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Keywords:

  • Epilepsy;
  • Obstructive sleep apnea

Abstract

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Summary: Purpose: The aim of this study was to evaluate the rate and features of obstructive sleep apnea (OSA) in adult epilepsy patients.

Methods: Two hundred eighty-three adult epilepsy patients (137 men; mean age, 33 years; range, 18–70  years) were prospectively screened for OSA by means of a structured interview. Those in whom OSA was clinically suspected were monitored for a full night by using a portable device (Polymesam), and OSA was diagnosed when they had an Apnea/Hypopnea Index greater than five.

Results: Coexistence of OSA with epilepsy was found in 10.2% (15.4% of the male and 5.4% of the female) epilepsy patients investigated. The OSA was mild in 66.6%, moderate in 22.2%, and severe in 11.1% of the cases. The “epilepsy + OSA” patients were older, heavier, more frequently male, and sleepier (p < 0.05) than those with “epilepsy only.” Furthermore, they experienced their first seizure at an older age (p < 0.05).

Conclusions: Systematic investigation reveals that OSA is frequent in epilepsy patients. The major risk factors for OSA in our epilepsy patients were the same as those typically found in the general population. Of the epilepsy-related factors, older age at onset of seizures appears to be significantly related to comorbidity with OSA (p < 0.05). The presence in epilepsy patients of these features should alert the clinician to the possibility of an underlying OSA.

The coexistence of epilepsy and obstructive sleep apnea (OSA) has been documented in different case series (1–5). This comorbidity represents a diagnostic challenge, because OSA can mimic seizures during sleep (6).

Furthermore, the association of epilepsy and OSA is considered potentially able to aggravate the clinical course of the two disorders. Sleep fragmentation in OSA can facilitate the occurrence of seizures and increase drowsiness in epilepsy patients (2), whereas epileptic seizures can induce apneas (7).

Antiepileptic drugs (AEDs) can lead to a decrease in arousal threshold and upper airway muscle tone and also induce weight gain, all factors that can adversely affect OSA (8,9). Continuous positive airway pressure treatment of patients with epilepsy and OSA has been suggested to improve seizure control (2,4,10).

Epilepsy and OSA are highly prevalent disorders in the general population, thus their association in a single subject could be merely fortuitous. No definite evidence exists that the rate of OSA in subjects with epilepsy is higher than that in the general population. However, Malow (5) recently documented OSA in one third of patients with medically refractory epilepsy who were candidates for epilepsy surgery, OSA being particularly prevalent among older, male patients and in those who experience seizures during sleep.

Greater knowledge of this complex comorbidity would lead to better management of “epilepsy + OSA” patients in the clinical setting, and probably to improvements in the disease course and quality of life of patients with epilepsy (11,12).

We set out to evaluate the prevalence of OSA and the features of the association of epilepsy with OSA in a series of adult epilepsy patients referred to a specialist epilepsy center, who had not previously been investigated either for OSA or for other sleep disorders.

METHODS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Setting

Over a period of 1 year, the subjects were recruited prospectively and consecutively among patients referred to the Epilepsy Centre of the C. Mondino Institute of Neurology in Pavia, Italy. Subjects attending the center for a scheduled appointment were selected for inclusion in the study only if they: were aged 18 or older; had been diagnosed with epilepsy according to the International Classification of Epileptic Disorders (13); and had never previously been investigated for sleep disorders. We did not include subjects with epilepsy who also had an underlying cerebral disease (such as malignancies or degenerative progressive diseases), cardiopulmonary and/or metabolic diseases (such as diabetes or renal or hepatic failure), alcohol abusers, or subjects regularly taking hypnotics or sedative drugs.

Once the patients had given their informed consent to the study, sleep investigations were performed at the institute's Sleep Centre.

Procedure

Part I: Clinical screening for obstructive sleep apnea

The patients were preliminarily investigated by means of an interview based on a symptom checklist that investigates nocturnal sleep, daytime sleepiness, and daytime function, in reference to the previous 3 months. The interview included screening questions about the symptoms most predictive of OSA (14,15): loud snoring, apneas observed by bed partner, gasping during sleep, excessive daytime sleepiness, daytime fatigue, and impaired concentration.The frequency of each symptom was specified according to a 4-level scale (never, rarely, often, always). This interview was proved to have a sensitivity of 90% and a specificity of 75% in identifying OSA patients (PSG OSA threshold: AHI > 5) in our specialist sleep disorders setting.

