High-Dose Pulse Glucocorticoid Treatment Prevents White Matter Spinal Cord Pseudoatrophy in Newly Diagnosed Multiple Sclerosis

Abstract

Objective: Spinal cord (SC) atrophy correlates with and predicts the underlying progressive biology in active and non-active multiple sclerosis (MS), thereby providing a biomarker for clinical trials and patient management. Initiation of disease-modifying therapy (DMT) may be followed by early pronounced central nervous system (CNS) volume loss due to resolution of inflammation (pseudoatrophy) and confounding the interpretation of atrophy. High-dose glucocorticoids (HDGs) reduce inflammation and might therefore modify pseudoatrophy.

Methods: One hundred twenty-three newly diagnosed and DMT-naïve MS participants (relapsing-remitting, 70% female participants, median age = 36 years, Expanded Disability Status Scale [EDSS] 2.0) were followed for up to 3 years. Forty-two participants received HDG before baseline magnetic resonance imaging (MRI; DMT-HDG; median = 52 days, interquartile range [IQR] = 37-71), whereas 60 did not (DMT/no-HDG). Twenty-one participants remained untreated (no-DMT), and 102 started DMT after baseline MRI. SC total cervical cord cross-sectional area (TCA), gray matter area (GMA), and white matter area (WMA) and regional brain volumes were analyzed using mixed effects models.

Results: The DMT-HDG, DMT/no-HDG, and no-DMT groups had similar demographic, clinical, and radiological features. Pronounced SC pseudoatrophy was observed based on more year 1 versus year 2 volume loss for DMT/no-HDG (-2.06% vs. 0.83%; P = 0.02) but not DMT-HDG (-0.51% vs. 0.66%; P = 0.8) and more year 1 volume loss for DMT/no-HDG compared to DMT-HDG (-2.06% vs. 0.51%; P = 0.02).

Interpretation: HDG preceding baseline MRI suppresses CNS white matter (WM) pseudoatrophy after DMT initiation, most conspicuously for the SC. Suppression of pseudoatrophy with HDG may improve the fidelity of clinical trials and enhance the feasibility for short-term trials with SC and brain MRI outcomes in active MS by pretreatment with HDG. ANN NEUROL 2025;98:837-850.

FIGURE 1

Flow chart for participants’ selection.

FIGURE 2

Boxplots of TCA, WMA (A), and GMA (B) measurements in the different time points within different subgroups. (A) TCA (green colors) and WMA (yellow colors) measurements within the different subgroups reveal similar volumes for the no‐DMT and DMT‐HDG groups across the different time points (baseline, first year, and second year from left to right, respectively). Only the DMT/no‐HDG shows statistically significant changes in WMA and GMA volumes (*), and only in the passage from baseline to the first year, with stability of volumes from the first year to the second year. (B) GMA (orange) measurements within the different subgroups reveal similar volumes for all groups across different time points (baseline, first year, and second year from left to right, respectively). DMT = disease‐modifying therapy; GMA = gray matter area; HDG = high‐dose glucocorticoid; TCA = total cervical cord cross‐sectional area; WMA = white matter area. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 3

Hypothesis. We hypothesize that a recent exposure to HDG is associated with less pronounced DMT‐related volumetric changes within the spinal cord. DMT = disease modifying therapy; DMT‐HDG (A) = received HDG up to 5 months before baseline; DMT/no‐HDG (B) = did not receive HDG in the 5 months before baseline; HDG = high dose glucocorticoid treatment; TCA = total cord area assessed at C2 to C3. [Color figure can be viewed at www.annalsofneurology.org]

FIGURE 4

The first year and second year TCA and WMA % change when excluding participants with non‐enhancing lesions at the C2 to C3 level. (A) When excluding participants with non‐enhancing lesions at the C2 to C3 level, the DMT/no‐HDG group (red; n = 43) showed a trend toward bigger first year TCA change (^) when compared to the DMT‐HDG group (blue; n = 32, p = 0.06). The TCA change is similar among groups in the second year. (B) When excluding participants with non‐enhancing lesions at the C2 to C3 level, the DMT/no‐HDG group (red; n = 43) showed a bigger first year WMA change (*) when compared to the DMT‐HDG group (blue; n = 32, p = 0.03). The WMA change is similar among groups in the second year. DMT = disease modifying therapy; DMT‐HDG (A) = received HDG up to 5 months before baseline; TCA = total cord area assessed at C2 to C3. [Color figure can be viewed at www.annalsofneurology.org]