Current Opinion: Sleep and Epilepsy

Carl W. Bazil, M.D., Ph.D.
The Neurological Institute
710 West 168th Street
New York, NY 10032
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For: Current Opinion in Neurology
Editor: William Theodore, M.D.

SUMMARY

Sleep disturbance in patients with epilepsy is frequently overlooked, but may contribute to decreased daytime functioning and increased seizure activity. Although complicated, the relationship between sleep and epilepsy is becoming clearer. Sleep, and particularly deep non-REM sleep, increase interictal epileptiform activity. Sleep increases certain seizure types and the rate of generalization of partial seizures, however REM sleep seems to suppress seizures. Sleep disorders, particularly sleep apnea, exacerbate seizures. Seizures, in turn, can disrupt sleep structure, particularly REM. Understanding of these relationships is important in seizure control and in maximizing quality of life for patients with epilepsy.

INTRODUCTION

The relationship between sleep and epilepsy is complicated and reciprocal. Understanding of the influences of each on the other often has important clinical implications. Sleep has direct effects on interictal epileptiform discharges (IEDs) and on the occurrence of certain seizures. Specific syndromes of sleep and epilepsy have been described and are being clarified. Sleep disturbance and sleep disorders are common, and therefore frequently coexist in patients with epilepsy. Finally, seizures (and anticonvulsants) interfere with normal sleep patterns, which affects both the daytime performance of patients with uncontrolled seizures and their prognosis for seizure control. Reviews of these sleep-epilepsy interactions have been published for adults1 ( Malow 1996) and children2 (Bourgeois 1996). Circadian distribution of ictal and interictal events were specifically reviewed by Shouse3 (1996).

Another important aspect of sleep and epilepsy is the areas of potential confusion in diagnosing various paroxysmal disorders, including both non-REM (sleep terrors, sleep enuresis, periodic limb movements, and confusional arousals) and disorders of REM sleep (particularly cataplexy, hypnogogic hallucinations, sleep paralysis, and REM behavior disorder). This area is not specifically addressed here, but a complete discussion was recently published by Roberts4 (1998?).

Recent work demonstrates an increased appreciation for the theoretical importance and clinical implications of the sleep-epilepsy relationship. In this article, I will review developments in each area described above.

Effects of sleep on interictal epileptiform activity

It has been known for decades that sleep deprivation and recording of sleep increases the yield of interictal epileptiform activity on EEG. Recent studies have confirmed and refined this knowledge. In a study of 24 patients with refractory temporal lobe epilepsy, Malow et al5 (1999?) compared interictal discharges in routine daytime EEGs with overnight EEG recordings. All showed IEDs in the overnight study (as opposed to 11/24 during daytime) and there was high concordance with seizure onset site. This further confirms the value of sleep recordings when routine EEG is normal. In a retrospective report comparing routine EEG with sleep to subsequent sleep deprived EEG with sleep, a 52% activation rate for epileptiform activity was seen in the latter group 6(Fountain et al 1998?) independent of sleep duration or depth. Therefore, sleep deprivation is useful independent of sleep.

Conversely, Beun and Dekker7 (1997) cautioned that sharp transients are common in normal patients during sleep. During two consecutive nights of continuous EEG recording, frontal or temporal sharp waves were seen in 68% and 37% of patients without epilepsy, respectively. True epileptiform spike-wave activity was seen in 13%. They appropriately caution that the EEG must always be interpreted within the clinical context.

Specific increases in interictal spikes and sharp waves during slow wave sleep, with decreases during REM, was convincingly demonstrated by Sammaritano et al 8 (1991). An increase in spike frequency is also seen with increasing delta power, a measure of increasing sleep depth9 (Malow 1998?). It has also been shown that IEDs occurring during REM are more accurate for focus localization 8,10 (Malow and Aldrich, in press; Sammaritano ).

