- Email: [email protected]
Seizure modulation by sleep and sleep state
Brain Research 1703 (2019) 13–17
Contents lists available at ScienceDirect
Brain Research journal homepage: www.elsevier.com/locate/bres
Review
Seizure modulation by sleep and sleep state Carl W. Bazil Comprehensive Epilepsy Center, Columbia University, 710 West 168th Street, New York, NY 10032, USA
a r t i c l e
i n f o
Article history: Received 4 January 2018 Received in revised form 29 March 2018 Accepted 1 May 2018 Available online 18 May 2018 Keywords: Sleep Epilepsy Anticonvulsant drug Sleep disorder
a b s t r a c t Sleep is a dynamic process, during which the electrical rhythms of the brain orchestrate a complicated progression of changing frequencies, patterns and connectivity. Each stage of sleep is different electrophysiologically from wakefulness, and from other sleep stages. It should be no surprise, then, that the various sleep states influence the origin, suppression, and spread of seizures, and that different seizure types are affected in individual (and sometimes contradictory) ways. While much of the electrical symphony that occurs in both normal and epileptic brains is incompletely understood, at the basic level some interesting and often clinically important influences of the various sleep states have been identified. While interictal epileptiform activity is not a seizure, these markers of epilepsy are affected by sleep. Both initiation and propagation of various seizure types are affected by sleep, and these are discussed separately. Finally, the relationship between sleep and epilepsy is clearly reciprocal, and the final sections will explore the changes in sleep that seizures and antiepileptic drugs can induce. Ó 2018 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Sleep effects on interictal epileptiform discharges. . . . . . . . . . . . . . . . . . . . . . . . Sleep affects the onset of seizures – But this varies by the epilepsy syndrome Effects of the sleep state on seizure propagation . . . . . . . . . . . . . . . . . . . . . . . . . Effects of seizures and the epileptic condition on sleep . . . . . . . . . . . . . . . . . . . Effects of anticonvulsant drugs on sleep and sleep disorders . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sleep is a dynamic process, during which the electrical rhythms of the brain orchestrate a complicated progression of changing frequencies, patterns and connectivity. Each stage of sleep is different electrophysiologically from wakefulness, and from other sleep stages. It should be no surprise, then, that the various sleep states influence the origin, suppression, and spread of seizures, and that different seizure types are affected in individual (and sometimes contradictory) ways. While much of the electrical symphony that occurs in both normal and epileptic brains is incompletely understood, at the basic level some interesting and often clinically important influences of the various sleep states have been identified. While interictal epileptiform activity is not a seizure, these markers of epilepsy are affected by sleep. Both initiation and E-mail address: [email protected] https://doi.org/10.1016/j.brainres.2018.05.003 0006-8993/Ó 2018 Elsevier B.V. All rights reserved.
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propagation of various seizure types are affected by sleep, and these are discussed separately. Finally, the relationship between sleep and epilepsy is clearly reciprocal, and the final sections will explore the changes in sleep that seizures and antiepileptic drugs can induce. 1. Sleep effects on interictal epileptiform discharges While not thought to be seizures, the electrical signal known as interictal epileptiform discharges are clinically important markers of susceptibility to seizures. It is well known that recording of sleep will increase the likelihood of recording these. Recording of overnight sleep improves the yield of interictal epileptiform discharges compared to routine daytime EEGs (Malow et al., 1999), and sleep deprivation has been shown to activate epileptiform discharges independent of sleep duration or depth (Fountain
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C.W. Bazil / Brain Research 1703 (2019) 13–17
et al., 1998). Now that good quality ambulatory EEGs can be obtained, patients can more easily have a full night of recording as an outpatient; while there has been no comparison with inoffice routine EEGs an inpatient EMU study suggest that (if present) interictal epileptiform discharges (IEDs) will be seen in 86% of patients in the first 48 h. Only an additional 3% had IEDs after this time and 12% never had IEDs (Friedman and Hirsch, 2009). Increased epileptiform spikes and sharp waves are seen particularly during the deeper stages of non-REM sleep. Although they are less frequent, interictal epileptiform discharges occurring during REM can be more accurate for definitive localization when patients are evaluated for epilepsy surgery. When more than one epileptic focus is seen during wakefulness or non-REM sleep, discharges persisting during REM sleep are more likely the site of onset for the patient’s seizures (Sammaritano et al., 1991; Malow and Aldrich, 2000). Nobili et al. looked at one syndrome of sleep related epilepsy, continuous spike-waves during slow wave sleep, and correlated epileptiform activity with delta activity (a measure of delta sleep) and sigma activity (related to sleep spindles, and therefore to stage 2 sleep) (Nobili et al., 2001). These authors found that epileptiform activity was increased in lighter non-REM (Stage 2), decreased in slow wave (delta) sleep, and severely decreased in REM. Interictal activity in different syndromes may have distinct associations with sleep, as the decreases shown here during slow wave sleep are clearly different that increases seen with partial epilepsy. Reduction in discharges during REM sleep is, however, consistent in all syndromes. 2. Sleep affects the onset of seizures – But this varies by the epilepsy syndrome The timing of seizures themselves is perhaps the most fascinating, as well as clinically important, aspect of sleep effects on epilepsy. Seizures that occur exclusively during sleep are less disruptive and, while not without risk, are less likely to be associated
with patient injury. Overall seizures that happen exclusively during sleep carry a better prognosis (Park et al., 1998), although this may be less so for focal epilepsy (Yaqub et al., 1997). Some epilepsy syndromes are known to have close relationships with sleep state. Llandau-Kleffner syndrome is a condition of acquired aphasia, with a markedly epileptiform EEG, particularly in sleep and frequently (but not always) with epileptic seizures. Epileptiform activity typically increases during sleep; language deficits have been hypothesized to result from the persistent epileptic discharges, as evidenced by hypometabolism on SPECT (O’Regan et al., 1998). In electrical status epilepticus of sleep (ESES), epileptic discharges are nearly continuous throughout non-REM sleep but resolve with wakefulness. If seizures occur they resolve in adolescence; neurocognitive status also improves around this time however some patients have residual deficits (Loddenkemper et al., 2011). There are a number of syndromes where seizures almost invariably occur during sleep or during sleep-wake transition. Benign epilepsy with centrotemporal spikes (BECTS) has a characteristic clinical picture. Seizures occur predominantly or exclusively during sleep, and consist of hemifacial twitching lasting less than two minutes rarely leading to secondarily generalized convulsions. Characteristic centrotemporal spikes always increase with sleep, typically dramatically (Lerman and Kivity, 1975) Fig. 1). The diagnosis is often possible with clinical description in classic cases, although an EEG is usually performed for confirmation. The universally benign prognosis makes this a particularly important diagnosis. Childhood epilepsy with occipital paroxysms (CEOP, also known as Panayiotopoulos Syndrome) consists of seizures with predominantly visual hallucinations, rarely with secondary generalization and commonly with coexisting migraine symptoms (Kumar and Raju, 2001). There are similarities with BECTs, including age of onset (peaking at 5–6 years of age) and overall good prognosis (Caraballo et al., 2007). In Awakening Grand Mal epilepsy, seizures occur exclusively in the morning hours. In patients with Juvenile Myoclonic Epilepsy,
Fig. 1. Right centrotemporal spikes in a 12 year old boy with benign roldandic epilepsy, seen during N2 sleep.
