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Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial
Epilepsy & Behavior Epilepsy & Behavior 5 (2004) 316–321 www.elsevier.com/locate/yebeh
Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial Madhur Gupta,a Satinder Aneja,b and Kamlesh Kohlia,* a
Department of Pharmacology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India b Department of Pediatrics, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India Received 19 November 2003; revised 28 January 2004; accepted 29 January 2004 Available online 5 March 2004
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 CronbachÕs a 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. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Melatonin; Valproate; Sleep; Epilepsy; Children; Quality of life
1. 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 * Corresponding author. Fax: +91-11-23340566. E-mail address: [email protected] (K. Kohli).
1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.01.012
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.
M. Gupta et al. / Epilepsy & Behavior 5 (2004) 316–321
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 (5methoxy-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 childÕs 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 [4–15] 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, antiexcitotoxic, and free radical scavenging properties within the central nervous system [17–19]. 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.
2. Patients and methods The study was a randomized, double-blind, placebocontrolled trial. Epileptic children, aged between 3 and 12 years of either sex, who presented to the seizure clinic at the Kalawati Saran ChildrenÕs Hospital, Lady Hardinge Medical College, New Delhi, India, between April 2002 and February 2003, were enrolled. All patients were assessed and screened for inclusion/exclusion criteria (n ¼ 45). The institutional scientific and ethical committee approved the study protocol, and written informed consent was obtained from the accompanying parent/ relative. As part of the consent procedure, information
317
was read aloud from a consent form to ensure consistency, and any questions from the parents/relatives were answered to their 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 at least for the last 6 months. All children with a history of psychiatric or other progressive neurological disorder or a chronic hematological, cardiac, hepatic, renal, or thyroid disorder were excluded. Only those children were included who had been taking sodium valproate (10 mg/kg/day) for the last 6 months, were seizure-free, and, at the time of inclusion in the study, had serum blood levels in the range 75–125 lg/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 ¼ 16), and the other received placebo (n ¼ 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. The placebo tablets contained dicalcium phosphate in place of melatonin along with other similar excipients. The dose of melatonin was 6 mg (2 tablets) for children younger than 9 years/weighing less than 30 kg and 9 mg (3 tablets) for children older than 9 years/weighing more than 30 kg. QOL was assessed using the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire [3]. This parental questionnaire has proven validity and reliability. For most of the multi-item scales the internal consistency (CronbachÕs a) reliabilities were calculated, and it was found that the 13 multi-item scales had internal consistency (CronbachÕs a) reliabilities that exceeded the generally accepted criterion of 0.50 for adequate reliability when making group comparisons. These reliabilities ranged from 0.59 to 0.94 in our study population. The questionnaire was administered before add-on melatonin/placebo and 4 weeks after (28–32 days). The patients were called for regular follow-up visits at weekly intervals. Clinical laboratory tests (liver function tests, hemoglobin, etc.) were performed at baseline and at each visit during the study period. Each patient was provided with a diary and instructed to record any side effects or unusual symptoms observed. 2.1. Statistical analysis Descriptive statistics were calculated for all outcome variables, and expressed as means SD or medians and ranges as appropriate. The v2 test was used to compare the categorical variables (e.g., sex, type of seizure, family,
318
M. Gupta et al. / Epilepsy & Behavior 5 (2004) 316–321
history of epilepsy, CT, etc.) between two different groups. Scores on the different scales derived from the QOLCE questionnaire were compared among the groups using the Kruskal–Wallis test. The baseline scores on the multi-item scales and the scores after treatment (add-on melatonin/placebo) were compared using the Wilcoxon rank-sum test. For multi-item scales, the internal consistency (CronbachÕs a) reliabilities were calculated and reported. All data were analyzed using STATA 7.0 (intercooled version). Differences with a P value <0.05 were considered significant.
