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Sleep influence on seizures and epilepsy effects on sleep in partial frontal and temporal lobe epilepsies
Clinical Neurophysiology 111, Suppl. 2 (2000) S54±S59
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Sleep in¯uence on seizures and epilepsy effects on sleep in partial frontal and temporal lobe epilepsies Arielle Crespel*, Philippe Coubes, Michel Baldy-Moulinier Epilepsy Unit, Gui de Chauliac Hospital, Montpellier, France
Abstract Objectives: A reciprocal effect is observed between sleep and epilepsy. Sleep effect on epilepsy is protective and facilitating. Reciprocally epilepsy alters sleep organization and microarchitecture. This interelationship is well established for some epilepsies but remains unde®ned for cryptogenic and symptomatic frontal and temporal lobe epilepsies. In order to research sleep in¯uence on seizures and epilepsy effects on sleep we carried out two studies in patients with cryptogenic/symptomatic frontal or temporal lobe epilepsies. Methods: The occurrence of seizures in relation to the state of alertness was analyzed in patients with (1) mesial temporal and frontal lobe epilepsy, and (2) in patients with mesio-lateral temporal and mesial temporal lobe epilepsy in several conditions. Sleep analysis (organization and microarchitecture) was realized. Results: We found: (1) a precise relationship between sleep and seizures in frontal lobe epilepsy (FLE); (2) a precise relationship between wakefulness and seizures in temporal lobe epilepsy (TLE); (3) sleep organization was normal in FLE and altered in TLE; (4) alterations of sleep microarchitecture in FLE and TLE. Conclusions: Seizure occurrence was mainly in relation to sleep for FLE and to wakefulness for TLE. Sleep organization appeared more altered for TLE than FLE. These results allow practical applications to localize and study FLE and TLE. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Epilepsy; Frontal lobe epilepsy; Temporal lobe epilepsy; Sleep; Sleep organization
1.1.1. Effect of sleep on epilepsy It appears that according to the kind of epilepsy, sleep may have a facilitating or precipitating effect on seizures or else a protective effect against epilepsy (Baldy-Moulinier, 1986). The protective effect is suggested by the occurrence
of seizures after sleep deprivation. This effect was well established for the grand mal epilepsies of awakening de®ned by Janz (1953). The facilitating effect is suggested by: (1) the existence of sleep epilepsies, called `morpheic epilepsies' (Passouant et al., 1951; Baldy-Moulinier et al., 1984); (2) the increase of interictal discharging during sleep (Gibbs and Gibbs, 1947; Broughton, 1984); and (3) the relationship between the production of sleep spindles and epileptic discharges (Gloor, 1979; Kostopoulos et al., 1981; Niedermeyer, 1982). The different stages of sleep may have a different effect on interictal discharge production. In slowwave (non-rapid eye movement or NREM) sleep, particularly in stage 2, a synchronizing effect is shown by an increase and a spreading of the interictal abnormalities. Rapid eye movement (REM) sleep prevented generalized discharges of generalized epilepsies and facilitated localized abnormalities of partial epilepsies (Baldy-Moulinier, 1982; Cadilhac, 1982; Passouant, 1982; Billiard et al., 1987; Shouse, 1987).
* Corresponding author. Service Explorations Neurologiques et Epileptologie, HoÃpital Gui de Chauliac, 80 avenue A. Fliche, 34295 Montpellier Cedex 05, France. Tel.: 133-4-67-33-72-40; fax: 133-4-67-33-76-23. E-mail address: [email protected] (A. Crespel).
1.1.2. Effect of epilepsy on sleep Reciprocally, epilepsy alters the organization and microarchitecture of sleep: ®rstly, by the acute effect of a seizure
1. Introduction In ancient times, Aristotle and Hippocrates indicated the relationship between sleep and epilepsy and inaugurated research studies on the distribution of seizures during the sleep-waking cycle. After a long period limited to clinical observation, the study of this relationship has bene®ted from the contribution of electroencephalography and, more recently, of nocturnal polygraphic and video EEG recordings (Broughton, 1990). 1.1. Relationship between sleep and epilepsy: a reciprocal effect
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during sleep, disrupting continuity, and secondly, by the chronic effect of epilepsy, impairing the organization and altering the microarchitecture of sleep. These modi®cations differ according to the kind of epilepsy. A decrease in total sleep time, wakefulness after sleep onset and sleep ef®ciency index, an increase in sleep onset latency, ®rst REM delay and percentage of the stage 2 non-REM rate with a decrease in the percentage of REM sleep rate have been reported (Baldy-Moulinier, 1982; Besset, 1982; Declerck, 1982; Hamel and Sterman, 1982; Montplaisir et al., 1982; Touchon et al., 1991). This reciprocal acute and chronic action of sleep and epilepsy may constitute a spiral, enabling the facilitation of seizure and/or diurnal sleepiness by chronic sleep deprivation. An alteration of sleep microarchitecture is also observed. The K-complexes have medial frontal localization (Niedermeyer, 1982), and are preceded and followed by spikes (`K-epileptic complex'; Passouant, 1982). There is a decrease of spindle density (Declerck, 1982; Hamel and Sterman, 1982). An anti-epileptic drug action was reported. Thus, on the newly-diagnosed temporal epilepsies it has been shown that carbamazepine improves the altered organization of sleep (Touchon and BaldyMoulinier, 1987). The possibility of modi®cation or not of sleep organization by different anti-convulsants has been shown in other studies (Gigli et al., 1998; Placidi et al., 2000; Sammaritano and Sherwin, 2000). The physiopathological mechanisms that underlie this relationship between sleep and epilepsy remain unclear and hypothetical. An action of the inputs of the ascending neurotransmitter systems and their changes with sleep-waking states and the subcortical synchronizing systems or inhibitory systems may be involved. The thalamo-cortical volleys, the local conditions and the different degrees of responsiveness to sleep-regulating factors may play a role in this interrelationship between sleep and epilepsy. 