Neurogenetic
Disorders & Insomnia
About Neurogenetic Disorders l Sleep & Insomnia in Children l Insomnia in NGDs l Etiology of insomnia in NGDs l Insomnia Management
Insomnia in NGDs
Rationale for melatonin use in children with NGDs
and insomnia
The prevalence of insomnia in children ranges from 1-6% in the pediatric general population and is as high as 80% in children with neurodevelopmental disorders, including those with neurogenetic disorders (NGDs).
​
Many factors may contribute to the high prevalence of sleep disorders in individuals with NGDs; Neurobiological factors, such as alterations in dopamine levels, circadian rhythm disturbances, and abnormalities in the brain regions responsible for regulating sleep-wake cycles, may play a role in both NGD and insomnia conditions. Furthermore, behavioral factors associated with NGDs, such as difficulties with time management, bedtime routines, and self-regulation, can also contribute to disrupted sleep patterns.
​
There are a number of neurogenetic disorders with well described behavioral phenotypes that are associated with severe sleep problems. Most of these disorders have documented abnormal or impaired melatonin production and/or aberrant circadian clock (Etiology of insomnia in NGDs ). For example, in Smith-Magenis syndrome (SMS), a genetic disorder characterized by mental retardation and extreme severely disordered sleep, patients manifest a marked phase shift in circadian rhythm associated with inverted rhythm of melatonin secretion with high levels during the day and low levels during the night.
When nocturnal melatonin production/secretion is inappropriately timed or impaired in relation to the environment, timed melatonin replacement therapy will often be beneficial. Indeed, there is substantial data indicating that the use of melatonin to treat the sleep disorders in these subjects is widespread (Etiology of insomnia in NGDs).
​
Prolonged release melatonin matters in NGDs
Several published studies performed in Canada and France (mostly open label) have investigated the use of prolonged release melatonin (Circadin® or Slenyto® ) to treat sleep-wake cycle disturbances in children with neurodevelopmental or neurogenetic disorders (e.g. Smith-Magenis Syndrome; SMS). Treatment with Circadin® (4 to 6 mg/day) in children who presented with Smith-Magenis Syndrome (SMS), mental retardation, encephalopathy, Autism, Angelman syndrome, Rett syndrome, Bourneville syndrome, blindness, and Delayed-Sleep-Phase Syndrome aged 3 to 18 years as a single evening dose over a treatment duration which ranged from 6 to 72 months resulted after 3 months in parents reported improvements in sleep latency (decreased by 44.0% ; p-value <0.001), sleep duration (increased by 10.1% ;p-value <0.001) and the number of midnight awakenings (decreased by 75% ; p‑value <0.001) compared with baseline. Additionally, sleep quality improved by 75% compared with baseline (2.1±0.34 vs. 1.2±0.4, respectively, p-value <0.001). No serious adverse events (SAEs) or treatment related co-morbidities were reported over the 72 months treatment period. Another study in children with ASD included 5 patients with SMS followed up for 2 years. Efficacy and safety of Slenyto (2-10 mg daily) in the SMS subpopulation was not different from the rest of the ASD populations.
Providing children with a well-designed medication that delivers melatonin steadily throughout the night- mimicking the natural pattern seen in neurotypical children- is a logical and effective approach to addressing this issue.
​
Insomnia treatment goals
In line with DSM 5, when treating insomnia in children with NGD we should evaluate the child sleep according to the following treatment goals:
-
Total sleep time (TST) within the acceptable range recommended by the national sleep foundation (NSF)
-
Sleep onset latency (SOL) < 30 minutes
-
Longest (uninterrupted) sleep episode (LSE)>6 hours
​​
In addition to the above sleep outcomes, when evaluating treatment success, a clinician should also evaluate the improvement in the child’s behavior and parents’ satisfaction from child sleep.
​
​
Sleep duration recommendation by the National Sleep Foundation:
Current insomnia treatment in children with NGD's
Current practices recommend parent-directed sleep hygiene interventions including establishing bedtime routines as first-line treatment for pediatric insomnia in NGD. ​Pharmacotherapy is often provided when sleep hygiene intervention fails. Physicians often prescribe off-label drugs (e.g., antihistamines, a-adrenergic agonists [clonidine], antidepressants, antipsychotics) for their sedative side effects without proven safety, efficacy, or dosing regimen.
​
Melatonin replacement therapy to address the deficiency or timing in the endogenous sleep-regulating hormone has been shown to improve sleep and restore the daily sleep-wake cycle. However, unlicensed melatonin preparations or food supplements are also used, despite considerable concerns over the quality, efficacy and potential safety hazards. Moreover, as melatonin has a very short half-life (40 minutes), immediate release preparations may improve only sleep initiation but do not affect sleep maintenance and cause early awakenings.