3. 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, and data for this patient could not be included in the analysis. Thus, 16 patients in the add-on melatonin group and 14 in the add-on placebo group could be assessed. The valproate + melatonin group and valproate + placebo group did not differ significantly with respect to median age, sex, and weight (Table 1). The groups were quite comparable with respect to these characteristics, and there were no statistically significant differences. The hematological and biochemical investigations (liver function tests, hemoglobin, etc.) carried out at weekly intervals were found to be within normal limits in all patients. No adverse event warranting discontinuation of the therapy was reported. The QOLCE administered to the study groups was a 72-item instrument with 16 subscales. These subscales measured Physical Restrictions, Energy/ Fatigue, Attention/Concentration, Language, Other Cognitive Processes, Depression, Anxiety, Control/
Helplessness, Self-esteem, Social interactions, Social activities, Stigma, Behavior, General Health, and QOL. All scores on the 16 subscales are listed in Table 2. The Attention (P ¼ 0:001), memory (P ¼ 0:05), and language (P ¼ 0:004) subscales showed significant intragroup improvement in the VPA + MEL group after addition of melatonin. The median score on the Other Cognitive Processes subscale for the VPA + MEL group was 4.0 (range: 1.0–5.0) pretreatment, as compared with 4.7 (range: 2.5–5.0) posttreatment, the difference being statistically significant (P ¼ 0:05) within the group. On the Anxiety subscale, the difference between the pretreatment and posttreatment scores within the VPA + MEL group was significant (P ¼ 0:02). Within the VPA + MEL group, the pretreatment Behavior subscale median score was 3.2 (range: 2.65–3.5), as compared with 3.3 posttreatment (range: 2.6–3.5), the difference being statistically significant (P ¼ 0:004). In the same group, the difference on the General Health score before and after addition of melatonin was marginally significant (P ¼ 0:08). The difference between pre- and posttreatment QOL scores was also marginally significant (P ¼ 0:08). The median total QOL score was 3.7 (range: 2.6–4.0). The median QOL score posttreatment in the VPA + MEL group was 4.0 (range: 3.0–4.0), as compared with 3.0 (range: 2.0–4.0) in the VPA + P group, the difference being marginally significant (P ¼ 0:08) in the VPA + MEL group Table 3. Although the effect on appetite was not objectively assessed in the study, parents of 13 of 16 children in the melatonin group reported a perceptible increase in appetite as compared with 4 of 15 in the placebo group.
4. Discussion To our knowledge, this is the first study assessing QOL in epileptic children with add-on melatonin
Table 1 Demographic characteristics of the study groups Study variable Age (years) Sex Female Male Weight (kg) Age at onset of seizures (years) Type of seizure Absence Complex partial Generalized tonic–clonic seizures Lennox–Gastaut syndrome a
Mean (SD). Median (range). P < 0:05, significant. b
Valproate + placebo group (n ¼ 14) a
Valproate + melatonin group (n ¼ 16) a
P value
6.6 (3.9)
7.4 (3.2)
0.56
4 10 18.3 (10.4)a 5.0 (5.0–5.0)b
8 8 19.5 (6.8)a 2.0 (0.6–11.0)b
0.4
3 3 7 1
5 2 7 2
0.72 0.5
0.3
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319
Table 2 QOLCE subscales: VPA + MEL group versus VPA + P group Scale 1. Physical restrictions
2. Energy/fatigue
3. Attention/concentration
4. Memory
5. Language
6. Other cognitive processes
7. Depression
8. Anxiety
9. Control/helplessness
10. Self-esteem
11. Social interactions
12. Social activities
13. Stigma
14. Behavior
15. General health
16. QOL
*
Study variable
VPA + MEL
VPA + P
Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/ placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value
2.67 (2–4) 2.7 (2.1–4) 0.38 3 (2.5–3) 3.0 (2.5–3.0) 1.0 3.2 (1.4–4.8) 3.9 (1.8–4.8) 0.001 5.0 (1.0–5.0) 5.0 (2.4–5.0) 0.05 3.9(1.0–5.0) 4.2 (1.0–5.0) 0.004 4.0 (1.0–5.0) 4.7 (2.5–5.0) 0.05 3.0 (1.5–3.3) 3.0 (1.5–3.75) 0.86 4.2 (2.0–5.0) 4.8 (3.0–5.0) 0.02 5.0 (1.0–5.0) 5.0 (2.0–5.0) 0.31 2.6 (1.5–4.0) 2.9 (1.5–3.75) 0.5 5.0 (2.0–5.0) 5.0 (5.0–5.0) 0.32 2.6 (2.0–3.3) 2.6 (2.0–3.3)
2.67 (2.4–3.3) 2.67 (2.2–3.3) 0.16 3.5 (3–3.5) 3.0 (2.5–3.5) 0.08 3.8 (2.0–4.6) 4.0 (2.0–5.0) 0.09 4.7 (1.0–5.0) 4.8 (1.0–5.0) 0.32 4.5 (2.3–4.9) 4.6 (2.5–4.9) 0.48 3.3 (2.0–5.0) 3.0 (2.0–5.0) 0.48 3.7 (2.3–5.0) 3.7 (2.3–5.0) 0.77 5.0 (4.0–5.0) 5.0 (4.0–5.0) 0.43 4.5 (3.7–5.0) 4.5 (3.7–5.0) 0.38 3.2 (3.0 – 4.0) 3.2 (3.0–3.8) 0.08 5.0 (4.0–5.0) 5.0 (3.7–5.0) 0.32 2.0 (2.0–2.7) 2.0 (2.0–2.7)
—
—
5.0 (5.0–5.0) 5.0 (5.0–5.0)
5.0 (5.0–5.0) 5.0 (5.0–5.0)
—
—
3.2 (2.65– 3.5) 3.3 (2.6–3.5) 0.05 4.0 (3.0–5.0) 4.0 (3.0–4.0) 0.08 4.0 (3.0–5.0) 4.0 (3.0–4.0) 0.08
3.5 (3.2–3.54) 3.4 (3.3–3.6) 0.49 4.6 (3.0–4.0) 3.0 (3.0–4.0) 0.16 3.0 (3.0–4.0) 3.0 (2.0–4.0) 0.16
P < 0:05, significant.