C.W. Bazil / Brain Research 1703 (2019) 13–17
seizures (both myoclonic and generalized tonic-clonic) tend to occur shortly after awakening; the former can be misdiagnosed as simple morning clumsiness. Frontal lobe epilepsies are frequently a diagnostic challenge for several reasons. The seizures are often unwitnessed, and (when seen) the associated movements can appear random or even voluntary. Awareness during violent movements can suggest nonepileptic events. Prominent choking and abnormal motor activity can lead to a misdiagnosis of sleep apnea (Oldani et al., 1998) or other sleep disturbance (Tachibana et al., 1996). In a review of 100 consecutive cases of nocturnal frontal lobe epilepsy (NFLE) (Provini et al., 1999) twenty-eight percent occurred in stage 3–4 sleep and only 3% during REM. Diagnosis is also more challenging as epileptiform abnormalities on routine EEG are less frequent than in other focal epilepsies (occurring in less than half of patients). Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by enuresis, sudden awakenings with dystonic or dyskinetic movements, complex behavior and violent behavior in sleep (Oldani et al., 1998). Most patients showed ictal or rhythmic activity over the frontal region. Most cases demonstrate autosomal dominant inheritance with reduced penetrance, but not all (Nakken et al., 1999). Focal (or localization related) epilepsy is by far the most common. These patients may have seizures arising from any part of the cerebral cortex, and the semiology is usually defined by the lobe of origin. Independent of the above syndrome of ADNFLE, frontal onset focal seizures occur more frequently during sleep compared to temporal lobe seizures (Crespel et al., 1998; Bazil and Walczak, 1997). Prolonged recordings of electrographic seizures in patients implanted with the responsive neurostimulator also demonstrate different patterns depending on onset. Frontal seizures began preferentially during the night (midnight to 5 a. m.); whereas temporal neocortical and mesial temporal seizures had a more random distribution over the 24 h cycle (Spencer et al., 2016). The circadian pattern of focal seizures may have clinical significance in that seizures occurring exclusively during sleep may represent a subset with an excellent prognosis compared to those that occur in both sleep and wakefulness (Park et al., 1998). One of the most interesting and robust findings across many studies is the relative protection of REM against the occurrence of focal seizures. Several studies in epilepsy patients suggest that seizures are rare during REM (24,25,28) (Bazil and Walczak, 1997; Herman et al., 2001; Kumar and Raju, 2001). It is not clear how the REM state could inhibit the occurrence of seizures or (in the case of temporal lobe seizures) increase the rate of secondary generalization. Electrophysiologically, cerebral activity during REM more closely resembles wakefulness or light sleep, however the above studies show that seizures occur less frequently during REM than either of these states. It may be that relative hypersynchrony present during non-REM sleep may facilitate onset and/or spread of certain partial seizures. This is an important area for future research, as understanding the mechanism whereby REM sleep inhibits seizure onset and propagation could lead to novel treatments for intractable epilepsy.
3. Effects of the sleep state on seizure propagation Sleep not only affects seizure onset, but also influences seizure propagation. Temporal lobe partial seizures, but not frontal lobe seizures, are more likely to generalize when beginning during sleep compared to wakefulness, suggesting differential seizure spread in sleep depending on site of onset (Bazil and Walczak, 1997). Most clinicians believe that sleep deprivation will increase the occurrence of most (if not all) seizure types. This is frequently part of routine counseling for patients in avoiding seizures, and many if
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not most epilepsy monitoring units (where patients actually want to have seizures occur for definitive diagnosis) use sleep deprivation as a provocative measure. While quality sleep is definitely important for epilepsy patients, the relationship with seizure occurrence is actually not clear. In a controlled study of patients with refractory epilepsy in an epilepsy monitoring unit, where patients were randomized to either sleep deprivation every other night or no sleep deprivation, the sleep deprived patients did not have seizures sooner (Malow et al., 2002). It could not be distinguished in this study whether specific subtypes of epilepsy might be sensitive to sleep deprivation. 4. Effects of seizures and the epileptic condition on sleep Not only does sleep affect seizure onset, but seizures have effects on sleep. The epileptic condition itself, however, may not have profound effects on sleep when well controlled. In a polysomnographic study of epilepsy patients without seizures (Crespel et al., 1998), there were no differences in percentage in each sleep stage between frontal and temporal lobe epilepsy patients or between either group and controls. Temporal lobe patients showed increased wakefulness after sleep onset compared with frontal lobe patients, and therefore decreased sleep efficiency. The specific effects of temporal onset focal seizures on sleep structure has been examined in patients undergoing video-EEG monitoring (Bazil et al., 2000). When patients with temporal lobe epilepsy were compared under baseline conditions (seizure free) and following daytime complex partial or secondarily generalized seizures, there was a significant decrease in REM the following night without significant changes in other sleep stages or in sleep efficiency. When seizures occurred at night, this decrease in REM was more pronounced (16% vs. 7%) and there were increases in stage 1 and decreases in sleep efficiency. Perhaps not surprisingly, a report of sleep following partial status epilepticus showed severe inhibition of REM sleep for several days (Bazil and Anderson, 2001). All of these studies show that partial seizures have the capacity for long term disruption of normal sleep, particularly REM, lasting at least through the following night and (in the case of status epilepticus) for several days. This may help explain why many patients with seizures report difficulty functioning the following day, particularly with nocturnal seizures. 5. Effects of anticonvulsant drugs on sleep and sleep disorders Studies looking at the effects of anticonvulsant medications on sleep must be interpreted with caution. As seizures clearly affect sleep, addition of anticonvulsant medications may improve sleep through improved seizure control. When medications are used in polytherapy, there may be pharmacokinetic or pharmacodynamic interactions affecting sleep. Studies in normal subjects would control for these variables, however have not been performed with most medications. Even so, it is possible that anticonvulsants would have different effects on patients with epilepsy, independent of seizures. Placebo controlled studies in patients with epilepsy, while perhaps useful from a scientific standpoint, would place patients at risk for seizures, and these seizures would further confound the results. Despite the above limitations, there is a fair amount known about various anticonvulsants in epilepsy patients. Drowsiness is increased in patients taking carbamazepine, phenytoin, valproic acid, and phenobarbital by the maintenance of wakefulness test (Salinsky et al., 1996) although this study could not distinguish between the drugs. Many agents have been reported to depress REM sleep, including phenobarbital (Kay, 1973; Wolf et al., 1984), phenytoin (Wolf et al., 1984; Legros and Bazil, 2003;
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C.W. Bazil / Brain Research 1703 (2019) 13–17
Table 1 Effects of some AEDs on sleep parameters and disorders.
