Neuropediatrics 2006; 37 - FV17
DOI: 10.1055/s-2006-973995

Valproic Acid associated encephalopathy –19 new cases in Germany from 1994 to 2003– a side effect associated to VPA-therapy not only in young children

T Gerstner 1, D Büsing 1, E Longin 1, C Bendl 1 S König 1, VPA-induced Side-Effects Study Group
  • 1Universitätskinderklinik Mannheim, Neuropädiatrie, Mannheim, Germany

Summary: Valproic acid (VPA) is a broad-spectrum antiepileptic drug and is usually well tolerated, Rare serious complications may occur in some patients, including haemorrhagic pancreatitis, bone marrow suppression, VPA-induced hepatotoxicity and VPA-induced encephalopathy. The typical signs of VPA-induced encephalopathy are impaired consciousness, sometimes marked EEG background slowing, increased seizure frequency, with or without hyperammonemia.

There is still no proof of causative effect of VPA in patients with encephalopathy, but only of an association with an assumed causal relation.

Method: We sent a questionnaire asking for side effects of VPA therapy from 1994 to 2003, to all 1200 members (Paediatricians, Neurologists) of the „German Section of the International League against Epilepsy“. We specially inquired about severe side effects such as hepatopathy, pancreatitis, encephalopathy and coagulation disorders.

Results: We report 19 patients with VPA-associated encephalopathy in Germany from the years 1994–2003, none of whom had been published previously.

Conclusion: The following 4 types of VPA-induced encephalopathy have to be distinguished.

- 1a. Encephalopathy with normal ammonia in 13 patients in our study, a direct effect on neurotransmitters postulated

- 1b. Encephalopathy with hyperammonemia without liver failure in six patients in this study – An inhibition of urea cycle is considered to be the pathomechanism, but this could not be the only reason, because some patients show encephalopathy with a moderate hyperammonemia by inhibiting the urea cycle, some do not

- 2a. Encephalopathy with hyperammonemia and liver failure. We have found 9 cases of lethal hepatopathies, with increased ammonia levels (average 271 γmol/l) and signs of an encephalopathy.

- 2b. Encephalopathy without hyperammonemia but liver failure

VPA-induced encephalopathy is an important and severe side effect of AED-therapy. In contrast to previous publications, not only young children with metabolic defects were affected in our series, but also adults.