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Sleep disorders in adults with epilepsy: past, present, and future directions

Grigg-Damberger, Madeleine M.a; Ralls, Frankb,c

Current Opinion in Pulmonary Medicine: November 2014 - Volume 20 - Issue 6 - p 542–549
doi: 10.1097/MCP.0000000000000101
SLEEP AND RESPIRATORY NEUROBIOLOGY: Edited by Lee K. Brown and Adrian Williams

Purpose of review To summarize recent studies on the complex relationships between sleep disorders, sleep, and epilepsy.

Recent findings Insomnia in adults with epilepsy (AWE) warrants consideration of depression, anxiety, and suicidal ideation. Daytime sleepiness in AWE is more often due to undiagnosed sleep disorders. Sleep deprivation is an important provoker of seizures in juvenile myoclonic epilepsy. Abnormalities in frontal lobe executive function with difficulties making advantageous decisions may explain failure of juvenile myoclonic epilepsy patients to adhere to treatment recommendations and regulate their sleep habits. Sleep architecture in AWE is more likely to be abnormal if seizures are poorly controlled or occur during sleep. Obstructive sleep apnea is much more common in AWE who are man, older, heavier, or whose seizures are poorly controlled. Chronobiology and chronopharmacology of epilepsy is an emerging field worthy of future research and clinical applications.

Summary Identifying and treating unrecognized sleep disorders and understanding the impact of circadian rhythms on epilepsy can improve quality of life and seizure control in AWE.

aDepartment of Neurology

bUNM Sleep Disorder Center

cDivision of Pulmonary, Critical Care, and Sleep Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, New Mexico, USA

Correspondence to Madeleine M. Grigg-Damberger, MD, Professor of Neurology, Department of Neurology, University of New Mexico School of Medicine, MSC10 5620, One University of New Mexico, Albuquerque, NM 87131-0001, USA. Tel: +1 505 272 3342; fax: +1 505 272 6692; e-mail:

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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:

  1. Seizures occurring upon awakening from sleep:
    1. primary generalized seizures upon awakening;
    2. juvenile myoclonic epilepsy (JME);
  2. Seizures occurring during sleep:
    1. nocturnal frontal lobe epilepsy;
    2. benign focal epilepsy of childhood with centrotemporal spikes;
    3. Panayiotopoulos syndrome;
    4. tonic seizures of Lennox–Gastaut syndrome;
    5. 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.

Box 1

Box 1

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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%) [2]. Another study of 486 adults with focal epilepsy found 39% reported sleep complaints vs. 18% of controls [1].

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 [8]. A study of 117 AWE found that 20% complained of EDS (vs. 7% of 30 controls) [6]. EDS in 140 AWE correlated with age, male sex, presence of secondarily generalized seizures, and phenobarbital use [9].

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 [11]. 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 [12].

EDS is the second most common sleep/wake complaint in PWE [5–7,9]. A recent systematic literature review [14] 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].

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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 [16], 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 [17]. Seizures in JME are facilitated by sleep deprivation and sudden arousal [18]. The mean number and duration of IEDs during sleep and upon awakening has been shown to increase in JME following sleep deprivation [19].

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 [20]. 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 [28]. A recent prospective study [28] 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%.

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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 [29]. 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 [33]. 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%) [34]. 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 [34].

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 [36].

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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) [37]. 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 [38]. 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 [39]. A recent retrospective analysis [40] 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 [41]. 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 [42]. 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 [41]. 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.

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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 [51]. 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 [52]. 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 [53]. 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 [69], general anxiety disorder [70], sleep bruxism [71], menopausal women with insomnia with or without hot flashes [72–75], and autistic children with refractory insomnia [76]. The evidence suggests that the positive effects of pregabalin are distinct from its analgesic, anxiolytic, and anticonvulsant effects [77]. 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 [78].

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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 [79]. 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 [83]: 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 [85]; 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 ( or expand the possibilities for tracking circadian and clock timing of seizures [92,93].

Table 1

Table 1

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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 [99].

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 [100] 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 [101] 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 [102]. 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].

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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.

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Conflicts of interest

There are no conflicts of interest.

