Sleep in Neurodevelopmental and Neurodegenerative Disorders Suresh Kotagal, MD There is a close relationship between sleep and childhood neurodevelopmental/neurodegenerative disorders. Understanding the sleep issues may provide greater insight into pathophysiology and treatment of these disorders. Semin Pediatr Neurol 22:126-129 C 2015 Elsevier Inc. All rights reserved.
Introduction There is a bidirectional relationship between many neurodevelopmental and neurodegenerative disorders and sleep. In some of these disorders, sleep-wake function gets disrupted early in the clinical course, for example, SmithMagenis syndrome (SMS) and autism. In other conditions such as neuronal ceroid lipofucsinosis, sleep disruption develops in the middle to late stages. Attention to sleepwake function can help in improving the quality of life of these patients. This article provides an overview of the common static and progressive disorders of the nervous system and the associated sleep disorders.
Down Syndrome In a prospective study that used clinical examination, lateral radiographs of the nasopharynx and polysomnography combined, the prevalence of sleep-disordered breathing was 54%. The mean age of the subgroup with sleepdisordered breathing was lower, that is, 6.4 years, vs that of the subgroup without sleep-disordered breathing, that is, 9.6 years.1 Obstructive sleep apnea-hypopnea syndrome in Down syndrome is multifactorial—as in typically developing children, there may be a component of adenotonsillar hypertrophy, but superimposed on this are also other factors such as midface hypoplasia, hypotonic upper airway musculature, central sleep apnea syndrome, hypoventilation, and pulmonary hypertension. The American Academy of Pediatrics now recommends routine evaluation of all children with Down syndrome for sleep-disordered breathing as From the Department of Neurology, Mayo Clinic, Rochester, MN. Address reprint requests to Suresh Kotagal, MD, Division of Child Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: [email protected]
126
a standard of care.2 The evaluation process should include physical examination coupled at the very least with overnight oximetry to assess for recurrent episodes of oxygen desaturation. Nocturnal polysomnography is recommended when oximetry result is abnormal. The management requires a team approach—consultation with otolaryngology service for possible adenotonsillectomy; it is the first step to be followed if necessary with repeat polysomnography. Positive-pressure breathing devices (continuous or bi-level) are used if there is obstructive hypoventilation (obstructive sleep apnea þ levels of end-tidal carbon dioxide that are larger than 50 mm for 25% or more of the total recording time on polysomnography) and no surgically correctable upper airway lesion.
Prader-Willi Syndrome This disorder is linked to abnormal methylation on chromosome 15q11-q13. This is associated with deletion of the paternally inherited gene in most cases, but a small percentage of cases might have uniparental disomy or genetic imprinting. The patients are profoundly hypotonic in infancy, but manifest hyperphagia, hypersomnolence, and behavioral problems during childhood. Obesity develops in middle to late half of the first decade, and is likely related to elevated levels of ghrelin, an appetite-stimulating peptide that is secreted by the stomach.3 Daytime sleepiness in PraderWilli syndrome (PWS) may be associated with sleep-onset rapid eye moment (REM) periods (SOREMP), though not to the degree seen in narcolepsy. An isolated case report has shown low cerebrospinal fluid level of hypocretin in a patient with combined PWS and Kleine-Levin syndrome.4 Children with PWS respond favorably from the motor development standpoint to treatment with growth hormone, which seems to accelerate their motor milestones. There is a suspected but not definitively proven link between growth hormone
1071-9091/15/$-see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.spen.2015.03.003
Sleep in neurological disorders therapy and obstructive idea.5 It is a good idea, however, to monitor patients with PWS receiving growth hormone therapy with nocturnal polysomnography if there is development of periods of snoring or suspected sleep apnea.
Cerebral Palsy Using the Sleep Disturbance Scale for Children, a validated scale, Romeo et al6 found a 13% prevalence of sleep disturbance in preschool-age children with cerebral palsy. There was an association of sleep disturbance with pathologic internalizing scores on the Child Behavior Check List and active epilepsy. Motor disability and antiepileptic agents may also contribute to sleep disturbance.7 Children with obstructive sleep apnea may present with irritability, choking, and gagging on feeds and increased night awakenings.7 Nocturnal polysomnography in children with cerebral palsy may need to be combined with an extended 16-channel electroencephalography montage if there is a suspicion of the night awakenings being related to sleep-related epileptic events. The management is best accomplished through a team approach—for instance obstructive sleep apnea requires adenotonsillectomy, neurogenic dysphagia may necessitate gastrostomy tube placement, and difficulty in handling oral secretions may require salivary duct ligation or botulinum toxin injections to the salivary gland.
