Melatonin Supplementation for Severe and Intractable Sleep Disturbance In

793 REVIEW J Med Genet: first published as 10.1136/jmg.40.11.793 on 19 November 2003. Downloaded from Melatonin supplementation for severe and intractable sleep disturbance in young people with genetically determined developmental disabilities: short review and commentary J Turk ............................................................................................................................... J Med Genet 2003;40:793–796 Serious childhood developmental disabilities are common, Melatonin has acquired publicity in relation to its use for jet lag. Less attention has been paid to and are debilitating for the individual and their family. its potential in treating intractable sleep distur- Increasingly these are being shown to have genetic bance in young people with developmental bases. Associated challenging behaviours are frequent, disabilities. Such problems are common,1 partic- ularly in children with multiple neurological one of the commonest being severe and intractable sleep disabilities,2 and often fail to respond to beha- disturbance. This is associated with daytime behaviour vioural and social interventions. problems, poor developmental and academic progress, and substantial familial psychopathology. Social and SLEEP DIFFICULTIES IN CHILDREN AND behavioural approaches ("sleep hygiene" measures) YOUNG PEOPLE WITH INTELLECTUAL DISABILITY have, to an extent, revolutionised management; however, Quine2 found sleep problems to be extremely many individuals remain unresponsive. Modern frequent in young people with severe learning medications therefore play increasingly important difficulties (mental handicap); 51% of 200 children had settling problems, 67% had waking complementary roles in conjunction with psychological, problems, and 32% of parents reported rarely educational, and social strategies. This paper reviews getting enough sleep. Sleep problems were evidence for the frequency and severity of sleep associated with poor communication, academic and self help skills, incontinence, daytime disturbance in children and young people with severe behavioural problems, and epilepsy. Sleep prob- intractable neurodevelopmental disabilities. The lems also related to parental stress and irrit- potential benefits of judicious and carefully monitored use ability, and familial impact generally. Problems persisted over time and were related to diagnoses http://jmg.bmj.com/ of medication are described, with a focus on the of cerebral palsy and other named conditions, importance of melatonin as a sleep inducer. It is with the exception of Down’s syndrome. This concluded that melatonin is a potentially useful finding, along with the association with epilepsy, supports the hypothesis of strong neurological and safe adjunct to psychological and social components in sleep disorder in young people approaches for severe sleep disturbance in this client with developmental disabilities. This contrasts group. with primarily social determinants of sleep (zeitgebers) in people with average intellectual on September 24, 2021 by guest. Protected copyright. ........................................................................... abilities. Quine found no relationships between sleep problems and family variables such as elatonin (N-acetyl-5-methoxytrypta- social class, income, family composition, or mine) is a naturally occurring indole housing tenure, and concluded that families Mserotonin derivative, secreted by the containing children with irregular sleeping prob- pineal gland in response to falling light levels lems are often families with many other prob- as picked up by the eyes. Melatonin is synthe- lems of family functioning. However, direction of sised in the pineal gland from tryptophan as causality in this relationship is often unclear, and shown below: can be misattributed, with family dysfunction- ality and psychopathology being seen as the Tryptophan R serotonin R N-acetylserotonin cause of the child’s sleep disturbance, rather R melatonin (N-acetyl-5- than its consequence. methoxytryptamine). Intellectual disability itself predisposes to ....................... marked sleep difficulties. These include irregular Nerve impulses are conveyed from retina to Correspondence to: sleep/wake patterns, diminished responses to Dr J Turk, Department of pineal gland by a well documented neuronal external stimuli, prolongation of sleep/wake Clinical Developmental pathway: cycle, diminished rapid eye movement sleep, Sciences, St. George’s Hospital Medical School, Retina R suprachiasmatic nucleus of Cranmer Terrace, London hypothalamus R reticular system R spinal ................................................... SW17 0RE, UK; [email protected] cord R cervical ganglia R postganglionic Abbreviations: ADHD, attention