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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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1. de Weerd A, de Haas S, Otte 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; 45:1397–1404.
2. Khatami R, Zutter D, Siegel A, et al. Sleep-wake habits and disorders in a series of 100 adult epilepsy patients: a prospective study. Seizure 2006; 15:299–306.
3. Piperidou C, Karlovasitou A, Triantafyllou N, et al. Influence of sleep disturbance on quality of life of patients with epilepsy. Seizure 2008; 17:588–594.
4. Jenssen S, Gracely E, Mahmood T, et al. Subjective somnolence relates mainly to depression among patients in a tertiary care epilepsy center. Epilepsy Behav 2006; 9:632–635.
5. Stefanello S, Marin-leon L, Fernandes PT, et al. Depression and anxiety in a community sample with epilepsy in Brazil. Arq Neuropsiquiatr 2011; 69:342–348.
6. Chen NC, Tsai MH, Chang CC, et al. Sleep quality and daytime sleepiness in patients with epilepsy. Acta Neurol Taiwan 2011; 20:249–256.
7. van Eeghen AM, Numis AI, Staley BA, et al. Characterizing sleep disorders of adults with tuberous sclerosis complex: a questionnaire-based study and review. Epilepsy Behav 2011; 20:68–74.
8. Giorelli AS, Neves GS, Venturi M, et al. Excessive daytime sleepiness in patients with epilepsy: a subjective evaluation. Epilepsy Behav 2011; 21:449–452.
9. Maglajlija V, Walker MC, Kovac S. Severe ictal hypoxemia following focal, subclinical temporal electrographic scalp seizure activity. Epilepsy Behav 2012; 24:143–145.
10▪. Wigg CM, Filgueiras A, Gomes Mda M. The relationship between sleep quality, depression, and anxiety in patients with epilepsy and suicidal ideation. Arq Neuropsiquiatr 2014; 72:344–348.

A study examining relationships among suicidal ideation, sleep, depression, anxiety, and effects on 98 unselected outpatients with epilepsy using Beck Depression Scale. The prevalence of suicidal ideation was 13%. The differences between cases with or without suicidal ideation were statistically significant in relation to sleep quality (P = 0.005) and symptoms of depression (P = 0.001) and anxiety (P = 0.002). Authors concluded that depression and anxiety were associated with sleep quality, daytime sleepiness, and suicidal ideation and that depression and sleep disturbance were good predictors of suicide in patients with epilepsy.

11. Kwan P, Yu E, Leung H, et al. Association of subjective anxiety, depression, and sleep disturbance with quality-of-life ratings in adults with epilepsy. Epilepsia 2009; 50:1059–1066.
12. Lopez MR, Cheng JY, Kanner AM, et al. Insomnia symptoms in South Florida military veterans with epilepsy. Epilepsy Behav 2013; 27:159–164.
13▪. Vendrame M, Yang B, Jackson S, Auerbach SH. Insomnia and epilepsy: a questionnaire-based study. J Clin Sleep Med 2013; 9:141–146.

Study evaluating the prevalence, severity, clinical features, and quality of life related to insomnia in 152 AWE using a battery of insomnia, sleep, and mood questionnaires. Patients with other known primary sleep disorders including sleep apnea were excluded. Authors found that 55% of patients reported insomnia. Insomnia and poor sleep quality were significantly correlated with the number of AEDs and depressive symptom scores. After controlling for covariates, insomnia and poor sleep quality were significant predictors of lower quality of life.

14. Giorelli AS, Passos P, Carnaval T, Gomes Mda M. Excessive daytime sleepiness and epilepsy: a systematic review. Epilepsy Res Treat 2013; 2013:629469.
15▪. Serafini A, Rubboli G, Gigli Gl, et al. Neurophysiology of juvenile myoclonic epilepsy. Epilepsy Behav 2013; 28 (Suppl 1):S30–S39.

A concise review of the clinical and electrophysiological features of JME discussing impact of sleep and sleep deprivation on clinical seizures and EEG. Report focused on the seizures and on the EEG findings with the help, if necessary, of long-term video-EEG monitoring. Summarizes transmagnetic stimulation used to assess cortical excitability contributing to circadian timing of seizures in patients with JME.