Neuronal Ceroid Lipofuscinosis (Batten Disease) There are several variants of Batten disease, and not all have been studied from the sleep-wake standpoint. Patients with a variant form of late infantile form of neuronal ceroid lipofuscinosis (CLN5) have been reported to show increased total sleep at night and excessive daytime napping.8 Patients with more advanced disease may show increased shifts in sleep stages at night and loss of circadian rhythmicity. It is possible that blindness as a consequence of the retinal degeneration that occurs in infantile and late infantile forms also contributes to disruption in the timing of sleep and wakefulness.
Smith-Magenis Syndrome This disorder is associated with severe insomnia that has onset in early childhood. Physical features of SMS include a square-shaped forehead, rotated pinnae, hoarse voice, speech developmental delay, brachycephaly, hyperactivity, compulsive behaviors, and insomnia.9 There may be inversion of the melatonin secretion rhythm, with low levels at night and high levels during the day.10 This may partially explain daytime drowsiness and hyperactivity. Approximately 70% of patients have a deletion in the SMS gene, which is localized to 17p11.2. However, in some patients, heterozygous point mutations have been reported on the RAI1 gene within the SMS critical region, without detectable
127 deletions on fluorescent in situ hybridization testing.11 Wrist actigraphy and sleep logs may help in evaluating the circadian rhythm disturbance. Treatment of the sleep disturbance is complicated. There are only a small number of reported cases and no systematic clinical trials. Nevertheless, bright light therapy combined with propranolol may inhibit daytime increase in melatonin; this needs to be combined with melatonin supplementation at night to facilitate sleep.
Autism Spectrum Disorder Parental surveys indicate a 50%-80% prevalence of sleep disorders as compared with 9%-50% prevalence in typically developing children.12 Within the autism spectrum disorder (ASD), the subtype with abrupt developmental regression seems to show more sleep disruption in comparison with children with ASD who have been delayed since early infancy or childhood or typically developing children.13 The type of sleep problems that can be seen in children with ASD include bedtime resistance, increased awakenings, and decreased sleep duration. Patients with ASD might also have an intrinsic defect in melatonin synthesis, which might underlie insomnia in some patients.14 Risperidone is commonly used to treat behavioral problems in autism, but high doses can lead to exacerbation of restless legs syndrome by virtue of its dopamine antagonist effect. Behavioral insomnia syndromes such as sleep-onset association disorder and limit-setting disorder may also develop. The sleep problems in ASD are best studied by clinical history, sleep logs, and wrist actigraphy. If there are episodes of unusual nocturnal behavior such as yelling or screaming, REM sleep behavior disorder (RBD) may need to be considered, in which case nocturnal polysomnography is indicated.15,16 The overnight polysomnogram may reveal REM sleep without atonia if RBD is present. Periodic limb movements in sleep (normally o5/h of sleep) may be increased in those with associated systemic iron deficiency. The management of sleep problems in ASD needs to be individualized, based upon the most likely precipitating factors. Keeping a quiet, unexciting routine for 2-3 hours before bedtime facilitates settling. In the author’s opinion, the bedroom environment should be cozy and “cocoon like.” The use of weighted blankets sometimes facilitates sleep. A dose of 3-10 mg of melatonin administered 30-60 minutes before the desired bedtime is also helpful. Counseling of the parents is indicated in patients with behavioral insomnia.
Niemann-Pick Disease Type C This is a primary biochemical defect of impairment in transport of endocytosed cholesterol, which is caused by mutations in both alleles of either the NPC-1 or NPC-2 gene.17 Patients manifest delayed motor development since infancy or early childhood, gait unsteadiness, frequent falls,
S. Kotagal
128 impaired vertical gaze, dystonic gait, and cataplexy. The cataplexy, which leads to abrupt head drops or falls in response to an emotional trigger such as laughter, can be mistaken as being due to ataxia or dystonia. The brainstem neurodegeneration in Niemann-Pick disease type C (NPC) may progress in severe cases to frank narcolepsy-cataplexy, whereas in milder cases, the sleep-wake disturbance may stay restricted to cataplexy. There is an interesting comparison of the sleep disturbance in NPC with that of idiopathic narcolepsy—in NPC, cataplexy is the key component whereas daytime sleepiness appears only in severe cases. On the contrary, in idiopathic narcolepsy, excessive sleepiness is invariably present at the onset, and cataplexy develops only in approximately twothird of cases. Video clips of the patient’s falls provided by parents, nocturnal polysomnography, and multiple sleep latency tests can aid in the diagnosis of cataplexy or narcolepsycataplexy. The treatment of cataplexy is symptomatic, and includes tricyclic agents18 or miglustat (an inhibitor of the enzyme glucosylceramide synthase, which is one of the enzymes that catalyzes the first step in biosynthesis of glycosphingolipids in NPC19).