1.1.3. Sleep and localized epilepsies In the nineteenth and early twentieth centuries, a long series of large scale studies on the distribution of seizures along the sleep-waking cycle was undertaken. Without analyses of the kind and localization of the epilepsy, these studies ± which covered a large number of epileptic patients ± classi®ed epilepsy according to its sensitivity to sleep (Gowers, 1885; FeÂreÂ, 1890; Langdon-Brown and Brain, 1929). Sleep, diffuse and daytime (later called awakening) epilepsies were de®ned. The results were similar among the different studies: 21±24% of seizures occurred in sleep with a maximal occurrence at onset (22:00±23:00 h) and at the end of the night (04:00 and 05:00 h). During the day, 42± 43% of seizures occurred, with a maximal occurrence 1±2 h after awakening. Thirty-three to 37% of the seizures occurred indifferently during day or night. Janz was the ®rst to have an etiological approach with his studies of 2110 (Janz, 1962) and 2825 (Janz, 1974) patients. He showed that sleep epilepsies corresponded to partial epilepsies (44 and 45% of the epilepsies, respectively),
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that awakening epilepsies corresponded to idiopathic generalized epilepsies (34 and 33% of the cases, respectively) and that diffuse epilepsies corresponded to symptomatic epilepsies (21 and 23% of the epilepsies, respectively). Other authors have also suggested that secondary generalized seizures in partial epilepsies were facilitated by sleep (Bazil and Walczak, 1997). According to the international classi®cation of epilepsy that is used today (Commission on Classi®cation and Terminology of the International League Against Epilepsy, 1981), certain partial epileptic syndromes can be regarded as `sleep epilepsies'. This relationship is well established for the generalized idiopathic epilepsies, cryptogenic or symptomatic generalized epilepsies (Lennox±Gastaut syndrome), generalized/partial epilepsies (continuous spike waves during sleep syndrome) (Patry et al., 1971; Tassinari et al., 1985), and certain partial idiopathic epilepsies (benign epilepsy with centro-temporal spike waves) (Beaussart, 1972; Dalla Bernardina et al., 1984) and familial nocturnal frontal lobe epilepsies (Scheffer et al., 1995). This relationship remains unclear for symptomatic and cryptogenic partial epilepsies, in particular for frontal and temporal lobe epilepsies. Temporal lobe epilepsies (TLE), which were initially classi®ed as sleep epilepsies, are diffuse epilepsies. Seizures may occur during sleep, wakefulness or awakening. Although nocturnal or sleep-related occurrence of seizures originating in the different parts of the frontal lobe is clinically common, this characteristic is poorly documented in most major reviews of frontal lobe epilepsies (FLE) (Williamson et al., 1985; Quesney, 1986; Bancaud and Talairach, 1992; Wieser et al., 1992). 2. Studies to understand the relationship between sleep and epilepsy in patients with clearly de®ned cryptogenic or symptomatic frontal and temporal lobe epilepsy In order to establish whether the localization of the epilepsy is a factor of seizure facilitation by sleep, two studies were carried out. The ®rst is a study of 30 patients (15 with FLE and 15 with TLE). The occurrence of seizures over 5 days in relation to the state of alertness and the sleep organization and microarchitecture were analyzed. The patients all had a refractory partial epilepsy and were candidates for surgery (Crespel et al., 1998). The second study analyzed the sleep±epilepsy relationship between 90 patients with pure mesial TLE and 20 patients with mesio-lateral and lateral TLE. The same methods were used in both studies. 2.1. Study 1: patients and methods This study (Crespel et al., 1998) included 30 patients with intractable complex partial seizures who were candidates for surgery. In these patients, localization was controlled by intensive video EEG monitoring and surgery outcome. This study should help us to understand the relationship
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Table 1 Percentage of patients having at least one seizure for the 5 days on different states of alertness
Frontal lobe epilepsy (%) Temporal lobe epilepsy (%) Mann±Whitney comparative test (P value)
Sleep
Wakefulness
Awakening
78 20 0.01
80 94 NS
44.5 27 NS
Table 2 Percentage of patients with at least one seizure on different days under all the conditions in sleep a
Frontal lobe epilepsy (%) 67 Temporal lobe epilepsy (%) 0 Mann±Whitney comparative ,0.0002 test (P value)
D1 Frontal lobe epilepsy (%) 73.5 Temporal lobe epilepsy (%) 13.5 Mann±Whitney comparative ,0.003 test (P value)
between sleep and partial epilepsies. Fifteen patients had FLE and 15 had mesial TLE. The localization was evaluated from a set of data including history, clinical examination, EEG, MRI and SPECT. All these were performed as part of the investigations which were done prior to surgery. The two groups were identical concerning age, epilepsy onset and duration, and treatment received. The epileptogenic zone was con®rmed by post-surgical outcome in the 20 patients who underwent surgery. All patients were monitored continuously for several days with progressive antiepileptic drug discontinuation to record the frequency, type and distribution of seizures in the different states of alertness in 4 conditions: baseline conditions, effect of a decrease of anti-epileptic drugs, effect of sleep deprivation and return to baseline conditions. The patients underwent the following video EEG protocol: the ®rst night served as an habituation night, during the ®rst day their treatment was