16. da Silva Sousa P, Lin K, Garzon E, et al. Self-perception of factors that precipitate or inhibit seizures in juvenile myoclonic epilepsy. Seizure 2005; 14:340–346.
17. Sokic D, Ristic AJ, Vojvodic N, et al. Frequency, causes and phenomenology of late seizure recurrence in patients with juvenile myoclonic epilepsy after a long period of remission. Seizure 2007; 16:533–537.
18. Genton P, Thomas P, Kasteleijn-Nolst Trenite DG, et al. Clinical aspects of juvenile myoclonic epilepsy. Epilepsy Behav 2013; 28 (Suppl 1):S8–S14.
19. Sousa NA, Sousa Pda S, Garzon E, et al. EEG recording after sleep deprivation in a series of patients with juvenile myoclonic epilepsy. Arq Neuropsiquiatr 2005; 63:383–388.
20. Pung T, Schmitz B. Circadian rhythm and personality profile in juvenile myoclonic epilepsy. Epilepsia 2006; 47 (Suppl 2):111–114.
21▪. de Araujo Filho GM, de Araujo TB, Sato JR, et al. Personality traits in juvenile myoclonic epilepsy: evidence of cortical abnormalities from a surface morphometry study. Epilepsy Behav 2013; 27:385–392.

Cluster B personality disorders, characterized as emotional instability, immaturity, lack of discipline, and rapid mood changes, have been observed among patients with JME and have been associated with a worse seizure outcome. Used brain MRI with three-dimensional cortical surface reconstruction and psychiatric evaluation in 22 patients with JME with cluster B personality disorders, 44 patients with JME without psychiatric disorders, and 23 healthy controls. Researchers found significant cortical alterations in mesiofrontal, frontobasal regions, and other limbic and paralimbic regions primarily in JME patients with personality disorders. The present study adds evidence to the hypothesis of frontal and limbic involvement in the pathophysiology of cluster B personality disorders in JME, regions linked to mood and affective regulation, as well as to impulsivity and social behavior.

22. de Araujo Filho GM, Yacubian EM. Juvenile myoclonic epilepsy: psychiatric comorbidity and impact on outcome. Epilepsy Behav 2013; 28 (Suppl 1):S74–S80.
23. Crespel A, Gelisse P, Reed RC, et al. Management of juvenile myoclonic epilepsy. Epilepsy Behav 2013; 28 (Suppl 1):S81–86.
24. Wandschneider B, Thompson PJ, Vollmar C, Koepp MJ. Frontal lobe function and structure in juvenile myoclonic epilepsy: a comprehensive review of neuropsychological and imaging data. Epilepsia 2012; 53:2091–2098.
25▪▪. Zamarian I, Hofler J, Kuchukhidze G, et al. Decision making in juvenile myoclonic epilepsy. J Neurol 2013; 260:839–846.

A study examining decision making in 22 patients with JME and 33 healthy controls using the Iowa Gambling Task and functional brain MRI. Fifty percent of JME patients had medically resistant seizures. In the gambling task, patients with JME showed difficulty in learning to choose soundly compared to healthy controls. Difficulty was enhanced for the patients with pharmacoresistant seizures. Difficulty in decision making may impair functioning of patients with JME in everyday life and affect their adherence to treatment plans.

26▪▪. Telzer EH, Fuligni AJ, Lieberman MD, Galvan A. The effects of poor quality sleep on brain function and risk taking in adolescence. Neuroimage 2013; 71:275–283.

A study examining how poor sleep quality impacts upon cognitive control and reward-related brain function during risk taking in 46 adolescents. Patients participated in a functional magnetic imaging scan during which they completed a cognitive control and risk-taking task. Behaviorally, adolescents who reported poorer sleep also exhibited greater risk-taking. This association was paralleled by less recruitment of the dorsolateral prefrontal cortex during cognitive control, greater insula activation during reward processing, and reduced functional coupling between the dorsolateral prefrontal cortex and affective regions including the insula and ventral striatum during reward processing. Collectively, these results suggest that poor sleep may exaggerate the normative imbalance between affective and cognitive control systems, leading to greater risk-taking in adolescents.

27▪. Womack SD, Hook JN, Reyna SH, Ramos M. Sleep loss and risk-taking behavior: a review of the literature. Behav Sleep Med 2013; 11:343–359.

A nice review of the literature on the relationship between sleep loss and risk-taking behavior (RTB). Overall, sleep loss was positively associated with RTB, and there was evidence that changes in sleep loss are causally related to changes in RTB. One possible mediator of the relationship between sleep loss and RTB was reduced functioning of the ventromedial prefrontal cortex (VMPFC). Possible moderators of this relationship included type of RTB measure and general versus specific RTB.

