Correlation between Daytime Sleepiness and Antiepileptic Drugs in
Generalized Tonic Clonic Epilepsy Patients in Epilepsy Outpatient Clinic at
Neurology Department University of Sumatera Utara, Medan, Indonesia
Silvana Asrini, Aldy S. Rambe, dan Darulkutni Nasution
Department of Neurology, North Sumatera Medical Faculty And Haji Adam Malik Hospital
Medan, Indonesia
Abstract: Drowsiness is frequently reported in patients taking antiepileptic drugs (AEDs), but it seems more prominent with some AEDs, and it is invariably enhanced by drug combination. This study was aimed to assess correlation between daytime sleepiness and AEDs in generalized tonic clonic epilepsy patients. A cross sectional study with subjects consisted of 40 consecutive adult patients with generalized tonic clonic epilepsy, receiving AEDs monotherapy or polytherapy was performed. Each patient was asked regarding the type and the dose of AEDs. Patients were self-rated their own degree of sleepiness by using Epworth Sleepiness Scale and Stanford Sleepiness Scale. In this research, 27 (67.5%) patients took monotherapy (phenytoin or carbamazepine), 13 (32.5%) patients took polytherapy (phenytoin-carbamazepine, phenytoin-phenobarbital or phenytoin-valproic acid). Correlation between daytime sleepiness and AEDs in generalized tonic clonic epilepsy patients was significant (p < 0.05). Epworth Sleepiness Scale and Stanford Sleepiness Scale showed that there was a different level of sleepiness in each kind of AED. Most subjects reported that they had moderate and severe daytime sleepiness after taking combination of phenytoin and carbamazepine. Daytime sleepiness in patients receiving AEDs polytherapy was higher than monotherapy (p < 0,05). There is a significant relationship between AEDs and daytime sleepiness in patients with generalized tonic clonic epilepsy (p < 0.05). Sleepiness is relatively higher in AEDs polytherapy than in monotherapy.
Keywords: antiepileptic drugs - daytime sleepiness – epilepsy
Abstrak: Mengantuk sering dilaporkan pada pasien yang mengkonsumsi obat anti epilepsi (OAE), tetapi terlihat lebih menonjol pada beberapa OAE, dan bertambah lagi dengan kombinasi obat. Penelitian ini bertujuan untuk menilai hubungan antara daytime sleepiness dan OAE pada pasien epilepsi umum tonik klonik. Suatu penelitian potong lintang dengan subjek yang terdiri dari 40 pasien dewasa epilepsi umum tonik klonik secara konsekutif, yang mendapat OAE monoterapi atau politerapi. Setiap pasien ditanya mengenai tipe dan dosis OAE. Pasien disuruh menilai sendiri tingkat mengantuknya dengan menggunakan Epworth Sleepiness Scale dan Stanford Sleepiness Scale. Pada penelitian ini, 27 (67,5%) pasien menggunakan monoterapi (fenitoin atau karbamazepin), 13(32,5%) pasien menggunakan politerapi (karbamazepin, fenitoin-fenobarbital atau fenitoin-asam valproat). Hubungan antara daytime sleepiness dan OAE pada epilepsi umum tonik klonik adalah signifikan (p < 0.05). Epworth Sleepiness Scale dan Stanford Sleepiness Scale telah menunjukkan bahwa terdapat perbedaan tingkat rasa mengantuk pada masing-masing OAE. Kebanyakan subjek melaporkan bahwa mereka memiliki daytime sleepiness yang sedang dan berat setelah mengkonsumsi kombinasi antara fenitoin dan karbamazepin. Daytime sleepiness pada pasien yang mendapat OAE politerapi lebih tinggi dibanding monoterapi (p < 0,05). Terdapat hubungan yang signifikan antara OAE dan daytime sleepiness pada pasien epilepsi umum tonik klonik. Rasa mengantuk relatif lebih tinggi pada OAE politerapi dibanding monoterapi.
