ATLAS DE PATOLOGIE ȘI TRATAMENT CHIRURGICAL

Melatonina în neurologia pediatrică

 Melatonin in pediatric neurology

First published: 27 noiembrie 2016

Editorial Group: MEDICHUB MEDIA

DOI: 10.26416/Orl.33.4.2016.168

Abstract

Melatonin  is a hormone produced by the pineal gland during the night, as a response to the light-darkness variation. The endogenous melatonin levels have a cyclic evolution throughout the entire life. Various roles have been cited such as the in utero developement of the fetus through its action on the placenta, neurons and glial cells, a major role in the regulation of the cyrcadian rhythm, antioxidative, antiinflammatory roles, as well as celullar and umoral immunity modulation. In the European Union, exogenous melatonin has been evaluated by the European Food Safety Authority (EFSA) for reducing sleep onset latency and the conclusion was that it has efficacy studies in this regard.
 

Keywords
melatonin, sleep, neurology

Rezumat

Melatonina este un hormon produs de glanda pineală în timpul nopții, ca răspuns la variațiile lumină-întuneric. Nivelurile de melatonină endogenă au o evoluție ciclică de-a lungul întregii vieți. Au fost citate variate roluri ale acesteia, cum ar fi dezvoltarea in utero a fătului prin acțiunea sa asupra placentei, neuronilor și celulelor gliale, un rol major în reglarea ritmului circadian, rol antioxidativ și antiinflamator, precum și rol în modularea imunității celulare și umorale. În Uniunea Europeană, melatonina exogenă a fost evaluată de Autoritatea Europeană de Siguranță a Alimentelor (EFSA) pentru reducerea latenței instalării somnului, iar concluzia a fost că există o eficiență dovedită prin studii în acest sens.
 

Cuvinte cheie

Introduction

Melatonin is a hormone produced by the pineal gland during the night, as a response to the light-darkness variation and part of the indoleamines group. Other sites of production include the bone marrow, various epithelial cells, lymphocites, the retina and the gastrointestinal tract.

Various roles have been cited such as the in utero develepement of the fetus through its action on the placenta, neurons and glia cells, a major role in the regulation of the cyrcadian rhythm, antioxidative, antiinflammatory roles as well as celullar and umoral immunity modulation(1). These roles make exogenous melatonin therapy an important part of the management of various neuropediatric pathologies, often associated with sleep disorders.

Physiopathology

Melatonin (N-acetyl-5-methoxytryptamin) is mainly produced by the pineal gland starting from the tryptophane aminoacid which goes through a process of hydroxilation by the triptophane decarboxylase, followed by decarboxylation by the aromatic L-aminoacid decarboxylase, leading to its transformation into serotonin that remains inside the pinealocytes during daytime(2).

At night, the sympathetic postganglionic eflux to the pineal glad rises, followed by release of noradrenaline which allows:

  • the usage of serotonin in intracelular metabolic processes;
  • the activation of the serotonin-N-acethyltransferase and hydroxy indol-O-methyltransferase enzimes which transform serotonin into liposoluble melatonin. The resulting melatonin is then able to easily cross the brain-blood barrier, making its way into the blood stream and the cerebrospinal fluid(3,4).

Once at a hepatic level, 70% of the circulating melatonin is inactivated by a P-450 dependent oxidase, then conjugated and excreted through urine and saliva (which allows a gross estimation of the plasmatic concentration)(5).

The overall concentration has a cyclic evolution and it encompasses the melatonin secreted by the pineal gland, the influx/eflux at a tisular level (as a response to increases/decreases in plasma hormone concentration), the degarded melatonin at the hepatic site and its secretion through urine and saliva.

