CRITICAL REVIEW AND INVITED COMMENTARY

Effects of epilepsy treatments on sleep architecture and daytime sleepiness: An evidence-based review of objective sleep metrics Sejal V. Jain and Tracy A. Glauser Epilepsia, 55(1):26–37, 2014 doi: 10.1111/epi.12478

SUMMARY

Dr. Sejal Jain is the Director of NeurologySleep program and a researcher in sleep and epilepsy.

Objective: Sleep is considered restorative, and good quantity and quality sleep is required for memory consolidation and synaptic plasticity. Sleep disorders are common in patients with epilepsy. Poor sleep quality or quantity may worsen seizure control. On the other end, seizures and epilepsy may worsen the sleep quality and set a vicious cycle. In addition, antiepileptic drugs have an effect on sleep architecture. We performed a systemic literature review with a goal to evaluate the effect of antiepileptic drugs and nondrug treatments for epilepsy on sleep architecture to help better understand treatment effects, especially in patients with epilepsy and sleep problems. Methods: We searched PubMed and identified studies that evaluated objective sleep outcomes for an antiepileptic drug. We also searched for studies with objective sleep outcomes that evaluated other epilepsy treatments such as epilepsy surgery, vagus nerve stimulation, and ketogenic diet. Results: The studies were categorized based on evidence class and study population for an individual antiepileptic drug or treatment. We identified that most antiepileptic drugs and nondrug treatments for epilepsy affect sleep architecture. Significance: We identified that gabapentin, tiagabine, pregabalin, clobazam, and carbamazepine reduce sleep latency and/or improve sleep efficiency. Phenobarbital, valproic acid, and higher-dose levetiracetam aggravate daytime sleepiness, whereas topiramate and zonisamide do not. Vagus nerve stimulation reduces daytime sleepiness, and ketogenic diet improves slow-wave sleep. Epilepsy surgery may improve nocturnal sleep only in a subgroup of patients with improved seizure frequency. Further studies are needed to evaluate the dose-dependent sleep effects of antiepileptic drugs and nondrug treatments independent of the improvement of epilepsy, and to identify if these changes are clinically significant. KEY WORDS: Epilepsy surgery, Vagus nerve stimulator, Ketogenic diet, Clobazam, Lamotrigine, Ethosuximide, Phenytoin, Topiramate, Vigabatrin.

Sleep is a reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment.1 It consists of rapid eye movement (REM) sleep or dream sleep and non-REM (NREM) sleep. NREM sleep is further divided into stage N1, N2, and N3 sleep based on electroen-

cephalography (EEG) patterns. N3 is also termed slow-wave sleep (SWS) or deep sleep, and comprises stages 3 and 4 of older nomenclature.2 In adult humans, sleep consists of about 5% wake, 5% N1, 50% N2, 15% N3, and 25% of REM sleep. There is continued debate about the primary function of sleep. There are metabolic, endocrine, cardiac, respiratory, and almost all other systems changes that occur during sleep.1 Among various hypotheses for primary function of sleep, restorative and cognitive effects are most accepted. There is increasing evidence that sleep is required for neural plasticity and memory consolidation.3 Duration, timing, and type of sleep all are important.4 Slow-wave sleep is

Accepted October 16, 2013; Early View publication December 2, 2013. Division of Neurology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, U.S.A. Address correspondence to Sejal V. Jain, Division of Neurology, Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave, MLC 2015, Cincinnati, OH 45229, U.S.A. E-mail: [email protected] Wiley Periodicals, Inc. © 2013 International League Against Epilepsy

26

27 Antiepileptic Treatments and Sleep important for declarative memory consolidation, whereas REM sleep helps nondeclarative and emotional memory. NREM spindle density is positively linked to verbal memory, and slow-wave density is positively linked to retention of same day memory.4 Other hypotheses suggest that cycling of sleep in NREM and REM sleep is important for consolidation.5 Hence, sleep is important. Sleep disorders are common in patients with epilepsy. Sleep problems are twice prevalent in epilepsy patients compared to controls.6 Even in children with new-onset seizures, 45% reported sleep problems.7 Insomnia was reported in up to 52% and sleepiness in up to 70% of the subjects with epilepsy.8,9 One third of the patients with medically refractory epilepsy have obstructive sleep apnea (OSA).10 Among patients with epilepsy, referred to a sleep lab, 5% have periodic limb movement disorder (PLMD),11 18–35% have restless leg syndrome (RLS),8,12 and 3.7% have central sleep apnea (CSA).13 Hence, sleep disorders are common in epilepsy. Antiepileptic drugs and other treatments also affect sleep architecture. The purpose of this systemic review was to identify the effect of antiepileptic drugs and nondrug treatments on sleep to better understand treatment effects, especially in patients with epilepsy and sleep problems.

