Clinical relevance of paramagnetic rim lesion heterogeneity in multiple sclerosis

Abstract Objective Previous studies reveal heterogeneity in terms of paramagnetic rim lesions (PRL) associated tissue damage. We investigated the physiopathology and clinical implications of this heterogeneity. Methods In 103 MS patients (72 relapsing and 31 progressive), brain lesions were manually segmented on 3T 3D‐FLAIR and rim visibility was assessed with a visual confidence level score (VCLS) on 3D‐EPI phase. Using T1 relaxation time maps, lesions were categorized in long‐T1 and short‐T1. Lesion age was calculated from time of first gadolinium enhancement ( N = 84 lesions). Results on clinical scores were validated in an extended cohort of 167 patients using normalized T1w‐MPRAGE lesion values. Results Rim visibility (VCLS analysis) was associated with increasing lesional T1 ( P / P FDR < 0.001). Of 1680 analyzed lesions, 427 were categorized as PRL. Long‐T1 PRL were older than short‐T1 PRL (average 0.8 vs. 2.0 years, P / P FDR = 0.005/0.008), and featured larger lesional volume ( P / P FDR < 0.0001) and multi‐shell diffusion‐measured axonal damage ( P / P FDR < 0.0001). The total volume of long‐T1‐PRL versus PRL showed 2× predictive power for both higher MS disability (EDSS; P / P FDR = 0.003/0.005 vs. P / P FDR = 0.042/0.057) and severity (MSSS; P / P FDR = 0.0006/0.001 vs. P / P FDR = 0.004/0.007). In random forest, having ≥1 long‐T1‐PRL versus ≥4 PRL showed 2‐4× higher performance to predict a higher EDSS and MSSS. In the validation cohort, long‐T1 PRL outperformed (~2×) PRL in predicting both EDSS and MSSS. Interpretation PRL show substantial heterogeneity in terms of intralesional tissue damage. More destructive, likely older, long‐T1 PRL improve the association with MS clinical scales. This PRL heterogeneity characterization was replicated using standard T1w MRI, highlighting its potential for clinical translation.