Rett Syndrome This is an X-linked severe neurodegenerative disorder occurring predominantly in females, which is due to mutations in the MECP2 (methyl–CPG-binding protein 2) gene. It is characterized by developmental regression, acquired microcephaly, tendency for stereotyped hand wringing movements, gait apraxia, and loss of purposeful hand movements.20
Patients exhibit breathing abnormalities predominantly during wakefulness but also to some extent in sleep. While asleep, breathing is faster as compared with age-matched controls, and more irregular.21 During wakefulness, there may be periods of rapid and deep breathing followed by pauses.22 These abnormalities are related to developmental dysfunction in the ventral medulla and pons. Longitudinal studies have also disclosed unusual behaviors during sleep in patients with Rett syndrome. Wong et al23 followed 320 families in the Australian Rett Syndrome database over a 12-year period. Subjects were 2-35 years of age. Of these, 80% of the patients manifested sleep disturbance, which was more common in younger subjects, and diminished with age. Night laughter was recorded in 77% of subjects and night screaming in 49%. Those with large deletions had a higher incidence of night laughter. It is possible that these episodes of night laughing or screaming represent RBD,15,16 but this is still a conjecture as the episodes have not been characterized using nocturnal polysomnography.
General Comments and Conclusion The attached Table and the Figure show some of the common comorbidities that accompany neurodegenerative and neurodevelopmental disorders. These may be primary, or related to accompanying systemic disorders. There is often a need for a multidisciplinary team approach for the management of systemic comorbidities. Feelings of guilt or denial on behalf of the parents can become a barrier in rendering optimal care for sleep disorders. Actigraphy, sleep logs and
Table Category of Sleep Disturbance in Neurodegenerative or Neurodevelopmental Disorders Symptom
Underlying Sleep Disorder
Comments
Sleep initiation difficulty
a. b. c. d.
a. b. c. d.
Sleep maintenance difficulty
a. Obstructive sleep apnea
Nocturnal spells
Restless legs syndrome Behavioral insomnia of childhood Separation anxiety Circadian rhythm disturbance
b. Restless legs syndrome c. Sleep-related epilepsy a. Nocturnal seizures b. NREM parasomnias c. REM parasomnias d. Gastroesophageal reflux
Associated with low serum ferritin level (o30 mg/L)12 Limit-setting disorder or sleep-onset association disorder12 Highly prevalent in autism Smith-Magenis syndrome, blindness from ocular pathology
a. Adenotonsillar hypertrophy, craniofacial anomalies, and acid reflux are common etiologies b. Correct iron deficiency; gabapentin for symptomatic relief c. Sleep may be disrupted by seizures, antiepileptic drugs or vagus-nerve stimulator, and anxiety a. Nocturnal frontal lobe epilepsy, electrical status epilepticus in sleep, and focal seizures of temporal lobe onset predominate b. Sleep walking and confusional arousals predominate c. Nightmares and REM sleep behavior disorder predominate d. Night awakenings with tonic posturing or cough
Hypersomnolence Medication effect, Smith-Magenis Monitor antiepileptic drug levels, when indicated syndrome, and secondary narcolepsy Cataplexy
Niemann-Pick disease type C, Coffin- Video recordings of spells made by parents may help in diagnosis Lowry syndrome, and Norrie disease
NREM, non–rapid eye moment; REM, rapid eye moment.
Sleep in neurological disorders
129
6. Anxiety
7. Depression
Pain
8.
9. Sleep disturbance in neurodevelopmental or degenerave Disorder
10. Learnt maladapve associaons (behavioral insomnia)
Gastroesophageal reflux
11. 12. 13.