* +
Sleep parameter/disorder
Drugs that can worsen
Drugs that can improve
Sleep onset Slow wave sleep REM sleep Sleep apnea Restless legs syndrome
Felbamate (rarely levetiracetam, lamotrigine, topiramate, zonisamide) Benzodiazepines Benzodiazepines, phenytoin Benzodiazepines, pregabalin*, valproate* Lamotrigine
Benzodiazepines, phenytoin? Gabapentin, pregabalin Topiramate*, zonisamide* Carbamazepine+, gabapentin+, pregabalin+
Through weight change. Not FDA approved for treatment (gabapentin enacarbil is FDA approved).
Drake et al., 1990), and carbamazepine (43) (Drake et al., 1990; Placidi et al., 2000) but decreased REM may not be present when carbamazepine is used chronically (Placidi et al., 2000). Studies of valproate have shown mild sleep disruption manifested by increased stage 1 sleep (Legros and Bazil, 2003). Of the benzodiazepines, clonazepam and clobazam are used for chronic treatment of seizures. This class of drugs is known to decrease sleep latency (a possible benefit in epilepsy patients with insomnia) however they also decrease the amount of both slow wave and REM sleep (Hindmarch et al., 2005). One study of lamotrigine as add-on therapy showed increased REM (Placidi et al., 2000), but another add-on study showed decreased slow wave sleep with no change in other stages (Foldvary et al., 2001), and a monotherapy study showed no effect on sleep (Legros and Bazil, 2003). Gabapentin has been shown to increase slow wave sleep as monotherapy (Legros and Bazil, 2003) and as add-on therapy (Placidi et al., 2000). REM was increased in one study (Placidi et al., 2000), and sleep quality is improved (Biyik et al., 2013). Pregabalin also increases slow wave sleep and decreases arousals (Bazil et al., 2012). A randomized study of levetiracetam in normal volunteers showed no effect on sleep compared with placebo (Bazil et al., 2005). In a single small study in normal, elderly subjects, tiagabine increased sleep efficiency and slow wave sleep (Mathias et al., 2001). Studies of oxcarbazepine, zonisamide, and topiramate have not previously been published. It is interesting, and perhaps frustrating, that agents with very different mechanisms have similar effects on sleep structure. Probably like many drugs, anticonvulsants affect sleep through multiple potential mechanisms. Anticonvulsants with very different mechanisms can also affect sleep disorders, as outlined in Table 1.
6. Conclusions The complex interplay between sleep, sleep disorders, and epilepsy is important for the care of epilepsy patients on many levels. Diagnostically, the usefulness of sleep and sleep deprived recordings in the complete characterization of patients is well demonstrated. Relationship of seizures to sleep and wakefulness can help in classifying epilepsy syndromes and in prognosis. Even when restricted to sleep, seizures can affect quality of life through sleep disruption, possibly contributing to the memory problems many patients report. Many aspects of memory are known to require quality sleep (Ellenbogen et al., 2007, 2006), particularly REM and slow wave sleep (Stickgold et al., 2000; Beijamini et al., 2014) therefore this should be a consideration not only in counseling patients about sleep but also in choice of anticonvulsant drug. Newer research (including using intracranial electrodes in patients with epilepsy) suggests that the slow oscillations seen during sleep may influence the consolidation of memories from the hippocampus, which could be particularly important in patients with uncontrolled hippocampal onset seizures (Staresina et al., 2015). While exclusively or predominantly nocturnal seizures may be less
disruptive to patients on certain levels, their elimination should still be a primary goal. Finally, the choice of treatment can affect sleep, and this is an important consideration in the total care of the patient with epilepsy. References Bazil, C.W., Anderson, C.T., 2001. Sleep structure following status epilepticus. Sleep Med. 2, 447–449. Bazil, C.W., Castro, L.H., Walczak, T.S., 2000. Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy. Arch. Neurol. 57, 363–368. Bazil, C.W., Walczak, T.S., 1997. Effects of sleep and sleep stage on epileptic and nonepileptic seizures. Epilepsia 38, 56–62. Bazil, C.W., Battista, J., Basner, R.C., 2005. Effects of levetiracetam on sleep in normal volunteers. Epilepsy Behav. 7, 539–542. Bazil, C.W., Dave, J., Cole, J., Stalvey, J., Drake, E., 2012. Pregabalin increases slowwave sleep and may improve attention in patients with partial epilepsy and insomnia. Epilepsy Behav. 23, 422–425. Beijamini, F., Pereira, S.I., Cini, F.A., Louzada, F.M., 2014. After being challenged by a video game problem, sleep increases the chance to solve it. PLoS One 9, e84342. Biyik, Z., Solak, Y., Atalay, H., Gaipov, A., Guney, F., Turk, S., 2013. Gabapentin versus pregabalin in improving sleep quality and depression in hemodialysis patients with peripheral neuropathy: a randomized prospective crossover trial. Int. Urol. Nephrol. 45, 831–837. Caraballo, R., Cersosimo, R., Fejerman, N., 2007. Panayiotopoulos syndrome: a prospective study of 192 patients. Epilepsia 48, 1054–1061. Crespel, A., Baldy-Moulinier, M., Coubes, P., 1998. The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathologic considerations. Epilepsia 39, 150–157. Drake Jr., M.E., Pakalnis, A., Bogner, J.E., Andrews, J.M., 1990. Outpatient sleep recording during antiepileptic drug monotherapy. Clin. Electroencephalogr. 