Multifactorial Influences, Including Comorbidities, Contributing to Sleep Disturbance in Children with a Neurodevelopmental Disorder

Summary

The term neurodevelopmental disorder (NDD) implies an impairment of the growth and development of the CNS caused by genetic, metabolic, toxic, or traumatic factors. Childhood neuropsychiatric disorder is a subset of NDD. Sleep disturbance is reported in many children with NDD although the details of this association, including extent and types of sleep disturbance, etiology, and assessment and treatment issues, need to be clarified by further research. This review considers the nature of sleep disturbance in NDD. Emphasis is placed on sleep disorders (i.e., the specific conditions that cause sleep problems) of which many are now recognized in the International Classification of Sleep Disorders (ICSD‐3), and also intrinsic pathophysiological factors, physical and psychiatric comorbidities, and pharmacological and parental influences, which might contribute to the sleep disorders in children with NDD. The implications of this complexity for assessment and treatment in such children are then discussed. Appropriate treatment based on precise diagnosis of the causes of sleep disturbance is required to mitigate the harmful developmental effects of disordered sleep on children with NDD and their families.

Introduction

Children with a neurodevelopmental disorder can present special challenges in the diagnosis and treatment of the sleep disturbance to which many of them are subject. The cause of such challenges not least arises from the multifocal etiology of their sleep problems, which has important implications for the assessment of such children. Comorbidities have a central role in this problem. By the same token, it is likely that the care of the children will need to be particularly comprehensive taking into account the variety of factors affecting not only their sleep but also their general well‐being and that of their families. These points have been well illustrated in, for example, the case of autism spectrum disorders 1.

Neurodevelopmental Disorders

“Neurodevelopmental Disorders (NDD)” refers to an impairment of the growth and development of the central nervous system. Such impairment can be caused by genetic, metabolic, toxic, or traumatic factors. “Neuropsychiatric disorder” in children is a variety of NDD in which psychiatric disturbance due to neurological dysfunction (sometimes ill‐defined) is prominent; examples are autism spectrum disorder and ADHD. In the UK, children with this type of neurodevelopmental disorder generally attend child psychiatric services perhaps with contributions from pediatricians. Other forms of NDD, such as syndromes of genetic origin, are mainly the clinical responsibility of pediatric neurologists.

Some degree of intellectual disability, ranging from mild to profound, is a common feature of children with a NDD. In the UK, “learning disability” (or “intellectual disability”) is defined as a significantly reduced ability to understand new or complex information, and to learn new skills, along with a limited ability to cope independently (impaired social functioning) these limitations having started before adulthood with a lasting effect on development 2. In the USA, “learning disability” refers to specific developmental delays such as dyslexia, dyscalculia, and dysgraphia. “Intellectual disability” replaces “mental retardation” in DSM‐5 and ICD‐11. “Learning difficulties” is a nonspecific term implying conditions that affect the ability to learn.

Sleep Disturbance

“Sleep disturbance” covers both sleep problems and sleep disorders; the distinction between them is important for clinical practice and research, yet it is not always observed. “Sleep behavior” refers to behavior associated with sleep, which may or may not be clinically significant.

There are three basic sleep problems:

1. Insomnia (or sleeplessness), that is, difficulty settling to sleep, difficulty staying asleep and/or waking early, and not returning to sleep.

2. Excessive daytime sleepiness (hypersomnolence).

3. Behaving in unusual ways, having strange experiences or exhibiting unusual movements in relation to sleep (parasomnias and abnormal sleep‐related movements).

Just as “breathlessness” or “pain”, for which there are many possible causes, are not diagnoses, sleep problems are not diagnoses or precise conditions in their own right. It is necessary to identify the underlying cause(s) of a sleep problem (i.e., the sleep disorder(s) in order to provide appropriate advice and to identify the correct form of treatment.