Sleep disorders in patients with epilepsy

Sleepiness is a nearly universal among certain populations with epilepsy, however sleep disorders are grossly under diagnosed. Many practitioners may attribute consistent tiredness to an unavoidable adverse effect of antiseizure medication. In fact, current research confirms that coexistence of sleep disorders is common, and has important implications for treatment.

An investigation into the overall prevalence of sleep disorders in the epilepsy population was performed by Malow et al 11 (1997). Patients with epilepsy were more drowsy by the Epworth Sleepiness Scale compared to control patients. Epilepsy was not a predictor of high score when a sleep apnea scale was included. They conclude that excessive daytime sleepiness is common in both epilepsy subjects and controls, and that much of this may be due to treatable conditions. A similar investigation was performed prospectively in children by Stores et al12 (1998?) using a nonstandardized sleep questionnaire and the Conners Revised Parent Rating Scale. Children with epilepsy showed higher scores for poor quality sleep, anxiety about sleep, and disordered breathing. Only anxiety was affected by seizure number. Similar findings were seen in a survey given to parents of 89 children with idiopathic epilepsy 13 (Cortesi et al 1999?). Children with epilepsy showed more sleep problems than did controls, and these were associated with seizure frequency, age, paroxysmal activity on EEG, duration of illness, and behavioral problems.

In a retrospective study of 63 epilepsy patients who underwent polysomnography 14 (Malow et al 1997), the vast majority of patients (49, or 78%) were referred for obstructive sleep apnea, with many others (46%) for excessive sleepiness, and 12 (19%) for characterization of nocturnal spells. Studies diagnosed obstructive sleep apnea in 71% of referrals, 96% of whom were referred for that reason. Other diagnoses found were one patient each with narcolepsy and insufficient sleep syndrome, and four with nocturnal seizures. Six patients had frequent periodic limb movements, but these were not clinically significant. In a similar investigation, Beran 15(1999??) reported on 50 patients with epilepsy referred to a sleep laboratory for all night polysomnography. Fifty-four percent had sleep apnea, and 32% had periodic limb movements of sleep (6 requiring medication). Of the 36 patients who were prescribed therapy based on the evaluation, 6 had significant improvement in seizures.

Both of these studies stress the prevalence of sleep disorders (particularly obstructive sleep apnea) in the epilepsy population, and the underutilization of polysomnography in these patients. The authors rightly point out the importance of diagnosing sleep apnea, as previous studies 16,17 (Vaughn et al 1996, Devinsky et al 1994) show that treatment of this condition improves seizure control. The direct effects of seizures on sleep structure are discussed later in this article.

Specific syndromes of sleep and epilepsy

Many and varied syndromes of sleep related epilepsy have been described, including childhood epilepsy with occipital paroxysms, childhood epilepsy with centrotemporal spikes, juvenile myoclonic epilepsy, awakening grand-mal epilepsy, and nocturnal frontal lobe epilepsy. Recent work involves frontal lobe epilepsies and the Landau-Kleffner syndrome.

Frontal lobe epilepsies may represent a diagnostic dilemma for a number of reasons. The seizures are frequently unwitnessed, and semiology is often bizarre. Prominent choking and abnormal motor activity can lead to a misdiagnosis of sleep apnea 18(Oldani et al 1998) or other sleep disturbance 19 (Tachibana et al 1996). A review of 100 consecutive cases of nocturnal frontal lobe epilepsy (NFLE) was performed by Provini et al 20 (1999??). Three types of episodes were described, which included sudden awakening with bizarre posture or ambulation and lasted seconds to minutes. Twenty-eight percent occurred in stage 3-4 sleep and only 3% during REM. Only 33% of patients showed clear epileptiform abnormalities on routine EEG (45% with sleep). Forty two patients showed a clear ictal discharge on polysomnography. Mean seizure frequency was 20 /- 11/month, with only 34% reporting rare seizures during daytime wakefulness. Twenty-five percent showed a familial occurrence. Oldani et al 21 (1998?) reported on forty patients with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). The clinical picture included enuresis, sudden awakenings with dystonic or dyskinetic movements (42%), complex behavior (13%)and violent behavior in sleep (5%). Most patients showed ictal or rhythmic activity over the frontal region. Pedigree analysis was consistent with autosomal dominant inheritance with reduced penetrance in 81%. Locus heterogeneity was seen with DNA analysis. Another study 22 (Nakken at a 1999) showed heterogeneity in families with ADNFL from Norway and Australia. Ictal recordings showed epileptiform activity in only 3/10 patients. All of these studies suggest that nocturnal frontal lobe epilepsies are frequently misdiagnosed but easily controlled with medication.