unchanged, and during the second, third and fourth days progressive anti-epileptic drug discontinuation was performed. On the fourth night, patients were deprived of sleep and on the ®fth day they received the baseline treatment once again. With this protocol, we could analyze the frequency and distribution of seizures during the 3 states of alertness (sleep, awakening and wakefulness) under these circumstances. A polysomnography was performed in order to analyze the organization and microarchitecture of sleep. During the whole observation period, a signi®cant difference was found between the two groups in the percentage of patients having at least one seizure occurring during sleep (Table 1). The frontal group had more seizures in sleep with a signi®cant difference compared to the temporal group. When the two groups were compared day by day the same results were found again. There was no difference between
D1
Table 3 Percentage of patients having at least one seizure for each day on overall states of alertness
D2
D3
D4
60 7 ,0.008
70 7 ,0.008
67 11 13.5 7 0.02 NS
D2
D3
D4
D5
86.7 26.7 ,0.003
100 66.7 NS
88.9 60 NS
11.2 40 NS
the two groups in wakefulness and awakening. In sleep, regardless of the conditions, there was a signi®cant difference between frontal and temporal groups. Whatever the conditions, the patients with FLE had more seizures occurring in sleep compared to patients who had TLE (Table 2). The patients with FLE had more seizures in baseline conditions and had seizures more quickly after anti-epileptic drug discontinuation compared to patients with TLE (Table 3). No secondary generalized sleep seizures were observed. The occurrence of seizures after sleep deprivation seemed more important in patients with TLE compared to the patients with FLE. 2.1.1. Sleep organization and microarchitecture The patients with TLE had an important sleep fragmentation with a decrease in ef®ciency index. There is no difference of sleep organization in patients with FLE compared to controls. Fig. 1 shows an example of a sleep histogram for a FLE patient. This patient had 11 arousals with 28 min of wakefulness after sleep onset (WASO). The ef®ciency index was 0.95. Fig. 2 shows an example of a sleep histogram for a TLE patient. This patient had 22 arousals with 123 min of WASO. The ef®ciency index was 0.72. The sleep microarchitecture showed `K-epileptic complexes' which were frequently followed by an awakening reaction (Fig. 3). The spindles were often better organized on the non-epileptic EEG side. The epileptic abnormalities focused on REM sleep especially for patients with TLE (Fig. 4, patient with right TLE). The occurrence of seizures during sleep was usually in NREM sleep (stage 2). Only two patients (one with TLE and one with FLE) had a seizure in REM sleep. 2.2. Study 2: analysis of the relationship between sleep and epilepsy in 90 patients with pure mesial TLE and 20 patients with mesio-lateral and lateral TLE A second study including 3 kinds of TLE was carried out.
D5
a D1, baseline conditions; D2 and D3, anti-epileptic drugs discontinuation; D4, following partial sleep deprivation; D5, return to baseline conditions.
Fig. 1. Example of a sleep histogram of a FLE patient.
A. Crespel et al. / Clinical Neurophysiology 111, Suppl. 2 (2000) S54±S59
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Table 4 Percentage of patients having at least one seizure in sleep over the 5 day period: study 2
Fig. 2. Example of a sleep histogram of a TLE patient.
Ninety patients had pure mesial TLE and 20 had either mesio-lateral TLE or lateral TLE. The protocol and analysis of seizure occurrence in a state of alertness were the same as in the previous study. The occurrence of seizure was analyzed in sleep and wakefulness only. The following results are preliminary. In this study our questions were (1) is the occurrence of seizures during sleep a characteristic of lateral localization? and (2) is the occurrence of seizures during wakefulness a characteristic of mesial TLE? The occurrence of seizures during sleep and wakefulness over the 5 days was compared. A trend towards a signi®cant difference for seizures occurring in wakefulness was observed (Table 4). The patients with mesial TLE had more seizures occurring in wakefulness compared to the patients with a lateral component (Table 4).
3. Conclusion and practical applications All the above results concerning the relationship between sleep and epilepsy in partial epilepsy with clearly de®ned localization should allow for practical applications in order
Pure medial temporal lobe epilepsy (%) Medial-lateral and lateral temporal lobe epilepsy (%) Mann±Whitney comparative test (P value)
Sleep
Wakefulness
30
90
33
76
NS
0.07
to classify and study these epilepsies. In these studies, the occurrence of seizures for cryptogenic or symptomatic FLE is (1) more frequent and related to sleep, and (2) quicker after anti-epileptic drug discontinuation than for TLE. There is no alteration of sleep organization. A monitoring of sleep during spontaneous sleep and after sleep deprivation is necessary to study, diagnose and record seizures in FLE. For cryptogenic or symptomatic TLE, seizures are delayed and less frequent after anti-epileptic drug discontinuation. These seizures occur more often in wakefulness, particularly for the mesial TLE group. The organization of sleep is altered, with a strong decrease in the ef®ciency index. Diagnosis of epilepsy would bene®t from wakefulness monitoring to record seizures, especially after sleep deprivation. In this kind of epilepsy, the lack of seizure occurrence in sleep could be the result of the absence of the directly facilitating effect of sleep. The occurrence of seizures in wakefulness could be explained by chronic sleep deprivation due to sleep fragmentation.
Fig. 3. `K-Epileptic complexes' and awakening reaction.
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Fig. 4. Focused epileptic discharges in REM sleep: patient with right TLE.