Methods Eligibility criteria Studies with the following criteria were selected: (1) prospective study, (2) objective sleep outcomes measures, (3) study population including healthy volunteers and/or patients with epilepsy, (4) medical and nondrug treatments for epilepsy (5), and outcomes reported for specific antiepileptic drugs (AEDs) or treatment. Search strategies PubMed was repeatedly searched (last on May 15, 2013) with the following mesh terms. “Antiepileptic drug” and “sleep” with “human” and “English” as limits. The search was also performed using an individual AED name, and an individual treatment name, and “sleep” with “human,” and “English” as limits, that is, “valproic acid,” and “sleep”; “ketogenic diet” and “sleep” and so on. The AEDs searched included valproic acid, phenobarbital, phenytoin, carbamazepine, topiramate, ethosuximide, oxcarbazepine, lamotrigine, levetiracetam, clobazam, lacosamide, vigabatrin, felbamate, tiagabine, pregabalin, gabapentin, zonisamide, ezogabine, and rufinamide. The nondrug treatments searched included epilepsy surgery, vagus nerve stimulator (VNS), and ketogenic diet. Study selection Figure 1 shows the flow chart of how the articles were selected.

Study methodologies The studies selected for the review assessed objective sleep outcomes with standard polysomnography (PSG), home sleep study, ambulatory PSG, and actigraphy as well as maintenance of wakefulness test (MWT) and multiple sleep latency test (MSLT). PSG is the gold standard test during which EEG, eye movements, airflow, respiratory movement, muscle tone, electrocardiography (ECG), heart rate, and oxygen saturation are recorded. All home sleep studies utilized in the research studies included in the review used EEG, EMG (electromyography), and electrooculography (EOG) channels. Ambulatory PSG included the same standard leads as regular PSG. Actigraphy is a wristwatch-like device that measures movements and based on reduced movements during sleep, records sleep onset, offset, awakening, and nap timing and duration. MWT and MSLT are used to test daytime alertness and sleepiness, respectively. Summary measures The objective sleep outcomes used to summarize the studies were sleep latency (SL), total sleep time (TST), sleep efficiency (SE), arousals, awakenings, wake after sleep onset (WASO), and percentage of sleep stages, that is, N1%, and so on. SL is the time from lights out (initiation of the study) to sleep onset. TST is defined as the total time spent in nonwake stages in minutes from the beginning of recording to the end of recording. SE is computed as TST in minutes, divided by total recording time in min 9 100. Percentages of sleep stages (N1, N2, N3, or REM%) are the percentages of total sleep time spent in the particular sleep stage. Because studies that used older classification reported stage 3 and stage 4, these results are reported here as SWS. For newer studies that report N3, N3 is used instead of SWS. Arousals are episodes of at least 3 s of fast EEG activity or change from the baseline EEG activity of that stage. Prolonged arousals are termed awakenings. WASO is defined as number of minutes of wakefulness after the onset of persistent sleep to the end of the PSG recording. Synthesis of the results The American Academy of Neurology Classification of Evidence was used to classify the studies for a specific AED or treatment.14,15

Results Forty-five studies met the eligibility criteria. Results of all 45 studies are summarized in Table 1 (AEDs) and Table 2 (nondrug treatments). The best evidence for individual AEDs for each sleep outcome is compiled in Table 3. Because all studies for nondrug treatments were class III, they are only represented in Table 2. Epilepsia, 55(1):26–37, 2014 doi: 10.1111/epi.12478

28 S. V. Jain and T. A. Glauser

Figure 1. Flow diagram to show the process for study selection Epilepsia ILAE

Characteristics of the studies for the AEDs Thirty-one studies focused on a single AED, seven on two AEDs, one on three, and one on multiple AEDs. In the study by Legros and Bazil, multiple AEDs were studied in patients with epilepsy, in the epilepsy monitoring unit (EMU) with EEG. Chronic therapy at a minimal dose or a minimum drug level for a particular AED was used for inclusion. If a patient was on other AEDs, which were stopped for monitoring, this patient was also included.16 Three AEDs were studied separately in the study reporting results of three AEDs simultaneously.17 Studies for individual AEDs Carbamazepine In healthy adults, three class III studies were reviewed.18–20 These studies used dosage ranging from 400 to 700 mg/ day and comparisons were made between sleep outcomes at baseline and after acute monotherapy. The common findings were reduction in sleep latency and arousals, and increase in sleep efficiency and SWS. In a class II study, increased N3 was seen in patients with newly diagnosed epilepsy.21 In this study, the patients were randomized to receive levetiracetam or controlled-release carbamazepine. Outcomes were analyzed as comparisons between the drugs, and at baseline and after 4–6 weeks of treatment. In class III studies, on MSLT, one study reported Epilepsia, 55(1):26–37, 2014 doi: 10.1111/epi.12478

