# Improved Cervical Cord Lesion Detection with 3D-MP2RAGE Sequence in Patients with Multiple Sclerosis

S. Demortière, P. Lehmann, Jean Pelletier, Bertrand Audoin, Virginie Callot

► To cite this version:

S. Demortière, P. Lehmann, Jean Pelletier, Bertrand Audoin, Virginie Callot. Improved Cervical Cord Lesion Detection with 3D-MP2RAGE Sequence in Patients with Multiple Sclerosis. American Journal of Neuroradiology, 2020, 41 (6), pp.1131-1134. 10.3174/ajnr.A6567. hal-02992331

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Distributed under a Creative Commons Attribution 4.0 International License
Improved cervical cord lesion detection with 3D MP2RAGE sequence

in patients with multiple sclerosis

Sarah Demortière<sup>1,2</sup>, Pierre Lehmann<sup>2,3</sup>, Jean Pelletier<sup>1,2</sup>, Bertrand Audoin<sup>1,2</sup> and Virginie Callot<sup>1,4,*</sup>

<sup>1</sup> APHM, Hôpital Universitaire Timone, CEMEREM, Marseille, France

<sup>2</sup> Department of Neurology, CHU Timone, AP-HM, Marseille, France

<sup>3</sup> Department of Neuroradiology, CHU Timone, AP-HM, Marseille, France

<sup>4</sup> Aix-Marseille Univ, CNRS, CRMBM, Marseille, France

*Corresponding author:

Virginie CALLOT

CRMBM-CEMEREM, UMR 7339, CNRS - Aix-Marseille Université, Faculté de Médecine
27, bd Jean Moulin, 13385 Marseille Cedex 5, France.

E-mail : virginie.callot@univ-amu.fr

Tel : +33 4 91 38 84 65

Grant support :

This work was performed within a laboratory member of France Life Imaging network (grant ANR-11-INBS-0006) and supported by ARSEP (Fondation pour l'Aide à la Recherche sur la Sclérose En Plaques) and CNRS (Centre National de la Recherche Scientifique).
**Abstract**

Spinal cord lesions have a real diagnostic and prognostic role in multiple sclerosis. Thus, optimizing their detection on MRI has become a central issue with direct therapeutic impact. In this study, we compared the 3D MP2RAGE sequence to the conventional MAGNIMS set for cervical cord lesion detection in 28 patients with multiple sclerosis. 3D MP2RAGE allowed for better detection of cervical lesions (+62%) in this population, with better confidence, thanks to optimized contrast and high spatial resolution.
# Introduction

Since the last revision of the Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS) guidelines¹ and McDonald's criteria of 2017², all spinal cord (SC) lesions must be counted to increase the sensitivity and specificity of multiple sclerosis (MS) diagnosis³. In this context, standardized acquisition protocols have been proposed¹. For SC MRI, at least two sagittal sequences among T2-weighted (T2-w), STIR, double inversion recovery, T1-w with gadolinium injection and/or T2-w axial acquisitions¹ are recommended. Nonetheless, different sequences are often necessary because of motion and flux artifacts⁴, which is time-consuming.

The Magnetization Prepared 2 Rapid Acquisition Gradient Echoes (MP2RAGE) sequence⁵ has been shown to significantly improve the detection of cerebral lesions that are difficult to visualize on conventional sequences, such as cortical lesions⁶. This T1-w MRI sequence, which creates a composite image limiting field inhomogeneity bias while providing a quantitative T1 map, has recently been optimized for SC⁷ but not yet evaluated in the context of MS.

The aim of this study was to compare the MP2RAGE sequence to the conventional set of routine sequences for detecting SC lesions in patients with MS.

# Materials and methods

## Patients

This retrospective study, approved by the local ethics committee with written informed consent, included 28 patients with MS from January 2017 to January 2019. Inclusion criteria were diagnosis of MS according to the revised McDonald criteria², age>18 years, clinical symptoms suggesting SC involvement, and MR exam at least 3 months after steroid infusion.
## Image acquisition

Sequences were acquired on a 3T system (MAGNETOM Verio, Siemens Healthineers, Erlangen, Germany) during the same examination. The protocol was as follows (see Table 1 for MR parameters):

- one sagittal 3D MP2RAGE sequence, providing two contrasted images, T1v1 and T1v2, from which a uniform image (UNI) free of B1 inhomogeneities and a T1 map were derived⁵, and

- a conventional set with sagittal 2D T2-w, STIR-w and T1-w post-gadolinium sequences, with axial 2D T2*-w MRI for confirmation of suspicious lesions on a sagittal set