Medicaon side effects
14.
Figure Health-related conditions impacting sleep-wake function in children with neurodevelopmental / neurodegenerative disorders.
15.
16.
video electroencephalography polysomnography, and pediatric sleep specialist consultation may facilitate specific diagnoses, enhance care, and improve overall quality of life.
17.
18.
References 1. De Miguel-Diez J, Villa-Assensi J, Alvarez-Sala JL: Prevalence of sleep disordered in children with Down syndrome: Polygraphic findings in 108 children. Sleep 26:1006-1009, 2003 2. American Academy of Pediatrics. Committee on Genetics: Health supervision for children with Down syndrome. Pediatrics 107: 442-449, 2001 3. Erdie-Lalena C, Holm V, Kelly P, et al: Ghrelin levels in young children with Prader-Willi syndrome. J Pediatr 149:199-204, 2006 4. Dauvilliers Y, Politini L, Nobili I, et al: CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry 74:1667-1673, 2003 5. Festen DAM, de Weerd W, van den Bossche RAS, et al: Sleep-related breathing disorders in prepubertal children with Prader-Willi
19.
20. 21.
22.
23.
syndrome and effects of growth hormone treatment. J Clin Endocrinol Metab 91:4911-4915, 2006 Romeo DM, Brogna C, Musto E, et al: Sleep disturbances in preschool age children with cerebral palsy: A questionnaire study. Sleep Med 15:1089-1093, 2014 Kotagal S, Gibbons VP, Stith J: Sleep abnormalities in children with severe cerebral palsy. Dev Med Child Neurol 36:304-311, 1994 Kirveskari E, Partinen M, Santavouri P: Sleep and its disturbance in a variant form of late infantile neuronal ceroid lipofuscinosis (CLN5). J Child Neurol 16:707-713, 2001 Gropman AL, Duncan WC, Smith AC: Neurological and developmental features of the Smith-Magenis syndrome (del 17 p11.2). Pediatr Neurol 34:337-350, 2006 De Leersynder H, De Bois B, Claustrat B: Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome. J Pediatr 139:111-116, 2001 Gropman AL, Elsea S, Duncan WC, et al: New developments in SmithMagenis syndrome (del 17p11.2). Curr Opin Neurol 20:125-134, 2007 Kotagal SD, Broomall E: Sleep in children with autism spectrum disorder. Pediatr Neurol 47:242-251, 2012 Giannotti F, Cortesi A, Cerquiglini A, et al: An investigation of sleep characteristics, electroencephalogram abnormalities and epilepsy in developmentally regressed and non-regressed children with autism. J Autism Dev Disord 38:1888-1897, 2008 Melke J, Goubran BH, Chaste P, et al: Abnormal melatonin synthesis in autism spectrum disorder. Mol Psychiatry 13:90, 2008 Lloyd R, Tippman-Piekert M, Slocumb N, et al: Characteristics of REM sleep behavior disorder in childhood. J Clin Sleep Med 8:127-131, 2012 Kotagal S: Rapid eye movement sleep behavior disorder during childhood. Sleep Med Clin 2015. [Epub ahead of print] Patterson MC, Hendriksz CJ, Walterfang M, et al: Recommendations for the diagnosis and management of Niemann-Pick disease type C: An update. Mol Genet Metab 106:330-344, 2012 Halime TC, Haliloglu G, Duzgun G, et al: Successful treatment of cataplexy in patients with early-infantile Niemann-Pick disease type C: Use of tricyclic antidepressants. Eur J Pediatr Neurol 18:811-815, 2014 Zarowski M, Steinborn B, Grda B, et al: Treatment of cataplexy in Niemann-Pick disease type C with use of miglustat. Eur J Pediatr Neurol 15:84-87, 2011 Lyst MJ, Bird A: Rett syndrome: A complex disorder with simple roots. Nat Rev Genet 2015:261-275, 2015 Weese-Mayer DE, Lieske SP, Boothby CM, et al: Autonomic dysregulation in young girls with Rett syndrome during night-time in-home recordings. Pediatr Pulmonol 43:1045-1060, 2008 Ramirez-JM, Scott Ward C, Neul JL: Breathing challenges in Rett syndrome: Lessons learned from humans and animal models. Respir Physiol Neurobiol 189:280-287, 2013 Wong K, Leonard H, Jacoby P, et al: The trajectory of sleep disturbance in Rett syndrome. J Sleep Res 24:223-233, 2015
Introduction There is a bidirectional relationship between many neurodevelopmental and neurodegenerative disorders and sleep. In some of these disorders, sleep-wake function gets disrupted early in the clinical course, for example, SmithMagenis syndrome (SMS) and autism. In other conditions such as neuronal ceroid lipofucsinosis, sleep disruption develops in the middle to late stages. Attention to sleepwake function can help in improving the quality of life of these patients. This article provides an overview of the common static and progressive disorders of the nervous system and the associated sleep disorders.
