Effects of Levetiracetam on Sleep Architecture and Daytime Sleepiness

Sleep is a reversible behavioural state of perceptual disengagement from and unresponsiveness to the environment, which is required for neural plasticity and memory consolidation. Sleep disorders are common in patients with epilepsy. The main causes of sleep disturbances are coexisting sleep disorders, impact of seizures and epileptic activity, and the effects of antiepileptic drugs. Sleep and epilepsy have reciprocal effects – on one hand electrical brain activity during sleep is a strong modulator of epileptic activity and on the other epileptic activity during sleep may disrupt sleep architecture. The most common side effects of anticonvulsants include alterations in sleep architecture and variation in the degree of daytime sleepiness. Their effects on sleep and daytime sleepiness are variable and it is often difficult to distinguish whether the improved seizure control and epileptic activity is a direct result of anticonvulsants or associated with improved sleep quality. Levetiracetam is a new generation anticonvulsant used to treat both focal and generalized epilepsy. Its satisfactory safety and tolerability explain its wide usage in the clinical practice and necessitates more profound knowledge on its effects on sleep quality. There have been few reports about its effects on sleep architecture and daytime sleepiness. A short summary of the studies concerning this topic is presented. Main disadvantages of the studies are: the small sample size, comparison of the results obtained in healthy volunteers with patients with epilepsy, short observation duration, variations of dosage, different evaluation modalities and concomitant AED therapy. Future prospective studies on subjective and objective effects of Levetiracetam on sleep architecture and daytime sleepiness are needed to better understand its impact on sleep in order to improve epilepsy patients’ quality of life, seizure control and sleep disturbances.


INTRODUCTION
Sleep is a reversible behavioural state of perceptual disengagement from and unresponsiveness to the environment. 1 It consists of rapid eye movement (REM) sleep and non-REM (NREM) sleep. NREM sleep is further divided into stage N1, N2, and N3 sleep based on electroencephalography patterns. 2 N3 is also termed slow-wave sleep (SWS), and comprises stages 3 and 4 of older nomenclature. 3 In adult humans, sleep consists of about 5% wake, 5% N1, 50% N2, 15% N3, and 25% of REM sleep. 2 The physiologi-cal function of sleep is controversial and still to be explored. There are metabolic, endocrine, cardiac, respiratory, and almost all other systems changes that occur during sleep. 1 Among various hypotheses about the primary function of sleep, restorative and cognitive effects have received an upsurge of attention. There is increasing evidence that sleep is required for neural plasticity and memory consolidation. 4 SWS is important for declarative memory consolidation, whereas REM sleep supports nondeclarative and emotional memory. 2 Patients with epilepsy often suffer from inadequate or ineffective sleep. 5,6 Sleep disorders are common in these patients. Frequently patients with epilepsy complain of sleep disruption and report daytime sleepiness. 5,7,8 The main causes of sleep disturbances are coexisting sleep disorders, impact of seizures and epileptic activity, and the effects of antiepileptic drugs (AEDs). 9 Seizures themselves can disrupt sleep, even when they occur during wakefulness. 10 Sleep may also be disrupted in the absence of seizures and anticonvulsant therapy, mainly related to the effects of interictal epileptic activity. 6 Poor sleep quality can cause considerable impairment of daytime functioning and quality of life. [11][12][13] On the other hand, inadequate sleep can induce daytime sleepiness and memory dysfunction, which can lead to persistent seizures. 12 Sleep and epilepsy have reciprocal effects. Electrical brain activity during sleep is a strong modulator of epileptic activity, and vice versa, epileptic activity during sleep may impair the sleep-wake cycle and sleep architecture. 14 All this can result in sleep deprivation, which in turn may provoke subsequent seizures. 15 The effects of AEDs on sleep and daytime sleepiness are variable and it is often difficult to distinguish whether the improved seizure control and epileptic activity is a direct result of AEDs or associated with improved sleep quality. The most common side effects of AEDs include alterations in sleep architecture and variation in the degree of daytime sleepiness. 16 The main difference between older and newer AEDs concerns especially daytime sleepiness, more often associated with conventional traditional AEDs, newer AEDs are reported to be less sleep disruptive. 9,15 Older generation AEDs typically reduce the percentage of REM sleep and SWS, increase fragmentation, and induce daytime sleepiness. 8 Levetiracetam (LEV) is a new generation AED, the S-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine acetamide, used to treat both focal and generalized epilepsy. Its pharmacodynamics appears to be distinct from that of older AEDs and unrelated to voltage-gated sodium channels, gamma-amino-butyric acid or glutamate-mediated synaptic transmission. 17 LEV has a specific mechanism of action -it binds to the synaptic vesicle protein SV2A, interfering with the release of the neurotransmitter stored within the vesicle. 18 The reported adverse effects of LEV associated with sleep are daytime sleepiness (5-40.4%), insomnia (2-4.8%). Nightmares and somniloquy are less frequent. 19 The broad spectrum of LEV and the satisfactory safety and tolerability explain its wide usage in the clinical practice nowadays. This necessitates more profound knowledge on its effects on sleep quality.
There have been few reports about the effects of LEV on sleep architecture and daytime sleepiness. We present a short summary of the studies (in ascending chronological order of publishing) concerning this topic.

