Determinants of disability in multiple sclerosis at various disease stages

Objective: To investigate whether diffusion-tensor magnetic resonance imaging and whole brain N-acetylaspartate (WBNAA) proton magnetic resonance spectroscopy can provide complementary pieces of information to achieve a better understanding of the factors associated with disability in multiple sclerosis (MS). Design: Cross-sectional survey. Setting: Referral hospital-based MS center. Patients: Ten healthy control subjects, 27 patients with a clinically isolated neurological syndrome, 21 patients with relapsing-remitting MS, and 29 patients with secondary progressive MS. Main Outcome Measures: Conventional and diffusion tensor magnetic resonance imaging, as well as WBNAA proton magnetic resonance spectroscopy, of the brain was performed. T2-hyperintense lesion volumes were measured. The mean values of mean diffusivity (MD) and fractional anisotropy of T2-visible lesions were computed. Histograms of MD and fractional anisotropy values were produced for normal-appearing white matter and gray matter (GM). Results: Patients with a clinically isolated neurological syndrome had a significantly (P=.002) lower WBNAA concentration than control subjects. Patients with relapsing-remitting MS had significantly higher T2 lesion volume (P=.007), mean lesion MD (P=.003), normal-appearing white matter fractional anisotropy peak height (P=.03), and a lower WBNAA concentration (P<.001) than patients with a clinically isolated neurological syndrome. Patients with secondary progressive MS had significantly higher T2 lesion volume (P=.01),lower mean normal-appearing white matter fractional anisotropy (P=.003), higher mean GM MD(P=.004), and lower GM MD peak height (P=.01) than patients with relapsing-remitting MS. Disease duration, GM MD peak height, and WBNAA concentration entered a multivariate model, explaining nearly 70% of the disability variance. Conclusions: The accumulation of macroscopic lesions and normal-appearing white matter damage seems to occur mainly during the earliest clinical phases of MS, whereas pathological features of GM may be a hallmark of the late progressive stage of the disease. This supports the notion of MS as a "2-stage" disease.