Sleep, Seizures, and the Effects of Medication

Carl W. Bazil, MD, PhD, is an Associate Professor of Clinical Neurology, College of Physicians and Surgeons at Columbia University. He is the Director of Clinical Anticonvulsant Drug Trials and of the Neurology Division of the Columbia Comprehensive Sleep Center at the Neurological Institute in New York City.

Active in various organizations in his field of study, Dr. Bazil is a Board Member of the American Clinical Neurophysiology Society. He has been a Contributing Editor for Epilepsy Currents, and is a Member of the Editorial Board of Epilepsy Research and Epilepsy.com. He is also an Ad Hoc Reviewer for Epilepsia, European Journal of Neurology, Physiology and Behavior, Annals of Neurology, Archives of Neurology, Sleep, Brain, Clinical Therapeutics, and Neuroscience Letters.

Dr. Bazil has published over 60 articles in professional journals, has written a book for patients on epilepsy, has edited a book on sleep and epilepsy, and has contributed 14 chapters to various texts in his field. Dr. Bazil has been an invited lecturer at numerous national and international meetings mainly on the topic of sleep and epilepsy.

Sleep, Seizures, and the Effects of Medication

By Carl Bazil, MD, PhD

Despite the importance of sleep to general health and optimal cognitive functioning, the busy modern world leads many people to minimize sleep and overlook sleep problems. Lack of sleep can result in drowsiness, inattention, and sluggish memory. Chronic sleep deprivation, even by only an hour or two per night, can result in significant cognitive impairments. Persons with epilepsy are at increased risk for sleep related problems for these reasons as well as additional factors – all of which can worsen cognitive function. These factors include seizures, underlying conditions causing epilepsy, medication effects, depression and anxiety.

How sleep and epilepsy interact

First, sleep influences the frequency of interictal epileptiform discharges, with partial discharges occurring most commonly in deep, non-REM sleep.[1] For this reason, sleep EEGs can be important diagnostically. Second, sleep influences the occurrence and secondary generalization of seizures, and even brief seizures can result in prolonged alternation in sleep structure. Third, seizures can disrupt sleep. Fourth, many sleep disorders are more common in patients with epilepsy than in the general population. Finally, anticonvulsant drugs have the potential to either worsen or improve sleep overall, and many affect specific sleep disorders.

Effects of anticonvulsant medications

Early studies of anticonvulsant medications showed an increase in sleep stability with all agents. In retrospect, much of this effect was likely due to a reduction in seizure activity, rather than an independent effect of the drug. More recently, the effects of anticonvulsant drugs have been studied independently of seizures, showing different effects (both detrimental and beneficial) of various anticonvulsants on both sleep and specific sleep disorders.

• Benzodiazepines and barbiturates are used less commonly for chronic treatment of seizure disorders, but have the most convincing evidence for detrimental effects on sleep. While both classes of medications reduce sleep latency, they also decrease the amount of REM sleep and benzodiazepines reduce slow wave sleep.[29, 30] The effects of other anticonvulsant drugs are somewhat variable between studies, but some conclusions can be made.
• Phenytoin --increases light sleep and decreases sleep efficiency, and most studies show decreased REM sleep. [29, 31, 32]
• Carbamazepine -- findings are more variable, but there also seems to be a reduction in REM sleep[31] particularly with acute treatment.[33, 34]
• Valproate --may increase stage 1 sleep [32] and (at least theoretically) could worsen obstructive sleep apnea (OSA) through weight gain.

Newer AEDs and sleep

Studies of newer agents in general suggest fewer detrimental effects on sleep.

• Lamotrigine – this has been shown to have no effect on sleep in one study,[33] but another showed decreases in slow wave sleep.[35]
• Gabapentin, pregabalin, and tiagabine -- these enhance slow wave sleep and sleep continuity in patients with epilepsy [32, 33] and in normal volunteers.[30, 36-40] Furthermore, gabapentin is effective in the treatment of one common sleep disorder, restless legs syndrome,[41] although carbamazepine and lamotrigine have also been used .
• Levetiracetam – studies in epilepsy patients showed little effect; [42] studies in normal volunteers have either shown little effect[42] or an increase in sleep continuity and slow wave sleep.[43]
• Zonisamide, oxcarbazepine, and topiramate effects are unknown on sleep and sleep disorders.

