A 33-year-old male patient has been treated with valproic acid 1200 mg three times daily (Ergenyl)

Fråga: A 33-year-old male patient has been treated with valproic acid 1200 mg three times daily (Ergenyl) for at least four years. Recently he has developed Guillain-Barre-like symptoms. Within a few days he will be admitted to the hospital and treatment with plasmapheresis is to be considered. Is there any documentation indicating that valproic acid drug treatment can induce Guillain-Barre-like symptoms? The plasma concentration levels of valproate are not known.

Sammanfattning: No case report concerning Guillain-Barre-like symptoms caused by valproic acid therapy has been found. Since unsteady gait, muscle jerks and twitches, as well as encephalopathy, have occasionally been found in patients treated with valproic acid one cannot exclude the possibility that a Guillain-Barre-like syndrome can in fact be induced by valproic acid therapy.

Svar: Our conclusions are based on a thorough Medline search, a review of reference handbooks and an evaluation of adverse drug reaction reports to Swedish Adverse Drug Reactions Advisory Committee (SADRAC). We have not found any documentation of valproic acid-induced Guillain-Barre-like symptoms in international literature. There have been no reports to SADRAC concerning Guillain-Barre-like symptoms suspected to be caused by valproic acid treatment. Between 1977 and 1993 SADRAC received a total of 143 reports concerning suspected valproic acid-induced adverse reactions, 117 of which were considered to be caused by drug treatment. There was one case of encephalitis, one case of balance disturbances, one case of dyskinesia and four of tremor, respectively, considered to be related to drug treatment (1).

We have found one published case report concerning neurotoxicity linked to treatment with valproic acid in a patient with hypoalbuminaemia (2). A 40-year-old patient was admitted to the Neurology Department because of increasingly unsteady gait, ataxia, muscle jerks and twitches. The onset of symptoms was gradual. Two months before admission he had been evaluated because of gait disturbances and sudden loss of muscle tone resulting in drop attacks. Nerve conduction examination revealed a mild sensory and motor polyneuropathy. His total plasma valproic acid concentration was within the normal range, 330 to 700 umol/l, but the free concentration was at least double the upper normal range.

A number of adverse effects can be seen during valproic acid therapy. Concentration-related tremor has been reported in up to 10 per cent of treated patients (3). Involuntary movements and twitching of the case reports concerning possible encephalopathy during treatment with valproic acid are cited (3). The symptoms are considered to be induced by metabolic changes during valproic acid therapy and the symptoms resolved by reduction of the dose. Valproic acid is known to induce asymptomatic hyperammonaemia as high as 140 umol/l and a number of suggested mechanisms including increased renal production of ammonemia and inhibition of nitrogen elimination have been suggested (3). Another mechanism could be carnitine deficiency, which is known to be induced by valproic acid (3). Single cases of hyperglycinaemia and hyperglycinuria, usually without clinical symptoms, have been reported (3).

This case should be reported to the Swedish Adverse Drug Reactions Advisory Committee. It is recommended that both total and free drug concentrations of valproic acid be measured in this case because of the relatively high dose given.