Original articlePlasma free carnitine in epilepsy children, adolescents and young adults treated with old and new antiepileptic drugs with or without ketogenic diet
Introduction
Carnitine (beta-hydroxy-gamma-trimethylaminobutyric acid) is a water-soluble quaternary amine with important intracellular functions [1], [2] and only biologically active in the L isoform [1], [3]. It acts as cofactor for mitochondrial fatty acid oxidation by transferring long-chain fatty acids as acylcarnitine esters across the inner mitochondrial membrane; facilitates branched-chain alfa-ketoacid oxidation; shuttles acyl-CoA products of peroxisomal beta-oxidation to mitochondrial matrix in the liver; modulates the acyl-CoA-to-CoA ratio in mammalian cells; esterifies potentially toxic acyl-CoA metabolites that impair the citric acid cycle, urea cycle, gluconeogenesis and fatty acid oxidation during acute clinical crises [4]. In omnivores, approximately 75% of carnitine comes from the diet and 25% from endogenous biosynthesis [5]. Human skeletal muscle (the major tissue reservoir of carnitine), heart, liver, kidney and brain are capable of carnitine biosynthesis [6].
Carnitine deficiency was defined as a plasma free concentration of ≤20 μM/L at an age older than 1 week after term or a plasma esterified-to-free ratio of ≥0.4 at an age older than 1 week after term [7]. A subnormal concentration of total carnitine may result from decreased biosynthesis, inadequate dietary intake, inadequate absorption, defective tissue transport, excessive renal excretion, inborn errors of metabolism. Carnitine deficiency may be classified as primary or secondary. The criteria for diagnosis of primary syndromes are: severe reduction of plasma or tissue carnitine levels, evidence that the low carnitine levels impairs fatty acid oxidation, correction of the disorder when carnitine levels are restored and exclusion of other primary defects in fatty acid oxidation [8]. Much more common are secondary syndromes, which produce a decrease in the levels of carnitine in plasma (<20 μM/L) or tissues or increased ratio (>0.4) of esterified to free carnitine or both. They may be associated with genetically determined metabolic errors, acquired medical conditions or iatrogenic factors such as drug administration [7].
Carnitine deficiency is not uncommon in patients with epilepsy. Risk factors for carnitine deficiency include young age (less than 10 years old), neurologic disabilities (mental retardation, cerebral palsy, microcefaly, blindness), diet low in meat and dairy products, on tube feeding or intravenous hyperalimentation, therapy with multiple anticonvulsant drugs including valproate, hyperammonemia, hypoglycemia, metabolic acidosis and evidence of an underlying inborn error of metabolism [9].
Numerous studies have shown that the total or free plasma carnitine concentrations, or both, are significantly lower in patients taking multiple AEDs, including VPA or VPA alone [10], [11], [12], [13], [14], [15], [16]. Some studies report hypocarnitinemia in patients taking anticonvulsant drugs other than valproate, such as carbamazepine, phenytoin or phenobarbital [15], [17], [18]; other studies have found no difference [19]. No data are available relative to the more recently introduced AEDs.
In the present study levels of free carnitine were evaluated in a large series of epilepsy children, adolescents and young adults treated with old and new AEDs, in monotherapy or in combination, in order to better understand the clinical significance of carnitine deficiency, and which of the old drugs other than valproate or which of the new drugs as topiramate and lamotrigine can cause carnitine deficiency. Moreover, a subset of patients was administered ketogenic diet in addition to their baseline AEDs.
Section snippets
Material and methods
Patients were recruited among those followed in the Epilepsy Unit of the Clinic of Child Neuropsychiatry from January 2002 to June 2003.
Inclusion criteria were: (1) epilepsy patients on mono or polytherapy from 3 months and over; or (2) patients who started topiramate or lamotrigine as mono or add-on therapy; or (3) patients who started ketogenic diet in combination to their baseline antiepileptic drugs.
Exclusion criteria were the following: (1) primary carnitine deficiency; (2) chronic
Results
The study group is composed by 164 patients (73 females and 91 males), aged between 7 months and 30 years (mean 10.8 years), with generalised (78 pts; 47.6%) or partial (86 pts; 52.4%) epilepsies. The overall duration of epilepsy ranged from 2 months and 26 years (mean 7.6 years), and the time on antiepileptic drug therapy was comprised between 1 month and 26 years (mean 7.5 years). At the time of enrolment, the patients were assuming 1 (75; 45.7%), 2 (44; 26.8%), 3 (31; 18.9%), 4 (13; 7.9%), 5
Discussion
In the present study a large series of epilepsy children, adolescents and young adults, assuming old and new antiepileptic drugs both in mono or add-on therapy, has been reported. In addition, a few patients were administered ketogenic diet as adjunctive treatment to their own baseline drugs.
The overall data show carnitine deficiency in about 25% of our patients, to be mainly linked to valproate assumption both as mono or add-on. Literature data show a carnitine deficiency in patients taking
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