21, 170–173. Ellenbogen, J.M., Hulbert, J.C., Stickgold, R., Dinges, D.F., Thompson-Schill, S.L., 2006. Interfering with theories of sleep and memory: sleep, declarative memory, and associative interference. Curr. Biol. 16, 1290–1294. Ellenbogen, J.M., Hu, P.T., Payne, J.D., Titone, D., Walker, M.P., 2007. Human relational memory requires time and sleep. Proc. Natl. Acad. Sci. USA 104, 7723–7728. Foldvary, N., Perry, M., Lee, J., Dinner, D., Morris, H.H., 2001. The effects of lamotrigine on sleep in patients with epilepsy. Epilepsia 42, 1569–1573. Fountain, N.B., Kim, J.S., Lee, S.I., 1998. Sleep deprivation activates epileptiform discharges independent of the activating effects of sleep. J. Clin. Neurophys. 15, 69–75. Friedman, D.E., Hirsch, L.J., 2009. How long does it take to make an accurate diagnosis in an epilepsy monitoring unit? J. Clin. Neurophys. 26, 213–217. Herman, S.T., Walczak, T.S., Bazil, C.W., 2001. Distribution of partial seizures during the sleep–wake cycle: differences by seizure onset site. Neurology 56, 1453–1459. Hindmarch, I., Dawson, J., Stanley, N., 2005. A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep 28, 187–193. Kay, D.C., 1973. Sleep and some psychoactive drugs. Psychosomatics 14, 108–124. Kumar, P., Raju, T.R., 2001. Seizure susceptibility decreases with enhancement of rapid eye movement sleep. Brain Res. 922, 299–304. Legros, B., Bazil, C.W., 2003. Effects of antiepileptic drugs on sleep architecture: a pilot study. Sleep Med. 4, 51–55. Lerman, P., Kivity, S., 1975. Benign focal epilepsy of childhood. A follow-up study of 100 recovered patients. Arch. Neurol. 32, 261–264. Loddenkemper, T., Fernandez, I.S., Peters, J.M., 2011. Continuous spike and waves during sleep and electrical status epilepticus in sleep. J. Clin. Neurophys. 28, 154–164. Malow, B.A., Aldrich, M.S., 2000. Localizing value of rapid eye movement sleep in temporal lobe epilepsy. Sleep Med. 1, 57–60. Malow, B.A., Selwa, L.M., Ross, D., Aldrich, M.S., 1999. Lateralizing value of interictal spikes on overnight sleep-EEG studies in temporal lobe epilepsy. Epilepsia 40, 1587–1592. Malow, B.A., Passaro, E., Milling, C., Minecan, D.N., Levy, K., 2002. Sleep deprivation does not affect seizure frequency during inpatient video-EEG monitoring. Neurology 59, 1371–1374.
C.W. Bazil / Brain Research 1703 (2019) 13–17 Mathias, S., Wetter, T.C., Steiger, A., Lancel, M., 2001. The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects. Neurobiol. Aging 22, 247–253. Nakken, K.O., Magnusson, A., Steinlein, O.K., 1999. Autosomal dominant nocturnal frontal lobe epilepsy: an electroclinical study of a Norwegian family with ten affected members. Epilepsia 40, 88–92. Nobili, L., Baglietto, M.G., Beelke, M., et al., 2001. Distribution of epileptiform discharges during nREM sleep in the CSWSS syndrome: relationship with sigma and delta activities. Epilepsy Res. 44, 119–128. Oldani, A., Zucconi, M., Smirne, S., Ferini-Strambi, L., 1998. The neurophysiological evaluation of nocturnal frontal lobe epilepsy. Seizure 7, 317–320. Oldani, A., Zucconi, M., Asselta, R., et al., 1998. Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome. Brain 121 (Pt 2), 205–223. O’Regan, M.E., Brown, J.K., Goodwin, G.M., Clarke, M., 1998. Epileptic aphasia: a consequence of regional hypometabolic encephalopathy? Dev. Med. Child Neurol. 40, 508–516. Park, S.A., Lee, B.I., Park, S.C., et al., 1998. Clinical courses of pure sleep epilepsies. Seizure 7, 369–377. Placidi, F., Diomedi, M., Scalise, A., Marciani, M.G., Romigi, A., Gigli, G.L., 2000. Effect of anticonvulsants on nocturnal sleep in epilepsy. Neurology 54, S25–S32. Provini, F., Plazzi, G., Tinuper, P., Vandi, S., Lugaresi, E., Montagna, P., 1999. Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases. Brain 122 (Pt 6), 1017–1031.
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Salinsky, M.C., Oken, B.S., Binder, L.M., 1996. Assessment of drowsiness in epilepsy patients receiving chronic antiepileptic drug therapy. Epilepsia 37, 181–187. Sammaritano, M., Gigli, G.L., Gotman, J., 1991. Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology 41, 290–297. Spencer, D.C., Sun, F.T., Brown, S.N., et al., 2016. Circadian and ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring. Epilepsia 57, 1495–1502. Staresina, B.P., Bergmann, T.O., Bonnefond, M., et al., 2015. Hierarchical nesting of slow oscillations, spindles and ripples in the human hippocampus during sleep. Nat. Neurosci. 18, 1679–1686. Stickgold, R., Whidbee, D., Schirmer, B., Patel, V., Hobson, J.A., 2000. Visual discrimination task improvement: a multi-step process occurring during sleep. J. Cogn. Neurosci. 12, 246–254. Tachibana, N., Shinde, A., Ikeda, A., Akiguchi, I., Kimura, J., Shibasaki, H., 1996. Supplementary motor area seizure resembling sleep disorder. Sleep 19, 811– 816. Wolf, P., Roder-Wanner, U.U., Brede, M., 1984. Influence of therapeutic phenobarbital and phenytoin medication on the polygraphic sleep of patients with epilepsy. Epilepsia 25, 467–475. Yaqub, B.A., Waheed, G., Kabiraj, M.M., 1997. Nocturnal epilepsies in adults. Seizure 6, 145–149.
