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Naging Lung Disease and Sleep Disordered Breathing in Children With Cerebral Palsy, PRR, Marzo2009
Naging Lung Disease and Sleep Disordered Breathing in Children With Cerebral Palsy, PRR, Marzo2009
CME Article
Assessing and managing lung disease and sleep disordered breathing in children
with cerebral palsy
Dominic A. Fitzgerald 1,3,*, Jennifer Follett 2, Peter P. Van Asperen 1,3
1
Department of Respiratory Medicine, University of Sydney, Sydney, New South Wales, Australia
2
Department of Physiotherapy, The Children’s Hospital at Westmead, University of Sydney, Sydney, New South Wales, Australia
3
The Children’s Hospital at Westmead Clinical School, Discipline of Paediatrics & Child Health, University of Sydney, Sydney, New South Wales, Australia
EDUCATIONAL AIMS
To appreciate the insidious evolution of suppurative lung disease in children with cerebral palsy (CP).
To be familiar with the management of excessive oral secretions in children with CP.
To understand the range of sleep problems that are more commonly seen in children with CP.
To gain an understanding of the use of non-invasive respiratory support for the management of airway clearance and sleep
disordered breathing in children with CP.
A R T I C L E I N F O S U M M A R Y
Keywords: The major morbidity and mortality associated with cerebral palsy (CP) relates to respiratory compromise.
Cerebral palsy This manifests through repeated pulmonary aspiration, airway colonization with pathogenic bacteria,
Pulmonary aspiration the evolution of bronchiectasis and sleep disordered breathing. An accurate assessment involving a
Suppurative lung disease
multidisciplinary approach and relatively simple interventions for these conditions can lead to
Physiotherapy
significant improvements in the quality of life of children with CP as well as their parents and carers. This
Airway clearance techniques
Obstructive sleep apnoea review highlights the more common problems and potential therapies with regard to suppurative lung
Sleep disordered breathing disease and sleep disordered breathing in children with CP.
ß 2008 Elsevier Ltd All rights reserved.
Cerebral palsy (CP) is a condition commonly seen in paediatric Lung disease is an important cause of morbidity and mortality
practice. It is defined as a non-progressive disorder of motor in children with CP. Reddihough et al2 published an audit of child
function and occurs in approximately 1 in 500 live births. European deaths from the CP Register in Victoria, Australia. The majority of
figures suggest it is associated with comorbidities of severe the 155 children who died between 1970 and 1995 had severe
developmental delay/mental retardation in 31%, seizures in 21%, spastic quadriplegia, intellectual disability and epilepsy. Infection
severe developmental delay and non-ambulant status in 20% and was felt to be the cause of death in almost half of the children with
blindness in 11%.1 Despite the fact that respiratory and sleep pneumonia (including aspiration) in 61 (39.4%) and sepsis in a
problems are common in children with CP, there is comparatively further 7 (4.5%). In two publications, Baikie et al3,4 studied 63
little in the literature to guide management of the everyday children with non-ambulant spastic quadriplegic CP to document
problems of cough, pulmonary aspiration and sleep disruption. the prevalence of and the best method to detect pulmonary
aspiration (Fig. 1). Respiratory symptoms were common in these
patients with daily cough or wheeze in 58%, cough with feeding at
least 1 day per week in 84%, ‘asthma’ episodes in the last 6 months
* Corresponding author. Department of Respiratory Medicine, The Children’s
Hospital at Westmead, Locked Bag 4001, Westmead, NSW, Australia, 2145.
in 34% and snoring in 44% with documented apnoeas in 10%.3 Focal
Tel.: +61 2 9845 3397; Fax: +61 2 9845 3396.. respiratory signs were present in 24% with crackles in 19% and
E-mail address: dominif2@chw.edu.au (D.A. Fitzgerald). wheeze in 17%, while cough during a milk feed occurred in 44%.3
1526-0542/$ – see front matter ß 2008 Elsevier Ltd All rights reserved.