## Lesion detection and scoring confidence

The cervical SC from C1-C7 was evaluated. Two operators, a senior neuroradiologist and neurologist, who were blinded to patient data, read the results of the conventional set and 3D MP2RAGE sequence (T1 map and UNI image). Identification took place during a consensus session⁸, on a high-resolution monitor, by using syngo.via Siemens image analysis software. MS lesions were detected based on hyperintensity on T2-w, STIR, MP2RAGE T1 map, and T1-w post-gadolinium images in case of inflammatory lesions or hypointensity seen on MP2RAGE uniform images, as compared with normal cord signals. The lesion had to be visible on at least two slices in a row for the millimetric MP2RAGE sequence. According to the MAGNIMS criteria, a lesion was validated if visible on at least two sequences of the conventional set. Lesion detection was reevaluated (reproducibility assessment) 3 weeks later, to minimize recall bias.
Confidence in detection was defined during the consensus session by use of a qualitative
scale⁹: 0, no lesion detected; 1, low detection confidence; 2, moderate-to-high detection
confidence; and 3, very high detection confidence.

Statistical analysis

Wilcoxon tests (JMP9, SAS Institute, Cary, USA) were used to compare the number of detected lesions between conventional and MP2RAGE datasets, as well as the reader's confidence between sequences. P < 0.05 was considered statistically significant.

Results

Demographic and clinical characteristics

We included 28 patients with MS (19 women; median age 34.5 years [interquartile range 28-41]; 23 had relapsing-remitting MS, 4 secondary-progressive MS and 1 primary-progressive MS. The mean Expanded Disability Status Scale score was 1.5±1.4 (range 0-6.5). The median disease duration was 4.8 years [interquartile range 1.7-10.1].

Spinal cord lesions

In total, 27 patients had at least 1 identifiable SC lesion and 2 had an active enhancing lesion.
A total of 117 lesions were detected. All lesions identified during the first image-analysis
session were found during the second session (100% reproducibility). MP2RAGE
significantly revealed more lesions than the conventional set (p < 0.0001) (Figure 1). All
lesions seen by the conventional sagittal set were detected in MP2RAGE.

Conversely, 13 lesions (7 patients) were detected only by MP2RAGE. These lesions had an
average [min/max] diameter of 2.6 [1.9/4.1] mm. They all fulfilled the characteristics of MS
lesions¹⁰ in terms of size and location (54% posterior, 31% lateral and 15% anterior), and
their presence was carefully double-checked in the axial/coronal plane. The image quality of
the conventional set for the corresponding slices was carefully re-evaluated and was
satisfactory. Among these 7 patients, 3 had no visible lesions at all on conventional set
detection (supplementary table 1 and Figure 2).

## Detection confidence

Mean reading confidence was significantly higher with MP2RAGE than STIR (2.1±0.7 vs 1.5±1.2, p = 0.0011) and T2 (2.1±0.7 vs 0.7±0.9, p < 0.0001) sequences. Confidence did not differ between lesions detected by MP2RAGE alone and those seen jointly by MP2RAGE and the conventional set (2.0±0.6 vs 2.2±0.8, p = 0.11).

## Discussion

The present study highlights for the first time in MS that the 3D MP2RAGE method is able to detect cervical cord lesions with higher confidence and higher sensitivity than the recommended conventional MAGNIMS set. Given the essential diagnostic and prognostic significance of SC lesions in MS, these results could have some critical added value for clinical practice, as previously demonstrated using phase-sensitive inversion recovery or double inversion recovery contrast<sup>9-11</sup>.

In this work, 3D MP2RAGE detected significantly more lesions than did STIR, T2-w and MAGNIMS set sequences. Importantly, it also allowed for detecting lesions in patients classified as not having cord lesions with the conventional set (11%). Of note, the validation of these undetected lesions was the subject of consensus between two experienced operators, repeated once with blinding to the previous assessment. Furthermore, the detection confidence for all the lesions visualized by MP2RAGE alone (2.0±0.6, n=13 lesions) was as high as for those visualized by both MP2RAGE and the conventional set, which consolidates
our findings. Finally, the characteristics of these lesions were typical for MS¹⁰ showing, for
the first time in the cord, similar results than previously reported in the brain¹²⁻¹⁴. Recent study
also demonstrated good correlation between cerebral lesions detected with MP2RAGE and
histological findings⁶, however such data were not available in the present study and similar
work remains to be done.