similar sleep latency (SL) as controls,22 whereas the other reported reduced SL but only in the polytherapy treatment group.23 Both studies reported results as compared to controls. Several other class III studies evaluating sleep in patients with chronic therapy reported conflicting results.16,24–26 Clobazam Only one class I study was identified that evaluated the acute effects of clobazam (at 10 and 20 mg doses), triflubazam, and placebo in a randomized double-blind study in healthy adults.27 The study showed that clobazam reduced sleep latency, N1, SWS, and WASO, and increased N2. Ethosuximide Only one class III study in patients with absence epilepsy was identified, which showed increased N1 and REM sleep and reduced SWS.28 Different treatment sequences with VPA were evaluated, and results were reported for individual drugs, as compared to baseline. Gabapentin In a class I study in healthy men, gabapentin was shown to increase SWS at 600- and 900-mg doses.29 Similar results were reported in a class III study, where doses up to 1,800 mg/day were used and comparisons were made with baseline.30

III III II

III III

III III

III

III

I III I

III III III III

Yang et al.20

Riemann et al.19

Gann et al.18

Cho et al.21

Legros and Bazil16

Manni et al.26

Manni et al.22

Gigli et al.25

Bonanni et al.23

Drake et al.24

Nicholson et al.27

Wolf et al.28

Rao et al.29

Foldvary et al.30

Placidi et al.17

Legros and Bazil16

Placidi et al.32

Carbamazepine

Clobazam

Ethosuximide

Gabapentin

Lamotrigine

Class III

Study

Medication

Focal epilepsy

Healthy volunteers and controls Epilepsy patients

Healthy men

Absence epilepsy

Healthy adults

Monotherapy or polytherapy with PHB Epilepsy patients

Controlled focal epilepsy Newly diagnosed TLE

Focal epilepsyrefractory (R) and controlled (C)

Focal epilepsy

Newly diagnosed partial epilepsy

Healthy adults

Healthy adults

Healthy males

Population

Method

13

3

10

10

6

8

6

5

Chronic monotherapy (comparison to VPA, phenytoin groups) Randomized placebocontrolled Monotherapy compared to B Randomized double-blind placebo-controlled cross-over Acute effects compared to B Add-on GBP compared to B Single AED during EMU admission

Chronic therapy compared to C

15 + 15

7

Chronic monotherapy compared to C Acute and chronic therapy compared to C

Acute monotherapy compared to B Acute monotherapy compared to B Acute monotherapy compared to B Randomization to LEV or CBZ; compared to B and LEV Single AED during EMU admission Chronic monotherapy compared to C

10

14

10

15

12

12

7

N

Minimum dose/drug level for each AED 200

1,800

1,800

600 and 900

NA

10 and 20 mg/day

NA

600–1,600

400 CR

15 mg/kg

Minimum dose/drug level for each AED 15–20 mg/kg

400

400

400

700

Dose (mg/day)

PSG & MSLT

EEG

PSG

Home sleep study

Only EEG part of PSG

PSG

EEG, EMG, EOG

1 channel EEG, EMG, EOG

PSG; MSLT

EEG, EOG and EMG; MSLT EEG, EOG and EMG; MSLT

EEG, EOG and EMG

EEG

PSG

EEG, EOG and EMG

EEG, EMG, EOG

EEG, EMG, EOG

Procedures

Table 1. The summary of studies evaluating the effects of AEDs on sleep architecture Results

Continued

Increased REM sleep, reduced awakenings and N1 Increased SWS

Increased SWS

Reduced REM, increased entries in REM sleep (fragmented REM) [acute] No difference in MSLT; no difference in chronic Increased N2, Decreased REM, decreased SL on MSLT (polytherapy only) Increase SL, arousals and WASO, decreased TST and REM Decreased SL, N1, SWS and WASO; increased N2 Increased N1, and REM; decreased SWS Increased SWS

Increased REM latency, arousals, stage shifts and shift to N1 in both R and C groups; Decreased REM sleep and increased WASO in R group SL 12.5 min (control- 12.9 min)

No change

Increased SWS, decreased REM sleep Increased SE, SWS; decreased SL, arousals and WASO Increased TST, SWS; reduced REM, SL and arousals Increased N3

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Epilepsia, 55(1):26–37, 2014 doi: 10.1111/epi.12478

Phenobarbital

Levetiracetam

Medication

Class

III

III III III I

II I

II

III

III I

III

III III III

III

Study

Bonanni et al.31

Foldvary et al.33

Placidi et al.17

Legros and Bazil16

Cicolin et al.34

Bazil et al.61

Bell et al.35

Cho et al.21

Yilmaz et al.36

Zhou et al.37

Karacan et al.8

Gabriel and Albani39

Prinz et al.62

Manni et al.22

Bonanni et al.23

Wolf et al.40

Controlled focal epilepsy Epilepsy on polytherapy with CBZ Epilepsy patients

Healthy adults

30–34 week preemie neonates

Focal epilepsy and controls Healthy adults

Focal epilepsy and controls

Newly diagnosed partial epilepsy

Epilepsy patients

Healthy adults

Patients with focal epilepsy Healthy adults

Refractory epilepsy

Drug resistant focal epilepsy Newly diagnosed epilepsy and healthy controls Focal epilepsy

