Pilot Study of Melatonin and Epilepsy

Hypothesis 1: Melatonin treatment improves the quality of sleep in patients with epilepsy.

Various studies evaluating sleep problems in patients with epilepsy using questionnaires have
shown that 34-45% patients have sleep related problems [1-3]. Cortesi et al reported that
children with seizures had higher sleep difficulties than their siblings and controls[4].
Bedtime difficulties, sleep fragmentation, daytime sleepiness, snoring and parasomnia were
reported as sleep problems in this population [2, 4]. Patients with refractory seizures and
using multiple antiepileptic drugs(AED) showed worse problems[5]. On polysomnography (PSG)
these patients show increased arousal index, increased sleep onset latency, fragmented or
reduced REM sleep, increased stage shifts and increased Stage 1 sleep and decreased stage 2
and slow wave sleep. [6-9] Melatonin has been shown to decrease sleep onset latency and
increase total sleep time and subjectively improve sleep in healthy individuals.[10-15].
Various studies using fast release and sustained release formulations have suggested
improvement in sleep efficiency and decreased arousals as well.[16-18] In a randomized
placebo controlled study by Gupta et al[19], Melatonin was shown to subjectively improve
sleep in patients with epilepsy. Studies in children with neurodevelopmental delay and autism
along with epilepsy have also reported similar findings.[17, 20-23] Rationale: There are
significant sleep disturbances in children with epilepsy. Melatonin has been shown to improve
sleep in this group of patients. However, all these studies report improvement based on
parent report and only one study is placebo-controlled. Our study will assess this in
randomized placebo controlled fashion and will provide both subjective and objective
improvement in sleep with the primary outcome being improved sleep efficiency on PSG.

Hypothesis 2: Melatonin improves daytime functioning in terms of cognition, behavior and
quality of life in the patients with epilepsy.

Poor sleep and epilepsy both have detrimental effect on cognition.[24-27] Melatonin by
improving sleep may improve cognitive functioning in these patients.

Some patients with epilepsy have poor behavior and psychiatric function.[28-30] Severity of
these problems are related to the worsening of the sleep problems.[2, 4] Melatonin by
improving sleep may improve the behavior in these patients.

Epilepsy has negative effect on various aspects of the patients' life including social,
behavioral, and academic [31, 32]. Questionnaires have been developed to assess the impact on
overall quality of life of the patients [33, 34]. These tools are helpful to quickly and
subjectively assess quality of life. Based on these studies, it has been shown that patients
with refractory seizures have poor quality of life [33-37] and an improvement is seen if the
seizure frequency is decreased.[38-41] There has been only one study reporting quality of
life (QOL) after use of melatonin in patients with epilepsy. In this randomized placebo
controlled study, significant improvement was seen in the cognitive, anxiety and behavior
subscales of the QOLCE after use of melatonin.[42] To date, there are no studies reporting on
the effect of melatonin on cognition or behavior in epilepsy patients.

Rationale: Poor behavior, cognition and quality of life have been reported in children with
epilepsy and sleep disturbances. By improving the quality of sleep, melatonin will improve
all these domains. QOLCE has been validated and used in epilepsy patients and will assess the
QOL in these patients. Vigilance is the component of cognition that is most consistently and
drastically affected by sleep deprivation. PVT measures "vigilant attention" and has been
used widely in adult patients to assess the effect of sleep deprivation on cognition. It has
been described as a very sensitive measure to see both acute and chronic effects of sleep
deprivation. BASC-PRS has been used to assess behavior in children and is found equally
useful in epilepsy patients as child behavior check list (CBCL). It is a sensitive tool to
compare changes over shorter time span.

Hypothesis 3: Melatonin treatment decreases epileptic potential. Sleep deprivation has been
known to induce seizures and epileptic discharges on EEG[43]. Seizures are also known to
occur with change in the depth or rhythmicity of sleep.[43] Patients with epilepsy report
sleep deprivation as a significant seizure precipitating factor [44, 45]. In a recent study,
Haut et al reported that one hour of additional sleep on the preceding night decreased
relative odds of a seizure on the subsequent day to 0.91[46]. In a study Oliveira reported
that treatment of obstructive sleep apnea (OSA) decreased interictal epileptiform
discharges.[47] The belief that fewer epileptiform discharges represent better seizure
control is controversial. But a study suggested that decreasing epileptiform discharges on
EEG improves behavior.[48] Studies investigating obstructive sleep apnea in patients with
epilepsy have reported improvement in seizure control with treatment of OSA [49-54]. These
suggest that stabilizing sleep has a beneficial effect on seizure control.

Many studies that evaluated melatonin in epilepsy patients report overall improvement in
seizure control[17, 21], while others report no worsening of seizure control after the use of
melatonin[20, 22, 23]. Coppola et al reported inconclusive results with regards to seizure
control after melatonin use[55]. However, these studies are not powered to account for
variability in seizure occurrence reported with epilepsy patients.

Rationale: There are no randomized controlled studies available to evaluate the effect of
melatonin on seizure control in the children with epilepsy. This study will identify the
effect of short term use of melatonin compared with placebo and will provide pilot data to
evaluate this effect in a larger trial in future.

Inclusion Criteria:

- Age 6-11 years (prepubertal based on tanner staging)

- Patients with epilepsy (diagnosis based on ILAE).

- Normal intelligence based on school placement (defined as age appropriate; an IEP due
to epilepsy related causes is acceptable as is placement in a higher grade) or IQ>70
(testing done with in 12 months of enrollment)

- No history of significant snoring- loud snoring every night outside of a room with
closed door

- Combined score of 30 or more on sleep fragmentation, parasomnia and daytime drowsiness
subscales on SBQ.

Exclusion Criteria:

- History of significant snoring- loud snoring every night heard outside of a room with
closed door

- Diagnosis of obstructive sleep apnea (OSA) or periodic limb movement disorder on PSG

- Vagus nerve stimulator implanted

- History of a major psychiatric disease (e.g. psychosis, major depression)

- History of autism or pervasive development disorder

- Severe neuro-developmental disabilities, as determined by PI

- Clinically significant systemic organic disease, as determined by PI

- Current use of melatonin or sustained release melatonin

- Prior use of sustained release melatonin

- Current use of any hypnotic medications except for medications used as a rescue
treatment for seizures

- Use of psychoactive or stimulant medication for attention deficit disorders

- Subjects with immune disorders, lympho-proliferative disorders, and those taking oral
corticosteroids or other immuno-suppressants

- Subject or parent/legal guardian might not be reasonably expected to be compliant with
or to complete the study.