Sleep disorders can have a profound impact on seizure frequency for epilepsy patients.

Epilepsy is a debilitating and unpredictable disorder of the central nervous system (CNS) and is diagnosed by the chronic occurrence of unprovoked seizures. Epilepsy also has detrimental effects on sleep. Historically, since Hippocrates and Aristotle, the interrelationship between epilepsy and sleep has been noted.1 Daytime sleepiness and sleep disturbance are common complaints among epilepsy patients. A study of a university-based clinic reported more than two thirds of epilepsy patients had sleep-related complaints.2 A questionnaire-based study of patients with temporal lobe epilepsy noted the prevalence of subjective sleep disturbance was twice that of age-matched controls (36% vs 18%). Quality of life information was also collected using the SF-36, a standardized measure of health-related quality of life. The authors noted that sleep disturbance was associated with significantly impaired quality of life independent of having epilepsy.3 Medication effects, seizures, mood disturbance, and sleep disorders are all factors that may cause or exacerbate daytime sleepiness.

Advancement of EEGs and polysomnography in the last 15 years has resulted in further growth in exploring the interrelationship between sleep and epilepsy. A major advantage of currently used digital systems is that the analysis is not restricted by the recorded montage or paper speed. Polysomnograms augmented with a full complement of 10 to 20 scalp electrodes can be viewed at any desirable “paper speed” suitable for sleep scoring or analysis of epileptic activity, such as seizures and interictal epileptiform discharges (IEDs). Digital systems also allow for montages suitable for EEG analysis postrecording and are not limited by the specific montage recorded. Eye and chin leads can be added to long-term EEG recordings to accommodate both EEG analysis and sleep scoring. The flexibility of the digital systems over paper recordings is one area that has facilitated exponential growth in the field of sleep and epilepsy. Other recent advances in basic science have also resulted in greater insight in neuronal activity as it relates to both sleep and epilepsy.

Seizures and Sleep
Unprovoked recurrent seizures are the clinical manifestation of epilepsy. Seizures result from excessive hypersynchronous activity in the brain. There are two basic categories of epileptic seizures: partial and generalized. Partial seizures start in one location of the brain and may spread to other regions. Simple partial seizures do not impair retention of memory and consciousness, whereas complex partial seizures result in loss of memory and consciousness. Generalized seizures begin over both hemispheres of the brain resulting in a wide variety of behaviors. Absence seizures are comprised of staring episodes. Atonic seizures result in sudden loss of muscle tone (person may fall suddenly), and tonic seizures involve sudden stiffening (abrupt increase in muscle tone). Clonic and myoclonic seizures involve muscle jerking.4 On the EEG, seizures are noted by rhythmic waveforms that evolve in frequency and field (areas of the brain affected). A seizure during wakefulness often results in a postictal period of sleepiness. Seizures that occur from sleep often result in postictal waveforms that resemble delta sleep waveforms in amplitude. Pathological postictal waveforms are usually more homogenous than sleep waveforms. They may persist for up to an hour after a seizure before elements of sleep such as spindles and k-complexes are visible in the EEG.5 In addition to disrupting normal sleep waveforms, seizures also disrupt sleep architecture by inhibiting REM sleep. Bazil et al6 studied patients with temporal lobe epilepsy and noted that REM is significantly inhibited after a nocturnal seizure. The same study documented that REM is also suppressed on nights following a diurnal seizure, indicating that the effects of seizures on sleep extend past the postictal period.

The relationship between seizures and sleep also is highly dependent on the type of epilepsy presenting. Seizures originating in the frontal lobe areas occur most commonly from sleep, whereas other types of seizures are prone to occur shortly after awakening, such as juvenile myoclonic epilepsy.7 During sleep, seizures are most common from non-REM stage 2 (after adjusting for time spent in each stage). Seizures are least common during REM sleep. Seizures may be propagated by the progressive synchronization of CNS neurons associated with the deepening of sleep.8 Conversely, activation of thalamocortical neurons associated with arousal from sleep may be related to seizures. The exact mechanism by which the sleep or arousal process facilitates seizures is unclear and probably varies according to the epilepsy etiology.


Figure 1. This 30-second epoch depicts non-REM sleep in an epilepsy patient. The IEDs are so frequent that non-REM sleep cannot be differentiated accurately into stages.5


Figure 2. This 30-second epoch depicts REM sleep in the same epilepsy patient as the previous figure. Note the dramatic reduction of IED and clear REM patterns.5

Interictal Epileptiform Discharges
IEDs, sometimes referred to as spike and wave complexes, consist of a sharp spike component followed by a slow wave. IEDs usually coexist with epilepsy and are of interest and use to physicians because of their increased frequency relative to seizures. While it is rare to observe a seizure during the usual 20-minute EEG test, IEDs frequently occur. The IED reflects the simultaneous depolarization of millions of neurons. The repolarization of the cell membranes is reflected in the slow wave that follows the spike component. These IEDs are of diagnostic value to physicians in that they can provide information as to the originating area of the seizures. Sleep and IEDs are intimately related. Sleep, specifically non-REM sleep, facilitates IEDs and epileptic activity (Figure 1, page 32). Several studies have demonstrated that IEDs are most frequent during slow-wave sleep.9-11 A proposed mechanism is that slow-wave sleep involves synchronous firing of neurons in the thalamus and cortical regions of the brain. This thalamocortical synchronization leans toward a propensity for IEDs.12,13 Conversely, IEDs and seizures are suppressed by REM sleep (Figure 2, page 35). REM is considered to be a neuronally desynchronized state and therefore inhibitory of epileptic activity. Studies have presented data indicating the usefulness of IEDs during REM for depicting the focus of epileptic seizures in the surgical evaluation of patients.14 Hence, in general non-REM sleep is useful for facilitating IEDs, whereas REM sleep suppresses epileptic activity. IEDs that are present may indicate the true focus of epileptic activity.

