Sleep and childhood epilepsy
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《美国医学杂志》
1 Departments of Pediatrics, Lady Hardinge Medical College, New Delhi, India
2 Departments of Pharmacology, Lady Hardinge Medical College, New Delhi, India
Abstract
The inter-relationship between sleep and epilepsy is well recognized. Sleep is known to activate inter-ictal epileptiform 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 diurnal sedation are frequent side effects of anti-epileptic drugs. Thus epilepsy and its treatment can affect sleep leading to adverse effect on behavior, cognition and seizure control. Lack of sleep is an important trigger for epileptic seizures, therefore regular sleep must be a part of management strategy in children with epilepsy.
Keywords: Sleep; Anti-epileptic drug; EEG
Sleep is a physiological state during which vigilant consciousness is temporarily abolished and responses to environmental stimuli are decreased. It is cyclic and associated with various changes in behavior, endocrinal, and other physiological functions. Epilepsy is a state of recurrent unprovoked seizures. During a seizure a population of cortical neurons from a part of brain or from both hemispheres fire an abnormal synchronized electrical discharge. The existence of relationship between sleep and epilepsy has been observed for a long time but was first validated by Gibbs and Gibbs when they found that paroxysmal discharges occurred more frequently in sleep.[1]
Effect of Sleep on Seizures and Childhood Epileptic Syndromes
The sleep/wakefulness cycle (SWC) is regulated by several mechanisms and some of them also affect the expression of epilepsy. In non -REM sleep thalamic nuclei provide diffuse synchronized afferent inputs to cortex and are responsible for rhythmic sleep spindles. This diffuse cortical synchronization can lead to activation of ictal focus in susceptible person. Thus non-REM sleep appears to have a proconvulsant effect. On the other hand in REM sleep there is inhibition of thalamocortical synchronization mechanism and there is also reduction of interhemispheric transmission which prevents generalization of epileptiform discharge.[2]
Both clinical seizures and interictal epileptiform abnormalities are facilitated by non-REM sleep. It has been seen that lighter stages of non-REM sleep (stage 1 & 2) promote seizures in susceptible patients. The interictal epileptiform discharges are activated by deeper non-REM sleep (stage 3 & 4).[3] Loss of sleep or disruption of sleep is recognized as a trigger of epileptic seizures.
Sleep is widely recognized as an activator of interictal epileptiform discharges (IED) during EEG recording. In a significant proportion of patients IED may occur only in sleep portion of EEG record.[4] Sleep deprivation not only increases the occurrence of IED by inducing sleep but also increase the likelihood of occurrence of IED during the subsequent awake record. Sleep can induce or increases interictal EEG abnormalities associated with most types of epilepsies. Some types of seizure discharges (primary generalized epilepsy) are suppressed in REM sleep. A special timing of seizure in relation to sleep wake cycle is seen in many childhood epileptic syndromes. Epileptic syndromes which are affected by sleep wake cycle 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 going children. The seizures which are characteristically oro-bucco-lingual and facial occur mostly in drowsiness and sleep. Awareness is preserved but there may be arrest of speech. The seizures occur mostly at night though they may occur sometimes in daytime sleep as well. The interictal EEG in awake state is usually normal but in sleep shows centrotemporal or rolandic spikes. The centrotemporal spikes are invariably activated by sleep and often become bilateral during sleep. This epileptic syndrome has good prognosis with cessation of seizure by 13-20 years.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE): It is a dominant form of partial epilepsy with the onset in childhood. This disorder is characterized by clusters of brief nocturnal motor seizures, with hyperkinetic or tonic manifestations. Subjects often experience an aura, and remain aware throughout the attacks. Seizures occur in clusters typically as the individual dozes, or shortly before awakening. Seizures are often misdiagnosed as benign nocturnal parasomnias.[5]
Juvenile myoclonic epilepsy (JME) is an idiopathic epilepsy characterized by juvenile onset of myoclonic seizures with normal neurologic development. The onset is typically in second decade. It is characterized by myoclonic seizures, associated at times with generalized tonic-clonic seizures or absence seizures. It is an epilepsy with strong relation to sleep wake cycle. Both the myoclonic seizures and generalized tonic-clonic seizures have a special circadian pattern, i.e., they occur almost exclusively on or soon after awakening, either from all-night sleep or from a nap The seizures are characterized by myoclonic jerks involving upper limbs in the morning shortly after awakening. Because the jerks in JME are brief, without loss of consciousness, and take place in the morning soon after awakening, they are often interpreted as "clumsiness" until generalized convulsions occur. The interictal awake EEG is characterized by paroxysmal generalized 4-6 Hz polyspike and wave discharge. This discharge is exacerbated by onset of sleep but suppressed during sleep.
