**Daytime Sleepiness and Changes of Sleep in Patients with Epilepsy**

Katarína Klobučníková and Branislav Kollár *I st Department of Neurology University Hospital of Medical Faculty, Comenius University,Bratislava, Slovak Republic* 

#### **1. Introduction**

28 Novel Aspects on Epilepsy

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It is well known, that patients with epilepsy suffer from excessive daytime sleepiness, fatigue and insufficient sleep. These problems are often overlooked or referred to epileptic seizures or antiepileptic drugs. It should be noticed, that patients with epilepsy suffer from sleep disorders more often than general population (Bazil 2003). Health outcome of patients with comorbidity of epilepsy and sleep disorders is worse as sleep disorders may aggravate epilepsy. Changes in amount and severity of epileptic seizures may lead to pharmacoresistency of epilepsy in patients with untreated sleep disorders. That is the reason why attention to quality of sleep and daytime vigility in patients with epilepsy should be payed. The cooperation of neurologist, pneumologist, somnologist and psychologist is very important in correct management of patients with epilepsy and sleep disorders.

Daytime sleepiness is defined as the inability to stay awake during waking episodes of the day. It results in unintended lapses into drowsiness or sleep. Sleepiness occurs mainly in boring situations. Sometimes it is associated with increase of total amnount of sleep without feeling of restoration. In most cases excessive daytime sleepiness (EDS) is a chronic symptom and it must occur for at least three months prior to diagnosis (ICSD-2, 2005).

Excessive daytime sleepiness is often result of self-imposed sleep deprivation espetially in young people. More often it is effect of disturbed nocturnal sleep or misaligned circadian rhytms. It may be side effect of many often-used drugs, for example hypnotics or alcohol. Nocturnal sleep disturbances, which lead to EDS, should be carefully assessed and treated. In several conditions EDS is not an outcome of night-sleep loss and should be considered as primary hypersomnia of central origin. These hypersomnias according to ICSD-2 include narcolepsy with or without cataplexy, recurrent hypersomnia, idiopathic hypersomnia with or without long sleep time and hypersomnias due to different medical and neurological conditions. Narcolepsy with cataplexy is characretized with daytime sleepiness and unwanted episodes of sleep, which occur several times a day. The duration of episodes may vary from a few minutes to more than an hour, patients wake up refreshed. Cataplexy is paroxyzmal, abrupt and reversible loss of muscule tone often elicited with emotional experience. Manifestations of disociated REM sleep (sleep paralysis and hypnagogic halucinations) are also exposed (Chokverty, 1994). Narcolepsy without cataplexy is associated with snoozing in daytime, sleep paralysis and hypnagogic hallucinations may occur. Secondary narcolepsy may be caused by tumors of brain or multiple sclerosis, if

Daytime Sleepiness and Changes of Sleep in Patients with Epilepsy 31

Malow & Sammaritano, 2002), what is widely used in EEG evaluation. Influence of antiepileptic medication on daytime vigility and quality of sleep is also important. Unrecognised primary sleep disorders, which cause fragmentation of sleep, may aggravate epilepsy and increase amount of epileptic seizures. Distinction of sleep-related epileptic seizures and non-epileptic paroxymal events in sleep is frequently problematic and requires

Unrecognised sleep-related generalised epileptic seizures disturb sleep achritecture as they cause arousals. Generalized epileptic seizures reduce total sleep time and elongate latency to REM sleep. Amount of NREM1 and NREM2 stages may be extended (Foldvary-Schaefer, 2002). Partial epileptic seizures during sleep do not disrupt night sleep markedly, only in case of their secondary generalization (Dasheiff, 2003). Epileptic seizures during daytime influence night sleep too. They reduce REM sleep, what may be cause of fatigue in

Antiepileptic therapy is considered to have influence on daytime vigility and quality of sleep. Barbiturates and benzodiazepines have sedative effect and cause daytime sleepiness (Bazil, 2003, Rang & Dale, 1991). Carbamazepine also induces daytime sleepiness, elongates slow-wave sleep and reduces REM sleep, mainly in the beginning of medication. Approximately after one month of medication these effects are not more noticeable (Placidi et al., 2000). Valproate according to literature elongates NREM1 and abbreviates NREM2 (Foldvary-Schaefer, 2009). It elevates number of arousals and elongates slow-wave sleep (Moráň, 2005). Put on weight may be unfavorable for patients with sleep apnoe syndrome

