Department of Neurology University of Munich Munich, Germany
Relations of Epileptic Seizures to Sleep-Wake Cycle Sleep Pattern of Patients with Generalized Epilepsy Relation of Epileptiform Discharges to the Sleep-Wake Cycle and Sleep Stages in Generalized Epilepsy Sleep Deprivation
Effects of Antiepileptic Drugs on Sleep
There are several relationships between generalized epilepsy and sleep, both clinically and electroencephalographically. It has been known since the days of Aristotle (Aristoteles, 1924) that epileptic seizures may occur exclusively during sleep. Several authors observed that epileptic seizures may show a tendency to occur during sleep or waking periods and recognized the relation to the sleep-wake cycle (Gowers, 1885; Langdon-Down and Brain, 1929; Patry, 1931; Hopkins, 1933; Magnussen, 1936; Griffiths and Fox, 1938; Janz, 1953). It was
Epilepsy and Sleep: Physiological and Clinical Relationships
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later recognized that epileptiform discharges occur more frequently during nonrapid eye movement (NREM) sleep than in rapid eye movement (REM) sleep and waking periods (Gibbs and Gibbs, 1947; Gloor et al., 1958; Shouse et al., 1996). Arousals and transition periods between sleep stages were considered to facilitate epileptiform discharges (Terzano et al., 1989; Haläsz, 1991; Gigli et al., 1992). In this chapter, we discuss clinical and electroencephalographic (EEG) relations between generalized epilepsy and sleep and the effects of antiepileptic drugs on the sleep of patients with generalized epilepsy.
relations of epileptic seizures to sleep-wake cycle
Langdon-Down and Brain (1929) were the first to subdivide epilepsy patients according to the occurrence of their seizures. They described (1) a "diurnal type," that seizure occurred predominantly during the day with a maximum following morning awakening and two smaller peaks in the afternoon; (2) a "nocturnal type," that seizures occurred during the night with maxima shortly after falling asleep and in the early morning hours; and (3) a group without any discernible pattern, the "diffuse type" (Langdon-Down and Brain, 1929). Relations of epileptic seizures to the sleep-wake cycle were evident from the observation that the times at which the seizures occurred changed when the sleep regimen was altered (Gowers, 1885; Marchand, 1931). Generalized tonic-clonic seizures show a clearer relation to the sleep-wake cycle than "minor seizures" show (Janz, 1962). However, myoclonic seizures tend to occur predominantly in the early morning hours shortly after awakening from night sleep in patients with juvenile myoclonic epilepsy (Janz and Christian, 1957; Gigli et al., 1992). Based on the patients' recollections of their seizures and the patients' histories Janz (1962) classified epilepsies according to the time of occurrence of the "grand mal" seizures. He coined the term "awakening" epilepsy for patients, whose generalized tonic-clonic seizures predominantly occur in the first 2 h after awakening (Janz, 1962). A second peak was described in the afternoon (Feierabend) (Janz, 1962). Janz (1953) reported that in 45% of his 2110 patients with grand mal epilepsies, seizures happened predominantly during sleep: in 34% they occurred in the first 2 h after awakening from night sleep, and in 21%, no relation to the sleep-waking cycle was found. During the course of the epilepsy, the pattern may change, such as fewer patients having an awakening predominance (31 %) and more patients showing a diffuse pattern (26%) (Janz, 1974). The awakening type seemed to be associated with idiopathic generalized epilepsy (Janz, 1962). Half of Janz's patients with hereditary idiopathic epilepsy belonged to the awakening group, whereas most patients with epilepsy secondary to brain tumors (53%) had a diffuse pattern of seizure occurrence and only 8% showed an awakening pattern (Janz, 1962). Of the 2110 patients 1059 also had "minor attacks" (Janz, 1962). The minor seizures in patients with epilepsy on awakening comprised predominantly absence seizures (94%), myoclonic seizures (96%), and less frequently psychomotor seizures (16%) or jacksonian seizures (9%) (Janz, 1962). A major bias of the study of Janz (1962) is the observation that the recollection of epileptic seizures is unreliable (Blum et al., 1996). Patients, their caregivers, and families are usually not able to accurately report on the seizure frequency and seizure occurrence, which could be demonstrated in an epilepsy monitoring unit using video recordings of seizures (Blum et al., 1996). A considerable number of seizures, particularly minor seizures pass unnoticed (Blum et al., 1996). The etiologic diagnoses are subject to uncertainties in the study of Janz (1962) because at that time no modern imaging studies were available. Few more current studies have dealt with the relation of the occurrence of generalized tonic-clonic seizures to the sleep-wake cycle (Billiard, 1982; Touchon et al., 1982). The distribution of generalized tonic-clonic seizures was as follows in 77 of 141 patients with generalized epilepsy, in whom generalized tonic-clonic attacks were observed (Billiard, 1982): (1) 16.8% have had seizures after awakening, (2) 36.3% have had seizures during waking hours of the day, (3) 28.5% have had seizures during night sleep, and (4) 18.1% have had seizures both during night sleep and during waking periods of the day. Morning and nocturnal awakenings accounted for 36 of 51 seizures in 33 patients with juvenile myoclonic epilepsy, whereas the evening relaxation period (n = 6), sleep onset (n = 3), and sleep (n = 6) were less frequently associated with seizures (Touchon et al., 1982).