doi:10.1016/j.prrv.2008.10.003
D.A. Fitzgerald et al. / Paediatric Respiratory Reviews 10 (2009) 18–24 19
In children the suction catheter is only passed as far as the Upper airway obstruction: glossoptosis, poor pharyngeal muscle
pharynx to stimulate a cough; then the secretions are produced tone, adenoid and tonsillar enlargement;
and suctioned out. Suction is a traumatic experience and there are Severe visual impairment: altered timing and maintenance of
necessary precautions that need to be followed. Hands should be sleep;
washed and gloved. There is a risk of vomiting so the child should Brainstem dysfunction: cardiac and respiratory control may be
be positioned on their side and routine suction following chest altered as well as level of alertness;
physiotherapy should be performed when the child has an empty Postural limitations and discomfort: muscle spasms resulting
stomach or at least 1 h after eating. Swaddling of the child may be from dislocated hips, scoliosis and joint contractures together
necessary to prevent unnecessary struggling and to decrease with an inability to alter posture in response to discomfort;
trauma to the mouth or nose. The suction pressure (vacuum Epilepsy treatment with anticonvulsants may have excessive
pressure) should be sufficient to draw the secretions up the somnolence as a side effect which may disrupt normal
catheter but no greater than 10–20 kPa (75–150 mmHg). Suction sleep wake patterns;
pressure should only be applied on extraction of the catheter. The Pulmonary aspiration: micro-aspiration and cough will disrupt
catheter should not be too large, generally an 8 or 10 French sleep architecture.
gauge.25 Suction can cause adverse effects which include mucosal
trauma, hypoxia, tachycardia or bradycardia and bronchospasm so Upper airway obstruction
close monitoring of the child is required.26
An external tracheal stimulation may also be used to stimulate This is an underappreciated issue in sleep in many children with
a cough. This is done by applying manual pressure to the trachea in CP and may not be considered until the question of obstructive sleep
the sternal notch below the cricoid cartilage. This should be done apnoea (OSA) is raised because of a lengthy history of snoring. A
with care and used judiciously as there are currently no guidelines, recent retrospective small case series described eight children with
consensus or research on this technique. severe spastic quadriplegic CP presenting over an 8-month period to
a large paediatric teaching hospital with upper airway obstruction.
Alternative therapies Seven required admission to the intensive care unit for a median stay
Due to the time consuming and physically demanding nature of of 8 days.31 Seven underwent awake nasendoscopy which demon-
the modified PD with percussion and vibrations, many more ACTs strated enlarged adenoids in two patients. However, in the remaining
have been developed that allow independence of the child and less six patients, no structural abnormality was found at endoscopy of the
physical involvement of the carer. A group of therapists in Sweden supraglottic regions, but collapse of the pharyngeal/supraglottic
have performed research on the use of positive expiratory pressure structures was noted.31 Only two of the eight subjects had been
(PEP) on a small group of severely disabled CP children. They found referred for sleep studies. Two of the patients had tracheostomies and
that the transcutaneous oxygen tension improved after PEP in the one had an adenotonsillectomy and continued on nocturnal CPAP.
short term but there was no change in the respiratory rate. The The eighth patient, with a 7-month history of upper airway
children accepted the treatment without any problems. The long obstruction, was shown to have a diffuse malignant brainstem
term effect or amount of secretions produced were not men- glioma, was managed palliatively and died 6 months later.
