Pediatric Neurology 50 (2014) 474e478
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Sleep Abnormalities in Children With Dravet Syndrome Radhika Dhamija MBBS a, Maia K. Erickson c, Erik K. St Louis MD b, c, Elaine Wirrell MD b, Suresh Kotagal MD b, c, * a
Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota Department of Neurology, Mayo Clinic, Rochester, Minnesota c Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota b
abstract BACKGROUND: Mutations in the voltage-gated sodium channel SCN1A gene are responsible for the majority of Dravet syndrome cases. There is evidence that the Nav1.1 channel coded by the SCN1A gene is involved in sleep regulation. We evaluated sleep abnormalities in children with Dravet syndrome using nocturnal polysomnography. METHODS: We identified six children at our institution with genetically confirmed Dravet syndrome who had also undergone formal sleep consultation with nocturnal polysomnography. Indications for polysomnography were parental concern of daytime fatigue or sleepiness, hyperactivity, inattention, disruptive behavior, nighttime awakenings, or nocturnal seizures. Sleep studies were scored according to guidelines of the American Academy of Sleep Medicine and nonerapid eye movement cyclic alternating pattern was visually identified and scored according to established methods. RESULTS: The mean age of the subjects at the time of polysomnography was 6 years. Standard polysomnography did not show any consistent abnormalities in the obstructive or central apnea index, arousal index, sleep efficiency, or architecture. Cyclic alternating pattern analysis on five patients showed an increased mean rate of 50.3% (vs 31% to 34% in neurological normal children) with a mild increase in A1 subtype of 89.4% (vs 84.5%). A2/A3 subtype (5.3% vs 7.3%) and B phase duration (22.4 vs 24.7 seconds) were similar to previously reported findings in neurologically normal children. CONCLUSION: Despite parental concerns for sleep disturbance in patients with Dravet syndrome, we could not identify abnormalities in sleep macroarchitecture. Nonerapid eye movement sleep microarchitecture was, however, abnormal, with increased A1 subtype, somewhat resembling a tracé alternant pattern of neonates and possibly suggestive of cortical synaptic immaturity in Dravet syndrome. Larger studies are needed to replicate these results. Keywords: Dravet syndrome, sleep abnormalities, polysomnography, cyclic alternating patterns
Pediatr Neurol 2014; 50: 474-478 Ó 2014 Elsevier Inc. All rights reserved.
Background
Dravet syndrome is an epileptic encephalopathy that presents with prolonged seizures, often triggered by hyperthermia within the first 18 months of life. Mutations in the voltage-gated sodium channel SCN1A gene are responsible for most cases of Dravet syndrome.1,2
Article History: Received December 12, 2013; Accepted in final form January 1, 2014 * Communications should be addressed to: Dr. Suresh Kotagal; Department of Neurology and Center for Sleep Medicine; Mayo Clinic; 200 First Street SW; Rochester, MN 55905. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.017
There is an intimate relationship between epilepsy and sleep.3 Sleep deprivation leads to lowering of seizure threshold and patients with epilepsy have a high prevalence of sleep disorders.4-8 Sleep abnormalities may be overlooked however in children with epilepsy. Sleep disturbance in children may lead to neurocognitive impairment, often in the form of attention deficit/hyperactivity, poor school performance, and poor memory.9-11 Although there is recognition that sleep architecture is in general altered in patients with epilepsy,4,5,12,13 abnormalities of sleep in Dravet syndrome have not been systematically studied. There are limited data on other epileptic syndromes as well. In a recent prospective study of 40 patients with juvenile myoclonic epilepsy, a statistically significant poor sleep quality based on Epworth Sleepiness
R. Dhamija et al. / Pediatric Neurology 50 (2014) 474e478