Llandau-Kleffner syndrome is a condition of acquired aphasia, frequently (but not always) with epileptic seizures and a markedly epileptiform EEG, particularly during sleep. O’Regan et al 23 (1998) studied 25 children with an acquired disorder of communication and seizures, but not strictly meeting criteria for the Landau-Kleffner syndrome (LKS). EEGs were uniformly epileptiform, usually (16/25) worsening with sleep. MRI was typically normal, but SPECT was abnormal (22/25). Most were considered to have a receptive aphasia. They hypothesize that the language deficits result from the persistent epileptic discharges, as evidenced by hypometabolism on SPECT. A study of 32 patients with continuous spike-wave activity during slow wave sleep (CSWS: 24Veggiotti et al 1999) showed a variety of clinical syndromes, including LKS, acquired opercular syndromes, typical CSWS syndrome, and other symptomatic epilepsies.

Effect of sleep and sleep deprivation on the occurrence of seizures (especially partial onset)

Sleep has been shown to influence seizure onset in both animals and humans. Both rats with a model of limbic epilepsy and humans with medial temporal or extratemporal seizures were examined by Quigg et al 25 (1998?). Limbic seizures in both animals and humans occurred more often during daylight hours, but extratemporal and lesional temporal lobe seizures in humans did not show this pattern. The authors conclude that a circadian pattern exists for mesial temporal lobe epilepsy, however the specific influence of sleep on occurrence remains unknown. This is particularly interesting in that a predominantly nocturnal animal, the rat, and diurnal humans both showed increased seizures during daylight hours.

Although sleep deprivation has long been thought to increase seizures, a controlled study of patients with refractory epilepsy failed to show this 26 (Malow et al 1999). Seventeen patients were sleep deprived on alternate nights, and 13 received eight hours of sleep per night. There was no difference in the number of seizures or time to first seizure.

Crespel et al 27 (1998??) specifically examined the occurrence of frontal and temporal lobe seizures in fifteen patients with each, using five days of continuous video-EEG monitoring. Sixty one percent of frontal and 11% of temporal lobe seizures occurred during sleep. This difference in state of occurrence persisted after AED withdrawal and sleep deprivation. Nocturnal frontal lobe epilepsy is diagnosed by video-polysomnography in 87% of patients, and by daytime video-EEG following sleep deprivation in 52% 18 (Oldani et al 1998).

In a large study of refractory epilepsy patients, Bazil and Walczak 28 (1997) retrospectively studied over a thousand seizures in 188 consecutive patients. Overall, 20% of seizures occurred during sleep. Most (54%) of sleep seizures occurred during stage 2, with only 13% during slow wave sleep and few (3%) during REM. Complex partial seizures were found to last longer when arising during slow wave sleep compared to wakefulness or stage 2. Frontal lobe seizures began during sleep more often than temporal lobe seizures (37% compared with 26%), a finding which has been appreciated clinically. Temporal lobe seizures were more likely to secondarily generalize when beginning during sleep, but frontal lobe seizures were not. In a retrospective study of 14 patients with temporal lobe epilepsy, seizures occurred most frequently during non-REM sleep and specifically preceding arousals 29(Malow et al, in press?). These studies suggest that the hypersynchrony present during non-REM sleep may facilitate onset and/or spread of certain partial seizures.

