Summary:Purpose: To evaluate the efficacy and tolerability of levetiracetam (LEV, Keppra) as add-on therapy in patients with refractory partial seizures.Methods: In this European multicenter, double-blind, randomized, placebo-controlled trial, LEV (500 or 1,000 mg twice daily) was compared with placebo as add-on therapy in 324 patients with uncontrolled simple or complex partial seizures, or both, with or without secondary generalization. After enrollment, three parallel groups were assessed during a baseline period of 8 or 12 weeks, followed by a 4-week titration interval and a 12-week evaluation period.Results: LEV significantly decreased partial seizure frequency compared with placebo. A reduction in seizure frequency of 250% occurred in 22.8% of patients in the 1,000-mg group and 3 1.6% of patients in the 2,000-mg group, compared with 10.4% of patients in the placebo group. Administration of LEV did not affect plasma concentrations of concomitant antiepileptic drugs or alter vital signs or laboratory parameters. No significant difference in the incidence of adverse events was observed between treatment groups (70.8% for the 1,000-mg group and 75.5% for the 2,000-mg group), or between the LEV and placebo groups (73.2% for placebo group). The most commonly reported adverse effects in the LEV group were asthenia, headache, and somnolence.Conclusions: The antiepileptic efficacy and tolerability of LEV (1,000 mg/d and 2,000 mg/d, administered in two divided doses) as add-on therapy was established in patients with refractory partial seizures in this clinical study.

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ABSTRACT. The aim of this collaborative study was to normalized by therapy, the levels of the catabolites of investigate whether guanidino compound analyses in the arginine are still elevated. (Pediatr Res 27: 297-303,1990) biologic fluids can be used as a complementary diagnostic parameter for hyperargininemia. Guanidino compounds were determined in the biologic fluids of all known living hyperargininemic patients using a cation exchange chromatographic system with a fluorescence detection method. The serum arginine, homoarginine, a-keto-6-guanidinoDeficiency of arginase, the last enzyme of the urea cycle, leads valeric acid, argininic acid, and N-a-acetylarginine levels to hyperargininemia. The first clinical and biochemical descripof all the hyperargininemic patients are higher than the tions of two sisters affected with hyperargininemia were pubnormal range. Similar increases were seen for the urinary lished in 1969 (1) and 1970 (2, 3). Five y later, another sister was excretion of a-keto-6-guanidinovaleric acid and argininic diagnosed shortly after birth (4). Since then, 19 other cases from acid. Untreated hyperargininemic patients have the highest 17 families have been reported (5-22). Patients with hyperargiguanidino compound levels in cerebrospinal fluid. How-ninemia present a neuropsychiatric syndrome consisting of varyever, even under therapy, the arginine, homoarginine, a-ing degrees of mental retardation, epilepsy, and progressive spasketo-6-guanidinovaleric acid, and argininic acid levels in ticity. This latter symptom is at variance with other defects of cerebrospinal fluid are still increased. Protein restriction the urea cycle. Some patients have, in addition, recurrent epialone is not sufficient to normalize the hyperargininemia, sodes of vomiting and irritability accompanied by moderate but protein restriction together with supplementation of hyperammonemia. As a consequence of the arginase deficiency, essential amino acids with or without sodium benzoate the patients accumulate excessive arginine. Some secondary cadecreases further the arginine levels. However, whereas tabolites of arginine, guanidino compounds, are massively exthe argininemia can be normalized, the catabolites of ar-creted in the urine of these patients (23). Figure 1 shows some ginine are still increased. We conclude that the urinary proposed catabolic pathways of arginine in patients with hyperamino acid levels may remain normal in hyperargininemia, argininemia. whereas consistent increases of the guanidino compounds In hyperargininemia it is unclear whether ammonia is the are observed. Thus, guanidino compound analyses can be principal toxin. Indeed, the presence of normal or only slightly used as a complementary biochemical diagnostic parameter elevated ammonia levels has been demonstrated in several pafor hyperargininemia. Although the argininemia can be tients (6,7,9,15), and the progressive spasticity typically en-

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