sleep pattern of patients with generalized epilepsy
Janz (1953, 1974) described that patients with awakening epilepsy and patients with sleep epilepsy had distinct sleep patterns and sleep habits. According to Janz (1953, 1974) patients with generalized epilepsy like to stay up late in the evening and often have difficulty falling asleep. Their sleep appeared to be disrupted. In the morning, they felt drowsy and unrefreshed, and preferred to get up late if they could (Janz, 1953, 1974). A different pattern was reported to occur in patients with focal epilepsy, who would fall easily into deep sleep and awake refreshed early in the morning (Janz, 1974). Early poly graphic studies seemed to support this concept (Christian, 1961; Jovanovic, 1967). The sleep EEG recordings were discontinuous in the study of Christian (1961), which does not allow interpretation of the sleep structure. Other investigators found no differences in the sleep patterns of patients with awakening and sleep epilepsy (Maxion et al., 1973). Other polygraphic sleep studies in patients with idiophatic generalized epilepsy found normal sleep patterns unless seizures occurred during the night (Sato et al., 1973; Tassinari et al., 1974; Passouant et al., 1975). These studies were performed either with patients on chronic antiepileptic medication or with patients for whom the drugs (usually phenobarbital and phenytoin) were discontinued a few days prior to the sleep investigations. Thus, chronic drug effects or rebound effects after discontinuation, which may influence the results, cannot be excluded.
Only one study (Roder-Wanner et al., 1985) investigated the night sleep of unmedicated epilepsy patients. Adaptation nights to the sleep lab were also included in this study (Roder-Wanner et al., 1985) to avoid "first night" effects (Agnew et al, 1966). Photosensitive patients with generalized epilepsy had significantly more slow-wave sleep (sleep stages 3 and 4) and less light sleep (sleep stages 1 and 2) than the other patients with generalized epilepsy (Roder-Wanner et al., 1985). No differences of global or structural sleep parameters were found between patients with generalized epilepsy (n = 19) and focal epilepsy (n = 21) as long as photosensitive patients with generalized epilepsy were excluded from the comparison (Roder-Wanner et al., 1985). Likewise, no differences existed between patients with awakening epilepsy (n = 12) and patients with sleep epilepsy (n = 12) (Roder-Wanner et al., 1985). Thus, the systematic polysomnography evaluation of unmedicated patients with generalized epilepsy (Roder-Wanner et al., 1985) did not reveal distinct sleep patterns in patients with awakening and sleep epilepsy hypothesized by Janz (1953) based on unstructured interviews.