Sleep Architecture and Epilepsy
Several studies have indicated that patients with epilepsy have disrupted sleep architecture independent of the occurrence of seizures. Epilepsy patients tend to have increased stage 1 sleep, and decreased REM sleep as compared to normal controls. Increased sleep latency, increased arousals from sleep, and decreased sleep efficiency have also been reported.15 A review of sleep recordings in epilepsy patients indicated abnormally slow waveforms during wakefulness in some patients. Conversely, intrusion of fast activity into sleep not explained by evide
nt arousals was noted in other recordings. In some cases, sleep waveforms of epileptic patients may have EEG activity so intrusive that sleep staging is limited to non-REM and REM.5

Sleep Deprivation
Sleep deprivation can cause seizures in people with no history or a remote history of seizures. Often this has been accompanied by factors such as emotional and physical stress, fatigue, and/or alcohol consumption.16,17 In a study of 100 patients with seizures upon awakening, 83% of seizures were associated with sleep deprivation.18 Sleep deprivation is routinely used in long-term monitoring units to provoke seizures and epileptic activity; however, this strategy is controversial due to the burden placed on the patient and their caregivers (particularly in the pediatric population). One study of medically resistant temporal lobe epilepsy patients did not find a difference in seizure frequency in patients that were sleep deprived as compared to those allowed to sleep normally.19 Another study of pediatric EEGs concluded that sleep deprivation did not increase the odds of abnormal discharges during the 20- to 30-minute recording.20 The 20- to 30-minute recordings were done in the morning and so the duration and time may have influenced the results. While the effect of sleep deprivation may vary, it remains a commonly used practice for evoking epileptic activity.

Sleep Disorders
OSA is common among epilepsy patients. One study of 283 adults with various epilepsy syndromes reported 10.2% (15.4% of males and 5.4% of females) of participants had OSA.21 Another study found a third of medically refractory epilepsy patients to have OSA in a sample of 22. OSA coexisting with epilepsy may be easily overlooked as its symptoms among the general population (daytime sleepiness, gasping for air at night, and night sweats) may also be related to having seizures and not attributed to apnea.23 As sleep and epilepsy are interrelated, it follows that OSA that affects sleep may exacerbate epilepsy. Studies have shown improved seizure control after patients received treatment for OSA.24-26 In 1981, Wyler was the first to note this relationship by reporting significant reduction in number and severity of seizures in a patient after a tracheostomy to treat OSA (the only available treatment at the time).24 Vaughn et al25 reported on 40% of patients achieving freedom from seizures after treatment of OSA (n=10). A prospective study with four participants (three adults and one child) using CPAP therapy reported at least a 45% reduction in seizure frequency. Seizure frequency for one participant was reduced 72%. One adult treated with an oral appliance experienced a reduction in nocturnal seizures.27 Sleep fragmentation resulting from OSA is particularly detrimental to epilepsy patients as it can exacerbate daytime sleepiness and possibly worsen seizure control. A multicenter pilot clinical trial is currently under way to explore the relationship between treatment of OSA, improvement in seizure control, and quality of life.

Vagus Nerve Stimulation
Vagus nerve stimulation (VNS) is a form of treatment for epilepsy that involves intermittent electrical stimulation applied to the CNS via the left vagus nerve. The device is surgically implanted in the upper chest inferior to the clavicle. Electrodes encircle the vagus nerve to supply electrical stimulation usually for 30 seconds every 5 minutes. The device is programmable externally, and these parameters can be changed. The exact mechanism by which VNS reduces seizures is unknown. It is hypothesized that the intermittent electrical stimulus may interrupt the hypersynchronous activity characteristic of seizures. VNS is associated with decreased daytime sleepiness28 and is also used as a treatment for medically resistant depression; however, VNS is associated with respiratory disturbance in some patients. One study noted respiratory events associated with the activation of the VNS and that these were ameliorated by reducing the frequency of the stimulus from 30 Hz to 20 Hz (or 10 Hz).29 Other studies have concurred with these findings that VNS affects respiration during sleep.30-32 In most cases patients have not reported symptoms of excessive daytime somnolence (EDS) associated with VNS; however, one case study reports a 21-year-old woman with intractable generalized epilepsy that experienced EDS after implantation of the VNS. Polysomnography showed respiratory events associated exclusively with VNS activation. Options such as reducing the current flow or deactivating the device during sleep were offered. The patient chose to have the device discontinued, resulting in complete resolution of the EDS.33 This study reports only one patient, and the clinical significance of VNS-related respiratory events during sleep requires further study.

Periodic Leg Movements
The prevalence of periodic leg movements (PLMs) of sleep is unknown in the epilepsy population. Similar to OSA, symptoms of leg jerking during sleep may be attributed to the epilepsy and therefore not evaluated separately. As PLMs may contribute to sleep fragmentation, they may also exacerbate seizure frequency. Currently, this remains an understudied area.

Conclusion
Sleep and epilepsy are intimately interrelated, and increased knowledge in either area has implications for both. Daytime sleepiness contributes to an impaired quality of life independent of having epilepsy. Sleep disorders can have a profound impact on seizure frequency and quality of life for epilepsy patients. The differential diagnosis of a sleep disorder can be complicated due to similarity of symptoms often associated with epilepsy; however, increased awareness of sleep disorders offers hope for improved prognosis in treating epilepsy.

Mary L. Marzec, RPSGT, MS, is a research associate in sleep research at the University of Michigan Michael S. Aldrich Sleep Laboratory, Ann Arbor.

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