Population

34

15

10

5

7

8

10

22

16

28

14

14

4

13

10

15

N

Monotherapy compared to placebo Chronic monotherapy compared to C Chronic therapy compared to C

Add on PHB compared to B

Add-on LEV compared to B and C Placebo controlled study

Add-on LTG compared to B Add-on LTG compared to B Single AED during EMU admission Randomized, doubleblind, placebocontrolled cross-over Randomized, doubleblind, placebo-controlled Randomized, doubleblind, placebocontrolled, cross-over; add on to existing treatment Randomization to LEV or CBZ; compared to B and CBZ Add-on LEV to CBZ; compared to B and C

Add-on LTG compared to B Initiation of LTG compared to B

Method

Table 1. Continued.

50

100

1.5 mg/kg

100

5 mg/kg for 3 days

80, 140 and 240

1,000

2,000

1,000

Single dose, 1,000

2,000

Minimum dose/drug level for each AED 2,000

300

200

200

Dose (mg/day)

PSG

EEG, EMG, EOG; MSLT PSG; MSLT

PSG

PSG for 200 min

PSG

PSG & MSLT

Actigraphy and MWT

PSG

Home sleep study

PSG

PSG

EEG

PSG

Home sleep study

PSG & MSLT

Procedures

Results

Continued

Increased N2, Decreased REM, decreased SL on MSLT

Decreased WASO and increased SE compared to baseline Reduced MWT wake time, increased nap duration and episodes Reduced REM sleep, no change in MSLT Dose dependent decrease in REM sleep, awakenings; Dose dependent increase in N2 75% decrease in Active sleep, corresponding increase in Quite sleep Decreased SL, SWS (only after 9 days of treatment) SL 9 min (control- 12.9 min)

Increased awakenings in the medication group Increased N2 in both the healthy volunteers and patients and reduced N4 in patients

Increased TST, SE, N2, SWS; Decrease REM and WASO

Increased REM sleep, reduced phase shifts and SWS No change

Increased N2 and reduced SWS

Increased REM sleep, no change in daytime sleepiness No changes before and after

30

S. V. Jain and T. A. Glauser

I

III I I

III

III

Bazil et al.43

Romigi et al.63

Mathias et al.45

Walsh et al.46

Bonanni et al.47

Harding et al.48

Topiramate

Valproic acid

Tiagabine

III

I

De Hass et al.44

Drake et al.24

I

Hindmarch et al.42

III

III

Roder-Wanner et al.41

Legros and Bazil16

III

Wolf et al.40

III

III

Drake et al.24

Schmitt et al.50

III

Legros and Bazil16

Phenytoin

Pregabalin

Class

Study

Medication

Epilepsy patients

Focal epilepsy

Children with epilepsy

Healthy adults

New onset focal epilepsy and controls

Elderly (60–80 years) without sleep dis

Healthy adults

Focal epilepsy

Focal epilepsy

Focal epilepsy

Healthy adults

New onset epilepsy

Epilepsy patients

Epilepsy patients

Focal epilepsy

Population

5

2

46

10

14

26

10

12

9

17

24

31

31

5

7

N

Single-blind, compared to baseline Single AED during EMU admission

Placebo and high and low dose VPA

Monotherapy compared to B and C

Randomized double-blind placebo-controlled Randomized double-blind placebo-controlled Randomized double-blind placebo-controlled cross-over Add-on pregabalin compared to B Randomized double-blind placebo-controlled Randomized double-blind placebo-controlled, dose –response

Randomized study with cross-over to phenytoin Single AED during EMU admission Chronic monotherapy (comparison to VPA, CBZ groups) Randomized study with cross-over to PHB Randomized placebocontrolled cross-over with PHB

Method

Table 1. Continued.