Contents lists available at ScienceDirect
Brain Research journal homepage: www.elsevier.com/locate/bres
Review
Seizure modulation by sleep and sleep state Carl W. Bazil Comprehensive Epilepsy Center, Columbia University, 710 West 168th Street, New York, NY 10032, USA
a r t i c l e
i n f o
Article history: Received 4 January 2018 Received in revised form 29 March 2018 Accepted 1 May 2018 Available online 18 May 2018 Keywords: Sleep Epilepsy Anticonvulsant drug Sleep disorder
a b s t r a c t Sleep is a dynamic process, during which the electrical rhythms of the brain orchestrate a complicated progression of changing frequencies, patterns and connectivity. Each stage of sleep is different electrophysiologically from wakefulness, and from other sleep stages. It should be no surprise, then, that the various sleep states influence the origin, suppression, and spread of seizures, and that different seizure types are affected in individual (and sometimes contradictory) ways. While much of the electrical symphony that occurs in both normal and epileptic brains is incompletely understood, at the basic level some interesting and often clinically important influences of the various sleep states have been identified. While interictal epileptiform activity is not a seizure, these markers of epilepsy are affected by sleep. Both initiation and propagation of various seizure types are affected by sleep, and these are discussed separately. Finally, the relationship between sleep and epilepsy is clearly reciprocal, and the final sections will explore the changes in sleep that seizures and antiepileptic drugs can induce. Ó 2018 Elsevier B.V. All rights reserved.
Contents 1. 2. 3. 4. 5. 6.
Sleep effects on interictal epileptiform discharges. . . . . . . . . . . . . . . . . . . . . . . . Sleep affects the onset of seizures – But this varies by the epilepsy syndrome Effects of the sleep state on seizure propagation . . . . . . . . . . . . . . . . . . . . . . . . . Effects of seizures and the epileptic condition on sleep . . . . . . . . . . . . . . . . . . . Effects of anticonvulsant drugs on sleep and sleep disorders . . . . . . . . . . . . . . . Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Sleep is a dynamic process, during which the electrical rhythms of the brain orchestrate a complicated progression of changing frequencies, patterns and connectivity. Each stage of sleep is different electrophysiologically from wakefulness, and from other sleep stages. It should be no surprise, then, that the various sleep states influence the origin, suppression, and spread of seizures, and that different seizure types are affected in individual (and sometimes contradictory) ways. While much of the electrical symphony that occurs in both normal and epileptic brains is incompletely understood, at the basic level some interesting and often clinically important influences of the various sleep states have been identified. While interictal epileptiform activity is not a seizure, these markers of epilepsy are affected by sleep. Both initiation and E-mail address: [email protected] https://doi.org/10.1016/j.brainres.2018.05.003 0006-8993/Ó 2018 Elsevier B.V. All rights reserved.
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propagation of various seizure types are affected by sleep, and these are discussed separately. Finally, the relationship between sleep and epilepsy is clearly reciprocal, and the final sections will explore the changes in sleep that seizures and antiepileptic drugs can induce. 1. Sleep effects on interictal epileptiform discharges While not thought to be seizures, the electrical signal known as interictal epileptiform discharges are clinically important markers of susceptibility to seizures. It is well known that recording of sleep will increase the likelihood of recording these. Recording of overnight sleep improves the yield of interictal epileptiform discharges compared to routine daytime EEGs (Malow et al., 1999), and sleep deprivation has been shown to activate epileptiform discharges independent of sleep duration or depth (Fountain
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C.W. Bazil / Brain Research 1703 (2019) 13–17
et al., 1998). Now that good quality ambulatory EEGs can be obtained, patients can more easily have a full night of recording as an outpatient; while there has been no comparison with inoffice routine EEGs an inpatient EMU study suggest that (if present) interictal epileptiform discharges (IEDs) will be seen in 86% of patients in the first 48 h. Only an additional 3% had IEDs after this time and 12% never had IEDs (Friedman and Hirsch, 2009). Increased epileptiform spikes and sharp waves are seen particularly during the deeper stages of non-REM sleep. Although they are less frequent, interictal epileptiform discharges occurring during REM can be more accurate for definitive localization when patients are evaluated for epilepsy surgery. When more than one epileptic focus is seen during wakefulness or non-REM sleep, discharges persisting during REM sleep are more likely the site of onset for the patient’s seizures (Sammaritano et al., 1991; Malow and Aldrich, 2000). Nobili et al. looked at one syndrome of sleep related epilepsy, continuous spike-waves during slow wave sleep, and correlated epileptiform activity with delta activity (a measure of delta sleep) and sigma activity (related to sleep spindles, and therefore to stage 2 sleep) (Nobili et al., 2001). These authors found that epileptiform activity was increased in lighter non-REM (Stage 2), decreased in slow wave (delta) sleep, and severely decreased in REM. Interictal activity in different syndromes may have distinct associations with sleep, as the decreases shown here during slow wave sleep are clearly different that increases seen with partial epilepsy. Reduction in discharges during REM sleep is, however, consistent in all syndromes. 2. Sleep affects the onset of seizures – But this varies by the epilepsy syndrome The timing of seizures themselves is perhaps the most fascinating, as well as clinically important, aspect of sleep effects on epilepsy. Seizures that occur exclusively during sleep are less disruptive and, while not without risk, are less likely to be associated
with patient injury. Overall seizures that happen exclusively during sleep carry a better prognosis (Park et al., 1998), although this may be less so for focal epilepsy (Yaqub et al., 1997). Some epilepsy syndromes are known to have close relationships with sleep state. Llandau-Kleffner syndrome is a condition of acquired aphasia, with a markedly epileptiform EEG, particularly in sleep and frequently (but not always) with epileptic seizures. Epileptiform activity typically increases during sleep; language deficits have been hypothesized to result from the persistent epileptic discharges, as evidenced by hypometabolism on SPECT (O’Regan et al., 1998). In electrical status epilepticus of sleep (ESES), epileptic discharges are nearly continuous throughout non-REM sleep but resolve with wakefulness. If seizures occur they resolve in adolescence; neurocognitive status also improves around this time however some patients have residual deficits (Loddenkemper et al., 2011). There are a number of syndromes where seizures almost invariably occur during sleep or during sleep-wake transition. Benign epilepsy with centrotemporal spikes (BECTS) has a characteristic clinical picture. Seizures occur predominantly or exclusively during sleep, and consist of hemifacial twitching lasting less than two minutes rarely leading to secondarily generalized convulsions. Characteristic centrotemporal spikes always increase with sleep, typically dramatically (Lerman and Kivity, 1975) Fig. 1). The diagnosis is often possible with clinical description in classic cases, although an EEG is usually performed for confirmation. The universally benign prognosis makes this a particularly important diagnosis. Childhood epilepsy with occipital paroxysms (CEOP, also known as Panayiotopoulos Syndrome) consists of seizures with predominantly visual hallucinations, rarely with secondary generalization and commonly with coexisting migraine symptoms (Kumar and Raju, 2001). There are similarities with BECTs, including age of onset (peaking at 5–6 years of age) and overall good prognosis (Caraballo et al., 2007). In Awakening Grand Mal epilepsy, seizures occur exclusively in the morning hours. In patients with Juvenile Myoclonic Epilepsy,
Fig. 1. Right centrotemporal spikes in a 12 year old boy with benign roldandic epilepsy, seen during N2 sleep.