Scale was found in patients compared with controls (P ¼ 0.02).14,15 Another study demonstrated longer N1 stage percentage and initial rapid eye movement (REM) latency in children with primary generalized epilepsy when compared with controls, and epilepsy patients had worse attention and emotional-behavioral symptoms.16 Children with rolandic epilepsy have also been reported to manifest significantly more daytime sleepiness, shorter sleep duration, and more frequent parasomnias than controls.17 In another study that aimed to investigate parental concerns of children with Dravet syndrome, most children had trouble falling and staying asleep, and this added to parental stress.18 Obstructive sleep apnea is thought to be common in children with epilepsy and sleep problems, but this has not been investigated in Dravet syndrome.19 In a mouse model, the Nav1.1channel coded by SCN1A is coexpressed in brain regions that are important for sleep regulation (thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei) and seizure generation. SCN1A mutant mice show increased wakefulness and decreased nonerapid eye movement (NREM) and REM sleep, potentially because of altered interactions of Nav1.1channel with serotonergic, cholinergic, and orexinergic neurons of sleep-wake pathway.20,21 The aim of this study was to evaluate polysomnogram findings (macro- and microstructure of sleep) in children with Dravet syndrome. Methods We conducted a retrospective chart review of consecutive patients younger than age 18 years with a diagnosis of Dravet syndrome who had undergone polysomnogram seen between 2005 and 2013. The study was approved by the Mayo Clinic Institutional Review Board. Inclusion criteria
We included children G c.4112 G > T c.1076 A > G c.2796 G > A c.677 C > T c.677 C > T
p.Leu844* p.1371Gly > Val p.359 Asp > Ser p.Tryp932* p.Thr226Met p.Thr226Met
*
Truncated protein.
syndrome have high mortality approaching 25% and are also at high risk of sudden death.31,32 Several theories have been proposed for sudden death in this syndrome, including increased cardiac electric activity33 and altered central respiratory control mechanism.34 We can theorize that impaired thalamocortical inputs that are important for arousal mechanisms play a role in the inability to arouse in the face of asphyxia (an important defense mechanism). Impaired arousals from sleep have been implicated in sudden infant death syndrome.35 Further studies are needed to see if our findings of decreased cortical arousals are replicated in a larger cohort of patients. Sleep-wake regulation and its relationship to Dravet syndrome
Sleep-wake mechanisms in humans are modulated by thalamocortical transmission with inputs from cholinergic nuclei in the pons, including the pedunculopontine and laterodorsal tegmental nuclei.36 Additional input is also TABLE 2. Demographic Details of the Six Patients
Number Age at Age at Genetic Age at Current Onset of Confirmation Polysomnography Seizure Seizures of Dravet Frequency Syndrome 1
4 mo
13 mo
3 yr
2 3 4 5 6
4 2 3 2 2
4 9 6 6 1
4 yr, 2 mo 15 yr 5 yr 6 yr 1 yr
mo yr mo mo mo
yr, 10 mo mo mo mo mo
Seizures only in setting of fever Monthly Monthly Daily Daily Monthly
R. Dhamija et al. / Pediatric Neurology 50 (2014) 474e478
477
TABLE 3. Details of the Polysomnographic Variables
Serial Number
AHI
Lowest Oxygen Saturation %
AI
N1%
N2%
N3%
REM%
PLMI
Overall CAP Rate
A1%
A2/A3%
B Dur.
1 2 3 4 5 6
13 1 0 1 10 11
90 95 94 91 86 79
3.6 5.9 3.7 7.8 2.3 5.9
0.1 3 8.1 1.5 1.1 1.6
58 71.6 63.3 56.2 28.2 15.3
18.6 9.2 19.9 30.2 70.7 59.8
23.3 16.2 8.7 12.1 0 23.2
0 0 7.1 1.5 0 45.8
51.8% NA 34.1% 58.4% 50.7% 56.6%
94.7 NA 56.7 96.6 99.9 99.5
5.3 NA 43.4 3.4 0.1 0.5
21.8 NA 28.2 18.0 21.0 23.3
Abbreviations: AHI ¼ Apnea-hypopnea index A1 and A2/A3% ¼ CAP subtype A1 and combined A2/A3 as percent of NREM sleep time AI ¼ Arousal index B Dur ¼ CAP phase B duration (seconds) CAP ¼ Cyclic alternating pattern CAP% ¼ Overall cyclic alternating pattern rate as percent of NREM sleep time N1, N2, N3, and REM% ¼ Sleep percent of total sleep time NA ¼ Not available (subject’s polysomnogram data could not be converted to necessary format for analysis) NREM ¼ Nonerapid eye movement PLMI ¼ Periodic limb movement index REM ¼ Rapid eye movement No REM reading because this patient had multiple seizures on the day of polysomnography.