tioned.27 It has also been suggested that the low flow Acapella The interrelationship between awake upper airway obstruction
(oscillating PEP) may be an alternate ACT, however there is no and OSA is not clear-cut. It is possible to have neither, one without
research in this area. The high frequency chest wall oscillation vest the other or indeed both. For those children with stridor and
has been effective in patients with cystic fibrosis in the US, helping obstructive symptoms when awake, but not in sleep, the
clear their secretions,28 but due to its high cost and limited symptomatology has been attributed to laryngeal dystonia, and
availability it has not been widely used worldwide. reported in a small cohort of children with dystonic CP32 or severe
In conclusion, not all children with CP need daily chest laryngomalacia.31 The laryngomalacia seen in older children with
physiotherapy. If they have difficulty clearing excessive secretions CP reflects the reduced tone of the supraglottic structures, which
of the lower respiratory tract then chest physiotherapy is on forceful inspiration collapse into the airway, reducing the
indicated, but the need should be reassessed regularly. There calibre of the airway, compromising airflow and resulting in
are limited guidelines to influence clinical practice.29 The fact must stridor. The concurrent presence of a pseudobulbar palsy may
be recognized that ACTs impose an extra demand on carers who serve to predispose to this tendency.31,32
already have a significant workload in caring for a disabled child. This suggests that the clinician should consider both waking
and sleeping upper airway obstruction in children with CP, be
mindful of changes in symptomatology related to the upper airway
SLEEP BREATHING PROBLEMS and consider the morbidity that may follow from an under-
appreciation of upper airway obstruction and its management.
Children with CP have a higher prevalence of sleep breathing
problems than otherwise healthy children reported in community Altered sleep cycles
based surveys.30 The disruption of normal sleep patterns may have
an enormous impact upon the interactive and cognitive skills of the The establishment and maintenance of normal sleep patterns in
child with CP, adversely affect their quality of life and interfere young children with CP is often challenging. In addition to the
with the normal sleeping patterns of siblings and parents. Indeed, negative impact upon the child with CP, altered sleep cycles are
sleep problems in children with CP are under-reported, under- frustrating for the parents and siblings as they are often disruptive
recognized and under-treated. to their sleep requirements. Sleep may be affected by a seizure
Disturbed sleep patterns may involve fragmented sleep, disorder and its treatment, altered perception of light with visual
increased nocturnal awakenings and even inversion of the impairment as well as pain and physical discomfort.
sleep wake cycle.30 A range of factors predispose children with
CP to sleep disordered breathing. Children with CP may be Insomnia
vulnerable to sleep problems for a variety of reasons which may The prevalence of difficulties in settling off to sleep in the
include, but are by no means limited to: general paediatric population is generally high and is higher again
22 D.A. Fitzgerald et al. / Paediatric Respiratory Reviews 10 (2009) 18–24
in special needs populations, including children with CP.33,34 apparent in the supine position during sleep and therefore a full
Figures quoted relate to difficulty settling and frequent night history of sleep breathing concerns should include consideration of
awakenings in 40% of infants; delayed sleep onset and disruptive cough, its aetiology, GOR and oral secretion management.
night awakenings in up to 50% of preschoolers and bed-time
resistance in up to 27% of school-aged children.34 These events may MANAGEMENT OF SLEEP PROBLEMS IN CHILDREN WITH
be disruptive for the child whilst tiring and distressing for the CEREBRAL PALSY
family.34,35 Poor sleep quality will adversely impact upon
behaviour, mood, attention, cognition, memory and school After considering the history of sleep breathing concerns and
performance.35 In children with CP, and indeed with many other completing a physical examination of the chest and upper airway,
neurocognitive abnormalities, the mechanisms of sleep disruption it is likely that the possible problems will fall into either
are not well understood. obstructive breathing patterns or altered sleep cycles which have
resulted in fragmented sleep. The presence of snoring on the
Seizure disorders majority of nights, with or without a clear history of witnessed
Sleep patterns may be adversely affected by the existence and apnoea, would favour the possibility of OSA. Conversely, the
treatment of a coexisting seizure disorder.33,36 The interaction presence of predominantly lengthy periods of wakefulness and
between epilepsy and sleep disorders is not well understood, but some daytime sleepiness may favour a problem with altered sleep
the most frequently reported problems are those of sleep cycles. Certainly, both problems can occur concurrently but the
fragmentation with reduced sleep efficiency and more frequent approach to their management differs.
