sleep and childhood epilepsy

Indian Journal of Pediatrics, Volume 72August, 2005 687

Special Article

Correspondence and Reprint requests : Prof. S. Aneja, Readers FlatNo 4, LHMC campus, New Delhi-110001.

Sleep is a physiological state during which vigilantconsciousness is temporarily abolished and responses toenvironmental stimuli are decreased. It is cyclic andassociated with various changes in behavior, endocrinal,and other physiological functions. Epilepsy is a state ofrecurrent unprovoked seizures. During a seizure apopulation of cortical neurons from a part of brain or fromboth hemispheres fire an abnormal synchronizedelectrical discharge. The existence of relationship betweensleep and epilepsy has been observed for a long time butwas first validated by Gibbs and Gibbs when they foundthat paroxysmal discharges occurred more frequently insleep.1

Effect of Sleep on Seizures and Childhood EpilepticSyndromes

The sleep/wakefulness cycle (SWC) is regulated byseveral mechanisms and some of them also affect theexpression of epilepsy. In non REM sleep thalamic nucleiprovide diffuse synchronized afferent inputs to cortexand are responsible for rhythmic sleep spindles. Thisdiffuse cortical synchronization can lead to activation ofictal focus in susceptible person. Thus non-REM sleepappears to have a proconvulsant effect . On the otherhand in REM sleep there is inhibition of thalamocorticalsynchronization mechanism and there is also reductionof interhemispheric transmission which preventsgeneralization of epileptiform discharge.2

Both clinical seizures and interictal epileptiformabnormalities are facilitated by non-REM sleep. It hasbeen seen that lighter stages of non-REM sleep (stage 1 &2) promote seizures in susceptible patients. The interictalepileptiform discharges are activated by deeper non-REMsleep (stage 3 & 4).3 Loss of sleep or disruption of sleep is

Sleep and Childhood EpilepsyS. Aneja and M. Gupta1

Departments of Pediatrics and 1Pharmacology, Lady Hardinge Medical College, New Delhi

recognized as a trigger of epileptic seizures.Sleep is widely recognized as an activator of interictal

epileptiform discharges (IED) during EEG recording. In asignificant proportion of patients IED may occur only insleep portion of EEG record.4 Sleep deprivation not onlyincreases the occurrence of IED by inducing sleep butalso increase the likelihood of occurrence of IED duringthe subsequent awake record. Sleep can induce orincreases interictal EEG abnormalities associated withmost types of epilepsies. Some types of seizure discharges(primary generalized epilepsy) are suppressed in REMsleep. A special timing of seizure in relation to sleep wakecycle is seen in many childhood epileptic syndromes.Epileptic syndromes which are affected by sleep wakecycle are described below.

Epileptic syndromes with specific relation to sleep wake cycle

Benign focal epilepsy with rolandic spikes (BERS)accounts for nearly 20% of epilepsy in school goingchildren. The seizures which are characteristically oro-bucco-lingual and facial occur mostly in drowsiness andsleep. Awareness is preserved but there may be arrest ofspeech. The seizures occur mostly at night though theymay occur sometimes in daytime sleep as well. Theinterictal EEG in awake state is usually normal but insleep shows centrotemporal or rolandic spikes. Thecentrotemporal spikes are invariably activated by sleepand often become bilateral during sleep. This epilepticsyndrome has good prognosis with cessation of seizure by13-20 years.

Autosomal dominant nocturnal frontal lobe epilepsy(ADNFLE) : It is a dominant form of partial epilepsy withthe onset in childhood. This disorder is characterized byclusters of brief nocturnal motor seizures, withhyperkinetic or tonic manifestations. Subjects often

Abstract. The inter-relationship between sleep and epilepsy is well recognized. Sleep is known to activate inter-ictalepileptiform discharges. A special timing of seizure in relation to sleep wake cycle is certainly a childhood epileptic syndrome.Children with epilepsy commonly have sleep problems which may be due to seizures or due to anxiety. Somnolence and diurnalsedation are frequent side effects of anti-epileptic drugs. Thus epilepsy and its treatment can affect sleep leading to adverseeffect on behavior, cognition and seizure control. Lack of sleep is an important trigger for epileptic seizures, therefore regularsleep must be a part of management strategy in children with epilepsy. [Indian J Pediatr 2005; 72 (8) 687-690]E-mail : [email protected]; [email protected]

Key words : Sleep; Anti-epileptic drug; EEG

S. Aneja and M. Gupta

688 Indian Journal of Pediatrics, Volume 72August, 2005

experience an aura, and remain aware throughout theattacks. Seizures occur in clusters typically as theindividual dozes, or shortly before awakening. Seizuresare often misdiagnosed as benign nocturnalparasomnias.5