The 3rd edition of the International Classification of Sleep Disorders (ICSD‐3) 3 is the foremost source of information about the many sleep disorders now officially recognized. The following sections of ICSD‐3 illustrate its comprehensive nature (an example of each category of sleep disorder is shown in brackets):

1. Insomnia (behavioral insomnia of childhood)

2. Sleep‐related breathing disorders (obstructive sleep apnea)

3. Central disorders of hypersomnolence (narcolepsy)

4. Circadian rhythm sleep‐wake disorders (irregular sleep‐wake rhythm disorder)

5. Parasomnias (sleep terrors)

6. Sleep‐related movement disorders (sleep‐related rhythmic movement disorder)

7. Other sleep disorder (environmental sleep disturbance)

8. Sleep‐related medical and neurological disorders (sleep‐related epilepsy).

Of these categories, sleep‐related breathing disorders (SRBD) deserve special mention because they are widespread in the field of NDD. ICSD‐3 groups them into obstructive sleep apnea (OSA) disorders, central sleep apnea syndromes, sleep‐related hypoventilation disorders, sleep‐related hypoxemia disorder, and isolated symptoms and normal variants. NDD associated with SRBD (mainly OSA) include Down syndrome, mucopolysaccharidoses, Prader–Willi syndrome, craniofacial syndromes, cerebral palsy, Rett syndrome, and achondroplasia. Other predisposing conditions include chronic nasal obstruction and obesity 4, 5.

Children with a NDD can be considered to have basically the same types of sleep disorders compared with children in general. However, their sleep problems can be more prevalent, severe, and persistent if untreated. Also the clinical manifestations of their sleep disorder can be somewhat different. As discussed shortly, sleep disturbance in these children may well be multifactorial in origin with comorbidities playing an important role. This has important implications for assessment and treatment which will need to be more comprehensive than is usual in typically developing children.

Some Basic Points About Sleep Disturbance in Children Including Those with NDD

1. Sustained sleep loss or poor quality (nonrestorative) sleep is reported to predispose to adverse effects on various aspects of child development such as disturbed emotional state and behavior 6 and impaired cognitive function with poor concentration, memory, and general ability to learn 7. In addition, evidence is accumulating that various physical disorders such as vascular disease, metabolic dysfunction, and obesity may be linked with persistent sleep loss 8. Children with NDD run the risk that developmental limitations imposed by their basic condition will be worsened if serious sleep disturbance is an additional problem. That being so, successful treatment of the sleep disturbance may well lessen the child's difficulties and those of the family.

2. It is unfortunate considering the point just made that there are significant shortcomings concerning sleep and its disorders in the training of clinical professionals. This seems to be almost internationally true regarding medical students 9, and clinical psychology training is also unsatisfactory in this respect 10. Sleep problems may well be overlooked in primary care 11, and it has been reported that only relatively few pediatricians enquire about sleep problems 12, or to possess basic knowledge about children's sleep 13. Ways in which such shortcomings might be corrected have been identified but they have yet to be achieved 14.

   Inevitably, these shortcomings have important implications regarding the care of children with disturbed sleep. Many opportunities to help such children and their families must be missed 15, which can be particularly unfortunate if a child has a serious sleep disturbance as may be the case in children with a NDD. For lack of information to the contrary, parents of such children may fail to seek help because they assume that the sleep problem is inevitable and untreatable 16.

3. Parenting issues (often relevant to childhood sleep problems in general) can be particularly prominent where children with a developmental disorder are concerned. Possibly because of understandable but excessive concern about their child's welfare and safety, parents of such children may inadvertently reinforce their child's problem behavior at night by paying it too much attention, rather than employing sleep hygiene principles or behavioral treatment procedures. Parents' difficulties are likely to be intensified if they themselves are sleep deprived, anxious, or depressed because of their child's sleep problem or for some other reason 17, 18, and if their knowledge about children's sleep is limited or mistaken as may well be the case without informed help and advice. Limited knowledge of children's sleep on the part of parents can add to the risk of misinterpretation of their child's behavior and inappropriate handling 19. Because of the various pressures of rearing a child with a developmental delay, parents' mental health and relationships are likely to suffer, further affecting their ability to cope 20. There have been suggestions that marital discord and separation, and even physical abuse of children may result 21.

4. High rates of medical misdiagnosis in general have been reported 22. The most common examples cited in adults are physical conditions that are generally well taught at undergraduate and postgraduate levels. Given the shortcomings in professional training regarding sleep and its disorders, there is the risk that misdiagnosis will be particularly high in both children and adults with a sleep problem 23. This might be especially so in the case of children with neurodevelopmental disorders where the clinical manifestations of their disordered sleep can be particularly complicated and unfamiliar to clinicians. Such diagnostic mistakes are likely to lead to inappropriate referrals to various clinical services and ineffective interventions.

Multifactorial Etiology of Sleep Disturbance in Children with NDD

A child's sleep disturbance may have more than one cause. NDD clearly illustrates this possibility. A review of approximately 40 different neurodevelopmental disorders for which sleep disturbance has been reported 5 demonstrates the complex of physical and psychological factors capable of contributing to sleep disturbance that might need to be taken into account in explaining the individual child's disordered sleep. These factors can be grouped as follows.