arousals from sleep.37 Conversely, poor sleep quality may also
increase seizure frequency.38 Possible contributory factors include Management of obstructive sleep apnoea
associated psychological and mood disturbance and an alteration
in sleep architecture that may persist after seizures.39 For children who snore, it would be reasonable to consider a
A child with frequent seizures may have post-ictal phases with lateral airways radiograph to assess the size of adenoidal tissue
somnolence as the initial symptom. Alternatively, the treatment of in relation to the airway. If there was a lengthy history of
a difficult seizure disorder, often with a number of anticonvulsants, witnessed apnoea, it would be appropriate to obtain a venous
may also result in somnolence as a side effect of the medications.40 blood gas or serum bicarbonate as a quick screen for carbon
A range of antiepileptic medications have been shown to alter dioxide retention. The definitive test is a polysomnogram to
sleep architecture.41 The alteration and more typically reduction in characterize the presence and severity of sleep disordered
an anticonvulsant regimen may improve sleep-wake cycling and breathing. This will also demonstrate the presence of excessive
reduce somnolence. This frequently will reduce sleep related central apnoea (oxygen desaturation), a more common finding in
hypoventilation and perhaps concurrent OSA with a resulting children with central neurological abnormalities. Where poly-
improvement in gas exchange. somnography is not available, the clinician can rely on a
combination of clinical judgement, the lateral airways radiograph,
Altered light perception a measure of serum bicarbonate (if not a blood gas) and perhaps
The presence of blindness or greatly reduced vision may impair oximetry during sleep.
the benefits of natural light and its facilitation of wakefulness The therapeutic response to the presence of significant
during the daytime. A reduction in the perception of natural light obstructive apnoea (an obstructive apnoea index > 5 episodes/h
will disrupt the natural secretion of the sleep-inducing hormone with oxygen desaturation of > 3%) would be adenoidectomy and
melatonin, released from the pineal gland. The secretion of tonsillectomy. In more severe cases, or in those children deemed to
melatonin is inhibited by light and enhanced during darkness.42 have too great an operative risk, a period of non-invasive
In healthy human controls, melatonin secretion will increase soon respiratory support with nasal CPAP during sleep will improve
after dark, peak in the middle of the night and steadily decline gas exchange, reset altered chemoreceptors and provide a bridge to
during the second half of the night.43 The consequences of reduced surgery to remove enlarged tonsils or adenoids. In children
or absent light perception upon sleep can be dramatic. Children without enlarged tonsils or adenoids, and presumably low
with CP and blindness may have a free running circadian rhythm or pharyngeal muscle tone in sleep, the use of CPAP in sleep should
even an inverted sleep-wake cycle.44 overcome upper airway obstruction. Those with altered respira-
tory drive may benefit from a more complex form of non-invasive
Pain and physical discomfort respiratory support with bi-level pressure devices which can be set
The effect of physical discomfort and the impaired ability to at a guaranteed rate, generally of up to 30 breaths/min. Both
adjust position in sleep may also impact adversely upon sleep devices can be established at the bedside with an approximation of
quality. The children may present with increased tiredness, the pressures required to overcome snoring and minimize
restless sleep, night time crying or agitation. Initial responses paradoxical respirations. Importantly, fine tuning of the pressures
may be to offer the child sedation with antihistamines or and rate would take place during further polysomnography as a
benzodiazepines, but such responses may overlook the underlying titration study. With growth over time and alterations in airway
problem such as a dislocated hip or pressure sores on dependent dimensions, such as after surgery on adenoids or tonsils, the need
areas. The physical examination should always consider these for ongoing respiratory support will need reassessment.
possibilities. Interestingly, the sedative agents may also influence
upper airway muscle tone, increasing snoring and problems with Management of altered sleep cycles
the coordinated swallowing of oral secretions, which may further
complicate the assessment. It is useful to begin with a sleep diary, filled in by the parents
over a 10–14-day period which will demonstrate the sleeping
Cough and pulmonary aspiration patterns, length of sleep and duration of overnight awakenings.