Continuous spike and wave during sleep (CSWS) is a rare childhood disorder. The onset of seizures is at a mean age of 4 years. Initially the EEG shows generalized spike and wave activity with maximum intensity over frontotemporal or centrotemporal regions. At around 8 years or so the characteristic pattern of generalized 2-2.5 Hz continuous spike and wave EEG discharges during slow wave sleep (seen during at least 85% of non-REM sleep) is seen. These discharges are suppressed by REM sleep. During wake state, bursts of generalized spike and wave discharge are seen. With appearance of CSWS there is deterioration of neuropsychological functions with deterioration in intellect, language and behavior.[6] No primary sleep disturbance has been reported except for difficulty in waking up in morning.
Similar electrical status in sleep may be seen in Landau-Kleffner syndrome - also called as acquired epileptic aphasia. The awake EEG in this syndrome shows parietal or temporal spikes which are activated during onset of sleep and may get generalized and unlike most other disorders, get more prominent during REM sleep.
Effect of sleep on other epileptic syndromes
West syndrome: West syndrome is triad of infantile spasms, psychomotor regression and hypsarrythmia on EEG. The infantile spasms occur in clusters notably on waking up from sleep or while the infant is about to sleep. The spasms do not occur during sleep. The typical high and chaotic hypsarrhythmia pattern which is seen during awake state is modified during sleep. During non-REM sleep there is increased synchrony of the background with appearance of generalized bursts of diffuse polyspike and wave pattern followed by low amplitude activity mimicking the burst suppression pattern. During REM sleep the hypsarrhythmia is suppressed and EEG may appear quite normal.
Lennox-Gastaut Syndrome. This epileptic syndrome is a catastrophic childhood epileptic encephalopathy which may arise de novo or may evolve from other childhood epileptic encephalopathies such as west syndrome. The patient has multiple type of seizures including drop attacks (atonic seizures), myoclonic seizures and tonic seizures. Tonic seizures in LGS typically are activated by sleep and may occur repetitively throughout the night. They are much more frequent during non-REM sleep than during the awake state and usually do not occur during REM sleep.
The awake EEG shows 1-2.5 Hz slow spike and wave discharge with variable degree of synchrony. Sleep increases the frequency of the discharges. During non-REM sleep, slow spike-and-wave discharges become bilaterally synchronous may be replaced by polyspike-and-wave discharges.[7] In REM sleep, there is marked reduction of paroxysmal activity. The typical ictal EEG correlate of tonic seizures is the occurrence of fast-rhythm discharges of 10 to 13 Hz, usually followed by a few slow waves or spike-waves rather than post-ictal EEG depression
Effect of Epilepsy on Sleep
The SWC is regulated by several mechanisms. These mechanisms can possibly lead to modifications of the SWC in epileptic patients. Children with epilepsy commonly have sleep problems particularly poor quality sleep and anxiety related to sleep.[8] Parental fears regarding seizure occurrence at night may be a major factor causing changes in sleeping arrangements, or passing anxiety to the child.[9] A significant association between seizure frequency and anxiety related to sleeping has been observed.[10] Seizures per se can disrupt sleep structure, particularly rapid-eye-movement (REM) sleep. It has been seen that increasing severity of epilepsy and even interictal epileptiform activity is associated with increasing sleep disturbance.[11]
In children with other co-morbid developmental disabilities the sleep disturbance may be due to coexisting sleep apnea or gastroesophageal reflux disorder.