C.W. Bazil / Brain Research 1703 (2019) 13–17
seizures (both myoclonic and generalized tonic-clonic) tend to occur shortly after awakening; the former can be misdiagnosed as simple morning clumsiness. Frontal lobe epilepsies are frequently a diagnostic challenge for several reasons. The seizures are often unwitnessed, and (when seen) the associated movements can appear random or even voluntary. Awareness during violent movements can suggest nonepileptic events. Prominent choking and abnormal motor activity can lead to a misdiagnosis of sleep apnea (Oldani et al., 1998) or other sleep disturbance (Tachibana et al., 1996). In a review of 100 consecutive cases of nocturnal frontal lobe epilepsy (NFLE) (Provini et al., 1999) twenty-eight percent occurred in stage 3–4 sleep and only 3% during REM. Diagnosis is also more challenging as epileptiform abnormalities on routine EEG are less frequent than in other focal epilepsies (occurring in less than half of patients). Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is characterized by enuresis, sudden awakenings with dystonic or dyskinetic movements, complex behavior and violent behavior in sleep (Oldani et al., 1998). Most patients showed ictal or rhythmic activity over the frontal region. Most cases demonstrate autosomal dominant inheritance with reduced penetrance, but not all (Nakken et al., 1999). Focal (or localization related) epilepsy is by far the most common. These patients may have seizures arising from any part of the cerebral cortex, and the semiology is usually defined by the lobe of origin. Independent of the above syndrome of ADNFLE, frontal onset focal seizures occur more frequently during sleep compared to temporal lobe seizures (Crespel et al., 1998; Bazil and Walczak, 1997). Prolonged recordings of electrographic seizures in patients implanted with the responsive neurostimulator also demonstrate different patterns depending on onset. Frontal seizures began preferentially during the night (midnight to 5 a. m.); whereas temporal neocortical and mesial temporal seizures had a more random distribution over the 24 h cycle (Spencer et al., 2016). The circadian pattern of focal seizures may have clinical significance in that seizures occurring exclusively during sleep may represent a subset with an excellent prognosis compared to those that occur in both sleep and wakefulness (Park et al., 1998). One of the most interesting and robust findings across many studies is the relative protection of REM against the occurrence of focal seizures. Several studies in epilepsy patients suggest that seizures are rare during REM (24,25,28) (Bazil and Walczak, 1997; Herman et al., 2001; Kumar and Raju, 2001). It is not clear how the REM state could inhibit the occurrence of seizures or (in the case of temporal lobe seizures) increase the rate of secondary generalization. Electrophysiologically, cerebral activity during REM more closely resembles wakefulness or light sleep, however the above studies show that seizures occur less frequently during REM than either of these states. It may be that relative hypersynchrony present during non-REM sleep may facilitate onset and/or spread of certain partial seizures. This is an important area for future research, as understanding the mechanism whereby REM sleep inhibits seizure onset and propagation could lead to novel treatments for intractable epilepsy.
3. Effects of the sleep state on seizure propagation Sleep not only affects seizure onset, but also influences seizure propagation. Temporal lobe partial seizures, but not frontal lobe seizures, are more likely to generalize when beginning during sleep compared to wakefulness, suggesting differential seizure spread in sleep depending on site of onset (Bazil and Walczak, 1997). Most clinicians believe that sleep deprivation will increase the occurrence of most (if not all) seizure types. This is frequently part of routine counseling for patients in avoiding seizures, and many if
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not most epilepsy monitoring units (where patients actually want to have seizures occur for definitive diagnosis) use sleep deprivation as a provocative measure. While quality sleep is definitely important for epilepsy patients, the relationship with seizure occurrence is actually not clear. In a controlled study of patients with refractory epilepsy in an epilepsy monitoring unit, where patients were randomized to either sleep deprivation every other night or no sleep deprivation, the sleep deprived patients did not have seizures sooner (Malow et al., 2002). It could not be distinguished in this study whether specific subtypes of epilepsy might be sensitive to sleep deprivation. 4. Effects of seizures and the epileptic condition on sleep Not only does sleep affect seizure onset, but seizures have effects on sleep. The epileptic condition itself, however, may not have profound effects on sleep when well controlled. In a polysomnographic study of epilepsy patients without seizures (Crespel et al., 1998), there were no differences in percentage in each sleep stage between frontal and temporal lobe epilepsy patients or between either group and controls. Temporal lobe patients showed increased wakefulness after sleep onset compared with frontal lobe patients, and therefore decreased sleep efficiency. The specific effects of temporal onset focal seizures on sleep structure has been examined in patients undergoing video-EEG monitoring (Bazil et al., 2000). When patients with temporal lobe epilepsy were compared under baseline conditions (seizure free) and following daytime complex partial or secondarily generalized seizures, there was a significant decrease in REM the following night without significant changes in other sleep stages or in sleep efficiency. When seizures occurred at night, this decrease in REM was more pronounced (16% vs. 7%) and there were increases in stage 1 and decreases in sleep efficiency. Perhaps not surprisingly, a report of sleep following partial status epilepticus showed severe inhibition of REM sleep for several days (Bazil and Anderson, 2001). All of these studies show that partial seizures have the capacity for long term disruption of normal sleep, particularly REM, lasting at least through the following night and (in the case of status epilepticus) for several days. This may help explain why many patients with seizures report difficulty functioning the following day, particularly with nocturnal seizures. 5. Effects of anticonvulsant drugs on sleep and sleep disorders Studies looking at the effects of anticonvulsant medications on sleep must be interpreted with caution. As seizures clearly affect sleep, addition of anticonvulsant medications may improve sleep through improved seizure control. When medications are used in polytherapy, there may be pharmacokinetic or pharmacodynamic interactions affecting sleep. Studies in normal subjects would control for these variables, however have not been performed with most medications. Even so, it is possible that anticonvulsants would have different effects on patients with epilepsy, independent of seizures. Placebo controlled studies in patients with epilepsy, while perhaps useful from a scientific standpoint, would place patients at risk for seizures, and these seizures would further confound the results. Despite the above limitations, there is a fair amount known about various anticonvulsants in epilepsy patients. Drowsiness is increased in patients taking carbamazepine, phenytoin, valproic acid, and phenobarbital by the maintenance of wakefulness test (Salinsky et al., 1996) although this study could not distinguish between the drugs. Many agents have been reported to depress REM sleep, including phenobarbital (Kay, 1973; Wolf et al., 1984), phenytoin (Wolf et al., 1984; Legros and Bazil, 2003;
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Table 1 Effects of some AEDs on sleep parameters and disorders.