obtained from monoaminergic nuclei including dorsal and median raphe nuclei containing serotonin and the locus coeruleus containing noradrenaline.36,37 In mouse models, SCN1A expression is seen in thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei.38 Though the exact mechanism is unknown, sleep disruption is potentially the result of altered interactions of Nav1.1channel with serotonergic, cholinergic, and orexinergic neurons of sleep-wake pathway.20,21 Our study is the first report of polysomnographic variables in children with Dravet syndrome with analysis of both sleep macro- and microarchitecture, including CAP. However, our study has several limitations, including a small number of patients, analysis limited to Dravet patients referred specifically for sleep complaints that may have led to selection bias, and lack of a control group for CAP analyses. However, we plan to conduct a future in-depth study concentrating on CAP analysis in Dravet patients with age- and gender-matched control subjects. Strengths of our study include that the patients carried an unequivocal diagnosis of Dravet syndrome, and sleep evaluations and polysomnography interpretations were conducted by board-certified sleep specialists, with CAP sleep microarchitecture analysis. We conclude that evaluation of sleep in Dravet syndrome by traditional sleep macrostructure may be incomplete and that NREM microstructural analysis using CAP may provide a more nuanced evaluation of arousal propensity and sleep organization. References 1. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001; 68:1327-1332. 2. Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J Med Genet. 2009;46:183-191. 3. St Louis EK. Sleep and epilepsy: strange bedfellows no more. Minerva Pneumol. 2011;50:159-176. 4. Bazil CW. Sleep and epilepsy. Curr Opin Neurol. 2000;13:171-175.
5. Beran RG, Plunkett MJ, Holland GJ. Interface of epilepsy and sleep disorders. Seizure. 1999;8:97-102. 6. Derry CP, Duncan S. Sleep and epilepsy. Epilepsy Behav. 2013;26: 394-404. 7. Klobucnikova K, Kollar B, Martiniskova Z. Daytime sleepiness and changes of sleep architecture in patients with epilepsy. Neuro Endocrinol Lett. 2009;30:599-603. 8. Malow BA, Fromes GA, Aldrich MS. Usefulness of polysomnography in epilepsy patients. Neurology. 1997;48:1389-1394. 9. Chervin RD, Dillon JE, Bassetti C, Ganoczy DA, Pituch KJ. Symptoms of sleep disorders, inattention, and hyperactivity in children. Sleep. 1997;20:1185-1192. 10. Perez-Chada D, Perez-Lloret S, Videla AJ, et al. Sleep disordered breathing and daytime sleepiness are associated with poor academic performance in teenagers. A study using the Pediatric Daytime Sleepiness Scale (PDSS). Sleep. 2007;30:1698-1703. 11. Stein MA, Mendelsohn J, Obermeyer WH, Amromin J, Benca R. Sleep and behavior problems in school-aged children. Pediatrics. 2001; 107:E60. 12. Bazil CW, Castro LH, Walczak TS. Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy. Arch Neurol. 2000;57:363-368. 13. Hoeppner JB, Garron DC, Cartwright RD. Self-reported sleep disorder symptoms in epilepsy. Epilepsia. 1984;25:434-437. 14. Ramachandraiah CT, Sinha S, Taly AB, Rao S, Satishchandra P. Interrelationship of sleep and juvenile myoclonic epilepsy (JME): a sleep questionnaire-, EEG-, and polysomnography (PSG)based prospective case-control study. Epilepsy Behav. 2012;25: 391-396. 15. Krishnan P, Sinha S, Taly AB, Ramachandraiah CT, Rao S, Satishchandra P. Sleep disturbances in juvenile myoclonic epilepsy: a sleep questionnaire-based study. Epilepsy Behav. 2012;23: 305-509. 16. Maganti R, Sheth RD, Hermann BP, Weber S, Gidal BE, Fine J. Sleep architecture in children with idiopathic generalized epilepsy. Epilepsia. 2005;46:104-109. 17. Tang SS, Clarke T, Owens J, Pal DK. Sleep behavior disturbances in rolandic epilepsy. J Child Neurol. 2011;26:239-343. 18. Nolan KJ, Camfield CS, Camfield PR. Coping with Dravet syndrome: parental experiences with a catastrophic epilepsy. Dev Med Child Neurol. 2006;48:761-765. 19. Jain SV, Horn PS, Simakajornboon N, Glauser TA. Obstructive sleep apnea and primary snoring in children with epilepsy. J Child Neurol. 2013;28:77-82. 20. Ogiwara I, Miyamoto H, Morita N, et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J Neurosci. 2007;27:5903-5914.