There is evidence that sleep disorders may influence seizure frequency. Successful treatment of sleep apnea reduced the seizure frequency in a group of patients with partial epilepsy.[12] The exacerbation of seizure may be due to hypoxemia caused by sleep apnea or disruption of sleep pattern such as frequent arousal which may act as trigger of epileptic seizures.
Effect of Anti-epileptic drugs (AEDs) on sleep
Somnolence and diurnal sedation are among the most frequent common side effects of AEDs. AEDs can modify both sleep architecture and the sleep wake cycle. AEDs also affect sleep by reducing the muscle tone of the upper airways, and increasing the arousal threshold. This effect is more pronounced when the AED therapy is started. Patients on polytherapy often report excessive daytime sleepiness.[13] Children with well controlled idiopathic generalized epilepsy have also been reported to have abnormal sleep architecture as compared to controls.[14] Daytime sleepiness has been reported in adult patients on stable AED therapy.[15] This daytime sleepiness is greater with phenobarbitone as compared to valproic acid.[16] Other AEDs also affect sleep. Patients on carbamazepine (CBZ) therapy were seen to have reduction and fragmentation of REM sleep and increase in number of sleep stage shifts. This sleep disruption with CBZ is maximum during initial administration and these effects reverse after 1 month of therapy.[17]
Whether it is epilepsy itself or AEDs which cause abnormal sleep architecture is difficult to determine by these studies. This adverse effect on sleep is specially relevant to AED effect on cognitive functions. It is likely that cognitive effects of AEDs on memory and concentration are related to drug effect on central nervous system mediating arousal rather than the specific effect on cognitive functions. Of the newer AEDs, Lamotrigine and Gabapentin improve the quality of sleep.[18],[19] Both Lamotrigine and Gabapentin increase REM sleep. Paradoxical effects on sleep behavior with hyperactivity are noted in children treated with phenobarbitone
Effect of Sleep on Cognitive Functions
Sleep appears to be important for early brain development. In fact young children who have maximum brain growth spend most of the time in sleep. Language processing occurs in natural sleep.[20] The deficits in cognitive functions and language in CSWS, even when there are no clinical seizures, may be due to the importance of sleep in these functions. A high proportion of children with developmental dysphasia have paroxysmal activity during sleep and this may be the cause of language deterioration.[21] In children with BERS, presence of IED was associated with disorders in visuo-spatial memory and other cognitive function; and this improved with remission of the epileptiform discharges.[22]
There is also evidence that children often reveal cognitive, emotional and behavioral manifestations of inadequate sleep without showing frank sleepiness.[23] Hyperactivity and inattention are commonly seen in children with sleep disorders. Thus epilepsy per se and by disrupting sleep may cause difficulty in learning in children and thus adversely affect children with epilepsy.
Implications for Management
Lack of sleep is an important trigger for epileptic seizures, therefore regular sleep must be a part of management strategy in children with epilepsy. Poor sleep hygiene leads to fragmentation of sleep that can exacerbate seizures and daytime sleepiness. Clinicians should watch out for sleep disorders in children with epilepsy. Excess daytime sleepiness in children with epilepsy may be due to seizures, side effect of AEDs, poor sleep hygiene or coexisting sleep disorder. In children with additional disabilities e.g., CP, sleep disorders may be due to obstructive sleep apnea or gastro-esophageal reflux disorder which may require treatment.[24] Primary sleep disorder should be suspected in patients with excess daytime sleepiness specially in those who are treated with monotherapy and have well controlled seizures. Sleep problems in young children may present with hyperactivity or behavioral problems rather than excessive somnolence. Ideally the AED chosen to treat epilepsy should have least effect on sleep. This may not be always possible. Behavioral therapy and regular sleeping habits may reduce the problem to some extent.