Juvenile myoclonic epilepsy (JME) is an idiopathicepilepsy characterized by juvenile onset of myoclonicseizures with normal neurologic development. The onsetis typically in second decade. It is characterized bymyoclonic seizures, associated at times with generalizedtonic-clonic seizures or absence seizures. It is an epilepsywith strong relation to sleep wake cycle. Both themyoclonic seizures and generalized tonic-clonic seizureshave a special circadian pattern, i.e., they occur almostexclusively on or soon after awakening, either from all-night sleep or from a nap The seizures are characterizedby myoclonic jerks involving upper limbs in the morningshortly after awakening. Because the jerks in JME arebrief, without loss of consciousness, and take place in themorning soon after awakening, they are often interpretedas clumsiness until generalized convulsions occur. Theinterictal awake EEG is characterized by paroxysmalgeneralized 46 Hz polyspike and wave discharge. Thisdischarge is exacerbated by onset of sleep but suppressedduring sleep.

Continuous spike and wave during sleep (CSWS) is a rarechildhood disorder. The onset of seizures is at a mean ageof 4 years. Initially the EEG shows generalized spike andwave activity with maximum intensity overfrontotemporal or centrotemporal regions. At around 8years or so the characteristic pattern of generalized 2-2.5Hz continuous spike and wave EEG discharges duringslow wave sleep (seen during at least 85% of non-REMsleep) is seen. These discharges are suppressed by REMsleep. During wake state, bursts of generalized spike andwave discharge are seen. With appearance of CSWS thereis deterioration of neuropsychological functions withdeterioration in intellect, language and behavior.6 Noprimary sleep disturbance has been reported except fordifficulty in waking up in morning.

Similar electrical status in sleep may be seen inLandau-Kleffner syndrome also called as acquiredepileptic aphasia. The awake EEG in this syndromeshows parietal or temporal spikes which are activatedduring onset of sleep and may get generalized and unlikemost other disorders, get more prominent during REMsleep.

Effect of sleep on other epileptic syndromes

West syndrome: West syndrome is triad of infantilespasms, psychomotor regression and hypsarrythmia onEEG. The infantile spasms occur in clusters notably onwaking up from sleep or while the infant is about to sleep.The spasms do not occur during sleep. The typical highand chaotic hypsarrhythmia pattern which is seen duringawake state is modified during sleep. During non-REMsleep there is increased synchrony of the background with

appearance of generalized bursts of diffuse polyspike andwave pattern followed by low amplitude activitymimicking the burst suppression pattern. During REMsleep the hypsarrhythmia is suppressed and EEG mayappear quite normal.

Lennox-Gastaut Syndrome. This epileptic syndromeis a catastrophic childhood epileptic encephalopathywhich may arise de novo or may evolve from otherchildhood epileptic encephalopathies such as westsyndrome. The patient has multiple type of seizuresincluding drop attacks (atonic seizures), myoclonicseizures and tonic seizures. Tonic seizures in LGStypically are activated by sleep and may occurrepetitively throughout the night. They are much morefrequent during non-REM sleep than during the awakestate and usually do not occur during REM sleep.

The awake EEG shows 1-2.5 Hz slow spike and wavedischarge with variable degree of synchrony. Sleepincreases the frequency of the discharges. During non-REM sleep, slow spike-and-wave discharges becomebilaterally synchronous may be replaced by polyspike-and-wave discharges.7 In REM sleep, there is markedreduction of paroxysmal activity. The typical ictal EEGcorrelate of tonic seizures is the occurrence of fast-rhythmdischarges of 10 to 13 Hz, usually followed by a few slowwaves or spike-waves rather than post-ictal EEGdepression

Effect of Epilepsy on Sleep

The SWC is regulated by several mechanisms. Thesemechanisms can possibly lead to modifications of theSWC in epileptic patients. Children with epilepsycommonly have sleep problems particularly poor qualitysleep and anxiety related to sleep.8 Parental fearsregarding seizure occurrence at night may be a majorfactor causing changes in sleeping arrangements, orpassing anxiety to the child.9 A significant associationbetween seizure frequency and anxiety related to sleepinghas been observed.10 Seizures per se can disrupt sleepstructure, particularly rapid-eye-movement (REM) sleep.It has been seen that increasing severity of epilepsy andeven interictal epileptiform activity is associated withincreasing sleep disturbance.11

In children with other co-morbid developmentaldisabilities the sleep disturbance may be due to coexistingsleep apnea or gastroesophageal reflux disorder.