478
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21. Papale LA, Makinson CD, Christopher Ehlen J, et al. Altered sleep regulation in a mouse model of SCN1A-derived genetic epilepsy with febrile seizures plus (GEFSþ). Epilepsia. 2013;54:625-634. 22. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012;8:597-619. 23. Iber C. The AASM Manual for the Scoring of Sleep and Associated Events. Deerfield, IL: American Academy of Sleep Medicine;2007. 24. Parrino L, Halasz P, Tassinari CA, Terzano MG. CAP, epilepsy and motor events during sleep: the unifying role of arousal. Sleep Med Rev. 2006;10:267-285. 25. Terzano MG, Parrino L, Sherieri A, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med. 2001;2:537-553. 26. Terzano MG, Parrino L, Rosa A, Palomba V, Smerieri A. CAP and arousals in the structural development of sleep: an integrative perspective. Sleep Med. 2002;3:221-229. 27. Parrino L, Boselli M, Spaggiari MC, Smerieri A, Terzano MG. Cyclic alternating pattern (CAP) in normal sleep: polysomnographic parameters in different age groups. Electroencephalogr Clin Neurophysiol. 1998;107:439-450. 28. Fujiwara T. Clinical spectrum of mutations in SCN1A gene: severe myoclonic epilepsy in infancy and related epilepsies. Epilepsy Res. 2006;70(Suppl 1):S223-S230.
29. Bruni O, Ferri R, Miano S, et al. Sleep cyclic alternating pattern in normal school-age children. Clin Neurophysiol. 2002;113:1806-1814. 30. Curzi-Dascalova L, Mirmiran M. Manual of methods for recording and analyzing sleep-wakefulness states in preterm and full-term infant. Paris: Editions Inserm;1996. 31. Le Gal F, Korff CM, Monso-Hinard C, et al. A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation. Epilepsia. 2010;51:1915-1918. 32. Genton P, Velizarova R, Dravet C. Dravet syndrome: the long-term outcome. Epilepsia. 2011;52(Suppl 2):44-49. 33. Auerbach DS, Jones J, Clawson BC, et al. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLoS One. 2013;8:e77843. 34. Kalume F. Sudden unexpected death in Dravet syndrome: respiratory and other physiological dysfunctions. Respir Physiol Neurobiol. 2013;189:324-328. 35. Kahn A, Groswasser J, Franco P, et al. Sudden infant deaths: arousal as a survival mechanism. Sleep Med. 2002;3(Suppl 2): S11-S14. 36. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001;24:726-731. 37. Stenberg D. Neuroanatomy and neurochemistry of sleep. Cell Mol Life Sci. 2007;64:1187-1204. 38. Papale LA, Makinson CD, Ehlen C, et al. Altered sleep regulation in a mouse model of SCN1A-derived genetic epilepsy with febrile seizures plus (GEFS+). Epilepsia. 2013;54:625-634.