​
The USA National Sleep Foundation has developed a consensus statement where it has summarized the profile of the ideal pharmacological therapy for pediatric insomnia. One such therapy should be able to positively affect sleep parameters, be easy to administer, dose adjustable, have good safety profile, sustainable benefits and will not impair sleep architecture.
References: 1. Dosier LBM, Vaughn BV, Fan Z. Children (Basel). 2017 Sep 12;4(9):82.; 2. De Leersnyder et al. (2003). Rev Neurol (Paris), 159, 6S21-26.; 3. De Leersnyder et al.(2011) Pediatr Neurol, 45, 23-26.; 4. Jan et al., (2012).Eur J Paediatr Neurol, 16, 403-412. 5. CARR, R., WASDELL, M. B., HAMILTON, D., WEISS, M. D., FREEMAN, R. D., TAI, J., RIETVELD, W. J. & JAN, J. E. (2007). Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders. J Pineal Res, 43, 351-359.; 6. DE LEERSNYDER, H. (2006). Inverted rhythm of melatonin secretion in Smith-Magenis syndrome: from symptoms to treatment. Trends Endocrinol Metab, 17, 291-298.; 7. DE LEERSNYDER, H., DE BLOIS, M. C., CLAUSTRAT, B., ROMANA, S., ALBRECHT, U., VON KLEIST-RETZOW, J. C., DELOBEL, B., VIOT, G., LYONNET, S., VEKEMANS, M. & MUNNICH, A. (2001a). Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome. J Pediatr, 139, 111-116.; 8. DE LEERSNYDER, H., DE BLOIS, M. C., VEKEMANS, M., SIDI, D., VILLAIN, E., KINDERMANS, C. & MUNNICH, A. (2001b). beta(1)-adrenergic antagonists improve sleep and behavioural disturbances in a circadian disorder, Smith-Magenis syndrome. J Med Genet, 38, 586-590.; 9. GRINGRAS, P., NIR, T., BREDDY, J., FRYDMAN-MAROM, A. & FINDLING, R. L. (2017). Efficacy and Safety of Pediatric Prolonged-Release Melatonin for Insomnia in Children with Autism Spectrum Disorder. Journal of the American Academy of Child & Adolescent. Psychiatry, 56, 948-957.e944.; 10. JAN, J. E., HAMILTON, D., SEWARD, N., FAST, D. K., FREEMAN, R. D. & LAUDON, M. (2000). Clinical trials of controlled-release melatonin in children with sleep-wake cycle disorders. J Pineal Res, 29, 34-39.; 11. Elrod, MG & Hood BS., J Dev Behav Pediatr, 2015; 36(3):166-77;12. Richdale, AL. & Schreck, KA., Sleep Med Rev, 2009; 13(6):403-1.; 13. Veatch, O. J. S., et al., Autism Res. 2017;10(7):1221-1238.; 14. Schroder, C. M., et al., Expert Opin Pharmacother. 2021; 1-10.; 15. Yavuz-Kodat, E., et al., J Clin Med. 2020 ;9(6):1978.; 16. Tauman, MD et al., Pediatr Neurol, 2002; 26(5):379-82; 17. Leu, RM. et al.,J Autism Dev Disord, 2011; 41(4):427-33; 18. Melke J., et al., Mol Psychiatry, 2008; 13(1):90-8; 19. Banaschewski, T., et al., J Autism Dev Disord. 2021; 20. Hirshkowitz, M., et al., Sleep Health. 2015; 1(1):40-43. 21. Gringras, P., et al., BMJ, 2012; 345:e6664; 22. Howes, OD., et al., J Psychopharmacol, 2018; 32(1):3-29; 23. Mindell, J.A., et al., Pediatrics, 2006; 117(6):e1223-32; 24. Felt, BT., & Chervin RD.,Neurol Clin Pract, 2014; 4(1): 82-7; 25. Hack, S., Chow, B., J Child Adolesc Psychopharmacol,2001; 11(1):59-67;26. Owens JA., et al., J Clin Sleep Med, 2005; 1(1):49-59; 27. Schroder, C. M. et al., J Autism Dev Disord . 2019; 49(8):3218-3230. 28. NGD Variation Assessment Report, https://www.ema.europa.eu/en/documents/variation-report/slenyto-h-c-004425-ii-0025-epar-assessment-report-variation_en.pdf