Primidone abbreviates latency of sleep and may improve quality of sleep. Phenytoin extends NREM1 and NREM2, shorten REM period and multiplies arousals. Gabapentin improves sleep stability and elongates slow-wave sleep as well as REM sleep (Foldvary-Schaefer, 2009). Lamotrigine reduces NREM3 and NREM4 and elongates REM sleep (Foldvary, 2002). As alerting drug should be dosed early in the day. Sleep latency may be shortened by topiramate (Foldvary-Schaefer, 2009). Levetiracetam consolidates sleep and does not modify vigilance (Cicolin, 2006). According to othe study (Cho, Kim & Motamendi, 2011) levetiracetam increase sleep efficiency without major effects on sleep structure. Antiepileptic drugs may be helpful in treatment of some sleep disorders. For example gabapentin, carbamazepine or lamotrigine

Exact evidence about incidence of sleep disorders in patients with epilepsy is not available, but it is supposed, that the amount is higher in patients with epilepsy than in general population. For example patients with partial epilepsy have twice higher appearence of sleep disorders as in healthy group (39% vs 18%) (Bazil, 2003). According to this study

According to Foldvary-Schaefer (2002) patients with epilepsy have problems with initialization of sleep and have worse quality of sleep. Meatiness of these problems, as well as wores control of epileptic seizures, was higher in group of patients with partial epilepsy. Some literature indicates, that patients with epilepsy have also higher appearance of sleep related breathing disorders than general population. Sleep apnoe syndromes are present in 0,8 – 2,2% of general adult population (Marin et at., 1997), however 28-55% patients with

careful diagnostic approach with video-polysomnography (Moráň, 2005).

have good effect on restles leg syndrome (Garcia-Borreguero et al, 2002).

higher presence of sleep disorders did not correlate with antiepileptic therapy.

epilepsy suffer for sleep related disorders (Foldvary, 2002).

postparoxysmal period (Bazil, Castro & Walczak, 2000).

(Moráň, 2003).

**1.3 Sleep disorders and epilepsy** 

hypothalamus is harmed. Recurrent hypersomnia, Kleine-Levin syndrome, is characterized by atacs of hypersomnia, which lasts for several days and occur several times per year. Episodes are accompanied by disturbances of behaviour (agression), bulimia and hypersexiality. Idiopathic hypersomnia with long sleep time is characterized by constant and sever EDS with unrefreshing naps of up to four hours and prolonged major sleep episode up to 10 – 14 hours. There are great difficulties with morning waking up and sleep drunkeness. Idiopathic hypersomnia without long sleep time, or essential hypersomnia is characterized with constant and sever EDS, which results in unintended naps of nonrefreshing nature. Cataplexa is absent. The major sleep episode is either normal, or slightly prolonged (to 10 hours). Post-wakening confusion of often reported.

Behaviorally induced insufficient sleep syndrome is another reason of EDS. A therapeutic trial of a longer sleep episode can reverse the symptoms. Hypersomnia has been described also in association with a large range of medical conditions, including head trauma, stroke, encephalitis, inflammatory conditions, tumors and neurodegenerative diseases as M.Parkinson (ICSD-2), (Overeem & Readings , 2010).

#### **1.1 Diagnostic evaluation of sleepiness in patient with epilepsy**

Obtaining an accurate 24-hour-sleep-wake history is extremly important. History should be focused also on relevant factors as medical history, compensation of epilepsy, type and frequency of epileptic seizures, their incidence according to circadian cycle and actual antiepileptic medication, or other drug and medication use. Also social, enviromental or psychological conditions, which may interfere with sleep quality, should be evaluated.

Neurological examination in connection with neuroimaging methods (MRI) can detect cerebral leasions as the reason of sleep problems. Standard EEG evaluation is recommended to detect abnormalities in EEG activity and interictal epileptic discharges. Epworth Scale of Sleepiness (ESS) is widely used questionnaire to quantify severity of daytine sleepiness. Score above 9 indicates elevated daytime sleepiness (Johns, 1991).

Multiple Sleep Latency Test (MSLT) can objectively evaluate daytime sleepiness. When used as diagnostic prosedure of central hypersomnia it should be done during the day after polysomnographically documented adequate night sleep, which lasts at least six hours and after two weeks of regular sleep. (Carscadon & Dement, 1982, American sleep disorders association, 1992) (ICSD-2, 2005). Evaluation of MSLT starts 1,5-3 hours after morning awakening and consists of 5, or at least 4 records of polysomnography, each lasting 20minutes (Littner et al., 2005). Latency of sleep and occurence and latency of REM sleep is in each record noted. A mean sleep latency below five minutes is generally considered as indicative of sleepiness, latency over ten minutes is generally considered indicative of normal alertness (American Sleep Disorders Association, 1992).

