LAUSR

To the Editor, Levetiracetam (LEV) is an antiepileptic drug with widespread use for the treatment of both focal and generalized seizures. Until recently, it was generally deemed to be one of the safest antiepileptic drugs, although early mild to moderate adverse effects had been reported, i.e. somnolence, headache, dizziness or behavioural disturbances, most commonly during the first month of therapy. Indeed, very few LEV-induced severe adverse effects, like Lyell’s syndrome, Stevens-Johnson syndrome or hepatic failure, were reported. However, there has been a rise in rhabdomyolysis cases, starting immediately after LEV therapy, between 2005 and 2017, particularly from 2014 to date [1, 2]. Herein we report a case of a 48-year-old female, admitted for her first generalized epileptic seizure, with a history of surgery for a left fronto-basal grade II astrocytoma 18 years previously and chemo/radiotherapy 15 years previously. Her clinical and radiological follow-up had always been unremarkable until the occurrence of her generalized epileptic seizure. LEV treatment was started on admission and titrated up to 1000 mg within 2 days. Administration was intravenous on the first day, then oral. Serum creatine phosphokinase (CK) levels, which were only slightly elevated at admission (428 IU/L; normal 38–145), interpreted as being due to muscle breakdown from the seizure, rose to 7234 IU/L on the third day, peaking at 8199 IU/L on day 4. A causative role for LEV was then suspected, as there had been no muscle trauma, infection, metabolic derangement or concomitant medication that might have accounted for the rhabdomyolysis, which was then diagnosed as iatrogenic and LEV-induced. Therefore, LEV was replaced by phenobarbital and serum CK levels dropped to 3193 IU/L 2 days later, reaching almost normal levels (369 IU/L) on post-withdrawal day 6 at discharge. There was a slight rise in myoglobin levels (165 ng/ mL; normal 14–66) on the fourth day of therapy, which normalized after LEV discontinuation. Concomitantly to the CK rise, the patient complained of myalgia, which rapidly subsided after LEV withdrawal. No muscle weakness was detected at the follow-up neurological examination. Creatinine levels remained constantly within the normal range, as did the electrolytes and the other routine laboratory tests. To the best of our knowledge, this is the first Italian case of LEV-induced rhabdomyolysis. Such a potentially severe side effect of LEV has been increasingly reported in the last years, both in paediatric and in adult populations, as reviewed by Carnovale et al. [2]. They analysed 48 reports, 8 children, 35 adults; the remaining 5 lacked information about age retrieved from the Food and Drug Administration’s Adverse Event Reporting System Database. LEV was the only drug suspected to have played a role in the rhabdomyolysis in 19 patients (39.5%), whilst it was hypothesized that various other pharmacological adjunctive treatments, e.g. lamotrigine, phenytoin or valproic acid, had contributed to the muscle damage in the remaining cases. The time course of CK levels in our case is in line with those in the other cases reported in literature. Indeed, a quick CK rise was observed during the LEV loading phase, within a few days (1–7, only in one case 15) from starting LEV therapy [3]. CK levels decreased rapidly within 1 week after LEV discontinuation, although full normalization required 30– 40 days in some cases [3]. CK levels increased remarkably in LEV-treated patients in most cases, peaking at 49,539 IU/L (normal 30–220) in the case reported by Di Lorenzo et al. [4]. Rhabdomyolysis in LEV-treated patients was accompanied by clinical symptoms, like myalgia, in about 50% of the reported cases, whilst muscle weakness was a rare complication [3]. Only 1 patient had electromyographic abnormalities consistent with myopathy, which disappeared as the CK level normalized, 1 week after LEV withdrawal [5]. Fortunately, to date, only one case of rhabdomyolysis has been reported to have had adverse effects on renal function [1]. * Eugenia Rota [email protected]