OBJECTIVE To prospectively evaluate diffusion indexes of the corticospinal tract (CST), corpus callosum (CC), optic radiation (OR), and cingulum in patients with neuromyelitis optica (NMO) without visible lesions in the brain. METHODS All participants provided informed consent, and the study was approved by the institutional review board. Nineteen patients with NMO (one man, 18 women; mean age, 35.1 years; range, 19-55 years) with normal brain magnetic resonance (MR) imaging findings and 19 sex- and age-matched healthy control subjects were examined with diffusion-tensor MR imaging. The CST, CC, OR, and cingulum were globally and regionally analyzed by using mean diffusivity, fractional anisotropy, and primary (lambda1) and transverse (lambda23) eigenvalues. Correlations of diffusion indexes of the CST and OR with the pyramidal and visual components of the Kurtzke Functional Systems (KFS) and Expanded Disability Status Scale scores were also investigated. Student t testing and Pearson correlation were performed. RESULTS As compared with values in control subjects, both global and regional analyses showed significant (P < .01) increases in mean diffusivity and lambda23 of the CST and OR but not in any of the diffusion indexes of the CC and cingulum in patients with NMO. In patients with NMO, mean diffusivity (r = 0.556, P = .013) and lambda1 (r = 0.556, P = .013) of the CST were correlated with pyramidal KFS scores, and mean diffusivity (r = 0.523, P = .022) and lambda1 (r = 0.504, P = .027) of the OR were correlated with visual KFS scores. CONCLUSIONS Axonal degeneration secondary to lesions in the spinal cord and optic nerves is a cause of normal-appearing white matter damage in NMO. BACKGROUND http://radiology.rsnajnls.org/cgi/content/full/2461062075/DC1.