This interrelationship between sleep and epilepsy is an important element of the clinical history of a patient and helps to establish the localization of partial epilepsy. The occurrence or not of seizures in sleep, and the existence or not of alteration of sleep organization can help us to establish a diagnosis. Because of this difference in the occurrence of seizures according to the stage of alertness and the organization of sleep, different physiopathological mechanisms for FLE and TLE could be involved. Up until now, no explanation has been found for both the disturbance of sleep organization and the preferential occurrence of seizures during daytime and waking in TLE patients. A particular kind of epilepsy has recently been described in FLE patients: autosomal dominant nocturnal frontal lobe epilepsy (Scheffer et al., 1995). In this kind of epilepsy, a missense mutation of the alpha 4 subunit of the nicotinic acetylcholine receptor was reported (Steinlein et al., 1995). A role of acetylcholine receptor alteration may be suggested. The difference observed between TLE and FLE may be in relation to this acetylcholine transmission impairment. Further studies of surgical FLE and TLE human tissues may help us to understand these differences in seizure occurrence between FLE and TLE. References Baldy-Moulinier M. Temporal lobe epilepsy and sleep organization. In: Sterman MB, Shouse MN, Passouant P, editors. Sleep and epilepsy, New York: Academic Press, 1982. pp. 347±359. Baldy-Moulinier M. Inter-relationships between sleep and epilepsy. In:
Pedley TA, Meldrum BS, editors. Recent advances in epilepsy, 3. Edinburgh: Churchill Livingstone, 1986. pp. 37±55. Baldy-Moulinier M, Touchon J, Besset A, Billiard M, Cadilhac J, Passouant P. Sleep architecture and epileptic seizures. In: Degen R, Niedermeyer E, editors. Epilepsy, sleep and sleep deprivation, Amsterdam: Elsevier, 1984. pp. 109±117. Bancaud J, Talairach J. Clinical semeiology of frontal lobe seizures. In: Chauvel P, Delgado-Escueta AV, Halgren E, Bancaud J, editors. Frontal lobe seizures and epilepsies, Advances in neurology, 57. New York: Raven Press, 1992. pp. 3±58. Bazil CW, Walczak TS. Effects of sleep and sleep stage on epileptic and non epileptic seizures. Epilepsia 1997;38(1):56±62. Beaussart M. Benign epilepsy in children with rolandic (centro-temporal) paroxysmal foci: a clinical entity study of 221 cases. Epilepsia 1972;13:795±811. Besset A. In¯uence of generalized seizures on sleep organization. In: Sterman M, Shouse M, Passouant P, editors. Sleep and epilepsy, New York: Academic Press, 1982. pp. 339±348. Billiard M, Besset A, Cadilhac J, Passouant P. Relation of seizures and seizures discharges to sleep stages. In: Wolf P, Dam M, Janz D, Dreifuss F, editors. Advances in epileptology, XIVth Epilepsy International SymposiumNew York: Raven Press, 1987. pp. 681±686. Broughton RJ. Epilepsy and sleep: a synopsis and prospectus. In: Degen R, Niedermeyer E, editors. Epilepsy, sleep and sleep deprivation, Amsterdam: Elsevier, 1984. pp. 317±356. Broughton RJ. Sleep and sleep deprivation studies in epilepsy. In: Wada JA, Ellingsen RJ, editors. Clinical neurophysiology of epilepsy, EEG handbook (revised series), 4. Amsterdam: Elsevier, 1990. pp. 89±119. Cadilhac J. Complex partial seizures and REM sleep. In: Sterman M, Shouse M, Passouant P, editors. Sleep and epilepsy, New York: Academic Press, 1982. pp. 315±324. Commission on Classi®cation and Terminology of the International League Against Epilepsy. Proposal for revised clinical and electroencephalographic classi®cation of epileptic seizures. Epilepsia 1981;22:489±501. Crespel A, Baldy-Moulinier M, Coubes P. The relationship between sleep
A. Crespel et al. / Clinical Neurophysiology 111, Suppl. 2 (2000) S54±S59 and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathological considerations. Epilepsia 1998;39(2):150±157. Dalla Bernardina B, Calamaria V, Caporilla G. Nocturnal sleep and benign rolandic epilepsy. In: Degen R, Niedermeyer E, editors. Epilepsy, sleep and sleep deprivation, Amsterdam: Elsevier, 1984. pp. 119±133. Declerck AC. A normative study of sleep in different forms of epilepsy. In: Sterman M, Shouse M, Passouant P, editors. Sleep and epilepsy, New York: Academic Press, 1982. pp. 329±338. FeÂre L. Les eÂpilepsies et les eÂpileptiques, 1. Paris: Alcan, 1890. Gibbs E, Gibbs FA. Diagnosis and localizing value of electroencephalographic studies in sleep. Res Publ Assoc Nerv Ment Dis 1947;26:366± 376. Gigli GL, Placidi F, Diomedi M, Maschio M, Sylvestri G, Scalise A, Marciani MG. Nocturnal sleep and daytime somnolence in untreated patients with temporal lobe epilepsy: changes after treatment with controlled-release carbamazepine. Epilepsia 1998;38(6):696±701. Gloor P. Generalized epilepsy with spike and wave discharge: a re-interpretation of its electrographic and clinical manifestation. Epilepsia 1979;20:571±588. Gowers WR. Epilepsy and other chronic convulsive disease, London: William Wood, 1885. Hamel AR, Sterman M. Sleep and epileptic abnormalities during sleep. In: Sterman M, Shouse M, Passouant P, editors. Sleep and epilepsy, New York: Academic Press, 1982. pp. 361±380. Janz D. Aufwach-Epilepsien. Arch Psychiatr Nervenkr 1953;191:53±98. Janz D. The grand mal epilepsies and the sleeping-waking cycle. Epilepsia 1962;3:69±109. Janz D. Epilepsy and the sleep waking cycle. In: Vinken PJ, Bruyn GW, editors. Handbook of clinical neurology: the epilepsies, Amsterdam: North Holland, 1974. pp. 57±490. Kostopoulos G, Gloor P, Pellegrini A, Gotman J. A study of the transition from spindles to spike and wave discharge in feline generalized penicillin epilepsy: microphysiological features. Exp Neurol 1981;73:55± 73. Langdon-Brown M, Brain WR. Time of day in relation to convulsions in epilepsy. Lancet 1929;11:1028±1032. Montplaisir J, Laverdiere M, Saint Hilaire JM. Sleep and focal epilepsy: contribution of depth recording. In: Sterman M, Shouse M, Passouant P, editors. Sleep and epilepsy, New York: Academic Press, 1982. pp. 301± 314. Niedermeyer E. Petit mal, primary generalized epilepsy and sleep. In: Sterman MB, Shouse MN, Passouant P, editors. Sleep and epilepsy, New York: Academic Press, 1982. pp. 191±208. Passouant P. Historical views on sleep and epilepsy. In: Sterman M, Shouse M, Passouant P, editors. Sleep and epilepsy, New York: Academic Press, 1982. pp. 1±6.
