Add-On Melatonin Improves Sleep Behavior in Children With Epilepsy

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Add-On Melatonin Improves Sleep Behavior in Children With Epilepsy: Randomized, Double-Blind, Placebo-Controlled Trial

Madhur Gupta MD; Satinder Aneja MD; Kamlesh Kohli, MD J Child Neurol. 2005; 20 (2): 112-115. ©2005 BC Decker, Inc.

Abstract and Introduction

Abstract

This double-blind, randomized, placebo-controlled study in epileptic children, aged 3 to 12 years, evaluated the effect of add-on melatonin on the sleep behavior of these children on sodium valproate monotherapy using a parental questionnaire. Of the 31 patients, 16 randomly received add-on melatonin, whereas 15 received add-on placebo. The questionnaire showed good internal consistency in our patient population (Cronbach's α = .83). The percentage decrease in the median total sleep score was 24.4 (range 0.0-34.9) in the valproate + melatonin group compared with 14.0 (range -2.2-18.8) in the valproate + placebo group, the difference being statistically significant ( P < .05). The median percentage decrease in the parasomnias score was 60 (range 0.0-70.8) in the valproate + melatonin group compared with 36.4 (range 0.0-63.2) in the valproate + placebo group, the difference being statistically significant (P < .05). There was no significant difference between the percentage decrease in the daytime drowsiness scores and sleep fragmentation scores. Parent-child interaction subscale scores were not significantly different between age groups. The age at onset of seizures and the type of seizures did not correlate significantly to the total sleep scores. Given that sleep problems are known to complicate epilepsy, add-on melatonin, which has a wide safety window, can be of promise in the pharmacotherapy of pediatric epilepsy.

Introduction

Studies on sleep problems in children with epilepsy are promising but limited. Zaiwalla and Stores found a generally higher rate of severe and persistent sleep problems, especially sleeplessness, daytime lethargy, and unrefreshing sleep, in children with epilepsy.[1] In a parental questionnaire study, they investigated the sleep problems and daytime behavior of schoolchildren with mild forms of epilepsy. Compared with normal controls, children with epilepsy showed a higher rate of sleep problems and disturbed daytime behavior.[1] Chronic sleep disorders can affect the child's development adversely because sleep plays a major role in the early maturational processes in the brain.[2] Sleep deprivation leads to reduced attention span, low frustration threshold, mood changes, impaired social interactions, and difficulties with memory formation and recall.[3] There is an association of epilepsy being exacerbated by sleep deprivation.[4] Sleep disorders have also been reported to resemble seizures.[5] Some children with incompletely controlled epilepsy experience fewer seizures following melatonin treatment once they are no longer sleep deprived.[6] There is evidence that children often reveal cognitive, emotional, and behavioral manifestations of inadequate sleep without showing frank sleepiness.[7]

Antiepileptic drugs might also affect sleep patterns differentially. Patients on valproate monotherapy have been shown to have some impairment in attention, with increased daytime sleepiness.[8] Valproic acid, a γ-aminobutyric acid (GABA)ergic drug, has been found to suppress nocturnal plasma melatonin levels in young, healthy adults, suggesting increased sleep problems in these patients owing to the drug's action on endogenous melatonin synthesis.[9]

In the last decade, much interest in melatonin has arisen. Melatonin helps regulate sleep-wake cycles through its action on the suprachiasmatic nucleus in the hypothalamus. Melatonin (5-methoxy- N -acetyltryptamine), a pineal hormone, has been extensively tried in the treatment of sleep-wake cycle disorders.[10] However, melatonin treatment has been studied mostly in uncontrolled trials. Therefore, a randomized, double-blind, placebo-controlled trial was conducted on epileptic children to assess the effects of add-on melatonin administration on sleep problems in epileptic children on valproate monotherapy.