There is evidence that sleep disorders may influenceseizure frequency. Successful treatment of sleep apneareduced the seizure frequency in a group of patients withpartial epilepsy.12 The exacerbation of seizure may be dueto hypoxemia caused by sleep apnea or disruption ofsleep pattern such as frequent arousal which may act astrigger of epileptic seizures.

Effect of Anti-epileptic drugs (AEDs) on sleep

Somnolence and diurnal sedation are among the mostfrequent common side effects of AEDs. AEDs can modify

Sleep and Childhood Epilepsy


both sleep architecture and the sleep wake cycle. AEDsalso affect sleep by reducing the muscle tone of the upperairways, and increasing the arousal threshold. This effectis more pronounced when the AED therapy is started.Patients on polytherapy often report excessive daytimesleepiness.13 Children with well controlled idiopathicgeneralized epilepsy have also been reported to haveabnormal sleep architecture as compared to controls.14

Daytime sleepiness has been reported in adult patients onstable AED therapy.15 This daytime sleepiness is greaterwith phenobarbitone as compared to valproic acid.16

Other AEDs also affect sleep. Patients on carbamazepine(CBZ) therapy were seen to have reduction andfragmentation of REM sleep and increase in number ofsleep stage shifts. This sleep disruption with CBZ ismaximum during initial administration and these effectsreverse after 1 month of therapy.17

Whether it is epilepsy itself or AEDs which causeabnormal sleep architecture is difficult to determine bythese studies. This adverse effect on sleep is speciallyrelevant to AED effect on cognitive functions. It is likelythat cognitive effects of AEDs on memory andconcentration are related to drug effect on centralnervous system mediating arousal rather than the specificeffect on cognitive functions. Of the newer AEDs,Lamotrigine and Gabapentin improve the quality ofsleep.18,19 Both Lamotrigine and Gabapentin increase REMsleep. Paradoxical effects on sleep behavior withhyperactivity are noted in children treated withphenobarbitone

Effect of Sleep on Cognitive Functions

Sleep appears to be important for early braindevelopment. In fact young children who have maximumbrain growth spend most of the time in sleep. Languageprocessing occurs in natural sleep.20 The deficits incognitive functions and language in CSWS, even whenthere are no clinical seizures, may be due to theimportance of sleep in these functions. A high proportionof children with developmental dysphasia haveparoxysmal activity during sleep and this may be thecause of language deterioration.21 In children with BERS,presence of IED was associated with disorders in visuo-spatial memory and other cognitive function; and thisimproved with remission of the epileptiform discharges.22

There is also evidence that children often revealcognitive, emotional and behavioral manifestations ofinadequate sleep without showing frank sleepiness.23

Hyperactivity and inattention are commonly seen inchildren with sleep disorders. Thus epilepsy per se and bydisrupting sleep may cause difficulty in learning inchildren and thus adversely affect children with epilepsy.

Implications for Management

Lack of sleep is an important trigger for epilepticseizures, therefore regular sleep must be a part ofmanagement strategy in children with epilepsy. Poor

sleep hygiene leads to fragmentation of sleep that canexacerbate seizures and daytime sleepiness. Cliniciansshould watch out for sleep disorders in children withepilepsy. Excess daytime sleepiness in children withepilepsy may be due to seizures, side effect of AEDs, poorsleep hygiene or coexisting sleep disorder. In childrenwith additional disabilities e.g., CP, sleep disorders maybe due to obstructive sleep apnea or gastro-esophagealreflux disorder which may require treatment.24 Primarysleep disorder should be suspected in patients with excessdaytime sleepiness specially in those who are treatedwith monotherapy and have well controlled seizures.Sleep problems in young children may present withhyperactivity or behavioral problems rather thanexcessive somnolence. Ideally the AED chosen to treatepilepsy should have least effect on sleep. This may notbe always possible. Behavioral therapy and regularsleeping habits may reduce the problem to some extent.

Considering that a significant number of patients withepilepsy have sleep disorder melatonin may improve thesleep and quality of life in children with epilepsy whoreport to have sleep problems. This is specially relevantsince exogenous melatonin has hardly any serious sideeffects. Ross et al studied the effect of melatonin on sleepof patients with neurodevelopmental disabilities andfound improvement in 34/46 patients studied.25

Melatonin can exert a positive effect on the frequency ofepileptic attacks in children with sleep disturbances ofvarious etiologies.26 In a recent randomized controlledstudy conducted in the authors' center co-administrationof melatonin with valproate was perceived to improve thesleep score of patients with epilepsy.27 In another placebocontrolled trial which recruited children and adolescentswith mental retardation with or without epilepsy,melatonin administration was shown to improve thesleep pattern.28 It has been shown to normalize the sleepbehavior and favorably influence the underlying epilepsyas well.29 There is a single report of melatonin worseningseizures.30 Further randomized controlled trials arenecessary before recommending routine use of melatonin.