This can serve as a useful baseline and can be repeated at
This has been highlighted earlier with regard to the develop- subsequent intervals if needed to demonstrate progress. Once the
ment of lung disease. Interestingly, the symptoms may be more sleep pattern is documented, the use of sleep settling routines
D.A. Fitzgerald et al. / Paediatric Respiratory Reviews 10 (2009) 18–24 23
should be the first action. This is designed to make the 2. Reddihough DS, Baikie G, Walstab JE. Cerebral palsy in Victoria, Australia: Mortality
and causes of death. J Paediatr Child Health 2001; 37: 183–186.
environment, usually the child’s bedroom, more conducive to 3. Baikie G. Inhalation pneumonitis in children with severe cerebral palsy. MD 1999
sleep. A regular meal time, bathing routine and a lack of University of Melbourne, Melbourne, Victoria, Australia.
stimulation from computers, television or DVDs in the pre-bed 4. Baikie G, South MJ, Reddihough DS et al. Agreement of aspiration tests using barium
videofluroscopy, salivagram, and milk scan in children with cerebral palsy. Dev Med
hours is often helpful. Typically, whilst helpful, these measures are Child Neurol 2005; 47: 86–93.
insufficient to normalize the sleeping patterns of a child with a 5. Mori N, Kurosawa H, Yosida M et al. What factors are related to respiratory
delayed sleep phase or an inverted sleep cycle. dysfunction in patients with severe cerebral palsy? Eur Respir J 2007; 30: 376s.
6. Camp-Bruno JA, Winsberg BG, Green-Parsons AR, Abrams JP. Efficacy of benztropine
Cognitive behavioural therapies have been shown to be
therapy for drooling. Dev Med Child Neurol 1989; 31: 309–319.
successful in children with insomnia.45 In a survey of American 7. Blasco PA, Stansbury JCK. Glycopyrrolate treatment of chronic drooling. Arch Pediatr
community-based paediatricians, Owens and colleagues reported Adolesc Med 1996; 150: 932–935.
8. Bachrach SJ, Walter RS, Trzcinski K. Use of glycopyrollate and other anticholinergic
that the prescription of sedatives and hypnotics is common for
medications for sialorrhea in children with cerebral palsy. Clin Pediatr 1998; 37: 485–
treating paediatric insomnia despite reservations regarding this 490.
practice and the lack of specific clinical guidelines in this area.45 9. Blasco PA. Management of drooling: 10 years after the Consortium on Drooling, 1990.
Over-the-counter sedating antihistamines are widely recom- Dev Med Child Neurol 2002; 44: 778–781.
10. Tscheng DZ. Sialorrhea - therapeutic drug options. Ann Pharmacother 2002; 36:
mended followed by melatonin. 1785–1790.
The use of melatonin has become common for the treatment of 11. Dogu O, Apaydin D, Sevim S, Talas DU, Aral M. Ultrasound-guided versus ‘‘blind’’
circadian rhythm disorders (especially delayed sleep phase intraparotid injections of botulinum toxin-A for the treatment of sialorrhea in patients
with Parkinson’s disease. Clin Neurol Neurosurg 2004; 106: 93–96.
syndrome).44 Generally administered in doses of 3–6 mg as a 12. Prasad A. Physiotherapy in cystic fibrosis. J R Soc Med 2000; 93(Suppl. 38): 27–36.
liquid or tablet 30 min before desired sleep onset at night, the 13. Society T. The nomenclature of bronchopulmonary anatomy. Thorax 1950; 5: 222–
medication has become popular and has been considered 228.