28. Haut SR, Hall CB, Borkowski T, et al. Clinical features of the preictal state: mood changes and premonitory symptoms. Epilepsy Behav 2012; 23:415–421.
29. Matos G, Andersen ML, do Valle AC, Tufik S. The relationship between sleep and epilepsy: evidence from clinical trials and animal models. J Neurol Sci 2010; 295:1–7.
30. Touchon J, Baldy-Moulinier M, Billiard M, et al. Sleep organization and epilepsy. Epilepsy Res Suppl 1991; 2:73–81.
31. Montplaisir J, Laverdiere M, Saint-Hilaire JM, Rouleau I. Nocturnal sleep recording in partial epilepsy: a study with depth electrodes. J Clin Neurophysiol 1987; 4:383–388.
32. Manni R, Galimberti CA, Zucca C, et al. Sleep patterns in patients with late onset partial epilepsy receiving chronic carbamazepine (CBZ) therapy. Epilepsy Res 1990; 7:72–76.
33. Zanzmera P, Shukla G, Gupta A, et al. Markedly disturbed sleep in medically refractory compared to controlled epilepsy: a clinical and polysomnography study. Seizure 2012; 21:487–490.
34. Bazil CW, Castro IH, Walczak TS. Reduction of rapid eye movement sleep by diurnal and nocturnal seizures in temporal lobe epilepsy. Arch Neurol 2000; 57:363–368.
35▪. Zanzmera P, Shukla G, Gupta A, et al. Effect of successful epilepsy surgery on subjective and objective sleep parameters: a prospective study. Sleep Med 2013; 14:333–338.

A prospective cohort study in 17 patients with medically refractory epilepsy undergoing epilepsy surgery. They found that the patients with good surgical outcome (n=12) showed reduced seizure frequency (p=0.01) and reduced subjective EDS with corresponding reduction in arousal index and increase in total sleep time after surgery. Epilepsy surgery can have beneficial effects on sleep architecture and daytime sleepiness in patients with medically refractory epilepsy.

36. De Paolis F, Colizzi E, Milioli G, et al. Effects of antiepileptic treatment on sleep and seizures in nocturnal frontal lobe epilepsy. Sleep Med 2013; 14:597–604.
37. Manni R, Terzaghi M, Arbasino C, et al. Obstructive sleep apnea in a clinical series of adult epilepsy patients: frequency and features of the comorbidity. Epilepsia 2003; 44:836–840.
38. Chihorek AM, Abou-Khalil B, Malow BA. Obstructive sleep apnea is associated with seizure occurrence in older adults with epilepsy. Neurology 2007; 69:1823–1827.
39. Hollinger P, Khatami R, Gugger M, et al. Epilepsy and obstructive sleep apnea. Eur Neurol 2006; 55:74–79.
40. Vendrame M, Jackson S, Syed S, et al. Central sleep apnea and complex sleep apnea in patients with epilepsy. Sleep Breath 2014; 18:119–124.
41. Foldvary-Schaefer N, Andrews ND, Pornsriniyom D, et al. Sleep apnea and epilepsy: who's at risk? Epilepsy Behav 2012; 25:363–367.
42. Vendrame M, Auerbach S, Loddenkemper T, et al. Effect of continuous positive airway pressure treatment on seizure control in patients with obstructive sleep apnea and epilepsy. Epilepsia 2011; 52:e168–e171.
43▪▪. Economou NT, Dikeos D, Andrews N, Foldvary-Schaefer N. Use of the Sleep Apnea Scale of the Sleep Disorders Questionnaire (SA-SDQ) in adults with epilepsy. Epilepsy Behav 2014; 31:123–126.

Researchers validated use of the SA-SDQ in 90 AWE from a tertiary epilepsy center. Receiver operating characteristics were constructed to assess optimal sensitivity and specificity for predicting OSA (defined as an AHI > 5). OSA was diagnosed in 44 individuals. For all individuals, an SA-SDQ cut-off score of 25 provided good sensitivity (73%) and specificity (72%) for OSA diagnosis. The same cut-off score provided optimal sensitivity (94%) and specificity (83%) for men, whereas for women, it provided lower sensitivity (55%) and specificity (68%). In women, a cutoff of 24 improved sensitivity (68%) but not specificity (58%).

44▪. Derry CP, Duncan S. Sleep and epilepsy. Epilepsy Behav 2013; 26:394–404.

A well written and referenced review of sleep and epilepsy.