INTRODUCTION
Sleep is important for the general health of all, but is particularly essential for individuals with epilepsy. In these patients, a complex relationship exists between seizures and sleep.1
Historically, Hippocrates and Aristotle, the interrelationship between epilepsy and sleep has been noted.2
Individuals with epilepsy commonly report excessive daytime sleepiness (EDS) and fatigue that are typically attributed to the effects of seizure or antiepileptic drugs (AEDs). However, in patients with epilepsy, sleep is disrupted by frequent arousals, awakenings, and stage shift, even in the absence of seizures and AEDs. 3-5
Drowsiness is frequently reported in patients taking antiepileptic drugs (AEDs), but it seems more prominent with some AEDs, and it is invariably enhanced by drug combination. It is well known that sleepiness is highly related to polipharmacy, particularly with older AEDs. 6
A number of the older epilepsy drugs have adverse effects on sleep and daytime vigilance. Recent studies suggest that some of the newer AEDs may be neutral or even have positive effects on sleep consolidation and alertness. Whether primary sleep disorders are a significant cause of EDS in patients with epilepsy remains to be determined. 7
This study was aimed to assess correlation between daytime sleepiness and AEDs in generalized tonic clonic epilepsy patients.
METHODS Subjects
A cross sectional study with subjects consisted of 40 consecutive adult patients with generalized tonic clonic epilepsy, who visited Epilepsy Outpatient Clinic Haji Adam Malik Hospital, Tembakau Deli Hospital and Kesdam I Putri Hijau Hospital, from December 2005 through March 2006. All subjects fulfilled inclusion criteria: (a) age > 15 years: (b) have been used AEDs more than 3 months: (c) seizure-free more than 3 months. Exclusion criteria included (a) use of sedatives, hypnotics, anxiolitics and antihistamines drugs: (b) evidence of sleep disorders: (c) epilepsy patients with alcoholic and other drug abuse: (d) psychiatric disorders: and (e) patients with consciousness, auditory, aphasia and visual disorders.
Procedure
After giving written informed consent, subjects were interviewed by physician. Each subject was asked to fill up questionnaire which adaptation from Epworth Sleepiness Scale (ESS) and Stanford Sleepiness Scale (SSS). The ESS is an eight-item survey designed to ascertain sleep propensity during activities of daily living. Subjects rate the chance of dozing in each of eight activities of daily living from 0 (never) to 3 (high).The scores for the eight activities are tallied, producing a total score ranging from 0 to 24, with a score until 6-7 (normal), 8-12 (mild), 13-17 (moderate) and score > 18 indicating severe daytime sleepiness.3
The SSS is an eight-item survey designed to ascertain sleep propensity during subject was interviewed. Subjects was asked to choose one of the item. Score > 3 (severe) and <3 indicating mild daytime sleepiness. 8
Statistical analysis
A nonparametric statistical analysis of data was performed. Description of drowsiness in epilepsy patients was present in tabulation and description type. The chi square test was used to analyze the correlation between AEDs and daytime sleepiness; and to analyze the correlation between daytime sleepiness severity with AEDs monotherapy and polytherapy. A p value of <0.05 was considered to be statistically significant. All analyses were performed by using SPSS 12.0 for Windows.
RESULTS
Table 1. Demographic characteristic of patients
Variable n %
Sex
• Male 27 67.5
• Female 13 32.5
Age (yr)
• 15-24 18 45
• 25-34 10 25
• 35-44 5 12.5
• 45-54 2 5
• 55-64 4 10
• 65-74 1 2.5
Education
• Illiterate 1 2.5
• Elementary school 2 5
• Junior high school 4 10
• Senior high school 17 42.5
• Academic/University 16 40
Occupation
• Entrepreneur 9 22.5
• Government employee 7 17.5
• Private employee 5 12.5
• Housewife 3 7.5
• Student/University student 12 30
• Others 4 10
Ethnic Group
• Batak-Tobanese 15 37.5
• Javanese 10 25
• Malayans 4 10
• Mandailingnese 4 10
• Batak-Karonese 7 17.5
Number of drug
• Monotherapy 27 67.5
• Politherapy 13 32.5
Correlation between daytime sleepiness and AEDs in generalized tonic clonic epilepsy patients was significant with p<0.05 (not shown). ESS and SSS showed that there was a different level of sleepiness in each kind of AED.