administration. This randomized, double-blind, placebo-controlled trial has shown the benefit of add-on melatonin administration on QOL in epileptic children on valproate monotherapy. No side effects warranting discontinuation of therapy were observed. The doses of melatonin administered were based on the favorable results of Jan and Donnell, who successfully treated more than 100 mentally handicapped children with 2.5– 10 kg melatonin [8]. The questionnaire was designed to assess a variety of age-relevant domains, such as physical function, emotional well-being, cognitive function,
social function, behavior, and general health. The questionnaire, which was translated as well as validated in Hindi (national language), had good internal consistency reliability, as most of the multi-item scales had a Cronbach a reliability exceeding 0.5 (range: 0.59–0.94). This shows that the questionnaire was reliable in the patients in our study. A perceptible increase in appetite as well as improvement in sleep was reported by most of the patients in the VPA + MEL group, although these factors were not objectively assessed. The VPA + MEL group exhibited
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M. Gupta et al. / Epilepsy & Behavior 5 (2004) 316–321
Table 3 QOLCE: descriptive statistics and reliabilities Scale
Number of items
Median
Range
CronbachÕs a
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
6 2 5 6 8 3 4 6 4 5 3 3 1 14 1 1 72
2.7 3.0 4.0 5.0 4.5 5.0 3.0 4.8 4.7 3.5 5.0 2.3 5.0 3.3 4.0 4.0 3.7
1.3–4.0 2.0–3.5 1.4–5.0 1.0–5.0 1.0–5.0 1.0–5.0 1.5–5.0 1.3–5.0 1.0–5.0 1.5–5.0 2.0–5.0 2.0–3.3 1.0–5.0 2.6–3.5 3.0–5.0 3.0–5.0 2.6–4.0
0.69 0.88 0.77 0.90 0.83 0.59 0.72 0.94 0.85 0.46 0.74 0.30
a *
Physical Restrictions Energy/Fatigue Attention/Concentration Memory Language Other Cognitive Processes Depression Anxiety Control/Helplessness Self-esteem Social Interactions Social Activities Stigma Behavior General Health QOL Total QOL
a
0.49 a a
Single-item scales, unable to calculate CronbachÕs a. Not significant, all others significant.
significant intragroup improvement on the Attention, Memory, Language, Other Cognitive Processes, Anxiety, and Behavior multi-item subscales posttreatment. To our knowledge, this is the first study assessing QOL in epileptic children with add-on melatonin administration. On the basis of our results, it may be postulated that the improved QOL in the add-on melatonin group, as compared with the placebo group, can be attributed to the diverse properties of melatonin, such as its anticonvulsant, antioxidant, and free radical scavenging properties and its favorable effects on sleep. Moreover, melatonin at doses of 1–300 mg in human studies has been shown to be safe, with no adverse effects observed [22]. Recently, in a double-blind, placebocontrolled clinical trial, no toxicological effects of melatonin (10 mg) were observed [23]. Further studies that employ both epilepsy-specific and generic measures of HRQOL and larger sample sizes are needed to provide a more comprehensive picture of the QOL of children with epilepsy.
Acknowledgments The authors acknowledge Dr. R.M. Pandey, Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India, for his kind help in statistical analysis.