relation of epileptiform discharges to the sleep-wake cycle and sleep stages in generalized epilepsy
The circadian sleep-wake cycle significantly influences the occurrence of epileptiform discharges (Shouse et al., 1996). During non-REM sleep, generalized epileptiform discharges are more frequent than during waking and REM sleep (Gibbs and Gibbs, 1947; Gloor et al., 1958; Billiard et al., 1987). This observation is the rationale for performing sleep EEGs in patients, for whom the diagnosis of epilepsy is not established or the epilepsy syndrome is unclear and the waking EEG is unrevealing. Generalized epileptiform discharges increase gradually with deepening of NREM sleep (Ross et al., 1966; Sato et al., 1973). In patients with absence epilepsy the lowest discharge rates were found during REM sleep (Sato et al., 1973). Because deep sleep stages are most pronounced during the first sleep cycle, it is not surprising that the highest rate of interictal epileptiform discharges were found during the first sleep cycle (Sato et al., 1973). The morphology of generalized spike-wave complexes is more irregular during NREM sleep and is similar in waking and REM sleep (Ross et al., 1966; Sato et al., 1973; Tassinari et al., 1974).
The hypothesis of Patry (1931) that transitional states between wake and sleep and vice versa may be epileptogenic in selected patients, was supported by polygraphic studies. Several authors demonstrated the facilitating effects of transitional states of sleep such as sleep onset, changes between sleep stages, and arousals on the occurrence of epileptiform discharges in patients with generalized (absence) epilepsy (Tassinari et al., 1974; Passouant et al., 1975; Halasz, 1991). Niedermeyer (1982) emphasized that an abnormal paroxysmal response to arousal and the influx of upward traveling stimuli seem to be the most important epileptogenic mechanisms in primary generalized epilepsy. The concept of the cyclic alternating pattern (CAP), which is based on these observations, provides a new approach and supports the idea that transitional cyclic sleep patterns activate epileptiform discharges (Terzano et al, 1989).
Sleep deprivation is one of the most potent precipitators of epileptic seizures and epileptiform discharges in patients with generalized epilepsy. Janz (1957) reported that sleep deprivation and/or excessive alcohol consumption precipitated the first seizure in 28 of 47 patients with juvenile myoclonic epilepsy. Sleep deprivation also facilitates epileptiform discharges in patients with generalized epilepsy (Janz and Christian, 1957; Pratt et al, 1968; Bechinger et al, 1973). However, there is some debate as to whether sleep deprivation has a genuine activating effect on epileptiform discharges or acts by way of sleep induction (Degen and Degen, 1983). Direct comparison of drug-induced sleep EEG and EEG after sleep deprivation in patients with normal or borderline waking EEG revealed epileptic discharge activation in 44% after sleep deprivation versus 14% during drug-induced sleep (Rowan et al, 1982). Another study compared the rate of epileptiform discharges of waking EEGs after sleep deprivation with sleep EEG after sleep deprivation and concluded that sleep deprivation had an independent activating effect because the waking EEGs after sleep deprivation showed more epileptiform discharges than the sleep EEGs after sleep deprivation (Klingler et al, 1991).
effects of anti epi leptic drugs on sleep
Many antiepileptic drugs exert some effects on sleep (some are also hypnotics). It was hypothesized that some of their antiepileptic effects may be mediated through an influence on sleep (Janz, 1974). Most studies evaluated short-term effects of the drugs often with healthy volunteers or patients with psychiatric disorders. The sleep studies of patients on chronic treatment were compared with what was considered normal sleep (Wolf et al, 1985). One study compared the therapeutic effects of phenobarbital and phenytoin on the sleep of epileptic patients (generalized epilepsy, n = 19; focal epilepsy, n = 18; unclassified epilepsy, n = 3) intraindividually with their unmedicated baseline sleep, which is the best way to evaluate drug effects (Wolf et al, 1984). Phenobarbital statistically significantly reduced the sleep onset latency from 11 to 5.6 min and the percentage of REM sleep from 18.5 to 14.5%. The number of periods of waking and movement time after sleep onset was reduced from 19.7 to 11.3
(p < .01), and sleep stage 2 was increased from 43.7 to 47.9% [according to Rechtschaffen and Kales (1968)] (Wolf et al., 1984). Sleep stage 4 was increased in the first sleep cycle only (from 25.4 to 45.1 min and REM sleep started later in each sleep cycle (Wolf et al., 1984). Thus, the usual sleep pattern with maximal deep sleep at the beginning and maximal REM sleep during the second half of the night was accentuated by phenobarbital as deep sleep became still longer early in the night, and REM sleep was further postponed (Wolf et al., 1984). The comparison of the patients with generalized and focal epilepsies revealed the following differences: whereas in patients with generalized epilepsy sleep stages 1-3 were decreased, stages 2-4 of focal patients were increased (Wolf et al.,
1984). Phenobarbital reduced the number of REM interruptions only in the patients with generalized epilepsy (including the patients with awakening epilepsy), which is an interesting finding with respect to the observation that transitions between sleep stages seem to provoke seizure discharges in these patients (Passouant et al, 1975; Billiard, 1982; Halasz, 1991).