14. Campanozzi A, Capano G, Miele E et al. Impact of malnutrition on gastrointestinal
efficacious.46 The only reservation may relate to an inconsistent disorders and gross motor abilities in children with cerebral palsy. Brain Dev 2007; 29:
decrease in seizure control.30,47 The effect is to reduce the time to 25–29.
sleep onset (typically by 30–60 min), increase total sleep time 15. Button BM, Heine RG, Catto-Smith AG, Phelan PD, Olinsky A. Postural drainage and
gastro-oesophageal reflux in infants with cystic fibrosis. Arch Dis Child 1997; 76: 148–
(typically by 45–60 min) and decrease the frequency of night
150.
awakenings. The medication has been used continuously in clinical 16. Vandenplas Y, Diericx A, Blecker U, Lanciers S, Deneyer M. Esophageal pH
studies for 6 months with no suggestion of tachyphylaxis. monitoring data during chest physiotherapy. J Pediatr Gastroenterol Nutr 1991;
13: 23–26.
Other therapies that have been used in children include
17. Button BM, Heine RG, Catto-Smith AG, Phelan PD. Postural drainage in cystic fibrosis:
alternative medicines such as herbal preparations, chloral hydrate, is there a link with gastro-oesophageal reflux? J Paediatr Child Health 1998; 34: 330–
benzodiazepines, barbiturates, phenothiazines and diphenhydra- 334.
mine.45 It is presumed that these medications are also being used 18. Button BM, Heine RG, Catto-Smith AG et al. Chest physiotherapy in infants with
cystic fibrosis: to tip or not? A five-year study. Pediatr Pulmonol 2003; 35: 208–
in children with CP and neurocognitive deficits, again with little in 213.
the way of evidence to guide practice. 19. Cecins N, Jenkins S, Pengelly J, Ryan G. The active cycle of breathing techniques - to tip
or not to tip? Respir Med 1999; 93: 660–665.
20. McDonnell T, McNicholas WT, FitzGerald MX. Hypoxaemia during chest physiother-
apy in patients with cystic fibrosis. Ir J Med Sci 1986; 155: 345–348.
21. Gallon A. The use of percussion. Physiotherapy 1992; 78: 85–89.
PRACTICE POINTS 22. Pryor JA, Parker RA, Webber BA. A comparison of mechanical and manual percussion
as adjuncts to postural drainage in the treatment of cystic fibrosis in adolescents and
Lung disease is common particularly in children with adults. Physiotherapy 1981; 67: 140–141.
23. van der Schans CP, Postma DS, Koeter GH, Rubin BK. Physiotherapy and bronchial
severe CP.
mucus transport. Eur Respir J 1999; 13: 1477–1486.
The aetiology is multifactorial, including pulmonary 24. McCarren B, Alison JA, Herbert R. Vibration and its effect on the respiratory system.
aspiration, decreased mucociliary clearance, suppuration, Aust J Physiotherapy 2006; 52: 39–43.
kyphoscoliosis and airway obstruction. 25. Parker A, Prassad A. In: Pryor J, Webber B, eds: Physiotherapy for Respiratory and
Cardiac Problems 2nd edn. Edinburgh: Churchill Livingstone.
Asthma is over-diagnosed and over-treated with wheeze 26. MacMillan C. Nasopharyngeal suction study reveals knowledge deficit. Nurs Times
usually due to other aetiologies. 1995; 91: 28–30.
CP is also commonly associated with sleep disordered 27. Lagerkvist A, Sten G, Westerberg B, Ericsson-Sagsjo A, Bjure J. Positive expiratory
pressure (PEP) treatment in children with multiple severe disabilities. Acta Paediatr
breathing that is under-recognized and under-treated. 2005; 94: 538–542.
Management needs to address the relatively predictable 28. Hansen LG, Warwick WJ, Hansen KL. Mucus transport mechanisms in relation to the
lung and sleep breathing problems. effect of high frequency chest compression (HFCC) on mucous clearance. Pediatr
Pulmonol 1994; 17: 113–118.
