Sleep and epilepsy are common but often poor bedfellows. Nonrapid eye movement (NREM) sleep is a state of electroencephalography (EEG) synchronization and preserved skeletal muscle tone. Sleep spindles, K-complexes, and slow wave activity of NREM 3 sleep appear to promote interictal epileptiform discharges (IEDs), seizure propagation, and expression of seizure-related movements. Desynchronization of EEG and skeletal muscle atonia present during rapid eye movement (REM) sleep inhibit seizures and spread of IEDs. Certain epilepsies occur exclusively or primarily during sleep (sleep-related epilepsies), and others primarily upon awakening. These state-dependent epilepsies are summarized as follows:
- Seizures occurring upon awakening from sleep:
- primary generalized seizures upon awakening;
- juvenile myoclonic epilepsy (JME);
- Seizures occurring during sleep:
- nocturnal frontal lobe epilepsy;
- benign focal epilepsy of childhood with centrotemporal spikes;
- Panayiotopoulos syndrome;
- tonic seizures of Lennox–Gastaut syndrome;
- electrical status epilepticus during sleep and Landau–Kleffner syndrome.
Recently published studies have expanded knowledge of the complex interrelationships between sleep disorders and epilepsy. We review these here.
DIFFICULTY STAYING ASLEEP AND EXCESSIVE DAYTIME SLEEPINESS ARE MOST COMMON SLEEP/WAKE COMPLAINTS IN ADULTS WITH EPILEPSY
Recent prospective case-control studies found poor sleep quality, difficulty sleeping, and/or excessive daytime sleepiness (EDS) are two to three times more common in adults with epilepsy (AWE) than in healthy controls [1–4]. The most common sleep/wake complaint among AWE is sleep maintenance insomnia (difficulty staying asleep). One prospective study found that 30% of 100 AWE reported sleep complaints, compared with 10% of 90 controls: sleep maintenance insomnia (52 vs. 38%), sleep-onset insomnia (34 vs. 28%), EDS (19 vs. 14%), restless legs (18 vs. 12%), and sleep apnea (9 vs. 3%) . Another study of 486 adults with focal epilepsy found 39% reported sleep complaints vs. 18% of controls .
Excessive sleepiness is the second most common sleep/wake complaint in AWE [5–8]. One recent study found that 48% of 99 unselected AWE complained of EDS and the symptom correlated the most with anxiety . A study of 117 AWE found that 20% complained of EDS (vs. 7% of 30 controls) . EDS in 140 AWE correlated with age, male sex, presence of secondarily generalized seizures, and phenobarbital use .
A complaint of insomnia or EDS in AWE warrants consideration of comorbid depression, anxiety, and suicidal ideation [10▪,11,12,13▪]. Fifty-five percent of 152 consecutive AWE (mean age 46) complained of insomnia and correlated with the number of antiepileptic drugs (AEDs) prescribed and depressive symptoms [13▪]. Reports of poor sleep quality and depression were good predictors of suicide in 98 unselected AWE [10▪]. Complaints of disturbed sleep, depression, and anxiety exerted more effect on multivariate regression models on quality of life than short-term seizure control among 247 consecutive AWE . Insomnia present in 40% of 165 consecutive military veterans (85% man, age 56 + 15 years) was associated with mood and psychotic disorders, post-traumatic epilepsy, and particular AED prescribed .
EDS is the second most common sleep/wake complaint in PWE [5–7,9]. A recent systematic literature review  of EDS in epilepsy found that the prevalence varied from 10 to 48%, seems to be related more often to undiagnosed sleep disorders rather than to epilepsy-related factors, and can be improved by treating comorbid sleep disorders. Predictors for EDS in AWE in two recent studies were as follows: anxiety, a large neck circumference, age, male sex, presence of secondarily generalized seizures, and phenobarbital use [8,9].
SLEEP DEPRIVATION A TRIGGER FOR SEIZURES DEPENDS UPON EPILEPSY TYPE
Since antiquity, physicians have cautioned avoiding sleep deprivation as a trigger for seizures. We have come to understand the role of sleep deprivation in provoking seizures depends upon the seizure type, epilepsy syndrome, and particular individual. Sleep deprivation is an important provoker of seizures in patients with idiopathic (now called genetic) generalized epilepsies, especially those who have JME [15▪]. Seventy-seven percent of 75 JME patients reported that sleep deprivation triggered their seizures , and it (often coupled with acute drug withdrawal and/or alcohol use) caused recurrence of seizures after a long period of remission in 105 patients with JME . Seizures in JME are facilitated by sleep deprivation and sudden arousal . The mean number and duration of IEDs during sleep and upon awakening has been shown to increase in JME following sleep deprivation .