Contents lists available at ScienceDirect
Pediatric Neurology journal homepage: www.elsevier.com/locate/pnu
Original Article
Sleep Abnormalities in Children With Dravet Syndrome Radhika Dhamija MBBS a, Maia K. Erickson c, Erik K. St Louis MD b, c, Elaine Wirrell MD b, Suresh Kotagal MD b, c, * a
Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota Department of Neurology, Mayo Clinic, Rochester, Minnesota c Center for Sleep Medicine, Mayo Clinic, Rochester, Minnesota b
abstract BACKGROUND: Mutations in the voltage-gated sodium channel SCN1A gene are responsible for the majority of Dravet syndrome cases. There is evidence that the Nav1.1 channel coded by the SCN1A gene is involved in sleep regulation. We evaluated sleep abnormalities in children with Dravet syndrome using nocturnal polysomnography. METHODS: We identified six children at our institution with genetically confirmed Dravet syndrome who had also undergone formal sleep consultation with nocturnal polysomnography. Indications for polysomnography were parental concern of daytime fatigue or sleepiness, hyperactivity, inattention, disruptive behavior, nighttime awakenings, or nocturnal seizures. Sleep studies were scored according to guidelines of the American Academy of Sleep Medicine and nonerapid eye movement cyclic alternating pattern was visually identified and scored according to established methods. RESULTS: The mean age of the subjects at the time of polysomnography was 6 years. Standard polysomnography did not show any consistent abnormalities in the obstructive or central apnea index, arousal index, sleep efficiency, or architecture. Cyclic alternating pattern analysis on five patients showed an increased mean rate of 50.3% (vs 31% to 34% in neurological normal children) with a mild increase in A1 subtype of 89.4% (vs 84.5%). A2/A3 subtype (5.3% vs 7.3%) and B phase duration (22.4 vs 24.7 seconds) were similar to previously reported findings in neurologically normal children. CONCLUSION: Despite parental concerns for sleep disturbance in patients with Dravet syndrome, we could not identify abnormalities in sleep macroarchitecture. Nonerapid eye movement sleep microarchitecture was, however, abnormal, with increased A1 subtype, somewhat resembling a tracé alternant pattern of neonates and possibly suggestive of cortical synaptic immaturity in Dravet syndrome. Larger studies are needed to replicate these results. Keywords: Dravet syndrome, sleep abnormalities, polysomnography, cyclic alternating patterns
Pediatr Neurol 2014; 50: 474-478 Ó 2014 Elsevier Inc. All rights reserved.
Background
Dravet syndrome is an epileptic encephalopathy that presents with prolonged seizures, often triggered by hyperthermia within the first 18 months of life. Mutations in the voltage-gated sodium channel SCN1A gene are responsible for most cases of Dravet syndrome.1,2
Article History: Received December 12, 2013; Accepted in final form January 1, 2014 * Communications should be addressed to: Dr. Suresh Kotagal; Department of Neurology and Center for Sleep Medicine; Mayo Clinic; 200 First Street SW; Rochester, MN 55905. E-mail address: [email protected] 0887-8994/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pediatrneurol.2014.01.017
There is an intimate relationship between epilepsy and sleep.3 Sleep deprivation leads to lowering of seizure threshold and patients with epilepsy have a high prevalence of sleep disorders.4-8 Sleep abnormalities may be overlooked however in children with epilepsy. Sleep disturbance in children may lead to neurocognitive impairment, often in the form of attention deficit/hyperactivity, poor school performance, and poor memory.9-11 Although there is recognition that sleep architecture is in general altered in patients with epilepsy,4,5,12,13 abnormalities of sleep in Dravet syndrome have not been systematically studied. There are limited data on other epileptic syndromes as well. In a recent prospective study of 40 patients with juvenile myoclonic epilepsy, a statistically significant poor sleep quality based on Epworth Sleepiness
R. Dhamija et al. / Pediatric Neurology 50 (2014) 474e478
Scale was found in patients compared with controls (P ¼ 0.02).14,15 Another study demonstrated longer N1 stage percentage and initial rapid eye movement (REM) latency in children with primary generalized epilepsy when compared with controls, and epilepsy patients had worse attention and emotional-behavioral symptoms.16 Children with rolandic epilepsy have also been reported to manifest significantly more daytime sleepiness, shorter sleep duration, and more frequent parasomnias than controls.17 In another study that aimed to investigate parental concerns of children with Dravet syndrome, most children had trouble falling and staying asleep, and this added to parental stress.18 Obstructive sleep apnea is thought to be common in children with epilepsy and sleep problems, but this has not been investigated in Dravet syndrome.19 In a mouse model, the Nav1.1channel coded by SCN1A is coexpressed in brain regions that are important for sleep regulation (thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei) and seizure generation. SCN1A mutant mice show increased wakefulness and decreased nonerapid eye movement (NREM) and REM sleep, potentially because of altered interactions of Nav1.1channel with serotonergic, cholinergic, and orexinergic neurons of sleep-wake pathway.20,21 The aim of this study was to evaluate polysomnogram findings (macro- and microstructure of sleep) in children with Dravet syndrome. Methods We conducted a retrospective chart review of consecutive patients younger than age 18 years with a diagnosis of Dravet syndrome who had undergone polysomnogram seen between 2005 and 2013. The study was approved by the Mayo Clinic Institutional Review Board. Inclusion criteria
We included children G c.4112 G > T c.1076 A > G c.2796 G > A c.677 C > T c.677 C > T
p.Leu844* p.1371Gly > Val p.359 Asp > Ser p.Tryp932* p.Thr226Met p.Thr226Met
*
Truncated protein.