Daytime sleepiness was further investigated by the Epworth Sleepiness Scale (ESS), completed and interpreted according to standard indications (16).

Although excessive daytime sleepiness, daytime fatigue, and impaired concentration are considered important symptoms contributing to a clinical diagnosis of OSA, they were not taken to form the basis of clinical suspicion of OSA in our patients because these symptoms in epilepsy patients are highly likely to be biased by other factors, such as treatment with AEDs and seizure recurrence (17). As such, they were not deemed suitable for the primary clinical screening of OSA in the context of our specialist epilepsy center.

Thus, in our sample, clinical suspicion of OSA was based on the presence of the following symptoms: habitual (“often” or “always”) loud snoring; loud snoring that occurs rarely but is accompanied by apneas observed by bed partner or gasping during sleep; or apneas during sleep observed by bed partner or gasping during sleep (even when these symptoms occur rarely).

Part II: Instrumental investigations of obstructive sleep apnea

Subjects suspected of having OSA were further investigated, within 2 weeks of the clinical screening, by means of an overnight sleep recording. This was performed by using a portable device, Polymesam (MAP, Medizin-Technologie Gmbh, Martinsried, Germany), a well-known, validated tool for the diagnosis of OSA (18), which allows measurement of thoracic and abdominal respiratory movements (by means of strain gauges), airflow (by means of thermocouples located at the nostrils and mouth), snoring sounds (by means of a microphone), arterial oxyhemoglobin saturation (HbSao2) (by means of a pulse oximeter with finger probe), heart rate, and body position. The recordings were performed according to standard indications (19). The patients were prepared at the Sleep Laboratory and slept at home, after being instructed to fill in a sleep diary in which they were required to report bedtime, waking time, and the presumed total sleep time during the monitored night. The recordings were scored by a physician with particular expertise in polysomnography, who was blind to the patient's clinical interview and ESS scores.

An airflow arrest that lasted ≥10 s and was accompanied by persistence of thoracoabdominal movements was classified as obstructive apnea, whereas an arrest of both airflow and thoracoabdominal movements of ≥10 s was classified as central apnea.

A hypopnea was defined as a polygraphic pattern, lasting ≥10 seconds, characterized by a >50% decrease in airflow amplitude and a >4% decrease in HbSao2 versus baseline during the previous 2 min. We included the decrease in HbSao2 as an additional hypopnea definition criterion because, although rather conservative, it appeared to be, in the absence of EEG recording and thus of the possibility of scoring EEG arousal, the only criterion able to support the polygraphic one.

Obstructive sleep apnea: diagnostic criteria and measurements

The Apnea/Hypopnea Index (AHI) was the measure used to describe OSA. It represented the ratio of apneas plus hypopneas to reported total sleep time during the monitored night. Subjects were given a definite diagnosis of OSA when they fulfilled the chosen clinical criteria and when overnight polygraphic testing resulted in an AHI >5.

OSA was rated according to the AHI as follows: 5 < mild ≤ 15; 16 < moderate ≤ 30; >30 severe. The criteria we used to define and measure OSA are in accordance with official standards and recommendations (14).

Patient series

Two hundred eighty-three subjects entered the study (137 men; mean age, 33.7 years; SD, 12.7; range, 18–70 years; mean years of education, 10; SD, 3). Table 1 summarizes the demographic and main epilepsy features of the epilepsy patients investigated.

Table 1. Clinical features and drug treatment in the entire patient series
 No.%
  1. Of 283 subjects, 137 (48.4%) were men; mean age, 33.7 ± 12.7 years; range, 16–70 years).

Epilepsy syndrome  
 Generalized idiopathic epilepsy 6523.0
 Localization-related cryptogenic epilepsy12142.8
 Localization-related symptomatic epilepsy 6924.5
 Epilepsy of undetermined type (focal or generalized) 26 9.2
Seizures during sleepy7827.5
Seizure frequency in last year:  
 >1 seizure per month12443.8
Drug treatment  
 Patients under treatment25991.4
 Monotherapy16157.0
 More than one antiepileptic drug 9835.0

Seizures were considered to be sleep related when they occurred solely, or in >50% of instances, during sleep. Most of the patients were being treated with AEDs, and in most cases, in monotherapy. Carbamazepine (CBZ) and valproate (VPA) were most frequently the drugs being taken, whereas phenobarbital (PB) accounted for only 10% of the drug treatments.