Minimum dose/drug level for each AED NA

Taper

500 and 1,000

200

2, 4 and 8

5

No target dose

300

300

150

Dose to achieve 10– 20 lg/ml drug level

100

Minimum dose/drug level for each AED NA

Dose (mg/day)

EEG

Actigraphy

EEG, EMG, EOG

EEG, EOG, EMG, ECG; MSLT

PSG

Ambulatory sleep study PSG

PSG, EEG

Ambulatory PSG

Home sleep study

PSG

PSG

1 channel EEG, EMG, EOG

EEG

Procedures

Results

Continued

T2 no change; T4 increased TST, SWS, and reduced WASO; T8 increased SWS, and reduced REM and calculated sleep fragmentation No significant changes in nocturnal sleep or daytime sleepiness on MSLT No significant changes in nocturnal sleep on visual analysis Reduced total sleep time (including naps) Increased N1

Increased REM sleep and reduced N2 Increased SWS and SE

Increased N3, decreased N1

Decreased N2 and SL; Increased N1 and SWS Acute (day 2): decreased SL Short term (4–6 week): decreased SL, N1, N2; increased SWS Long-term (6 months): decreased SL [compared to baseline] Increased SE, SWS and reduced awakenings and REM sleep Reduced arousals and WASO

Increased N2; decreased SL, REM and arousals Reduced SWS and REM and increased N1 Increase SL, and WASO, decreased TST

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Antiepileptic Treatments and Sleep

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Epilepsia, 55(1):26–37, 2014 doi: 10.1111/epi.12478

N, number of subjects; AEDs, antiepileptic drugs; PSG, polysomnography; MWT, maintenance of wakefulness test; MSLT, multiple sleep latency test; N1, stage N1; N2, stage N2; N3, stage N3; N4, stage N4; SWS, slow-wave sleep; REM, stage REM; TST, total sleep time, SE, sleep efficiency; WASO, wakefulness after sleep onset; LEV, levetiracetam, LTG, lamotrigine; CBZ, carbamazepine; GBP, gabapentin; VPA, valproic acid; PHB, phenobarbital; T2, tiagabine at 2 mg; T4, tiagabine at 4 mg; T8, tiagabine at 8 mg; RCT, randomized placebo controlled trial; EMU, epilepsy monitoring unit; Tx, treatment; A, active group; B, baseline; C, controls; HC, healthy controls; TLE, temporal lobe epilepsy.

200–300 12 Focal epilepsy III Romigi et al.52 Zonisamide

14 Focal epilepsy on CBZ monotherapy III Bonanni et al.51 Vigabatrin

10 Epilepsy patients III Manni et al.49

9 III Wolf et al.28

Absence epilepsy

Add on zonisamide compared to B

2–3 G

Ambulatory sleep study, MSLT

No significant changes in nocturnal sleep, SL 12.5 min No significant changes in nocturnal sleep or daytime sleepiness on MSLT (compared to baseline) No significant changes in nocturnal sleep or daytime sleepiness Home sleep study, MSLT Portable sleep study; MSLT Different doses

Results

Increased N1 and REM PSG NA

1 channel EEG, EMG, EOG

Procedures Dose (mg/day) Method

Chronic monotherapy (comparison to phenytoin, CBZ groups) Monotherapy compared to B Monotherapy compared to C Add on vigabatrin compared to B and C

N Population Class Study Medication

Table 1. Continued.

Decrease SL, and WASO, increased TST

S. V. Jain and T. A. Glauser Two class III studies in patients with epilepsy evaluating the effects of gabapentin were identified. In one study, increased SWS was seen.16 The other study reported that gabapentin increased REM sleep and reduced awakenings and N1 in patients with epilepsy when it was added to the existing AEDs.17 However, this addition also reduced seizure frequency in 60% of the patients. Lamotrigine A total of five class III studies were identified in patients with epilepsy. In patients with newly diagnosed epilepsy no change was seen in PSG and MSLT on lamotrigine monotherapy at the dose of 200 mg/day as compared to baseline.31 In two other studies in patients with refractory epilepsy, lamotrigine increased REM sleep and reduced SWS.17,32 Lamotrigine was added on to the existing AED regimen, and significant improvement in seizure frequency was also seen. These two studies appear to have enrolled the same patients; however, different doses and outcomes were used. Another similar study showed increased N2 and reduced SWS at a 200 mg/day dose.33 With chronic therapy, in another study, no change was seen.16 Two studies using MSLT reported no change in daytime sleepiness.31,32 Only one study evaluated subjective nocturnal sleep, which showed that no subjects reported insomnia.33 Levetiracetam In healthy adults, in a class I study, levetiracetam increased TST, SE, and N2, and reduced REM sleep and WASO at 2,000 mg/day dose.34 In a class I study in patients with epilepsy, after a 1,000 mg single dose, N2 was increased and N4 was reduced as compared to placebo.35 In a class II study, on 1,000 mg/day of levetiracetam, decreased WASO and increased SE was seen as compared to baseline.21 In a class III study, sleepiness was assessed on 2,000 mg/day dose, which showed reduced wake times on MWT and increased nap duration and episodes.36 However, in another class III study, at 1,000 mg daily dose, no changes were seen in daytime sleepiness on MSLT.37 Phenobarbital A class I study in healthy volunteers showed a dosedependent reduction in REM sleep and arousals, and increase in N2 sleep. In this study, 80, 140, or 240 mg/day of phenobarbital was used in combination with placebo to test 24 different treatment sequences in eight healthy adult males.38 In a study in premature neonates also, phenobarbital reduced active sleep.39 In patients with epilepsy, three class III studies were identified.23 A reduction in sleep latency and REM sleep were consistent findings.22,40 On MSLT, comparisons were made with a control group and carbamazepine treatment group.22 The sleep latency for a 14 h nap was significantly lower for all groups, and compared to the other two groups, subjects

