged lesions at follow-up MRI when modern three-dimensional sequences performed at a field strength of 3.0 T are used together with longitudinal subtraction maps. We therefore performed this study to investigate whether the use of contrast material has an effect on the detection of new or enlarged MS lesions and, consequently, the assessment of interval progression.

Materials and Methods

This retrospective study was approved by the local institutional review board, and written informed consent was obtained from all patients.

Cohort

We performed a retrospective analysis of a prospective observational single-center cohort of patients with clinically isolated syndrome, MS, or radiologically isolated syndrome. Patients who had undergone at least two MRI examinations at our institution with a full imaging protocol, including contrast-enhanced T1-weighted MRI, between January 2014 and December 2016 were eligible. Of 481 potentially eligible patients, 117 were excluded owing to lack of a follow-up examination or an incomplete imaging protocol (Fig 1). In addition, five patients were excluded for technical reasons: three because there was insufficient suppression of white matter signal on images from the DIR sequence, one because of severe foreign body artifacts, and one because of severe artifacts in the calculated subtraction maps. Thus, 359 patients who underwent 866 MRI examinations were included in data analysis. There were 507 pairs of baseline and follow-up images. The time between baseline and follow-up imaging varied between 1 month and more than 2 years. In addition, the reason for MRI (routine follow-up vs clinical suspicion of disease activity) was noted.

Figure 1:

Figure 1: Flowchart shows inclusion and exclusion criteria. DIR = double inversion recovery, FLAIR = fluid attenuated inversion recovery.

Imaging Protocol

Images were acquired with a 3.0-T system (Achieva; Philips Healthcare, Best, the Netherlands) and included a three-dimensional fluid-attenuated inversion-recovery (FLAIR) sequence, a three-dimensional DIR sequence, and a three-dimensional T1-weighted sequence performed before and at least 5 minutes after administration of 0.1 mmol/kg gadolinium-based contrast material (Dotarem [gadoterate meglumine]; Guerbet, Villepinte, France). The following parameters were used for three-dimensional DIR imaging: acquired voxel size, 1.2 × 1.2 × 1.3 mm3; repetition time msec/echo time msec, 5500/328; acquisition time, 6 minutes; plane, sagittal. The following parameters were used for three-dimensional FLAIR imaging: acquired voxel size, 1.03 × 1.03 × 1.5 mm3; 10 000/140; acquisition time, 5 minutes; plane, axial. The following parameters were used for three-dimensional T1-weighted gradient-echo imaging: acquired voxel size, 1 × 1 × 1 mm3; 9/4; acquisition time, 6 minutes; plane, sagittal.

Image Postprocessing

All images were coregistered with rigid registration (SPM 12 open source software; Functional Imaging Laboratory, Wellcome Trust Centre for Neuroimaging, London, England), with the latest DIR volume used as the reference image. For every pair of baseline and follow-up images, a longitudinal DIR subtraction map and a longitudinal FLAIR subtraction map were generated as described in an earlier study (13). When more than one follow-up image was available for a patient, the immediately preceding image was used as a baseline. Analogously, to better visualize contrast enhancement, the T1-weighted images obtained after contrast material administration were subtracted from those obtained before contrast material administration after applying a regression-based intensity adjustment.

Image Analysis

“Interval progression” was defined as the presence of at least one new or unequivocally enlarged (>50% diameter increase) lesion with a diameter of at least 3 mm (14) on follow-up MR images. Two neuroradiologists (P.E. and S.S., with 6 and 8 years of experience, respectively) assessed the MR images in three different readouts. First, baseline and follow-up images were read side by side and analyzed for new or enlarged lesions by using DIR-based subtraction maps together with the respective source images. Areas of high signal intensity on these subtraction images were classified as new or enlarged lesions if they were not present at baseline MRI and if they could be verified on the nonprocessed source images. New or enlarged lesions were marked with open-source software (ITK-SNAP version 3.6; www.itksnap.org) (15). In a second readout, FLAIR-based subtraction maps (and source images) were analogously assessed for new or enlarged lesions. In the final readout, images were assessed for contrast-enhancing lesions. For this analysis, we used the T1-weighted images obtained before and after contrast material administration and the corresponding subtraction images obtained with the T1-weighted sequences. In this readout, no images from earlier examinations or other information regarding preexisting lesions was available to the readers. Contrast-enhancing lesions were also marked with ITK-SNAP.

For all MRI interpretations, readers were blinded to each other’s findings and to clinical information. The order in which the images were read was randomized to minimize the risk of potential recall bias. The time between readings was 4–8 weeks.