1. Intrinsic pathophysiological factors such as intellectual disability with which disturbed sleep can be associated by virtue of maldevelopment of or damage to anatomical and neurotransmitter systems in the brain involved in the control of sleep and wakefulness 24. Associated communication problems may well impair the acquisition of good sleep habits. Intrinsic melatonin abnormalities have been suggested in Angelman syndrome, Smith–Magenis syndrome, and autism 5.

2. Physical comorbidities. Epilepsy (which features prominently in NDD) is an example. It may disturb sleep in various ways 25 both directly, especially in severe and difficult to control nighttime convulsive seizures, and indirectly by means of certain forms of anti‐epileptic medication or comorbid conditions in some pediatric epilepsy syndromes 26. Other physical comorbidities capable of disrupting sleep include sleep‐related breathing disorders, painful conditions, sensory impairments, and obesity 27.

3. Psychiatric comorbidities, according to the findings in the review mentioned above 5, are commonly reported especially as anxiety and depression, ADHD, autism spectrum disorder, and antisocial behavior of various types. Associations between these and other child psychiatric disorders are well documented 6.

4. Medication effects such as stimulants for ADHD might cause insomnia and sedative drugs can cause excessive sleepiness 28.

5. Parenting practices such as lack of consistent routine in preparing their child for bed, poor limit‐setting when their child resists settling to sleep, and inadvertent reinforcement of their child's troublesome behavior by paying it too much attention. These and other aspects of the importance of parental practices in the etiology and management of bedtime problems and nightwaking in children in general are considered elsewhere 29. As already mentioned, anxiety or depression is likely to impair parents' ability to teach their child satisfactory sleep habits.

Down syndrome (DS), the most commonly identified genetic cause of intellectual disability, illustrates the combination of such factors that careful enquiry might reveal in NDD 30. Parental reports of disturbed sleep vary from 31 to 54% 31. The sleep problems reported in such children are principally insomnia of different types and daytime sleepiness to which OSA, reported in 30–100% of children with DS 32, might well contribute. Little mention has been made of parasomnias in such children. (Previous half sentence with reference deleted).

Over 40 possible medical problems have been listed in children with DS 33. The range of intellectual disability in DS is wide. Physical comorbidities include a number which are capable of disturbing sleep such as OSA, cardiac and other respiratory problems, epilepsy, and obesity. Not all examples of such comorbidities are likely to be present at any one time although combinations are likely. Reported psychiatric comorbidities include anxiety states, depression, conduct disorder, ADHD, and autism spectrum disorder all of which are associated with disturbed sleep. According to a US national survey 34, compared to other children with special healthcare needs, those with DS have more comorbid conditions, unmet needs including those of a medical nature, and adverse effects on the family.

Implications for Assessment and Treatment

The possibility of multifactorial etiology of sleep disturbance in children with a NDD has clear implications for assessment and treatment both of which need to be comprehensive and probably multidisciplinary.

Assessment

Screening

Detection and assessment of sleep problems and their causes should be a routine part of pediatric practice in general. Whatever the presenting complaints, it is appropriate for history‐taking to include screening for sleep disturbance. This can be accomplished at least by means of the following basic enquiries:

1. Bedtime resistance or difficulty settling to sleep?

2. Waking during the night?

3. Snoring or breathing problems while asleep?

4. Unusual behaviors, experiences, or movements at night?

5. Difficulty waking up in the morning?

6. Very sleepy or “overtired” during the day?

7. Regularity, timing, and amount of sleep?

Further details can be obtained by means of one of the relatively brief sleep questionnaires for completion by parents or other carers 35, 36, 37. Follow‐up and repeated screening for sleep disturbance and the possible emergence of further etiological factors should form part of continuing care.

Parental accounts are necessarily the basic source of information about the nature of their children's sleep problems as children with a neurodevelopmental disorder themselves may be unable to contribute because of their intellectual limitations and communication difficulties. Accurate description of parasomnias may be aided by home video recordings.

Diagnosis

Positive findings on screening are only a starting point because detection of sleep problems does not constitute an adequate diagnosis. As in the case of children in general, such positive results call for diagnosis of the child's sleep disorder(s) by means of clinical enquiries and possibly special investigations 38. For some sleep disorders, such as SRBD or circadian rhythm sleep‐wake cycle disorders, objective clarification by means of polysomnography or actometry may be required. Compliance with such special recordings can be difficult to achieve in children with limited understanding and poor cooperation, but experienced staff may be able to minimize such difficulties 39.