Patients taking anticonvulsants known to disrupt sleep (phenobarbital, phenytoin, carbamazepine, or valproic acid) have increased drowsiness compared to epilepsy patients who are not taking anticonvulsants.[44]

The important aspect of AEDs and sleep

An important question is whether sleep changes due to AEDs actually affect performance. A study of tiagabine used during sleep deprivation did just that.[40] Thirty eight healthy adults were restricted to five hours of sleep for four consecutive nights, and randomized to tiagabine 8 mg at bedtime or placebo. In a measure of attention (psychomotor vigilance task), subjects on placebo deteriorated during sleep restriction but subjects receiving tiagabine did not (See chart).

Sleep disruption can affect many aspects of cognitive functioning. There appears to be growing evidence that sleep in general, and REM and/or slow wave sleep in particular, are required for optimal performance. There is also growing evidence that chronic sleep restriction by as little as 2 hours per night can severely impair neurobehavioral functions in normal individuals.[8]

Both REM and slow wave sleep are considered to be “essential sleep”, and subjects who are deprived of sleep (at least in the short term) will “rebound” or make up most of the REM and slow wave sleep that are lost. Very little stage 1 or 2 sleep is regained.[25] Although the function of REM sleep remains speculative, there is considerable information suggesting that increased REM is correlated with enhanced learning of certain tasks.[49-51] Additionally, enhancement of REM sleep occurs with drugs useful in Alzheimer’s disease[52, 53] and REM enhancement due to donepezil correlates with improved memory in normal individuals.[54] Increased slow wave sleep has also been correlated with certain types of learning in one human study.[49]

Optimal care of the epilepsy patient with regard to sleep

The most important aspect of sleep for the epilepsy patient is awareness of its importance. Too often, drowsiness and inattention are considered unavoidable effects of medication and/or seizures, but it is clear that sleep disruption is very common and can contribute to dysfunction. Seizures, sleep disorders, and mood disorders can easily form a cycle of dysfunction, with each independent problem contributing and worsening the others. Without attention to all aspects of the patient’s conditions that potentially affect sleep, optimal quality of life cannot be obtained.

In patients with persistent drowsiness, inattention, or cognitive problems a systematic approach is best. Asking about sleep habits will help to ascertain whether the patient is receiving sufficient sleep or has problems with sleep hygiene. Any patient who shows persistent drowsiness and inattention without adequate explanation could have a coincident sleep disorder.

A good subjective screen is the Epworth Sleepiness Test; and patients with a score of 10 or more on this simple test should be considered for further workup. Medications taken by the patient should be considered, including anticonvulsant drugs, for possible adverse effects on sleep. A careful history may also show signs of specific sleep disorders. Even without demonstrable drowsiness, patients with snoring, subjective insomnia or hypersomnia, limb movements in sleep, or lack of other explanations for cognitive problems may have sleep disorders.
When in doubt, referral to a sleep specialist for evaluation and possible testing should be considered.

Some of these results are derived from small clinical studies, and the effects may not occur in all patients.

This is a brief adaptation from the chapter "Sleep" by Dr. Bazil in Behavioral Aspects of Epilepsy, editors, Schachter SC, Holmes GL, Trenite DK, Demos Medical Publishing, New York, in press with an anticipated publication date of mid-October 2007.