#### **1.2 Correlation of sleep and epilepsy**

Relationship of sleep and epilepsy is complex and reciprocal. Epilepsy may distrub sleep with night and also daytime epileptic seizures. On the other hand sleep modulates probabality of epileptic discharges and seizures in different sleep stages.

Specific types of epilepsy are bounded to specific part of sleep-wake cycle, as night sleep, awakening, or appear randomly during circadian rhytm. Typical night epilepsy is for example nocturnal frontal lobe epilepsy (Zucconi, 2007), juvenile myoclonical epilepsy is typically connected to awakening. Sleep deprivation elevates probabality of epileptic seizure (Bazil,

hypothalamus is harmed. Recurrent hypersomnia, Kleine-Levin syndrome, is characterized by atacs of hypersomnia, which lasts for several days and occur several times per year. Episodes are accompanied by disturbances of behaviour (agression), bulimia and hypersexiality. Idiopathic hypersomnia with long sleep time is characterized by constant and sever EDS with unrefreshing naps of up to four hours and prolonged major sleep episode up to 10 – 14 hours. There are great difficulties with morning waking up and sleep drunkeness. Idiopathic hypersomnia without long sleep time, or essential hypersomnia is characterized with constant and sever EDS, which results in unintended naps of nonrefreshing nature. Cataplexa is absent. The major sleep episode is either normal, or

Behaviorally induced insufficient sleep syndrome is another reason of EDS. A therapeutic trial of a longer sleep episode can reverse the symptoms. Hypersomnia has been described also in association with a large range of medical conditions, including head trauma, stroke, encephalitis, inflammatory conditions, tumors and neurodegenerative diseases as

Obtaining an accurate 24-hour-sleep-wake history is extremly important. History should be focused also on relevant factors as medical history, compensation of epilepsy, type and frequency of epileptic seizures, their incidence according to circadian cycle and actual antiepileptic medication, or other drug and medication use. Also social, enviromental or psychological conditions, which may interfere with sleep quality, should be evaluated. Neurological examination in connection with neuroimaging methods (MRI) can detect cerebral leasions as the reason of sleep problems. Standard EEG evaluation is recommended to detect abnormalities in EEG activity and interictal epileptic discharges. Epworth Scale of Sleepiness (ESS) is widely used questionnaire to quantify severity of daytine sleepiness.

Multiple Sleep Latency Test (MSLT) can objectively evaluate daytime sleepiness. When used as diagnostic prosedure of central hypersomnia it should be done during the day after polysomnographically documented adequate night sleep, which lasts at least six hours and after two weeks of regular sleep. (Carscadon & Dement, 1982, American sleep disorders association, 1992) (ICSD-2, 2005). Evaluation of MSLT starts 1,5-3 hours after morning awakening and consists of 5, or at least 4 records of polysomnography, each lasting 20minutes (Littner et al., 2005). Latency of sleep and occurence and latency of REM sleep is in each record noted. A mean sleep latency below five minutes is generally considered as indicative of sleepiness, latency over ten minutes is generally considered indicative of

Relationship of sleep and epilepsy is complex and reciprocal. Epilepsy may distrub sleep with night and also daytime epileptic seizures. On the other hand sleep modulates

Specific types of epilepsy are bounded to specific part of sleep-wake cycle, as night sleep, awakening, or appear randomly during circadian rhytm. Typical night epilepsy is for example nocturnal frontal lobe epilepsy (Zucconi, 2007), juvenile myoclonical epilepsy is typically connected to awakening. Sleep deprivation elevates probabality of epileptic seizure (Bazil,

slightly prolonged (to 10 hours). Post-wakening confusion of often reported.

**1.1 Diagnostic evaluation of sleepiness in patient with epilepsy** 

Score above 9 indicates elevated daytime sleepiness (Johns, 1991).

normal alertness (American Sleep Disorders Association, 1992).

probabality of epileptic discharges and seizures in different sleep stages.

**1.2 Correlation of sleep and epilepsy** 

M.Parkinson (ICSD-2), (Overeem & Readings , 2010).

Malow & Sammaritano, 2002), what is widely used in EEG evaluation. Influence of antiepileptic medication on daytime vigility and quality of sleep is also important. Unrecognised primary sleep disorders, which cause fragmentation of sleep, may aggravate epilepsy and increase amount of epileptic seizures. Distinction of sleep-related epileptic seizures and non-epileptic paroxymal events in sleep is frequently problematic and requires careful diagnostic approach with video-polysomnography (Moráň, 2005).

