Melatonin as an add-on anti-seizure medication in children with epilepsy: An open-label randomized controlled trial

INTRODUCTION

Childhood seizure disorder is the “transient occurrence of signs and symptoms resulting from abnormal, hypersynchronous neuronal activity in the brain.” According to the International League against epilepsy (ILAE, 2017), seizures are classified into focal, generalized, unknown onset, and unclassified based on the mode of seizure onset.^[1] Out of 70 million persons with epilepsy worldwide, approximately one-sixth of them reside in India. In a recently published study from India, the overall prevalence was reported to be 3.0–11.9/1,000 population, whereas incidence was 0.2–0.6/1000 population/year.^[2] Although no definitive data is available on the prevalence of pediatric epilepsy in India, a study published in Kashmir found it to have a prevalence of 3.74/1000 in boys and 3.13/1000 in girls.^[3] Almost 60–70% of the children with epilepsy respond well to available anti-seizure medications (ASMs) as monotherapy if given at adequate doses, but 10– 20% remain refractory and require additional drugs in the form of polytherapy.^[4] Hence, there is a need for an add-on ASM with a good safety profile.

Drug-resistant epilepsy is defined as “failure of adequate trials of two tolerated, appropriately chosen and used ASM schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom (all types of seizures) for 12 months, or three times the inter seizure interval before treatment started” (ILAE, 2017).^[5] Studies on drug-resistant epilepsy in children from India are scarce. With the availability of newer antiepileptics, identifying this drug-resistant epilepsy is of utmost importance for better management. Despite polytherapy, many of these children continued to be symptomatic. Hence, the need for newer antiepileptics with lesser side effects is warranted. Melatonin is a promising drug with better seizure control and acceptable tolerability, which has been used in limited studies.^[6-8]

Melatonin has been widely used in the treatment of sleep disorders. Studies have shown that melatonin increases the quality of life (QOL) in children and adults with epilepsy.^[9,10] When compared to normal children, children with epilepsy are shown to have more sleep-related problems. These chronic sleep disorders can have adverse effects on a child’s development. Studies have shown that sleep deprivation exacerbates epilepsy.^[11,12] Studies in children with poorly controlled epilepsy showed a decrease in seizure frequency following melatonin treatment when they were no longer sleep-deprived.^[13] Melatonin is helpful in the prevention of febrile seizures in children.^[14] The anticonvulsant property of melatonin is attributed to its antioxidant, antiexcitotoxic, and free radical scavenging action in the central nervous system providing neuroprotection and hence decreasing the seizure frequency. Blood levels of melatonin are also lower in children with epilepsy compared to normal children.^[15] In our proposed study, we tried to measure the efficacy of melatonin as an add-on drug in children with drug-resistant epilepsy.

MATERIALS AND METHODS

This was an open-label randomized controlled trial conducted from July 2020 to December 2022 at a tertiary care center in eastern India. Children with drug-resistant epilepsy (defined by ILAE, 2017), aged 2–14 years, were enrolled in the Pediatric and Neurology outpatients or inpatients. Children with hepatic dysfunction, a history of recent traumatic head injury, status epilepticus, history of allergy to valproate, and melatonin, who were on melatonin products in the last three months were excluded from the study. Ethical approval was obtained from the Institute Ethics Committee (IEC). The trial was registered under Clinical Trials Registry - India before the initiation of the study.

Children attending the Pediatric and Neurology outpatient department (OPD) and inpatient department with drug-resistance epilepsy were included in this study after considering all the inclusion and exclusion criteria. Before enrolling, consent was taken from the parents after explaining the study process in their language. The dose of existing ASMs was optimized at the start of the study. If the child requires adding one more ASM to control seizure frequency, it is added according to existing treatment protocols. Parents were appropriately counseled regarding the maintenance of seizure dairy, which was assessed after one month to know the baseline seizure frequency. Then, the children were randomized.

RESULTS

Fifty-two children were screened, and 37 were enrolled based on inclusion and exclusion criteria [Figure 1]. Of 37 children, 18 (48.6%) were enrolled in the melatonin group, and the rest, 19 (51.4%), were in the control group. The mean (SD) age of study participants in years in the melatonin group was 6.2 (±3.19) years, and in the control group was 5.6 (±3.73) years, which was not statistically significant. More than 50% of the children had a single type of seizure (GTCS) semiology, whereas the rest had multiple types (GTCS, tonic, and myoclonic). Most children had brief seizure episodes lasting <5 min in both groups. The median age of seizure onset was 24 months in the melatonin group, whereas 36 months in the control group. There was no difference in the duration of seizure onset in either group [Table 1].