33 Antiepileptic Treatments and Sleep Table 2. The summary of studies evaluating the effects of nondrug treatments on sleep architecture Treatment

Study 54

Class

Population

N

Procedures

Results No change in nocturnal sleep In postoperative Engel class I and II groups, increased TST and reduced AI Increased SL on MSLT, increased SOREMs in posttreatment MSLT No change

Epilepsy surgery

Zanzmera et al.

III

Medically refractory epilepsy

17

PSG

VNS

Malow et al.53

III

15

PSG, MSLT

Galli et al.55

III

Hallbook et al.56

III

Hallbook et al.57

III

Medically refractory epilepsy Medically refractory epilepsy Pediatric medically refractory epilepsy Pediatric medically refractory epilepsy

Ketogenic diet

8

MSLT

15

Home sleep study Home sleep study

18

Increased SWS and decreased N1 Decreased TST and N2, increased REM sleep

VNS, vagus nerve stimulator; PSG, polysomnography; MSLT, multiple sleep latency test; SL, sleep latency; SOREMs, sleep onset REMs; TST, total sleep time.

Table 3. Best evidence for individual AEDs for each sleep outcome Carbamazepine Healthy adults Patients Clobazam Healthy adults ETH Patients Gabapentin Healthy adults Patients Lamotrigine Patients Levetiracetam Healthy adults Patients Phenobarbital Healthy adults Patients Phenytoin Patients Pregabalin Healthy adults Patients Tiagabine Healthy adults Topiramate Patients Valproic acid Healthy adults Patients Vigabatrin Patients Zonisamide Patients

Level of evidence

SE/TST

SL

WASO

Arousals/awake

N1

N2

N3/SWS

REM

MSLT/MWT

III II

↑ –

↓ –

↓ –

↓ –

– –

– –

↑ ↑

↓ –

NA NA

I

















NA

III

















NA

I III

– –

– –

– –

– ↓

– ↓

– –

↑ ↑

– ↑

NA NA

III











↑/–

↓/–

↑/–



I I

↑ –

– –

↓ –

– –

– –

↑ ↑

↑ ↓

↓ –

↓ Wake time (III)/ – (III)

I III

– –

– ↓

– –

↓ ↓

– –

↑ ↑

– –

↓ ↓

NA SL 9 min/↓

III













↓/↑



NA

I I

↑ –

– –

– –

↓ –

– ↓

– –

↑ ↑

– –

NA NA

I





–/↓









–/↓

NA

III



















III III









– ↑







NA SL 12.5 min

III



















III







NA

NA

NA

NA

NA



MWT, maintenance of wakefulness test; MSLT, multiple sleep latency test; N1, stage N1; N2, stage N2; N3, stage N3; N4, stage N4; SWS, slow-wave sleep; REM, stage REM; TST, total sleep time, SE, sleep efficiency; WASO, wakefulness after sleep onset; ↓, decrease; ↑, increase; –, no change; NA, not available.

on phenobarbital had lower sleep latency. In another study also, reduced sleep latency compared to controls was seen.23

Phenytoin Four class III studies were included in the review, which included patients with epilepsy only.16,24,40,41 One of the studEpilepsia, 55(1):26–37, 2014 doi: 10.1111/epi.12478