Recurrent suppurative lung disease is often amenable to 29. AARC Clinical Practice Guideline. Postural drainage therapy. Resp Care 1991; 36:
simple and inexpensive therapies that will improve the 1418–1426.
quality of life of the person with CP and their family and 30. Kotagal S, Gibbons VP. Sleep disorders in severe cerebral palsy. Dev Med Child Neurol
1994; 36: 304–311.
carers.
31. Wilkinson DJ, Baikie G, Berkowitz RG, Reddihough DS. Awake upper airway obstruc-
A range of airway clearance techniques are available for tion in children with spastic quadriplegic cerebral palsy. J Paediatr Child Health 2006;
children with CP. 42: 44–48.
32. Worley G, Witsell DL, Hulka GF. Laryngeal dystonia causing inspiratory stridor in
Non-invasive respiratory support is useful for airway
children with cerebral palsy. Laryngoscope 2003; 113: 2192–2195.
clearance and sleep disordered breathing. 33. Quine L. Sleep problems in children with mental handicap. J Ment Defic Res 1991; 35:
Life expectancy for children with CP is improving due in 269–290.
part to a more aggressive approach to the use of 34. Owens J, Palmermo T, Rosen C. Overview of current management of sleep distur-
bances in children: II Behavioural interventions. Curr Ther Res 2002; 63(Suppl B):
respiratory therapies. B38–B52.
35. Wiggs L, Stores G. Behavioural treatment for sleep problems in children with severe
learning disabilities and challenging daytime behaviour. J Child Psychol Psychiatry
1999; 40: 627–635.
36. Coppola G, Iervolino G, Mastrosimone M, La Torre G, Ruiu F, Pascotto A. Melatonin
REFERENCES in wake-sleep disorders in children, adolescents and young adults with mental
retardation with or without epilepsy: a double-blind, cross-over, placebo-controlled
1. Johnson A. Prevalence and characteristics of children with cerebral palsy in Europe. trial. Brain Dev 2004; 26: 373–376.
Dev Med Child Neurol 2002; 44: 633–640. 37. Bazil CW. Epilepsy and sleep disturbance. Epilepsy Behav 2003; 4(Suppl 2): S39–45.
24 D.A. Fitzgerald et al. / Paediatric Respiratory Reviews 10 (2009) 18–24
38. Bazil CW. Sleep and epilepsy. Curr Opin Neurol 2000; 13: 171–175. 44. Jan MM. Melatonin for the treatment of handicapped children with severe sleep
39. De Haas S, Otte A, de Weerd A, van Erp G, Cohen A, van Gerven J. Exploratory disorders. Pediatr Neurol 2000; 23: 229–232.
polysomnographic evaluation of pregabalin on sleep disturbance in patients with 45. Owens JA, Rosen CL, Mindell JA. Medication use in the treatment of pediatric
epilepsy. J Clin Sleep Med 2007; 3: 473–478. insomnia: results of a survey of community-based pediatricians. Pediatrics 2003;
40. Kothare SV, Kalevius J. The adverse effects of anti-epileptic drugs in children. Expert 111: e628–e635.
Opin Drug Saf 2007; 6: 251–265. 46. Wasdell MB, Jan JE, Bomben MM et al. A randomized, placebo-controlled trial of
41. Sammaritano M, Sherwin A. Effect of anticonvulsants on sleep. Neurology 2000; 54: controlled release melatonin in the treatment of delayed sleep phase syndrome and
S16–S24. impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal
42. Fischer S, Smolnik R, Herms M, Born J, Fehm H. Melatonin acutely improves the Res 2008; 44: 57–64.
neuroendocrine architecture of sleep in blind individuals. J Clin Endocrinol Metab 47. Braam W, Didden R, Smits M, Curfs L. Melatonin treatment in individuals with
2003; 88: 5315–5320. intellectual disability and chronic insomnia: a randomized placebo-controlled study. J
43. Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336: 186–195. Intellect Disabil Res 2008; 52: 256–264.