Seizures which occur only during sleep have been studied retrospectively by Park et al 30 (1998?) and prospectively by Yaqub et al 31 (1997?). Both studies showed an excellent prognosis, although one (Park) showed that partial seizures were more difficult to control and frequently developed daytime seizures; this group frequently had a history of head trauma or CNS lesion.

Effects of seizures and anticonvulsant medications on sleep structure

Intuitively, nocturnal seizures will disrupt sleep structure. Most will cause a least a brief awakening, and normal sleep is unlikely during a postictal state. Several authors have reported polysomnographic findings following partial seizures, particularly frontal 19,27 (Tachibana et al 1996, Crespel et al 1998??) and temporal 27,32 (Crespel et al 1998??, Bazil et al in press??). Tachibana et al 19 (1996) specifically report on two patients with supplementary motor area seizures who were misdiagnosed with sleep disorders. Treatment resulted in improved sleep efficiency, increased slow wave sleep and (in one case) increased REM sleep. In a more extensive study, twelve patients with temporal lobe epilepsy and ten with frontal lobe epilepsy were studied with polysomnography in the absence of seizures 27 (Crespel et al 1998??). There were no differences in percentage in each sleep stage between the two groups 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 lobe seizures on sleep structure was examined by Bazil et al 32(in press??). Patients in an epilepsy monitoring unit were recorded with polysomnography under baseline conditions (seizure free) and compared to the same patients following complex partial or secondarily generalized seizures. Following daytime seizures, there was a significant decrease in REM the following night (18 % vs. 12 % for baseline) 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. Both day and night seizures resulted in a delay in the first REM period. The authors conclude that diurnal and particularly nocturnal seizures disrupt sleep structure, which may be partly responsible for decreased performance the following day.

Patients with mental retardation and seizures (usually of multiple types) represent a distinct population studied by Espie et al 33 (1998?). These patients had frequent seizures and most were taking multiple antiseizure medications. The studies were somewhat limited in that they were performed in an outpatient setting. In two of 28 subjects it was not possible to distinguish between sleep and wakefulness. Only 43% had REM sleep recorded, and in these cases mean time in REM was limited to an average of 30 minutes. Decreased REM was thought due to mental retardation and antiseizure medications, although seizure activity was not mentioned in this study.

All of the above studies show sleep disruption with uncontrolled seizures, with REM specifically affected. Clinically, this may explain some of the dullness many patients feel even a day or two following seizures. The effects of certain antiseizure medications, particularly phenytoin and carbamazepine, may independently reduce REM 34(Bazil et al 1998).

Conclusions

Attention to sleep in patients with epilepsy has important implications for diagnosis, seizure control, and quality of life. Recent advances have helped clarify the value of recording sleep EEG in diagnosing and localizing partial epilepsy. Syndromes of sleep and epilepsy, particularly nocturnal frontal lobe epilepsy, are better understood. Finally, it is becoming clearer that independent sleep disorders frequently coexist with epilepsy, and that seizures themselves cause sleep disturbance. The common complaint of drowsiness can no longer be dismissed in patients with refractory epilepsy, in whom sleep studies and diagnosis can clearly improve both seizure control and sleep. Study of these patients with polysomnography or video-EEG polysomnography may be indicated.

References

1 Malow BA. Sleep and Epilepsy. Neurol Clin 1996; 14(4):765-89.

2 Bourgeois B The relationship between sleep and epilepsy in children. Seminars Ped Neurol 1996; 3(1):29-35. /p>

3 Shouse MN, Martins da Silva A, Sammaritano M. Circadian rhythm, sleep, and epilepsy. J Clin Neurophysiol 1996; 13(1):32-50.

4?Roberts R. Differential diagnosis of sleep disorders, non-epileptic attacks and epileptic seizures. Curr Opin Neurol 1998; 11:135-9.