REFERENCES

1. Sammaritano, M., G.L. Gigli, and J. Gotman, Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology, 1991. 41(2 ( Pt 1)): p. 290-7.
2. Bazil, C.W. and T.S. Walczak, Effects of sleep and sleep stage on epileptic and nonepileptic seizures. Epilepsia, 1997. 38(1): p. 56-62.
3. Herman, S.T., T.S. Walczak, and C.W. Bazil, Distribution of partial seizures during the sleep--wake cycle: differences by seizure onset site. Neurology, 2001. 56(11): p. 1453-9.
4. Touchon, J., et al., [Organization of sleep in recent temporal lobe epilepsy before and after treatment with carbamazepine]. Rev Neurol (Paris), 1987. 143(5): p. 462-7.
5. Tachibana, N., et al., Supplementary motor area seizure resembling sleep disorder. Sleep, 1996. 19(10): p. 811-6.
6. Crespel, A., M. Baldy-Moulinier, and P. Coubes, The relationship between sleep and epilepsy in frontal and temporal lobe epilepsies: practical and physiopathologic considerations. Epilepsia, 1998. 39(2): p. 150-7.
7. Bazil, C.W., L.H. Castro, and T.S. Walczak, Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy. Arch Neurol, 2000. 57(3): p. 363-8.
8. Van Dongen, H.P., et al., The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep, 2003. 26(2): p. 117-26.
9. Xu, X., et al., Sleep Disturbances Reported by Refractory Partial-onset Epilepsy Patients Receiving Polytherapy. Epilepsia, 2006. 47(7): p. 1176-83.
10. de Weerd, A., et al., Subjective sleep disturbance in patients with partial epilepsy: a questionnaire-based study on prevalence and impact on quality of life. Epilepsia, 2004. 45(11): p. 1397-404.
11. Jefferson, C.D., et al., Sleep hygiene practices in a population-based sample of insomniacs. Sleep, 2005. 28(5): p. 611-5.
12. Bazil, C.W., T. DaGiau, and E.A. Salerni, Sleep disturbance in patients with epilepsy. Epilepsia, in press.
13. Khatami, R., et al., Sleep-wake habits and disorders in a series of 100 adult epilepsy patients--a prospective study. Seizure, 2006. 15(5): p. 299-306.
14. Malow, B.A., R.J. Bowes, and X. Lin, Predictors of sleepiness in epilepsy patients. Sleep, 1997. 20(12): p. 1105-10.
15. Cortesi, F., F. Giannotti, and S. Ottaviano, Sleep problems and daytime behavior in childhood idiopathic epilepsy. Epilepsia, 1999. 40(11): p. 1557-65.
16. Chervin, R.D. and C. Guilleminault, Obstructive sleep apnea and related disorders. Neurol Clin, 1996. 14(3): p. 583-609.
17. Malow, B.A., G.A. Fromes, and M.S. Aldrich, Usefulness of polysomnography in epilepsy patients. Neurology, 1997. 48(5): p. 1389-94.
18. Beran, R.G., M.J. Plunkett, and G.J. Holland, Interface of epilepsy and sleep disorders. Seizure, 1999. 8(2): p. 97-102.
19. Devinsky, O., et al., Epilepsy and sleep apnea syndrome. Neurology, 1994. 44(11): p. 2060-4.
20. Malow, B.A., et al., Obstructive sleep apnea is common in medically refractory epilepsy patients. Neurology, 2000. 55(7): p. 1002-7.
21. Yaggi, H.K., et al., Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med, 2005. 353(19): p. 2034-41.
22. Chesson, A.L., Jr., et al., Practice parameters for the nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep, 1999. 22(8): p. 1128-33.
23. Strine, T.W., et al., Psychological distress, comorbidities, and health behaviors among U.S. adults with seizures: results from the 2002 National Health Interview Survey. Epilepsia, 2005. 46(7): p. 1133-9.
24. Jones, J.E., et al., Clinical assessment of Axis I psychiatric morbidity in chronic epilepsy: a multicenter investigation. J Neuropsychiatry Clin Neurosci, 2005. 17(2): p. 172-9.
25. Lavigne, G.J. and J.Y. Montplaisir, Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep, 1994. 17(8): p. 739-43.
26. Bixler, E.O., et al., Nocturnal myoclonus and nocturnal myoclonic activity in the normal population. Res Commun Chem Pathol Pharmacol, 1982. 36(1): p. 129-40.
27. Ancoli-Israel, S., et al., Sleep apnea and periodic movements in an aging sample. J Gerontol, 1985. 40(4): p. 419-25.
28. Mosko, S.S., et al., Sleep apnea and sleep-related periodic leg movements in community resident seniors. J Am Geriatr Soc, 1988. 36(6): p. 502-8.