Patients and Methods

Epileptic children of either sex, aged between 3 and 12 years, who presented to the seizure clinic at the Kalawati Saran Children's Hospital, Lady Hardinge Medical College, New Delhi, India, between April 2002, and February 2003 were enrolled. All patients were assessed and screened for inclusion and exclusion criteria ( n = 45). The institutional scientific and ethical committee approved the study protocol, and written informed consent was obtained from the accompanying parent or relative. As part of the consent procedure, information was read aloud from a consent form to ensure consistency, and any questions from the parent or relative were answered to his or her satisfaction. Only those patients were included who were on valproate monotherapy, had a confirmed diagnosis of epilepsy limited to partial or generalized seizures as classified according to the International Classification of Epileptic Seizures, and were seizure free for at least the last 6 months. All of the children with a history of psychiatric or other progressive neurologic disorder or a chronic hematologic, cardiac, hepatic, renal, or thyroid disorder were excluded. Only those children were included who had been receiving sodium valproate (10 mg/kg/d) for the last 6 months, who were seizure free, and, at the time of inclusion in the study, whose serum blood levels ranged between 75 and 125 µg/mL.

A randomization code list was prepared by a statistician, who was not connected to the study. The permutation of code numbers was computer generated for the treatment groups. Patients were then randomly divided into two groups: one group received add-on melatonin ( n = 16), whereas the other received placebo ( n = 15) 1 hour before bedtime. Melatonin (fast release) tablets of 3 mg strength (Aristo Pharmaceuticals Ltd, Mumbai, India) were used. The placebo tablets, identical in shape, size, color, and packaging, were specially prepared for the study by Aristo Pharmaceuticals Ltd. They contained dicalcium phosphate in place of melatonin, along with other similar excipients. The dose of melatonin was 6 mg (two tablets) for children under 9 years who weighed less than 30 kg and 9 mg (three tablets) for children older than 9 years who weighed more than 30 kg. Sleep, which was one of the outcome measures in the study, was assessed by means of a parental questionnaire, the Sleep Behavior Questionnaire.[11] The questionnaire is a validated instrument to facilitate investigation on sleep behavior in the general pediatric population. It was meant to assess the quantity and quality of sleep, usual bedtime and waking time, sleep latency, parental involvement at the time of sleep onset, night wakings, cosleeping, nighttime events, daytime drowsiness, and unrefreshing sleep. Each item was rated on a Likert scale from 1 (never) to 5 (always) by rating how often each item occurred in the last 6 months. Each item was rated on a Likert scale from 1 (never) to 5 (always) by rating how often each item occurred in the last 6 months. Thus, Sleep Behavior Questionnaire scores can range from 26 to 130. A decrease in score signifies fewer sleep problems. To each patient, the questionnaire was administered before add-on melatonin or placebo and after 4 weeks (28-32 days). The patients were called for regular follow-ups at weekly intervals. Clinical laboratory tests were performed at baseline and at each visit during the study period. For each patient, a daily diary was provided with the instruction to immediately record any side effects or unusual symptoms observed.

Descriptive statistics were calculated for all of the outcome variables and were expressed as mean ± SD or median and range as appropriate. The Wilcoxon rank sum (Mann-Whitney) test was used to compare the effects of add-on melatonin versus placebo. The chi-square test was used to compare the categorical variables (ie, sex and type of seizure) with two different groups. A P value < .05 was considered significant. All of the data were analyzed using STATA 7.0 (intercooled version) (STATA-Corp LP, College Station, TX).

Results

Between April 2002 and February 2003, 31 patients met the entry criteria. Sixteen patients were randomly allocated to receive add-on melatonin and 15 to receive placebo 1 hour before bedtime. One patient in the placebo group was lost to follow-up; thus, data from this patient could not be included in analysis. Thus, 16 patients in the add-on melatonin group and 14 in the add-on placebo group could be assessed (Figure 1). The valproate + melatonin group and the valproate + placebo group did not differ significantly with respect to median age, sex, and weight ( Table 1 ). The questionnaire showed good internal consistency in our patient population (Cronbach's α = .83). The percentage decrease in the median total sleep score was 24.4 (range 0.0-34.9) in the valproate + melatonin group compared with 14.0 (range -2.2-18.8) in the valproate + placebo group, the difference being statistically significant ( P < .05). The median percentage decrease in the parasomnias score was 60 (range 0.0-70.8) in the valproate + melatonin group compared with 36.4 (range 0.0-63.2) in the valproate + placebo group, the difference being statistically significant (P < .05) ( Table 2 ). There was no significant difference between the percentage decrease in the bedtime difficulties scores, parent-child interaction scores, daytime drowsiness scores, and sleep fragmentation scores. The patients were followed up clinically for another 4 weeks (total 8 weeks), during which all patients remained seizure free and no adverse effects were observed. No sex differences emerged with regard to sleep problems.