Down Syndrome In a prospective study that used clinical examination, lateral radiographs of the nasopharynx and polysomnography combined, the prevalence of sleep-disordered breathing was 54%. The mean age of the subgroup with sleepdisordered breathing was lower, that is, 6.4 years, vs that of the subgroup without sleep-disordered breathing, that is, 9.6 years.1 Obstructive sleep apnea-hypopnea syndrome in Down syndrome is multifactorial—as in typically developing children, there may be a component of adenotonsillar hypertrophy, but superimposed on this are also other factors such as midface hypoplasia, hypotonic upper airway musculature, central sleep apnea syndrome, hypoventilation, and pulmonary hypertension. The American Academy of Pediatrics now recommends routine evaluation of all children with Down syndrome for sleep-disordered breathing as From the Department of Neurology, Mayo Clinic, Rochester, MN. Address reprint requests to Suresh Kotagal, MD, Division of Child Neurology, Mayo Clinic, 200 First St SW, Rochester, MN 55905. E-mail: [email protected]
126
a standard of care.2 The evaluation process should include physical examination coupled at the very least with overnight oximetry to assess for recurrent episodes of oxygen desaturation. Nocturnal polysomnography is recommended when oximetry result is abnormal. The management requires a team approach—consultation with otolaryngology service for possible adenotonsillectomy; it is the first step to be followed if necessary with repeat polysomnography. Positive-pressure breathing devices (continuous or bi-level) are used if there is obstructive hypoventilation (obstructive sleep apnea þ levels of end-tidal carbon dioxide that are larger than 50 mm for 25% or more of the total recording time on polysomnography) and no surgically correctable upper airway lesion.
Prader-Willi Syndrome This disorder is linked to abnormal methylation on chromosome 15q11-q13. This is associated with deletion of the paternally inherited gene in most cases, but a small percentage of cases might have uniparental disomy or genetic imprinting. The patients are profoundly hypotonic in infancy, but manifest hyperphagia, hypersomnolence, and behavioral problems during childhood. Obesity develops in middle to late half of the first decade, and is likely related to elevated levels of ghrelin, an appetite-stimulating peptide that is secreted by the stomach.3 Daytime sleepiness in PraderWilli syndrome (PWS) may be associated with sleep-onset rapid eye moment (REM) periods (SOREMP), though not to the degree seen in narcolepsy. An isolated case report has shown low cerebrospinal fluid level of hypocretin in a patient with combined PWS and Kleine-Levin syndrome.4 Children with PWS respond favorably from the motor development standpoint to treatment with growth hormone, which seems to accelerate their motor milestones. There is a suspected but not definitively proven link between growth hormone
1071-9091/15/$-see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.spen.2015.03.003
Sleep in neurological disorders therapy and obstructive idea.5 It is a good idea, however, to monitor patients with PWS receiving growth hormone therapy with nocturnal polysomnography if there is development of periods of snoring or suspected sleep apnea.
Cerebral Palsy Using the Sleep Disturbance Scale for Children, a validated scale, Romeo et al6 found a 13% prevalence of sleep disturbance in preschool-age children with cerebral palsy. There was an association of sleep disturbance with pathologic internalizing scores on the Child Behavior Check List and active epilepsy. Motor disability and antiepileptic agents may also contribute to sleep disturbance.7 Children with obstructive sleep apnea may present with irritability, choking, and gagging on feeds and increased night awakenings.7 Nocturnal polysomnography in children with cerebral palsy may need to be combined with an extended 16-channel electroencephalography montage if there is a suspicion of the night awakenings being related to sleep-related epileptic events. The management is best accomplished through a team approach—for instance obstructive sleep apnea requires adenotonsillectomy, neurogenic dysphagia may necessitate gastrostomy tube placement, and difficulty in handling oral secretions may require salivary duct ligation or botulinum toxin injections to the salivary gland.