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and delineation of the epileptic syndrome. Brain 1998; 121: 205-223.

6. Tassinari CA, Rubboli G, Volpi L, Meletti S, dOrsi G, FrancaM, Sabetta AR,Riguzzi P, Gardella E, Zaniboni A, MichelucciR. Encephalopathy with electrical status epilepticus duringslow sleep or ESES syndrome including the acquired aphasia.Clin Neurophysiol 2000 ;111(Suppl 2) :S94-S102

7. Crumrine PK. Lennox-Gastaut Syndrome. J Child Neurol.2002;17(Suppl 1) :S70-75.

8. Cortesi F, Gianotti F, Ottaviano S. Sleep problems anddaytime behavior in childhood idiopathic epilepsy. Epilepsia1999; 40 : 1557-1565.

9. Williams J, Lange B, Sharp G, Griebel M, Edgar T, Haley T etal. Altered sleeping arrangements in pediatric patients withepilepsy. Clin Pediatr 2000; 39 : 635-642.

10. Stores G, Wiggs L, Campling G. Sleep disorders and theirrelationship to psychological disturbance in children withepilepsy. Child Care Health Dev 1998; 24: 5-19.

11. Bell C, Vanderlinden H, Hiersemenzel R, Otoul C, Nutt D,Wilson S. The effects levetiracetam on objective and subjectivesleep parameters in healthy volunteers and patients withpartial epilepsy. J Sleep Res 2002; 11 : 255-263.

12. Devinsky O, Ehrenberg B, Barthlen GM et al. Epilepsy andsleep apnea syndrome. Neurology 1994; 44 : 2060-2064.

13. Foldvary N. Sleep and epilepsy. Curr Treat Options Neurol2002; 4 : 129-135.

14. Maganti R, Sheth RD, Hermann BP, Weber S, Gidal BE, Fine J.Sleep architecture in children with idiopathic generalizedepilepsy. Epilepsia 2005; 46 : 104-109.

15. Salinsky MC, Oken BS, Binder LM. Assessment of drowsinessin epilepsy patients receiving chronic anti-epileptic drugtherapy. Epilepsia 1996; 37 : 181-187.

16. Manni R, Ratti MT, Perucca E, Galimberti CA, Tartara A. Amultiparametric investigation of daytime sleepiness andpsychomotor functions in epileptic patients treated withphenobarbital and sodium valproate: a comparative controlledstudy. Electroenceph Clin Neurophysiol 1993; 86: 322-328.

17. Gilgli GL, Placidi F, Diomedi M, Maschio M, Silvestri G et al.Nocturnal sleep and daytime somnolence in untreated patientswith temporal lobe epilepsy: changes after treatment withcontrolled release carbamazepine. Epilepsia 1997; 38 : 696-701.

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GL. Effect of anticonvulsants on nocturnal sleep in epilepsy.Neurology 2000; 54: (suppl 1) : S25-32.

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The Indian Journal of PediatricsBest Theses Research Award 2004

This year we received 24 applications from 18 medical colleges a gratifying response. We are happy to say thatover all, quality of the researches carried out by the candidates was very good. It varied from clinical topics likeevaluation in neonatal jaundice, asthma treatment guidelines and control trial of drugs to molecular diagnosis oftuberculosis and typhoid. While evaluating these thesis consideration was given to relevance of the study, themethods used, quality of data and results and contribution of the candidate to actual work.

We are happy to announce the winners of the Research Award 2004.

1st Position : Utpal S. BhalalaThesis title : Calcium and Vitamin D status of exclusively breast-fed infant from birth to 3 months of age.From Department of Pediatrics, Sir H.N. Hospital and Research Centre, Mumbai.

2nd Position : Agnihotri BiswasThesis title: Intergenerational Study on Trends in Human Birth Weight Across Two Successive GenerationsFrom Department of Child Health, Christian Medical College, Vellore, Tamil Nadu.

3rd Position : (i) Ravishankar N.Thesis title : A. Randomized Placebo Controlleld Trial of Risperidone in Children with AutismFrom Department of Pediatrics, Advanced Pediatric Centre, Postgraduate Institute of Medical Education andResearch, Chandigarh.