Unrecognised sleep-related generalised epileptic seizures disturb sleep achritecture as they cause arousals. Generalized epileptic seizures reduce total sleep time and elongate latency to REM sleep. Amount of NREM1 and NREM2 stages may be extended (Foldvary-Schaefer, 2002). Partial epileptic seizures during sleep do not disrupt night sleep markedly, only in case of their secondary generalization (Dasheiff, 2003). Epileptic seizures during daytime influence night sleep too. They reduce REM sleep, what may be cause of fatigue in postparoxysmal period (Bazil, Castro & Walczak, 2000).

Antiepileptic therapy is considered to have influence on daytime vigility and quality of sleep. Barbiturates and benzodiazepines have sedative effect and cause daytime sleepiness (Bazil, 2003, Rang & Dale, 1991). Carbamazepine also induces daytime sleepiness, elongates slow-wave sleep and reduces REM sleep, mainly in the beginning of medication. Approximately after one month of medication these effects are not more noticeable (Placidi et al., 2000). Valproate according to literature elongates NREM1 and abbreviates NREM2 (Foldvary-Schaefer, 2009). It elevates number of arousals and elongates slow-wave sleep (Moráň, 2005). Put on weight may be unfavorable for patients with sleep apnoe syndrome (Moráň, 2003).

Primidone abbreviates latency of sleep and may improve quality of sleep. Phenytoin extends NREM1 and NREM2, shorten REM period and multiplies arousals. Gabapentin improves sleep stability and elongates slow-wave sleep as well as REM sleep (Foldvary-Schaefer, 2009). Lamotrigine reduces NREM3 and NREM4 and elongates REM sleep (Foldvary, 2002). As alerting drug should be dosed early in the day. Sleep latency may be shortened by topiramate (Foldvary-Schaefer, 2009). Levetiracetam consolidates sleep and does not modify vigilance (Cicolin, 2006). According to othe study (Cho, Kim & Motamendi, 2011) levetiracetam increase sleep efficiency without major effects on sleep structure. Antiepileptic drugs may be helpful in treatment of some sleep disorders. For example gabapentin, carbamazepine or lamotrigine have good effect on restles leg syndrome (Garcia-Borreguero et al, 2002).

#### **1.3 Sleep disorders and epilepsy**

Exact evidence about incidence of sleep disorders in patients with epilepsy is not available, but it is supposed, that the amount is higher in patients with epilepsy than in general population. For example patients with partial epilepsy have twice higher appearence of sleep disorders as in healthy group (39% vs 18%) (Bazil, 2003). According to this study higher presence of sleep disorders did not correlate with antiepileptic therapy.

According to Foldvary-Schaefer (2002) patients with epilepsy have problems with initialization of sleep and have worse quality of sleep. Meatiness of these problems, as well as wores control of epileptic seizures, was higher in group of patients with partial epilepsy.

Some literature indicates, that patients with epilepsy have also higher appearance of sleep related breathing disorders than general population. Sleep apnoe syndromes are present in 0,8 – 2,2% of general adult population (Marin et at., 1997), however 28-55% patients with epilepsy suffer for sleep related disorders (Foldvary, 2002).

Daytime Sleepiness and Changes of Sleep in Patients with Epilepsy 33

Noticed abnormalities were rated as regional or generalised, with continual of intermitent

In both groups (patients with epilepsy and healthy controls) we used a questionnaire Epworth Scale of Sleepiness (ESS) (Johns, 1991). By answering eight questions about probability of falling asleep in standard situations we came to the result, i.e. score of daytime sleepiness ranging from 0 to 24. Rate 0-9 is considered as normal value, above 9 as elevated daytime sleepiness and value above 16 is considered as remarkably elevated

All patients with epilepsy were evaluated by Multiple Sleep Latency Test (MSLT) (Carscadon & Dement, 1982) in order to objectivise the daytime sleepiness. The latency of sleep was measured in five 20 minute polysomnographic registrations in this test. Between the registrations the patient should be awake (Usui et al., 2008). Mean latency of sleep and appearance of REM sleep was noticed. Mean latency of sleep shorter than 6 minutes was considered as indicative of elevated sleepiness (American sleep disorders association, 1992).