45. Roder-Wanner UU, Noachtar S, Wolf P. Response of polygraphic sleep to phenytoin treatment for epilepsy. A longitudinal study of immediate, short- and long-term effects. Acta Neurol Scand 1987; 76:157–167.
46. Wolf P, Roder-Wanner UU, Brede M. Influence of therapeutic phenobarbital and phenytoin medication on the polygraphic sleep of patients with epilepsy. Epilepsia 1984; 25:467–475.
47. Cho YW, Kim do H, Motamedi GK. The effect of levetiracetam monotherapy on subjective sleep quality and objective sleep parameters in patients with epilepsy: compared with the effect of carbamazepine-CR monotherapy. Seizure 2011; 20:336–339.
48. Alfaro-Rodriguez A, labra-Ruiz N, Carrasco-Portugal M, et al. Effect of carbamazepine on sleep patterns disturbed by epilepsy. Proc West Pharmacol Soc 2002; 45:62–64.
49. Gigli Gl, Placidi F, Diomedi M, et al. Nocturnal sleep and daytime somnolence in untreated patients with temporal lobe epilepsy: changes after treatment with controlled-release carbamazepine. Epilepsia 1997; 38:696–701.
50. Yang JD, Elphick M, Sharpley AI, Cowen PJ. Effects of carbamazepine on sleep in healthy volunteers. Biol Psychiatry 1989; 26:324–328.
51. Zhou JY, Tang XD, Huang II, et al. The acute effects of levetiracetam on nocturnal sleep and daytime sleepiness in patients with partial epilepsy. J Clin Neurosci 2012; 19:956–960.
52. Cho YW, Kim do H, Motamedi GK. The effect of levetiracetam monotherapy on subjective sleep quality and objective sleep parameters in patients with epilepsy: compared with the effect of carbamazepine-CR monotherapy. Seizure 2011; 20:336–339.
53. Kanner AM. The treatment of depressive disorders in epilepsy: what all neurologists should know. Epilepsia 2013; 54 (Suppl 1):3–12.
54. Bowen RC, Balbuena I, Baetz M. Lamotrigine reduces affective instability in depressed patients with mixed mood and anxiety disorders. J Clin Psychopharmacol 2014; [Epub ahead of print].
55. Katayama Y, Terao T, Kamei K, et al. Therapeutic window of lamotrigine for mood disorders: a naturalistic retrospective study. Pharmacopsychiatry 2014; 47:111–114.
56. Oncu B, Er O, Colak B, Nutt DJ. lamotrigine for attention deficit-hyperactivity disorder comorbid with mood disorders: a case series. J Psychopharmacol 2014; 28:282–283.
57. Sajatovic M, Thompson TR, Nanry K, et al. Prospective, open-label trial measuring satisfaction and convenience of two formulations of lamotrigine in subjects with mood disorders. Patient Prefer Adherence 2013; 7:411–417.
58. Foldvary N, Perry M, Lee J, et al. The effects of lamotrigine on sleep in patients with epilepsy. Epilepsia 2001; 42:1569–1573.
59. Placidi F, Diomedi M, Scalise A, et al. Effect of anticonvulsants on nocturnal sleep in epilepsy. Neurology 2000; 54:S25–32.
60. Placidi F, Marciani MG, Diomedi M, et al. Effects of lamotrigine on nocturnal sleep, daytime somnolence and cognitive functions in focal epilepsy. Acta Neurol Scand 2000; 102:81–86.
61. Sadler M. Lamotrigine associated with insomnia. Epilepsia 1999; 40:322–325.
62. Biyik Z, Solak Y, Atalay H, et al. Gabapentin versus pregabalin in improving sleep quality and depression in hemodialysis patients with peripheral neuropathy: a randomized prospective crossover trial. Int Urol Nephrol 2013; 45:831–837.
63. Biyik Z, Solak Y, Atalay H, et al. Gabapentin versus pregabalin in improving sleep quality and depression in hemodialysis patients with peripheral neuropathy: a randomized prospective crossover trial. Int Urol Nephrol 2013; 45:831–837.
64. Boyle J, Eriksson ME, Gribble I, et al. Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic 15 diabetic peripheral neuropathic pain: impact on pain, polysomnographic sleep, daytime functioning, and quality of life. Diabetes Care 2012; 35:2451–2458.
65. Sabatowski R, Galvez R, Cherry DA, et al. Pregabalin reduces pain and improves sleep and mood disturbances in patients with postherpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004; 109:26–35.
66. van Seventer R, Feister HA, Young JP Jr, et al. Efficacy and tolerability of twice-daily pregabalin for treating pain and related sleep interference in postherpetic neuralgia: a 13-week, randomized trial. Curr Med Res Opin 2006; 22:375–384.