Figure 1. Flow of patients through the trial.

Because there was a large age range, three age groups were examined separately: 3 to 5 years, 6 to 9 years, and 10 to 13 years. We found that children aged 6 to 9 and 10 to 13 years reported more sleep problems, showing a significantly higher Sleep Behavior Questionnaire total score (0 vs 62 vs 60; P = .04). Parasomnias, sleep fragmentation, daytime drowsiness, bedtime difficulties, and parent-child interaction subscale scores were not significantly different between the age groups. The age at onset of seizures and the type of seizures did not correlate significantly with the total sleep scores. Although the effect on appetite was not objectively assessed in the study, the parents of 13 of 16 children in the melatonin group reported a perceptible increase in appetite compared with 4 of 15 in the placebo group.

Discussion

This double-blind, randomized, placebo-controlled trial has shown the benefit of add-on melatonin administration in epileptic children on valproate monotherapy. No side effects warranting discontinuation of therapy were observed. In our study, a significant median percentage decrease in the total sleep score was found in the valproate + melatonin group compared with the valproate + placebo group ( P < .05). This signifies that sleep problems in the melatonin combination group occurred relatively less frequently than in the placebo group. One of the most common sleep-wake cycle disorders in children is sleep fragmentation.[6] However, there was no significant difference between the percentage decrease in the sleep fragmentation scores after adding on melatonin or placebo. Hoeppner et al. reported a higher rate of parasomnias in epileptic children.[12] In our study, the parasomnias score showed a significant median percentage decrease in the valproate + melatonin group versus the valproate + placebo group post-treatment ( P = .03).

The doses of melatonin administered were based on the favorable results of Jan and O'Donnell, who successfully treated more than 100 mentally handicapped children with 2.5 to 10 mg of melatonin.[6] Melatonin exerts sedative, chronobiotic, and hypothermic effects, but it is still unclear how much benefit is derived from each of these properties.[13]

Hoeppner et al. found more sleep problems in partial epilepsy, suggesting that seizure type can influence the severity of sleep disturbances. In our study, no significant relationship of variables such as age at onset of seizures and seizure type to the total sleep scores was found. Sheldon reported the use of melatonin in six children with neurologic disabilities who had sleep difficulties. Although their sleep improved, four of five children experienced increased seizures.[14] Because melatonin exhibited an anticonvulsant action in animal studies and in clinical set-up, this is attributed most likely to interference with antiepileptic drugs. Our observations are not in agreement with those of Sheldon because none of the children experienced any increase in seizures or adverse effects, and their sleep improved markedly.

The accuracy of the parental reports is a point of consideration, but a good correlation between a sleep diary and questionnaires and objective sleep recordings has been found in some studies.[15]

Although, in children, no significant side effects except sedation have been reported,[6] the potential reproductive effects of melatonin in children are a consideration.[16]

Considering that a significant number of children with epilepsy have sleep disorders, melatonin can improve the sleep behavior and quality of life of these children. On the basis of our results, we suggest that improved sleep behavior and a wide safety margin make melatonin a useful adjunct in the therapy of pediatric epilepsy.

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Table 1. Demographic Characteristics of the Study Groups

Study Variables

Valproate + Placebo(n = 14)

Valproate + Melatonin(n = 16)

P Value

Age (yr), mean (SD)

6.6 (3.9)

7.4 (3.2)

..56

Sex

Female

4

8

..4

Male

10

8

Weight (kg), mean (SD)

18.3 (10.4)

19.5 (6.8)

..72

Age at onset of seizures (yr), median (range)

5.0 (5.0-5.0)

2.0 (0.6-11.0)

..5

Seizure type

Absence

3

5

Complex partial

3

2

..3

Generalized tonic-clonic

7

7

Lennox-Gastaut syndrome

1

2

P < .05, significant.