Neuronal Ceroid Lipofuscinosis (Batten Disease) There are several variants of Batten disease, and not all have been studied from the sleep-wake standpoint. Patients with a variant form of late infantile form of neuronal ceroid lipofuscinosis (CLN5) have been reported to show increased total sleep at night and excessive daytime napping.8 Patients with more advanced disease may show increased shifts in sleep stages at night and loss of circadian rhythmicity. It is possible that blindness as a consequence of the retinal degeneration that occurs in infantile and late infantile forms also contributes to disruption in the timing of sleep and wakefulness.
Smith-Magenis Syndrome This disorder is associated with severe insomnia that has onset in early childhood. Physical features of SMS include a square-shaped forehead, rotated pinnae, hoarse voice, speech developmental delay, brachycephaly, hyperactivity, compulsive behaviors, and insomnia.9 There may be inversion of the melatonin secretion rhythm, with low levels at night and high levels during the day.10 This may partially explain daytime drowsiness and hyperactivity. Approximately 70% of patients have a deletion in the SMS gene, which is localized to 17p11.2. However, in some patients, heterozygous point mutations have been reported on the RAI1 gene within the SMS critical region, without detectable
127 deletions on fluorescent in situ hybridization testing.11 Wrist actigraphy and sleep logs may help in evaluating the circadian rhythm disturbance. Treatment of the sleep disturbance is complicated. There are only a small number of reported cases and no systematic clinical trials. Nevertheless, bright light therapy combined with propranolol may inhibit daytime increase in melatonin; this needs to be combined with melatonin supplementation at night to facilitate sleep.
Autism Spectrum Disorder Parental surveys indicate a 50%-80% prevalence of sleep disorders as compared with 9%-50% prevalence in typically developing children.12 Within the autism spectrum disorder (ASD), the subtype with abrupt developmental regression seems to show more sleep disruption in comparison with children with ASD who have been delayed since early infancy or childhood or typically developing children.13 The type of sleep problems that can be seen in children with ASD include bedtime resistance, increased awakenings, and decreased sleep duration. Patients with ASD might also have an intrinsic defect in melatonin synthesis, which might underlie insomnia in some patients.14 Risperidone is commonly used to treat behavioral problems in autism, but high doses can lead to exacerbation of restless legs syndrome by virtue of its dopamine antagonist effect. Behavioral insomnia syndromes such as sleep-onset association disorder and limit-setting disorder may also develop. The sleep problems in ASD are best studied by clinical history, sleep logs, and wrist actigraphy. If there are episodes of unusual nocturnal behavior such as yelling or screaming, REM sleep behavior disorder (RBD) may need to be considered, in which case nocturnal polysomnography is indicated.15,16 The overnight polysomnogram may reveal REM sleep without atonia if RBD is present. Periodic limb movements in sleep (normally o5/h of sleep) may be increased in those with associated systemic iron deficiency. The management of sleep problems in ASD needs to be individualized, based upon the most likely precipitating factors. Keeping a quiet, unexciting routine for 2-3 hours before bedtime facilitates settling. In the author’s opinion, the bedroom environment should be cozy and “cocoon like.” The use of weighted blankets sometimes facilitates sleep. A dose of 3-10 mg of melatonin administered 30-60 minutes before the desired bedtime is also helpful. Counseling of the parents is indicated in patients with behavioral insomnia.
Niemann-Pick Disease Type C This is a primary biochemical defect of impairment in transport of endocytosed cholesterol, which is caused by mutations in both alleles of either the NPC-1 or NPC-2 gene.17 Patients manifest delayed motor development since infancy or early childhood, gait unsteadiness, frequent falls,
S. Kotagal
128 impaired vertical gaze, dystonic gait, and cataplexy. The cataplexy, which leads to abrupt head drops or falls in response to an emotional trigger such as laughter, can be mistaken as being due to ataxia or dystonia. The brainstem neurodegeneration in Niemann-Pick disease type C (NPC) may progress in severe cases to frank narcolepsy-cataplexy, whereas in milder cases, the sleep-wake disturbance may stay restricted to cataplexy. There is an interesting comparison of the sleep disturbance in NPC with that of idiopathic narcolepsy—in NPC, cataplexy is the key component whereas daytime sleepiness appears only in severe cases. On the contrary, in idiopathic narcolepsy, excessive sleepiness is invariably present at the onset, and cataplexy develops only in approximately twothird of cases. Video clips of the patient’s falls provided by parents, nocturnal polysomnography, and multiple sleep latency tests can aid in the diagnosis of cataplexy or narcolepsycataplexy. The treatment of cataplexy is symptomatic, and includes tricyclic agents18 or miglustat (an inhibitor of the enzyme glucosylceramide synthase, which is one of the enzymes that catalyzes the first step in biosynthesis of glycosphingolipids in NPC19).