Considering that a significant number of patients with epilepsy have sleep disorder melatonin may improve the sleep and quality of life in children with epilepsy who report to have sleep problems. This is specially relevant since exogenous melatonin has hardly any serious side effects. Ross et al studied the effect of melatonin on sleep of patients with neurodevelopmental disabilities and found improvement in 34/46 patients studied.[25] Melatonin can exert a positive effect on the frequency of epileptic attacks in children with sleep disturbances of various etiologies.[26] In a recent randomized controlled study conducted in the authors' center co-administration of melatonin with valproate was perceived to improve the sleep score of patients with epilepsy.[27] In another placebo controlled trial which recruited children and adolescents with mental retardation with or without epilepsy, melatonin administration was shown to improve the sleep pattern.[28] It has been shown to normalize the sleep behavior and favorably influence the underlying epilepsy as well.[29] There is a single report of melatonin worsening seizures.[30] Further randomized controlled trials are necessary before recommending routine use of melatonin.
References
1. Gibbs EL and Gibbs FA. Diagnostic and localizing value of electroencephalographic studies in sleep. Res Publ Assoc Res Nerv Ment Dis 1947; 26: 366-376.
2. Quinto C, Chokroverty S. Sleep, epilepsy and Sudden death. In Culebras A, eds. Sleep Disorders and Neurological Disease . Marcel Dekker Inc, New York. 2000; 303-322.
3. Minecan D, Natarajan A, Marzec M, Malow B. Relationship of epileptic seizures to sleep stage and sleep depth. Sleep 2002;25: 899-904.
4. El-Ad B,Neufeld MY, Korcyzn AD. Should sleep EEG record always be performed after sleep deprivation Electroencephalogr Clin Neurophysiol 1994; 90: 313-315
5. Oldani A, Zucconi M, Asselta R, Modugno M, Bonati MT, Dalpra L, Malcovati M, Tenchini ML, Smirne S, Ferini-Strambi L. Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome. Brain 1998; 121: 205-223.
6. Tassinari CA, Rubboli G, Volpi L, Meletti S, d'Orsi G, Franca M, Sabetta AR,Riguzzi P, Gardella E, Zaniboni A, Michelucci R. Encephalopathy with electrical status epilepticus during slow 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 and daytime behavior in childhood idiopathic epilepsy. Epilepsia 1999; 40: 1557-1565.
9. Williams J, Lange B, Sharp G, Griebel M, Edgar T, Haley T et al. Altered sleeping arrangements in pediatric patients with epilepsy. Clin Pediatr 2000; 39: 635-642.
10. Stores G, Wiggs L, Campling G. Sleep disorders and their relationship to psychological disturbance in children with epilepsy. 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 subjective sleep parameters in healthy volunteers and patients with partial epilepsy. J Sleep Res 2002; 11: 255-263.
12. Devinsky O, Ehrenberg B, Barthlen GM et al. Epilepsy and sleep apnea syndrome. Neurology 1994; 44: 2060-2064.
13. Foldvary N. Sleep and epilepsy. Curr Treat Options Neurol 2002; 4: 129-135.
14. 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.
15. Salinsky MC, Oken BS, Binder LM. Assessment of drowsiness in epilepsy patients receiving chronic anti-epileptic drug therapy. Epilepsia 1996; 37: 181-187.
16. Manni R, Ratti MT, Perucca E, Galimberti CA, Tartara A. A multiparametric investigation of daytime sleepiness and psychomotor functions in epileptic patients treated with phenobarbital and sodium valproate: a comparative controlled study. 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 patients with temporal lobe epilepsy: changes after treatment with controlled release carbamazepine. Epilepsia 1997; 38: 696-701.
18. Placidi F, Diomedi M, Scalise A, Marciani MG, Romigi A, Gigli GL. Effect of anticonvulsants on nocturnal sleep in epilepsy. Neurology 2000; 54: (suppl 1): S25-32.
19. Foldvary N, Perry M, Lee J, Dinner D, Morris HH. The effects of lamotrigine on sleep in patients with epilepsy. Epilepsia 2001; 42: 1569-1573.
20. Wilke M, Holland SK, Ball WS Jr. Language processing during natural sleep in a 6-year-old boy, as assessed with functional MR imaging. Am J Neuroradiol 2003; 24: 42-44.
21. Picard A; Cheliout, Heraut F, Bouskraoui M, Lemoine M, Lacert P, Delattre J. Sleep EEG and developmental dysphasia. Dev Med Child Neurol 1998; 40: 595-599.