Recommendations to get sufficient sleep and maintain regular bedtimes too often go unheeded in patients with JME. Why unheeded given the dire consequences? Recent research provides clues. Compared with patients with temporal lobe epilepsy (TLE), JEM patients were far more likely to prefer late bedtimes and wake-times . Night owl preferences predisposed them to sleep deprivation and convulsions when not permitted to sleep late into the morning after a late night out. Abnormalities in frontal lobe executive function with difficulties making advantageous decisions in JME may explain their failure to follow adherence to treatment plans and regulate their sleep/wake habits [18,21▪,22–24,25▪▪]. Studies combining cognitive testing and functional magnetic imaging show inadequate sleep in adolescents and young adults, and are associated with increased risk-taking and reward-seeking behaviors [26▪▪,27▪].
Sleep deprivation probably plays a far weaker role for triggering seizures in focal epilepsy . A recent prospective study  found that sleep deprivation did not predict a seizure would occur 12–24 h later in 19 patients with focal epilepsy who kept detailed electronic diaries, tracking seizures and potential premonitory features over 12–14 weeks. Feeling emotional, tired/weary, or difficulty thinking or concentrating increased the likelihood that a seizure would occur within 12 h by odds ratios ranging from 2.0 to 3.4, whereas improvements in mood reduced the risk for seizures by 25%.
OBJECTIVE EFFECTS OF EPILEPSY ON SLEEP ARCHITECTURE
Sleep architecture in patients with epilepsy is often altered, particularly for those whose seizures are poorly controlled, occur during sleep, or have certain types of epilepsy . Sleep architecture abnormalities most often reported in AWE include reduced REM sleep time, prolonged REM latency, increased wake after sleep onset resulting in reduced total sleep time and sleep efficiency, and/or increased number of arousals, awakenings, and stage shifts [30–32].
A case-control study found among 20 adults with medically refractory epilepsy found that they had less sleep time on overnight polysomnographies (PSGs) (340 vs. 450 min), poorer sleep efficiency (81 vs. 96%), increased wake after sleep onset (20 vs. 4%), and greater number of arousals (10 vs. 5/h) compared with 20 whose epilepsy was well controlled . A study compared the effect of seizures on sleep architecture if a seizure occurred at night or earlier that day in a group of patients with temporal lobe epilepsy (TLE) undergoing prolonged inpatient monitoring with PSG. They found a seizure at night reduced mean time spent in REM sleep from 16% to 7%; a seizure in the day reduced REM sleep time less (18% to 12%) . Night seizures (but not daytime seizures) also reduced sleep efficiency, lengthened REM latency, increased stage 1, reduced stage 2 and 4 sleep, and increased drowsiness on the Maintenance of Wakefulness test in this study cohort .
Control of the epilepsy by surgery or medication has been shown to improve sleep architecture in AWE [35▪,36]. Twelve AWE who became seizure-free 3 months after epilepsy surgery had increased sleep time, fewer arousals, and less daytime sleepiness postoperatively compared to their preoperative PSGs [35▪]. No significant change in subjective or objective sleep parameters was seen in five who continued to have seizures following surgery. Another recent PSG study found sleep architecture usually normalized in 40 adults with nocturnal frontal lobe epilepsy whose seizures were controlled by carbamazepine (CBZ) but abnormalities in sleep microarchitecture (cyclic alternating pattern) remained .
OBSTRUCTIVE SLEEP APNEA MORE COMMON IN ADULTS WITH EPILEPSY THAN GENERAL POPULATION
An increasing number of recent studies find obstructive sleep apnea (OSA) occurs with far greater frequency in AWE than in the general population, especially those who are older, obese, have poorer seizure control, and/or have their first seizure or status epilepticus when older. OSA [(defined as apnea–hypopnea index (AHI) > 5/h of sleep] was more likely to be found in AWE who were men (15% men, 5% women), older (mean age 46 vs. 33 years), sleepier (23 vs. 9%), heavier (mean BMI 28.5 vs. 23.3 kg/m2), and had their first seizure when older (32 vs. 19 years) . Higher AHI and more EDS have been found in patients with late onset or worsening seizures compared with AWE with improving or good seizure control . The appearance of OSA symptoms coincided with the first episode of status epilepticus or a clear increase in seizure frequency in another cohort of AWE . A recent retrospective analysis  of 416 AWE found sleep apnea was predominantly of the obstructive variety in 75%, complex in 8%, and central in 4%. Complex or central apnea was not more prevalent in AWE than in the general population but was more likely to occur in AWE who were men or had focal seizures.