67. Roth T, Lankford DA, Bhadra P, et al. Effect of pregabalin on sleep in patients with fibromyalgia and sleep maintenance disturbance: a randomized, placebo-controlled, 2-way crossover polysomnography study. Arthritis Care Res (Hoboken) 2012; 64:597–606.
68. Russell IJ, Crofford lJ, Leon T, et al. The effects of pregabalin on sleep disturbance symptoms among individuals with fibromyalgia syndrome. Sleep Med 2009; 10:604–610.
69. Misra UK, Kalita J, Kumar B, Prasad S. Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study. Neurology 2011; 76:408.
70. Holsboer-Trachsler E, Prieto R. Effects of pregabalin on sleep in generalized anxiety disorder. Int J Neuropsychopharmacol 2013; 16:925–936.
71. Madani AS, Abdollahian E, Khiavi HA, et al. The efficacy of gabapentin versus stabilization splint in management of sleep bruxism. J Prosthodont 2013; 22:126–131.
72. Agarwal N, Singh S, Kriplani A, et al. Evaluation of gabapentin in management of hot flushes in postmenopausal women. Post Reprod Health 2014; 20:36–38.
73. Saadati N, Mohammadjafari R, Natanj S, Abedi P. The effect of gabapentin on intensity and duration of hot flashes in postmenopausal women: a randomized controlled trial. Glob J Health Sci 2013; 5:126–130.
74. Guttuso T Jr. Nighttime awakenings responding to gabapentin therapy in late premenopausal women: a case series. J Clin Sleep Med 2012; 8:187–189.
75. Pinkerton JV, Kagan R, Portman D, et al. Phase 3 randomized controlled study of gastroretentive gabapentin for the treatment of moderate-to-severe hot flashes in menopause. Menopause 2014; 21:567–573.
76. Robinson AA, Malow BA. Gabapentin shows promise in treating refractory insomnia in children. J Child Neurol 2013; 28:1618–1621.
77. Roth T, Arnold lM, Garcia-Borreguero D, et al. A review of the effects of pregabalin on sleep disturbance across multiple clinical conditions. Sleep Med Rev 2014; 18:261–271.
78. Bazil CW, Dave J, Cole J, et al. Pregabalin increases slow-wave sleep and may improve attention in patients with partial epilepsy and insomnia. Epilepsy Behav 2012; 23:422–425.
79. Kaur G, Phillips C, Wong K, Saini B. Timing is important in medication administration: a timely review of chronotherapy research. Int J Clin Pharm 2013; 35:344–358.
80. Panzer SE, Dodge AM, Kelly EA, Jarjour NN. Circadian variation of sputum inflammatory cells in mild asthma. J Allergy Clin Immunol 2003; 111:308–312.
81. Kelly EA, Houtman JJ, Jarjour NN. Inflammatory changes associated with circadian variation in pulmonary function in subjects with mild asthma. Clin Exp Allergy 2004; 34:227–233.
82. Durrington HJ, Farrow SN, Loudon AS, Ray DW. The circadian clock and asthma. Thorax 2014; 69:90–92.
83. Kasteleijn-Nolst Trenite DG, de Weerd A, Beniczky S. Chronodependency and provocative factors in juvenile myoclonic epilepsy. Epilepsy Behav 2013; 28 (Suppl 1):S25–29.
84. Loddenkemper T, Lockley SW, Kaleyias J, Kothare SV. Chronobiology of epilepsy: diagnostic and therapeutic implications of chrono-epileptology. J Clin Neurophysiol 2011; 28:146–153.
85. Dhanuka AK, Jain BK, Daljit S, Maheshwari D. Juvenile myoclonic epilepsy: a clinical and sleep EEG study. Seizure 2001; 10:374–378.
86. Manganotti P, Bongiovanni IG, Fuggetta G, et al. Effects of sleep deprivation on cortical excitability in patients affected by juvenile myoclonic epilepsy: a combined transcranial magnetic stimulation and EEG study. J Neurol Neurosurg Psychiatry 2006; 77:56–60.
87. Badawy RA, Macdonell RA, Jackson GD, Berkovic SF. Why do seizures in generalized epilepsy often occur in the morning? Neurology 2009; 73:218–222.
88. Del Felice A, Fiaschi A, Bongiovanni GI, et al. The sleep-deprived brain in normals and patients with juvenile myoclonic epilepsy: a perturbational approach to measuring cortical reactivity. Epilepsy Res 2011; 96:123–131.
89. Puri V, Sajan PM, Chowdhury V, Chaudhry N. Cortical excitability in drug naive juvenile myoclonic epilepsy. Seizure 2013; 22:662–669.
90. Loddenkemper T, Vendrame M, Zarowski M, et al. Circadian patterns of pediatric seizures. Neurology 2011; 76:145–153.
91▪. Sanchez Fernandez I, Ramgopal S, Powell C, et al. Clinical evolution of seizures: distribution across time of day and sleep/wakefulness cycle. J Neurol 2013; 260:549–557.