References [1] Jacoby A. Epilepsy and quality of everyday life, findings from a study of people with well controlled epilepsy. Soc Sci Med 1992;34:657–66.
[2] Cortesi F, Gianotti F, Ottaviano S. Sleep problems and daytime behavior in childhood idiopathic epilepsy. Epilepsia 1999;40: 1557–65. [3] Sabaz M, Cairns D, Lawson J, Nheu N, Bleasel A, Bye A. Validation of a new quality of life measure for children with epilepsy. Epilepsia 2000;41:765–74. [4] Kurekci AE, Alpay F, Tanindi S, et al. Plasma trace element, plasma glutathione peroxidase, and superoxide dismutase levels in epileptic children receiving antiepileptic drug therapy. Epilepsia 1995;36:600–4. [5] Cengiz M, Yukcel A, Seven M. The effects of carbamazepine and valproic acid on the erythrocyte glutathione, glutathione peroxidase, superoxide dismutase and serum lipid peroxidation in epileptic children. Pharmacol Res 2000;41:423–5. [6] Gilgun-Sherki Y, Rosenbaum Z, Melamed E, Offen D. Antioxidant therapy in acute central nervous system injury: current state. Pharmacol Rev 2002;54:271–84. [7] Maertens P, Dyken P, Graf W, et al. Free radicals, anticonvulsants, and the neuronal ceroid lipofuscinoses. Am J Med Genet 1995;57:225–8. [8] Jan JE, OÕDonnell ME. Use of melatonin in the treatment of paediatric sleep disorders. J Pineal Res 1996;21:193–9. [9] Zaiwalla Z, Stores G. Sleep and arousal disorders in childhood epilepsy. Electroencephoger Clin Neurophysiol 1989;72:107. [10] Dahl RE. The regulation of sleep and arousal. Dev Psychobiol 1996;8:3–27. [11] 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. [12] Rajna P, Veres J. Correlation between night sleep deprivation and seizure frequency in temporal lobe epilepsy. Epilepsia 1993;34:574–9. [13] Morrell MJ. Differential diagnosis of seizures. Neurol Clin 1993;11:737–54. [14] Mevissen M, Ebert U. Anticonvulsant effects of melatonin in amygdala kindled rats. Neurosci Lett 1998;257:6–13. [15] Srivastava AK, Gupta SK, Jain S, Gupta YK. Effect of melatonin and phenytoin on an intracortical ferric chloride model of posttraumatic seizures in rats. Methods Find Exp Clin Pharmacol 2002;24:145–9. [16] Molina-Carballo A, Munoz-Hoyos R, Reiter RJ, et al. Utility of high dose of melatonin as adjunctive anticonvulsant therapy in a
M. Gupta et al. / Epilepsy & Behavior 5 (2004) 316–321 child with severe myoclonic epilepsy: two years experience. J Pineal Res 1997;23:97–105. [17] Espinar A, Garcia-Olivia A, Isorna EM, Quesada A, Prada FA, Guerrero JM. Neuroprotection form glutamate induced excitotoxicity during development of cerebellum in chick embryo. J Pineal Res 2000;28:81–8. [18] Reiter RJ, Tan DX, Cabrera J, Darpa D. Melatonin and tryptophan derivatives as free radical scavengers and antioxidants. Adv Exp Med Biol 1999;467:379–87. [19] Allegra M, Reiter RJ, Tan DX, Gentile C, Tesoriere L, Livrea MA. The chemistry of melatoninÕs interaction with reactive species. J Pineal Res 2003;34:1–10.
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[20] Reiter RJ, Tan DX, Poeggler B, Menedez-Palaez A, Chen LD, Saarela S. Melatonin as a free radical scavenger: implications for ageing and age related diseases. Ann NY Acad Sci 1994;719:1–19. [21] Reiter RJ, Tan DX, Cabrera J, Arpa D. Melatonin and tryptophan derivatives as free radical scavangers and antioxidants. Adv Exp Med Biol 1999;58:321–34. [22] James SP, Sack DA, Rosenthal NE, Mendelson WB. Melatonin administration in insomnia. Neuropsychopharmacology 1990;3: 19–23. [23] De Lourdes V, Seabra M, Bignotto M, et al. Randomized, double blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 2000;29:193–200.
Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial Madhur Gupta,a Satinder Aneja,b and Kamlesh Kohlia,* a
Department of Pharmacology, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India b Department of Pediatrics, Lady Hardinge Medical College and Associated Hospitals, New Delhi, India Received 19 November 2003; revised 28 January 2004; accepted 29 January 2004 Available online 5 March 2004
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 CronbachÕs a 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. Ó 2004 Elsevier Inc. All rights reserved. Keywords: Melatonin; Valproate; Sleep; Epilepsy; Children; Quality of life
1. 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 * Corresponding author. Fax: +91-11-23340566. E-mail address: [email protected] (K. Kohli).
1525-5050/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.yebeh.2004.01.012
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.
M. Gupta et al. / Epilepsy & Behavior 5 (2004) 316–321
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 (5methoxy-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 childÕs 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 [4–15] 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, antiexcitotoxic, and free radical scavenging properties within the central nervous system [17–19]. 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.
2. Patients and methods The study was a randomized, double-blind, placebocontrolled trial. Epileptic children, aged between 3 and 12 years of either sex, who presented to the seizure clinic at the Kalawati Saran ChildrenÕs Hospital, Lady Hardinge Medical College, New Delhi, India, between April 2002 and February 2003, were enrolled. All patients were assessed and screened for inclusion/exclusion criteria (n ¼ 45). The institutional scientific and ethical committee approved the study protocol, and written informed consent was obtained from the accompanying parent/ relative. As part of the consent procedure, information
317
was read aloud from a consent form to ensure consistency, and any questions from the parents/relatives were answered to their 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 at least for the last 6 months. All children with a history of psychiatric or other progressive neurological disorder or a chronic hematological, cardiac, hepatic, renal, or thyroid disorder were excluded. Only those children were included who had been taking sodium valproate (10 mg/kg/day) for the last 6 months, were seizure-free, and, at the time of inclusion in the study, had serum blood levels in the range 75–125 lg/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 ¼ 16), and the other received placebo (n ¼ 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. The placebo tablets contained dicalcium phosphate in place of melatonin along with other similar excipients. The dose of melatonin was 6 mg (2 tablets) for children younger than 9 years/weighing less than 30 kg and 9 mg (3 tablets) for children older than 9 years/weighing more than 30 kg. QOL was assessed using the Quality of Life in Childhood Epilepsy (QOLCE) questionnaire [3]. This parental questionnaire has proven validity and reliability. For most of the multi-item scales the internal consistency (CronbachÕs a) reliabilities were calculated, and it was found that the 13 multi-item scales had internal consistency (CronbachÕs a) reliabilities that exceeded the generally accepted criterion of 0.50 for adequate reliability when making group comparisons. These reliabilities ranged from 0.59 to 0.94 in our study population. The questionnaire was administered before add-on melatonin/placebo and 4 weeks after (28–32 days). The patients were called for regular follow-up visits at weekly intervals. Clinical laboratory tests (liver function tests, hemoglobin, etc.) were performed at baseline and at each visit during the study period. Each patient was provided with a diary and instructed to record any side effects or unusual symptoms observed. 2.1. Statistical analysis Descriptive statistics were calculated for all outcome variables, and expressed as means SD or medians and ranges as appropriate. The v2 test was used to compare the categorical variables (e.g., sex, type of seizure, family,
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history of epilepsy, CT, etc.) between two different groups. Scores on the different scales derived from the QOLCE questionnaire were compared among the groups using the Kruskal–Wallis test. The baseline scores on the multi-item scales and the scores after treatment (add-on melatonin/placebo) were compared using the Wilcoxon rank-sum test. For multi-item scales, the internal consistency (CronbachÕs a) reliabilities were calculated and reported. All data were analyzed using STATA 7.0 (intercooled version). Differences with a P value <0.05 were considered significant.