The effects of phenytoin on the sleep of epileptic patients as derived from in-traindividual comparison to unmedicated baseline sleep were as follows (Wolf et al., 1984): patients fell asleep more rapidly (5.2 versus 11 min), deep sleep was increased (from 25.9 to 34.2%), and light sleep was decreased (stage 1 from 7.9 to 5.5% and stage 2 from 43.7 to 39.3%). These effects were more pronounced in the second part of the night (third to fifth sleep cycle). Unlike with phenobarbital, the amount and the interruptions of REM sleep remained unchanged with phenytoin. The usual sleep structure seemed to be leveled by phenytoin (Wolf et al., 1984). The comparison of patients with generalized and focal epilepsy revealed only minor insignificant differences. The long-term study (at least 6 months) of phenytoin showed that, as mentioned earlier, the increase of deep sleep and the decrease of light sleep returned to baseline values and only the reduced sleep latency was lasting (R5der-Wanner et al., 1987).
Ethosuximide showed increased light sleep (stage 1) and decreased deep sleep (stages 3 and 4) as compared with unmedicated baseline in patients with generalized epilepsy (Wolf et al., 1985). REM sleep was prolonged in the first sleep cycle (Wolf et al., 1985). Valproic acid led to an increase of light sleep stage 1, but no deep sleep changes occurred; as with ethosuximide, the first sleep cycle was prolonged (Wolf et al., 1985). The effects of valproic acid and ethosuximide on the first sleep cycle may be related to the fact that these drugs were evaluated in patients with generalized epilepsy and these patients showed similar influences of phenytoin and phenobarbital on the first sleep cycle (Wolf et al.,
In summary, there are several effects of antiepileptic drugs on the sleep of patients with generalized epilepsy. However, most drug effects on sleep are nonspecific or temporary. Based on our present knowledge about the sleep of patients with generalized epilepsy, it appears that the antiepileptic effect of the drugs is only little, if at all, related to drug effects on sleep.
Generalized epilepsy and sleep are related in several respects. Epileptic seizures occur predominantly in the first hours after awakening from night sleep or daytime naps in patients with generalized epilepsy such as juvenile myoclonic epilepsy. Sleep deprivation precipitates epileptic seizures.
Electroencephalogram (EEG) studies demonstrated that there is a tendency toward higher discharge rates of generalized epileptiform discharges during NREM sleep than in REM sleep and waking. Arousal and transitions between sleep than in REM sleep and waking. Arousal and transitions between sleep stages seem to facilitate generalized epileptiform discharges.
Very little information is available on the sleep of unmedicated epilepsy patients. Unmedicated patients with generalized epilepsy, who were photosensitive, show significantly more deep sleep than the nonphotosensitive patients with generalized epilepsy (34 versus 27%). No significant difference was found between generalized and focal epilepsy as long as photosensitive patients with generalized epilepsy were excluded.
Antiepileptic drugs have different effects on the sleep of patients with generalized epilepsy. However, there were only minor differences, particularly in the first REM cycle, between patients with generalized epilepsy as compared with patients with focal epilepsy.
In summary, conventional sleep analysis reveals no differences of sleep structure in unmedicated patients with generalized epilepsy as compared with patients with focal epilepsy (if photosensitive patients with generalized epilepsy were excluded). The analysis of sleep microstructure using the cyclic alternating pattern (CAP) may provide a more sophisticated approach to analyze the relation of sleep and generalized epilepsy.
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