Praninskiene et al. (2012) studied melatonin’s concentration variation over 24 hours in 31 children and adolescents using salivary melatonin and urinary 6-sulfatoxymelatonin levels. The results showed a high variability in salivary melatonin concentrations peaks between 5.6 and 128.2 pg/ml and between 39.3 and 122.7 ng/ml in urinary 6-sulfatoxymelatonin. Mean values showed a concentration variation from 1.5 pg/ml (3 p.m.) to 34.1 pg/ml (6 a.m.) in salivary melatonin and from 11 pg/ml (3 p.m.) to 61.3 (6 a.m.) in 6-sulfatoxymelatonin. Salivary melatonin levels were high for aproximately 6 to 12 hours, with a maximum between 9 p.m. and 9 a.m. (peaking between 3 a.m. and 6 a.m.), while 6-sulfatoxymelatonin reached its maximum levels between 9 p..m and 3 p.m.(6)

The endogenous melatonin levels have a cyclic evolution throughout the entire life. In children, melatonin has a very early influence, as early as the 24th week of gestation, as it is transmitted through the placenta from the mother, the concentration being tightly influenced by her circadian rhythm. The infant will start producing melatonin after the age of 3 months and the concentrations will keep rising until the ages of 3 to 7(6). It has also been suggested that breast milk has an initial supportive role, helping the infants stabilize their wake-sleep cycle until their own cyrcadian rhythm matures(1).

Afterwards, the melatonin levels will slowly drop until they reach a plateau at 23-30 years old, mostly due to an increase in total body area, rather than a decreased secretion in the pineal gland(1).

There are three probable melatonin receptors:

  • MT1 (in the suprachiasmatic nucleus of the hypothalamus, the tuberal lobe of the pineal gland and the cardiac blood vessels) - acting on REM sleep and inhibiting night-time neural discharge;
  • MT2 (retina and the hipocampus) - acting on the CNS’s own circadian rhythm and on non-REM sleep;
  • MT3 (the kidney, the brain and other peripheral organs).

Both MT1 and MT2 receptors are sussceptible to downregulaton phenomena by overexposure to melatonin, with great implications for any medium to long-term therapeutic plan involving melatonin(1,3).

 

Table 1. Melatonin prescription reccommendations in children with sleep-wake rhythm disorders or sleep onset insomnia
Table 1. Melatonin prescription reccommendations in children with sleep-wake rhythm disorders or sleep onset insomnia

Exogenous melatonin

Exogenous melatonin has proven to be useful in numerous pediatric pathologies, especially in the neuro­psy­chiatric field. However, the effects vary due to a great variation in etiology.

The timing of administration is of paramount importance as the maximum effect can be achieved 3 to 5 hours before DLMO (dim light melatonin onset - the beggining of the melatonin secretion once the surrounding environment light starts to decrease -, an important tool when evaluating the suprachiasmatic nucleus, by which it can be established whether an individual has a light-darkness cycle of 24 hours or it is functioning freely, or whether there are delays or accelerations of sleep phase). DLMO cannot be established by sleep diaries, actigraphy or polisomnography, but it can be established by measuring salivary melatonin levels. Basically, the child is asked to take in his mouth and chew easily a cotton pad for 1-2 minutes every hour (or every half hour) between 7-11 p.m. Salivary melatonin is determined. DMLO occurs when salivary melatonin levels reach 3-4 pg/ml (which corresponds to a plasma level of about 9-10 pg/ml). Testing is recommended prior to treatment with melatonin and where no positive response was obtained after the administration of melatonin a few weeks after stopping the treatment(7).

Initiating and maintaining sleep, as well as altering the cyrcadian rhythm phases are the effects closest to the effects of endogenous melatonin secretion, making exogenous melatonin an important treatment option in a large number of sleep disturbances both in normal children and the ones affected by neurological or neuropsychiatric disorders. It should be noted that in countries like USA and Canada melatonin is considered a “dietary supplement” and in Australia it is an unregistered product. In the European Union, melatonin has been evaluated by the European Food Safety Authority (EFSA) for reducing sleep onset latency and the conclusion was that it has efficacy studies in this regard(1,3).

Sleep disturbances

Melatonin has proved effective in several sleep disorders, mainly in those where children have a disorder of initiating sleep and less in the sleep maintenance.

Delayed sleep phase syndrome is mainly characterized by a cyrcadian rhythm over 24 hours long, due to a delay of minimum 2 hours both of bed time and wake time, without any influence on the quality or length of sleep, whereas chronic sleep onset insomnia represents difficulty in initiating sleep, with important negative consequences.

On October 4th 2014, in Rome, it was held the first European conference where a consensus was reached on the use of melatonin(1). Rome group recommendations regarding treatment of the delayed sleep phase syndrome and insomnia are shown in Table 1.