29. Wolf, P., U.U. Roder-Wanner, and M. Brede, Influence of therapeutic phenobarbital and phenytoin medication on the polygraphic sleep of patients with epilepsy. Epilepsia, 1984. 25(4): p. 467-75.
30. Hindmarch, I., J. Dawson, and N. Stanley, A double-blind study in healthy volunteers to assess the effects on sleep of pregabalin compared with alprazolam and placebo. Sleep, 2005. 28(2): p. 187-93.
31. Drake, M.E., Jr., et al., Outpatient sleep recording during antiepileptic drug monotherapy. Clin Electroencephalogr, 1990. 21(3): p. 170-3.
32. Legros, B. and C.W. Bazil, Effects of antiepileptic drugs on sleep architecture: a pilot study. Sleep Med, 2003. 4(1): p. 51-5.
33. Placidi, F., et al., Effect of anticonvulsants on nocturnal sleep in epilepsy. Neurology, 2000. 54(5 Suppl 1): p. S25-32.
34. Yang, J.D., et al., Effects of carbamazepine on sleep in healthy volunteers. Biol Psychiatry, 1989. 26(3): p. 324-8.
35. Foldvary, N., et al., The effects of lamotrigine on sleep in patients with epilepsy. Epilepsia, 2001. 42(12): p. 1569-73.
36. Foldvary-Schaefer, N., et al., Gabapentin increases slow-wave sleep in normal adults. Epilepsia, 2002. 43(12): p. 1493-7.
37. Bazil, C., J. Battista, and R. Basner, Gabapentin improves sleep in the presence of alcohol. Journal of Clinical Sleep Medicine, 2005. 1: p. 284-7.
38. Mathias, S., et al., The GABA uptake inhibitor tiagabine promotes slow wave sleep in normal elderly subjects. Neurobiol Aging, 2001. 22(2): p. 247-53.
39. Walsh, J.K., et al., Dose-response effects of tiagabine on the sleep of older adults. Sleep, 2005. 28(6): p. 673-6.
40. Walsh, J.K., et al., Tiagabine is associated with sustained attention during sleep restriction: evidence for the value of slow-wave sleep enhancement? Sleep, 2006. 29(4): p. 433-43.
41. Garcia-Borreguero, D., et al., Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology, 2002. 59(10): p. 1573-9.
42. Bell, C., et al., The effects of levetiracetam on objective and subjective sleep parameters in healthy volunteers and patients with partial epilepsy. J Sleep Res, 2002. 11(3): p. 255-63.
43. Cicolin, A., et al., Effects of levetiracetam on nocturnal sleep and daytime vigilance in healthy volunteers. Epilepsia, 2006. 47(1): p. 82-5.
44. Salinsky, M.C., B.S. Oken, and L.M. Binder, Assessment of drowsiness in epilepsy patients receiving chronic antiepileptic drug therapy. Epilepsia, 1996. 37(2): p. 181-7.
45. Berg, A.T., et al., Driving in adults with refractory localization-related epilepsy. Multi-Center Study of Epilepsy Surgery. Neurology, 2000. 54(3): p. 625-30.
46. Weinger, M.B. and S. Ancoli-Israel, Sleep deprivation and clinical performance. Jama, 2002. 287(8): p. 955-7.
47. Grantcharov, T.P., et al., Laparoscopic performance after one night on call in a surgical department: prospective study. Bmj, 2001. 323(7323): p. 1222-3.
48. Veasey, S., et al., Sleep loss and fatigue in residency training: a reappraisal. Jama, 2002. 288(9): p. 1116-24.
49. Stickgold, R., et al., Visual discrimination task improvement: A multi-step process occurring during sleep. J Cogn Neurosci, 2000. 12(2): p. 246-54.
50. Stickgold, R., et al., Sleep, learning, and dreams: off-line memory reprocessing. Science, 2001. 294(5544): p. 1052-7.
51. Maquet, P., The role of sleep in learning and memory. Science, 2001. 294(5544): p. 1048-52.
52. Holsboer-Trachsler, E., et al., Effects of the novel acetylcholinesterase inhibitor SDZ ENA 713 on sleep in man. Neuropsychopharmacology, 1993. 8(1): p. 87-92.
53. Schredl, M., et al., The effect of rivastigmine on sleep in elderly healthy subjects. Exp Gerontol, 2000. 35(2): p. 243-9.
54. Schredl, M., et al., Donepezil-induced REM sleep augmentation enhances memory performance in elderly, healthy persons. Exp Gerontol, 2001. 36(2): p. 353-61.

CHART: Effects of tiagabine on reaction time and slow wave sleep in sleep deprivation. Top: Effects on reaction time with the psychomotor vigilance task. Bottom: Effects on total slow wave sleep. SR2: second night of sleep restriction. SR 4: fourth night of sleep restriction. Adapted from [40]

Back to top

Return to Articles and Publications