Improved Assessment of Longitudinal Spinal Cord Atrophy in Multiple Sclerosis Using a Registration-Based Approach: Relevance for Clinical Studies

Background Reliable measurements of cervical cord atrophy progression may be useful for monitoring neurodegeneration in multiple sclerosis (MS). Purpose To compare a new, registration-based (Reg) method with two existing methods (active surface [AS] and propagation segmentation [PropSeg]) to measure cord atrophy changes over time in MS. Study Type Retrospective. Subjects Cohort I: Eight healthy controls (HC) and 28 MS patients enrolled at a single institution, and cohort II: 25 HC and 63 MS patients enrolled at three European sites. Field Strength/Sequence 3D T1-weighted gradient echo sequence, acquired at 1.5 T (cohort I) and 3.0 T (cohort II). Assessment Percentage cord area changes (PCACs) between baseline and follow-up (cohort I: 2.34 years [interquartile range = 2.00-2.55 years], cohort II: 1.05 years [interquartile range = 1.01-1.18 years]) were evaluated for all subjects using Reg, AS, and PropSeg. Reg included an accurate registration of baseline and follow-up straightened cord images, followed by AS-based optimized cord segmentation. A subset of studies was analyzed twice by two observers. Statistical Tests Linear regression models were used to estimate annualized PCAC, and effect sizes expressed as the ratio between the estimated differences and HC error term (P < 0.05). Reproducibility was assessed by linear mixed-effect models. Annualized PCACs were used for sample size calculations (significance: alpha = 0.05, power: 1 - beta = 0.80). Results Annualized PCACs and related standard errors (SEs) were lower with Reg than with other methods: PCAC in MS patients at 1.5 T was -1.12% (SE = 0.22) with Reg, -1.32% (SE = 0.30) with AS, and -1.40% (SE = 0.33) with PropSeg, while at 3.0 T PCAC was -0.83% (SE = 0.25) with Reg, -0.92% (SE = 0.32) with AS, and -1.18 (SE = 0.53) with PropSeg. This was reflected in larger effect sizes and lower sample sizes. Intra- and inter-observer agreement range was 0.72-0.91 with AS, and it was >0.96 with Reg. Data Conclusion The results support the use of the registration method to measure cervical cord atrophy progression in future MS clinical studies. Level of Evidence 3 Technical Efficacy Stage 2

Automated summary

Reliable measurements of cervical cord atrophy progression in multiple sclerosis can be achieved using a new registration-based method, which showed lower sample sizes and higher reliability compared to existing methods.