Progressive Elevation of Liver Enzymes in a Child Treated with Sulthiame

Sir,

Sulthiame (STM) is considered an effective and safe drug for the treatment of benign epilepsy with centrotemporal spikes (BECTS) or “Rolandic” epilepsy, as well as other seizures of focal origin [[2], [4], [8]]. STM acts as a carbonic anhydrase inhibitor; its chemical structure is related to sulfonamides. Adverse effects including paraesthesia, tachypnoea, and headache are dose-dependent and were observed only when the recommended dosage of 3 - 8 mg/kg/day was exceeded. These side-effects show prompt remission after dose reduction, they are rare and relatively minor, compared to potential adverse effects observed with other antiepileptic drugs [[3]]. We report a precipitous increase of liver enzyme concentrations in a boy treated with STM for BECTS and rapid normalization of enzyme levels after discontinuation of this therapy.

A 10-year-old boy, the second of two children of unrelated healthy parents, was born at term after an uneventful pregnancy. He showed normal motor and mental development and attended a regular school. There was no history of seizures or liver disease in his family. His past medical history was negative for a metabolic disorder or transient disturbance of liver functions. At the age of 8 years he had a first focal seizure involving the face during sleep. Physical and neurological examination showed no abnormalities, his mental state was normal. EEG in the waking state revealed typical centrotemporal spikes. Cranial MRI was normal. At the age of 9 years treatment with sulthiame (4.3 mg/kg/day, Ospolot® 50 mg twice daily) was started, which led to a reduction of seizure frequency. After initiating the treatment, the boy's liver function was examined twice with normal results.

At a routine follow-up examination at the age of 10 years and 6 months 4 Rolandic seizures during the last 9 months were reported. The boy's neurological status was normal, there was no hepatosplenomegaly or jaundice. Laboratory investigations revealed a slight elevation of alanine aminotransferase (ALT) to 58 U/l and of aspartate aminotransferase (AST) to 33 U/l. All other routine laboratory values were normal. As seizure control was unsatisfactory, the dosage of STM was increased to 6.7 mg/kg/day. The boy's general practitioner was asked to check the liver enzyme concentrations and detected a further mild rise of serum aminotransferases.

In the course of the following 10 weeks the parents reported 2 more generalized tonic-clonic seizures during sleep. The boy had no other complaints, he was alert and well, he had no pruritus. On physical examination, there was no jaundice or petechiae. Abdominal examination showed a soft, non-tender abdomen without hepatomegaly or splenomegaly. The neurologic examination revealed no abnormalities. Laboratory investigations revealed a further increase of ALT to 108 U/l and of AST to 58 U/l. Gammaglutamyltranspeptidase (GGT) was slightly elevated to 31 U/l as well. The values for blood cell count, glucose, sodium, potassium, creatinine, total protein, C-reactive protein, lactate dehydrogenase, alkaline phosphatase, cholinesterase, bilirubin (total and conjugated), ammonia, and erythrocyte sedimentation rate were normal. Coagulation tests (APTT, PT, TT, fibrinogen) were normal. Serology for hepatitis A, B, and C, Epstein-Barr, and cytomegalovirus was negative. Antinuclear antibodies and smooth muscle antibodies were positive in low concentrations. Antimitochondrial, liver kidney microsomal antibodies and antibodies to soluble liver antigen were negative, as was lipoprotein X. Ultrasonography of the liver, biliary tract and spleen revealed no abnormalities. Treatment with sulthiame was continued with 6.7 mg/kg/day. He received no other medication.

Two weeks later the boy still felt perfectly well, physical examination was normal, there was no fever, rash, icterus or hepatomegaly. Serum concentrations of ALT were increased to 946 U/l, of AST to 416 U/l, of GGT to 68 U/l. Total bilirubin was now elevated to 1.2 mg/dl, conjugated bilirubin was normal. Sulthiame was discontinued. Laboratory checks during the next days revealed a prompt decrease of concentrations of both aminotransferases. Six weeks later the values were within normal limits again (Fig. [1]).

Fig. 1 Sulthiame was given in a dosage of 4.3 to 6.7 mg/kg/day for 21 months. Serum values of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gammaglutamyltranspeptidase (GGT) are shown.

At follow-up examination 9 months later, the boy was without any medication. He reported one short Rolandic seizure. There were no abnormalities on physical examination. Serum concentrations of ALT, AST and GGT remained normal.

In the 1950s the anticonvulsant effect of carbonic anhydrase inhibitors was discovered and further evaluation revealed the potency of sulthiame in the treatment of focal seizures [[5], [6]]. Open label studies from the 1980s and 1990s pointed to a superior efficacy of STM in benign partial epilepsy with centrotemporal spikes [[2], [4]]. STM is absorbed rapidly and almost completely in the upper intestinal tract [[3]]. Maximum serum levels are reached 2 - 10 hours after ingestion. The drug is metabolized mainly by hydroxylation in the liver and excreted predominantly renally [[1]]. Studies of acute and chronic toxicity in animals revealed loss of appetite and weight, low serum potassium, renal changes, and fatal kidney damage, when the highest doses were administered [[7]]. Liver damage has not been observed in animal experiments. In humans, typical side effects of STM therapy include hyperventilation, paraesthesia, headache and gastrointestinal complaints. They occur during treatment with high doses and are always reversible after dose reduction. Reversible neuropsychological impairment with poor concentration, depressed mood, fatigue, and lack of drive caused by the treatment of BECTS with sulthiame in recommended dosages leading to blood levels within the therapeutic range has been observed [[10]]. Thus, the overall incidence of serious adverse effects of STM is very low. Serious hepatic or myelo-depressive reactions have not been described so far [[7]].

Our patient showed mildly increased aminotransferase levels 18 months after the onset of therapy with STM. Over the next 12 weeks a precipitous rise in liver enzyme activities occurred without any clinical signs or symptoms of liver disease or dysfunction. No other cause for this disturbance of liver function could be found in evaluation, physical examination and laboratory investigation. There were no sufficient signs or symptoms to suggest anticonvulsant hypersensitivity syndrome, which is characterized by fever, rash, lymphadenopathy, and multiorgan-system abnormalities [[9]]. Discontinuation of STM intake led to an immediate decline of liver enzymes, which normalized completely within 6 weeks. This time period convincingly implicates STM as the cause of liver dysfunction in our patient. To our knowledge, this adverse effect has not been described before and should be taken into consideration in patients treated with STM.

References

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