The present study has some additional limitations. First, the sample size was small and did not
include patients with clinical isolated syndrome, for which it will be necessary to assess the
potential value of MP2RAGE diagnosis. Second, the respective contrast-to-noise ratios of the
different sequences were not compared because of different spatial resolutions and partial
volume effects. According to the present study design, we cannot exclude that the better
sensitivity of the MP2RAGE is mostly related to its 3D isotropic nature rather than its better
ability for visualizing lesions whatever their size. Indeed, some authors reported a gain in
sensitivity in 3D sequences¹⁵,¹⁶ from 28% to 65% for cervical lesion detection⁹,¹¹,¹⁷.
Comparison between 3D MP2RAGE, 3D STIR and 3D T2-WI is left for future specific
studies. Concerning the 3 patients for whom no lesions were detected by the conventional set,
missed lesions were mainly due to their small size with regard to sequence spatial resolutions.
However, 8/13 lesions detected only with the MP2RAGE sequence exceeded the spatial
resolution of the conventional set, which suggests that the better sensitivity of MP2RAGE
may be related more to its better contrast than its 3D isotropic resolution.

Finally, the MP2RAGE acquisition time (7 min) may seem relatively long as compared with
the 2D individual sequences. However, the volume acquired here covered the whole brain and
the entire cervical SC with isotropic sub-millimetric resolution. This offers promising
opportunities for global assessment of the upper part of the central nervous system (brain and
upper cervical cord). Brain evaluation was beyond the scope of this study. Finally, a
compressed-sensing version of the sequence is now proposed¹⁸, which may further improve
the added clinical value of the MP2RAGE sequence.

Further assessments and multi-centric studies must now be promoted to improve lesion
detection capabilities, clinical evaluation and bring additional proofs of specificity.

Conclusion

In this study, an optimized 3D MP2RAGE sequence was demonstrated to allow a significant gain in the detection of MS cervical lesions (including in patients otherwise presenting no lesions on conventional MRI), with high reader confidence assessment, as compared to conventional set. This MP2RAGE protocol, allowing brain and cervical cord coverage in 7 min, could be promising to improve clinical practice. Future study using larger samples are necessary to confirm these preliminary results.

Acknowledgements

The authors thank V.Gimenez, L.Pini, C.Costes and MP.Ranjeva for study logistics; A.Rico for patient recruitment; A.Massire, JP.Ranjeva and A.Maarouf for helpful discussions; and T.Kober (Siemens Healthcare) for MP2RAGE sequence provision.

This work was performed within a laboratory member of France Life Imaging network (grant ANR-11-INBS-0006) and was supported by the ARSEP Fundation (Fondation pour l'Aide à la recherche sur la Sclérose en Plaques) and CNRS (Centre National de la Recherche Scientifique).

References

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Tables and figures

<table><caption>Table 1. Main sequence parameters.</caption><thead><tr><th></th><th>MP2RAGE-w</th><th>STIR-w</th><th>T2-w</th><th>T1-w post-gadolinium</th></tr></thead><tbody><tr><th>Orientation/readout</th><td>3D sagittal/GRE</td><td>2D sagittal/TSE</td><td>2D sagittal/TSE</td><td>2D sagittal/TSE</td></tr><tr><th>TE/TR</th><td>2.48/4000 ms</td><td>53/4000 ms</td><td>113/3200 ms</td><td>10/700 ms</td></tr><tr><th>FOV</th><td>300 mm</td><td>320 mm</td><td>280 mm</td><td>220 mm</td></tr><tr><th>Voxel size</th><td>0.9x0.9x1 mm³</td><td>0.9x0.7x3 mm³</td><td>1.1x0.9x2 mm³</td><td>0.8x0.6x3 mm³</td></tr><tr><th>T<sub>acq</sub></th><td>7min18s</td><td>2min18s</td><td>1min54s</td><td>4min31s</td></tr><tr><th>Spatial coverage</th><td>Brain+C1-C7</td><td>C1-C7</td><td>C1-C7</td><td>C1-C7</td></tr><tr><th>Phase encoding direction</th><td>A>>P</td><td>H>>F</td><td>H>>F</td><td>H>>F</td></tr><tr><th>Other parameters</th><td colspan="4">TI1/TI2:650/2000 ms<br>α1/α2:4/5°</td></tr><tr><th>Reconstruction image</th><td colspan="4">T1 quantitative map<br>and UNI</td></tr></tbody></table>

