Adjunctive medications for epilepsy

Epilepsy is 1 of the most frequently diagnosed chronic neurologic conditions in children. The International League Against Epilepsy (ILAE) defines seizure as a transient occurrence of signs and/or symptoms due to abnormal excessive or synchronous neuronal activity in the brain; whereas epilepsy is a disease of the brain, which is characterized by an enduring predisposition to generate seizures.¹

Based on whether a seizure starts in 1 hemisphere or both hemispheres simultaneously, it is classified as focal onset or generalized onset, respectively. Levetiracetam (LEV) and valproic acid (VPA) are 2 commonly used broad-spectrum antiepileptic medications that can be used as first-line or adjunctive therapy in the treatment of seizures. Adjunctive medications for LEV and VPA, pyridoxine (vitamin B6) and carnitine, respectively, will be reviewed in this paper.

Levetiracetam

The mechanism of action of LEV is thought to be unknown. It is hypothesized that it blocks the presynaptic release of neurotransmitters through blocking synaptic vesicle protein SV2A. Pyridoxine can be used to ameliorate the adverse effects (AEs) of LEV, which include aggression, agitation, and risk of suicide, though, the mechanism by which it does so is unknown. Few recent controlled studies have evaluated the clinical benefit of adding pyridoxine to curtail the behavior AEs of LEV.

Marino et al evaluated pyridoxine as an add-on treatment for the control of AEs that have been induced by LEV in pediatric patients.² This clinical case-control prospective trial included pediatric patients, aged 7 to 16 years, with generalized or focal idiopathic epilepsy. The study included 50 patients on LEV monotherapy, who were randomized into 2 groups: LEV or LEV with pyridoxine. Dosing for LEV was similar in both groups, starting from 5 mg/kg per day up to 60 mg/kg per day. Pyridoxine was added at day 30, at a dose of 7 mg/kg per day, with a maximum of 350 mg per day. AEs noted after starting LEV in both groups were aggression (48%-50%), confusion (10%-12%), and depression (15%-20%). Intriguingly, these AEs resolved within 6 to 12 days after the start of pyridoxine. Moreover, 92% of patients initiated on pyridoxine did not need to change or stop treatment versus 76% of patients in the LEV group (P < .001).

Mahmoud et al conducted the first randomized double-blind controlled trial to quantify the effect of pyridoxine in decreasing neuropsychiatric events in children while on LEV.³ Children who had behavioral symptoms that coincided with initiation of LEV therapy were included in this study. The treatment group was initiated at a dose of 10 mg/kg daily (maximum of 200 mg) of pyridoxine, whereas the placebo group was initiated at 0.5 mg/kg daily. Daily doses were then titrated up, as needed, to 15 mg/kg in the treatment group and 0.75 mg/kg in the placebo group. The effects of pyridoxine were quantified through a behavioral checklist, which was filled out at baseline, and then at several points throughout the study. Overall, the average maintenance dose of LEV was found to be higher in the pyridoxine group versus the placebo group. The authors concluded that pyridoxine reduced behavioral symptoms by 11% in the treatment group compared with 6% in the placebo group at week 6 of therapy (P < .05). Furthermore, it was concluded that discontinuation of LEV was not needed with the addition of pyridoxine. Pyridoxine was well tolerated, with only 4% of patients reporting transient nausea that later subsided without intervention.

Valproic acid

VPA is a short-chain, branched fatty acid, the exact antiepileptic mechanism of which is unknown. However, some identified mechanisms include potentiation γ-aminobutyric acid, inhibition of voltage sensitive sodium channels, antagonism of N-methyl D-aspartate receptor–mediated neuronal excitation, and inhibition of histone deacetylase. VPA is generally well tolerated, but serious AEs including pancreatitis, bone marrow suppression, hepatotoxicity, and hyperammonemic encephalopathy may infrequently occur. Knowledge of the complex metabolism of VPA has led to further understanding of its hepatic complications and offers insights into its treatment. In addition to glucuronic acid conjugation catalyzed by UDP-glucuronosyltransferase enzyme, which is the principal VPA metabolic pathway, mitochondrial β-oxidation and cytochrome P450 (CYP)–mediated ω-oxidation pathway are the other mechanisms by which VPA is metabolized.⁴ Mitochondrial β-oxidation of VPA requires carnitine, an amino acid derivative, which transports VPA from the cytoplasm into the matrix of the mitochondria. VPA, when used long term or in high doses, depletes carnitine and in turn shifts the metabolism of VPA via mitochondrial β-oxidation to the CYP-mediated ω-oxidation pathway, which produces metabolites that are hepatotoxic and interferes with and prevents the elimination of ammonia. Additionally, VPA itself through its effect on kidneys contributes to the hyperammonemia, which may lead to encephalopathy. Depletion of carnitine inhibits mitochondrial fatty acid beta oxidation, causing further liver injury.⁵

Studies have shown that VPA causes dose-related increase in ammonia and decrease in carnitine.^5-8 Since carnitine deficiency plays a part in VPA induced liver injury, carnitine is used in treating or reversing the hepatotoxic effects of VPA. Carnitine is generally well tolerated with only mild gastrointestinal upset and unpleasant fishy odor reported.^9,10 VPA induced liver toxicity can range from asymptomatic elevation of liver enzymes or hyperammonemia to much rarer VPA-induced hepatotoxicity and hyperammonemic encephalopathy. Mild elevation in liver enzymes are usually reversible with time or dose reduction. Asymptomatic hyperammonemia, which is sometimes seen even in patients with normal liver function, may also be reversed with VPA dose adjustment or oral L-carnitine supplementation without necessarily discontinuing VPA.^11-13 In cases of severe hepatotoxicity, discontinuation of VPA and early administration of L-carnitine could improve survival.⁵ VPA-induced hyperammonemic encephalopathy is another serious complication, but often reversible if promptly identified and requires discontinuation of VPA and treatment with L-carnitine, which has shown to reduce the ammonia level.^{14, 15, 16, 17, 18} Decrease in ammonia levels do not always translate to clinical improvement.¹⁹ Finally, L-carnitine may be used prophylactically to prevent VPA toxicity in certain high-risk populations, although there is a lack of controlled studies backing this. In 1998, the Pediatric Neurology Consensus Conference published recommendations for carnitine administration in children with epilepsy.²⁰ The committee recommended L-carnitine supplementation to be considered in children who are at high risk of hepatotoxicity, such as those younger than 2 years of age with complex neurologic disorder or poor nutritional status; patients on a ketogenic diet; and those receiving polytherapy including VPA. In such vulnerable populations, measurement of serum carnitine may also be necessary. The recommended daily dose for oral carnitine is 50 to 100 mg/kg or 3 g, whichever is less. The intravenous dose, when used for metabolic rescue in acutely ill children, is higher at 150 to 500 mg/kg a day.²⁰

In conclusion, pyridoxine and L-carnitine can be safely used when indicated to ameliorate the AEs of LEV and VPA, respectively.

References

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2. Marino S, Vitaliti G, Marino SD, et al. Pyridoxine add-on treatment for the control of behavioral adverse effects induced by levetiracetam in children: a case-control prospective study. Ann Pharmacother. 2018;52(7):645-649. doi:10.1177/1060028018759637

3. Mahmoud A, Tabassum S, Al Enazi S, et al. Amelioration of levetiracetam-induced behavioral side effects by pyridoxine. a randomized double blind controlled study. Pediatr Neurol. 2021;119:15-21. doi:10.1016/j.pediatrneurol.2021.02.010

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