RESULTS
In 2002, Bell et al. published the results of a study on the effects of LEV on objective and subjective sleep parameters in healthy volunteers and patients with focal epilepsy on stable chronic (>1 year) CBZ monotherapy. 20 The data on the study design and results are presented in Table 1.
Disadvantages of this study are: 1. The usage of a single dose of 1000 mg LEV resulting in the impossible evaluation of objective sleep parameters because of lacking LEV accumulation; 2. The difficulty to assess additive effects of CBZ and LEV in the patients' group; 3. The comparison of results in patients with epilepsy and healthy volunteers could not provide information about underlying epilepsy effects on sleep; 4. The relatively short duration of observation.
In 2005, Bazil et al. published the results of a study, focused on the effects of LEV on sleep using PSG in healthy subjects only. 21 The data on the study design and results are presented in Table 1. Disadvantages of this study are: 1. The participation of only healthy subjects excludes obtaining information about all possible correlation of interactions between LEV with epileptic activity during wakefulness and sleep and epilepsy associated sleep disorders; 2. The relatively small number of subjects.
In 2006 Cicolin et al. published the results of a study on the effect of LEV on nocturnal sleep and daytime vigilance in volunteers only. 14 The data on the study design and results are presented in Table 1. Disadvantages of this study: 1. The participation of only healthy subjects excludes obtaining information about all possible interactions between LEV and epileptic activity during wakefulness and sleep and epilepsy associated sleep disorders; 2. The relatively small number of subjects.
In 2007, Yilmaz published the results of a study evaluating the effects of LEV on motor activity, naps and SE. 22 The data on the study design and results are presented in Table 1. This is the first study to use actigraphic nap analytical methods comparing LEV-treated patients with a control group. The increased nap episodes were clustered in the morning (from 9 to 11 am) and in the evening (from 9 to 11 pm), which was considered as related to the times of LEV administration. Disadvantages of this study are: 1. The lack of satisfactory information about sleep architecture using solely actimetric analyses instead of a full night PSG; 2. The participation of only healthy subjects excludes obtaining information about all possible correlation of LEV with epileptic activity during wakefulness and sleep and epilepsy associated sleep disorders. 3. The questionable clinical significance of the increased number of nap episodes and the total nap duration, the last could be clarified using MSLT.
In 2007, Cho et al. published the results of a study focused on evaluation of the effects of LEV on subjective sleep quality and sleep structure in patients with focal epilepsy. 23 The data on the study design and results are presented in Table 1 24 The data on the study design and results are presented in Table 1. Disadvantages of this study are: 1. The relatively small number of subjects; 2. The comparison of results in patients with epilepsy and healthy volunteers could not provide information about underlying epilepsy effects on sleep; 3. The relatively short duration of observation.
A summary of all studies' disadvantages is presented in Table 2.  15 Bazil et al. 18 Cicolin et al. 7 Yilmaz 19 Cho et al. 20 Zhou et al. 21 1

DISCUSSION
As epilepsy and seizures affect sleep architecture, the effects observed after treatment initiation may be due to improved seizure control rather than a direct effect of AEDs. On the other hand, the observations of volunteers are inconsistent because of eliminating the impact of epilepsy and underlying associated sleep disorders and epileptic activity. Given the small sample size in most of these studies, it was not possible to assume that the obtained data were reliable and could be applied for the epilepsy population. Studies that compared only outcomes in patients with epilepsy with those of healthy controls rather than with the baseline or placebo were also unreliable to determining the true effect of LEV independent of effects of epilepsy. Findings on LEV effects were inconsistent because of differences among studies, including variations in study populations, drug dose, duration of treatment, failure to control seizures, different evaluation modalities and concomitant AED therapy. Due to the above mentioned limitations, it is impossible to reproduce the findings.

CONSLUSIONS
The negative effect of sleep disturbances on seizure control necessitates thorough knowledge about the sleep profile of AEDs. Therefore future prospective studies on subjective and objective effects of LEV on sleep architecture and daytime sleepiness are needed to better understand its impact on sleep in order to improve epilepsy patients' quality of life, seizure control and sleep disturbances.