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Passouant P, Latour H, Cadilhac J. Les epilepsies morpheÂiques. Ann Med Psychol 1951;109:526±540. Patry G, Lyagoubi S, Tassinari CA. Subclinical electrical status epilepticus induced by sleep in children. A clinical study of six cases. Arch Neurol 1971;24:42±252. Placidi F, Diomedi M, Scalise A, Marciani MG, Romigi A, Gigli GL. Effect of anticonvulsants on nocturnal sleep in epilepsy. Neurology 2000;54(5 Suppl 1):S25±S32. Quesney LF. Seizures of frontal lobe origin. In: Pedley TA, Meldrum BS, editors. Recent advances in epilepsy, 3. Edinburgh: Churchill Livingstone, 1986. pp. 81±110. Sammaritano M, Sherwin A. Effect of anticonvulsants on sleep. Neurology 2000;54(5 Suppl 1):S16±S24. Scheffer IE, Bhatia KP, Lopes-Cendes I, Fisch DR, Marsden CD, Andermann F. Autosomal dominant nocturnal frontal lobe epilepsy. A distinctive clinical disorder. Brain 1995;118:61±73. Shouse MN. Differences between two feline epilepsy models in sleep and waking state disorders, state dependency of seizures and seizure susceptibility amygdala kindling interferes with systemic penicillin epilepsy. Epilepsia 1987;28:399±408. Steinlein O, Mulley J, Propping T, Wallace R, Philips H, Sutherland G, Scheffer I, Berkovic SE. A missense mutation in the neuronal nicotinic acetylcholine receptor a4 subunits is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995;11:201±203. Tassinari CA, Bureau M, Dravet Ch, Dalla Bernardina B, Roger J. Epilepsy with continuous spikes and waves during slow sleep otherwise described as ESES (epilepsy with electrical status epilepticus during slow sleep). In: Roger J, Dravet Ch, Bureau M, Dreifuss FE, Wolf P, editors. Epileptic syndromes in infancy, childhood and adolescence, London: John Libbey, 1985. pp. 194±204. Touchon J, Baldy-Moulinier M. Sleep instability in temporal lobe epilepsy. In: Wolf P, Dam M, Janz D, Dreifuss F, editors. Advances in epileptology, XIVth Epilepsy International Symposium, New York: Raven Press, 1987. pp. 705±708. Touchon J, Baldy-Moulinier M, Billiard M, Besset A, Cadilhac J. Sleep organization and epilepsy. In: Degen R, Rodin EA, editors. Epilepsy, sleep and sleep deprivation, 2nd ed. Epilepsy Res (Suppl 2). Amsterdam: Elsevier, 1991. pp. 73±81. Wieser HG, Swartz BE, Delgado-Escueta AV, Bancaud J, Walsh GO, Maldonado H, Saint Hilaire JM. Differentiating frontal lobe seizures from temporal lobe seizures. In: Chauvel P, Delgado-Escueta AV, Halgren E, Bancaud J, editors. Advances in neurology, 57. New York: Raven Press, 1992. pp. 267±285. Williamson PD, Spencer DD, Spencer SS, Novelly RA, Mattson AH. Complex partial seizures of frontal lobe origin. Ann Neurol 1985;18:497±504.