3. 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, and data for this patient could not be included in the analysis. Thus, 16 patients in the add-on melatonin group and 14 in the add-on placebo group could be assessed. The valproate + melatonin group and valproate + placebo group did not differ significantly with respect to median age, sex, and weight (Table 1). The groups were quite comparable with respect to these characteristics, and there were no statistically significant differences. The hematological and biochemical investigations (liver function tests, hemoglobin, etc.) carried out at weekly intervals were found to be within normal limits in all patients. No adverse event warranting discontinuation of the therapy was reported. The QOLCE administered to the study groups was a 72-item instrument with 16 subscales. These subscales measured Physical Restrictions, Energy/ Fatigue, Attention/Concentration, Language, Other Cognitive Processes, Depression, Anxiety, Control/
Helplessness, Self-esteem, Social interactions, Social activities, Stigma, Behavior, General Health, and QOL. All scores on the 16 subscales are listed in Table 2. The Attention (P ¼ 0:001), memory (P ¼ 0:05), and language (P ¼ 0:004) subscales showed significant intragroup improvement in the VPA + MEL group after addition of melatonin. The median score on the Other Cognitive Processes subscale for the VPA + MEL group was 4.0 (range: 1.0–5.0) pretreatment, as compared with 4.7 (range: 2.5–5.0) posttreatment, the difference being statistically significant (P ¼ 0:05) within the group. On the Anxiety subscale, the difference between the pretreatment and posttreatment scores within the VPA + MEL group was significant (P ¼ 0:02). Within the VPA + MEL group, the pretreatment Behavior subscale median score was 3.2 (range: 2.65–3.5), as compared with 3.3 posttreatment (range: 2.6–3.5), the difference being statistically significant (P ¼ 0:004). In the same group, the difference on the General Health score before and after addition of melatonin was marginally significant (P ¼ 0:08). The difference between pre- and posttreatment QOL scores was also marginally significant (P ¼ 0:08). The median total QOL score was 3.7 (range: 2.6–4.0). The median QOL score posttreatment in the VPA + MEL group was 4.0 (range: 3.0–4.0), as compared with 3.0 (range: 2.0–4.0) in the VPA + P group, the difference being marginally significant (P ¼ 0:08) in the VPA + MEL group Table 3. Although the effect on appetite was not objectively assessed in the study, parents of 13 of 16 children in the melatonin group reported a perceptible increase in appetite as compared with 4 of 15 in the placebo group.
4. Discussion To our knowledge, this is the first study assessing QOL in epileptic children with add-on melatonin
Table 1 Demographic characteristics of the study groups Study variable Age (years) Sex Female Male Weight (kg) Age at onset of seizures (years) Type of seizure Absence Complex partial Generalized tonic–clonic seizures Lennox–Gastaut syndrome a
Mean (SD). Median (range). P < 0:05, significant. b
Valproate + placebo group (n ¼ 14) a
Valproate + melatonin group (n ¼ 16) a
P value
6.6 (3.9)
7.4 (3.2)
0.56
4 10 18.3 (10.4)a 5.0 (5.0–5.0)b
8 8 19.5 (6.8)a 2.0 (0.6–11.0)b
0.4
3 3 7 1
5 2 7 2
0.72 0.5
0.3
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Table 2 QOLCE subscales: VPA + MEL group versus VPA + P group Scale 1. Physical restrictions
2. Energy/fatigue
3. Attention/concentration
4. Memory
5. Language
6. Other cognitive processes
7. Depression
8. Anxiety
9. Control/helplessness
10. Self-esteem
11. Social interactions
12. Social activities
13. Stigma
14. Behavior
15. General health
16. QOL
*
Study variable
VPA + MEL
VPA + P
Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/ placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value Premelatonin/placebo Postmelatonin/placebo Intragroup P value
2.67 (2–4) 2.7 (2.1–4) 0.38 3 (2.5–3) 3.0 (2.5–3.0) 1.0 3.2 (1.4–4.8) 3.9 (1.8–4.8) 0.001 5.0 (1.0–5.0) 5.0 (2.4–5.0) 0.05 3.9(1.0–5.0) 4.2 (1.0–5.0) 0.004 4.0 (1.0–5.0) 4.7 (2.5–5.0) 0.05 3.0 (1.5–3.3) 3.0 (1.5–3.75) 0.86 4.2 (2.0–5.0) 4.8 (3.0–5.0) 0.02 5.0 (1.0–5.0) 5.0 (2.0–5.0) 0.31 2.6 (1.5–4.0) 2.9 (1.5–3.75) 0.5 5.0 (2.0–5.0) 5.0 (5.0–5.0) 0.32 2.6 (2.0–3.3) 2.6 (2.0–3.3)
2.67 (2.4–3.3) 2.67 (2.2–3.3) 0.16 3.5 (3–3.5) 3.0 (2.5–3.5) 0.08 3.8 (2.0–4.6) 4.0 (2.0–5.0) 0.09 4.7 (1.0–5.0) 4.8 (1.0–5.0) 0.32 4.5 (2.3–4.9) 4.6 (2.5–4.9) 0.48 3.3 (2.0–5.0) 3.0 (2.0–5.0) 0.48 3.7 (2.3–5.0) 3.7 (2.3–5.0) 0.77 5.0 (4.0–5.0) 5.0 (4.0–5.0) 0.43 4.5 (3.7–5.0) 4.5 (3.7–5.0) 0.38 3.2 (3.0 – 4.0) 3.2 (3.0–3.8) 0.08 5.0 (4.0–5.0) 5.0 (3.7–5.0) 0.32 2.0 (2.0–2.7) 2.0 (2.0–2.7)
—
—
5.0 (5.0–5.0) 5.0 (5.0–5.0)
5.0 (5.0–5.0) 5.0 (5.0–5.0)
—
—
3.2 (2.65– 3.5) 3.3 (2.6–3.5) 0.05 4.0 (3.0–5.0) 4.0 (3.0–4.0) 0.08 4.0 (3.0–5.0) 4.0 (3.0–4.0) 0.08
3.5 (3.2–3.54) 3.4 (3.3–3.6) 0.49 4.6 (3.0–4.0) 3.0 (3.0–4.0) 0.16 3.0 (3.0–4.0) 3.0 (2.0–4.0) 0.16
P < 0:05, significant.