22. Baglietto MG, Battaglia FM, Nobili L, Tortorelli S, De Negri E, Calevo MG, Veneselli E, De Negri M. Neuropsychological disorders related to interictal epileptic discharges during sleep in benign epilepsy of childhood with centrotemporal or Rolandic spikes. Dev Med Child Neurol 2001; 43: 407-412.
23. Dahl RE The impact of inadequate sleep on children's daytime cognitive function. Semin Pediatr Neurol 1996; 3: 44-50.
24. Koh S, Ward SL, Lin M, Chen LS Sleep apnea treatment improves seizure control in children with neurodevelopmental disorders. Pediatr Neurol 2000; 22: 36-39.
25. Ross C, Davies P, Whitehouse W. Melatonin treatment of for sleep disorders in children with neurodevelopmental disorders: an observational study. Dev Med Child Neurol 2002; 44: 339-344.
26. Fauteck J, Schmidt H, Lerchl A, Kurlemann G, Wittkowski W Melatonin in epilepsy: first results of replacement therapy and first clinical results. Biol Signals Recept 1999; 8: 105-110.
27. Gupta M, Aneja S, Kohli K. Add-on melatonin improves quality of life in epileptic children on valproate monotherapy: a randomized, double-blind, placebo-controlled trial. Epilepsy Behav 2004; 5: 316-321.
28. Coppola G, Iervolino G, Mastrosimone M, La Torre G, Ruiu F, Pascotto A. Melatonin in wake-sleep disorders in children, adolescents and young adults with mental retardation with or without epilepsy: a double-blind, crossover placebo-controlled trial. Brain Dev 2004; 26: 373-376.
29. Peled N, Shorer Z, Peled E, Pillar G. Melatonin effect on seizures in children with severe neurologic deficit disorders. Epilepsia 2001; 42: 1208-1210.
30. Sheldon SH. Proconvulsant action of oral melatonin in neurologically disabled children. Lancet 1998; 351: 1254(Aneja S, Gupta M)
2 Departments of Pharmacology, Lady Hardinge Medical College, New Delhi, India
Abstract
The inter-relationship between sleep and epilepsy is well recognized. Sleep is known to activate inter-ictal epileptiform 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 diurnal sedation are frequent side effects of anti-epileptic drugs. Thus epilepsy and its treatment can affect sleep leading to adverse effect on behavior, cognition and seizure control. Lack of sleep is an important trigger for epileptic seizures, therefore regular sleep must be a part of management strategy in children with epilepsy.
Keywords: Sleep; Anti-epileptic drug; EEG
Sleep is a physiological state during which vigilant consciousness is temporarily abolished and responses to environmental stimuli are decreased. It is cyclic and associated with various changes in behavior, endocrinal, and other physiological functions. Epilepsy is a state of recurrent unprovoked seizures. During a seizure a population of cortical neurons from a part of brain or from both hemispheres fire an abnormal synchronized electrical discharge. The existence of relationship between sleep and epilepsy has been observed for a long time but was first validated by Gibbs and Gibbs when they found that paroxysmal discharges occurred more frequently in sleep.[1]
Effect of Sleep on Seizures and Childhood Epileptic Syndromes
The sleep/wakefulness cycle (SWC) is regulated by several mechanisms and some of them also affect the expression of epilepsy. In non -REM sleep thalamic nuclei provide diffuse synchronized afferent inputs to cortex and are responsible for rhythmic sleep spindles. This diffuse cortical synchronization can lead to activation of ictal focus in susceptible person. Thus non-REM sleep appears to have a proconvulsant effect. On the other hand in REM sleep there is inhibition of thalamocortical synchronization mechanism and there is also reduction of interhemispheric transmission which prevents generalization of epileptiform discharge.[2]
Both clinical seizures and interictal epileptiform abnormalities are facilitated by non-REM sleep. It has been seen that lighter stages of non-REM sleep (stage 1 & 2) promote seizures in susceptible patients. The interictal epileptiform discharges are activated by deeper non-REM sleep (stage 3 & 4).[3] Loss of sleep or disruption of sleep is recognized as a trigger of epileptic seizures.
