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. 2019 Dec;25(14):1915-1925.
doi: 10.1177/1352458518814117. Epub 2018 Dec 19.

Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions

Colm Elliott  1 , Jerry S Wolinsky  2 , Stephen L Hauser  3 , Ludwig Kappos  4 , Frederik Barkhof  5 , Corrado Bernasconi  6 , Wei Wei  6 , Shibeshih Belachew  6 , Douglas L Arnold  7
Affiliations

Slowly expanding/evolving lesions as a magnetic resonance imaging marker of chronic active multiple sclerosis lesions

Colm Elliott et al. Mult Scler. 2019 Dec.

Abstract

Background: Chronic lesion activity driven by smoldering inflammation is a pathological hallmark of progressive forms of multiple sclerosis (MS).

Objective: To develop a method for automatic detection of slowly expanding/evolving lesions (SELs) on conventional brain magnetic resonance imaging (MRI) and characterize such SELs in primary progressive MS (PPMS) and relapsing MS (RMS) populations.

Methods: We defined SELs as contiguous regions of existing T2 lesions showing local expansion assessed by the Jacobian determinant of the deformation between reference and follow-up scans. SEL candidates were assigned a heuristic score based on concentricity and constancy of change in T2- and T1-weighted MRIs. SELs were examined in 1334 RMS patients and 555 PPMS patients.

Results: Compared with RMS patients, PPMS patients had higher numbers of SELs (p = 0.002) and higher T2 volumes of SELs (p < 0.001). SELs were devoid of gadolinium enhancement. Compared with areas of T2 lesions not classified as SEL, SELs had significantly lower T1 intensity at baseline and larger decrease in T1 intensity over time.

Conclusion: We suggest that SELs reflect chronic tissue loss in the absence of ongoing acute inflammation. SELs may represent a conventional brain MRI correlate of chronic active MS lesions and a candidate biomarker for smoldering inflammation in MS.

Keywords: Chronic active lesions; progressive multiple sclerosis; relapsing multiple sclerosis; slowly expanding/evolving lesions; smoldering plaques.

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Conflict of interest statement

Declaration of Conflicting Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: C.E. is an employee of NeuroRx Research and has served on an advisory board for F. Hoffmann-La Roche Ltd. J.S.W. has served on advisory boards, data monitoring or steering committees, and has consulting agreements from the following entities: AbbVie, Actelion, Alkermes, Bayer HealthCare Pharmaceuticals, Biogen, BioNEST, Celgene, Clene Nanomedicine, EMD Serono, Forward Pharma A/S, GeNeuro SA, MedDay Pharmaceuticals, Novartis, Otsuka, PTC Therapeutics, Roche Genentech, Sanofi Genzyme, Strategic Consultants International, Takeda, and Teva Pharmaceuticals; royalties are received for out-licensed monoclonal antibodies through UTHealth from Millipore Corporation. S.L.H. serves on the board of trustees for Neurona and on scientific advisory boards for Annexon, Bionure, and Symbiotix, and has received travel reimbursement and writing assistance from F. Hoffmann-La Roche Ltd for CD20-related meetings and presentations. L.K.’s institution, the University Hospital Basel, has received research support and payments that were used exclusively for research support for L.K.’s activities as principal investigator and member or chair of planning and steering committees or advisory boards for trials sponsored by Actelion, Addex, Almirall, Bayer HealthCare Pharmaceuticals, CSL Behring, F. Hoffmann-La Roche Ltd and Genentech, Inc., GeNeuro SA, Genzyme, Merck Serono, Mitsubishi Pharma, Novartis, Octapharma, Ono Pharmaceutical, Pfizer, Receptos, Sanofi, Santhera, Siemens, Teva, UCB, and XenoPort; has received license fees for Neurostatus products; and has received research grants from the European Union, Gianni Rubatto Foundation, Novartis Research Foundation, Roche Research Foundation, Swiss Multiple Sclerosis Society, and Swiss National Research Foundation. F.B. is an editorial board member for the publications Brain, European Radiology, Multiple Sclerosis Journal, Neurology, and Radiology; has received consultancy fees from Bayer Schering, Biogen, F. Hoffmann-La Roche Ltd, Genzyme, Janssen Research, Merck Serono, Novartis, Synthon, and Teva; has received grants from the Dutch MS Society (EU-FP7/Horizon 2020); has received payments for developing educational presentations, including service on speaker bureaus, for Biogen and IXICO; and was supported by the NIHR UCLH Biomedical Research Centre. C.B. is a contractor for F. Hoffmann-La Roche Ltd. W.W. is an employee and shareholder of F. Hoffmann-La Roche Ltd. S.B. is an employee and shareholder of F. Hoffmann-La Roche Ltd. D.L.A. has received personal fees for consulting from Acorda, Biogen, F. Hoffmann-La Roche Ltd, MedImmune, Mitsubishi, Novartis, Receptos, and Sanofi-Aventis; grants from Biogen and Novartis; and an equity interest in NeuroRx Research.

