- Lundborg Disease ( EPM 1 ) Päivi Koskenkorva Magnetic Resonance Imaging of Unverricht - Lundborg Disease ( EPM 1 )

Unverricht-Lundborg disease (EPM1), caused by mutations in the cystatin B gene (CSTB), is an autosomal recessively inherited disorder. It is the most common form of progressive myoclonus epilepsy. The prevalence of EPM1 is increased particularly in Finland where it is 4:100 000, offering a unique opportunity to study a large patient population. EPM1 is characterized by stimulus-sensitive and action-activated myoclonus, tonic-clonic seizures and ataxia. During the first 5-10 years, the symptoms progress and stabilize thereafter. About one-third of the patients become severely incapacitated. At the time of diagnosis, magnetic resonance imaging (MRI) of the brain is usually normal. Cerebral and cerebellar atrophy may develop subsequently. No large scale imaging studies of EPM1 have been reported thus far. The aim of this study was to explore whether advanced imaging techniques could reveal previously undetected morphological changes in the brains of patients with EPM1. The brains of altogether 62 patients with EPM1 were imaged with MRI and their findings were compared with those of healthy controls. Voxel-based morphometry (VBM) revealed regional bilateral gray matter volume loss in the motor cortex and thalamus of patients with EPM1, consistent with the motor symptoms of the disease. In addition, thinning of the sensorimotor, visual and auditory cortices was found by applying cortical thickness analysis. Cortical thickness correlated negatively with age, the duration of EPM1, and the severity of myoclonus. The findings parallel the stimulus-sensitive nature of the symptoms in EPM1. Diffusion tensor imaging with tractbased spatial statistics revealed widespread changes both in the supratentorial and infratentorial white matter (WM) of patients with EPM1, consistent with chronic WM degeneration. Directional diffusivity parameters indicate that the WM changes may reflect axonal and myelin loss. When comparing the clinical and imaging findings of patients who are compound heterozygous for the dodecamer repeat expansion and the c.202C>T mutation in the CSTB gene with those of patients who are homozygous for the dodecamer repeat expansion, the age at onset of symptoms seemed to be earlier in the compound heterozygotes. Furthermore, their myoclonic symptoms seemed to be more severe and the epileptic seizures were more drug-resistant than those of the homozygous patients. No differences were found between the MRI findings of the two groups. To summarize, previously undetected regional morphological changes in the brains of patients with EPM1 were discovered with modern imaging techniques. The changes are consistent with the clinical symptoms of EPM1, and combined with detailed neurophysiological evaluation, they offer new insight into the pathogenesis of EPM1. National Library of Medical Classification: WL 385, WN 185 Medical Subject Headings: Unverricht-Lundborg Syndrome; Magnetic Resonance Imaging; Cystatin B/genetics; Myoclonic Epilepsies, Progressive; Mutation/genetics; Brain Mapping; Finland