Nocturnal polysomnografy was used in both groups to evaluate quality of sleep. We used program Brain Quick System 98 for polysomnography. Scoring of sleep stages was done

Registration and scoring of sleep stages was done according to criteria of Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects (Rechtschaffen & Kales, 1968). We used four electrodes (C3, C4, O1, O2, A1, A2) in EEG registration. When topographical localization of epileptiform discharges was needed, we used 19 EEG electrodes located according to international system 10-20. Standard localization

The result of sleep analysis was hypnogram, amount of sleep stages (NREM S1, NREM S2, NREM S3+-S4, REM) in %, total sleep time in minutes and efficiency of sleep in %was marked. For purpose of registration of different abnormal movement manifestations (epilepsy, REM behavior diseases etc.), a video was recorded simultaneously with polysomnography.

We examined 100 patients with epilepsy who were admitted to the I. Neurology Clinic of Comenius University Hospital in Bratislava for diagnostic or therapeutic reasons in the period from January 2004 to January 2009. The group consisted of 49 men and 51 women, with the average age of 34.68 ± 13.55 years. Patients of the age 9 - 61 were included. Average duration of illness was 9.31 ± 9.93 years, ranging from 0.5 to 47 years. Medical history of duration and type of epilepsy was taken. International classification of epileptic seizures

According to this classification 50 patients had focal symptomatic epilepsy, 26 patients had focal cryptogenic epilepsy. Generalised symptomatic epilepsy was diagnosed by 15 pacients

Etiology of epilepsy was evaluated. Idiopathic or cryptogenic epilepsy have 35% patients and symptomatic epilepsy have 65% of patients. Detailed analysis of reasons of epilepsy in

of electrodes for electrooculogram and electromyogram m.mentalis was used.

occurence. Appearance of epileptiform ictal or interictal discharges was noted.

**3.1 Methods used to examine daytime sleepiness** 

daytime sleepiness (Watanabe et al., 2003).

**3.2 Methods used to register sleep architecture** 

with Sleep View Rembrandt Sleep Analysis Program.

**3.3 Characteristics of the group of patients with epilepsy** 

group of symptomatic patients showed these factors:

(1981, 1989) and International classification of epilepsy (1989) was used.

and 9 patients had generalised cryptogenic or idiopathic epilepsy (see Fig.1).

Even 33% pacients with medically refractory epilepsy have sleep apnoe syndrome (Malow et al., 2000). Reason of higher appearance of sleep related breathing disorders in patients with epilepsy is not clear. It may be connected with higher weight of patients as effect of anticonvulsant therapy (Manni & Terzaghi, 2010), or changes of endocrine system (valproate). Sleep apnoe syndrome leads to fragmented macroarchitecture of sleep with repeated hypoxemia of brain in consequence of repeated apnoic episodes. This may cause higher frequency of epileptic seizures. It is important, that correct therapy of sleep apnoe syndrome (reduction of weight, indication of CPAP or BiPAP) may bring improvement of epilepsy (Foldvary, 2002).

Sleep disorders should be considered especially when patient with epilepsy indicates hypersomnia, but has low frequency of epileptic seizures, is treated with monotherapy of antiepileptic drug and has low blood levels of medication.

#### **1.4 Management of patient with epilepsy and sleep disorders**

Patient with epilepsy and EDS reguires accurate evaluation to detect reason of hypersomnia. Compensation of epilepsy should be examined. EEG during daytime and overnight-EEG should detect interictal or ictal discharges. This may cause microarousals and fragmentation of sleep with secondary hypersomnia. Adjusting of antiepileptic medication should reduce amount of epileptic seizures and improve sleep. It is recommended to avoid antiepileptic therapy with sedative effects (barbiturates, benzodiazepines) and useless combination of too many antiepileptic drugs.

Correct sleep hygiene and life-style with regular and sufficient night-sleep and optimal surroundings is also important (Bazil, 2003, Happe, 2003).

Hypersomnia in patients with epilepsy may be caused by sleep apnoe syndrome. This should be considered particulary in obese patients with morning headache and hypertension. Diagnosis is estimated by polysomnography. According to literature 1/3 patients with refractory epilepsy have obstructive sleep apnoe syndrome (Malow et al., 2000). Correct therapy of sleep related breathing disorders may improve quality of sleep. Antiepileptic therapy, which increase weight (valproate) should be avoided, as it may worsten sleep apnoe syndrome (Bazil et al., 2002).

Insomnia is another possible reason of daytime hypersomnia and fatigue of patients with epilepsy. It should be treated by behavioral and relaxation methods, improvement of sleep habits or by sedative drugs. If antiepileptic therapy is considered as reason of insomnia, then it should be taken only in morning.