Concise, clear review of the differential diagnosis of sleep disorders and epilepsy.

5?Malow BA, Selwa LM, Ross D, Aldrich MS. Lateralizing value of interictal spikes on overnight sleep-EEG studies in temporal lobe epilepsy. Epilepsia 1999; 40(11):1587-92.

This paper demonstrates the value of obtaining overnight studies particularly when daytime routine EEGs are normal.

6?Fountain NB, Kim JS, Lee SI. Sleep deprivation activates epileptiform discharges independent of the activating effects of sleep. J Clin Neurophysiol 1998; 15(1):69-75.

This paper convincingly demonstrates increased IEDs following sleep deprivation compared with the same patients with sleep EEGs and no sleep deprivation, supporting an independent effect of sleep deprivation.

7 Beun AM, van Emde Boas W, Dekker E. Sharp transients in the sleep EEG of healthy adults: a possible pitfall in the diagnostic assessment of seizure disorders. 1998; Electroencephalogr clin Neurophysiol 106:44-51.

8 Sammaritano M, Gigli GL, Gotman J. Interictal spiking during wakefulness and sleep and localization of foci in temporal lobe epilepsy. Neurology 1991; 41:290-7.

9?Malow BA, Lin X, Kushwaha R, Aldrich MS. Interictal spiking increases with sleep depth in temporal lobe epilepsy. Epilepsia 1998; 39(12):1309-16.

This study uses the relatively novel concept of delta power to show that IEDs increase with sleep depth, as previously shown with conventional sleep staging.

10 Malow BA, Aldrich MS. Localizing value of rapid eye movement sleep in temporal lobe epilepsy. Sleep Medicine 2000;, in press.

11 Malow BA, Bowes RJ, Lin X. Predictors of sleepiness in epilepsy patients. Sleep 1997; 20(12):1105-10.

12?Stores G, Wiggs L, Campling G. Sleep disorders and their relationship to psychological disturbances in children with epilepsy. Child: Care, Health, and Development 1998; 24(1):5-19.

This study of sleepiness in children shows that, like adults, children with epilepsy are more likely to have sleep disturbances than normal control subjects.

13?Cortesi F, Giannotti F, Ottaviano S. Sleep problems and daytime behavior in childhood idiopathic epilepsy. 1999; Epilepsia 40(11):1557-65.

This study used surveys administered to parents of children with idiopathic epilepsy, showing increased sleepiness compared to control children.

14 Malow BA, Fromes G, Aldrich MS. Usefulness of polysomnography in epilepsy patients. Neurology 1997; 48:1389-94.

15??Beran RG, Plunkett MJ, Holland GJ. Interface of epilepsy and sleep disorders. 1999; Seizure 8:97-102.

This is a large study of epilepsy patients referred for polysomnography, showing a high prevalence of sleep apnea and other sleep disorders.

16 Devinsky O. Ehrenberg B, Barthlen GM, Abramson HS, Luciano D. Epilepsy and sleep apnea syndrome. Neurology 1994;44:2060-4

17 Vaughn BV, D’Cruz OF, Beach R, Messenheimer JA. Improvement of epileptic seizure control with treatment of obstructive sleep apnoea. Seizure 1996; 5:73-8.

18 Oldani A, Zucconi M, Smirne S, Ferini-Strambi L. The neurophysiological evaluation of nocturnal frontal lobe epilepsy. Seizure 1998; 7:317-20.

19 Tachibana N, Shinde A, Ikeda A, Akiguchi I, Kimura J, Shibasaki H. Supplementary motor area seizure resembling sleep disorder. Sleep 1996; 19(10):811-6.

20??Provini F, Plazzi G, Tinuper P, Vandi S, Lugaresi E, Montagna P. Nocturnal frontal lobe epilepsy. A clinical and polygraphic overview of 100 consecutive cases. Brain 1999; 122:1017-31.