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Sleep in¯uence on seizures and epilepsy effects on sleep in partial frontal and temporal lobe epilepsies Arielle Crespel*, Philippe Coubes, Michel Baldy-Moulinier Epilepsy Unit, Gui de Chauliac Hospital, Montpellier, France
Abstract Objectives: A reciprocal effect is observed between sleep and epilepsy. Sleep effect on epilepsy is protective and facilitating. Reciprocally epilepsy alters sleep organization and microarchitecture. This interelationship is well established for some epilepsies but remains unde®ned for cryptogenic and symptomatic frontal and temporal lobe epilepsies. In order to research sleep in¯uence on seizures and epilepsy effects on sleep we carried out two studies in patients with cryptogenic/symptomatic frontal or temporal lobe epilepsies. Methods: The occurrence of seizures in relation to the state of alertness was analyzed in patients with (1) mesial temporal and frontal lobe epilepsy, and (2) in patients with mesio-lateral temporal and mesial temporal lobe epilepsy in several conditions. Sleep analysis (organization and microarchitecture) was realized. Results: We found: (1) a precise relationship between sleep and seizures in frontal lobe epilepsy (FLE); (2) a precise relationship between wakefulness and seizures in temporal lobe epilepsy (TLE); (3) sleep organization was normal in FLE and altered in TLE; (4) alterations of sleep microarchitecture in FLE and TLE. Conclusions: Seizure occurrence was mainly in relation to sleep for FLE and to wakefulness for TLE. Sleep organization appeared more altered for TLE than FLE. These results allow practical applications to localize and study FLE and TLE. q 2000 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Epilepsy; Frontal lobe epilepsy; Temporal lobe epilepsy; Sleep; Sleep organization
1.1.1. Effect of sleep on epilepsy It appears that according to the kind of epilepsy, sleep may have a facilitating or precipitating effect on seizures or else a protective effect against epilepsy (Baldy-Moulinier, 1986). The protective effect is suggested by the occurrence
of seizures after sleep deprivation. This effect was well established for the grand mal epilepsies of awakening de®ned by Janz (1953). The facilitating effect is suggested by: (1) the existence of sleep epilepsies, called `morpheic epilepsies' (Passouant et al., 1951; Baldy-Moulinier et al., 1984); (2) the increase of interictal discharging during sleep (Gibbs and Gibbs, 1947; Broughton, 1984); and (3) the relationship between the production of sleep spindles and epileptic discharges (Gloor, 1979; Kostopoulos et al., 1981; Niedermeyer, 1982). The different stages of sleep may have a different effect on interictal discharge production. In slowwave (non-rapid eye movement or NREM) sleep, particularly in stage 2, a synchronizing effect is shown by an increase and a spreading of the interictal abnormalities. Rapid eye movement (REM) sleep prevented generalized discharges of generalized epilepsies and facilitated localized abnormalities of partial epilepsies (Baldy-Moulinier, 1982; Cadilhac, 1982; Passouant, 1982; Billiard et al., 1987; Shouse, 1987).
* Corresponding author. Service Explorations Neurologiques et Epileptologie, HoÃpital Gui de Chauliac, 80 avenue A. Fliche, 34295 Montpellier Cedex 05, France. Tel.: 133-4-67-33-72-40; fax: 133-4-67-33-76-23. E-mail address: [email protected] (A. Crespel).
1.1.2. Effect of epilepsy on sleep Reciprocally, epilepsy alters the organization and microarchitecture of sleep: ®rstly, by the acute effect of a seizure
1. Introduction In ancient times, Aristotle and Hippocrates indicated the relationship between sleep and epilepsy and inaugurated research studies on the distribution of seizures during the sleep-waking cycle. After a long period limited to clinical observation, the study of this relationship has bene®ted from the contribution of electroencephalography and, more recently, of nocturnal polygraphic and video EEG recordings (Broughton, 1990). 1.1. Relationship between sleep and epilepsy: a reciprocal effect
1388-2457/00/$ - see front matter q 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S13 88-2457(00)0040 2-8
CLINPH 1032
A. Crespel et al. / Clinical Neurophysiology 111, Suppl. 2 (2000) S54±S59
during sleep, disrupting continuity, and secondly, by the chronic effect of epilepsy, impairing the organization and altering the microarchitecture of sleep. These modi®cations differ according to the kind of epilepsy. A decrease in total sleep time, wakefulness after sleep onset and sleep ef®ciency index, an increase in sleep onset latency, ®rst REM delay and percentage of the stage 2 non-REM rate with a decrease in the percentage of REM sleep rate have been reported (Baldy-Moulinier, 1982; Besset, 1982; Declerck, 1982; Hamel and Sterman, 1982; Montplaisir et al., 1982; Touchon et al., 1991). This reciprocal acute and chronic action of sleep and epilepsy may constitute a spiral, enabling the facilitation of seizure and/or diurnal sleepiness by chronic sleep deprivation. An alteration of sleep microarchitecture is also observed. The K-complexes have medial frontal localization (Niedermeyer, 1982), and are preceded and followed by spikes (`K-epileptic complex'; Passouant, 1982). There is a decrease of spindle density (Declerck, 1982; Hamel and Sterman, 1982). An anti-epileptic drug action was reported. Thus, on the newly-diagnosed temporal epilepsies it has been shown that carbamazepine improves the altered organization of sleep (Touchon and BaldyMoulinier, 1987). The possibility of modi®cation or not of sleep organization by different anti-convulsants has been shown in other studies (Gigli et al., 1998; Placidi et al., 2000; Sammaritano and Sherwin, 2000). The physiopathological mechanisms that underlie this relationship between sleep and epilepsy remain unclear and hypothetical. An action of the inputs of the ascending neurotransmitter systems and their changes with sleep-waking states and the subcortical synchronizing systems or inhibitory systems may be involved. The thalamo-cortical volleys, the local conditions and the different degrees of responsiveness to sleep-regulating factors may play a role in this interrelationship between sleep and epilepsy. 1.1.3. Sleep and localized epilepsies In the nineteenth and early twentieth centuries, a long series of large scale studies on the distribution of seizures along the sleep-waking cycle was undertaken. Without analyses of the kind and localization of the epilepsy, these studies ± which covered a large number of epileptic patients ± classi®ed epilepsy according to its sensitivity to sleep (Gowers, 1885; FeÂreÂ, 1890; Langdon-Brown and Brain, 1929). Sleep, diffuse and daytime (later called awakening) epilepsies were de®ned. The results were similar among the different studies: 21±24% of seizures occurred in sleep with a maximal occurrence at onset (22:00±23:00 h) and at the end of the night (04:00 and 05:00 h). During the day, 42± 43% of seizures occurred, with a maximal occurrence 1±2 h after awakening. Thirty-three to 37% of the seizures occurred indifferently during day or night. Janz was the ®rst to have an etiological approach with his studies of 2110 (Janz, 1962) and 2825 (Janz, 1974) patients. He showed that sleep epilepsies corresponded to partial epilepsies (44 and 45% of the epilepsies, respectively),
