Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
Effect of Melatonin on Seizure Outcome, Neuronal Damage and Quality of Life in Patients With Generalized Epilepsy
Epilepsy is one of the most common and frequently encountered neurological conditions that
 impose a huge burden on the healthcare systems. Despite the abundance of antiepileptic drugs
 (AEDs) available, 30% of people continue to have seizures even after long-term therapy of 6-8
 years. This group of people requires a more aggressive treatment since monotherapy, the first
 choice scheme, is not sufficient to control seizure and its complications, multiple drug
 therapy or polytherapy often results in the culmination of unwanted effects. The need for an
 add-on AEDs with a good safety profile is of utmost importance.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 the quality of life in seizure patients. Various animal studies
 have suggested that melatonin receptors are the potential targets for anticonvulsant drug
 development. In animal studies, melatonin was found to suppress generalized seizure and
 seizure susceptibility and it also has neuroprotection and synapse modulating properties.
 Some clinical trials mostly on paediatric population also found that melatonin can improve
 the clinical outcome in epilepsy. Therefore, we have planned to conduct a randomized, add-on
 placebo-controlled clinical trial on the effect of melatonin on seizure outcome, neuronal
 damage and quality of life in adult patients with generalized seizure.
Epilepsy is a chronic disabling neurologic condition which often leads to numerous adverse
 long-term neurologic complications, such as behavioural and cognitive deficits, increased
 susceptibility to recurrent seizures, and neuronal injury or death. Cognitive dysfunction,
 depression, anxiety and sleep disorders are some of the highly prevalent and most
 debilitating complications of epilepsy. Despite the abundance of antiepileptic drugs (AEDs),
 even after long-term treatment of 6-8 years, 30% of patients continue having seizures. This
 group of patients requires a more aggressive treatment, since monotherapy fails to control
 seizures, considering the fact that the number of seizures is the single most important
 predictive factor for both early and long-term remission of seizures. Nevertheless,
 polytherapy often results in a number of adverse effects. The need for better-tolerated
 add-on therapy is the need of the hour to overcome this therapeutic hurdle.

 Melatonin, an endogenous hormone, acting through MT1 and MT2 receptors exert a depressive
 effect on brain excitability and have been shown to exert an anticonvulsant activity in
 various animal models. In some clinical trials also it has been found that add-on melatonin
 therapy improves the clinical outcome. Uberoset al evaluated the sleep-wake pattern, plasma
 melatonin levels and the urinary excretion of its metabolite among children with severe
 epileptic disorders, before and after a therapeutic trial with melatonin. They found sleep
 efficiency was significantly higher and better controls of convulsive episodes were achieved
 with among patients who received melatonin. Goldberg-Stern et aland Elkhayat et al concluded
 that melatonin could be effective and safe for decreasing seizure frequency and severity in
 patients with intractable epilepsy. Gupta et al found that melatonin has the potential to
 improve quality of life in pediatric epilepsy because of its beneficial effects on sleep, its
 wide safety window, and its ability to cross the blood-brain barrier. In another study by
 Jain SV et al melatonin resulted in a statistically significant decrease in sleep onset
 latency and wakefulness after sleep onset. Guptaet al also concluded that add-on melatonin
 can be of promise in the pharmacotherapy of pediatric epilepsy and as an adjunct, can be a
 putative neuroprotector in conditions involving oxidative stress like epilepsies. Dabak et al
 and Brazil et measured melatonin in febrile seizure and temporal lobe epilepsy and found to
 be lower in epilepsy in comparison to the controls.

 Our literature review reveals that till date most of the clinical studies on the effect of
 melatonin in epilepsy have been conducted in the pediatric population and there is no
 clinical trial done on its effect on seizure outcome, neuroprotective effect, sleep and
 circadian rhythm and quality of life in adult patients with epilepsy. So the present
 randomized clinical trial has been designed to fill the knowledge gap and evaluate the effect
 of add-on melatonin on seizure severity, neuronal damage and sleep quality in adult patients
 suffering from a generalized seizure.
Inclusion Criteria:

 -  All patients with the clinical diagnosis of generalized epilepsy with generalised
 onset motor seizure (ILAE 2017) with a history of an episode of seizure within 72
 hours of presentation.

 -  Patients aged 18-60 years, of either sex.

 -  Treatment-naive patients or patients who had not taken any treatment for at least 4
 weeks before inclusion.

 Exclusion Criteria:

 -  History of any recent traumatic brain injury, cerebral ischemia/TIA/stroke.

 -  Patients with neuroendocrinal tumors.

 -  History of any invasive neurosurgical/non-invasive neuropsychiatric procedure.

 -  Patients who are already under treatment for the presenting conditions.

 -  Medication history of psychoactive or central nervous system depressant drugs.

 -  Pregnant and nursing women.

 -  Patients with a history of allergy to valproate, melatonin or other melatonin
 agonists.

 -  Patients with drug/alcohol abuse.

 -  Patients with any hepatic dysfunction.