This large, comprehensive study of nocturnal frontal lobe epilepsy clearly describes typical clinical characteristics, EEG findings, and response to therapy.

21?Oldani A, Zucconi M, Asselta R, Modugno M, Bonati T, Dalpra L et al. Autosomal dominant nocturnal frontal lobe epilepsy. A video-polysomnographic and genetic appraisal of 40 patients and delineation of the epileptic syndrome. Brain 1998; 121:205-23.

A study of forty patients with familial nocturnal frontal lobe epilepsy, demonstrating that most families show autosomal dominant pattern with reduced penetrance.

22 Nakken KO, Magnusson A, Steinlein OK. Autosomal dominant nocturnal frontal lobe epilepsy: An electroclinical study of a Norweigian family with ten affected members. Epilepsia 1999; 40(1):88-92.

23 O’Regan ME, Brown JK, Goodwin GM, Clarke M. Epileptic aphasia: a consequence of regional hypometabolic encephalopathy? Dev Med Child Neurol 1998; 40:508-16.

24 Veggiotti P, Beccaria F, Guerrini R, Capvilla G, Lanzi G. Continuous spike-and-wave activity during slow-wave sleep: syndrome or EEG pattern? Epilepsia 1999; 40(11):1593-1601.

25?Quigg M, Straume M, Menaker M, Bertram EH. Temporal distribution of partial seiuzres: Comparison of an animal model with human partial epilepsy. Ann Neurol 1998; 43:748-55.

This paper includes both animal and human data showing a circadian distribution of temporal lobe seizures for both.

26 Malow BA, Passaro EA, Hall JH, Abdulrazzak M, Anderson W, Khan I et al. Sleep deprivation does not increase seizure frequency during long term monitoring. Epilepsia 1999; 40(Suppl 7):99-100 (abstract)

27??Crespel A, Baldy-Moulinier M, Coubes P. The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: Practical and physiopathologic considerations. Epilepsia 1998; 39(2):150-7.

This investigation of 30 epilepsy patients with video EEG and polysomnography shows a relative increase in frontal lobe onset seizures with sleep and sleep disruption by temporal (but not frontal) onset seizures.

28 Bazil CW, Walczak TS (1997) Effects of sleep and sleep stage on epileptic and nonepileptic seizures. Epilepsia 38(1):56-62.

29 Malow BA, Bowes RJ, Ross D. Relationship of temporal lobe seizures to sleep and arousal – a combined scalp-intracranial electrode study. Sleep 2000;, in press.

30?Park SA, Lee BI, Lee SJ, Kim WJ, Lee JH, Kim JY. Clinical courses of pure sleep epilepsies. Seizure 1998; 7:369-77.

This retrospective study of nocturnal seizures shows excellent prognosis for generalized seizures with more variable outcome for partial seizures.

31?Yaqub BA, Waheed G, Kabiraj MM. Nocturnal epilepsies in adults. Seizure 1997; 6:145-9.

This prospective study of 64 patients with nocturnal seizures shows the range of nocturnal seizure types anddemonstrates an overall excellent prognosis.

32??Bazil CW, Castro LHM, Walczak TS. Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy. 2000; Arch Neurol (in press).

This video-EEG polysomnography study of 21 patients with temporal lobe epilepsy clearly shows decreased REM with both nocturnal and diurnal seizures, and decreased sleep efficiency and increased Stage 1 sleep with nocturnal seizures.

33?Espie CA, Paul A, McFie J, Amos P, Hamilton D, McColl JH, Tarassenko L, Pardey J. Sleep studies of adults with severe of profound mental retardation and epilepsy. Am J Mental Retardation 1998; 103(1):47-59.

This is a study of 28 patients with severe mental retardation and epilepsy including overnight polysomnography, showing overall decreases in REM sleep.

34 Bazil CW and Walczak TS (1998) Anticonvulsants and seizures independently reduce REM sleep in patients with temporal lobe epilepsy. Epilepsia 39(Supp 6):69. abstract

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