syndrome have high mortality approaching 25% and are also at high risk of sudden death.31,32 Several theories have been proposed for sudden death in this syndrome, including increased cardiac electric activity33 and altered central respiratory control mechanism.34 We can theorize that impaired thalamocortical inputs that are important for arousal mechanisms play a role in the inability to arouse in the face of asphyxia (an important defense mechanism). Impaired arousals from sleep have been implicated in sudden infant death syndrome.35 Further studies are needed to see if our findings of decreased cortical arousals are replicated in a larger cohort of patients. Sleep-wake regulation and its relationship to Dravet syndrome
Sleep-wake mechanisms in humans are modulated by thalamocortical transmission with inputs from cholinergic nuclei in the pons, including the pedunculopontine and laterodorsal tegmental nuclei.36 Additional input is also TABLE 2. Demographic Details of the Six Patients
Number Age at Age at Genetic Age at Current Onset of Confirmation Polysomnography Seizure Seizures of Dravet Frequency Syndrome 1
4 mo
13 mo
3 yr
2 3 4 5 6
4 2 3 2 2
4 9 6 6 1
4 yr, 2 mo 15 yr 5 yr 6 yr 1 yr
mo yr mo mo mo
yr, 10 mo mo mo mo mo
Seizures only in setting of fever Monthly Monthly Daily Daily Monthly
R. Dhamija et al. / Pediatric Neurology 50 (2014) 474e478
477
TABLE 3. Details of the Polysomnographic Variables
Serial Number
AHI
Lowest Oxygen Saturation %
AI
N1%
N2%
N3%
REM%
PLMI
Overall CAP Rate
A1%
A2/A3%
B Dur.
1 2 3 4 5 6
13 1 0 1 10 11
90 95 94 91 86 79
3.6 5.9 3.7 7.8 2.3 5.9
0.1 3 8.1 1.5 1.1 1.6
58 71.6 63.3 56.2 28.2 15.3
18.6 9.2 19.9 30.2 70.7 59.8
23.3 16.2 8.7 12.1 0 23.2
0 0 7.1 1.5 0 45.8
51.8% NA 34.1% 58.4% 50.7% 56.6%
94.7 NA 56.7 96.6 99.9 99.5
5.3 NA 43.4 3.4 0.1 0.5
21.8 NA 28.2 18.0 21.0 23.3
Abbreviations: AHI ¼ Apnea-hypopnea index A1 and A2/A3% ¼ CAP subtype A1 and combined A2/A3 as percent of NREM sleep time AI ¼ Arousal index B Dur ¼ CAP phase B duration (seconds) CAP ¼ Cyclic alternating pattern CAP% ¼ Overall cyclic alternating pattern rate as percent of NREM sleep time N1, N2, N3, and REM% ¼ Sleep percent of total sleep time NA ¼ Not available (subject’s polysomnogram data could not be converted to necessary format for analysis) NREM ¼ Nonerapid eye movement PLMI ¼ Periodic limb movement index REM ¼ Rapid eye movement No REM reading because this patient had multiple seizures on the day of polysomnography.