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that awakening epilepsies corresponded to idiopathic generalized epilepsies (34 and 33% of the cases, respectively) and that diffuse epilepsies corresponded to symptomatic epilepsies (21 and 23% of the epilepsies, respectively). Other authors have also suggested that secondary generalized seizures in partial epilepsies were facilitated by sleep (Bazil and Walczak, 1997). According to the international classi®cation of epilepsy that is used today (Commission on Classi®cation and Terminology of the International League Against Epilepsy, 1981), certain partial epileptic syndromes can be regarded as `sleep epilepsies'. This relationship is well established for the generalized idiopathic epilepsies, cryptogenic or symptomatic generalized epilepsies (Lennox±Gastaut syndrome), generalized/partial epilepsies (continuous spike waves during sleep syndrome) (Patry et al., 1971; Tassinari et al., 1985), and certain partial idiopathic epilepsies (benign epilepsy with centro-temporal spike waves) (Beaussart, 1972; Dalla Bernardina et al., 1984) and familial nocturnal frontal lobe epilepsies (Scheffer et al., 1995). This relationship remains unclear for symptomatic and cryptogenic partial epilepsies, in particular for frontal and temporal lobe epilepsies. Temporal lobe epilepsies (TLE), which were initially classi®ed as sleep epilepsies, are diffuse epilepsies. Seizures may occur during sleep, wakefulness or awakening. Although nocturnal or sleep-related occurrence of seizures originating in the different parts of the frontal lobe is clinically common, this characteristic is poorly documented in most major reviews of frontal lobe epilepsies (FLE) (Williamson et al., 1985; Quesney, 1986; Bancaud and Talairach, 1992; Wieser et al., 1992). 2. Studies to understand the relationship between sleep and epilepsy in patients with clearly de®ned cryptogenic or symptomatic frontal and temporal lobe epilepsy In order to establish whether the localization of the epilepsy is a factor of seizure facilitation by sleep, two studies were carried out. The ®rst is a study of 30 patients (15 with FLE and 15 with TLE). The occurrence of seizures over 5 days in relation to the state of alertness and the sleep organization and microarchitecture were analyzed. The patients all had a refractory partial epilepsy and were candidates for surgery (Crespel et al., 1998). The second study analyzed the sleep±epilepsy relationship between 90 patients with pure mesial TLE and 20 patients with mesio-lateral and lateral TLE. The same methods were used in both studies. 2.1. Study 1: patients and methods This study (Crespel et al., 1998) included 30 patients with intractable complex partial seizures who were candidates for surgery. In these patients, localization was controlled by intensive video EEG monitoring and surgery outcome. This study should help us to understand the relationship
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Table 1 Percentage of patients having at least one seizure for the 5 days on different states of alertness
Frontal lobe epilepsy (%) Temporal lobe epilepsy (%) Mann±Whitney comparative test (P value)
Sleep
Wakefulness
Awakening
78 20 0.01
80 94 NS
44.5 27 NS
Table 2 Percentage of patients with at least one seizure on different days under all the conditions in sleep a
Frontal lobe epilepsy (%) 67 Temporal lobe epilepsy (%) 0 Mann±Whitney comparative ,0.0002 test (P value)
D1 Frontal lobe epilepsy (%) 73.5 Temporal lobe epilepsy (%) 13.5 Mann±Whitney comparative ,0.003 test (P value)
between sleep and partial epilepsies. Fifteen patients had FLE and 15 had mesial TLE. The localization was evaluated from a set of data including history, clinical examination, EEG, MRI and SPECT. All these were performed as part of the investigations which were done prior to surgery. The two groups were identical concerning age, epilepsy onset and duration, and treatment received. The epileptogenic zone was con®rmed by post-surgical outcome in the 20 patients who underwent surgery. All patients were monitored continuously for several days with progressive antiepileptic drug discontinuation to record the frequency, type and distribution of seizures in the different states of alertness in 4 conditions: baseline conditions, effect of a decrease of anti-epileptic drugs, effect of sleep deprivation and return to baseline conditions. The patients underwent the following video EEG protocol: the ®rst night served as an habituation night, during the ®rst day their treatment was unchanged, and during the second, third and fourth days progressive anti-epileptic drug discontinuation was performed. On the fourth night, patients were deprived of sleep and on the ®fth day they received the baseline treatment once again. With this protocol, we could analyze the frequency and distribution of seizures during the 3 states of alertness (sleep, awakening and wakefulness) under these circumstances. A polysomnography was performed in order to analyze the organization and microarchitecture of sleep. During the whole observation period, a signi®cant difference was found between the two groups in the percentage of patients having at least one seizure occurring during sleep (Table 1). The frontal group had more seizures in sleep with a signi®cant difference compared to the temporal group. When the two groups were compared day by day the same results were found again. There was no difference between
D1
Table 3 Percentage of patients having at least one seizure for each day on overall states of alertness
D2
D3
D4
60 7 ,0.008
70 7 ,0.008
67 11 13.5 7 0.02 NS
D2
D3
D4
D5
86.7 26.7 ,0.003
100 66.7 NS
88.9 60 NS
11.2 40 NS
the two groups in wakefulness and awakening. In sleep, regardless of the conditions, there was a signi®cant difference between frontal and temporal groups. Whatever the conditions, the patients with FLE had more seizures occurring in sleep compared to patients who had TLE (Table 2). The patients with FLE had more seizures in baseline conditions and had seizures more quickly after anti-epileptic drug discontinuation compared to patients with TLE (Table 3). No secondary generalized sleep seizures were observed. The occurrence of seizures after sleep deprivation seemed more important in patients with TLE compared to the patients with FLE. 2.1.1. Sleep organization and microarchitecture The patients with TLE had an important sleep fragmentation with a decrease in ef®ciency index. There is no difference of sleep organization in patients with FLE compared to controls. Fig. 1 shows an example of a sleep histogram for a FLE patient. This patient had 11 arousals with 28 min of wakefulness after sleep onset (WASO). The ef®ciency index was 0.95. Fig. 2 shows an example of a sleep histogram for a TLE patient. This patient had 22 arousals with 123 min of WASO. The ef®ciency index was 0.72. The sleep microarchitecture showed `K-epileptic complexes' which were frequently followed by an awakening reaction (Fig. 3). The spindles were often better organized on the non-epileptic EEG side. The epileptic abnormalities focused on REM sleep especially for patients with TLE (Fig. 4, patient with right TLE). The occurrence of seizures during sleep was usually in NREM sleep (stage 2). Only two patients (one with TLE and one with FLE) had a seizure in REM sleep. 2.2. Study 2: analysis of the relationship between sleep and epilepsy in 90 patients with pure mesial TLE and 20 patients with mesio-lateral and lateral TLE A second study including 3 kinds of TLE was carried out.
