Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial

Abstract

This randomized, double-blind, placebo-controlled study in epileptic children aged 3–12 years evaluated the effects of add-on melatonin administration on the quality of life of these children on sodium valproate (VPA) monotherapy using a parental questionnaire. Quality of Life in Childhood Epilepsy is a questionnaire designed to assess a variety of age-relevant domains such as physical function, emotional well-being, cognitive function, social function, behavior, and general health. Of the 31 patients, 16 randomly received add-on melatonin (MEL), whereas 15 received add-on placebo (P). The questionnaire had good internal consistency reliability, because for most of the multi-item scales Cronbach's α reliability exceeded 0.5 (range: 0.59–0.94). To our knowledge, this is the first study assessing quality of life in epileptic children with add-on melatonin administration in the form of a randomized, double-blind, placebo-controlled trial. The study suggests a potential use of melatonin as an adjunct to antiepileptic therapy due to its diverse spectrum of action as an antioxidant, neuroprotector, and free radical scavenger, thus offering the advantage of reducing oxidant stress and subsequent damage. The beneficial effects of melatonin on sleep, its wide safety window, and its ability to cross the blood–brain barrier have the potential to improve quality of life in pediatric epilepsy.

Introduction

Epilepsy is an example of a medical diagnosis that is retained even when signs and symptoms are well controlled and all laboratory tests are normal. Jacoby described epilepsy as “both a medical diagnosis and a social label” [1]. Epilepsy still remains a stigmatized disease in India.

Assessing quality of life (QOL) in pediatric epilepsy is especially important because it is during childhood when many cognitive and social skills are being developed. Failure to develop these skills at a developmentally appropriate stage may impair QOL. Antiepileptic drugs (AEDs) can compromise QOL through their side effects on behavior and cognitive functioning. AEDs may cause depression, increased irritability, conduct disorders, learning problems, anxiety, and hyperactivity [2]. Most epilepsy research to date has considered health-related QOL (HRQOL) in the adult population, with comparably minimal research in children [3].

Valproate is one of the antiepileptic drugs widely used as first-line treatment for epilepsy in children [4]. The metabolism of valproate may trigger oxygen-dependent tissue injury and elevate the levels of free radicals in the body [5]. The free radicals generated cause a cascade of neurochemical events leading to neurodegeneration and cell death [6]. Long-term use of AEDs has been shown to increase free radical formation and cause oxidative damage within neuronal cells [7]. Due to the limitations posed by the conventional AEDs, the endeavor to develop AEDs with predictable efficacy, safety, and tolerability and with neuroprotective and antioxidant action has continued.

In the last decade, much interest has arisen in melatonin, which helps to regulate sleep–wake cycles through the action on SCN in the hypothalamus. Melatonin (5-methoxy-N-acetyltryptamine), a pineal hormone, has been extensively tried in the treatment of sleep–wake cycle disorders [8]. Compared with normal controls, children with epilepsy have higher rates of sleep problems and disturbed daytime behavior [9]. Chronic sleep disorders can affect a child's development adversely, as sleep plays a major role in the early maturational processes in the brain [10]. Sleep deprivation leads to reduced attention span, low frustration threshold, mood changes, impaired social interactions, and difficulties with memory formation and recall [11]. Epilepsy is exacerbated by sleep deprivation [12]. Sleep disorders have also been reported to resemble seizures [13]. Some children with incompletely controlled epilepsy may experience fewer seizures following melatonin treatment once they are no longer sleep-deprived [8].

Melatonin, a neuromodulator, has been shown to have antiepileptic activity in animal studies using different seizure models [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15] as well as in cases of childhood epilepsy [16]. A few mechanisms for the anticonvulsant activity of melatonin have been suggested. It exerts neuroprotection due to its antioxidant, anti-excitotoxic, and free radical scavenging properties within the central nervous system [17], [18], [19]. In addition, it has been demonstrated to be safe in humans even at high pharmacological doses [20]. The function of melatonin as an oxidant and free radical scavenger is facilitated by the ease with which it crosses morphophysiological barriers, like the blood–brain barrier and intracellular and subcellular barriers [21]. However, effects of melatonin treatment on QOL parameters have not been studied. Therefore, a randomized, double-blind, placebo-controlled trial was conducted in epileptic children to assess the effects of add-on melatonin administration on QOL in epileptic children on valproate monotherapy. To our knowledge, this is the first study to assess the effect of add-on melatonin on QOL in a randomized, placebo-controlled trial.