Sleep is widely recognized as an activator of interictal epileptiform discharges (IED) during EEG recording. In a significant proportion of patients IED may occur only in sleep portion of EEG record.[4] Sleep deprivation not only increases the occurrence of IED by inducing sleep but also increase the likelihood of occurrence of IED during the subsequent awake record. Sleep can induce or increases interictal EEG abnormalities associated with most types of epilepsies. Some types of seizure discharges (primary generalized epilepsy) are suppressed in REM sleep. A special timing of seizure in relation to sleep wake cycle is seen in many childhood epileptic syndromes. Epileptic syndromes which are affected by sleep wake cycle 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 going children. The seizures which are characteristically oro-bucco-lingual and facial occur mostly in drowsiness and sleep. Awareness is preserved but there may be arrest of speech. The seizures occur mostly at night though they may occur sometimes in daytime sleep as well. The interictal EEG in awake state is usually normal but in sleep shows centrotemporal or rolandic spikes. The centrotemporal spikes are invariably activated by sleep and often become bilateral during sleep. This epileptic syndrome has good prognosis with cessation of seizure by 13-20 years.
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE): It is a dominant form of partial epilepsy with the onset in childhood. This disorder is characterized by clusters of brief nocturnal motor seizures, with hyperkinetic or tonic manifestations. Subjects often experience an aura, and remain aware throughout the attacks. Seizures occur in clusters typically as the individual dozes, or shortly before awakening. Seizures are often misdiagnosed as benign nocturnal parasomnias.[5]
Juvenile myoclonic epilepsy (JME) is an idiopathic epilepsy characterized by juvenile onset of myoclonic seizures with normal neurologic development. The onset is typically in second decade. It is characterized by myoclonic seizures, associated at times with generalized tonic-clonic seizures or absence seizures. It is an epilepsy with strong relation to sleep wake cycle. Both the myoclonic seizures and generalized tonic-clonic seizures have a special circadian pattern, i.e., they occur almost exclusively on or soon after awakening, either from all-night sleep or from a nap The seizures are characterized by myoclonic jerks involving upper limbs in the morning shortly after awakening. Because the jerks in JME are brief, without loss of consciousness, and take place in the morning soon after awakening, they are often interpreted as "clumsiness" until generalized convulsions occur. The interictal awake EEG is characterized by paroxysmal generalized 4-6 Hz polyspike and wave discharge. This discharge is exacerbated by onset of sleep but suppressed during sleep.
Continuous spike and wave during sleep (CSWS) is a rare childhood disorder. The onset of seizures is at a mean age of 4 years. Initially the EEG shows generalized spike and wave activity with maximum intensity over frontotemporal or centrotemporal regions. At around 8 years or so the characteristic pattern of generalized 2-2.5 Hz continuous spike and wave EEG discharges during slow wave sleep (seen during at least 85% of non-REM sleep) is seen. These discharges are suppressed by REM sleep. During wake state, bursts of generalized spike and wave discharge are seen. With appearance of CSWS there is deterioration of neuropsychological functions with deterioration in intellect, language and behavior.[6] No primary sleep disturbance has been reported except for difficulty in waking up in morning.
Similar electrical status in sleep may be seen in Landau-Kleffner syndrome - also called as acquired epileptic aphasia. The awake EEG in this syndrome shows parietal or temporal spikes which are activated during onset of sleep and may get generalized and unlike most other disorders, get more prominent during REM sleep.
Effect of sleep on other epileptic syndromes
West syndrome: West syndrome is triad of infantile spasms, psychomotor regression and hypsarrythmia on EEG. The infantile spasms occur in clusters notably on waking up from sleep or while the infant is about to sleep. The spasms do not occur during sleep. The typical high and chaotic hypsarrhythmia pattern which is seen during awake state is modified during sleep. During non-REM sleep there is increased synchrony of the background with appearance of generalized bursts of diffuse polyspike and wave pattern followed by low amplitude activity mimicking the burst suppression pattern. During REM sleep the hypsarrhythmia is suppressed and EEG may appear quite normal.