Finally, the two neuroradiologists compared every contrast-enhancing lesion documented in the segmentation files to the markings of new or enlarged lesions on the nonenhanced images and noted the number of new, enhancing, and discrepant lesions—that is, the lesions that showed contrast enhancement but were not designated as new or enlarged lesions on the nonenhanced images.

Statistical Analysis

Lesion counts in symptomatic patients were compared with those in patients who underwent imaging as part of a scheduled routine follow-up examination by using the Mann-Whitney U test. Binary data on the presence of contrast-enhancing lesions and the indication for imaging were compared with the Fisher exact test. Intraclass correlation coefficients were calculated to assess interrater reliability with use of single measures for absolute agreement from a two-way mixed model. Statistical computations were performed with software (SPSS Statistics for Windows, version 25.0; IBM, Armonk, NY). P < .05 was considered to indicate a statistically significant difference.

Results

Patient Demographics

Of the 359 patients included in this study, 246 (68.5%) were women. The mean patient age at baseline examination was 38.2 years ± 10.3 (women, 38.2 years ± 10.7; men, 38.1 years ± 9.4). Most patients (315 of 359, 88%) had a relapsing-remitting disease course. Of the 507 follow-up examinations, 335 (66%) were performed as part of a routine follow-up, whereas 172 (34%) were performed because of clinically suspected disease activity. All relevant patient demographics are summarized in Table 1.

Table 1: Patient Characteristics

Table 1:

Note.—Unless otherwise specified, data are numbers of patients, with percentages in parentheses.

*Data are numbers of examinations, with percentages in parentheses.

Data are medians, with ranges in parentheses.

New and Enhancing Lesions

In the assessment of nonenhanced MRI and with use of the DIR images together with the subtraction maps, new or enlarged lesions were identified on 264 of the 507 follow-up images depicting a total of 1992 lesions. The median number of new or enlarged lesions in patients who showed interval progression was three (25% quantile, one; 75% quantile, seven); the maximum was 182. All lesions found on the DIR subtraction maps could be successfully validated with the corresponding source images. The median number of new or enlarged lesions was not significantly different between images obtained for routine follow-up (median, one; 25% quantile, zero; 75% quantile, four) and those obtained for clinically suspected disease activity (median, one; 25% quantile, zero; 75% quantile, two) (P = .33, Mann-Whitney U test).

When combining the information from both readers as established during the consensus reading, 207 enhancing lesions (median, one; 25% quantile, one; 75% quantile, two; maximum, 58) were detected in 69 of the 507 examinations. The number of new contrast-enhancing lesions was higher in patients who underwent imaging for suspected disease activity (median, zero; 25% quantile, zero; 75% quantile, zero; maximum, 58) than in those who underwent imaging for routine follow-up (median, zero; 25% quantile, zero; 75% quantile, zero; maximum, 15). These differences were statistically significant (P = .02, Mann-Whitney U test). Analysis of binary data on the presence of contrast-enhancing lesions (yes or no) and reason for imaging (suspected disease activity or routine follow-up) concordantly showed a significantly higher proportion of images with contrast-enhancing lesions in patients with clinically suspected disease activity (31 of 172 vs 35 of 335; P = .02, Fisher exact test).

We detected 27.6% fewer new or enlarged lesions with FLAIR-based subtraction maps compared with DIR-based subtraction maps (1442 lesions vs 1992 lesions, respectively).

Discrepant Lesions

Of 207 contrast-enhancing lesions, 203 (98.1%) were detected as new or enlarged lesions on nonenhanced MR images together with the DIR subtraction maps (based on the consensus readings). The four undetected lesions (in three MRI examinations) were retrospectively confirmed as true new lesions that were missed by both readers on unenhanced MR images. Figures 24 show examples of such missed lesions. For those three MRI examinations, all showed a marked increase in lesion load. The first examination had 27 new and eight enhancing lesions, the second had 47 new and six enhancing lesions, and the third had 182 new and 58 enhancing lesions. In the last examination, two of the enhancing lesions were missed. Of these three examinations, two were performed as part of routine follow-up (with two new or enlarged lesions missed) and one was conducted because of clinically suspected disease activity (with two new or enlarged lesions missed). Overall, disease progression was not missed in any patient when only the nonenhanced images were assessed.

Figure 2:

Figure 2: Axial MR images obtained in 32-year-old woman with relapsing-remitting multiple sclerosis. Images were obtained with subtraction of unenhanced T1-weighted MR image from contrast-enhanced MR image (T1sub), fluid-attenuated inversion recovery (FLAIR), and double inversion recovery (DIR). The new lesion (arrow), a small, subcortical lesion in right parietal lobe, is seen only on contrast-enhanced image; it was overlooked on DIR and FLAIR images. Note that there are several other new or enlarged lesions that can be seen on nonenhanced images.

