Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions for the Diagnostic and Prognostic Workup of Multiple Sclerosis

Abstract

Background and objectives: The diagnosis of multiple sclerosis (MS) can be challenging in clinical practice because MS presentation can be atypical and mimicked by other diseases. We evaluated the diagnostic performance, alone or in combination, of the central vein sign (CVS), paramagnetic rim lesion (PRL), and cortical lesion (CL), as well as their association with clinical outcomes.

Methods: In this multicenter observational study, we first conducted a cross-sectional analysis of the CVS (proportion of CVS-positive lesions or simplified determination of CVS in 3/6 lesions-Select3*/Select6*), PRL, and CL in MS and non-MS cases on 3T-MRI brain images, including 3D T2-FLAIR, T2*-echo-planar imaging magnitude and phase, double inversion recovery, and magnetization prepared rapid gradient echo image sequences. Then, we longitudinally analyzed the progression independent of relapse and MRI activity (PIRA) in MS cases over the 2 years after study entry. Receiver operating characteristic curves were used to test diagnostic performance and regression models to predict diagnosis and clinical outcomes.

Results: The presence of ≥41% CVS-positive lesions/≥1 CL/≥1 PRL (optimal cutoffs) had 96%/90%/93% specificity, 97%/84%/60% sensitivity, and 0.99/0.90/0.77 area under the curve (AUC), respectively, to distinguish MS (n = 185) from non-MS (n = 100) cases. The Select3*/Select6* algorithms showed 93%/95% specificity, 97%/89% sensitivity, and 0.95/0.92 AUC. The combination of CVS, CL, and PRL improved the diagnostic performance, especially when Select3*/Select6* were used (93%/94% specificity, 98%/96% sensitivity, 0.99/0.98 AUC; p = 0.002/p < 0.001). In MS cases (n = 185), both CL and PRL were associated with higher MS disability and severity. Longitudinal analysis (n = 61) showed that MS cases with >4 PRL at baseline were more likely to experience PIRA at 2-year follow-up (odds ratio 17.0, 95% confidence interval: 2.1-138.5; p = 0.008), whereas no association was observed between other baseline MRI measures and PIRA, including the number of CL.

Discussion: The combination of CVS, CL, and PRL can improve MS differential diagnosis. CL and PRL also correlated with clinical measures of poor prognosis, with PRL being a predictor of disability accrual independent of clinical/MRI activity.

Figure 1. CONSORT Flowchart

Flow chart summarizing patients' progress through the study. Brussels = Saint Luc University Hospital (Brussels, Belgium); CHUV = Lausanne University Hospital (Lausanne, Switzerland); EPI = echo planar imaging; Milan = San Raffaele University Hospital (Milan, Italy); MS = multiple sclerosis; NIH = National Institutes of Health, Clinical Center (Bethesda, MD).

Figure 2. Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions in MS vs Non-MS

(A) Frequency of central vein sign–positive lesions, (B) number of cortical lesions and (C) of paramagnetic rim lesions in the 100 non-MS cases enrolled in the study (left vertical axis). Among the 185 enrolled MS cases (dotted lines, right vertical axis), most had ≥40% perivenular lesions (97%), ≥1 CL (84%) and ≥1 PRL (60%). Representative axial (D) FLAIR*, (E) DIR and MPRAGE, and (F) EPI-phase images showing, respectively, the CVS (arrow), CL (arrowhead) and PRL (arrowhead) biomarkers in an adult patient with RRMS. ANCA = ANCA-associated vasculitis; Behcet = Behçet disease; DIR = double inversion recovery images; HAM/TSP = human T-lymphotropic virus (HTLV)–associated myelopathy/tropical spastic paraparesis; HIV = HIV infection; MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disease; MPRAGE = magnetization prepared rapid gradient echo images; NIND = noninflammatory neurologic diseases; NMOSD = neuromyelitis optica spectrum disorder; Sjogren = Sjögren disease; SLE = systemic lupus erythematosus; Susac = Susac syndrome.

Figure 3. Diagnostic Performance of the Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions

(A) ROC curves showing the performance of the central vein sign (as proportion of CVS-positive lesions, Select3*, and Select 6*), cortical lesions, and paramagnetic rim lesions in discriminating MS from non-MS cases. (B) ROC curves showing the performance of the weighted combined biomarker model (logistic binomial regression) in differentiating MS vs non-MS cases based on the combination of the specific proportion of CVS-positive lesions (or CVS-positivity/negativity based on the simplified Select3* or Select 6* algorithms) with the exact number of CL and PRL. AUC = area under the curve; CL = cortical lesions; CVS = central vein sign; PRL = paramagnetic rim lesions.

Figure 4. Central Vein Sign, Cortical Lesions, and Paramagnetic Rim Lesions in Non-MS Conditions

(A) Axial 3D-FLAIR, 3D-FLAIR*, and 3D-EPI-phase images of an adult patient with sarcoidosis. MS-like lesions bearing a central vein (arrows) and a paramagnetic rim (arrowhead) can occasionally be found also in non-MS conditions. Of note, this patient did not have any visible cortical lesions. (B) Axial 3D-FLAIR and 3D-FLAIR* images of an adult patient with MOGAD. Although MS-like lesions bearing a central vein (arrows) can occasionally be found also in non-MS conditions. However, this patient did not have any visible cortical or paramagnetic rim lesions. (C) Axial FLAIR and Gd-MPRAGE of an adult patient with systemic lupus erythematosus, showing a contrast enhancing cortical lesion (arrows). In this patient, the majority of lesions did not bear a central vein and none of them showed a paramagnetic rim. (D) Axial 3D-EPI-T2* magnitude images of an adult patient with Susac syndrome, showing one corpus callosum lesion bearing a paramagnetic rim on susceptibility-based images. Of note, this patient did not have any cortical nor central vein sign–positive lesions. EPI = segmented T2*-weighted echo planar imaging; Gd-MPRAGE = magnetization prepared rapid gradient echo MRI acquired post-IV injection of a paramagnetic gadolinium-based contrast agent; MOGAD = myelin oligodendrocyte glycoprotein antibody–associated disease; SLE = systemic lupus erythematosus.