Lennox-Gastaut Syndrome. This epileptic syndrome is a catastrophic childhood epileptic encephalopathy which may arise de novo or may evolve from other childhood epileptic encephalopathies such as west syndrome. The patient has multiple type of seizures including drop attacks (atonic seizures), myoclonic seizures and tonic seizures. Tonic seizures in LGS typically are activated by sleep and may occur repetitively throughout the night. They are much more frequent during non-REM sleep than during the awake state and usually do not occur during REM sleep.
The awake EEG shows 1-2.5 Hz slow spike and wave discharge with variable degree of synchrony. Sleep increases the frequency of the discharges. During non-REM sleep, slow spike-and-wave discharges become bilaterally synchronous may be replaced by polyspike-and-wave discharges.[7] In REM sleep, there is marked reduction of paroxysmal activity. The typical ictal EEG correlate of tonic seizures is the occurrence of fast-rhythm discharges of 10 to 13 Hz, usually followed by a few slow waves or spike-waves rather than post-ictal EEG depression
Effect of Epilepsy on Sleep
The SWC is regulated by several mechanisms. These mechanisms can possibly lead to modifications of the SWC in epileptic patients. Children with epilepsy commonly have sleep problems particularly poor quality sleep and anxiety related to sleep.[8] Parental fears regarding seizure occurrence at night may be a major factor causing changes in sleeping arrangements, or passing anxiety to the child.[9] A significant association between seizure frequency and anxiety related to sleeping has been observed.[10] Seizures per se can disrupt sleep structure, particularly rapid-eye-movement (REM) sleep. It has been seen that increasing severity of epilepsy and even interictal epileptiform activity is associated with increasing sleep disturbance.[11]
In children with other co-morbid developmental disabilities the sleep disturbance may be due to coexisting sleep apnea or gastroesophageal reflux disorder.
There is evidence that sleep disorders may influence seizure frequency. Successful treatment of sleep apnea reduced the seizure frequency in a group of patients with partial epilepsy.[12] The exacerbation of seizure may be due to hypoxemia caused by sleep apnea or disruption of sleep pattern such as frequent arousal which may act as trigger of epileptic seizures.
Effect of Anti-epileptic drugs (AEDs) on sleep
Somnolence and diurnal sedation are among the most frequent common side effects of AEDs. AEDs can modify both sleep architecture and the sleep wake cycle. AEDs also affect sleep by reducing the muscle tone of the upper airways, and increasing the arousal threshold. This effect is more pronounced when the AED therapy is started. Patients on polytherapy often report excessive daytime sleepiness.[13] Children with well controlled idiopathic generalized epilepsy have also been reported to have abnormal sleep architecture as compared to controls.[14] Daytime sleepiness has been reported in adult patients on stable AED therapy.[15] This daytime sleepiness is greater with phenobarbitone as compared to valproic acid.[16] Other AEDs also affect sleep. Patients on carbamazepine (CBZ) therapy were seen to have reduction and fragmentation of REM sleep and increase in number of sleep stage shifts. This sleep disruption with CBZ is maximum during initial administration and these effects reverse after 1 month of therapy.[17]
Whether it is epilepsy itself or AEDs which cause abnormal sleep architecture is difficult to determine by these studies. This adverse effect on sleep is specially relevant to AED effect on cognitive functions. It is likely that cognitive effects of AEDs on memory and concentration are related to drug effect on central nervous system mediating arousal rather than the specific effect on cognitive functions. Of the newer AEDs, Lamotrigine and Gabapentin improve the quality of sleep.[18],[19] Both Lamotrigine and Gabapentin increase REM sleep. Paradoxical effects on sleep behavior with hyperactivity are noted in children treated with phenobarbitone
Effect of Sleep on Cognitive Functions
Sleep appears to be important for early brain development. In fact young children who have maximum brain growth spend most of the time in sleep. Language processing occurs in natural sleep.[20] The deficits in cognitive functions and language in CSWS, even when there are no clinical seizures, may be due to the importance of sleep in these functions. A high proportion of children with developmental dysphasia have paroxysmal activity during sleep and this may be the cause of language deterioration.[21] In children with BERS, presence of IED was associated with disorders in visuo-spatial memory and other cognitive function; and this improved with remission of the epileptiform discharges.[22]
There is also evidence that children often reveal cognitive, emotional and behavioral manifestations of inadequate sleep without showing frank sleepiness.[23] Hyperactivity and inattention are commonly seen in children with sleep disorders. Thus epilepsy per se and by disrupting sleep may cause difficulty in learning in children and thus adversely affect children with epilepsy.