Figure 3:

Figure 3: Axial MR images in 27-year-old man with relapsing-remitting multiple sclerosis. Images were obtained with subtraction of unenhanced T1-weighted MR image from contrast-enhanced MR image (T1sub), fluid-attenuated inversion recovery (FLAIR), and double inversion recovery (DIR). The new lesion (arrow), a small left periventricular lesion, is seen only on contrast-enhanced image; it was overlooked on DIR and FLAIR images. Note that there are several other new or enlarged lesions that are readily seen on nonenhanced images.

Figure 4:

Figure 4: Axial MR images in 24-year-old woman with relapsing-remitting multiple sclerosis. Images were obtained with subtraction of unenhanced T1-weighted MR image from contrast-enhanced MR image (T1sub), fluid-attenuated inversion recovery (FLAIR), and double inversion recovery (DIR). The new lesion, a small subcortical lesion in right frontal lobe, was detected only on contrast-enhanced image; it was overlooked on DIR and FLAIR images. Note that there are several other new or enlarged lesions readily seen on nonenhanced images.

For FLAIR-based subtraction maps, one reader missed eight of the enhancing lesions and the other missed 10. When readers used FLAIR data only, disease progression was not missed in any patient.

With subtraction-based approaches, interrater agreement was very high for all three readouts. The intraclass correlation coefficient was 0.99 for contrast-enhancing lesions, 0.94 for DIR-based subtraction maps, and 0.91 for FLAIR-based subtraction maps (Table 2).

Table 2: Intraclass Correlation Coefficients for Interrater Agreement

Table 2:

Note.—Data are intraclass correlation coefficients, with 95% confidence intervals in parentheses. DIR = double inversion recovery, FLAIR = fluid-attenuated inversion recovery.

Discussion

Our underlying hypothesis was that the administration of a gadolinium-based contrast material would not result in higher sensitivity in the detection of new or enlarged MS lesions at follow-up MRI when 3.0-T MRI was used together with current MRI protocols, including subtraction images from baseline and follow-up MRI examinations. In our cohort, contrast-enhanced T1-weighted MRI provided no benefit at a per-patient level over longitudinal subtraction maps obtained from nonenhanced sequences for detecting new or enlarged lesions in 507 follow-up examinations of patients with MS. In no case was interval progression missed when only nonenhanced sequences were analyzed. On a per-lesion basis, less than 1% of new or enlarged lesions were overlooked when only nonenhanced sequences were analyzed. Thus, our data do not support the notion that the use of contrast material results in higher sensitivity for the detection of new or enlarged lesions in MS compared with unenhanced MRI at 3.0 T.

There are several clinical scenarios in which the use of contrast material in MS is required owing to the additional temporal information. Contrast-enhanced MRI is used as the initial MRI examination in a patient presenting with symptoms suspicious for MS (14). Gadolinium-based contrast material may also be indicated for the first follow-up MRI examination after a recent change in medical treatment. Because lesion enhancement corresponds to a lesion age of only a few weeks (16), gadolinium-enhanced MRI provides information on whether a lesion developed before or after the current medication was expected to be efficacious. In addition, when it is unclear whether a clinical worsening is caused by MS relapse, contrast-enhanced MRI may help clinicians determine whether to administer steroids. However, for routine MRI follow-up of patients with a stable medication regimen and clinical status, temporal enhancement patterns of lesions at MRI are typically not relevant for clinical decision making.

In our study, we relied on longitudinal subtraction maps for detecting new or enlarged lesions. Several prior studies have reported the use of these maps to increase sensitivity for interval progression (11,13) or reduce reading time (17). These maps are easy to calculate, requiring only the coregistration of images, and have a high lesion-to-background ratio. In addition, these maps help identify changes in size (and shape) of pre-existing lesions, further increasing the sensitivity in the detection of interval progression. In our cohort of 508 pairs of images, calculation of subtraction maps failed in only one follow-up examination. This highlights the robustness of this approach. The tools to calculate these maps are available as open-source software (13), and several vendors now sell such software for inclusion in the routine workflow.

Several algorithms and tools for automatic detection (and segmentation) of MS lesions have been developed (1820). Besides focusing on segmenting images from a single time point, strategies have been proposed to assess longitudinal changes in images and thereby to assist radiologists in detecting interval progression (21,22); such strategies already partially use subtraction maps for improved detection (23). Recently, multiscale convolutional neural networks have been shown to deliver robust segmentation of white matter hyperintensities on FLAIR and unenhanced T1-weighted images, outperforming prior approaches (24). Acting as an independent reader, these algorithms have the potential to meaningfully support assessment of MR images and help the radiologist further improve sensitivity in the assessment of interval progression.