On enrollment in the study, all the patients had drug serum levels within the normal range.

Statistical analysis

Statistical analysis was carried out by using the statistical package for social sciences (SPSS). All the items were cross-tabulated, the dependent variable being coexistence of OSA with epilepsy (coded as 0, no OSA–epilepsy coexistence; 1, OSA–epilepsy coexistence). Patients with “epilepsy + OSA” (i.e., patients with epilepsy in whom nocturnal polysomnography confirmed the coexistence of OSA) and those with “epilepsy only” (i.e., patients with epilepsy in whom nocturnal polysomnography ruled out the coexistence of OSA) were compared for categoric (sex, ESS score <10 or >10, primary generalized vs. localization-related epilepsy syndromes, generalized vs. partial seizures, recurrent vs. controlled seizures, seizures during sleep vs. seizures during wakefulness, no AED treatment vs. AED treatment, monotherapy vs. polytherapy, VPA or PB treatment vs. treatment with other AEDs) and continuous variables (subject's age, age at onset of epilepsy). The χ2 test or Fisher's exact test was used to compare frequency data. The comparison of continuous variables was performed by means of Student's t or Kruskal–Wallis two-tailed tests, depending on the data distribution. The level of significance was set at <0.05.

The variables correlated with OSA coexistence/no OSA coexistence at bivariate or univariate analyses were included in logistic regression models to test their independent effects in a multivariate setting.

RESULTS

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Rate of OSA in epilepsy patients

Forty subjects met our clinical criteria for suspected OSA. They all underwent polygraphic monitoring. In three cases, nocturnal polygraphic recordings could not be adequately assessed because of artifacts and/or partial loss of data as a result of failure of one or more of the sensors. In such cases, the polygraphic recording was disregarded, and a new one was performed, which could be properly scored.

In 29 (21 men, eight women) of the 40 tested patients, polygraphic overnight monitoring resulted in an AHI >5, and these subjects were given a diagnosis of definite OSA. Thus the rate of OSA in our study group of epilepsy patients was 10.2% (15.4% in men and 5.4% in women).

Main features of OSA

Sleep apnea was mild in 66.6%, moderate in 22.2%, and severe in 11.1%. Further details of OSA measurements are given in Table 3. Table 2 compares the demographic and clinical features of the “OSA + epilepsy” patients and of the “epilepsy only” patients.

Table 3. Polygraphic findings in the 29 “Epilepsy + OSA” subjects
 MeanStandard deviationRange
  1. Twenty-one of 137 (15.4%) subjects were men; eight of 146 (5.4%) were women.

  2. aPercentage of time spent <90%.

  3. bAHI, apnea hypopnea index (see text); mild between 6 and 15; moderate between 16 and 30; severe >30.

AHI19.813.96–58
HbSao2 nadir81.7 5.968–90
HbSao2 <90%a 5.510.50–46
 
Severity of obstructive sleep apneab% 
 
Mild 66.6 
Moderate 22.2 
Severe 11.1 
Table 2. “Epilepsy + OSA” versus “epilepsy only” patients: comparison of demographic and clinical features: uni- and bivariate analysis
 “Epilepsy + OSA” 29 patients“Epilepsy only” 11 patients
  1. BMI, body mass index; AED, antiepileptic drug; VPA, valproate; PB, phenobarbital.

  2. ap < 0.05.

  3. bDefined as Epworth Sleepiness Scale score >10.

Age (yr)a45.6 ± 14.832.9 ± 12.2
BMI (kg/m2)a28.5 ± 3.623.3 ± 3.7
Gender (men%)a83.346.0
Age at epilepsy onset (yr)a31.6 ± 19.618.7 ± 12.8
Generalized epilepsy (%)17.623.8
Localization-related symptomatic epilepsy (%)22.224.5
Seizures during sleep (%)47.126.1
Generalized seizures (%)29.436.4
Recurrent seizures (%)47.158.3
More than one AED (%)41.234.6
Patients under treatment10090.2
Treatment with VPA or/plus PB23.524.0
Excessive daytime sleepinessab23.19.0

The “OSA + epilepsy” patients were predominantly men, and significantly older and heavier than those with “epilepsy only.” Furthermore they were more frequently sleepy and had their first seizure at an older age.