Abbreviations: -w: -weighted; GRE: gradient recalled echo; TSE: turbo spin echo; TE: echo time; TR: repetition time; FOV: field of view; T<sub>acq</sub>: acquisition time; TI: inversion time; A: anterior; P: posterior; H: head; F: feet; UNI: uniform image.
<table><caption>**Supplementary table.** Number of lesions detected, by patient and MR sequence</caption><thead><tr><th rowspan="2">Patients</th><th colspan="5">MR sequences</th></tr><tr><th>MP2RAGE</th><th>MAGNIMS *</th><th>STIR</th><th>T2-w</th><th>T1-w post-gadolinium</th></tr></thead><tbody><tr><td>Patient 1</td><td>7</td><td>5</td><td>6</td><td>5</td><td>0</td></tr><tr><td>Patient 2</td><td>6</td><td>4</td><td>5</td><td>3</td><td>1</td></tr><tr><td>Patient 3</td><td>7</td><td>7</td><td>7</td><td>6</td><td>0</td></tr><tr><td>Patient 4</td><td>4</td><td>2</td><td>3</td><td>0</td><td>0</td></tr><tr><td>Patient 5</td><td>6</td><td>6</td><td>6</td><td>4</td><td>0</td></tr><tr><td>Patient 6</td><td>9</td><td>7</td><td>9</td><td>5</td><td>0</td></tr><tr><td>Patient 7</td><td>4</td><td>3</td><td>3</td><td>3</td><td>0</td></tr><tr><td>Patient 8</td><td>1</td><td>1</td><td>1</td><td>0</td><td>0</td></tr><tr><td>Patient 9</td><td>1</td><td>1</td><td>0</td><td>1</td><td>0</td></tr><tr><td>Patient 10</td><td>5</td><td>3</td><td>4</td><td>3</td><td>0</td></tr><tr><td>Patient 11</td><td>1</td><td>1</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Patient 12</td><td>11</td><td>7</td><td>9</td><td>4</td><td>0</td></tr><tr><td>Patient 13</td><td>7</td><td>3</td><td>3</td><td>3</td><td>0</td></tr><tr><td>Patient 14</td><td>7</td><td>1</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Patient 15</td><td>5</td><td>4</td><td>4</td><td>4</td><td>0</td></tr><tr><td>Patient 16</td><td>6</td><td>4</td><td>5</td><td>2</td><td>0</td></tr><tr><td>Patient 17</td><td>2</td><td>1</td><td>1</td><td>1</td><td>0</td></tr><tr><td>Patient 18</td><td>2</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Patient 19</td><td>0</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Patient 20</td><td>2</td><td>1</td><td>1</td><td>1</td><td>NA</td></tr><tr><td>Patient 21</td><td>2</td><td>2</td><td>1</td><td>2</td><td>0</td></tr><tr><td>Patient 22</td><td>1</td><td>0</td><td>0</td><td>0</td><td>NA</td></tr><tr><td>Patient 23</td><td>3</td><td>2</td><td>2</td><td>2</td><td>0</td></tr><tr><td>Patient 24</td><td>7</td><td>3</td><td>4</td><td>0</td><td>0</td></tr><tr><td>Patient 25</td><td>5</td><td>3</td><td>4</td><td>2</td><td>1</td></tr><tr><td>Patient 26</td><td>4</td><td>1</td><td>3</td><td>0</td><td>0</td></tr><tr><td>Patient 27</td><td>1</td><td>0</td><td>0</td><td>0</td><td>0</td></tr><tr><td>Patient 28</td><td>1</td><td>1</td><td>1</td><td>0</td><td>0</td></tr></tbody></table>

NA: not available. *: according to the MAGNIMS criteria, a lesion was validated if visible on at least two sequences of the conventional set.
<figure><img src="image_2.png" /><figcaption>FIG 1. The number of lesions detected by sequence (Wilcoxon test; triple asterisks indicate *P* < .0001). The MP2RAGE sequence detected significantly more lesions than using the MAGNIMS criteria (according to the MAGNIMS criteria, a lesion was validated if visible on at least 2 sequences of the conventional set): 117 versus 72, *P* < .0001; for STIR, 117 versus 83, *P* < .0001; and for T2, 117 versus 52, *P* < .0001. There was +62%, +41%, and +12.5% lesion detection by MP2RAGE according to the respective sequences.</figcaption></figure>
<figure><img src="image_3.png" /><figcaption>**FIG 2.** Illustration of MR imaging with the different investigated sequences for patient 23 (a 33-year-old man with relapsing-remitting MS) and patient 16 (a 27-year-old woman with relapsing-remitting MS). White arrows indicate good confidence in the lesion; black arrows, moderate confidence or no lesion seen; UNI, uniform image.</figcaption></figure>