Implications for Management
Lack of sleep is an important trigger for epileptic seizures, therefore regular sleep must be a part of management strategy in children with epilepsy. Poor sleep hygiene leads to fragmentation of sleep that can exacerbate seizures and daytime sleepiness. Clinicians should watch out for sleep disorders in children with epilepsy. Excess daytime sleepiness in children with epilepsy may be due to seizures, side effect of AEDs, poor sleep hygiene or coexisting sleep disorder. In children with additional disabilities e.g., CP, sleep disorders may be due to obstructive sleep apnea or gastro-esophageal reflux disorder which may require treatment.[24] Primary sleep disorder should be suspected in patients with excess daytime sleepiness specially in those who are treated with monotherapy and have well controlled seizures. Sleep problems in young children may present with hyperactivity or behavioral problems rather than excessive somnolence. Ideally the AED chosen to treat epilepsy should have least effect on sleep. This may not be always possible. Behavioral therapy and regular sleeping habits may reduce the problem to some extent.
Considering that a significant number of patients with epilepsy have sleep disorder melatonin may improve the sleep and quality of life in children with epilepsy who report to have sleep problems. This is specially relevant since exogenous melatonin has hardly any serious side effects. Ross et al studied the effect of melatonin on sleep of patients with neurodevelopmental disabilities and found improvement in 34/46 patients studied.[25] Melatonin can exert a positive effect on the frequency of epileptic attacks in children with sleep disturbances of various etiologies.[26] In a recent randomized controlled study conducted in the authors' center co-administration of melatonin with valproate was perceived to improve the sleep score of patients with epilepsy.[27] In another placebo controlled trial which recruited children and adolescents with mental retardation with or without epilepsy, melatonin administration was shown to improve the sleep pattern.[28] It has been shown to normalize the sleep behavior and favorably influence the underlying epilepsy as well.[29] There is a single report of melatonin worsening seizures.[30] Further randomized controlled trials are necessary before recommending routine use of melatonin.
References
1. Gibbs EL and Gibbs FA. Diagnostic and localizing value of electroencephalographic studies in sleep. Res Publ Assoc Res Nerv Ment Dis 1947; 26: 366-376.
2. Quinto C, Chokroverty S. Sleep, epilepsy and Sudden death. In Culebras A, eds. Sleep Disorders and Neurological Disease . Marcel Dekker Inc, New York. 2000; 303-322.
3. Minecan D, Natarajan A, Marzec M, Malow B. Relationship of epileptic seizures to sleep stage and sleep depth. Sleep 2002;25: 899-904.
4. El-Ad B,Neufeld MY, Korcyzn AD. Should sleep EEG record always be performed after sleep deprivation Electroencephalogr Clin Neurophysiol 1994; 90: 313-315
5. Oldani A, Zucconi M, Asselta R, Modugno M, Bonati MT, Dalpra L, Malcovati M, Tenchini ML, Smirne S, Ferini-Strambi L. Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome. Brain 1998; 121: 205-223.
6. Tassinari CA, Rubboli G, Volpi L, Meletti S, d'Orsi G, Franca M, Sabetta AR,Riguzzi P, Gardella E, Zaniboni A, Michelucci R. Encephalopathy with electrical status epilepticus during slow 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 and daytime behavior in childhood idiopathic epilepsy. Epilepsia 1999; 40: 1557-1565.
9. Williams J, Lange B, Sharp G, Griebel M, Edgar T, Haley T et al. Altered sleeping arrangements in pediatric patients with epilepsy. Clin Pediatr 2000; 39: 635-642.
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