Spinal Cord Atrophy Predicts Progressive Disease in Relapsing Multiple Sclerosis

Abstract

Objective: A major challenge in multiple sclerosis (MS) research is the understanding of silent progression and Progressive MS. Using a novel method to accurately capture upper cervical cord area from legacy brain MRI scans we aimed to study the role of spinal cord and brain atrophy for silent progression and conversion to secondary progressive disease (SPMS).

Methods: From a single-center observational study, all RRMS (n = 360) and SPMS (n = 47) patients and 80 matched controls were evaluated. RRMS patient subsets who converted to SPMS (n = 54) or silently progressed (n = 159), respectively, during the 12-year observation period were compared to clinically matched RRMS patients remaining RRMS (n = 54) or stable (n = 147), respectively. From brain MRI, we assessed the value of brain and spinal cord measures to predict silent progression and SPMS conversion.

Results: Patients who developed SPMS showed faster cord atrophy rates (-2.19%/yr) at least 4 years before conversion compared to their RRMS matches (-0.88%/yr, p < 0.001). Spinal cord atrophy rates decelerated after conversion (-1.63%/yr, p = 0.010) towards those of SPMS patients from study entry (-1.04%). Each 1% faster spinal cord atrophy rate was associated with 69% (p < 0.0001) and 53% (p < 0.0001) shorter time to silent progression and SPMS conversion, respectively.

Interpretation: Silent progression and conversion to secondary progressive disease are predominantly related to cervical cord atrophy. This atrophy is often present from the earliest disease stages and predicts the speed of silent progression and conversion to Progressive MS. Diagnosis of SPMS is rather a late recognition of this neurodegenerative process than a distinct disease phase. ANN NEUROL 2022;91:268-281.

FIGURE 1

Graphical illustration of the study population and patient subsets. RR → RR = matched patients remaining relapsing remitting multiple sclerosis during the 12‐year observation period. RR → SP = patients who converted to secondary progressive multiple sclerosis during the 12‐year observation period. RR → RR_SilP = patients who developed silent progression but retained a clinical diagnosis of RRMS to study end. RR → RR_Stable = patients who remained stable RRMS to study end. RRMS = relapsing remitting multiple sclerosis. SPMS = secondary progressive multiple sclerosis. NW/W NR/R cohort = silent progression groups as defined by Cree et al. classifying RRMS and SPMS patients solely based on confirmed EDSS worsening (worsening/non‐worsening), i.e., silent progression, and disease activity (relapsing/non‐relapsing), thereby avoiding the dichotomy of the current RRMS/SPMS classification: NR = non‐relapsing. NW = non‐worsening, i.e., stable. R = relapsing. W = worsening.

FIGURE 2

C1A measurement level and effect of foramen magnum normalization on C1A measures. (A) Axial images for C1A measurement (red horizontal lines) were obtained by reformatting the sagittal T1‐weighted image perpendicular to the dorsal surface of the cervical cord in the midline plane (vertical blue line) and selecting five contiguous slices 8–12mm caudal to the obex (horizontal blue line, slice thickness 1mm). (B) C1A measures of three controls (Control 1–3) before (^ndcC1A, upper graph) and after (C1A, lower graph) normalization by the foramen magnum area (FMA), depicted as a function of distance of the center C1A slice from the scanner isocenter: Control 1: C1A 118.1 mm², standard deviation (SD) 3.9 before and 1.7 after normalization; Control 2: C1A 121.8 mm², SD 2.0/1.7 before/after normalization; Control 3: C1A 107.6 mm², SD 5.2/2.5 before/after normalization. Note decreasing ^ndcC1A values with increasing distance from isocenter if correction by FMA is not performed, potentially leading to apparent cord volume changes in longitudinal studies.

FIGURE 3

C1A atrophy rates and risk for conversion to SPMS and silent progression. Distribution of estimated annual C1A atrophy rates before conversion for the RR → RR and RR → SP groups (A, n = 108) and in the subsets with no significant difference in baseline EDSS (B, n = 90) and with baseline EDSS≤2.0 (C, n = 54); (D) Comparison of C1A rates over the first 5 study years between RR → SP and silent progression groups stratified by worsening (W)/non‐worsening (NW) and relapsing (R)/non‐relapsing (NR), modified from Cree et al. by extracting the group who converted to SPMS; (E/F) Risk of SPMS Conversion/Silent Progression: Time to SPMS conversion based on C1A atrophy rates (%/yr) for patients with an EDSS of 0 (blue), 2 (red) and 4 (green) at baseline. (F) Time to silent progression based on C1A atrophy (%/yr) and lateral ventricle enlargement rates (%/yr) for patients with a baseline EDSS of 2. BL = baseline. C1A = cervical cord area at C1 vertebral level; EDSS = expanded disability status scale; RR → RR = matched patients remaining relapsing remitting multiple sclerosis during the 12‐year observation period; RR → SP = patients who converted to secondary progressive multiple sclerosis during the 12‐year observation period; SPMS = secondary progressive multiple sclerosis.

FIGURE 4

Comparison of Brain Volumes and C1A between the Matched Control, RR→RR and RR→SP Groups at Baseline and Conversion. C1A = cervical cord area at C1 vertebral level (mm²); Control = healthy control; RR → RR = patients remaining relapsing remitting multiple sclerosis during the 12‐year observation period; RR → SP = patients who converted to secondary progressive multiple sclerosis during the 12‐yr observation period. Baseline volumes are cc (least squares mean), whiskers indicate the 95% lower and upper confidence interval. *0.005 < p ≤ 0.05. **0.0001 < p ≤ 0.005. ***p ≤ 0.0001.