Brain pseudoatrophy and mental regression on valproate and a mitochondrial DNA mutation

Nonhyperammonemic, reversible mental deterioration with brain pseudoatrophy in epilepsy children on valproate (VPA)1-4 is rare but potentially underestimated. VPA may trigger a not-otherwise clinically expressed mitochondrial disease.5 We describe a child who developed severe but reversible behavioral and cognitive dysfunctions with brain pseudoatrophy while receiving VPA. The child carried the rare, known6 heteroplasmic C8393T-Pro→Ser mutation in the MTATP8 gene. A 4-year-old, right-handed, Caucasian boy had an isolated febrile seizure. Since starting primary school, he showed mild learning difficulty. At age 8 years 1 month, an episode of loss of consciousness was suspected to be of epileptic origin. The CT showed normal patterns. Awake EEG documented focal and diffuse interictal epileptiform abnormalities (IEAs) on normal background activity. After the VPA (18 mg/kg/day), he showed increasing irritability and learning difficulties. At age 9 years 4 months, neurologic examination was normal. Awake EEG was unmodified (figure, B [a]). Whole-night sleep EEG showed marked activation of IEAs, with continuous spike-and-wave activity lasting up to 3 minutes for about 50% of the slow wave sleep (figure, B [a′]). Gradual VPA increase up to 27 mg/kg/day (serum levels within therapeutic range) coincided with further worsening of school performance and cognitive function. Figure. (A) MRI. Axial T2- and sagittal …