Analyzed 24-h clock distribution of 866 seizures in 215 patients with simple partial seizures that evolved to complex partial and 324 seizures in 87 patients that further evolved to secondary generalized convulsions. They found evolution into clonic seizures differed across time with peaks at 0–3 h and 6–9 h and during sleep, evolution into automotor seizures peaked during wakefulness, evolution into tonic seizures differed across time with peaks at 21–12 h and during sleep, and generalized tonic-clonic seizures peaked during sleep, but not for secondarily generalized seizures. Findings remained statistically significant following multivariable analysis after adjusting for particular seizure onset clinical semiology, age, sex, duration of long-term epilepsy monitoring, abnormal neuroimaging, number of AEDs, and seizure localization.

92. Haut SR, Hall CB, Borkowski T, et al. Modeling seizure self-prediction: an e-diary study. Epilepsia 2013; 54:1960–1967.
93. Fisher RS, Blum DE, DiVentura B, et al. Seizure diaries for clinical research and practice: limitations and future prospects. Epilepsy Behav 2012; 24:304–310.
94▪. Ramgopal S, Thome-Souza S, Loddenkemper T. Chronopharmacology of anticonvulsive therapy. Curr Neurol Neurosci Rep 2013; 13:339.

A comprehensive review of current knowledge of chronobiology and chronopharmacology in persons with epilepsy.

95. Romigi A, Izzi F, Marciani MG, et al. Pregabalin as add-on therapy induces REM sleep enhancement in partial epilepsy: a polysomnographic study. Eur J Neurol 2009; 16:70–75.
96. Kubota T, Fang J, Meltzer lT, Krueger JM. Pregabalin enhances nonrapid eye movement sleep. J Pharmacol Exp Ther 2001; 299:1095–1105.
97. Levi F, Okyar A, Dulong S, et al. Circadian timing in cancer treatments. Annu Rev Pharmacol Toxicol 2010; 50:377–421.
98. Ortiz-Tudela E, Mteyrek A, Ballesta A, et al. Cancer chronotherapeutics: experimental, theoretical, and clinical aspects. Handb Exp Pharmacol 2013; 217:261–288.
99. Thrall MM, Wood P, King V, et al. Investigation of the comparative toxicity of 5-FU bolus versus 5-FU continuous infusion circadian chemotherapy with concurrent radiation therapy in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 2000; 46:873–881.
100. Yegnanarayan R, Mahesh SD, Sangle S. Chronotherapeutic dose schedule of phenytoin and carbamazepine in epileptic patients. Chronobiol Int 2006; 23:1035–1046.
101. Guilhoto IM, Loddenkemper T, Vendrame M, et al. Higher evening antiepileptic drug dose for nocturnal and early-morning seizures. Epilepsy Behav 2011; 20:334–337.
102. Ohdo S, Nakano S, Ogawa N. Circadian changes of valproate kinetics depending on meal condition in humans. J Clin Pharmacol 1992; 32:822–826.
103. Ohdo S. Chrono-drug-delivery focused on biological clock: intra- and inter-individual variability of molecular clock. Adv Drug Deliv Rev 2010; 62:857–858.
104. Ohdo S. Chronotherapeutic strategy: rhythm monitoring, manipulation and disruption. Adv Drug Deliv Rev 2010; 62:859–875.
105. Ohdo S. Chronopharmaceutics: pharmaceutics focused on biological rhythm. Biol Pharm Bull 2010; 33:159–167.

chronopharmacology; insomnia and epilepsy; sleep apnea and epilepsy; sleep disorders and epilepsy; sleepwalking and frontal lobe epilepsy

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