administration. This randomized, double-blind, placebo-controlled trial has shown the benefit of add-on melatonin administration on QOL in epileptic children on valproate monotherapy. No side effects warranting discontinuation of therapy were observed. The doses of melatonin administered were based on the favorable results of Jan and Donnell, who successfully treated more than 100 mentally handicapped children with 2.5– 10 kg melatonin [8]. The questionnaire was designed to assess a variety of age-relevant domains, such as physical function, emotional well-being, cognitive function,
social function, behavior, and general health. The questionnaire, which was translated as well as validated in Hindi (national language), had good internal consistency reliability, as most of the multi-item scales had a Cronbach a reliability exceeding 0.5 (range: 0.59–0.94). This shows that the questionnaire was reliable in the patients in our study. A perceptible increase in appetite as well as improvement in sleep was reported by most of the patients in the VPA + MEL group, although these factors were not objectively assessed. The VPA + MEL group exhibited
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Table 3 QOLCE: descriptive statistics and reliabilities Scale
Number of items
Median
Range
CronbachÕs a
1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17.
6 2 5 6 8 3 4 6 4 5 3 3 1 14 1 1 72
2.7 3.0 4.0 5.0 4.5 5.0 3.0 4.8 4.7 3.5 5.0 2.3 5.0 3.3 4.0 4.0 3.7
1.3–4.0 2.0–3.5 1.4–5.0 1.0–5.0 1.0–5.0 1.0–5.0 1.5–5.0 1.3–5.0 1.0–5.0 1.5–5.0 2.0–5.0 2.0–3.3 1.0–5.0 2.6–3.5 3.0–5.0 3.0–5.0 2.6–4.0
0.69 0.88 0.77 0.90 0.83 0.59 0.72 0.94 0.85 0.46 0.74 0.30
a *
Physical Restrictions Energy/Fatigue Attention/Concentration Memory Language Other Cognitive Processes Depression Anxiety Control/Helplessness Self-esteem Social Interactions Social Activities Stigma Behavior General Health QOL Total QOL
a
0.49 a a
Single-item scales, unable to calculate CronbachÕs a. Not significant, all others significant.
significant intragroup improvement on the Attention, Memory, Language, Other Cognitive Processes, Anxiety, and Behavior multi-item subscales posttreatment. To our knowledge, this is the first study assessing QOL in epileptic children with add-on melatonin administration. On the basis of our results, it may be postulated that the improved QOL in the add-on melatonin group, as compared with the placebo group, can be attributed to the diverse properties of melatonin, such as its anticonvulsant, antioxidant, and free radical scavenging properties and its favorable effects on sleep. Moreover, melatonin at doses of 1–300 mg in human studies has been shown to be safe, with no adverse effects observed [22]. Recently, in a double-blind, placebocontrolled clinical trial, no toxicological effects of melatonin (10 mg) were observed [23]. Further studies that employ both epilepsy-specific and generic measures of HRQOL and larger sample sizes are needed to provide a more comprehensive picture of the QOL of children with epilepsy.
Acknowledgments The authors acknowledge Dr. R.M. Pandey, Department of Biostatistics, All India Institute of Medical Sciences, New Delhi, India, for his kind help in statistical analysis.
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