Rett Syndrome This is an X-linked severe neurodegenerative disorder occurring predominantly in females, which is due to mutations in the MECP2 (methyl–CPG-binding protein 2) gene. It is characterized by developmental regression, acquired microcephaly, tendency for stereotyped hand wringing movements, gait apraxia, and loss of purposeful hand movements.20
Patients exhibit breathing abnormalities predominantly during wakefulness but also to some extent in sleep. While asleep, breathing is faster as compared with age-matched controls, and more irregular.21 During wakefulness, there may be periods of rapid and deep breathing followed by pauses.22 These abnormalities are related to developmental dysfunction in the ventral medulla and pons. Longitudinal studies have also disclosed unusual behaviors during sleep in patients with Rett syndrome. Wong et al23 followed 320 families in the Australian Rett Syndrome database over a 12-year period. Subjects were 2-35 years of age. Of these, 80% of the patients manifested sleep disturbance, which was more common in younger subjects, and diminished with age. Night laughter was recorded in 77% of subjects and night screaming in 49%. Those with large deletions had a higher incidence of night laughter. It is possible that these episodes of night laughing or screaming represent RBD,15,16 but this is still a conjecture as the episodes have not been characterized using nocturnal polysomnography.
General Comments and Conclusion The attached Table and the Figure show some of the common comorbidities that accompany neurodegenerative and neurodevelopmental disorders. These may be primary, or related to accompanying systemic disorders. There is often a need for a multidisciplinary team approach for the management of systemic comorbidities. Feelings of guilt or denial on behalf of the parents can become a barrier in rendering optimal care for sleep disorders. Actigraphy, sleep logs and
Table Category of Sleep Disturbance in Neurodegenerative or Neurodevelopmental Disorders Symptom
Underlying Sleep Disorder
Comments
Sleep initiation difficulty
a. b. c. d.
a. b. c. d.
Sleep maintenance difficulty
a. Obstructive sleep apnea
Nocturnal spells
Restless legs syndrome Behavioral insomnia of childhood Separation anxiety Circadian rhythm disturbance
b. Restless legs syndrome c. Sleep-related epilepsy a. Nocturnal seizures b. NREM parasomnias c. REM parasomnias d. Gastroesophageal reflux
Associated with low serum ferritin level (o30 mg/L)12 Limit-setting disorder or sleep-onset association disorder12 Highly prevalent in autism Smith-Magenis syndrome, blindness from ocular pathology
a. Adenotonsillar hypertrophy, craniofacial anomalies, and acid reflux are common etiologies b. Correct iron deficiency; gabapentin for symptomatic relief c. Sleep may be disrupted by seizures, antiepileptic drugs or vagus-nerve stimulator, and anxiety a. Nocturnal frontal lobe epilepsy, electrical status epilepticus in sleep, and focal seizures of temporal lobe onset predominate b. Sleep walking and confusional arousals predominate c. Nightmares and REM sleep behavior disorder predominate d. Night awakenings with tonic posturing or cough
Hypersomnolence Medication effect, Smith-Magenis Monitor antiepileptic drug levels, when indicated syndrome, and secondary narcolepsy Cataplexy
Niemann-Pick disease type C, Coffin- Video recordings of spells made by parents may help in diagnosis Lowry syndrome, and Norrie disease
NREM, non–rapid eye moment; REM, rapid eye moment.
Sleep in neurological disorders
129
6. Anxiety
7. Depression
Pain
8.
9. Sleep disturbance in neurodevelopmental or degenerave Disorder
10. Learnt maladapve associaons (behavioral insomnia)
Gastroesophageal reflux
11. 12. 13.
Medicaon side effects
14.
Figure Health-related conditions impacting sleep-wake function in children with neurodevelopmental / neurodegenerative disorders.
15.
16.
video electroencephalography polysomnography, and pediatric sleep specialist consultation may facilitate specific diagnoses, enhance care, and improve overall quality of life.