* +
Sleep parameter/disorder
Drugs that can worsen
Drugs that can improve
Sleep onset Slow wave sleep REM sleep Sleep apnea Restless legs syndrome
Felbamate (rarely levetiracetam, lamotrigine, topiramate, zonisamide) Benzodiazepines Benzodiazepines, phenytoin Benzodiazepines, pregabalin*, valproate* Lamotrigine
Benzodiazepines, phenytoin? Gabapentin, pregabalin Topiramate*, zonisamide* Carbamazepine+, gabapentin+, pregabalin+
Through weight change. Not FDA approved for treatment (gabapentin enacarbil is FDA approved).
Drake et al., 1990), and carbamazepine (43) (Drake et al., 1990; Placidi et al., 2000) but decreased REM may not be present when carbamazepine is used chronically (Placidi et al., 2000). Studies of valproate have shown mild sleep disruption manifested by increased stage 1 sleep (Legros and Bazil, 2003). Of the benzodiazepines, clonazepam and clobazam are used for chronic treatment of seizures. This class of drugs is known to decrease sleep latency (a possible benefit in epilepsy patients with insomnia) however they also decrease the amount of both slow wave and REM sleep (Hindmarch et al., 2005). One study of lamotrigine as add-on therapy showed increased REM (Placidi et al., 2000), but another add-on study showed decreased slow wave sleep with no change in other stages (Foldvary et al., 2001), and a monotherapy study showed no effect on sleep (Legros and Bazil, 2003). Gabapentin has been shown to increase slow wave sleep as monotherapy (Legros and Bazil, 2003) and as add-on therapy (Placidi et al., 2000). REM was increased in one study (Placidi et al., 2000), and sleep quality is improved (Biyik et al., 2013). Pregabalin also increases slow wave sleep and decreases arousals (Bazil et al., 2012). A randomized study of levetiracetam in normal volunteers showed no effect on sleep compared with placebo (Bazil et al., 2005). In a single small study in normal, elderly subjects, tiagabine increased sleep efficiency and slow wave sleep (Mathias et al., 2001). Studies of oxcarbazepine, zonisamide, and topiramate have not previously been published. It is interesting, and perhaps frustrating, that agents with very different mechanisms have similar effects on sleep structure. Probably like many drugs, anticonvulsants affect sleep through multiple potential mechanisms. Anticonvulsants with very different mechanisms can also affect sleep disorders, as outlined in Table 1.
6. Conclusions The complex interplay between sleep, sleep disorders, and epilepsy is important for the care of epilepsy patients on many levels. Diagnostically, the usefulness of sleep and sleep deprived recordings in the complete characterization of patients is well demonstrated. Relationship of seizures to sleep and wakefulness can help in classifying epilepsy syndromes and in prognosis. Even when restricted to sleep, seizures can affect quality of life through sleep disruption, possibly contributing to the memory problems many patients report. Many aspects of memory are known to require quality sleep (Ellenbogen et al., 2007, 2006), particularly REM and slow wave sleep (Stickgold et al., 2000; Beijamini et al., 2014) therefore this should be a consideration not only in counseling patients about sleep but also in choice of anticonvulsant drug. Newer research (including using intracranial electrodes in patients with epilepsy) suggests that the slow oscillations seen during sleep may influence the consolidation of memories from the hippocampus, which could be particularly important in patients with uncontrolled hippocampal onset seizures (Staresina et al., 2015). While exclusively or predominantly nocturnal seizures may be less
disruptive to patients on certain levels, their elimination should still be a primary goal. Finally, the choice of treatment can affect sleep, and this is an important consideration in the total care of the patient with epilepsy. References Bazil, C.W., Anderson, C.T., 2001. Sleep structure following status epilepticus. Sleep Med. 2, 447–449. Bazil, C.W., Castro, L.H., Walczak, T.S., 2000. Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy. Arch. Neurol. 57, 363–368. Bazil, C.W., Walczak, T.S., 1997. Effects of sleep and sleep stage on epileptic and nonepileptic seizures. Epilepsia 38, 56–62. Bazil, C.W., Battista, J., Basner, R.C., 2005. Effects of levetiracetam on sleep in normal volunteers. Epilepsy Behav. 7, 539–542. Bazil, C.W., Dave, J., Cole, J., Stalvey, J., Drake, E., 2012. Pregabalin increases slowwave sleep and may improve attention in patients with partial epilepsy and insomnia. Epilepsy Behav. 23, 422–425. Beijamini, F., Pereira, S.I., Cini, F.A., Louzada, F.M., 2014. After being challenged by a video game problem, sleep increases the chance to solve it. PLoS One 9, e84342. Biyik, Z., Solak, Y., Atalay, H., Gaipov, A., Guney, F., Turk, S., 2013. Gabapentin versus pregabalin in improving sleep quality and depression in hemodialysis patients with peripheral neuropathy: a randomized prospective crossover trial. Int. Urol. Nephrol. 45, 831–837. Caraballo, R., Cersosimo, R., Fejerman, N., 2007. Panayiotopoulos syndrome: a prospective study of 192 patients. Epilepsia 48, 1054–1061. Crespel, A., Baldy-Moulinier, M., Coubes, P., 1998. The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathologic considerations. Epilepsia 39, 150–157. Drake Jr., M.E., Pakalnis, A., Bogner, J.E., Andrews, J.M., 1990. Outpatient sleep recording during antiepileptic drug monotherapy. Clin. Electroencephalogr. 