deficit hyperactivity ....................... sympathetic fibres R pineal gland. disorder; aMT6, sulphatoxymelatonin www.jmedgenet.com 794 Turk increased frequency of night time waking, and delays in The first successful report of treatment of sleep disturbance J Med Genet: first published as 10.1136/jmg.40.11.793 on 19 November 2003. Downloaded from returning to sleep.3 Certain genetic causes of intellectual with melatonin was by Miles et al.16 A blind man with sleep disability appear to have specific relationships with particular difficulties showed considerable improvement following sleep problems. In Down’s syndrome, despite sleep problems commencement of oral melatonin supplementation. The being rarer than in other children with intellectual disability, authors speculated on the relevance of the individual’s visual they are still far more common than in the general impairment to postulated disruption in endogenous melato- population, and contribute to parental stress, poor parent– nin secretion. Palm et al17 published a case report on a child relationships, and family cohesion issues.4 Obstructive multiply disabled, visually impaired 9 year old child with sleep apnoea is also commonly reported.5 Individuals with ocular blindness whose sleep was ‘‘normalised’’ by melatonin Prader-Willi syndrome may also have obstructive sleep 0.5 mg nightly, prescribed on a regular daily basis. apnoea, as well as initial insomnia, repeated night waking, There have been numerous reports of the value of and increased nocturnal sleep duration.6 Marked obesity melatonin in inducing sleep in other groups at risk of resulting from hyperphagia is a complicating factor, yet insomnia. For example, usefulness has been proposed for efforts at behavioural approaches to dietary control confirm those working shifts,18 or suffering jet lag,19 chronic insom- 20 21 15 just how entrenched and compulsive is eating behaviour. nia, or delayed sleep phase syndrome. Jan et al found Excessive daytime sleepiness with increased behavioural beneficial effects of melatonin in their 15 children (13 male) disturbance, and sleep onset rapid eye movement periods with severe chronic sleep disorders who had failed to respond have been reported, yet it has not proved possible to link to conventional psychological and social management. They these problems with particular genetic variants or a single also suggested occasional improvements in attention span, genetic model.7 Snoring and early morning waking also occur school performance, self injury, and even epilepsy control. significantly more frequently.8 Various authors have attrib- The authors hypothesised particular difficulty in formulating uted these problems to combinations of extreme obesity, appropriate cerebral signals for melatonin release in multiply upper airway obstruction, and hypothalamic dysfunction. disabled children. However, their study has a number of Individuals with mucopolysaccharidoses have increased limitations, including the following: rates of obstructive airways and sleep disordered breathing, N Six of 15 participants were given melatonin immediately 9 related to structural/anatomical abnormalities. Milder skel- after baseline assessments owing to ‘‘family crises’’. etal abnormalities in Sanfillipo syndrome make obstructive N The degree of visual impairment varied: nine had ocular or sleep apnoea less common. However, Bax & Colville10 report cortical visual impairment while the remainder had good high rates of settling and waking problems, short sleep visual acuity. duration, and frequent hyperkinetic tendencies in this subgroup. Gould et al11 found boys with fragile X syndrome N Reports of behavioural change were largely anecdotal and to have greater variability in total sleep time and difficulty in unstructured. sleep maintenance compared with age matched boys of N The nature and degree of reported improvement varied average intelligence. However, failure to match for intellect- substantially. ual level makes findings difficult to interpret. The authors N The type of sleep disturbance varied: nine fragmented also noted elevated nocturnal and daytime melatonin levels sleep patterns; three delayed sleep onset; and three ‘‘non- in the fragile X participants. specific sleep disturbance of unclear aetiology’’. Possibly the greatest interest in sleep disturbance of genetic N There was no structured follow up. aetiology has been in Smith-Magenis syndrome, caused by http://jmg.bmj.com/ interstitial chromosomal deletion 17p11.2. Individuals with In a subsequent letter, Jan & Espezel22 reported full or this syndrome have been documented as being prone to partial correction of sleep/wake cycle disturbance in almost intellectual disability, attention deficits, and overactivity, 90 children with a range

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