A recent prospective cross-sectional study of a diverse population of 130 consecutive AWE seen in a tertiary epilepsy center found the prevalence of OSA (AHI > 10/h of sleep) was 30%, moderate-to-severe (AHI > 15/h) in 16%, rates that markedly exceed general population estimates . Male sex, older age, higher BMI, hypertension, and dental problems were associated with higher AHI. The increased risk of OSA increased with age and AED load, regardless of sex, BMI, and/or seizure frequency.
Effective control of symptomatic OSA in AWE can lead to improved seizure control. Seizure frequency in the short term decreased from a mean of 1.8–1/month in 28 of 41 AWE with OSA who were continuous positive airway pressure (CPAP)-compliant, and in 16 the effect lasted for at least 6 months . No decrease in seizure frequency was noted in the noncompliant group (2.1–1.8/month). Sixteen of 28 CPAP-adherent patients became seizure-free vs. three of 13 nonadherent patients (relative risk 1.54).
Taken together, these findings support routine screening for OSA in patients with epilepsy . A recent study found the Sleep Apnea Scale of the Sleep Disorders Questionnaire (SA-SDQ) was a valid screening tool for OSA in AWE [43▪▪]. A cut-off score of 25 on the SA-SDQ identified OSA in AWE (present in 44% of 90) with a good sensitivity of 73% and a specificity of 72%. A cut-off score of 28 identified AWE likely to have AHI greater than 15/h.
EFFECTS OF ANTIEPILEPTIC MEDICATIONS ON SLEEP AND WAKEFULNESS
Whether a particular AED causes insomnia and/or hypersomnia continues to be debated [44▪] Studies abound but most are limited by small study sizes, lack of healthy controls, varying study designs, and confounding factors [44▪]. Phenytoin may disrupt sleep, causing increased arousals and reducing REM sleep time, although these effects may abate with chronic use [45,46]. CBZ appears to consolidate sleep, reducing awakenings and arousals while increasing NREM 3 and REM sleep time [47–50].
The newer AEDs, in general, have fewer long-term negative effects on sleep [44▪]. Acute levetiracetam (LEV) use was associated with decreased REM sleep time and percentage, subjective increases in sleepiness (on Epworth sleepiness scale) but no change in objective sleepiness on the multiple sleep latency test . A recent randomized controlled trial comparing LEV to extended release-CBZ in 31 AWE before and 4–6 weeks after treatment found no differences in sleep/wake complaints . The only objective changes on PSG were increased sleep efficiency in the LEV-treated group and increased NREM 3 sleep in the CBZ extended-release group.
Depression and anxiety are much more common in people with epilepsy than in the general population . In addition to its antiepileptic properties, lamotrigine is an excellent mood stabilizer [54–57], increases REM sleep and reduces stage shifts [58–60], and rarely worsens insomnia [12,61].
Pregabalin and/or gabapentin are two AEDs that have been shown to improve disturbed sleep in a variety of common conditions, including neuropathic pain [62–64], postherpetic neuralgia [65,66], fibromyalgia [67,68], restless legs syndrome , general anxiety disorder , sleep bruxism , menopausal women with insomnia with or without hot flashes [72–75], and autistic children with refractory insomnia . The evidence suggests that the positive effects of pregabalin are distinct from its analgesic, anxiolytic, and anticonvulsant effects . A double-blind, placebo-controlled crossover study showed that pregabalin increased NREM 3, decreased NREM 1 sleep, and improved attention in nine adults with well controlled epilepsy and sleep maintenance insomnia .
EMERGING FIELD OF CHRONOBIOLOGY BEING APPLIED TO EPILEPSY
An emerging and fascinating field of sleep medicine is chronobiology. Chronobiology explores rhythmic occurrences in human physiological processes and behaviors to identify the mechanisms and functional significance of biological timing . For example, asthma exhibits marked circadian rhythmicity [80–82]: exacerbations occur more often at night; airway responses to bronchial challenges are more severe and prolonged during evening hours or overnight; cortisol levels peak upon awakening and trough levels occur early morning contributing asthma is often worse in the early morning when serum cortisol levels are low; and pulmonary function significantly worse between midnight and early morning related to circadian increases in airway CD4+ lymphocytes, eosinophil recruitment and activation, and interleukin-5 production.