21, 170–173. Ellenbogen, J.M., Hulbert, J.C., Stickgold, R., Dinges, D.F., Thompson-Schill, S.L., 2006. Interfering with theories of sleep and memory: sleep, declarative memory, and associative interference. Curr. Biol. 16, 1290–1294. Ellenbogen, J.M., Hu, P.T., Payne, J.D., Titone, D., Walker, M.P., 2007. Human relational memory requires time and sleep. Proc. Natl. Acad. Sci. USA 104, 7723–7728. Foldvary, N., Perry, M., Lee, J., Dinner, D., Morris, H.H., 2001. The effects of lamotrigine on sleep in patients with epilepsy. Epilepsia 42, 1569–1573. Fountain, N.B., Kim, J.S., Lee, S.I., 1998. Sleep deprivation activates epileptiform discharges independent of the activating effects of sleep. J. Clin. Neurophys. 15, 69–75. Friedman, D.E., Hirsch, L.J., 2009. How long does it take to make an accurate diagnosis in an epilepsy monitoring unit? J. Clin. Neurophys. 26, 213–217. Herman, S.T., Walczak, T.S., Bazil, C.W., 2001. Distribution of partial seizures during the sleep–wake cycle: differences by seizure onset site. Neurology 56, 1453–1459. Hindmarch, I., Dawson, J., Stanley, N., 2005. A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep 28, 187–193. Kay, D.C., 1973. Sleep and some psychoactive drugs. Psychosomatics 14, 108–124. Kumar, P., Raju, T.R., 2001. Seizure susceptibility decreases with enhancement of rapid eye movement sleep. Brain Res. 922, 299–304. Legros, B., Bazil, C.W., 2003. Effects of antiepileptic drugs on sleep architecture: a pilot study. Sleep Med. 4, 51–55. Lerman, P., Kivity, S., 1975. Benign focal epilepsy of childhood. A follow-up study of 100 recovered patients. Arch. Neurol. 32, 261–264. Loddenkemper, T., Fernandez, I.S., Peters, J.M., 2011. Continuous spike and waves during sleep and electrical status epilepticus in sleep. J. Clin. Neurophys. 28, 154–164. Malow, B.A., Aldrich, M.S., 2000. Localizing value of rapid eye movement sleep in temporal lobe epilepsy. Sleep Med. 1, 57–60. Malow, B.A., Selwa, L.M., Ross, D., Aldrich, M.S., 1999. Lateralizing value of interictal spikes on overnight sleep-EEG studies in temporal lobe epilepsy. Epilepsia 40, 1587–1592. Malow, B.A., Passaro, E., Milling, C., Minecan, D.N., Levy, K., 2002. Sleep deprivation does not affect seizure frequency during inpatient video-EEG monitoring. Neurology 59, 1371–1374.
C.W. Bazil / Brain Research 1703 (2019) 13–17 Mathias, S., Wetter, T.C., Steiger, A., Lancel, M., 2001. The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects. Neurobiol. Aging 22, 247–253. Nakken, K.O., Magnusson, A., Steinlein, O.K., 1999. Autosomal dominant nocturnal frontal lobe epilepsy: an electroclinical study of a Norwegian family with ten affected members. Epilepsia 40, 88–92. Nobili, L., Baglietto, M.G., Beelke, M., et al., 2001. Distribution of epileptiform discharges during nREM sleep in the CSWSS syndrome: relationship with sigma and delta activities. Epilepsy Res. 44, 119–128. Oldani, A., Zucconi, M., Smirne, S., Ferini-Strambi, L., 1998. The neurophysiological evaluation of nocturnal frontal lobe epilepsy. Seizure 7, 317–320. Oldani, A., Zucconi, M., Asselta, R., et al., 1998. Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome. Brain 121 (Pt 2), 205–223. O’Regan, M.E., Brown, J.K., Goodwin, G.M., Clarke, M., 1998. Epileptic aphasia: a consequence of regional hypometabolic encephalopathy? Dev. Med. Child Neurol. 40, 508–516. Park, S.A., Lee, B.I., Park, S.C., et al., 1998. Clinical courses of pure sleep epilepsies. Seizure 7, 369–377. Placidi, F., Diomedi, M., Scalise, A., Marciani, M.G., Romigi, A., Gigli, G.L., 2000. Effect of anticonvulsants on nocturnal sleep in epilepsy. Neurology 54, S25–S32. Provini, F., Plazzi, G., Tinuper, P., Vandi, S., Lugaresi, E., Montagna, P., 1999. Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases. Brain 122 (Pt 6), 1017–1031.
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Salinsky, M.C., Oken, B.S., Binder, L.M., 1996. Assessment of drowsiness in epilepsy patients receiving chronic antiepileptic drug therapy. Epilepsia 37, 181–187. Sammaritano, M., Gigli, G.L., Gotman, J., 1991. Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology 41, 290–297. Spencer, D.C., Sun, F.T., Brown, S.N., et al., 2016. Circadian and ultradian patterns of epileptiform discharges differ by seizure-onset location during long-term ambulatory intracranial monitoring. Epilepsia 57, 1495–1502. Staresina, B.P., Bergmann, T.O., Bonnefond, M., et al., 2015. Hierarchical nesting of slow oscillations, spindles and ripples in the human hippocampus during sleep. Nat. Neurosci. 18, 1679–1686. Stickgold, R., Whidbee, D., Schirmer, B., Patel, V., Hobson, J.A., 2000. Visual discrimination task improvement: a multi-step process occurring during sleep. J. Cogn. Neurosci. 12, 246–254. Tachibana, N., Shinde, A., Ikeda, A., Akiguchi, I., Kimura, J., Shibasaki, H., 1996. Supplementary motor area seizure resembling sleep disorder. Sleep 19, 811– 816. Wolf, P., Roder-Wanner, U.U., Brede, M., 1984. Influence of therapeutic phenobarbital and phenytoin medication on the polygraphic sleep of patients with epilepsy. Epilepsia 25, 467–475. Yaqub, B.A., Waheed, G., Kabiraj, M.M., 1997. Nocturnal epilepsies in adults. Seizure 6, 145–149.