Multivariate analysis

In the global model, sex (OD, 11.3423; p = 0.0046) and body mass index (BMI) (OD, 1.4381; p = 0.0000), but not age (OD, 1.0331; p = 0.2316) and age at epilepsy onset (OD, 1.0367; p = 0.1142), correlated independently with the dependent variable (no OSA–epilepsy coexistence/OSA–epilepsy coexistence, coded as 0/1). To test the hypothesis that this finding could be due to colinearity between age and age at onset (linear correlation coefficient = 0.6164; p < 0.0001), we performed two further regression analyses, including in each model only one of these two parameters, in addition to sex and BMI. The second and third models show that both variables, when separately considered, were positively correlated with OSA–epilepsy coexistence/no OSA–epilepsy coexistence (age OD, 1.0661; p = 0.0023; epilepsy age at onset OD, 1.0564; p = 0.0022).

No further interactions between covariates were observed.

DISCUSSION

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Our data show that coexistence of OSA in epilepsy patients unselected for sleep disorders is not uncommon. Indeed, we found an association of OSA with epilepsy in 10.2% of cases (15.4% of men and 5.4% of women). Increased rate of OSA was reported by Malow et al. (5) in a specific group of epilepsy patients (i.e., patients with medically refractory epilepsy who were candidates for epilepsy surgery). Our findings confirm the increased rate of OSA in a larger epilepsy patient series that includes epilepsy patients with different epilepsy syndromes and various degrees of disease severity.

An increased rate of epilepsy was recently reported in a large clinical series of patients affected by OSA (20). The factors underlying the increased association between epilepsy and OSA are not fully understood. Because epilepsy and OSA are highly prevalent disorders in the general population, their association might be merely fortuitous. However, the increased rate of OSA in epilepsy patients and of epilepsy in OSA patients could derive from the fact that these two disorders, when present in a single subject, interact with each other, facilitating reciprocal manifestations and emphasizing the comorbidity.

Differences between our study and the other studies mentioned—differences in the criteria and procedures used to diagnose OSA, as well as in the sample sizes—limit the comparability of the data and suggest that any considerations advanced should be treated with caution. In particular, our study is limited by the fact that, in diagnosing OSA, we used a portable device that does not allow EEG recording. Thus nocturnal seizures occurring during the monitored night and the consequences of these on breathing patterns might have been missed. Furthermore, this device may underscore hypopneas.

Our “epilepsy + OSA” patients were older, more frequently male, and heavier than the “epilepsy only” subjects. These data indicate that the risk factors for OSA are the same in epilepsy subjects as in the general population. Similar features of “epilepsy + OSA” patients have been reported in two other studies (5,20). Several epilepsy-related parameters have been investigated to ascertain whether they are predictive of OSA in epilepsy patients, both in addition to and independent of common markers in the general population, but only a few, such as seizures during sleep (5,20) and late seizure onset (20), have been found to be significantly associated with OSA in epilepsy patients.

In our patient series, late epilepsy onset was found to be significantly associated with OSA. Conversely, our late-onset epilepsy patients were older than the other members of the sample and age at late epilepsy onset and patient's age were found to be colinear on multivariate analysis. Thus it remains uncertain whether the late age at seizure onset is really associated with having OSA. Finally, we found that “epilepsy + OSA” patients are significantly sleepier than those with “epilepsy only.” This is a predictable finding, given that increased sleepiness is one of the clinical markers of OSA. Drowsiness in epilepsy patients is known to complicate the clinical picture of the epilepsy, facilitating the occurrence of seizures and aggravating cognitive disabilities and behavioral problems (21).

Further prospective studies, based on large patient series, are needed to establish whether these and other epilepsy features are predictive of a coexistence of OSA in epilepsy patients and to better establish whether, and how, epilepsy per se increases the risk of OSA and vice versa.

Acknowledgments

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES

Acknowledgment: We thank Dr Enrico Marchioni for planning and performing the statistical analysis. This study was supported by a grant from the Italian Ministry of Health.

REFERENCES

  1. Top of page
  2. Abstract
  3. METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgments
  7. REFERENCES
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