In this study, carbamazepine 600 mg daily caused daytime sleepiness significantly (p=0.006 in ESS and 0.020 in SSS). Patients using this carbamazepine doses showed tendency to have daytime sleepiness. But subjects using phenytoin have tendency to fall more severe daytime sleepiness but not significant. In the other hand, combination of phenytoin and carbamazepine significantly caused daytime sleepiness (p=0.022 in ESS; p=0.001 in SSS). Most subjects reported that they had moderate and severe daytime sleepiness after taking combination of phenytoin and carbamazepine. Combination
of phenytoin and valproic acid or Phenobarbital not significantly caused daytime sleepiness (Table 2).
In Epworth Sleepiness Scale, 20 (50%) subjects have no daytime sleepiness while sitting and talking to someone or as passenger on the car during one hour without stopping. Seventeen (42.5%) subjects had tendency moderate to fall asleep while sitting and reading and 30% while watching television.
Twenty-two (55%) subjects had tendency severe daytime sleepiness and 18 (45%0 subject had mild daytime sleepiness when subjects were interviewed, based on Stanford Sleepiness Scale.
Table 2. Correlation between daytime sleepiness and type of anti-epileptic drugs
Phenytoin 100mg 3x1 +
carbamazepine 200mg 3x1 0 2 7 1 0.022 0 10 0.001
Phenytoin 100mg 3x1 +
valproic acid 250mg 2x1 0 0 1 0 0.592 0 1 0.360
Phenytoin 100mg 3x1 +
Phenobarbital 30 mg 3X1 0 0 2 0 0.271 1 1 0.884
AED, anti-epileptic drugs; ESS, epworth sleepiness scale; SSS, stanford sleepiness scale
Table 3. Comparison daytime sleepiness in tonic clonic epilepsy patients with monotherapy and polytherapy
AED, anti-epileptic drugs; ESS, epworth sleepiness scale; SSS, stanford sleepiness scale
DISCUSSION
In the present study, we found that carbamazepine 600 mg daily caused daytime sleepiness significantly (p=0.006 in ESS and 0.020 in SSS). But subjects that using phenytoin have tendency more severe daytime sleepiness but not significant.
The interpretation of prior studies addressing the effect of AEDs on sleep is limited because of methodologic variations, including composition of the study population, dose, timing and duration treatment, and failure to control seizure and concomitant AEDs. The older AEDs have been shown to have a variety of effects on sleep. 3
Drowsiness is increased in patients taking carbamazepine, phenytoin, valproic acid and Phenobarbital by the maintenance of wakefulness test, although this study could not distinguish between the drugs. 1
Phenobarbital reduces sleep latency and Rapid Eye Movement (REM) sleep and increases sleep efficiency and light (stage 1 and 2) non REM sleep. The effect of phenytoin and carbamazepine appear to vary with treatment duration. Short–term phenytoin therapy produces a reduction of sleep latency and stage 1 and increases in SWS and arousals, which reverses after several months of treatment. Similarly, a single dose of controlled-release carbamazepine produced a reduction in REM and increase in REM
fragmentation that was no longer observed after 1 month of treatment. Prolonged carbamazepine treatment has been shown to reduce REM sleep in patients with temporal lobe epilepsy. The effects of valproate on sleep range from a reduction in REM and increase in SWS to none.3
Chronic carbamazepine and valproate treatment do not seem to affect sleep. 9
It is well known that sleepiness is highly related to polypharmacy, particularly with older AEDs, where as a reduction number of concomitant medications is associated with a subjective increase of alertness in epilepsy patients. 9
This study demonstrates daytime sleepiness in patients receiving AEDs polytherapy was higher than monotherapy significantly (p<0.05), while most subjects reported that they had moderate and severe daytime sleepiness after taking combination of phenytoin and carbamazepine. Where as combination of phenytoin and valproic acid or Phenobarbital not significantly caused daytime sleepiness.
to fall asleep while wathing television and 41% while sitting or reading.10
This study demonstrates 20 (50%) subjects have no daytime sleepiness while sitting and talking to someone or as passenger on the car during one hour without stopping. Seventeen (42.5%) subjects had tendency moderate to fall asleep while sitting and reading and 30% while watching television. This result have resemblance with Mallow’s study.
In conclusion, our study demonstrates that There is a significant relationship between AEDs and daytime sleepiness in patients with generalized tonic clonic epilepsy (p < 0.05). Sleepiness is relatively higher in AEDs polytherapy than in monotherapy.
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