Our study had several limitations. Our results were achieved with 3.0-T MRI with use of three-dimensional sequences and a single contrast agent (gadoterate dimeglumine). It is unclear whether they can be translated to 1.5-T MRI and/or two- dimensional sequences. Furthermore, we used three-dimensional gradient-echo T1-weighted sequences to detect contrast enhancement. Although some studies have suggested that three-dimensional spin-echo sequences are more sensitive for contrast enhancement than gradient-echo sequences (25), others have come to the opposite conclusion (26,27). However, we improved sensitivity for contrast enhancement by calculating intensity-harmonized subtraction maps between pre- and postcontrast T1-weighted images. Also, the DIR sequence used in our study is not commonly included in MS protocols. Although the DIR sequence is mostly regarded as a tool for depicting cortical lesions, it has also been shown to be sensitive in the depiction of white matter lesions (10). Especially in combination with a subtraction approach, the DIR sequence proved to substantially improve sensitivity in the detection of new brain lesions (11,13). It is important to note that when readers relied on FLAIR-based subtraction maps, no interval progression was missed in our cohort, making our results relevant to centers in which the DIR sequence is not performed. Finally, although nonenhanced sequences are sufficient for the reliable assessment of interval progression, gadolinium enhancement reveals additional temporal information regarding lesion age. As discussed earlier, this information can help specifically identify active demyelination and obtain an accurate differential diagnosis and cannot be determined in nonenhanced sequences.

In conclusion, our data support the view that modern three-dimensional sequences at 3.0 T in combination with image subtraction are ready to supersede routine use of contrast material in most instances of follow-up investigations of patients with MS, reducing both imaging time and cost without missing new or enlarged lesions.

Disclosures of Conflicts of Interest: P.E. disclosed no relevant relationships. S.S. disclosed no relevant relationships. V.P. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: has grants/grants pending from Oppenheim Förderpreis (Novartis) disclosed no relevant relationships. Other relationships: disclosed no relevant relationships. H.W. disclosed no relevant relationships. H.Z. disclosed no relevant relationships. M.B. disclosed no relevant relationships. M.M.H. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is a paid consultant for AdBoard, Merck, and Serono; received honoraria for lectures from Biogen; received travel grants from Bayer Health Care and Biogen. Other relationships: disclosed no relevant relationships. J.K. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: institution has grants/grants pending from Deutsche Forschungsgemeinschaft, European Research Council, and Nivida; receives payment for lectures including service on speakers bureaus from Philips Healthcare; received travel/accommodations/meeting expenses unrelated to activities listed from Kaneka Healthcare. Other relationships: disclosed no relevant relationships. A.B. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is a paid consultant for Bayer Healthcare, Biogen, Merck, Mylan, Novartis, Sanofi Genzyme, Roche, and Teva; received payment for lectures including service on speakers bureaus from Bayer Healthcare, Biogen, Merck, Novartis, Sanofi Genzyme, and Roche. Other relationships: disclosed no relevant relationships. C.Z. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: receives payment for lectures including service on speakers bureaus from Bayer-Schering. Other relationships: disclosed no relevant relationships. B.H. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: is a paid consultant for Hoffmann-La Roche, Novartis, Bayer, Genetech, AllergyCare, and TG Therapeutics; institution has grants/grants pending from Chugai; institution receives payment for lectures including service on speakers bureaus from Hoffman-La Roche, Biogen, Idec, Teva Neuroscience, Merck Serono, Medimmune, Novartis, and Desitin. Other relationships: has patents issued and pending. M.M. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: institution has grants/grants pending from Merck and Novartis. Other relationships: disclosed no relevant relationships. B.W. Activities related to the present article: disclosed no relevant relationships. Activities not related to the present article: received payment for lectures including service on speakers bureaus from Bayer. Other relationships: disclosed no relevant relationships.

Author Contributions

Author contributions: Guarantors of integrity of entire study, P.E., C.Z., B.W.; study concepts/study design or data acquisition or data analysis/interpretation, all authors; manuscript drafting or manuscript revision for important intellectual content, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors; literature research, P.E., H.Z., J.K., A.B., C.Z., M.M., B.W.; clinical studies, P.E., S.S., H.W., M.M.H., J.K., C.Z., B.H., M.M., B.W.; statistical analysis, P.E., M.B., C.Z., M.M., B.W.; and manuscript editing, P.E., V.P., J.K., A.B., C.Z., B.H., M.M., B.W.

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Article History

Received: July 3 2018
Revision requested: Aug 15 2018
Revision received: Jan 14 2019
Accepted: Jan 24 2019
Published online: Mar 12 2019
Published in print: May 2019