In view of the various factors which can contribute to sleep disturbance, clinical evaluation of a child's sleep problem needs to include a systematic check for such factors. This is likely to require involvement of medical, psychiatric, and/or psychological colleagues followed, in light of the findings, by a coordinated multispecialty approach to treatment.

Treatment

Given an accurate diagnosis of a child's sleep disorder(s), choice of appropriate advice and treatment from the many forms now available should be possible applying the same basic treatment principles as for other children. The following are some general points. Further details are available elsewhere 40, 41 although it has to be said that this aspect of the care of children with disordered sleep is generally in need of much further scientific study.

1. Parents' knowledge concerning children's sleep and attitudes to treatment may need to be improved or modified. They may benefit from being acquainted with at least fundamental facts including the importance of adequate sleep for children's psychological and physical development.

   It can also be appropriate to convey that even severe and long‐lasting sleep problems might respond to treatment if it is correctly chosen and undertaken with conviction and persistence 42. Parents should be encouraged to seek help rather than assuming that the problems are inevitable and untreatable 16. The risk of disappointment is likely to be lessened if the selected treatment program is acceptable to parents and within their capabilities. It can also be appropriate to alert them to the fact that sometimes a sleep problem may worsen before it improves, and to provide them with professional help and support as required.

2. Principles of “sleep hygiene” are promoted as helping to achieve good sleep patterns at all ages including in children with NDD 43. The basic principles include ensuring that the sleeping environment is conducive to sleep, as well as encouraging certain sleeping practices while avoiding others. There is a need, however, for empirical studies on the effectiveness of such recommendations in adults 44 and the same applies to children.

3. Behavioral methods of treatment for insomnia are widely practiced with the intention of helping a child to learn good sleep habits and/or to unlearn inappropriate sleep behaviors. It might be assumed that such methods are likely to be unsuccessful in children with NDD especially those with intellectual disability because of poor compliance for example. However, this negative view is disputed 45 and such approaches of treatment are considered to have the advantages that they utilize nonverbal means of modifying behavior, and can be individually designed to suit the particular needs and circumstances of each child and also the family.

   Behavioral interventions receive some support from controlled trials of insomnia in young typical children, but adequate empirical research on other groups is lacking 46.

4. Indications for the use of pharmacological treatments for children with disturbed sleep have been discussed by Gringras 47. It is felt that medications for otherwise treatment‐resistant childhood insomnia might well be justified, especially in children with neurodevelopmental disorders, chronic medical conditions, and psychiatric disorders 48. Combinations of psychological and pharmacological treatments might be required although they have yet to be adequately assessed.

   Melatonin deserves a special mention because of its popularity mainly for the treatment of insomnia especially in children with a neurodevelopmental disorder. Convincing evidence in favor of its use has been limited but a recent comprehensive review 49, while still emphasizing the need for further well controlled studies, concluded that the best evidence for melatonin's efficacy is in primary sleep onset insomnia (as distinct from onset insomnia caused by medical, psychiatric or environmental causes), and delayed sleep phase syndrome. However, some children with neurodevelopmental disorders may also benefit.

5. Other treatments for which there are specific indications include chronotherapy (resetting the biological clock) for circadian sleep‐wake cycle disorders 50 and physical methods such as tonsillectomy, continuous positive airway pressure, and weight reduction for childhood OSA 4. As in other conditions causing the child or other family members serious emotional disturbance provision of psychological or psychiatric help is appropriate.

Concluding Remarks

In recent times, there has been a steady increase in knowledge about sleep and its disorders in children in general. However, despite sleep problems being common and potentially harmful to children's development and their families' well‐being, this new information has not been sufficiently incorporated into clinical practice in pediatrics and child psychiatry because of shortcomings in professional training. These shortcomings are prominent in the field of NDD where sleep disturbance can be particularly common and severe.

The evidence suggests that the origins of disordered sleep in children with such disorders can be especially complicated with combinations of pathophysiological, medical, psychological/psychiatric, and pharmacological factors potentially contributing to the disordered sleep. In these circumstances, assessment and treatment programs (as well as much needed further research) are likely to require a comprehensive and skilled multidisciplinary approach.

Conflict of Interest

The author received no financial support for the preparation of this article and declares no conflict of interest.