obtained from monoaminergic nuclei including dorsal and median raphe nuclei containing serotonin and the locus coeruleus containing noradrenaline.36,37 In mouse models, SCN1A expression is seen in thalamic reticular nuclei, dorsal raphe nuclei, pedunculopontine, and laterodorsal tegmental nuclei.38 Though the exact mechanism is unknown, sleep disruption is potentially the result of altered interactions of Nav1.1channel with serotonergic, cholinergic, and orexinergic neurons of sleep-wake pathway.20,21 Our study is the first report of polysomnographic variables in children with Dravet syndrome with analysis of both sleep macro- and microarchitecture, including CAP. However, our study has several limitations, including a small number of patients, analysis limited to Dravet patients referred specifically for sleep complaints that may have led to selection bias, and lack of a control group for CAP analyses. However, we plan to conduct a future in-depth study concentrating on CAP analysis in Dravet patients with age- and gender-matched control subjects. Strengths of our study include that the patients carried an unequivocal diagnosis of Dravet syndrome, and sleep evaluations and polysomnography interpretations were conducted by board-certified sleep specialists, with CAP sleep microarchitecture analysis. We conclude that evaluation of sleep in Dravet syndrome by traditional sleep macrostructure may be incomplete and that NREM microstructural analysis using CAP may provide a more nuanced evaluation of arousal propensity and sleep organization. References 1. Claes L, Del-Favero J, Ceulemans B, Lagae L, Van Broeckhoven C, De Jonghe P. De novo mutations in the sodium-channel gene SCN1A cause severe myoclonic epilepsy of infancy. Am J Hum Genet. 2001; 68:1327-1332. 2. Depienne C, Trouillard O, Saint-Martin C, et al. Spectrum of SCN1A gene mutations associated with Dravet syndrome: analysis of 333 patients. J Med Genet. 2009;46:183-191. 3. St Louis EK. Sleep and epilepsy: strange bedfellows no more. Minerva Pneumol. 2011;50:159-176. 4. Bazil CW. Sleep and epilepsy. Curr Opin Neurol. 2000;13:171-175.
5. Beran RG, Plunkett MJ, Holland GJ. Interface of epilepsy and sleep disorders. Seizure. 1999;8:97-102. 6. Derry CP, Duncan S. Sleep and epilepsy. Epilepsy Behav. 2013;26: 394-404. 7. Klobucnikova K, Kollar B, Martiniskova Z. Daytime sleepiness and changes of sleep architecture in patients with epilepsy. Neuro Endocrinol Lett. 2009;30:599-603. 8. Malow BA, Fromes GA, Aldrich MS. Usefulness of polysomnography in epilepsy patients. Neurology. 1997;48:1389-1394. 9. Chervin RD, Dillon JE, Bassetti C, Ganoczy DA, Pituch KJ. Symptoms of sleep disorders, inattention, and hyperactivity in children. Sleep. 1997;20:1185-1192. 10. Perez-Chada D, Perez-Lloret S, Videla AJ, et al. Sleep disordered breathing and daytime sleepiness are associated with poor academic performance in teenagers. A study using the Pediatric Daytime Sleepiness Scale (PDSS). Sleep. 2007;30:1698-1703. 11. Stein MA, Mendelsohn J, Obermeyer WH, Amromin J, Benca R. Sleep and behavior problems in school-aged children. Pediatrics. 2001; 107:E60. 12. Bazil CW, Castro LH, Walczak TS. Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy. Arch Neurol. 2000;57:363-368. 13. Hoeppner JB, Garron DC, Cartwright RD. Self-reported sleep disorder symptoms in epilepsy. Epilepsia. 1984;25:434-437. 14. Ramachandraiah CT, Sinha S, Taly AB, Rao S, Satishchandra P. Interrelationship of sleep and juvenile myoclonic epilepsy (JME): a sleep questionnaire-, EEG-, and polysomnography (PSG)based prospective case-control study. Epilepsy Behav. 2012;25: 391-396. 15. Krishnan P, Sinha S, Taly AB, Ramachandraiah CT, Rao S, Satishchandra P. Sleep disturbances in juvenile myoclonic epilepsy: a sleep questionnaire-based study. Epilepsy Behav. 2012;23: 305-509. 16. Maganti R, Sheth RD, Hermann BP, Weber S, Gidal BE, Fine J. Sleep architecture in children with idiopathic generalized epilepsy. Epilepsia. 2005;46:104-109. 17. Tang SS, Clarke T, Owens J, Pal DK. Sleep behavior disturbances in rolandic epilepsy. J Child Neurol. 2011;26:239-343. 18. Nolan KJ, Camfield CS, Camfield PR. Coping with Dravet syndrome: parental experiences with a catastrophic epilepsy. Dev Med Child Neurol. 2006;48:761-765. 19. Jain SV, Horn PS, Simakajornboon N, Glauser TA. Obstructive sleep apnea and primary snoring in children with epilepsy. J Child Neurol. 2013;28:77-82. 20. Ogiwara I, Miyamoto H, Morita N, et al. Nav1.1 localizes to axons of parvalbumin-positive inhibitory interneurons: a circuit basis for epileptic seizures in mice carrying an Scn1a gene mutation. J Neurosci. 2007;27:5903-5914.