Recent studies confirm JME is an epilepsy also profoundly affected by circadian rhythms : myoclonic jerks and photosensitivity in JME are more likely to occur in the early morning, and are enhanced by sleep deprivation [83,84]; rates of IEDs were highest between one hour prior to the final awakening and the first 30 minutes after awakening ; and cortical excitability measured using transcranial magnetic stimulation (TMS) was higher in the morning in IGE, especially those with JME [86–89].
Recent retrospective studies have been published analyzing whether particular seizure types are more likely to occur at a particular 24-h clock time, awake, asleep, during the day. or night, and establishing the preferential timing of different types of seizures in 1008 events in 225 children [90,91▪]. Sleep and wakefulness were better predictors of seizure types than whether it was day, night, or particular 24-h clock times (Table 1) [90,91▪]. The ever-growing availability of electronic seizure-tracking computer programs and smartphone technology (https://www.seizuretracker.com/ or http://www.epilepsy.com/) expand the possibilities for tracking circadian and clock timing of seizures [92,93].
THE BURGEONING PRACTICE OF CHRONOPHARMACOLOGY: TIMING FOR THERAPEUTIC PERFECTION
Chronopharmacology evaluates how circadian rhythms and/or sleep/wake states affect the pharmacokinetics and pharmacodynamics of a particular drug's absorption, metabolism, elimination, and distribution [94▪]. Absorption may be altered by dietary cues and circadian gene expression. For example, absorption of lipophilic drugs is faster in the morning than later in the day. Distribution may be affected by circadian changes in blood flow to various organs. Free levels of drugs also show cyclic variations. Elimination of drugs can vary with circadian changes in rates of metabolism and excretion. The goals of chronopharmacology are to determine whether a particular drug is affected by endogenous circadian rhythms; whether aligning the drug (or treatment) to the endogenous circadian rhythms results in optimal levels preferably with lowest adverse/toxic effects, and whether doses delivered at a particular clock time must vary to achieve stable plasma levels because of circadian changes in pharmacokinetics.
Chronopharmacological attributes are known for more than 100 drugs, most often clinically applied when treating cancers [95,96]. Circadian timing critically affects antitumor efficacy and toxicity of 28 anticancer medications [97,98]. Effectiveness of anticancer treatments can vary up to 50% and serious adverse events five-fold, depending upon when they are dosed [95–98]. Higher doses of a drug can be given with better efficacy and often lower toxicity at a particular circadian-appropriate time. When patients with rectal cancer were administered infusions of 5-FU peaking in a circadian pattern of treatment at the same time of external beam irradiation were able to tolerate twice the dose intensity, lower recurrence rates, and less bone marrow suppression, diarrhea and weight loss .
Only a few studies have examined chronopharmacology of AEDs. The maximum free concentrations of valproate occur between 2 and 6 a.m. One case-control study  compared the efficacy and safety of twice daily, or a single 8-p.m. dose of phenytoin or CBZ that was 66–75% of their usual total daily dose, in 102 patients with poorly controlled generalized tonic-clonic seizures and subtherapeutic AED levels. In 85% of the patients in the group taking the single larger 8-p.m. dose, AED levels were more often therapeutic, and toxic side-effects were fewer; in comparison, only 38% of the patients dosed twice daily became seizure-free. Another study  found 75–90% reductions in seizure frequencies when two-thirds of the daily AED(s) dose were given at night to 17 children with predominantly nocturnal epilepsies. Sixty-five percent became seizure-free. Patients taking equal doses of valproate morning and night have higher serum concentrations and decreased tmax following the morning dose . Chronomodulating infusion pumps and modified controlled release formulations are currently being developed with the goal of providing higher AED levels at times of increased seizure susceptibility [103–105].
The relationship between sleep and epilepsy is a fruitful and rewarding area for research. Much more research and knowledge is needed to better understand: why is sleep macro- and microarchitecture altered in patients with particular but not all epilepsies; whether treating OSA in patients with epilepsy improves seizure control; the impact of circadian rhythms on different epilepsies and AEDs; and whether frequent IEDs during sleep without few or no seizures should be treated. Better understanding of the link between particular epilepsies, nonepileptic parasomnias, sleep fragmentation, and arousal will further the development of management regimens that optimize overall function and confirm the dictum that a multidisciplinary model will best serve patients with these disorders.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
- ▪▪ of outstanding interest
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