34 S. V. Jain and T. A. Glauser ies reported acute, short-term and long-term effects of phenytoin in the patients as compared to baseline. Reduced sleep latency was seen at all the phases. In addition, with short-term use, decreased N1, N2, and increased SWS were seen.41 However, there were conflicting results with the other studies. Pregabalin One class I study was identified evaluating the effects of pregabalin in healthy adults. It showed increased SWS and SE and reduced awakenings and REM sleep compared to placebo.42 Two class I studies were identified, which evaluated the effects of pregabalin in patients with epilepsy. Pregabalin was added to the existing AED regimen for sleep problems/ insomnia.43,44 The study by Bazil et al. showed increased N3 and reduced N1, whereas the study by De Hass et al. showed reduced arousals and WASO. Tiagabine Two studies met the eligibility criteria, both in healthy subjects. In one class I study, tiagabine increased SE and SWS in healthy volunteers compared to placebo at 5 mg dose.45 In another class I, dose–response study in elderly, tiagabine at a 2-mg dose did not produce changes in sleep architecture. At a 4-mg dose, tiagabine increased SWS and TST along with the reduction in WASO. At an 8-mg dose, it increased SWS but reduced REM sleep.46 Topiramate Only one class III study in patients with new-onset focal epilepsy was identified, which showed no changes in nocturnal sleep architecture or daytime sleepiness as compared to baseline and controls at 200 mg/day dose.47 Subjective sleepiness was also assessed in the study, which showed that only 2 of 14 subjects, who were sleepy at baseline, had moderate sleepiness after treatment. However, even in these subjects, MSLT was comparable pretreatment and posttreatment. Valproic acid In healthy adults in a class III study, sequential testing were done on placebo, VPA 500 mg, VPA 1,000 mg, VPA 500 mg, and then placebo. There were no significant changes in sleep parameters on visual scoring.48 In patients with epilepsy, five class III studies met the eligibility criteria and showed conflicting results.16,24,28,49,50 These studies varied in study population from children to adults and multiple types of epilepsy. In a study in children with epilepsy, where sleep architecture changes were studied after discontinuation of valproic acid, TST including daytime naps was reduced in children with epilepsy after stopping valproic acid.50 Vigabatrin Only one class III study in patients with focal epilepsy was identified in which the patients on chronic carbamazepine Epilepsia, 55(1):26–37, 2014 doi: 10.1111/epi.12478

therapy were enrolled.51 Patients with poorly controlled seizures received vigabatrin as an adjunctive therapy. A healthy control group was also enrolled. The study showed no significant changes in nocturnal sleep as compared to baseline. Daytime sleepiness was increased at baseline as compared to healthy controls, and addition of vigabatrin did not make a significant difference. This study listed the results for nocturnal sleep; however, the actual data were not reported. Zonisamide Only one class III study was identified, which used actigraphy and MSLT to evaluate the effects of add on zonisamide as compared to baseline.52 The study showed that there were no changes in nocturnal sleep or daytime sleepiness. There was no statistical difference between pretreatment and posttreatment subjective sleepiness. Three of 12 subjects had increased sleepiness at baseline, which did not get worse posttreatment. Nondrug treatments All studies examining the effects of epilepsy surgery, VNS, or ketogenic diet were class III and included the intervention as an add-on to the existing treatment. Significant reduction in seizure frequencies was noticed in most of the subjects. Only one study evaluated the effect of VNS and reported no correlation between changes in SL on MSLT and the reduction in the seizure frequency.53 The single epilepsy surgery study reported differential findings based on seizure frequency postsurgery.54 The rest of the nondrug treatment studies did not provide correlation with seizure frequency. Epilepsy surgery One class III study was identified that evaluated sleep before and after epilepsy surgery.54 No significant changes were seen as a group before and after surgery. However, in a group of subjects with postoperative Engel classes I and II, increased TST and reduced arousals were seen. No changes were seen in the subjects who continued to have frequent seizures. Vagus nerve stimulator (VNS) Three class III studies were identified.53,55,56 In one study, increased SL was seen in MSLT, suggesting improved daytime sleepiness.53 In other study, no overall change in SL was seen.55 In this latter study, subjects with stimulation intensity lower than 1.75 mA had an improvement, and only one subject with higher intensity stimulation had worsening in SL.55 Increased SWS and decreased N1 were seen in the third study. At 9 months of follow-up, significant reduction in SL was seen for nocturnal sleep in this study.56 Ketogenic diet In a study in children with refractory epilepsy, decreased TST and N2 and increased REM sleep were seen after adding ketogenic diet to the regimen.57

35 Antiepileptic Treatments and Sleep

Discussion We identified that most AEDs have an effect on sleep architecture. Based on our review, the following evidence was identified. Class I studies in healthy adults suggest that REM sleep reducers are phenobarbital and levetiracetam, whereas gabapentin is an REM sleep enhancer. Clobazam reduces slow-wave sleep, whereas levetiracetam, tiagabine, and pregabalin are slow-wave sleep enhancers. Sleep latency is reduced on clobazam, whereas arousals/wake time are reduced by levetiracetam, clobazam, phenobarbital, tiagabine, and pregabalin. Class III evidence in healthy subjects suggests that SE/TST is increased by carbamazepine, whereas SL, arousals, and wake times are reduced by carbamazepine. SWS is increased by carbamazepine and REM sleep is reduced. Class I studies in patients with epilepsy showed that SWS is increased by pregabalin and reduced by levetiracetam. Class III evidence in patients with epilepsy suggests that SL is reduced by phenobarbital, phenytoin, and gabapentin. Reduced arousals are seen with phenobarbital and gabapentin. Increased SWS is seen with carbamazepine and gabapentin, whereas reduced SWS is seen with ethosuximide, and conflicting results were seen with phenytoin and LTG. REM sleep is reduced by phenobarbital and phenytoin, and increased by ethosuximide and gabapentin. Either increase or no change was seen in REM sleep with LTG. Based on class III evidence in patients with epilepsy, daytime sleepiness was not changed by topiramate, lamotrigine, zonisamide, and vigabatrin, and was increased by phenobarbital. Daytime sleepiness was unchanged at 1,000 mg daily dose for levetiracetam; however, wakefulness was reduced at a 2,000 mg daily dose. Class III studies for nondrug interventions for epilepsy suggested that VNS improves daytime sleepiness and SWS. Improved TST and reduced arousals are seen with epilepsy surgery if the seizure frequency is also improved. Ketogenic diet also improves nocturnal sleep. It is important to note that many of these studies did not analyze effects on sleep independent of improved seizure frequency. Sleepiness has been reported with zonisamide58 and topiramate59 but was not identified in the studies reviewed here. Patients with epilepsy report increased sleepiness, so it is possible that it was attributed to treatment in previous studies. It is also possible that only selective subgroups experience these effects and that these subgroups were not included in the studies reviewed herein. In addition, patients who reported sleepiness subjectively in these reviewed studies did not have objective sleepiness. Similarly, insomnia is reported with lamotrigine,60 whereas in studies reviewed here this was not seen. Based on the evidence, future research should explore possible therapeutic applications of antiepileptic drugs in epilepsy patients with a variety of sleep comorbidities. Clin-