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21. Papale LA, Makinson CD, Christopher Ehlen J, et al. Altered sleep regulation in a mouse model of SCN1A-derived genetic epilepsy with febrile seizures plus (GEFSþ). Epilepsia. 2013;54:625-634. 22. Berry RB, Budhiraja R, Gottlieb DJ, et al. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med. 2012;8:597-619. 23. Iber C. The AASM Manual for the Scoring of Sleep and Associated Events. Deerfield, IL: American Academy of Sleep Medicine;2007. 24. Parrino L, Halasz P, Tassinari CA, Terzano MG. CAP, epilepsy and motor events during sleep: the unifying role of arousal. Sleep Med Rev. 2006;10:267-285. 25. Terzano MG, Parrino L, Sherieri A, et al. Atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med. 2001;2:537-553. 26. Terzano MG, Parrino L, Rosa A, Palomba V, Smerieri A. CAP and arousals in the structural development of sleep: an integrative perspective. Sleep Med. 2002;3:221-229. 27. Parrino L, Boselli M, Spaggiari MC, Smerieri A, Terzano MG. Cyclic alternating pattern (CAP) in normal sleep: polysomnographic parameters in different age groups. Electroencephalogr Clin Neurophysiol. 1998;107:439-450. 28. Fujiwara T. Clinical spectrum of mutations in SCN1A gene: severe myoclonic epilepsy in infancy and related epilepsies. Epilepsy Res. 2006;70(Suppl 1):S223-S230.
29. Bruni O, Ferri R, Miano S, et al. Sleep cyclic alternating pattern in normal school-age children. Clin Neurophysiol. 2002;113:1806-1814. 30. Curzi-Dascalova L, Mirmiran M. Manual of methods for recording and analyzing sleep-wakefulness states in preterm and full-term infant. Paris: Editions Inserm;1996. 31. Le Gal F, Korff CM, Monso-Hinard C, et al. A case of SUDEP in a patient with Dravet syndrome with SCN1A mutation. Epilepsia. 2010;51:1915-1918. 32. Genton P, Velizarova R, Dravet C. Dravet syndrome: the long-term outcome. Epilepsia. 2011;52(Suppl 2):44-49. 33. Auerbach DS, Jones J, Clawson BC, et al. Altered cardiac electrophysiology and SUDEP in a model of Dravet syndrome. PLoS One. 2013;8:e77843. 34. Kalume F. Sudden unexpected death in Dravet syndrome: respiratory and other physiological dysfunctions. Respir Physiol Neurobiol. 2013;189:324-328. 35. Kahn A, Groswasser J, Franco P, et al. Sudden infant deaths: arousal as a survival mechanism. Sleep Med. 2002;3(Suppl 2): S11-S14. 36. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci. 2001;24:726-731. 37. Stenberg D. Neuroanatomy and neurochemistry of sleep. Cell Mol Life Sci. 2007;64:1187-1204. 38. Papale LA, Makinson CD, Ehlen C, et al. Altered sleep regulation in a mouse model of SCN1A-derived genetic epilepsy with febrile seizures plus (GEFS+). Epilepsia. 2013;54:625-634.