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Figure 1:

Study flow chart. OPD: Outpatient department, IPD: Inpatient department, LFT: Liver function test, AED: Antiepileptic drug.

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A total of 31 (83%) participants had abnormal electroencephalogram (EEG) findings. There was no significant difference in abnormal EEG findings between the two groups. More than half the participants had abnormal magnetic resonance imagings.

DISCUSSION

The present study mainly focused on the effect of add-on melatonin in children with drug-resistant epilepsy on seizure frequency. We observed a decrease in the percentage of seizure frequency by 51% in the melatonin group compared to the control though statistically insignificant. The baseline seizure frequency per month before randomization in the melatonin group was 25 (7–100), and in the control group was 20 (5–96). In a previously published double-blind placebo control cross-over pilot study done by Goldberg-stern et al., seizure frequency was documented to be 7.75 per day during the placebo treatment. In contrast, the melatonin group had a seizure frequency of 4.6/day, which was statistically significant. However, the study had a small sample size of 12, of which only ten patients completed the study, and follow-up was only for three weeks.^[6]

Similarly, Peled et al., observed a significant clinical improvement in daytime seizure frequency in all children with intractable seizures except one when treated with melatonin and followed up for three months. However, this study was done in only six children.^[16] Jain et al. observed a 50% reduction in seizure frequency in two children in their cohort who received melatonin, and eight seizure-free children remained seizure-free during the study. Hence, they did not observe any worsening in seizure frequency. However, children with refractory epilepsy were not enrolled in their study.^[7] In most of the studies, seizure control was not the study’s primary objective.

A randomized double-blinded cross-over and placebo-controlled trial by Coppola et al. was done among children with mental retardation age over 12 months, with/without seizures who were diagnosed with sleep disorders where melatonin was compared with placebo. It did not show any significant change in seizure frequency in either group. However, it did not mention an exact number of seizure frequencies in either group.^[17] Similarly, another randomized, double-blind, controlled, and cross-over trial by Hancock et al. done in children with tuberous sclerosis with a sleep disorder of age group 18 months–32 years where two different doses of melatonin were compared (5 mg vs. 10 mg). There was no significant change from baseline seizure frequency in either group. Three out of seven participants were seizure-free in this study on follow-up.^[18] A Cochrane meta-analysis published in 2016 could not conclude the role of melatonin in decreasing seizure frequency due to a lack of good, quality studies.^[19]

In a randomized controlled trial done by Verma et al. in adults with generalized epilepsy where melatonin was used as an add-on drug to valproate, there was a significant decrease in the median number of seizures for eight weeks from three episodes to no episode in the melatonin group as compared to a control group where the decrease was to one episode from three episodes over eight weeks.^[10] Melatonin inhibits brain excitability through MT1 and MT2 receptors, which are presumed to be a mechanism for anticonvulsant properties.^[20] An animal model has demonstrated the anticonvulsant properties of melatonin.^[21] Add-on melatonin is clinically improving seizure control in a study by Gupta et al. However, QOL was considered the primary outcome rather than seizure control in that study.^[9]

In our study, 4 out of 18 children in the melatonin group had minor side effects that did not require the stoppage of the drug. Two children had vomiting, relieved with a short course of anti-emetics, and two children had excessive daytime sleepiness in the first two weeks of starting melatonin. The present study’s side effects were similar to previous studies.^[22,23] However, none of these adverse drug reactions were observed in children by Coppola et al., Hancock et al., and Brigo et al. Neither melatonin needs to be withdrawn during the study period as in the present study.^[17-19]

The present study has limitations of having a small sample size with short-term follow-up and subjective outcomes. We could not repeat the EEG and monitor drug level too.

CONCLUSION

Melatonin had a more substantial effect on reducing seizure frequency compared to the control group, as evidenced by the more than 50% percentage decrease in seizures within the melatonin group without major adverse effects. However, it is important to note that the overall reduction in seizure frequency for both groups was not statistically significant. More research is needed in the future to determine the true effectiveness of melatonin in managing seizures. A large sample size study and a longer follow-up could give us better evidence to establish the findings and to assess the long-term effectiveness and safety of add-on melatonin in children with drug-refractory epilepsy.