Purpose: To study white matter (WM) changes in patients with Unverricht-Lundborg progressive myoclonus epilepsy (EPM1) caused by mutations in the cystatin B gene and in the cystatin B-deficient (Cstb-/-) mouse model and to validate imaging findings with histopathologic analysis of mice.

Materials and methods: Informed consent was obtained and the study was approved by an institutional ethics committee. Animal work was approved by the Animal Experiment Board of Finland. Diffusion-tensor imaging and tract-based spatial statistics (TBSS) were used to compare fractional anisotropic (FA) results and axial, radial, and mean diffusion among patients with EPM1 (n = 19) and control subjects (n = 18). Ex vivo diffusion-tensor imaging and TBSS were used to compare Cstb-/- mice (n = 9) with wild controls (n = 4). Areas of FA decrease in mice were characterized by means of immunohistochemical analysis and transmission electron microscopy. Student t test statistics were applied to report significant findings (threshold-free cluster enhancement, P < .05).

Results: Patients with EPM1 showed significantly (P < .05) reduced FA and increased radial and mean diffusion in all major WM tracts compared with those of control subjects, shown as global FA decrease along the TBSS skeleton (0.41 ± 0.03 vs 0.45 ± 0.02, respectively; P < 5 × 10(-6)). Cstb-/- mice exhibited significantly reduced FA (P < .05) and antimyelin basic protein staining. Transmission electron microscopy revealed degenerating axons in Cstb-/- mice vs controls (979 axons counted, 51 degenerating axons; 2.09 ± 0.29 per field vs 1072 axons counted, nine degenerating axons; 0.48 ± 0.19 per field; P = .002).

Conclusion: EPM1 is characterized by widespread alterations in subcortical WM, the thalamocortical system, and the cerebellum, which result in axonal degeneration and WM loss. These data suggest that motor disturbances and other symptoms in patients with EPM1 involve not only the cortical system but also the thalamocortical system and cerebellum.