D5
a D1, baseline conditions; D2 and D3, anti-epileptic drugs discontinuation; D4, following partial sleep deprivation; D5, return to baseline conditions.
Fig. 1. Example of a sleep histogram of a FLE patient.
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Table 4 Percentage of patients having at least one seizure in sleep over the 5 day period: study 2
Fig. 2. Example of a sleep histogram of a TLE patient.
Ninety patients had pure mesial TLE and 20 had either mesio-lateral TLE or lateral TLE. The protocol and analysis of seizure occurrence in a state of alertness were the same as in the previous study. The occurrence of seizure was analyzed in sleep and wakefulness only. The following results are preliminary. In this study our questions were (1) is the occurrence of seizures during sleep a characteristic of lateral localization? and (2) is the occurrence of seizures during wakefulness a characteristic of mesial TLE? The occurrence of seizures during sleep and wakefulness over the 5 days was compared. A trend towards a signi®cant difference for seizures occurring in wakefulness was observed (Table 4). The patients with mesial TLE had more seizures occurring in wakefulness compared to the patients with a lateral component (Table 4).
3. Conclusion and practical applications All the above results concerning the relationship between sleep and epilepsy in partial epilepsy with clearly de®ned localization should allow for practical applications in order
Pure medial temporal lobe epilepsy (%) Medial-lateral and lateral temporal lobe epilepsy (%) Mann±Whitney comparative test (P value)
Sleep
Wakefulness
30
90
33
76
NS
0.07
to classify and study these epilepsies. In these studies, the occurrence of seizures for cryptogenic or symptomatic FLE is (1) more frequent and related to sleep, and (2) quicker after anti-epileptic drug discontinuation than for TLE. There is no alteration of sleep organization. A monitoring of sleep during spontaneous sleep and after sleep deprivation is necessary to study, diagnose and record seizures in FLE. For cryptogenic or symptomatic TLE, seizures are delayed and less frequent after anti-epileptic drug discontinuation. These seizures occur more often in wakefulness, particularly for the mesial TLE group. The organization of sleep is altered, with a strong decrease in the ef®ciency index. Diagnosis of epilepsy would bene®t from wakefulness monitoring to record seizures, especially after sleep deprivation. In this kind of epilepsy, the lack of seizure occurrence in sleep could be the result of the absence of the directly facilitating effect of sleep. The occurrence of seizures in wakefulness could be explained by chronic sleep deprivation due to sleep fragmentation.
Fig. 3. `K-Epileptic complexes' and awakening reaction.
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Fig. 4. Focused epileptic discharges in REM sleep: patient with right TLE.
This interrelationship between sleep and epilepsy is an important element of the clinical history of a patient and helps to establish the localization of partial epilepsy. The occurrence or not of seizures in sleep, and the existence or not of alteration of sleep organization can help us to establish a diagnosis. Because of this difference in the occurrence of seizures according to the stage of alertness and the organization of sleep, different physiopathological mechanisms for FLE and TLE could be involved. Up until now, no explanation has been found for both the disturbance of sleep organization and the preferential occurrence of seizures during daytime and waking in TLE patients. A particular kind of epilepsy has recently been described in FLE patients: autosomal dominant nocturnal frontal lobe epilepsy (Scheffer et al., 1995). In this kind of epilepsy, a missense mutation of the alpha 4 subunit of the nicotinic acetylcholine receptor was reported (Steinlein et al., 1995). A role of acetylcholine receptor alteration may be suggested. The difference observed between TLE and FLE may be in relation to this acetylcholine transmission impairment. Further studies of surgical FLE and TLE human tissues may help us to understand these differences in seizure occurrence between FLE and TLE. References Baldy-Moulinier M. Temporal lobe epilepsy and sleep organization. In: Sterman MB, Shouse MN, Passouant P, editors. Sleep and epilepsy, New York: Academic Press, 1982. pp. 347±359. Baldy-Moulinier M. Inter-relationships between sleep and epilepsy. In:
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