Table 2. Effect on Sleep in the Valproate + Melatonin vs Valproate + Placebo Group

Study Variables

Valproate + Melatonin Group,Median (Range) (n = 16)

Valproate + Placebo Group,Median (Range) (n = 14)

P Value

Total sleep score

Pretreatment

67.0 (55.0-89.0)

66.0 (45.0-77.0)

..43

Post-treatment

52.5 (39.0-62.0)

55.0 (39.0-75.0)

..76

Percentage decrease

24.4 (0.0-34.9)

14.0 (-2.2-18.8)

..005*

Sleep fragmentation score

Pretreatment

6.0 (4.0-9.0)

4.0 (4.0-10.0)

..4

Post-treatment

4.5 (4.0-6.0)

4.0 (4.0-5.0)

..11

Percentage decrease

24.3 (0.0-43.0)

0.0 (0.0-50.0)

1.0

Parasomnias score

Pretreatment

17.5 (7.0-24.0)

14.0 (8.0-29.0)

..33

Post-treatment

7.0 (6.0-7.0)

7.0 (7.0-26.0)

..04*

Percentage decrease

60.0 (0.0-70.8)

36.4 (0.0-63.2)

..03*

Daytime drowsiness score

Pretreatment

9.5 (5.0-18.0)

9.5 (8.0-11.0)

..56

Post-treatment

8.0 (5.0-9.0)

8.0 (7.0-9.00)

..73

Percentage decrease

0.0 (0.0-50.0)

10.0 (0.0-30.0)

..96

* P < .05, significant.

References

Zaiwalla Z, Stores G. Sleep and arousal disorders in childhood epilepsy Electroencephalogr Clin Neurophysiol 1989;72:72-72. Dahl RE. The regulation of sleep and arousal Dev Psychobiol 1996;08:3-27. Jan JE, Freeman RD, Fast DK. Melatonin treatment of sleep wake cycle disorders in children and adolescents Dev Med Child Neurol 1999;41:491-500. Rajna P, Veres J. Correlation between night sleep deprivation and seizure frequency in temporal lobe epilepsy Epilepsia 1993;34:574-579. Morrell MJ. Differential diagnosis of seizures Neurol Clin 1993;11:737-754. Jan JE, O'Donnell ME. Use of melatonin in the treatment of paediatric sleep disorders J Pineal Res 1996;21:193-199. Dahl RE. The impact of inadequate sleep on children's daytime cognitive function Semin Pediatr Neurol 1996;03:44-50. Salinsky MC, Oken BS, Binder LM. Assessment of drowsiness in epilepsy patients receiving chronic antiepileptic drug therapy Epilepsia 1996;37:181-187. Monteleone P, Tortorella A, Borrielo R, et al. Suppression of nocturnal plasma melatonin levels by evening administration of sodium valproate in healthy humans Biol Psychiatry 1997;41:336-341. Ross C, B, Whitehouse W. Melatonin treatment of sleep-wake cycle disorders in children and adolescents Dev Med Child Neurol 1999;41:41-41. Cortesi F, Giannotti F, Ottaviano S. Sleep problems and daytime behavior in childhood idiopathic epilepsy Epilepsia 1999;40:1557-1565. Hoeppner JB, Garron DC, Cartwright RD. Self reported sleep disorder symptoms in epilepsy Epilepsia 1984;25:434-437. Middleton B, Arendt J, Stone BM. Complex effects of melatonin on human circadian rhythms in constant dim light J Biol Rhythms 1997;12:467-477. Sheldon SH. , Proconvulsant action of oral melatonin in neurologically disabled children Lancet ;351: 1254; 1998. . Wiggs L, Stores G. Children's sleep. How should it be assessed?. Assoc Child Psychol Psychiatry Rev Newsl 1995;17:153-157. Arendt J. Safety of melatonin in long term use.;: J Biol Rhythms 1997;12:6-6.

Acknowledgements

We acknowledge Drs R. M. Pandey, M. Kalaivani, and V. A. V. Guruprasad, Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India, for their kind help with statistical analysis.

Reprint Address

Address correspondence to Dr Kamlesh Kohli, Department of Pharmacology, Lady Hardinge Medical College, Shaheed Bhagat Singh Marg, New Delhi 110001,India. Fax: +91-11-23340566; e-mail: madhurgupta@... .

From the Departments of Pharmacology ( Drs Gupta and Kohli ) and Pediatrics ( Dr Aneja ), Lady Hardinge Medical College and Associated Hospitals, New Delhi, India.