17.
18.
References 1. De Miguel-Diez J, Villa-Assensi J, Alvarez-Sala JL: Prevalence of sleep disordered in children with Down syndrome: Polygraphic findings in 108 children. Sleep 26:1006-1009, 2003 2. American Academy of Pediatrics. Committee on Genetics: Health supervision for children with Down syndrome. Pediatrics 107: 442-449, 2001 3. Erdie-Lalena C, Holm V, Kelly P, et al: Ghrelin levels in young children with Prader-Willi syndrome. J Pediatr 149:199-204, 2006 4. Dauvilliers Y, Politini L, Nobili I, et al: CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, and other hypersomnias and neurological conditions. J Neurol Neurosurg Psychiatry 74:1667-1673, 2003 5. Festen DAM, de Weerd W, van den Bossche RAS, et al: Sleep-related breathing disorders in prepubertal children with Prader-Willi
19.
20. 21.
22.
23.
syndrome and effects of growth hormone treatment. J Clin Endocrinol Metab 91:4911-4915, 2006 Romeo DM, Brogna C, Musto E, et al: Sleep disturbances in preschool age children with cerebral palsy: A questionnaire study. Sleep Med 15:1089-1093, 2014 Kotagal S, Gibbons VP, Stith J: Sleep abnormalities in children with severe cerebral palsy. Dev Med Child Neurol 36:304-311, 1994 Kirveskari E, Partinen M, Santavouri P: Sleep and its disturbance in a variant form of late infantile neuronal ceroid lipofuscinosis (CLN5). J Child Neurol 16:707-713, 2001 Gropman AL, Duncan WC, Smith AC: Neurological and developmental features of the Smith-Magenis syndrome (del 17 p11.2). Pediatr Neurol 34:337-350, 2006 De Leersynder H, De Bois B, Claustrat B: Inversion of the circadian rhythm of melatonin in the Smith-Magenis syndrome. J Pediatr 139:111-116, 2001 Gropman AL, Elsea S, Duncan WC, et al: New developments in SmithMagenis syndrome (del 17p11.2). Curr Opin Neurol 20:125-134, 2007 Kotagal SD, Broomall E: Sleep in children with autism spectrum disorder. Pediatr Neurol 47:242-251, 2012 Giannotti F, Cortesi A, Cerquiglini A, et al: An investigation of sleep characteristics, electroencephalogram abnormalities and epilepsy in developmentally regressed and non-regressed children with autism. J Autism Dev Disord 38:1888-1897, 2008 Melke J, Goubran BH, Chaste P, et al: Abnormal melatonin synthesis in autism spectrum disorder. Mol Psychiatry 13:90, 2008 Lloyd R, Tippman-Piekert M, Slocumb N, et al: Characteristics of REM sleep behavior disorder in childhood. J Clin Sleep Med 8:127-131, 2012 Kotagal S: Rapid eye movement sleep behavior disorder during childhood. Sleep Med Clin 2015. [Epub ahead of print] Patterson MC, Hendriksz CJ, Walterfang M, et al: Recommendations for the diagnosis and management of Niemann-Pick disease type C: An update. Mol Genet Metab 106:330-344, 2012 Halime TC, Haliloglu G, Duzgun G, et al: Successful treatment of cataplexy in patients with early-infantile Niemann-Pick disease type C: Use of tricyclic antidepressants. Eur J Pediatr Neurol 18:811-815, 2014 Zarowski M, Steinborn B, Grda B, et al: Treatment of cataplexy in Niemann-Pick disease type C with use of miglustat. Eur J Pediatr Neurol 15:84-87, 2011 Lyst MJ, Bird A: Rett syndrome: A complex disorder with simple roots. Nat Rev Genet 2015:261-275, 2015 Weese-Mayer DE, Lieske SP, Boothby CM, et al: Autonomic dysregulation in young girls with Rett syndrome during night-time in-home recordings. Pediatr Pulmonol 43:1045-1060, 2008 Ramirez-JM, Scott Ward C, Neul JL: Breathing challenges in Rett syndrome: Lessons learned from humans and animal models. Respir Physiol Neurobiol 189:280-287, 2013 Wong K, Leonard H, Jacoby P, et al: The trajectory of sleep disturbance in Rett syndrome. J Sleep Res 24:223-233, 2015
