Association Between Thoracic Spinal Cord Gray Matter Atrophy and Disability in Multiple Sclerosis

Abstract

Importance: In multiple sclerosis (MS), upper cervical cord gray matter (GM) atrophy correlates more strongly with disability than does brain or cord white matter (WM) atrophy. The corresponding relationships in the thoracic cord are unknown owing to technical difficulties in assessing GM and WM compartments by conventional magnetic resonance imaging techniques.

Objectives: To investigate the associations between MS disability and disease type with lower thoracic cord GM and WM areas using phase-sensitive inversion recovery magnetic resonance imaging at 3 T, as well as to compare these relationships with those obtained at upper cervical levels.

Design, setting, and participants: Between July 2013 and March 2014, a total of 142 patients with MS (aged 25-75 years; 86 women) and 20 healthy control individuals were included in this cross-sectional observational study conducted at an academic university hospital.

Main outcomes and measures: Total cord areas (TCAs), GM areas, and WM areas at the disc levels C2/C3, C3/C4, T8/9, and T9/10. Area differences between groups were assessed, with age and sex as covariates.

Results: Patients with relapsing MS (RMS) had smaller thoracic cord GM areas than did age- and sex-matched control individuals (mean differences [coefficient of variation (COV)]: 0.98 mm2 [9.2%]; P = .003 at T8/T9 and 0.93 mm2 [8.0%]; P = .01 at T9/T10); however, there were no significant differences in either the WM area or TCA. Patients with progressive MS showed smaller GM areas (mean differences [COV]: 1.02 mm2 [10.6%]; P < .001 at T8/T9 and 1.37 mm2 [13.2%]; P < .001 at T9/T10) and TCAs (mean differences [COV]: 3.66 mm2 [9.0%]; P < .001 at T8/T9 and 3.04 mm2 [7.2%]; P = .004 at T9/T10) compared with patients with RMS. All measurements (GM, WM, and TCA) were inversely correlated with Expanded Disability Status Scale score. Thoracic cord GM areas were correlated with lower limb function. In multivariable models (which also included cord WM areas and T2 lesion number, brain WM volumes, brain T1 and fluid-attenuated inversion recovery lesion loads, age, sex, and disease duration), cervical cord GM areas had the strongest correlation with Expanded Disability Status Scale score followed by thoracic cord GM area and brain GM volume.

Conclusions and relevance: Thoracic cord GM atrophy can be detected in vivo in the absence of WM atrophy in RMS. This atrophy is more pronounced in progressive MS than RMS and correlates with disability and lower limb function. Our results indicate that remarkable cord GM atrophy is present at multiple cervical and lower thoracic levels and, therefore, may reflect widespread cord GM degeneration.

Figure 1. A-J. Phase sensitive inversion recovery images illustrating gray matter atrophy in Multiple Sclerosis

Axial 2D-phase sensitive inversion (PSIR) images at the intervertebral disc levels C2/C3, C3/C4, T8/T9 and T9/T10 of a woman with RMS and EDSS 1.0 (A, B, C, D) and an age-matched woman with primary progressive MS, EDSS 4.0 (E, F, G, H, respectively) illustrating GM atrophy in progressive MS. Segmentation of the cord area was conducted semi-automatically using an active surface model. Segmentation of the gray matter area was performed manually. Acquisition of the images perpendicular to the cord at the intervertebral disc levels C2/C3, C3/C4 (I), T8/T9 and T9/T10 (J).

Figure 2. Relative contributions of demographic, clinical and imaging variables to the Expanded Disability Status Scale

Relative contributions of the variables (cervical spinal cord gray matter (SGC) and white matter (SWC) areas at C2/C3, thoracic spinal cord gray matter (SGT) and white matter (SWT) at T9/T10, normalized brain gray matter volume (BG) and normalized brain white matter volume (BW), the number of spinal cord T2 lesions (SCL), brain T1 lesion volume (T1LV), brain FLAIR lesion volume (FLV), age, sex, and disease duration (DD)) to the Expanded Disability Status Score (EDSS) using a linear model.

Figure 3. A-D. Probability maps of a progressive disease course based on spinal cord gray matter assessments

Probability of a progressive disease course adjusted for age as assessed by spinal cord GM area (x-axis, in mm²) at the levels C2/C3 (A), C3/C4 (B), T8/T9 (C), and T9/T10 (D). Gray shades indicate 95% confidence intervals.

Figure 4. Receiver operating characteristic curves for the prediction of a progressive disease course based on gray matter assessments

Receiver operating characteristic (ROC) curves for the prediction of a progressive versus relapsing disease course by binary logistic models with a) the normalized brain gray matter (GM) volume as single predictor (red line), b) the normalized brain GM volume along with the thoracic spinal cord GM area at T9/T10 (yellow line) and c) the normalized brain GM volume along with the spinal cord GM areas at C2/C3 and T9/T10 (violet line) as combined predictors. The areas under the curve (AUC) were 0.68, 0.79 and 0.87, respectively.