Figures

Figure 1.
Figure 1.
Jacobian analysis and SEL candidates: (a), (b) An axial slice of linearly co-registered reference and follow-up T1-weighted scans. (c) The reference scan with a regular grid overlaid. (di) The non-linearly deformed image in (c) is shown to match the follow-up scan, and (dii) an enlarged lesion area of the deformation field. (e) The Jacobian determinant is shown as a heat map, where blue represents local contraction and red local expansion. The Jacobian determinant represents the local percent volume change at each voxel, after application of the non-linear deformation that warps (a) to match (b). (f) An axial slice of a reference T2-weighted scan with overlaid T2 lesion segmentation. (g) The Jacobian determinant within reference T2 lesions. (h) Initial SEL candidate boundaries based on JE1. (i) Refined SEL candidate boundaries based on JE2. JE: Jacobian Expansion; SEL: slowly expanding/evolving lesion.
Figure 2.
Figure 2.
Constancy and concentricity of expansion: (a), (b) Plots of amount of expansion as a function of time, where the dotted line represents the linear best fit of expansion as a function of time and markers (X) represent the actual expansion as measured by the Jacobian determinant at each intermediate timepoint. The plots represent examples of lesions with a fairly constant expansion ((a), Z-score for constancy = 1.02) and a poorly constant expansion ((b), Z-score for constancy = −1.56). Other examples are shown with a fairly concentric pattern of expansion ((c), Z-score for concentricity = 5.33) and a poorly concentric pattern of expansion ((d), Z-score for concentricity = −0.812). Note that colors in (c) and (d) represent percent local expansion.
Figure 3.
Figure 3.
SEL prevalence in RMS and PPMS populations: (a) Total number of SELs per patient detected from baseline to Week 48. (b) Total baseline T2 volume detected as SELs from baseline to Week 48. (c) Proportion of T2 volume associated to SELs within T2 mask at baseline. PPMS: primary progressive multiple sclerosis; RMS: relapsing multiple sclerosis; SEL: slowly expanding/evolving lesion. For patients without any SELs or without any SEL candidates, the number of SELs is set to 0. Baseline T2 volume associated with SELs is defined as the sum of baseline T2 volume associated with each SEL. Red asterisks represent the mean values. aVan Elteren test; stratified by treatment group (ocrelizumab, control), baseline T2 lesion volume category based on tertiles (⩽3.013 cm3, <3.013 to ⩽11.122 cm3, >11.122 cm3). bLog-transformed.
Figure 4.
Figure 4.
T1-weighted Gd enhancement in SELs. Gd: gadolinium; PPMS: primary progressive multiple sclerosis; RMS: relapsing multiple sclerosis; SEL: slowly expanding/evolving lesion. Box plot representation, where y-axis scale is based on arcsine transformation. Red asterisks represent the mean values. Consistent results were observed in both RMS and PPMS study populations, separately. aVolume normalized average: sum (proportion of baseline T2 lesion voxels that is Gd-enhancing for each lesion*T2 volume)/sum of T2 volume. T2 volume for SEL, new T2 lesion at Week 24, and new T2 lesion at Week 48 are T2 volume at baseline, Week 24, and Week 48, respectively. SELs identified using scans from all scheduled visits. bVan Elteren test; stratified by treatment group (ocrelizumab, control), baseline T2 lesion volume category based on tertiles (⩽3.013 cm3, <3.013 to ⩽11.122 cm3, >11.122 cm3).
Figure 5.
Figure 5.
T1-weighted signal intensity in SELs. CI: confidence interval; PPMS: primary progressive multiple sclerosis; RMS: relapsing multiple sclerosis; SEL: slowly expanding/evolving lesion. Last visit is Week 96 for OPERA I and OPERA II, and Week 120 for ORATORIO. aVan Elteren test; stratified by treatment group (ocrelizumab, control), baseline T2 lesion volume category based on tertiles (⩽3.013 cm3, <3.013 to ⩽11.122 cm3, >11.122 cm3). *p < 0.001a for the comparison of absolute T1 intensity of SELs versus non-SELs at each timepoint in RMS and PPMS. †p < 0.001a for the change in normalized T1 intensity from baseline to Week 24, Week 48, and Week 96/120 for SELs versus non-SELs in RMS and PPMS, respectively.
Figure 6.
Figure 6.
Heat map representation of a specific example of the lesion-level spatial distribution of T1 intensity change over time and corresponding Jacobian Expansion in SELs. MRI: magnetic resonance imaging; SEL: slowly expanding/evolving lesion. The edge of SELs (with heuristic score ⩾ 0) are represented by white arrows. T1 intensity change at the lesion edge results in a concentric inside-out pattern in the Jacobian. Red font “x” labels represent the time of brain MRI scanning acquisitions. An animated version of Figure 6 will also be available in Supplementary Material.
Figure 7.
Figure 7.
Probabilistic atlas of T2 hyperintense lesion, T1 hypointense lesion, and SEL spatial distributions. PPMS: primary progressive multiple sclerosis; RMS: relapsing multiple sclerosis; SEL: slowly expanding/evolving lesion. Each atlas represents the proportion of the lesion subtype occurring at a given anatomical location. Scales are consistent across all atlases.
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