ical trials are needed for epilepsy patients with problems initiating sleep. In this population, potential study AEDs that reduce sleep latency include phenytoin, phenobarbital, carbamazepine, or clobazam. Another need is for AED clinical trials involving epilepsy patients with difficulty maintaining sleep. In these trials, AEDs that increase N3 and aid sleep consolidation, such as gabapentin, tiagabine, or pregabalin, could be potential study drugs. A third area of research could be therapeutic trials for epilepsy patients with insomnia. In these patients, carbamazepine, tiagabine, and pregabalin could be potential study drugs given their favorable impact on total sleep time and efficiency. Lastly, in epilepsy patients with excessive daytime sleepiness, avoidance of drugs associated with daytime sleepiness such as phenobarbital, VPA, and levetiracetam should be considered. There are several limitations to the studies analyzed. Because epilepsy and seizures affect sleep architecture, the effects observed after adding a treatment may be due to improvement in seizure control and epilepsy, rather than a direct effect of an AED. Given the small sample size in most of these studies, it was not possible to determine the effects of epilepsy treatments on sleep architecture independent of seizure control. Studies that only compared outcomes with healthy controls, and not with baseline or placebo, were also unable to determine the true effect of AED independent of effects of epilepsy. Multiple studies for a particular AED used different doses, different evaluation modalities, and different study population, so it was not possible to determine the reproducibility of the findings. Most studies used a single dose or titration to a target dose except for a couple of studies. So it was not possible to determine if there is a dose–response effect. In several studies, doses were adjusted based on clinical response and therefore were not uniform. Studies that employed sleep assessment without any respiratory channels could not rule out coexisting sleep disorders, which could have also impacted the sleep architecture. The limitation of this review is that we only reviewed studies that objectively evaluated sleep architecture in these patients. Despite this, we believe that the information provided by the review is important in understanding the effects of epilepsy treatments on sleep. Future prospective studies of subjective and objective daytime sleepiness, sleep architecture, and other nocturnal sleep parameters will be necessary to better understand the impact of epilepsy treatments on sleep.

Conclusions Virtually, all AEDs have effects on sleep architecture. Sleep problems and disorders are common in epilepsy. We speculate that the effects of epilepsy treatments on sleep architecture are important in optimizing management for patients with epilepsy. Further prospective studies with larger sample size focused on dose–response relationships that Epilepsia, 55(1):26–37, 2014 doi: 10.1111/epi.12478

36 S. V. Jain and T. A. Glauser are independent of the effect of epilepsy are needed to evaluate the effects of epilepsy treatments on sleep architecture.

Acknowledgment SVJ acknowledges Dr. Carl Bazil for providing comments on the review and Dr. Mary Rae for edits on the initial version of the manuscript.

Disclosure of Conflict of Interest Dr. Jain has no conflict of interest to disclose. Dr. Glauser has received consulting fees from AssureRx Health, Eisai, UCB Pharma, Supernus, Sunovion, Questcor, Lundbeck, and Upsher Smith along with lecture fees from Supernus. He is on the speakers’ bureau for Supernus. He serves as an expert consultant for the U.S. Department of Justice. He receives royalties from a patent license from AssureRx Health. We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines.

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Epilepsia, 55(1):26–37, 2014 doi: 10.1111/epi.12478

Effects of epilepsy treatments on sleep architecture and daytime sleepiness: an evidence-based review of objective sleep metrics.

Sleep is considered restorative, and good quantity and quality sleep is required for memory consolidation and synaptic plasticity. Sleep disorders are...
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