3rd Position : (ii) Pankaj MittalThesis title : Comparative Study of Intranasal Midazolam and intravenous Diazepam selation for Procedures and Seizures.From Department of Pediatrics, S.S. Medical College and Associated Gandhi Memorial Hospital, Rewa, M.P.

It is heartening to note the increasing interest of young researchers in India. We are examining carefully how theIndian Journal of Pediatrics can encourage the young pediatricians and trainees to carry out original research. Aspecial volume will be published on Research Methodology based on our popular symposium on ResearchMethodology. We also propose to award special consolation prizes for deserving research work not included inthe winners list.

To give more encouragement and impetus to researchers, the theses submitted for the award will be publishedas original articles in the Journal to provide greater visibility to the research in India. We would like to remindour readers that the Journal offers grants for training as well as for attending conferences.

The following two theses were considered for Consolation Awards in view of their high quality.

Consolation Award : 1. Narendra Reddy DereddyThesis title : Electrophysiological Studies in Symmetrical and Asymmetrical Intrauterine Growth RetardationFrom Department of Pediatrics, Institute of Medical Sciences, Banaras Hindu University, Varanasi.

Consolation Award : 2. Anu ThukralThesis title : Determination of Predictors of Outcome in Children Admitted to Intensive Care UnitFrom Department of Pediatrics, All India Institute of Medical Sciences, New Delhi.

In this endeavor, we need the cooperation of all heads of departments of pediatrics in the medical colleges andmedical institutions in India and other faculty members. We must inspire and encourage our young trainees tothink out problems afresh, and to challenge traditional wisdom to make new discoveries.

I.C. VermaEditor-in-Chief


ARTICLES APPEARING IN THE FORTHCOMING ISSUES

Integrated Management of Childhood Illness (IMCI) Follow Up of Basic Health Workers : NidhiChaudhary, P.N. Mohanty and Minakshi Sharma

Oral Midazolam and Oral Butorphanol Premedication : Vinita Singh, Manu Pathak and G.P. Singh

Complement Component (C3, C4) in Asthma : FIE Najam, A.S.M. Giasuddin and A.H. Shembesh

Pain Response of Neonates to Venipuncture : Amar M. Taksande, K.Y. Vilhekar, M. Jain and D. ChitreLockhart

Tuberculosis Meningitis with and without Human Immunodeficiency : Sunil Karande, Vishal Gupta,Madhuri Kulkarni, Anagha and Mhisti Rele

Myelofibrosis with Myeloid Metaplasia in a Child with Juvenile Rheumatoid Arthritis : VandanaJain, Anu Maheshwari, Sheffali Gulati, Madhulika Kabra and Veena Kalra

Benign Recurrent Intrahepatic Cholesstasis: A Rare Cause of Cholestasis : V. Gupta, M. Kumar andB.D. Bhatia

Neonatal Hydrothorax Following Migration of a Central Venous Catheter: Sridhar S., Niranjan Thomas,Sathish Kumar T. and Atanu Kumar Jana

Infantile Endodermal Sinus Tumor Presenting with Vaginal Bleeding : Vijay Kumar, Pushpa Kini,Deepti Vepakomma and Basant M.

Infected Primary Intramuscular Echinococcosis of Thigh : Sanjay Marwah, P. Subramanian Nisha Marwah,K.N. Rattan and R.K. Karwasra

Benefits of Maternal Participation in Newborn Nurseries : C.K. Sasidharan, E. Gokul, P. Anoop et al

Familial Combined Hyperlipidemia in a North Indian Kindred : C.S. Sriram, Sheffali Gulati, VikasChopra, et al

SYMPOSIA SCHEDULE FOR 2005

Title Guest Editor(s)

Growth and its Disorders (Feb) P.S.N. MenonFest-Schrift for Late Dr. P.M. Udani (Apr) Vrajesh Udani (India)Common Pediatric Surgical Problems-II (May) D.K. Mitra (India)Pediatric Cardiology-I (June) Anita Saxena (India) and P.S. Rao (USA)Pediatric Cardiology-II (July) Anita Saxena (India) and P.S. Rao (USA)Nephrology Arvind Bagga (India)Newer Diagnostics A. Sibal (India) and I.C. Verma (India)New Drugs Antibiotics Arvind Taneja (India) and Ashir Kumar (USA)Gastroenterology & Hepatology N.K. Arora (India) and Anil Dhawan (UK)Developmental and Behavioral Disorders Nandini Mundkur (India) and D.R. Patel (USA)


sleep and childhood epilepsy

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