There are several randomized trials published that have been conducted in the pediatric population regarding the two sleep disorders, where a dosage between 1-5 mg of melatonin per night showed faster initiation of sleep, decreased daytime sleepiness and variable effects on cognitive performances.

Other studies which were centered on the posology of melatonin showed that a dosage between 0.05-0.15 mg/kg advanced sleep onset time and DLMO by one hour, while decreasing sleep initiating latency by 35 minutes, with no apparent adverse reactions both in short- and long-term usage. Current dosages range from 0.5-3.5 mg in infants (with a maximum of 5 mg), from 1-10 mg in children (with a maximum of 10 mg) and from 2-12 mg in adolescents (with a maximum of 18 mg) and a total treatment time between 0-200 days, with a 16.5-week average(1,8,9).

Attention deficit hyperkinetic disorder (ADHD)

ADHD is associated with sleep disturbances in 70% of the cases. In this particular group, sleep disturbances have a plurifactorial and heterogenous etiology and melatonin is considered a terapeuthic option when there is an associated delayed sleep phase syndrome alongside the chronic sleep onset insomnia seen most often in this group(10). A review of 5 randomized trials regarding the use of melatonin in sleep disturbances in ADHD patients showed that a dose between 3-6 mg per night led to a significant reduction of sleep onset time and increased overall sleep duration(11).

Autistic spectrum disorder

Approximately 30-53% of the children diagnosed with an autistic spectrum disorder suffer from a type of sleep disorder (longer sleep latency, overall sleep time reduction, frequent awakenings) with negative effects on their symptoms. Trials have shown that a melatonin dose between 1-3 mg given 30 minutes before bedtime accelerated sleep onset and increased total sleep duration in this group. Melatonin is an important element in the therapeutic scheme of these patients because of its effects on sleep, as well as its potential role in serotonin’s neurobiology at a central and peripheral level(12,13,14).

Epilepsy

Other uses revolve around the effects of melatonin in epilepsy, as most of the aforementioned pathologies associate epileptic manifestations. Results showed a decrease in the number of daytime seizures and that there is currently no connection between melatonin and seizure exacerbation. So, it has been concluded that it is highly unlikely that melatonin aggravates seizures and that it might even have a protective role. However, the conclu­sions do not have a definitive note due to the current lack of  thorough research(15).

Headache

It has been speculated that melatonin might have a role in the pathophysiology of headaches, due to a well-known relationship between sleep disturbances and headaches. Studies have shown that a dose of 3 mg given twice daily has reduced by more than 50% the intensity and length of headache episodes in children(16), whereas a dose of 0.3 mg/kg/day after daily administration over a period of 3 months has proven its efficiency in migraine prophylaxis in the pediatric population(17).

Neuroprotective effect

The neuroprotective effect (demonstrated on numerous animal studies)(18) make melatonin an excellent candidate for the management of neonatal encephalopathy due to the possible role of minimizing or even preventing brain lesions both before and after birth(1)

Jet-lag disorder

Melatonin is the second choice after benzodiazepines agonists with short half-life and it is considered to have a therapeutic effect if taken for sleep disorders (modifying sleep cycles, circadian and hipnotic rhythm). A Chochrane analysis, based on 8 from 10 studies comparing melatonin with placebo, concluded that it can reduce “jet-lag” symptomps in 50% of cases.

Premedication for diagnostic procedures

Melatonin is widely used as premedication for diagnostic procedures, in order to induce sleep, especially before EEG recordings. Melatonin-induced sleep in this case is short, but long enough to properly record an adequate EEG and it does not influence its interpretation, nor does it mask any possible epileptiform anomalies(19-22). Newton R (2012) consider that, usually, a dose of 2.5-5 mg in patients under 2 years of age is used as premedication for sleep-EEG, and 2.5-10 mg for children over this age.

It has also proven useful for its sedative purposes in the recording of evoked brainstem potentials as well as magnetic resonance imaging studies(23-25), although in current practice, general short-term anesthesia is preferred.

Conclusions

Melatonin is a multiple-function hormone, with numerous effects yet to be studied. Exogenous melatonin is steadily becoming an important part of the therapeutic scheme of various sleep disturbances, associated or not with neuropediatric disorders.

Melatonin and its effects are currently the focus of many ongoing studies, a consensus regarding posology and therapeutic indications having yet to be reached.

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